Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]([CH2:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26]C)=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CCOC(C)=O>CCO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]([CH2:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([OH:26])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(CCC(C)(C)C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(CCC(C)(C)C)c3ccc(F)c(C(=O)O)c3)cc2)cc1
Temperature: 65 °C
Yield: 85.8 %

Procedure:
Methyl 5-[{4-[(4-butylphenyl)ethynyl]benzyl}(3,3-dimethylbutyl)amino]-2-fluorobenzoate (541 mg; 1.08 mmol) was dissolved in 10 mL of EtOH and sodium hydroxide (649.63 μl; 5.00 M, 3.25 mmol) was added. The reaction mixture was stirred at 65° C. for 2h30. The reaction mixture was allowed to cool down and EtOAc (50 mL) was added. The organic layer was washed three times with HCl (1M), dried over MgSO4, filtered and concentrated under reduced pressure to afford 450 mg (86%) of the title compound as a yellow solid. HPLC, Rt: 5.97 min (purity: 98.9%); LC/MS M+(ESI): 486.2, M−(ESI)=484.0; 1H NMR (CDCl3) δ: 7.44 (m, 4H), 7.32 (m, 1H), 7.20 (d, J=9.8 Hz, 2H,), 7.14 (d, J=8.3 Hz, 2H), 6.97 (m, 1H), 6.91-6.75 (m, 1H), 4.48 (s, 2H), 3.42 (m, 2H), 2.60 (t, J=7.7 Hz, 2H), 1.65-1.46 (m, 4H), 1.40-1.28 (m, 2H), 0.99-0.87 (m, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][O:11][N:12]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][CH:3]=1.ClCCl>C(CN)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][O:11][NH2:12])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1OCC=Cc1ccc(Br)cc1
Solvent: NCCO
Solvent: ClCCl
Product: NOCC=Cc1ccc(Br)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
33.4 g (0.093 mol) of N-[3-(4-bromophenyl)-prop-2-enyloxy]phthalimide were introduced a little at a time in 50 ml of ethanolamine; the temperature increased to 30° C. during this procedure. Stirring was carried out for two hours at 60° C., after which the mixture was allowed to cool and 200 ml of dichloromethane were added. Extraction was effected by shaking with ice water. The organic phase was dried and evaporated down and the residue was crystallized from petroleum ether. Yield: 95.3%; m.p.: 35°-38° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35]>>[C@H:9]1([NH:8][C:6]2[N:7]=[C:2]([C:24]3[CH:23]=[CH:22][C:21]([OH:35])=[C:20]([O:19][CH3:18])[CH:25]=3)[CH:3]=[N:4][CH:5]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Clc1cncc(N[C@@H]2CCc3ccccc32)n1
Product: COc1cc(-c2cncc(N[C@@H]3CCc4ccccc43)n2)ccc1O
Yield: 69.6 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-[(1R)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine (136.8 mg, 0.56 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (153 mg, X0.61 mmol) furnished the product (130 mg, 70%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:28]=O)=[N:18][CH:19]=[C:20]([N:22]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH3:23])[N:21]=1.[CH2:30]([NH:37][CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:30]([N:37]([CH2:28][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]([CH:24]2[CH2:25][CH2:26][CH2:27]2)[CH3:23])=[CH:19][N:18]=1)[CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(c1cnc(C=O)c(Cl)n1)C1CCC1
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1)C1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
Sodium triacetoxyborohydride (0.71 g) was added to a solution of 3-chloro-5-[cyclobutyl(methyl)amino]pyrazine-2-carbaldehyde (0.50 g), N-benzylethanolamine (0.40 g) and acetic acid (0.38 mL) in acetonitrile (8 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10-*60% ethyl acetate/hexane) to give the title compound (0.74 g, 92%) as a pale-yellow oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH:29]1([NH:32][CH2:33][C:34]2[N:35]=[CH:36][N:37](C(OC(C)(C)C)=O)[CH:38]=2)[CH2:31][CH2:30]1>>[CH:29]1([N:32]([CH2:33][C:34]2[N:35]=[CH:36][NH:37][CH:38]=2)[S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=4[C:7]=3[CH:6]=2)(=[O:4])=[O:3])[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)n1cnc(CNC2CC2)c1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Solvent: CCN(CC)CC
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)N(Cc4c[nH]cn4)C4CC4)cc3c12

Procedure:
8-[Cyclopropyl-(1H-imidazol-4-ylmethyl)-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid is prepared according to synthesis 178, from 284 mg (0.87 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid, 605 μL (4.35 mmol) of triethylamine and 309 mg (1.3 mmol) of cyclopropyl-(1-tert-butoxycarbonyl-1H-imidazol-4-ylmethyl)-amine to give, after purification by precipitation and trituration in water, 350 mg (76%) of 8-[cyclopropyl-(1H-imidazol-4-ylmethyl)-sulfamoyl]-4-oxo-4,5-dihydro-3H -pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a beige solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:18]1[N:23]=[C:22]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (1.00 g, 4.97 mmol) was added to a suspension of sodium hydride (60 wt %, 0.238 g, 5.96 mmol) in DMF (16.56 mL) and stirred for 30 minutes at room temperature. 2,4-Dichloropyrimidine (1.11 g, 7.45 mmol) was added to the reaction mixture and stirred for 2 hours at room temperature. The mixture was then diluted with ethyl acetate (100 mL) and washed with 1:1 water:brine (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate as a colorless oil.
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.C(O)C.Br[CH2:19]/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23]>[OH-].[Na+]>[CH3:25][O:24][C:22](=[O:23])/[CH:21]=[CH:20]/[CH2:19][S:14][C:9]1[N:8]=[C:7]([NH2:6])[CH:12]=[C:11]([Cl:13])[N:10]=1
Reactant: COC(=O)/C=C/CBr
Reactant: Nc1cc(Cl)nc(S)n1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)/C=C/CSc1nc(N)cc(Cl)n1
Reaction time: 8.5 h

Procedure:
4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.30 g, 1.16 mmol) is dissolved in 3.25N sodium hydroxide (2 ml) and ethanol (1 ml) at ambient temperature followed by the addition of methyl 4-bromocrotonate (0.16 ml, 1.40 mmol). The reaction is stirred for 2 to 15 hours, quenched with excess water, extracted with methylene chloride (2×25 ml). The extracts are combined, washed with saline (25 ml), dried over sodium sulfate, concentrated in vacuo and recrystallized from hexane/ethyl acetate to give Cpd #193. mp 146-149° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:33])[C:31]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[CH2:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][N:9]([C:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:31]3[C:30]([Cl:33])=[CH:29][N:28]=[CH:27][C:26]=3[Cl:25])[CH2:2][CH2:3]2)=[O:8])[CH2:14][CH2:13]1)=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)C2CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C(OCc1ccccc1)N1CCN(C(=O)C2CCN(c3c(Cl)cncc3Cl)CC2)CC1
Yield: 36.8 %

Procedure:
General procedure C (See Example 1) was followed using benzyl-4-(piperidine-4-carbonyl)piperazine-1-carboxylate 12 (0.11 g, 0.33 mmol), 3,4,5-trichloropyridine (61 mg, 0.33 mmol), NMP (2.5 mL) and triethylamine (93 μL, 0.66 mmol). The crude product was purified by flash column chromatography on silica gel (hexane, EtOAc, 1:1) to furnish the title compound 13 as a white solid (58 mg, 36%), umax (CHCl3)/cm−1 3023, 1699, 1635, 1559, 1432, 1285, 1232, 1015; m/z (ESI) C23H27Cl2N4O3 requires 477.1455, found [M+H]+ 477.1457.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])[CH2:6][CH2:7]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccccc2F)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2F)CC1)c1ccccc1
Yield: 56.7 %

Procedure:
0.2 g (0.000956 mol) of 1-(2-fluoro-benzyl)-piperidin-4-ol and 0.16 ml (0.00147 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.122 ml (0.00105 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.17 g (57%) of 1-(2-fluoro-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil.
Reaction SMILES: CON(C)[C:4]([C:6]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]1)=[O:5].C[Si]([C:22]#[CH:23])(C)C.[NH4+].[Cl-]>C1COCC1>[C:4]([C:6]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:7][CH2:8]1)(=[O:5])[C:22]#[CH:23]
Reactant: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reaction time: 5 h

Procedure:
To a stirred solution of tert-butyl 1-(methoxy(methyl)carbamoyl)cyclopropylcarbamate (5.0 g, 20.49 mmol, 1.0 eq) in THF at −78° C. was added (trimethylsilyl)acetylene (6.36 g, 61.15 mmol, 3.0 eq), and the stirring continued at the same temperature for 5 hr. Product formation was confirmed by LCMS. Saturated NH4Cl solution was added to the reaction mixture, which was then extracted with EtOAC. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using silica gel (60-120). The desired compound was eluted with 15% EtOAC in Pet ether. Yield: 1.5 g (35.70%).
Reaction SMILES: [H-].[Na+].C(S)C.[Br:6][C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH:13]=[C:12]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[CH:10]=[C:9]([C:23](=[O:25])[CH3:24])[C:8]=1[O:26]C>CN(C)C=O>[Br:6][C:7]1[C:16]2[C:15]([CH3:17])([CH3:18])[CH2:14][CH:13]=[C:12]([C:19]([CH3:21])([CH3:20])[CH3:22])[C:11]=2[CH:10]=[C:9]([C:23](=[O:25])[CH3:24])[C:8]=1[OH:26]
Reactant: COc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CC(=O)c1cc2c(c(Br)c1O)C(C)(C)CC=C2C(C)(C)C

Procedure:
As described in General Procedure L-1, sodium hydride (211 mg, 5.28 mmol) and ethanethiol (0.39 mL, 5.28 mmol) was treated with a solution of 1-(4-bromo-8-tert-butyl-3-methoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-104, 536 mg, 1.47 mmol) in N,N-dimethylformamide to afford the title compound after purification by flash chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.Br[CH2:40][CH2:41][CH3:42]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][N:34]([CH2:40][CH2:41][CH3:42])[CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCNCC2)CO4)cc1
Reactant: CCCBr
Product: CCCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(N4CCCC4=O)cc2C)cc1)CC3

Procedure:
The title compound was prepared from 5-[2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E18) and 1-bromopropane using a similar procedure to Example 19, as a colourless oil (78%). This was converted to its hydrochloride salt and crystallised from acetone.
Reaction SMILES: [S:1]([CH2:5][C:6]([NH2:8])=[S:7])(=[O:4])(=[O:3])[NH2:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:13](=O)[CH2:14]Br>C(O)C>[Cl:9][C:10]1[CH:11]=[C:12]([C:13]2[N:8]=[C:6]([CH2:5][S:1]([NH2:2])(=[O:4])=[O:3])[S:7][CH:14]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: NC(=S)CS(N)(=O)=O
Solvent: CCO
Product: NS(=O)(=O)Cc1nc(-c2ccc(Cl)c(Cl)c2)cs1

Procedure:
A mixture of sulfamoylthioacetamide (7.7 g., 0.05 mol) and 3,4-dichlorophenacyl bromide (13.4 g., 0.05 mol) in ethanol (50 ml) was heated at reflux for 2 hours. After cooling and filtration there was obtained 11.5 g. of the desired intermediate, m.p. 187°-190° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[CH3:12][Sn:13](Cl)([CH3:15])[CH3:14]>CCOCC>[CH3:1][N:2]1[C:6]([Sn:13]([CH3:15])([CH3:14])[CH3:12])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1cccn1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cn1nccc1[Sn](C)(C)C
Reaction time: 1.5 h
Yield: 42.9 %

Procedure:
A solution of 1-methyl-1H-pyrazole (1.6 g, 20.0 mmole) in Et2O was treated with n-butyllithium (12.5 ml, 1.6 M in hexanes, 20.0 mmole) over a period of 10 minutes at room temperature. The yellow slurry was stirred for a further 90 minutes. Subsequently, trimethyltin chloride (4.0 g, 20.0 mmole) was added in one portion. The brown slurry was stirred for 30 minutes, filtered and the filtrate was concentrated, in vacuo, to a black oil (5.0 g). The product was isolated by distillation at 1.5 Torr (67-72° C.) as a clear oil (2.1 g, 42%): 1H-NMR (DMSO-d6, 400 MHz) δ7.40 (1H, d, J=1.5 Hz), 6.27 (1H, d, J=1.7 Hz), 3.84 (3H, s), 0.34 (9H, s). ESIMS m/z 243-247 ion cluster (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:16][CH3:17])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: Fc1ccc(N2CCNCC2)cc1Cl
Product: CCC1(CCCCN2CCN(c3ccc(F)c(Cl)c3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-4-fluoro-phenyl)-piperazine.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=2[F:28])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[C:20]([F:28])[CH:21]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cc3F)c2)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3F)c2)c1
Temperature: 80 °C

Procedure:
A suspension of 3-(1-cyano-1-methylethyl)-N-[3-(2-fluoro-4-nitrophenoxy)phenyl]benzamide (2.03 g, 4.83 mmol), calcium chloride (1.41 g, 12.1 mmol) and reduced iron (2.97 g, 53.1 mmol) in ethanol (300 mL)/water (30 mL) was stirred with heating at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, and passed through a pad filled with celite to separate insoluble material, and the insoluble materials were washed with ethanol. The filtrate and washing were combined and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogencarbonate solution (300 mL), water (200 mL×2) and saturated brine (200 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (1.94 g, quantitatively) as a yellow amorphous substance.
Reaction SMILES: CC([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[C:7]([F:15])[CH:6]=1)=O.Cl>>[F:14][C:8]1[C:7]([F:15])=[CH:6][C:5]([NH2:4])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=1
Reactant: CC(=O)Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: Cl
Product: Nc1cc(F)c(F)cc1[N+](=O)[O-]

Procedure:
A mixture of 6.51 g. of 4,5-difluoro-2-nitroacetanilide and 100 ml. of 6 N aqueous hydrochloric acid was heated to refluxing temperature for about 2 hours. The reaction mixture was then cooled. Crystals which formed were separated by filtration, and the separated crystals were washed with water, dried, and recrystallized from a hexane-dichloromethane solvent mixture. A yield of 5.0 g. of 4,5-difluoro-2-nitroaniline was obtained, melting at 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.Cl.C([O:25][C:26](=[O:35])[C@H:27]([NH2:34])[CH2:28][O:29]C(C)(C)C)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:14])[CH3:15])[CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([NH:34][C@H:27]([CH2:28][OH:29])[C:26]([OH:35])=[O:25])=[O:19])[N:3]=1
Reactant: CC(C)Oc1ccc2c(O)c(C(=O)O)nc(Cl)c2c1
Reactant: CC(C)(C)OC[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)Oc1ccc2c(O)c(C(=O)N[C@H](CO)C(=O)O)nc(Cl)c2c1

Procedure:
Prepared in analogy to Example A-2 e) and f) from 1-chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid (can be obtained according to U.S. Pat. No. 6,093,730, 10/1998, Weidmann et al.) and (R)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester hydrochloride; MS-(+)-ion: M+1=369.0 amu.
Reaction SMILES: C(O)=[O:2].[CH:4]1([N:10]=[C:11]=[N:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:11]([NH:10][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:2]
Reactant: O=CO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of formic acid (0.026 g, 0.556 mmol) in chloroform (1.5 mL) was added dropwise dicyclohexylcarbodiimide (DCC) (0.114 g, 0.56 mmol) in chloroform (1.5 mL) at 0° C. After 5 min the above solution was added to the compound 9 (0.10 g, 0.28 mmol) in pyridine (2 mL). The mixture was then stirred for 1 hours at room temperature. Evaporation of solvent was followed by addition of ether gave dicyclohexylurea which was removed via filtration and the solid was washed with ether. The combined filtrate was concentrated and purified by flash column chromatography to give the product 11, (EM 347) (0.075 g, 70%); 1H NMR (CDCl3): δ 0.66 (s,3H), 0.74-1.42 (m, 11H), 1.2-2.08 (m, 19H), 2.37-2.48 (m, 2H), 2.87 (s, 3H), 3.04 (dd, 1H, J=4, 13 Hz), 3.2-3.4 (m, 3H),8.12 (s, 0.8H), 8.24 (s, 0.2H); 13C NMR (CDCl3) δ 170.56, 164.54, 162.97, 68.59, 65.62, 51.99, 51.71, 44.11 ,36.85, 36.40, 34.12, 32.88, 30.64, 29.68, 29.04, 28.96, 25.20, 24.37, 22.86, 20.55, 20.21, 13.77, 12.34:. HRMS: calcd for C24H40N2O2, 388.3089; found 388.3147. ##STR12##
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[SH:9].[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[C:10]1([C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:9][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:3]=2[CH2:2][OH:1])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCc1ccncc1S
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: OCc1ccncc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 24.6 %

Procedure:
4-hydroxymethyl-3-mercaptopyridine (100 mg, 0.71 mmol) was dissolved in DMF (5 mL) and diisipropylethylamine (0.12 mL, 0.71 mmol) was added followed by triphenylmethylchloride (197 mg, 0.71 mmol). After 30 min. the reaction mixture was partitioned between water and ethyl acetate, and the organic layer was thoroughly washed with water and dried with anhydrous sodium sulfate. Purification by radial chromatography on silica gel produced pure title material (67 mg, 25% yield). 1H NMR (CDCl3) δ 4.17 (s, 2H), 7.20-7.40 (m, 15H), 7.42 (d, 1H, J=6), 8.22 (s, 1H), 8.40 (d, 1H, J=6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:23])=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16](OC)=[O:17])(=[O:11])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1.Cl>C1COCC1.CCOC(C)=O>[Cl:34][C:35]1[N:40]=[C:39]([CH2:41][C:16]([C:15]2[C:14]([F:23])=[C:13]([NH:12][S:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:10])=[O:11])[CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:38]=[CH:37][N:36]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Temperature: 20 °C
Yield: 70.7 %

Procedure:
In a 1000 mL flask was placed methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (9.64 g, 27.9 mmol) and THF (200 mL) was added. The flask was placed in an ice/water bath and LiHMDS (90 mL, 90 mmol) was added. 2-Chloro-4-methylpyrimidine (4.5 g, 35.0 mmol) in THF (60 mL) was added dropwise via addition funnel. After the addition was complete, the reaction was allowed to warm to 20° C. over 1 h. The THF volume was reduced to half under reduced pressure and then treated with 6 N HCl. EtOAc was added and the layers were separated. The aqueous layer was extracted twice with EtOAc and the combined organic layer was washed once with brine, dried over NaSO4, and concentrated. The residue was triturated with EtOAc/ether to afford 8.71 g (71%) of the title compound of Step D. MS (ESI): 442 [M+H]+.