Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)[C@@H](N1CC2C(=CC(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)=CC=2)C1=O)C(O)=O.[O:38]=[C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:48]3[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=4)=[O:56])=[CH:50][CH:49]=3)[CH:46]=2)[CH2:41][N:40]1[CH2:68][CH2:69][CH2:70][C:71]([O:73]C)=[O:72]>>[O:38]=[C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:48]3[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:66])([F:65])[F:67])[CH:59]=4)=[O:56])=[CH:50][CH:49]=3)[CH:46]=2)[CH2:41][N:40]1[CH2:68][CH2:69][CH2:70][C:71]([OH:73])=[O:72]
Reactant: COC(=O)CCCN1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Agent: CC(C)[C@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Product: O=C(O)CCCN1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Yield: 82 %

Procedure:
The compound of example 349 was prepared analogous to compound of example 331 by hydrolysis of the compound of example 348.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:26]C(=O)OC(C)(C)C)([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:13][C:12]([C:34]2[CH:39]=[C:38]([Cl:40])[C:37]([OH:41])=[C:36]([Cl:42])[CH:35]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:26][C:23]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:34]4[CH:35]=[C:36]([Cl:42])[C:37]([OH:41])=[C:38]([Cl:40])[CH:39]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])=[CH:22][CH:21]=1)([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 28.6 %

Procedure:
Following general procedure A-2, tert-butyl 2-{4-[3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-ylamino]phenyl}propan-2-ylcarbamate (0.145 mmol) was TFA (2 mL) to afford the desired product (21 mg, 28% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.33 (s, 1H), 8.26 (dd, J=8.8, 1.9 Hz, 1H), 8.19 (s, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 7.43 (s, 2H), 2.82-2.73 (m, 1H), 1.78 (s, 6H), 1.18-1.10 (m, 4H); ESI MS m/z 506 [C28H25Cl2N3O2+H]+; HPLC 98.7% (AUC), tR=11.00 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([NH2:21])=[C:4]([SH:22])[N:3]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32](O)=O)=[CH:26][CH:25]=1>>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]2[S:22][C:4]3[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]4[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]4)[C:5]=3[N:21]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc(S)c2N)CC1
Reactant: O=C(O)CCc1ccc(Br)cc1
Product: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(Br)cc3)sc2n1
Yield: 70 %

Procedure:
This compound was synthesized from tert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate using 3-(4-bromophenyl)propionic acid, yielding the title compound in 70% yield.
Reaction SMILES: [CH3:1][NH2:2].Cl[S:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2)(=[O:6])=[O:5]>C(Cl)(Cl)Cl.C(Cl)Cl.C(O)C>[CH3:1][NH:2][S:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2)(=[O:6])=[O:5]
Reactant: CN
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: ClCCl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Methylamine (2.7 ml of a 2.9M solution in chloroform) was added to a suspension of 5-chlorosulphonyloxindole (900 mg, 3.9 mmol), (prepared as described for the starting material in Example 60), in a mixture of methylene chloride (20 ml) and ethanol (20 ml). The mixture was stirred for 15 minutes at ambient temperature, the volatiles were removed by evaporation. The solid residue was suspended in water, collected by filtration, washed with water, ether, and dried under vacuum over phosphorus pentoxide to give 5-methylaminosulphonyloxindole (880 mg, 90%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[K].Cl[C:10]1[C:18]2[NH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[N:15][C:14]=2[C:13]([N+:23]([O-:25])=[O:24])=[CH:12][C:11]=1[N+:26]([O-:28])=[O:27].O>CN(C)P(=O)(N(C)C)N(C)C>[CH:1]1([O:7][C:10]2[C:18]3[NH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[N:15][C:14]=3[C:13]([N+:23]([O-:25])=[O:24])=[CH:12][C:11]=2[N+:26]([O-:28])=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Agent: [K]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1OC1CCCCC1
Reaction time: 8 h

Procedure:
Cyclohexanol (5.4 grams) and potassium (1.9 grams) were reacted in 50 milliliters of dry hexamethylphosphoric triamide. When reaction had ceased, the solution was stirred and 5 grams of 4-chloro-5,7-dinitro-2-trifluoromethylbenzimidazole were added. Stirring was continued overnight. The reaction mixture was then poured into water, acidified, and extracted with ethyl acetate. The ethyl acetate was then removed by evaporation, and the residue was chromatographed on 300 milliliters of silica gel using benzene as eluant. The benzene was removed by evaporation and the crude product was recrystallized from an aliphatic hydrocarbon fraction boiling at 60°-80° C., to which there had been added a trace of benzene. The resulting 4-cyclohexyloxy-5,7-dinitro-2-trifluoromethylbenzimidazole product melted at 151°-2° C. Its identity was confirmed by NMR and by elemental analysis.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21]([C:28]([O:30]C)=[O:29])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21]([C:28]([OH:30])=[O:29])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(C)C)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
In toluene/ethanol/water (=10/1/1, 20.4 ml) was dissolved methyl 7-bromo-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.50 g). To the solution were added 4-(2-butoxyethoxy)phenyl borate (0.48 g) and potassium carbonate (0.47 g), and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinepalladium (0.10 g), and the mixture was heated to reflux for 14 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=20/1→8/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.44 g). Methyl 7-[4-(2-butoxyethoxy)phenyl]-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.44 g) was dissolved in THF (8.8 ml)/methanol (8.8 ml). To the solution was added 1N sodium hydroxide (4.4 ml), and the mixture was stirred at 50° C. for 4 hours. After cooled to room temperature, pH was adjusted to approximate. 5 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate/THF, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (12/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (320 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]1)=[O:11].Cl[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]2)[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1ccc(Cl)nc1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 429 [M+1]+.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1)([CH3:3])[CH3:2].[Br:12]Br>CC(O)=O>[Br:12][CH:7]1[C:6](=[O:11])[CH2:5][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][C:8]1=[O:10]
Reactant: BrBr
Reactant: CC(C)C1CC(=O)CC(=O)C1
Solvent: CC(=O)O
Product: CC(C)C1CC(=O)C(Br)C(=O)C1
Yield: 96.8 %

Procedure:
To a stirred solution of 5-isopropylcyclohexane-1,3-dione (2 g, 12.9 mmol) in AcOH (20 mL) at r.t. was added bromine (2.06 g, 0.66 mL, 12.9 mmol) dropwise. The reaction was then carried out according to Method A to give the title compound (2.91 g, 96%) as a white solid. δH (DMSO-d6) 2.55-2.48 (4H, m), 2.38-2.32 (1H, m), 1.91-1.82 (1H, m), 1.79-1.54 (1H, m), 0.87 (6H, d, J 6.7 Hz). LCMS (ES+) 234.9 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]1[O:14][CH2:15][O:16][C:10]1=[CH:9][CH:8]=2)=[O:4].[Mg]>>[CH2:15]1[O:16][C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[NH:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:13]3)[O:14]1
Reactant: COC(=O)c1cc2c3c(ccc2[nH]1)OCO3
Agent: [Mg]
Product: O=C(O)C1Cc2c(ccc3c2OCO3)N1

Procedure:
This compound was prepared from 4,5-methylenedioxyindole-2-carboxylic acid methyl ester as described in example 1. However this time 10 equivalence of magnesium turnings were used instead of 2-3 eq. of magnesium turnings. The product was purified by column chromatography on silica gel using 7:3 petroleum spirit:ethyl acetate as eluent.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:45])[C@H:7]([CH3:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35]C(OC(C)(C)C)=O)[CH2:11][C:12]([CH3:34])([CH3:33])[CH2:13][C:14]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4]>Cl.O1CCOCC1>[CH2:1]([NH:5][C:6](=[O:45])[C@H:7]([CH3:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH2:35])[CH2:11][C:12]([CH3:34])([CH3:33])[CH2:13][C:14]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)OC(C)(C)C)Cc2ccccc21)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(C(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
28 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[3(R,S)-tert-butoxycarbonyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonyl]-octanoic acid (N-butyl)amide are dissolved in 2 ml of 4N hydrochloric acid in dioxane and the solution is stirred at 20° C. for 30 min. The reaction mixture is diluted with dioxane and lyophilized. The crude product is purified by means of FC (5 g of silica gel, mobile phases N and O). This gives the title compound as a diastereomer mixture: Rf (O)=0.32; Rt (I)=23.8 min; FAB-MS: (M+H)+ =532.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[F:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][C:28]=1[CH3:35]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:30]3[CH:31]=[CH:32][C:27]([F:26])=[C:28]([CH3:35])[CH:29]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc([Mg]Br)ccc1F
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)ccc1F

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2 mL THF and 0.49 mL 1M 4-fluoro-3-methylphenylmagnesium bromide. Yield: 40 mg of a white solid. LC-MSD, m/z for C23H16BrFN2O2 [M+H]+=451.0, 453.0; HPLC retention time: 2.5 min.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([N:12]([CH2:18][CH2:19][CH2:20][F:21])[C:13](=O)[CH2:14][O:15][CH3:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(OCC)(=O)C.CCCCCC>C1COCC1>[CH2:1]([C:3]1[C:11]([N:12]([CH2:18][CH2:19][CH2:20][F:21])[CH2:13][CH2:14][O:15][CH3:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccccc2c1N(CCCF)C(=O)COC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nn2ccccc2c1N(CCCF)CCOC
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A 0° C. solution of N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-(3-fluoropropyl)-2-methoxyacetamide (1.62 g, 5.5 mmol) in THF (25 mL) was treated with borane dimethyl sulfide complex (1.1 mL, 11.0 mmol). The reaction was stirred at room temperature for 5.5 hours. The reaction was quenched with 2N HCl then made basic with 4N NaOH. The mixture was extracted twice with ethyl acetate. The combined organic layers was washed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow oil which was subjected to column chromatography (40% ethyl acetate/hexane) to give 0.313 g (20%) of yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 8.99 (d, J=7.2 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.41–7.37 (m, 1H), 7.10–7.07 (m, 1H), 4.62 (dt, J=47.2, 5.7 Hz, 2H), 3.39–3.29 (m, 9H), 3.05 (q, J=7.5 Hz, 2H), 1.86–1.73 (m, 2H), 1.35 (t, J=7.5 Hz, 3H); MS (EI) m/z 280.24 (M++H).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[O:3][C:4]1[CH:42]=[CH:41][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][NH:23][C:22](=[O:26])[C:21]=4[N:27]=3)[CH2:15][CH2:14][N:13]2[S:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[O:11])=[CH:6][CH:5]=1.CO.[C:47]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:44][C:2]([F:1])([F:43])[O:3][C:4]1[CH:42]=[CH:41][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][N:23]([CH3:47])[C:22](=[O:26])[C:21]=4[N:27]=3)[CH2:15][CH2:14][N:13]2[S:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3c(=O)[nH]ncc3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ncc2sc(N3CCN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)[C@@H](C(=O)NCc4ccc(OC(F)(F)F)cc4)C3)nc2c1=O
Yield: 71 %

Procedure:
To a solution of the compound (40 mg) obtained in Step 6 in THF (0.8 ml) were added methanol (3.7 μl), triphenylphosphine (24 mg) and diisopropyl azodicarboxylate (18 μl) with stirring under ice-cooling, and the mixture was stirred overnight at room temperature. Methanol (1.2 μl), triphenylphosphine (8 mg) and diisopropyl azodicarboxylate (6 μl) was added at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:chloroform=5:95) to give the title compound (29 mg).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH:3]=1.[F:24][C:25]([F:30])([F:29])C([O-])=O.[Na+].ClCCl.Cl>CN(C)C(=O)C.O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:6][C:2]([C:25]([F:30])([F:29])[F:24])=[CH:3][C:4]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Reactant: O=C([O-])C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)sc2-c2ccc(F)cc2)cc1
Yield: 14.8 %

Procedure:
A mixture of 5-bromo-2-(4-fluorophenyl)-3-[4(methylsulfonyl)phenyl]thiophene (7.2 g), sodium trifluoroacetate (9.4 g) and cuprous iodide (6.5 g) in N,N-dimethylacetamide (109 ml), was stirred and refluxed for 5 hours. Dichloromethane (200 ml), 3N hydrochloric acid (100 ml) and water (100 ml) were added to the reaction mixture. The resulting mixture was filtered, and the filtrate was separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue (13.9 g) was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (50:1). The crude product (1.3 g) was recrystallized from ethanol to give pale brown crystal of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)thiophene (1.04 g).
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([NH:13][C:14]#[N:15])=[CH:5][CH:4]=[C:3]3[CH2:2]1.[ClH:16].[Cl:17][C:18]1[C:24]([Cl:25])=[C:23]([Cl:26])[CH:22]=[CH:21][C:19]=1[NH2:20]>ClC1C=CC=CC=1>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([NH:13][C:14]([NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:26])=[C:24]([Cl:25])[C:18]=2[Cl:17])=[NH:15])=[CH:5][CH:4]=[C:3]3[CH2:2]1.[ClH:16]
Reactant: N#CNc1ccc2c3c(cccc13)CC2
Reactant: Nc1ccc(Cl)c(Cl)c1Cl
Agent: Cl
Solvent: Clc1ccccc1
Product: N=C(Nc1ccc(Cl)c(Cl)c1Cl)Nc1ccc2c3c(cccc13)CC2
Temperature: 20 °C
Reaction time: 24 h
Yield: 72.2 %

Procedure:
A mixture of 5-acenaphthyl cyanamide (0.194 g, 1 mmol) and 2,3,4-trichloroaniline hydrochloride (0.221 g, 0.95 mmol; prepared from 2,3,4-trichloroaniline and 1. ON HCl-ether) were heated at reflux in 5 mL of chlorobenzene. Shortly after reflux temperature was reached all the solids had dissolved to give a clear solution. After a total of 2 hour reflux, the mixture was cooled to 20° C. and allowed to stand for 24 hours. The solid was collected by filtration and washed with excess of methylene chloride and dried in vacuo at 40° C. to give product (0.293 g, 68%) as an off white solid, mp: 208°-10° C.; 1H NMR (CD3OD): δ 7.70-7.58 (m, 3H, Ar--H), 7.48 (d, 2H, J=7.5Hz, Ar--H), 3.47-3.41 (m, 4H, 2×CH2); HRMS 389.0220 (389.0253 calcd. for C19H14N3Cl3); Anal Calcd. for C19H15N3CI4 (427.15): C, 53.42; H, 3.54; N, 9.84; Cl, 33.2; Found: C, 53.25: H, 3.57; N, 9.67; Cl, 33.75.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([CH3:26])([C:20]1[N:24]=[C:23]([CH3:25])[O:22][N:21]=1)[NH2:19]>>[CH3:17][C:18]([NH:19][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[N:24]=[C:23]([CH3:25])[O:22][N:21]=1)[CH3:26]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2cccc(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (Example 33 d, CAN 1153831-97-0) as starting materials, MS (LC/MS): 357.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-methoxy-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A8) (5.79 g, 17.2 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a yellow solid (5.36 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=O)=O)=[CH:4][C:3]=1[F:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1cc(S)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
4-Bromo-3-fluoro-benzenesulfonyl chloride (324 μl, 2.19 mmol) was added dropwise to a solution of triphenylphosphine (1.73 g, 6.58 mmol) in a mixture of dimethylformamide (125 μl) and dichloromethane (5 ml). The solution was stirred at room temperature for 16 hours, then 1 M aqueous hydrochloric acid (5 ml) was added and the layers were separated. The organic layer was concentrated in vacuo and the resultant residue taken up in 1 M aqueous sodium hydroxide (10 ml). The resulting suspension was filtered through Celite® and the filtrate washed with ether (10 ml×3), then neutralised by addition of 1 M aqueous hydrochloric acid (10 ml). The solution was extracted with ether (10 ml×3) and the combined organic extracts were dried (Na2SO4) then concentrated in vacuo to afford the title compound as a colourless oil (225 mg, 50%). 1H NMR (CDCl3, 300 MHz) 7.47 (1H, dd, J=8.4, 7.5 Hz), 7.06 (1H, dd, J=8.9, 2.2 Hz), 6.93 (1H, ddd, J=8.4, 2.1, 0.7 Hz), 3.54 (1H, br s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[O:19][C:18]([CH2:20][CH2:21][NH:22][C:23]([C:25]3[NH:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=3)=[O:24])=[CH:17][CH:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]>>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[O:19][C:18]([CH2:20][CH2:21][NH:22][C:23]([C:25]3[NH:29][N:28]=[C:27]([C:30]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:31])[CH:26]=3)=[O:24])=[CH:17][CH:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Reactant: C1COCCN1
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(C(=O)N2CCOCC2)n[nH]1
Yield: 17 %

Procedure:
The title compound was prepared as in Example 1 starting from morpholine and 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid. Crude product was purified by chromatography (CombiFlash, 1st column silica, eluent: 0-10% MeOH/DCM: 2nd column C-18 RP, eluent: 0-100% MeCN/water) to give 505 mg (17%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.95 (t, 1H), 3.56 (q, 1H), 3.62 (br s, 6H), 3.90 (br s, 2H), 6.34 (d, 1H), 7.02 (d, 1H), 7.08 (s, 1H), 7.62 (m, 2H), 7.85 (d, 1H), 8.61 (s, 1H), 13.94 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:12].[K+].[K+].C(Cl)Cl>C(#N)C.O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH:10]=[O:12])=[N:3][C:2]=1[Br:1]
Reactant: COc1ccc(C)nc1Br
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C=O)nc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
A stirred mixture of 2-bromo-3-methoxy-6-methyl-pyridine (2.00 g, 9.9 mmol), Cu(II) sulfate pentahydrate (2.47 g, 9.9 mmol), and potassium peroxydisulfate (8.03 g, 29.7 mmol) in 80 mL of acetonitrile/H2O (1:1) was heated under reflux. After 1 hour, the dark green mixture was cooled to room temperature and CH2Cl2 was added. The layers were separated and the aqueous layer further extracted with CH2Cl2. The organics were combined, dried (MgSO4), filtered and evaporated. The resulting crude product was purified on silica gel [Biotage, hexane:ethyl acetate (4:1)] to give a white solid (0.51 g, 24% yield).