Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]([CH3:15])[CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29].C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH3:15])[CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:16][CH:17]=2)=[O:24])=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc(NC(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDIC hydrochloride (0.33 mmol, 0.07 g) was added in one portion to a suspension of (4-amino-benzyl)-methyl-(tetrahydro-pyran-4-yl)-amine Compound 1d (0.25 mmol, 0.06 g), 4-chloro-3-trifluoromethyl-benzoic acid Compound 7a (0.22 mmol, 0.05 g) and HOBt (0.22 mmol 0.03 g) in DMF (5.0 mL) at 0° C. The resulting suspension was warmed to r.t. and a crystal of DMAP and Et3N (0.65 mmol, 0.1 mL) were added. The mixture was stirred overnight and produced an orange-yellow suspension. The suspension was poured into water and the aqueous layer was extracted with EtOAc (25 mL). The organic layer was washed with water (2×20 mL), then a solution of 5% NaOH (10 mL) and brine. The organic layer was separated, dried over Na2SO4 and filtered. The solvent was removed in vacuo to yield a residue, which was purified via preparative TLC (15:1 CH2Cl2:MeOH) to provide 4-chloro-N-(4-{[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}-phenyl)-3-trifluoromethyl-benzamide Compound 7b (0.06 g, 63%) as a pale yellow solid. MS m/e 427 (M+H, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:25]2[CH2:26][CH:22]([CH2:23][CH2:24]2)[C:21](=[O:27])[CH:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([O:15][C:19]3[CH:25]4[CH2:26][CH:22]([CH2:23][CH2:24]4)[C:21](=[O:27])[CH:20]=3)[CH3:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Reactant: O=C1C=C(Cl)C2CCC1C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(OC1=CC(=O)C2CCC1C2)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
To a solution of 1-[2-(4-chlorophenyl)thiazol-5-yl]ethanol (1.1 g, 4.6 mmol) in anhydrous tetrahydrofuran (20 ml) is added, in one portion, sodium hydride (60% dispersion in mineral oil, 184 mg, 4.6 mmol). The reaction mixture is stirred for 5 minutes at room temperature and 4-chlorobicyclo[3.2.1]oct-3-en-2-one (720 mg, 4.6 mmol) is added in one portion. The reaction mixture is stirred at room temperature overnight. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 4-{1-[2-(4-chlorophenyl)thiazol-5-yl]ethoxy}bicyclo[3.2.1]oct-3-en-2-one (1.24 g)
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[S:13].[OH-].[Na+]>O>[NH2:10][C:8](=[N:9][C:12](=[S:13])[O:14][CH3:15])[S:7][CH3:6]
Reactant: CSC(=N)N
Reactant: COC(=S)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=S)N=C(N)SC
Reaction time: 1 h

Procedure:
To 69.5 parts 2-methyl-2-thiopseudourea sulfate and 110 parts methyl chlorothioformate in 500 ml. of water is added dropwise at 0°-5°C. 120 parts 50% sodium hydroxide. The reaction mixture is stirred at 0°-5°C. for 1 hour and then at room temperature for 2 hours. The solution is extracted with methylene chloride. The methylene chloride extract is then dried and the solvent evaporated on a rotary evaporator to give 47 parts of methyl N-(1-amino-1-methylthiomethylene)thiocarbamate melting at 75°-76°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:29])=[C:15]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[O:38]1[CH2:43][CH2:42][CH:41]([C:44](=[S:46])[NH2:45])[CH2:40][CH2:39]1.O>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:46][C:44]([CH:41]3[CH2:42][CH2:43][O:38][CH2:39][CH2:40]3)=[N:45][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([F:29])=[C:15]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1ccc(F)c(NS(=O)(=O)c2cc(F)ccc2F)c1
Reactant: NC(=S)C1CCOCC1
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S(=O)(Nc1cc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)ccc1F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a solution of N-{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.910 g, 2.06 mmol) (prepared in a manner analogous to Intermediate 35) in DMA (8.24 mL) was added NBS (0.385 g, 2.16 mmol). The reaction stirred 30 min at rt and then tetrahydro-2H-pyran-4-carbothioamide (0.389 g, 2.68 mmol) was added. The reaction stirred 16 h at rt. The reaction mixture was poured into water (150 mL), causing precipitation of a solid. The solid was collected by vacuum filtration, redissolved in EtOAc (50 mL), and concentrated onto silica gel. Purification by chromatography (20 to 100% EtOAc:hexanes) afforded the title compound (690 mg, 1.21 mmol, 58.5% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.86 (s, 1H), 8.58 (d, J=5.3 Hz, 1H), 7.45-7.69 (m, 4H), 7.42 (dd, J=7.5, 2.0 Hz, 1H), 7.32 (dd, J=10.1, 8.8 Hz, 1H), 7.14 (d, J=5.3 Hz, 1H), 3.95 (dd, J=11.7, 2.0 Hz, 2H), 3.40-3.56 (m, 2H), 3.25-3.41 (m, 1H), 2.02 (dd, J=12.9, 1.6 Hz, 2H), 1.65-1.86 (m, 2H). MS (ESI): 567.09 [M+H]+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][C:11]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C.C(=O)(O)[O-].[Na+]>[O:1]([CH2:8][CH2:9][N:10]1[C:11](=[O:24])[CH2:12][N:13]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][CH:15]1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccccc2)CC(=O)N1CCOc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CN(Cc2ccccc2)CC(O)N1CCOc1ccccc1
Reaction time: 1 h
Yield: 93.2 %

Procedure:
1-(2-Phenoxyethyl)-4-benzyl-2,6-piperazinedione (2.24 g) in ethanol (60 ml) and saturated sodium bicarbonate solution (15 ml) was cooled to 5° and sodium borohydride (0.4 g) added. The mixture was stirred at 5° for 1 h, water (150 ml) added and the mixture extracted with chloroform (3×75 ml). Evaporation of the chloroform gave the title compound as an off-white solid (2.1 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:31])([OH:30])[CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1.C([O-])(=O)C.[K+].[N:37]#[C:38]Br>CO.O>[NH2:37][C:38]1[O:30][C:3]([CH2:4][NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[N:9]=[C:8]([N:17]3[CH2:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]3)[CH:7]=2)([CH3:31])[CH2:2][N:1]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(C)(O)CN)c2c1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(C)CN=C(N)O3)c2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
To a mixture of 1-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropan-2-ol (200 mg, 0.45 mmol, prepared in analogy to Example 11-4) and potassium acetate (240 mg, 2.4 mmol) in methanol (8 mL) and water (2 mL) which was cooled to 0° C., a cooled solution of cyanogen bromide (52.3 mg, 0.5 mmol) in methanol (2 mL) was added. After being stirred at room temperature for 4 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL), washed with water (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 80 mg of the product as a white powder. MS obsd. (ESI+) [(M+H)+] 466, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (d, J=7.6 Hz, 1 H), 7.83 (d, J=7.2 Hz, 1 H), 7.60 (m, 2 H), 7.46-7.39 (m, 2 H), 7.29 (dd, J=1.6, 8.8 Hz, 1 H), 6.19 (s, 1 H), 5.18-5.09 (m, 2 H), 4.51 (brs, 2 H), 3.82 (d, J=11.2 Hz, 1 H), 3.65 (s, 2 H), 2.57 (m, 3 H), 2.41 (s, 3 H), 1.62 (s, 3 H).
Reaction SMILES: CC1N([CH2:7][CH:8]2[C:21](=[O:22])[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[N:19]([CH3:20])[C:11]=3[CH2:10][CH2:9]2)C=CN=1.CN1C2CCCC(=O)C=2C2C1=CC=CC=2.C=O.N1CCOCC1>C(O)(=O)C>[CH3:20][N:19]1[C:11]2[CH2:10][CH2:9][C:8](=[CH2:7])[C:21](=[O:22])[C:12]=2[C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Agent: C=O
Agent: Cn1c2c(c3ccccc31)C(=O)CCC2
Solvent: C1COCCN1
Solvent: CC(=O)O
Product: C=C1CCc2c(c3ccccc3n2C)C1=O

Procedure:
Kim et al. (Heterocycles 1997, 45, 2041) disclose a two-step synthesis of ondansetron. In the first step of the synthesis, 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (compound of formula 1, Scheme 1) is reacted with a source of formaldehyde and morpholine in boiling glacial acetic acid to provide 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one (compound of formula 2, Scheme 1). In the second step of the synthesis, 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one is reacted with 2-methylimidazole in the presence of alumina (Al2O3) to provide ondansetron (See, Scheme 1).
Reaction SMILES: P(Cl)(Cl)[Cl:2].[CH2:5](O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:5]([Cl:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCO
Reactant: ClP(Cl)Cl
Product: CCCCCCCCCl
Reaction time: 0.05 h
Yield: 98 %

Procedure:
Into a reactor system in accordance with Example 1 there were pumped octyl alcohol and phosphorus trichloride in a molar ratio of 2.90 : 1. The pressure in the flow line was 30 atm. The residence time in reaction zone 1 was 3 minutes; in the preheater, 2 minutes; and, in reaction zone 2, 28 minutes. The temperature at the outlet of reaction zone 1 was 100° C. Following preheating to 150° C, an average temperature of 150° to 155° C was maintained in reaction zone 2. One obtained in the organic phase 96% octyl chloride in a yield of 98% with respect to octyl alcohol. The product contained 0.19% dioctyl ether. Space-time yield: 1.4 kg/hour, liter.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([N:5]2[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]2=[O:9])=[O:24])=[CH:18][CH:17]=1
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To a solution of (4S)-4-isopropyl-1,3-oxazolidin-2-one (2.0 g, 15.5 mmol) in dry THF (20 mL) at −78° C. under argon, was added dropwise a 2.5M solution of n-BuLi in hexanes (6.2 mL, 15.5 mmol). After stirring at −78° C. for 15 min, (4-fluorophenyl)acetyl chloride (2.55 mL, 18.6 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 30 min and 0° C. for 15 min, quenched with saturated NH4Cl (5 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with saturated Na2CO3 following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%–15% EtOAc/hexane) to give 2.83 g (10.7 mmol, 69%) of (4S)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.30–7.25 (m, 2H), 7.10 (t, 2H, J=8.5 Hz), 4.46–4.41 (m, 1H), 4.36–4.15 (m, 4H), 2.40–2.28 (m, 1H), 0.88 (d, 3H, J=7.6 Hz), 0.79 (d, 3H, J=7.6 Hz); ESMS m/e: 266.2 (M+H)+.
Reaction SMILES: [ClH:1].[C:2]([CH2:5][C@@H:6]1[NH:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7]1=[O:16])(=[O:4])[NH2:3].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O.C(OCC)(=O)C.Cl.C(OCC)(=O)C.CCOCC.O.O1CCOCC1>[ClH:1].[CH2:28]([O:14][C:13](=[O:15])[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C@@H:6]([CH2:5][C:2](=[O:4])[NH2:3])[C:7]1=[O:16])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)C[C@@H]1NCCN(CC(=O)O)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NC(=O)C[C@@H]1NCCN(CC(=O)OCc2ccccc2)C1=O
Yield: 50 %

Procedure:
To a mixture of 1.8 g of (S)-3-carbamoylmethyl-2-oxopiperazine-1-acetic acid hydrochloride, 3.0 g of sodium carbonate, 20 ml of dioxane and 20 ml of water was added, while stirring vigorously, 2.0 g of di-t-butyl bicarbonate. The mixture was stirred vigorously for 2 hours at 0° C. The reaction mixture was concentrated to half of its original volume. The concentrate was washed with ether and there was added 20 ml of a 10% aqueous solution of potassium hydrogensulfate, followed by extraction with methylene chloride. The extract solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give an oily product. The oily product was dissolved in 10 ml of dimethylformamide, to which were added 720 mg of potassium hydrogencarbonate and 1.0 g of benzyl bromide. The mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure to give a crude product. The crude product was dissolved in 30 ml of 2N HCl-ethyl acetate, and the solution was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure to give an oily product, which was processed with ether to afford 1.0 g of the title compound as amorphous powder.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:23][CH2:22][C@H:21](OS(C)(=O)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1>>[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[CH:21]1[CH2:22][CH2:23][CH:18]([C:15]2[CH:16]=[CH:17][C:12]([N:3]3[CH2:4][CH2:5][C:6]4([CH2:7][CH2:8][O:9][CH2:10][CH2:11]4)[C:2]3=[O:1])=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: C[C@H]1CCCCN1
Reactant: CS(=O)(=O)O[C@H]1CC[C@@H](c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1
Product: C[C@H]1CCCCN1C1CCC(c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 9 by condensing cis-methanesulfonic acid 4-[4-(1-oxo-8-oxa-2-aza-spiro[4.5]dec-2-yl)-phenyl]-cyclohexyl ester (Intermediate 21) (30 mg, 0.07 mmol, 1 equiv.) and (S)-2-methyl-piperidine.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[Li+].[OH-]>CO.O>[CH:16]1([CH2:15][N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1cnn(CC2CC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(CC2CC2)c1C(F)(F)F
Yield: 92.8 %

Procedure:
To a solution of 1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (120 mg, 0.46 mmol) in methanol (5 mL) and water (5 mL) was added LiOH (13 mg, 0.54 mmol). The reaction mixture was stirred at reflux overnight, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH=2 with concentrated HCL. The resulting mixture was then extracted with ethyl acetate three times. The combined organic layers were concentrated in vacuo to give 1-cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (100 mg, 93%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17](O)=[O:18])[C:11](=[O:23])[N:10]([CH2:24][C:25]([NH:27][C:28]([CH3:40])([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH3:29])=[O:26])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+].C(O)(=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:16]([CH2:17][OH:18])[CH:15]=3)[C:11](=[O:23])[N:10]([CH2:24][C:25]([NH:27][C:28]([CH3:40])([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=3)[CH3:29])=[O:26])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(C(=O)O)c2)c1=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(CO)c2)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30 mg (0.052 mmol) of 3-(3-(4-chlorophenyl)-1-[2-(1-methyl-1-[3-(trifluoromethyl)phenyl]ethylamino)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-ylmethyl)-benzoic acid (Example 471) are dissolved in 2 ml of THF and treated with 24 mg (0.24 mmol) of triethylamine and 33 mg (0.24 mmol) of isobutyl chloroformate. This is stirred for 1 hr at RT. Next, a solution of 24 mg (0.63 mmol) of sodium borohydride in 0.05 ml water is added slowly. After 1 hr, the mixture is treated with 0.06 ml (1.05 mmol) of acetic acid and then concentrated in vacuo. The residue is taken up in 10 ml of ethyl acetate, and washed with 10 ml of water. The aqueous phase is back-extracted once with 10 ml of ethyl acetate. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 23 mg (79% of theory) of the target compound are thus obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1.C([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[NH:53][C:33]3[N:34]=[CH:35][N:36]=[C:37]([O:38][C:39]4[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][CH:49]5[CH2:51][CH2:50]5)=[O:47])=[C:41]([Cl:52])[CH:40]=4)[C:32]=3[CH:31]=2)=[CH:26][CH:25]=1)C1C=CC=CC=1>>[Cl:52][C:41]1[CH:40]=[C:39]([O:38][C:37]2[C:32]3[CH:31]=[C:30]([C:27]4[CH:26]=[CH:25][C:24]([OH:23])=[CH:29][CH:28]=4)[NH:53][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:44]=[CH:43][C:42]=1[NH:45][C:46]([NH:48][CH:49]1[CH2:50][CH2:51]1)=[O:47]
Reactant: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(OCc5ccccc5)cc4)cc23)cc1Cl)NC1CC1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(O)cc4)cc23)cc1Cl)NC1CC1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
After adding 2 ml of trifluoroacetic acid and 0.1 ml of thioanisole to 24 mg of 1-{4-[6-(4-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl}-3-cyclopropylurea, the mixture was stirred at 45° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarnobate water was added to alkalinity, and then liquid separation and extraction were performed with ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and dried under reduced pressure to obtain 15 mg of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])[CH2:2][CH:3]=[CH2:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C@:52]1([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[C:63]([CH:73]=[CH2:74])[CH:62]=2)[CH2:56][NH:55][C@H:54]([C:57]([O:59][CH3:60])=[O:58])[CH2:53]1>C(Cl)Cl>[CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([N:55]1[CH2:56][C@:52]([O:51][CH3:50])([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[C:63]([CH:73]=[CH2:74])[CH:62]=2)[CH2:53][C@H:54]1[C:57]([O:59][CH3:60])=[O:58])=[O:12])=[O:7])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1cc([C@@]2(OC)CN[C@H](C(=O)OC)C2)ccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)c(C=C)c2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
(S)-2-((but-3-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (117 mg, 0.511 mmol), DIEA (0.179 mL, 1.022 mmol) and HATU (143 mg, 0.375 mmol) were added to a solution of (2S,4R)-methyl 4-methoxy-4-(2-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (115 mg, 0.341 mmol) in DCM (4 mL). The reaction was stirred at r.t. overnight. The reaction was evaporated and purified by flash chromatography on the Biotage (0-40% EtOAc:Hex) to give (2S,4R)-methyl 1-((S)-2-((but-3-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(2-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (150 mg, 0.273 mmol, 80% yield) as a white foam. LCMS: rt=1.89 min. [M+Na]+=571; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14]1.C(C1NC=CN=1)(C1NC=CN=1)=O.C(Cl)(=O)C(Cl)=O>>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]([N:13]3[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18]3)=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2ncoc2c1
Reactant: C1=CCNCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: O=C(c1ccc2ncoc2c1)N1CC=CCC1

Procedure:
Coupling of 1,3-benzoxazol-6-carboxylic acid with 1,2,3,6-tetrahydropyridine is performed in the same manner as described for the preparation of Invention Compound V through activation with carbonyl diimidazole or by activation with other suitable reagents such as oxalyl chloride. The product can be isolated by the same methods as described for the isolation of Invention Compound V and purified by chromatography on silica gel. EIMS m/z=228 (parent), 146 (base), and 118. 1H NMR δ 2.2 (br, 2), 3.4-4.3 (br m, 4), 5.7-5.95 (br m, 2), 7.52 (dd, 1, J=8.39, 1.49 Hz), 7.64 (d, 1, J=8.41 Hz), 7.87 (d, 1, J=1.32 Hz), and 8.16 ppm (s, 1.).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH3:43])[CH2:29][CH2:30][N:31]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[S:32]([CH3:35])(=[O:34])=[O:33].[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]([CH3:43])[CH2:29][CH2:30][N:31]([C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:41][CH:42]=1)[S:32]([CH3:35])(=[O:34])=[O:33]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CCN(c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Examples 1 and 187 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.