Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([SH:17])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:26][C:27](=[O:32])[C:28](Br)([CH3:30])[CH3:29])[CH3:25]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17][C:28]([CH3:30])([CH3:29])[C:27]([O:26][CH2:24][CH3:25])=[O:32])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Sc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Temperature: 60 °C

Procedure:
A mixture of 3.2 g of 3-(4-chlorophenyl)-6-mercapto-1,2-benzisoxazole, 2.52 g of potassium carbonate, 2.39 g of ethyl-2-bromo-2-methylpropionate and 75 ml dimethylformamide is heated at 60° C. for 8 hr. The reaction mixture is poured onto ice/dil hydrochloric acid and extracted with ether. The combined ether extracts are washed with dil sodium hydroxide solution, saturated sodium chloride solution and the solvent is removed in vacuo to afford a yellow oil. The oil is distilled in a Kugelrohr oven at 175° C. and 1.0 mm Hg to give an oil which crystallizes on standing. The solid is recrystallized from isopropyl ether using a brine-chilled Buchner funnel to afford ethyl 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:14])[C:9]2=[O:16])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[O:25]>O1CCCC1>[N:1]([C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:14])([CH3:15])[C:9]2=[O:16])[CH:5]=[CH:6][CH:7]=1)=[C:24]=[O:25]
Reactant: O=C(Cl)Cl
Reactant: CC1(C)CC(=O)N(c2cccc(N)c2)C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)N(c2cccc(N=C=O)c2)C1=O
Temperature: 25 °C

Procedure:
Seventy-three g. of N-m-aminophenyl-2,2-dimethylsuccinimide, as prepared in Example II, was dissolved in 800 ml. of tetrahydrofuran containing 75 g. of triethylamine, cooled in an ice bath, and added to 60 g. of phosgene in 400 ml. of tetrahydrofuran maintained at about 0° C. in a drying and isopropanol bath. The mixture was allowed to warm to room temperature and the triethylamine hydrochloride was filtered off and the tetrahydrofuran removed under vacuum on the rotary evaporator. Yield was 84 g. of material product having a nD30 of 1.5470. The product was identified as the title compound by analysis of infrared spectra and was used without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CC(=O)Nc1cccc(C=O)c1
Product: CC(=O)Nc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with N-(3-formylphenyl)acetamide was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N-[3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]acetamide.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[Na+].CC(=C)C(OCCC[CH2:15][CH2:16][CH2:17][O:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35]CC)[CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20])=O.[I-].[Na+].O>CN(C)C=O>[C:1]([O:5][CH2:15][CH2:16][CH2:17][O:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:28][CH2:29][CH:30]([CH2:33][CH2:34][CH3:35])[CH2:31][CH2:32]2)[CH2:23][CH2:22]1)=[O:20])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=C(C)C(=O)OCCCCCCOC(=O)C1CCC(C2CCC(CCCCC)CC2)CC1
Reactant: C=CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(=O)OCCCOC(=O)C1CCC(C2CCC(CCC)CC2)CC1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of sodium acrylate (2.5 g, 13.4 mmol), 4′-propyl-bicyclohexyl-4-carboxylic acid 3-bromo-propyl ester (synthesis described for preferred example 1) (5.0 g, 13.4 mmol) and sodium iodide (2.5 g, 16.7 mmol) in dimethylformamide (150 ml) is stirred at 130° C. overnight. The mixture is cooled to room temperature, poured into water, and this is extracted twice with diethyl ether. The ethereal solution is washed with water and then dried over sodium sulphate. The solution is evaporated to dryness and purified by flash column chromatography using DCM/petrol (1/1) as eluant to give upon evaporation of the appropriate fractions a colourless oil.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH:13]([CH3:15])[CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([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)=CC=1.C(O)C>[CH:13]([CH:9]1[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]([F:30])([F:29])[F:18])=[CH:3][CH:4]=2)[CH2:8]1)([CH3:15])[CH3:14]
Reactant: CC(C)C1CN(Cc2ccc(Br)cc2)CCO1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)C1CN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CCO1
Temperature: 120 °C

Procedure:
The above compound could be made in the following manner: 1 eq. of 4-(4-Bromo-benzyl)-2-isopropyl-morpholine could be combined with 1.5 eq. of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 6.7 eq. of 2M sodium carbonate solution, toluene and ethanol. The reaction mixture could be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture is filtered through Celite and concentrated in vacuo. The residue could be diluted with water and extracted with ethyl acetate. The combined organic phases could be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material could be purified by flash chromatography to afford product.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[C:27]([Cl:28])=[CH:26][C:11]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH2:23])[CH2:17][C@H:16]2[O:24][CH3:25])=[O:13])=[C:10]([O:29][CH3:30])[CH:9]=1>N1C=CC=CC=1>[NH2:7][C:8]1[C:27]([Cl:28])=[CH:26][C:11]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)[CH2:17][C@H:16]2[O:24][CH3:25])=[O:13])=[C:10]([O:29][CH3:30])[CH:9]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Reactant: Brc1nccs1
Solvent: c1ccncc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNc2nccs2)C[C@H]1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
A mixture of 2 parts of 2-bromothiazole and 4.28 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide was stirred for one hour at 60° C. Ths mixture solidified. It was suspended in 10 parts of pyridine and stirring was continued overnight at reflux. The reaction mixture was evaporated. The residue was taken up in a saturated sodium carbonate solution. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (93:7 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and the free base was liberated in the conventional manner and extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried, yielding 0.6 parts (11%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-(2-thiazolylamino)ethyl]-4-piperidinyl]benzamide; mp. 140.9° C. (compound 44).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=[O:14])[CH2:9][C:8]1=[O:20])#[N:2].[C:24](O)(C(F)(F)F)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:14])[CH3:24])[CH2:9][C:8]1=[O:20])#[N:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C#N)c2)C(=O)C1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(Cc2cccc(C#N)c2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(3-cyanobenzyl)-4-Boc-2-piperazinone (2.5 g, 7.9 mmol) in CH2Cl2 (20 mL) at 0° C. was added TFA (10 mL). The mixture was stirred at 0° C. for 2 h, then the solvents were removed in vacuo. The crude 1-(3-cyanobenzyl)-2-piperazinone TFA salt was partitioned between EtOAc (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL). To the stirred two-phase mixture was added acetic anhydride (1.5 mL, 15 mmol) dropwise over a period of 5 min. The mixture was stirred at ambient temperature for 16 h. The EtOAc layer was separated, dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was purified on a silica gel column using a gradient mobile phase of 2%, 3%, 4% MeOH in CH2Cl2. 1-(3-cyanobenzyl)-4-acetyl-2-piperazinone was obtained as a solid.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][C:7]([N:9]([C:11]1[C:12]([Cl:31])=[C:13]([C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]2)[CH3:10])=[O:8])=[O:4].[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1)([O-:34])=[O:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:31][C:12]1[C:11]([N:9]([CH3:10])[C:7](=[O:8])[CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:44]2[CH2:45][CH2:46][N:41]([C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=3)[CH2:42][CH2:43]2)=[CH:29][CH:28]=[C:27]([Cl:30])[C:13]=1[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CBr)c3Cl)c2n1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCN(c5ccc([N+](=O)[O-])cc5)CC4)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
A mixture of 8-[3-[N-(bromoacetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (90 mg), 4-nitro-1-(1-piperazinyl)benzene (48 mg) and potassium carbonate (94 mg) in dimethylformamide (2 ml) was stirred at ambient temperature for 1 hour and water added thereto. The mixture was extracted with ethyl acetate twice, and the combined organic layer was washed with water, dried and concentrated. The residue was purified by preparative thin-layer chromatography (10% methanol in dichloromethane) to give 8-[2,6-dichloro-3-[N-methyl-N-[2-[4-(4-nitrophenyl)piperazin-1-yl]acetylglycyl]amino]benzyloxy]-2-methylquinoline (44 mg).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=[C:11]([C:18](=O)[CH3:19])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)(O)[O-].[Na+].S(O)(O)(=O)=O.[CH3:31][O:32][C:33](=[NH:35])[NH2:34]>CN(C)C=O.C(OCC)(=O)C>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:11]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[C:18]([CH3:19])[NH:35][C:33]([O:32][CH3:31])=[N:34]3)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC(=N)N
Reactant: CC(=O)C(=Cc1cccc2nonc12)C(=O)OC(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1=NC(c2cccc3nonc23)C(C(=O)OC(C)C)=C(C)N1
Temperature: 65 °C
Yield: 24.4 %

Procedure:
A mixture of 2-[(2,1,3-benzoxadiazol-4-yl)methylene]-3-oxobutanoic acid, 1-methylethyl ester (2.04 g, 7.43 mmol), sodium bicarbonate (1.87 g, 22.3 mmol) and O-methylisourea hydrogen sulfate (1.66 g, 9.66 mmol) in dimethylformamide (7.5 ml) was heated at 65° C. (oil bath) overnight under argon. The reaction was then diluted with ethyl acetate, washed several times with water, washed with saturated sodium chloride, dried (potassium carbonate), and evaporated. The residue was flash chromatographed over Merck silica gel (400 ml) eluting with 10% ethyl acetate/dichloromethane to give 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2-methoxy-6-methyl-5-pyrimidinecarboxylic acid, 1-methylethyl ester as a dark solid (0.60 g, 25%). TLC (10% ethyl acetate/dichloromethane) single spot, Rf =0.17.
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[CH2:11]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O>[CH2:11]([C:17]1[S:18][C:19]([CH:3]=[O:4])=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCc1cccs1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCc1ccc(C=O)s1
Temperature: 5 °C
Yield: 85 %

Procedure:
In a 3 liter-four-necked flask, 173.7 (2.38 mol) of N,N-dimethylformamide was placed and cooled to 5° C., followed by addition of 201.4 g (1.31 mol) of POCl3 in 15 min. below 10° C. under stirring. After stirring for 30 min. below 10° C., 200 g (1.19 mol) of 2-hexylthiophene was added dropwise to the mixture in 10 min. at room temperature, followed by stirring for 1.5 hours and further stirring for 2 hours at 60° C. After the reaction, the reaction mixture was poured into 5 liter of iced water, subjected to 3 times of extraction with 2 liter of chloroform and washed 6 times with 2 liter of water. The organic layer was dried with CaCl2, followed by distilling-off of the solvent and reduced-pressure distillation in an atmosphere of nitrogen to obtain 199.2 g of a product (yield: 85.0%). Then, 20 g of the product obtained was purified by silica gel column chromatography with the use of an n-hexane/ethyl acetate=20/1 mixture solvent to obtain 18.2 g of a pure product (yield: 91.0%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.Cl.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:23]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[CH:28][C:27]=3[F:42])=[O:25])[CH2:22][C:21]3[CH:20]=[N:19][N:18]([CH3:43])[C:17]=3[NH:16][C:15]=2[CH:44]=1>CN(C=O)C.C(N(CC)CC)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:23]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][N:39]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:38][CH2:37]4)=[CH:28][C:27]=3[F:42])=[O:25])[CH2:22][C:21]3[CH:20]=[N:19][N:18]([CH3:43])[C:17]=3[NH:16][C:15]=2[CH:44]=1
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(OCCCN3CCNCC3)cc1F)C2
Reactant: CCCCCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCN1CCN(CCCOc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(Cl)ccc43)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of (6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[2-fluoro-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride from Example E5a (2.85 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=583.6
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH:5](=[O:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Cl-].[NH4+]>O1CCCC1>[CH2:1]=[CH:2][CH:5]([OH:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCC=O
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)CCCCCCCCCC
Reaction time: 6 h

Procedure:
To a solution of vinyl magnesium bromide in tetrahydrofuran (1M, 82.0 mL) at 0° C. was added a solution of undecanal i (7.00 g, 41.1 mmol) in tetrahydrofuran (25 mL) in about 10 min. After 6 h at 0° C., saturated ammonium chloride solution (50 mL) was added. The two layers were separated. The water layer was extracted with ether (2×50 mL). The combined organic solutions were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate in hexane) to give 7.94 g (98%) of i-a as a colorless oil: IR (neat) 3409, 3079, 1644, and 1463 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ5.80 (ddd, 1H, J=6.3, 10.7, and 17.2 Hz, CH=CH2), 5.55 (dd, 1H, J=17.2 and 1.4 Hz, CH=CH2), 5.05 (dd, 1H, J=10.7 and 1.4 Hz, CH=CH2), 3.99 (q, 1H, J=6.2 Hz, CHOH), 2.58 (br s, 1H, OH), 1.46-1.22 [m, 18H, C(4-12)H2 ], and 0.83 (t, J=6.4 Hz, CH2CH3); 13C NMR (CDCl3, 75.5 MHz) δ141.61, 114.50, 73.33, 37.24, 32.12, 29.83, 29.55, 25.57, 22.87, and 14.26.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[CH:14][N:13]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:11][C:12]1[CH:17]=[C:16]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:15]=[CH:14][N:13]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Fc1ccnc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1cc(N2CCC3(CC2)OCCO3)ccn1
Temperature: 120 °C
Yield: 73.1 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4.5]decane (895 μL, 6.98 mmol) and 2-chloro-4-fluoropyridine (1.01 g, 7.68 mmol) in dioxane (15 mL) was added N,N-diisopropylethylamine (1.83 mL, 10.5 mmol). Argon was bubbled through the reaction mixture for 5 minutes before it was heated to 120° C. in microwave for 3 hours. After evaporation, purification by chromatography (silica gel, 20 g, 30 to 10% ethyl acetate in heptane) afforded the title compound (1.3 g, 73%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCCC1>CO>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])/[C:24]/2=[CH:16]\[C:13]1[NH:12][C:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[C:6](=[O:18])[C:7]=2[C:14]=1[CH3:15]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Temperature: 25 °C
Yield: 75.1 %

Procedure:
5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c (53 mg, 0.2 mmol) was dissolved in 1 ml of methanol under stirring, and added with 5-chloro-1,3-dihydro-indol-2-one (34 mg, 0.2 mmol) and piperidine (0.1 ml) to the solution. Upon the completion of the addition, the mixture was stirred to mix well in dark, heated to reflux for 2 hours and lots of precipitate was formed. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, and filtered. The filter cake was washed with ethanol and dried to obtain the title compound (Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 23 (62 mg, yield 75%) as an orange powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][S:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:28])=[O:27])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccccc4)cc23)CC1
Yield: 70.8 %

Procedure:
To a solution of 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (4.75 g, 20.6 mmol) in dimethylformamide (25 mL), stirring at 0° C. under nitrogen, was added sodium hydride in one portion (0.83 g of a 60% dispersion in oil, 20.6 mmol). The green solution turned brown; after stirring for 30 minutes at 0° C. benzenesulfonyl chloride (2.63 mL, 20.6 mmol) was added in one portion, then the reaction mixture was allowed to stir until the reaction was complete. The solution was poured into water (125 mL), then extracted with ethyl acetate (4×125 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to a residue which was further purified on silica gel. Elution with a 9:1 mixture of dichloromethane and 2 N ammonia in methanol provided 5.40 g (70%) of benzenesulfonic acid 3-(1-methylpiperidin-4-yl)-1H-indol-5-yl ester as a tan solid: mp=189-194° C.; 1H NMR (400 MHz, dmso-d6): 10.97 (br s, 1H), 7.85-7.72 (m, 3H), 7.65-7.54 (mm, 2H), 7.24 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.0 Hz), 6.88 (d, 1H, J=1.2 Hz), 6.69 (dd, 1H, J=8.8, 1.6 Hz), 2.77 (br d, 2H, J=11.2 Hz), 2.52-2.40 (m, 1H), 2.16 (s, 3H), 1.91 (br t, 2H, J=11.2 Hz), 1.67 (br d, 2H, J=12.0 Hz), 1.58-1.44 (m, 2H); MS(ES+): m/e 371.0 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[C:23]([Cl:25])[CH:24]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:26]([C:21]1[CH:20]=[C:19]([Cl:18])[CH:24]=[C:23]([Cl:25])[CH:22]=1)(=[O:28])=[O:27]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Yield: 77.3 %

Procedure:
To a solution of 24.8 g (0.15 mol) of L-Proline methyl ester hydrochloride in 500 mL of CH2Cl2 was added 70 mL (0.5 mol) of triethylamine with stirring to give copious white precipitate. The mixture was filtered, and the filtrate cooled to 0° C. (ice bath) with stirring. To the cooled solution was added a solution of 36.8 g (0.15 mol) of 3,5-dichlorobenzenesulfonyl chloride in 70 mL of CH2Cl2 dropwise quickly over five minutes. The addition funnel was rinsed with an additional 30 mL of CH2Cl2, and the cloudy yellow mixture was allowed to warm to room temperature with stirring overnight. The mixture was washed twice with 400 mL of 1 N HCl, twice with 400 mL of 1 N NaOH, then brine, then dried (MgSO4), filtered, and concentrated to a yellow oil which crystallized on standing. The material was recrystallized three times from ethyl acetate/hexanes to give 39.3 g (0.116 mol, 77%) of N-(3,5-dichlorobenzenesulfonyl)-Proline methyl ester (MW=338) as white needles (TLC on silica vs. 2:1 hexanes/ethyl acetate, Rf=0.51). M/z=339.3 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15])[CH:18]([CH3:20])[CH3:19]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)COC(=O)Cl
Product: CC(C)COC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Treatment of L-phenylalanine with isobutyl chloroformate in a manner analogous to that described above, yielded yielded the desired acid as an oil [MS: 266 (M+H)+ ] which crystallized out upon standing and which was used directly in the next step.