Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:20]2[CH:28]=[CH:27][C:23]([C:24](=[O:25])[NH2:26])=[CH:22][N:21]=2)=[CH:15][CH:16]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCc1ccc(O)cc1)C(=O)OC(C)(C)C
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(CCc1ccc(Oc2ccc(C(N)=O)cn2)cc1)C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 87.9 %

Procedure:
Combine [2-(4-hydroxy-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (5.0 g, 19.9 mmol), 6-chloronicotinamide (3.1 g, 19.9 mmol), and cesium carbonate (12.9 g, 39.8 mmol), in N,N-dimethylformamide (90 mL), stir and heat at 85° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator to yield the crude product (9.5 g). The crude product is purified by flash column chromatography on silica gel eluting with (0.5% conc. ammonium hydroxide/5% ethanol) to (1% conc. ammonium hydroxide/10% ethanol) in chloroform to yield {2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-methyl-carbamic acid tert-butyl ester (6.5 g, 17.5 mmol): 1H NMR (CDCl3, 300.00 MHz): 8.60 (s, 1H); 8.18-8.14 (m, 1H); 7.24-7.24 (m, 2H); 7.07 (d, 2H); 6.94 (d, 1H); 5.98 (br, 2H); 3.47-3.42 (m, 2H); 2.85-2.85 (m, 5H); 1.42 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([SH:44])=[CH:40][CH:39]=1>CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([S:44][C:41]2[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(S)cc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Sc2cc(F)c(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3nncs3)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 2, 0.200 g, 0.433 mmol) and potassium carbonate (0.180 g, 1.30 mmol) were stirred in N,N-dimethylacetamide (1 mL). A solution of 4-methoxythiophenol (0.0576 g, 0.411 mmol) in N,N-dimethylacetamide (2 mL) was added dropwise to the reaction mixture and stirred at ambient temperature for 1 hour. The reaction was quenched with a 1M aqueous solution of sodium hydroxide whereupon a precipitate formed. The precipitate was collect by filtration to afford the title compound (0.224 g, 89%) and this was used in the next step without purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.O.CN(C)[CH:19]=[O:20]>>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:19]=[O:20]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2ccc(Cl)cc12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
18.5 g (0.12 mole) of phosphorus oxychloride are added to 75 ml of dry dimethylformamide at 5°C. 15.15 g (0.1 mole) of 5-chloroindole dissolved in 30 ml of dry dimethylformamide are then added at 5°C. This is stirred for 30 minutes at 20°C, then for 30 minutes at 40°C. 240 ml of water followed by 72 ml of 40% soda are then quickly added. The yellow solution obtained is maintained at 40°-45°C for one hour. After 11/2 hours stirring at ambient temperature the precipitate formed is filtered off and recrystallised from ethyl alcohol.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11]1)[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33].CCN(CC)CC>C(Cl)Cl>[CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11]1)[C:3]1[N:4]=[CH:5][C:6]([NH:9][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])=[CH:7][CH:8]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CN(c1ccc(N)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc(N(C)[C@@H]2CCN(c3ncnc4c3ccn4COCC[Si](C)(C)C)C2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
To a solution of (R)—N2-methyl-N-{1-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-pyridine-2,5-diamine (0.25 mmol) in DCM (5 mL) were subsequently added ethanesulfonyl chloride (0.3 mmol) and Et3N (0.3 mmol). The solution was stirred at the ambient temperature for 18 hours and then concentrated. The crude product was purified by preparative TLC to give the title compound in 42% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[CH:4][CH:5]=3)=[O:27])[C:12](=[O:26])[CH:13]=2)=[CH:20][CH:21]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cn1ccc(OCc2ccc(F)cc2)cc1=O)c1ccc(CCl)cc1
Product: CN1CCN(Cc2ccc(C(=O)Cn3ccc(OCc4ccc(F)cc4)cc3=O)cc2)CC1

Procedure:
4-(4-Fluoro-benzyloxy)-1-{2-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2-oxo-ethyl}-1H-pyridin-2-one is prepared following example 1.1b from 100 mg (0.26 mmol) 1-[2-(4-chloromethylphenyl)-2-oxo-ethyl]-4-(4-fluoro-benzyloxy)-1H-pyridin-2-one (preparation 32.1) and 65 mg (0.65 mmol) N-methylpiperazine.
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C(O)=O)(=O)=[O:21])CC3)=NC=2)=CC=1.C([C@@H]1COC(=O)N1[C:44](=[O:72])[C@H:45]([CH2:49][S:50]([N:53]1[CH2:58][CH2:57][CH:56]([C:59]2[N:64]=[CH:63][C:62]([C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=3)=[CH:61][N:60]=2)[CH2:55][CH2:54]1)(=[O:52])=[O:51])[CH:46]([CH3:48])[CH3:47])C1C=CC=CC=1>>[Cl:71][C:68]1[CH:67]=[CH:66][C:65]([C:62]2[CH:61]=[N:60][C:59]([CH:56]3[CH2:57][CH2:58][N:53]([S:50]([CH2:49][C@H:45]([CH:46]([CH3:48])[CH3:47])[C:44]([OH:21])=[O:72])(=[O:51])=[O:52])[CH2:54][CH2:55]3)=[N:64][CH:63]=2)=[CH:70][CH:69]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)O
Yield: 90 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-chlorophenyl)pyrimidin-2-yl]piperidine-1-sulfonylmethyl}-3-methylbutyryl)oxazolidin-2-one (0.275 g), to give the title compound as a white solid (0.184 g, 90%).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[C:18]2[N:17]=[C:16]([CH3:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[H-].[Na+]>CN(C=O)C.CO>[CH2:1]([N:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:9])[C:18]=2[N:17]=[C:16]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(Br)cccc2[nH]1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nc2c(Br)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloride (1.527 mL) was added to a solution of 4-bromo-2-methyl-1H-benzimidazole (1.40 g) and sodium hydride (0.531 g) in DMF (10 mL) at 0° C. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (1.88 g) as tan oil. The mixture of 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (496 mg), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (700 mg), Pd(Ph3P)4 (87 mg), sodium carbonate (476 mg) and THF (18 mL)-water (0.90 mL) was heated at 100° C. for 1 h under microwave irradiation. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to give 3-[4-(1-benzyl-2-methyl-1H-benzimidazol-4-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (450 mg) as white crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1O[C:14]([CH2:16][CH2:17][CH2:18][CH2:19]Br)([CH3:15])[O:13]C1.[BH4-].[Na+]>C(#N)C>[CH2:19]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[CH2:18][CH2:17][CH2:16][C:14](=[O:13])[CH3:15]
Reactant: CC1(CCCCBr)OCCO1
Reactant: c1cnc2ccncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)CCCCN1CCc2ncccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,6-naphthyridine (13.0 g, 0.1 mol) and 6-bromohexan-2-one ethylene ketal (26.8 g, 0.12 mol) in acetonitrile (100 ml) was refluxed for 10 hours. The reaction mixture was evaporated in vacuo, dissolved in methanol (600 ml) and water (200 ml). To the mixture, sodium borohydride (19.5 g, 0.5 mol) was added portionwise over the internal temperature range 0° to 20° C. After stirring overnight at room temperature, the reaction mixture was evaporated in vacuo, water added and extracted with ethyl acetate. The organic layer was dried over anhydrous potassium carbonate, evaporated in vacuo. The resulting residue was dissolved in 1 N-HCl and stirred overnight, neutralized with 33% NaOH solution and extracted with chloroform. The organic layer was dried over anhydrous potassium carbonate, evaporated in vacuo. The residue was purified by alumina column chromatography (eluted with chloroform-methanol (10:1)) and distilled, bp. 157°-158° C./0.6 mmHg, to afford the Compound No. 29 (9.3 g, 40.1%) as a light yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[CH2:8]([O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([N:19]1[CH2:18][CH2:17][CH:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:21][CH2:20]1)=[O:3])[CH3:6]
Reactant: c1ccc(COC2CCNCC2)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
3,4 g (0.033 mol) of ethyl chloroformate are added dropwise to a stirred mixture of 6.83 g (0.03 mol) of 4-benzyloxypiperidine hydrochloride, 7.74 g (0.056 mol) of dry K2CO3, 26 ml of water and 26 ml of chloroform. After stirring for 1 hour, the organic phase is decanted after dilution with 54 ml of chloroform, and washed 3 times with 20 ml of water and dried (MgSO4). Evaporation of the solvent in vacuo gives a liquid, which is distilled in vacuo.
Reaction SMILES: C1(N[C:8]([C:10]2[C:11]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([OH:20])[CH:14]=3)=[O:9])C=CC=CC=1.[O:29]1CCOCC1>Cl>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:11]1[C:10]([C:8]([OH:29])=[O:9])=[CH:19][C:18]2[C:13](=[CH:14][C:15]([OH:20])=[CH:16][CH:17]=2)[N:12]=1
Reactant: C1COCCO1
Reactant: O=C(Nc1ccccc1)c1cc2ccc(O)cc2nc1Nc1ccccc1Cl
Agent: Cl
Product: O=C(O)c1cc2ccc(O)cc2nc1Nc1ccccc1Cl

Procedure:
A suspension of 2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acid phenylamide (17 mg, 0.04 mmol) in 16N aqueous HCl (0.1 ml) and 1,4-Dioxane (0.1 ml) was heated at reflux for 5 days. After evaporating the solvent, the residue was recrystallized from methanol to give 2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acid as the white crystal; 13 mg (99%). 1H NMR (400 MHz, DMSO-d6) ppm 6.96 (dd, 1H, J=2.3, 8.6 Hz), 6.99 (d, 1H. J=2.3 Hz), 7.04 (ddd, 1H, J=1.5, 7.8, 8.8 Hz), 7.40 (ddd, 1H, J=1.5, 7.8, 8.8 Hz), 7.52 (dd, 1H, J=1.5, 7.8 Hz), 7.83 (d, 1H, J=8.8 Hz), 8.84 (s, 1H), 9.10 (d, 1H, J=11.2 Hz), 10.48 (s, 1H), 11.05 (s, 1H). LC/MS: m/z 315 (M+1)+, 313 (M−1)−.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+]>C(O)C>[N+:12]([CH:15]=[CH:6][C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1)([O-:14])=[O:13]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, step 1, benzo[b]thiophene-2-carbaldehyde (2.1 g, 0.012 mol) in ethanol (100 mL) was reacted with nitro methane (0.7 mL, 0.012 mol) and 10N NaOH (0.51 g, 0.012 mol). The resulting mixture was stirred at 0° C. for 1 hr to afford 2.1 g of the product (84% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C:10](=[O:12])[CH:9]=[CH:8][O:7]1)=[O:5])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1CC(=O)C=CO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(=O)CCO1
Yield: 33.1 %

Procedure:
A mixture of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (8.0 g, 46.0 mmol) and Pd/C (10%, 0.20 g) in EtOAc (70 mL) was shaken in a Parr bottle with hydrogen at 50 psi overnight and filtered through a pad of Celite. The filtrate was concentrated and the residue was distilled to give 2.62 g (33%) of yellowish oil: 1H NMR (CDCl3) δ 1.29 (t, 3H), 2.40 (d, 1H), 2.58-2.75 (m 3H), 3.79 (tt, 1H), 4.23 (q, 2H), 4.28 (m 1H), 4.40 (m, 1H).
Reaction SMILES: [C:1]([C@H:5]1[CH2:9]OS(=O)(=O)[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[F-:19].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:12]([NH:6][C@@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][F:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [F-]
Reactant: CC(C)(C)[C@H]1COS(=O)(=O)N1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](CF)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4S)-4-(tert-butyl)-3-(phenylmethyl)-1,2,3-oxathiazolidine-2,2-dioxide (6.22 g, 23.09 mmol) in THF (100 mL) was added a 1 M solution of tetrabutylammonium fluoride in THF (46.2 ml, 46.2 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. Solvent was evaporated, and ether (50 mL) and 20% H2SO4 aqueous solution (20 mL) were added. The reaction mixture was stirred for 2 h at room temperature, diluted with water, neutralized with solid NaHCO3 slowly then extracted with ethyl acetate. The combined organics were dried over anhydrous Na2SO4, filtered, then concentrated. The residue was purified by column chromatography to give the title compound (4.13 g) as a light yellow oil. LCMS m/z=210.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.96 (s, 9H), 2.41 (dt, J=24.7 and 4.3 Hz, 1H), 3.76 (d, J=13.1 Hz, 1H), 4.01 (d, J=13.1 Hz, 1H), 4.39-4.72 (m, 2H), 7.23-7.38 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]([NH2:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:14]([N:16]1[C:20](=[O:21])[C:19]([O:22]C)=[C:18]([C:24](O)=[O:25])[CH2:17]1)[CH3:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]([NH:13][C:24]([C:18]2[CH2:17][N:16]([CH2:14][CH3:15])[C:20](=[O:21])[C:19]=2[OH:22])=[O:25])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(N)CCc1ccc(Cl)c(Cl)c1
Reactant: CCN1CC(C(=O)O)=C(OC)C1=O
Product: CCN1CC(C(=O)NC(C)CCc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Yield: 15 %

Procedure:
By appropriate application of method described in Example 180, 4-(3,4-dichlorophenyl)butan-2-amine (racemic) (50 mg, 0.23 mmol) and 1-ethyl-4-methoxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (85 mg, 0.46 mmol) were converted to Example 225 (racemate) (12 mg, 0.032 mmol, 15% yield for two steps). HPLC/MS (Method D) RT=0.97 min, [M+1]+ 371.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16-1.39 (m, 6H) 1.74-1.95 (m, 2H) 2.67 (t, J=7.78 Hz, 2H) 3.62 (q, J=7.03 Hz, 2H) 4.12 (s, 1H) 4.14-4.28 (m, 1H) 6.98-7.10 (m, 1H) 7.30 (d, J=1.25 Hz, 1H) 7.34 (d, J=8.28 Hz, 1H).
Reaction SMILES: Cl[Si:2](Cl)([CH3:4])[CH3:3].[F:6][C:7]([F:13])([F:12])[S:8]([OH:11])(=[O:10])=[O:9].Cl>>[F:6][C:7]([F:13])([F:12])[S:8]([O:11][Si:2]([O:11][S:8]([C:7]([F:13])([F:12])[F:6])(=[O:10])=[O:9])([CH3:4])[CH3:3])(=[O:10])=[O:9]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: C[Si](C)(Cl)Cl
Agent: Cl
Product: C[Si](C)(OS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F
Yield: 60.1 %

Procedure:
An oven-dried 100 mL-RB flask is charged with dichlorodimethylsilane (6.45 g, 0.05 mol). Then trifluoromethanesulfonic acid (15 g, 0.10 mol) is added dropwise. The mixture is heated at 60° C. until no HCl evolves. The residue is distilled to yield 10.7 g (60%) of the product as a clear liquid. 1H NMR (500 MHz, CDCl3, in ppm) δ 0.88 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].IC.[C:11](=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:11]
Reactant: Fc1ccccc1S
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A deoxygenated solution of 2-fluorothiophenol (10 g, 78 mmol) in anhydrous DMF (10 mL) was treated with iodomethane (4.9 mL, 78 mmol) and potassium carbonate (10.8 g, 78 mmol). The reaction mixture was stirred at room temperature for 1 hour. A thin layer chromotography (100% hexanes) sample indicated that the reaction had not gone to completion, so an additional equivalent of base and iodomethane were added and the reaction mixture was stirred overnight at room temperature. The reaction was acidified with 10% aqueous citric acid and extracted with hexanes (2×125 mnL). The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide the desired compound as a pale yellow oil (yield: 6.68 g; 60%).
Reaction SMILES: C([C@@H]1CC[C@@H](C)C[C@H]1[O:11][C:12]([C@@H:14]1[CH2:27][C:26]2[CH:25]=[C:24]3[C:19]([O:20][C@@H:21]([C:30]4[CH:35]=[CH:34][C:33]([O:36]CC5C=CC(Cl)=C(Cl)C=5)=[CH:32][CH:31]=4)[C:22](=[O:29])[N:23]3[CH3:28])=[CH:18][C:17]=2[CH2:16][N:15]1[C@H:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][CH3:48])=[O:13])(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:21]2[O:20][C:19]3[C:24](=[CH:25][C:26]4[CH2:27][C@@H:14]([C:12]([OH:13])=[O:11])[N:15]([C@H:46]([C:49]5[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=5)[CH2:47][CH3:48])[CH2:16][C:17]=4[CH:18]=3)[N:23]([CH3:28])[C:22]2=[O:29])=[CH:31][CH:32]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 122.4 %

Procedure:
(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (0.80 g) was dissolved in 20 mL of dry DCM and cooled to 0° C. Boron trichloride (8 mL, 1M solution in hexanes) was added and the mixture stirred at 0° C. for 3.5 hours. The mixture was concentrated and treated with water/saturated sodium bicarbonate until pH 7. The aqueous mixture was extracted three times with ethyl acetate-THF (9-1) and organic layers combined. The combined organic layers were dried over sodium sulfate and concentrated to provide (3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (601 mg, LC/MS: m/z 474).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][CH:36]([CH3:41])[CH2:37][C:38](O)=[O:39].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][CH:36]([CH3:41])[CH3:35])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: CC(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)CC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by 3-methylbutyric acid (32 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-N-[cis-4-(3-methyl-butyrylamino)-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (112 mg) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:30]([NH2:32])[CH3:31])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:32]([CH:30]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[C:17]([CH3:16])[CH:18]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1OCCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCCC(F)(F)F
Yield: 61 %

Procedure:
The title compound is prepared in 61% yield (260 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (300 mg, 1.08 mmol) and 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (337 mg, 1.19 mmol, Amine-36, single enantiomer) in a similar manner to Intermediate-2.