Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:15]([C:9]2[C:10]3[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=3[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=2[CH3:18])=[O:16])=[CH:26][CH:25]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Product: COc1ccc(CNC(=O)c2c(C)c([N+](=O)[O-])cc3nc(OC)c(OC)nc23)cc1
Reaction time: 16 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and 4-methoxybenzylamine 0.11 mL (0.84 mmol). Reaction was continued for 16 hours, and the crude product was recrystallized from hexanes:ethyl acetate to give yellow needles, 156 mg (47%), mp 187-189° C.; 1H NMR (CDCl3): δ 8.32 (s, 1H, 8-H), 7.28 (d, 2H, J=8.5 Hz), 6.85 (d, 2H, J=8.5 Hz), 6.07 (bs, 1H), 4.61 (d, 2H, J=5.6 Hz), 4.05 (s, 3H), 3.97 (s, 3H), 3.76 (s, 3H), 2.56 (s, 3H); MS (APCI): m/z 413 (M+1). Anal. Calcd. for C20H20N4O6: C, 58.25; H, 4.89; N, 13.59. Found: C, 58.55; H, 4.85; N, 13.47.
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([F:13])[CH:6]=1.[ClH:14]>C(O)C.[Pd]>[ClH:14].[F:13][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH3:12])[CH2:4][NH2:3]
Reactant: CON=Cc1ccc(OC)c(F)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(CN)cc1F
Reaction time: 18 h

Procedure:
To a solution of 3-fluoro-4-methoxy-benzaldehyde O-methyl-oxime (0.60 g, 3.3 mmol) in ethanol (25 mL) is added concentrated ethanolic hydrogen chloride (2 mL) and palladium on carbon (10%, 250 mg). The suspension is hydrogenated at atmospheric pressure for 18 hours, then filtered through diatomaceous earth and finally concentrated to give 3-fluoro-4-methoxy-benzylamine hydrochloride as a white solid.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.C(Cl)(=O)C>C(OCC)(=O)C>[C:3]([NH:8][CH:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:19][CH:20]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])[CH3:2]
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(C)=O
Reaction time: 8 h

Procedure:
500 mg of the compound obtained in Step A of Example 12 are dissolved in 10 ml of ethyl acetate; 0.353 ml of triethylamine is then added and the temperature is lowered to 0° C. 0.121 ml of acetyl chloride is added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:15]3)[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:15]3)[CH:6]=[CH:5][CH:4]=1
Reactant: CNc1cccc(CCOc2ccc3[nH]c(CCC(=O)OC)cc3c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNc1cccc(CCOc2ccc3[nH]c(CCC(=O)O)cc3c2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 8.2 %

Procedure:
To a solution of methyl 3-(5-{2-[6-(methylamino)-2-pyridyl]ethoxy}indolyl)propanoate (0.023 g, 0.65 mmol), as prepared in the preceding step, in methanol (3 mL) was added sodium hydroxide (0.15 g, 3.8 mmol) in H2O (0.5 mL) and the reaction was stirred for 6 hours at ambient temperature. After evaporating the solvent in vacuo, the residue is taken up in H2O (5 mL) and acidified to pH 4-5 with 10% HCl, extracted with a mixture of ethyl acetate and butanol (2×50 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give the title compound as a solid (0.018 g, 82%). 1H-NMR (400 M Hz, CDCl3+CD3OD) δ 7.52 (t, J=7.3 Hz, 1H), 7.25 (d, J=8.9 Hz, 1H), 7.14 (d, J=3.1 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 6.81 (dd, J=8.9, 2.4 Hz, 1H), 6.60 (d, J=7.3 Hz, 1H), 6.38 (d, J=8.6 Hz, 1H), 6.33 (d, J=3.2 Hz, 1H), 4.38 (t, J=7.0 Hz, 2H), 4.24 (t, J=6.6 Hz, 2H), 3.06 (t, J=6.6 Hz, 2H), 2.89 (s, 3H), 2.77 (t, J=6.9 Hz, 2H). Mass spectrum (LCMS, ESI pos.) Calcd. for C19H21N3O3 340.3 (M+H); Found: 340.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[C:25]([N:33]1[CH:37]([CH3:38])[CH2:36][NH:35][C:34]1=[O:39])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O.O1CCOCC1>[C:25]([N:33]1[CH:37]([CH3:38])[CH2:36][N:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([F:24])[CH:3]=2)[C:34]1=[O:39])(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CC1CNC(=O)N1C(=O)c1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)N(C(=O)c5ccccc5)C4=O)cc3F)CC2)c(C)c1
Yield: 17 %

Procedure:
To a mixture of (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114, 1-benzoyl-5-methylimidazolidin-2-one (105 mg) described in Preparation Example 56, tripotassium phosphate (170 mg) and copper(I) iodide (76 mg) were added 1,4-dioxane (8 mL) and N,N′-dimethylethylenediamine (86 μL), and the mixture was stirred with heating under reflux for 10 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (35 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:18])[C:8]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:4].[Se](=O)=[O:20]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:18])[C:8]([C:11]2[CH:12]=[N:13][C:14]([CH:17]=[O:20])=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(-c2ccc(C)nc2)c(Cl)c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(-c2ccc(C=O)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
0.6 g of 3-chloro-6′-methyl-[2,3′]bipyridyl-5-carboxylic acid methyl ester (12) (2.3 mmol) prepared in Example 8 was dissolved in 10 mL of 1,4-dioxane, and 0.75 g of selenium dioxide (6.9 mmol) was added thereto. The mixture was refluxed under heating and stirring for 18 hours, and cooled to room temperature. The mixture was concentrated under reduced pressure, and then dissolved in ethyl acetate to be washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 0.51 g of yellow crystal, 3-chloro-6′-formyl-[2,3′]bipyridyl-5-carboxylic acid methyl ester (yield 81%)
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][C:13]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])=[CH:14][N:15]=1)([CH3:10])[CH3:9].C1(C)C=CC=CC=1>C(Cl)Cl>[CH:8]([C:11]1[S:12][C:13]([C:16]([N:18]2[CH2:23][C:22]3([CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)[O:21][CH2:20][CH2:19]2)=[O:17])=[CH:14][N:15]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ncc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)c1ncc(C(=O)N2CCOC3(CCNCC3)C2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (3.9 mL) was added to a solution of tert-butyl 4-(2-isopropylthiazole-5-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 113, step a) (0.765 g) in DCM (14.8 mL). The resulting mixture was stirred at RT for 1 h. Toluene (30 mL) was added and the mixture was evaporated in vacuo. The yellow residue was dissolved in MeOH and applied to a SCX cartridge pre-wetted with MeOH. The cartridge was washed with MeOH and eluted with 2M ammonia in MeOH. The eluent was evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 0.552 g.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11](Br)=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC.[F-].[Na+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([NH:8][C:9]1[S:10][C:11]([CH:27]=[CH2:28])=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOP(=O)(COC(=O)c1nc(NC(=O)OC(C)(C)C)sc1Br)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1sc(NC(=O)OC(C)(C)C)nc1C(=O)OCP(=O)(OCC)OCC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 2-[N-Boc(amino)]-5-bromo-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) and dichlorobis(triphenylphosphine)palladium(II) (0.1 mmole) in DMF (5 mL) was treated with tributyl(vinyl)tin (2.5 mmole) and the reaction was stirred at 60° C. for 2 h. The solvent was removed and the residue taken up in EtOAc and stirred with 2 mmol NaF in 5 ml water for 1 h. Extraction and chromatography gave 2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonomethoxycarbonylthiazole as a yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C@@H:45]([CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:46][C:47]([OH:49])=O)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.[NH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69]>CN(C=O)C>[CH2:34]([O:41][C:42](=[O:43])[NH:44][C@H:45]([CH2:46][C:47]([NH:62][CH2:63][CH2:64][NH:65][C:66]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:72])=[O:49])[CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)O)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)NCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
836.5 mg (2.2 mmol) of HATU and 517.0 mg (4 mmol) of N,N-diisopropylethylamine are added to a solution of 760.9 mg (2 mmol) of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoic acid in 25 ml of anhydrous DMF. After stirring at RT for 45 min 352.5 mg (2.2 mmol) of tert-butyl (2-aminoethyl)carbamate hydrochloride are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([NH:34]N)[C:28]=2[O:27][CH2:26]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([N:34]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[C:28]=2[O:27][CH2:26]1
Reactant: NNc1cccc2c1OCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4c3OCO4)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 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=437.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[CH:6][C:7]=1[CH:8]1[O:13][CH2:12][CH2:11][NH:10][CH2:9]1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17]>CC#N>[C:20]([O:19][C:15](=[O:18])[CH2:16][CH2:17][N:10]1[CH2:11][CH2:12][O:13][CH:8]([C:7]2[CH:6]=[CH:5][C:4]([OH:14])=[CH:3][C:2]=2[CH3:1])[CH2:9]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1cc(O)ccc1C1CNCCO1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CC#N
Product: Cc1cc(O)ccc1C1CN(CCC(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A mixture of 3-methyl-4-morpholin-2-yl-phenol (14.26 g; 73.8 mmol) and tert-butyl acrylate (21.4 ml; 147.6 mmol) in CH3CN (250 mL) was heated under reflux overnight. After cooling to RT the mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and 5% aqueous NaHCO3 solution. The organic layer was dried (Na2SO4), filtered, concentrated in vacuo, and purified by column chromatography (SiO2, CH2Cl2>Et2O/hexanes 1:1>Ether) to afford 3-[2-(4-hydroxy-2-methyl-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (22.62 g).
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[K].[OH:6][N:7]=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:9]#[N:10].C1OCCOCCOCCOCCOCCOC1.[OH-].[Na+].Cl>O.O1CCOCC1>[F:3][CH:2]([F:4])[O:6][N:7]=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:9]#[N:10]
Reactant: FC(F)Cl
Reactant: Cc1ccccc1C(C#N)=NO
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1C(C#N)=NOC(F)F
Reaction time: 3 h

Procedure:
Chlorodifluoromethane is passed at 20° C. into a suspension of 18.5 g of the potassium salt of α-hydroxyimino-o-tolylacetonitrile, 1.0 g of 18-crown-6 and 185 ml of dioxane. Simultaneously a solution of 15.96 g of sodium hydroxide in 16.1 ml of water is added dropwise thereto. After subsequently stirring for 3 hours, the reaction mixture is poured onto ice-water and acidified with 2N hydrochloric acid. After extraction with ethyl acetate, the combined organic phases are washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica gel with hexane/ethyl acetate (9:1) yields α-difluoromethoxyimino-o-tolylacetonitrile in the form of a yellow liquid.
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26].[ClH:32]>>[ClH:32].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][N:26]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:3][CH2:2]1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C1CCc2cc(C(=O)N3CCOCC3)ccc2N1
Agent: Cl
Product: COc1ccc(CN2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC

Procedure:
2.62 Grams of 6-morpholinocarbonyl-3,4-dihydrocarbostyril and 17.9 g of 3,4-dimethoxybenzylamine were placed in a sealed tube and heated at 170°-200° C. for 5 hours. Then 3,4-dimethoxybenzylamine was removed by distillation under a reduced pressure and the residue thus obtained was treated by means of a silica gel column chromatography, and the objective product was changed to a hydrochloride by adding concentrated hydrochloric acid. Recrystallized from methanol-water to obtain 0.35 g of 6-[4-(3,4-dimethoxybenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril monohydrochloride. Colorless granular crystals. Melting point: 240°-242° C. (decomposed)
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH3:8])[CH:6]=[N:5][N:4]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13].[BrH:14]>>[BrH:14].[BrH:14].[NH2:10][CH2:11][CH2:12][S:13][CH2:2][C:3]1[N:7]([CH3:8])[CH:6]=[N:5][N:4]=1
Reactant: Cn1cnnc1CO
Reactant: NCCS
Agent: Br
Agent: Cl
Product: Cn1cnnc1CSCCN

Procedure:
Reaction of 3-hydroxymethyl-4-methyl-1,2,4-triazole with cysteamine hydrochloride and hydrobromic acid by the procedure of Example 1 gives 3-[(2-aminoethyl)-thiomethyl]-4-methyl-1,2,4-triazole dihydrobromide, m.p. 175° -177°.
Reaction SMILES: [CH2:1]([CH2:4][C:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12](O[C:15](=[O:16])[CH:6]21)=[O:13])[CH:2]=[CH2:3].[NH3:17]>>[CH2:1]([CH2:4][C:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12](=[O:13])[NH:17][C:15](=[O:16])[CH:6]21)[CH:2]=[CH2:3]
Reactant: C=CCCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: N
Product: C=CCCC12C=CC(C1)C1C(=O)NC(=O)C12

Procedure:
A mixture of 30 g of allylmethylbicyclo[2.2.1]-hept-5-ene-2,3-dicarboxylic anhydride, prepared in accordance with Example 2 of U.S. Pat. No. 3,105,839, and 10.2 g of 25% aqueous ammonia solution is heated at 100°-108° C. for 2.5 hours, with stirring and reflux cooling. According to a gas chromatogram, this gives a mixture of 12 isomers having varying positions for the allyl group and the methyl group in the 1-, 4-, 5- and 6-positions in the bicycloheptene ring, and also exo-anhydrides and endo-anhydrides. Since this mixture of isomers cannot be separated by fractional distillation, it is used for further purposes as such. Water is then removed by distillation, excess ammonia is expelled and the imide is rectified at 140°-145° C. and 2.0 Pa.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:42]1[CH:43]=[C:44]2[CH:50]=[CH:49][NH:48][C:45]2=[N:46][CH:47]=1>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:48]1[C:45]2=[N:46][CH:47]=[C:42](/[CH:3]=[CH:2]/[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:43]=[C:44]2[CH:50]=[CH:49]1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]ccc2c1

Procedure:
tert-Butyl acrylate (5.9 mL, 40.6 mmol), diisopropylethylamine (3.5 mL, 20.3 mmol) and P(o-tolyl)3 (618 mg, 2.0 mmol) were successively added to a suspension of 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.0 g, 10.15 mmol) in propionitrile (40 mL) and dimethylformamide (10 mL). The resulting mixture was purged with argon prior to the addition of palladium acetate (227 mg, 1.0 mmol). The mixture was then purged with argon a second time and refluxed overnight. The reaction mixture was filtered on Celite®. The filtrate was concentrated to dryness and the residue was solubilized in ethyl acetate (3×100 mL). The organic layers were washed with a saturated solution of sodium chloride (3×50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/ethyl acetate (1:0 to 7:3) as eluent. The title compound was obtained as a yellow solid (465 mg, 28%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([CH3:11])[N:7]=1.[Cl-].[C:16]([O:20][C:21](=[O:24])[CH2:22][Zn+])([CH3:19])([CH3:18])[CH3:17]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:11][C:8]1[N:7]=[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([CH2:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:24])[CH:14]=[CH:13][CH:12]=2)[O:10][N:9]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Cc1noc(Cc2cccc(Br)c2)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1noc(Cc2cccc(CC(=O)OC(C)(C)C)c2)n1
Reaction time: 20 h
Yield: 52.8 %

Procedure:
To a solution of 5-(3-bromobenzyl)-3-methyl-1,2,4-oxadiazole 1098 (0.50 g, 1.97 mmol) in dioxane (1 mL), under an atmosphere of Argon, was added Bis(tri-t-butylphosphine)palladium(0) (0.15 g, 0.295 mmol) followed by the addition of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in diethyl ether, 4.92 mmol, 9.84 mL). The mixture was allowed to stir under argon for 20 hours and the volatiles were removed under reduced pressure. The residue was taken up in EtOAc (10 mL) and washed with water (2×5 mL), brine (2×5 mL) and dried over Na2SO4. The Na2SO4 was removed by filtration and the volatiles removed under reduced pressure. The crude material was purified by normal phase chromatography 0-50% EtOAc/Hexanes to give 0.300 g tert-butyl 2-(3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)phenyl)acetate 1099. 1H NMR 300 MHz CDCl3: δ 7.40-7.18 (m, 4H), 4.17 (s, 2H), 3.51 (s, 2H), 2.36 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [OH:1][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1C)[C:3]([OH:5])=[O:4].Br[CH2:20][O:21]C1C=CC=CC=1.C(C(O)=O)(=O)C1C=CC=CC=1.COC(C(C1C=CC=CC=1)=O)=O>>[OH:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:21][CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: Cc1ccccc1C(O)(C(=O)O)c1ccccc1
Reactant: BrCOc1ccccc1
Agent: COC(=O)C(=O)c1ccccc1
Agent: O=C(O)C(=O)c1ccccc1
Product: COc1ccccc1C(O)(C(=O)O)c1ccccc1

Procedure:
This compound is prepared by an analogous method to hydroxy-phenyl-o-tolyl-acetic acid (Intermediate M) by replacing bromotoluene with 2-bromomethoxy benzene and benzoyl formic acid with methyl benzoyl formate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:13][C:14]([CH3:19])=[CH:15][C:16](Cl)=[O:17].N1C=CC=CC=1.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([CH:10]([CH3:12])[CH3:11])[C:16](=[O:17])[CH:15]=[C:14]([CH3:19])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(C)C)cc1Br
Reactant: CC(C)=CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)=CC(=O)N(c1ccc(C)c(Br)c1)C(C)C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
(3-Bromo-4-methyl-phenyl)-isopropyl-amine (Compound 41, 36.78 g, 161.2 mmol) was dissolved in dichloromethane (200 mL) and the solution was cooled to 0° C. and treated with 3,3-dimethylacryloyl chloride (28.6 g, 241.8 mmol) and then pyridine (36 mL). The solution was stirred at 0° C. for 1 hour and at room temperature for 5 hours. The mixture was poured into separatory funnel containing dichloromethane and 10% aqueous HCl. The layers were separated and the aqueous layer extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried with MgSO4, filtered, and concentrated under reduced pressure to give the title compound, which was used directly for the next reaction without further purification, as a solid: Rf=0.48, 20% ethyl acetate in hexane:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH2:7][N:6]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:4].O.[OH-].[Li+]>O.O1CCOCC1>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:5]1[C:3]([OH:4])=[O:2])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)C1CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC1C(=O)O
Yield: 98.9 %

Procedure:
Azetidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (1.0 g) was added to a solution of lithium hydroxide monohydrate (0.586 g) in water (6 ml) and dioxane (12 ml) and the resultant mixture was stirred at room temperature for 2.5 hours. The mixture was evaporated to dryness and ice cold 1M HCl was added to the cooled residue. DCM was added and the organic layer was separated and washed with water, brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give azetidine-1,2-dicarboxylic acid-1-t-butyl ester (0.925 g) as a colourless oil.