Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[CH2:12]Cl)[CH3:2].[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[CH2:16]([O:15][P:14]([CH2:12][C:5]1[CH:6]=[C:7]([CH:8]=[O:9])[CH:10]=[CH:11][C:4]=1[O:3][CH2:1][CH3:2])(=[O:21])[O:18][CH2:19][CH3:20])[CH3:17]
Reactant: CCOc1ccc(C=O)cc1CCl
Reactant: CCOP(OCC)OCC
Product: CCOc1ccc(C=O)cc1CP(=O)(OCC)OCC

Procedure:
4-Ethoxy-3-chloromethylbenzaldehyde and triethyl phosphite were added together in a 1:1 ratio and heated until no more gas evolved. The reaction solution was then vacuum distilled to give the desired product. bp 170°-171° C. at 0.75mm Hg.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH:13]3[O:15][CH2:14]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:16]([NH2:19])[CH2:17][NH2:18]>>[NH2:18][CH2:17][CH2:16][NH:19][CH2:14][CH:13]([OH:15])[CH2:12][O:11][C:10]1[C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: NCCN
Reactant: c1cc2c(c(OCC3CO3)c1)OCCO2
Product: NCCNCC(O)COc1cccc2c1OCCO2

Procedure:
A mixture of 20.8 g. of 1-(benzodioxan-5-yloxy)-2,3-epoxypropane and 120 g. of ethylenediamine is heated at 90° C. for 18 hours and is then evaporated to dryness under reduced pressure. The residue is stirred with 100 ml. of water and the mixture is extracted four times with 100 ml. of chloroform each time. The combined chloroform extracts are dried and evaporated to dryness under reduced pressure and there is thus obtained as residue 3-β-aminoethylamino-1-(benzodioxan-5-yloxy)-2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].Cl[CH:29]([F:31])[F:30]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][O:17][CH:29]([F:31])[F:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc(C)cc2)cc1OC
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(CCNC(=O)C(=COC(F)F)c2ccc(C)cc2)cc1OC

Procedure:
Five hundred milligrams (500 mg) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide (1.46 mmol), 0.31 g (1.7 mmol) of 30% aqueous potassium hydroxide solution, 0.1 g (0.3 mmol) of tetrabutylammonium bromide and 10 ml of ethylene glycol dimethyl ether were mixed and chlorodifluoromethane gas was blown thereto at room temperature. After a small amount of 30% aqueous potassium hydroxide solution was further added, a sample was taken out from the reaction mixture and the disappearance of the starting material was confirmed by thin layer chromatograph analysis. Then, 5% hydrochrolic acid was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to give 474 mg of N-[2-(3,4-dimethoxyphenyl) ethyl]-3-difluoromethoxy-2-(4-methylphenyl)acrylamide (the present compound 1005).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[F:25][C:26]1([F:37])[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([NH:35]N)[C:28]=2[O:27]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:37][C:26]1([F:25])[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([N:35]3[C:17]([C:12]4[C:13](=[O:16])[CH:14]=[CH:15][N:10]([C:6]5[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:24])[F:1])[CH:5]=5)[N:11]=4)=[CH:18][CH:19]=[N:20]3)[C:28]=2[O:27]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: NNc1cccc2c1OC(F)(F)O2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1cccc2c1OC(F)(F)O2

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and 2,2-difluoro-benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=461.3 (M+H)+
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=1)[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1(P([Pd](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:16]2[CH:15]=[C:14]([C:7]3[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(Cc2cccc(Br)c2)CC1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(Cc2cccc(-c3ccc(C(=O)O)cc3)c2)CC1
Temperature: 25 °C
Yield: 103.6 %

Procedure:
98 mg 4-Carboxybenzeneboronic acid, 159 mg 1-(3-Bromo-benzyl)-4-methyl-piperazine, 410 mg potassium carbonate, and 69 mg tetrakis-triphenylphosphino-palladium were stirred under an argon atmosphere in a mixture of 1 ml dioxane and 1 ml water at 85 C for 16 hrs. The mixture was cooled to RT, diluted with 100 ml water and filtered. The filtrate was carefully treated with conc. HCl until the product precipitated. Filtration and drying of the residue yielded 190 mg of the title product.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][NH:39]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:47]>>[ClH:47].[ClH:47].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][NH2:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCNC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(N)n3)[C@H]2SC1
Yield: 93.1 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.5 g.) was treated with conc. hydrochloric acid (3.2 g.) in a similar manner to that of Example 23-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid dihydrochloride (syn isomer, 3.0 g.).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[C:4]2[C:9]([C:10](=O)[C:11]=1CC=C)=[CH:8][CH:7]=[CH:6][CH:5]=2.S(=O)(=O)(O)O>C(O)C>[CH:7]1[CH:8]=[C:9]2[CH:10]=[CH:11][C:2]([C:3](=[O:16])[C:4]2=[CH:5][CH:6]=1)=[O:1]
Reactant: C=CCC1=C(O)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: O=C1C=Cc2ccccc2C1=O

Procedure:
The process shown in Scheme 2 can be used for the preparation of compounds in Formula II, III and IV when R7 is not hydrogen and X is oxygen from same starting material 1-1 as shown in Scheme 1. The reaction of 2-hydroxy-1,4-naphthoquinone 1-1 with the appropriate allylbromide gives 2-allyloxy-1,4-naphthoquinone 2-2. Rearrangement of 2-2 in ethanol afford 2-hydroxy-3-allyl-1,4-naphthoquinone 2-3, which can be cyclized by sulfuric acid treatment to form orthonaphthoquinone 2-4. Oxidation of 2-4 with n-bromosuccinimide and lead tetraacetate gives 3-acetoxy-orthonaphthoquinone 2-5. Hydrochloric acid treatment of compound 2-5 gives 2-alkyl (or aryl)-3-alkyl (or aryl)-naphtha[2,3-b]furan-4,9-dione 2-6.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:29]=[CH:28][C:12]([O:13][CH2:14][C:15]3[N:16]=[C:17](/[CH:20]=[CH:21]/[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][CH:19]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C(O)C.[C].[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:29]=[CH:28][C:12]([O:13][CH2:14][C:15]3[N:16]=[C:17]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[O:18][CH:19]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C(=C/c1nc(COc2ccc(CCCn3ccnc3)cc2)co1)\c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CCc2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Yield: 56.4 %

Procedure:
To a solution of 4-[4-[3-(1-imidazolyl)propyl]-phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole (300 mg) in ethanol (100 ml) was added palladium-carbon (5%, wet, 300 mg). The mixture was subjected to catalytic hydrogenation at room temperature under atmospheric pressure. The catalyst was filtered off. The filtrate was concentrated to leave a crystalline product, which was recrystallized from ethyl acetate-hexane to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-phenylethyl)oxazole (170 mg, 57%) as colorless prisms, mp 67-68° C.
Reaction SMILES: [CH2:1]([CH:5]([CH:12]=[CH2:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>ClCCl>[CH2:1]([CH:5]([CH:12]=[CH2:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(CCCC)CCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(CCCC)CCCCC=O
Yield: 72.8 %

Procedure:
A dichloromethane (1 ml) solution of 6-butyloct-7-en-1-ol (400 mg, 2.17 mmol ) was oxidized with a suspension of pyridinium chlorochromate (0.65 g, 3 mmol) and sodium acetate (20 mg) in 2 ml of dichloromethane. Standard work-up followed by PMLPC yielded 288 mg (70%) of 6-butyloct-7-enaldehyde.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][N:14]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:15](=[O:27])[N:16]2[C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[C:11]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[CH:10]=1)(=[O:7])=[O:6].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(OCC)(=O)C>[Cl:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[C:11]1[CH:10]=[C:9]([NH:8][S:5]([CH2:4][CH2:3][CH2:2][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)(=[O:6])=[O:7])[CH:18]=[C:17]2[C:12]=1[CH2:13][N:14]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:15](=[O:27])[N:16]2[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NS(=O)(=O)CCCCl)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NS(=O)(=O)CCCN4CCOCC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 25 °C

Procedure:
3chloro-N-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]propane-1-sulfonamide (93 mg, 0.14 mmol) in morpholine (0.25 mL) was heated at 130° C. for 45 min. The reaction mixture was cooled to rt, diluted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated under reduced pressure. The product was purified by flash chromatography on a Biotage 40S column, eluting with 60:40 hexanes-acetone to yield N-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-3-morpholin-4-ylpropane-1-sulfonamide. Mass spectrum (ESI) 729 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9]>[Ru]>[CH3:7][C:4]1([CH3:8])[CH:5]([OH:6])[C:2]([CH3:10])([CH3:1])[CH:3]1[OH:9]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Agent: [Ru]
Product: CC1(C)C(O)C(C)(C)C1O
Temperature: 130 °C
Reaction time: 16.75 h

Procedure:
A 300 mL Parr autoclave was charged with 25 grams of 2,2,4,4-tetramethylcyclobutane-1,3-dione, 100 grams Isopar™ G, and 12.5 grams of 2% ruthenium on alumina (surface area=10 m2/g, purchased from BASF Catalysts). The autoclave was pressure purged three times with nitrogen and three times with hydrogen, and the pressure was increased to 3.5 MPa (500 psig) with hydrogen. The autoclave was heated to 130° C. with stirring at approximately 1400 rpm and held for 16.75 hours at 3.5 MPa (500 psig). Analysis of the product by gas chromatography indicated that complete conversion of the 2,2,4,4-tetramethylcyclobutane-1,3-dione was obtained with 96.1% selectivity to 2,2,4,4-tetramethycyclobutane-1,3-diol with a cis:trans ratio of 4.31:1. The main by-products are 2,2,4-trimethyl-3-pentanol at 1.59%, and 2,2,4-trimethyl-1,3-pentanediol at 2.01%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]>[Pd].C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCN(c3ccc([N+](=O)[O-])cn3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(N2CCN(c3ccc(N)cn3)CC2)cc1
Reaction time: 6 h
Yield: 74.6 %

Procedure:
10% Palladium on carbon (25 mg, 0.024 mmol) was added to a stirred suspension of 1-(4-cyanophenyl)-4-(5-nitropyridin-2-yl)-piperazine (150 mg, 0.48 mmol) in ethanol (50 ml) at ambient temperature and the reaction stirred for 6 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and the solvent evaporated in vacuo. Purification by flash chromatography on alumina, eluting with 0.5% methanol in dichloromethane yielded 1-(4-cyanophenyl)-4-(5-aminopyridin-2-yl)piperazine (100 mg, 74% yield):
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C@H:16]3[CH2:20][CH2:19][NH:18][C@@H:17]3[CH2:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:27]1[C:31]2([CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1>>[N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C@H:16]3[CH2:20][CH2:19][N:18]([CH:34]4[CH2:35][CH2:36][C:31]5([O:30][CH2:29][CH2:28][O:27]5)[CH2:32][CH2:33]4)[C@@H:17]3[CH2:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=NCCC[C@H]1NCC[C@@H]1Nc1nc(Cl)cc(N2CCCCCC2)n1
Reactant: O=C1CCC2(CC1)OCCO2
Product: [N-]=[N+]=NCCC[C@@H]1[C@@H](Nc2nc(Cl)cc(N3CCCCCC3)n2)CCN1C1CCC2(CC1)OCCO2

Procedure:
The same procedure as a series of reactions of Example 9 was carried out, except that 4-azepan-1-yl-N-[(2R,3S)-2-(3-azidopropyl)pyrrolidin-3-yl]-6-chloropyrimidin-2-amine was used in place of the compound 8 and 1,4-dioxaspiro[4.5]decan-8-one was used in place of cyclohexanone in the process of Example 9, to obtain the title compound (1.25 g) having the following physical properties.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)[CH2:2][CH3:3].[N+:15]([C:18]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[Br:35])=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16].O>CN(C)C=O>[N+:15]([C:18]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[Br:35])=[CH:23][C:19]=1[C:20]([N:10]1[C:11](=[O:12])[C:6]2=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=[C:7]2[C:8]1=[O:9])=[O:21])([O-:17])=[O:16]
Reactant: O=C(Cl)c1cc(Oc2ccc(Br)cc2Br)ccc1[N+](=O)[O-]
Reactant: CCCc1ccc2c(c1)C(=O)NC2=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1ccc2c(c1)C(=O)N(C(=O)c1cc(Oc3ccc(Br)cc3Br)ccc1[N+](=O)[O-])C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of 4-propylphthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-nitro-5-(2,4-dibromophenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-nitro-5-(2,4-dibromophenoxy)benzoyl]-4-propylphthalimide.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH2:14][CH2:15][C:16]([O-:18])=O.ON1C(=O)C2C=CC=CC=2N=N1.[NH2:37][CH2:38][C:39]1[CH:40]=[C:41]([CH2:45][OH:46])[CH:42]=[CH:43][CH:44]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:21]([O:20][C:13](=[O:19])[CH2:14][CH2:15][C:16]([NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][OH:46])[CH:40]=1)=[O:18])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCc1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)CCC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCC(=O)NCc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 54 %

Procedure:
At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (451 mg, 2.35 mmol) was added to a solution of mono-tert-butyl succinate (410 mg, 2.35 mmol) and 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazin (384 mg, 2.35 mmol) in a mixture of N,N-dimethylformamide (5 ml) and dichloromethane (5 ml). The reaction mixture was stirred for 25 min at 0° C. A solution of crude (3-(aminomethyl)phenyl)methanol (340 mg, 2.48 mmol) in N,N-dimethylformamide (5 ml) and ethyldiisopropylamine(0.40 ml, 2.48 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was slowly warming up to room temperature. It was diluted with ethyl acetate (150 ml) and washed with a 10% aqueous solution of sodium hydrogensulphate (100 ml). The aqueous phase was extracted with ethyl acetate (50 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (150 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatograpy on silica (60 g), using a mixture of ethyl acetate and heptane (2:1) as eluent to give 372 mg of N-(3-(hydroxymethyl)benzyl)succinamic acid tert-butyl ester.
Reaction SMILES: [OH-].[Na+].[ClH:3].Cl.[CH3:5][N:6]([CH3:15])[CH2:7][CH2:8][CH2:9][CH2:10][S:11]C(=N)N>O>[ClH:3].[CH3:5][N:6]([CH3:15])[CH2:7][CH2:8][CH2:9][CH2:10][SH:11]
Reactant: CN(C)CCCCSC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCCCS
Temperature: 95 °C
Yield: 60.2 %

Procedure:
A solution of sodium hydroxide (16.4 g) in water (16.5 ml) was added dropwise under nitrogen at 0° C. to a stirred solution of S-[4-(dimethylamino)butyl]-isothiourea dihydrochloride (51 g) in water (60 ml), then the mixture was heated at 95° C. for 2 hours and allowed to cool to ambient temperature. Water (100 ml) was added, and the product was extracted into ether (50 ml), dichloromethane (3×50 ml), and ether (2×50 ml). The combined organic solutions were dried over magnesium sulphate, then the solvents were removed in vacuo. The residue was dissolved in ether and the solution was saturated with hydrogen chloride. The resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 4-(dimethylamino)butanethiol hydrochloride as a white solid (21 g) which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([O:15][C:16]2[C:17]([C:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH:23]=3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:35]>C(Cl)Cl>[ClH:35].[ClH:35].[ClH:35].[Cl:35][C:22]1([C:17]2[C:16]([O:15][CH:13]3[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12]3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nccnc2OC2CN(C(=O)OCc3ccccc3)C2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC(Oc2nccnc2C2(Cl)CCNCC2)C1
Reaction time: 3 h

Procedure:
To a stirred solution of tert-butyl 4-(3-(1-(benzyloxycarbonyl) azetidin-3-yloxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (see PREPARATION P28.3; 0.72 g, 1.543 mmol) in DCM (5 ml) was added hydrogen chloride (3.09 mL, 12.35 mmol). The reaction mixture was stirred for 3 hours, concentrated to dryness and used in the next step. The mixture also contained 1:1 ratio of benzyl 3-((3-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)oxy)azetidine-1-carboxylate trihydrochloride salt. MS (m+2): 404.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[N:37][NH2:38])[NH2:36]>ClCCl.O>[NH2:36]/[C:35](/[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=1)=[N:37]\[NH:38][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: NN=C(N)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N/N=C(\N)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To as solution of 1-(tert-butoxycarbonyl) piperidine-4-carboxylic acid 37 g (167 mM) in dichloromethane (300 ml) is added carbonyl diimidazole (1 eq.) in small portion over a period of 30 min. pyridine-2-carbohydrazonamide is then added to reaction mixture and stirred at room temperature for 3 hrs. Dichloromethane is evaporated and reaction mass is then stirred in water for 30 min. solid precipitated is filtered and dried to afford the desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)[S:32]([CH3:31])(=[O:34])=[O:33])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the product from Example 1 (70 mg) dissolved in DCM was added methanesulfonyl chloride (16 μl) and TEA (28.3 μl) under nitrogen. The resulting solution was stirred at rt for 16 h. The solvents were evaporated, the residue redissolved in MeOH and the crude product was purified by RPHPLC to afford the title compound 32 mg.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:13]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][C:32]([OH:34])=O)[N:30]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:35][O:36][C:37]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[C:38]=1[NH2:39].Cl.C(N(CC)CC)C>C1COCC1>[CH2:13]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][C:32]([NH:39][C:38]2[C:40]([O:46][CH3:47])=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:37]=2[O:36][CH3:35])=[O:34])[N:30]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCCCCCc1nc(CC(=O)O)cs1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCc1nc(CC(=O)Nc2c(OC)cc(OC)cc2OC)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
Carbonyl dimidazole (0.38 g, 2.35 mmol) was added to a solution of 2-tridecyl-4-thiazole acetic acid (0.71 g, 2.28 mmol) in dry THF (50 mL), and the resulting mixture was stirred at room temperature for 1.5 hours, then 2,4,6-trimethoxyaniline made in situ [2,4,6-trimethoxyaniline.HCl (0.05 g, 2.28 mmol) and triethylamine (0.32 mL, 2.28 mmol) were stirred together at room temperature for 0.5 hour] was added and the solution stirred for 3 days at room temperature, then filtered, and the filtrate stirred with 3:1 chloroform/water (200 mL) for 1 hour. She organic layer was separated, washed with brine, dried over Na2SO4, filtered, concentrated, and triturated with hexanes to yield a grey solid (0.93 g, 82%) which was air dried.