Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=Cc2ccc(I)cc2OC1C(F)(F)F
Reactant: OB(O)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1=Cc2ccc(-c3ccco3)cc2OC1C(F)(F)F
Temperature: 80 °C
Yield: 20.6 %

Procedure:
The ethyl 7-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 9a, Step 2 (2.0 g, 5.02 mmol), 2-furylboronic acid (0.62 g, 5.52 mmol), K2CO3 (2.08 g, 15.06 mmol), and PdCl2(PPh3)2 (106 mg, 0.15 mmol) were mixed in dioxane (20 mL) in a sterling bomb. Carbon monoxide was bubbling to 40 psi. The reaction was heated to 80° C. for 12 h. After filtration, the reaction was quenched with NH4Cl and extracted with EtOAc. The organic layer was washed and dried over MgSO4. The filtrate was evaporated and dried in vacuo to afford crude which was purified Biotage Chromatography with 10 to 20% ethyl acetate in hexane to give yellow solid (350 mg, 21%): LCMS m/z 339.05 (M+H). 1H NMR (CDCl3/300 MHz) 7.74 (s, 1H), 7.51 (s, 1H), 8.97 (m, 3H), 6.76 (d, 1H, J=3.3 Hz), 6.51 (m, 1H), 5.73 (q, 1H, J=6.9 Hz), 4.34 (m,2H), 1.36 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>O>[F:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2ccc(F)cc12
Temperature: 160 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of 2-amino-5-fluorobenzoic acid (2.07 g) and formamide (4 ml) was heated at 160° C. for 2 hours, and for a further 2 hours at 180° C. The reaction mixture was allowed to cool and water was added. The reaction product was filtered off and washed with water and with diethyl ether to give 6-fluoro-3,4-dihydroquinazolin-4-one in 78% yield: m.p. 269-271° C.;
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[C:18](=[O:19])[N:11]4[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]4=[N:9][C:8]=3[S:20][C:5]=2[C:4](=[O:21])[CH2:3][CH2:2]1.[BH4-].[Na+]>C1COCC1.CCO>[OH:21][CH:4]1[C:5]2[S:20][C:8]3[N:9]=[C:10]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]4[C:18](=[O:19])[C:7]=3[C:6]=2[CH2:1][CH2:2][CH2:3]1
Reactant: O=C1CCCc2c1sc1nc3n(c(=O)c21)CCCCCC3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1c2c3c(sc2nc2n1CCCCCC2)C(O)CCC3
Reaction time: 0.25 h

Procedure:
To compound 3d (200 mg, 0.66 mmol) in 5 ml of THF and 15 ml of EtOH, NaBH4 (33 mg, 0.86 mmol) was added and the reaction mixture was stirred for 15 minutes. The reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with brine and dried with NaaSO2. After filtration the solvent was evaporated. The product was purified by flash chromatography using CH2Cl2/EtOAc 1:1 as an eluent.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-])=O)[CH2:3][CH2:2]1>CO>[NH2:12][C:11]1[CH:10]=[CH:9][C:8]([CH:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CC(C)C)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Solvent: CO
Product: CCOC(=O)C(CC(C)C)c1ccc(N)c(OCC2CC2)c1
Reaction time: 6 h
Yield: 93.8 %

Procedure:
To a stirred solution of ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate (2.0 g, 5.9 mmol), in dry MeOH (50 mL) Pd(OH)2 (1.1 g) was added. The mixture was reduced under an atmosphere of H2 for 6 h at room temperature. The reaction mixture was filtered off through a pad of Celite™, washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.69 g) as a thick liquid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:17].[C:18](OC)(OC)(OC)[CH2:19][CH2:20][CH3:21]>Cl.N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:18]1[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1cnc2ccccc2c1NCCCCCl
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCl
Yield: 55.6 %

Procedure:
Using the general method of Example 1 Part D, N4-(4-chlorobutyl)quinoline-3,4-diamine (˜21.45 mmol) was cyclized using trimethyl orthobutyrate (3.8 g, 25.74 mmol) in the presence of pyridine hydrochloride (0.1 g). The crude product was purified by chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 3.6 g of 1-(4-chlorobutyl)-2-propyl-1H-imidazo[4,5-c]quinoline as a light green oil which slowly solidified.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.7 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)1,3-dihydro-indol-2-one as a yellow solid (65 mg, 57%)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][N:3]=1.[F:13][C:14]1([F:60])[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[CH:28]([O:30]CC4C=CC(OC)=CC=4)[CH2:27][C:26]([CH3:41])([CH3:40])[CH2:25][C:24]=3[N:23]=[C:22]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[C:21]=2[CH:48]([F:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[CH2:16][CH2:15]1>>[F:60][C:14]1([F:13])[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[CH:28]([OH:30])[CH2:27][C:26]([CH3:40])([CH3:41])[CH2:25][C:24]=3[N:23]=[C:22]([CH:42]3[CH2:47][CH2:46][N:45]([C:2]4[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][N:3]=4)[CH2:44][CH2:43]3)[C:21]=2[CH:48]([F:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=2)[CH2:16][CH2:15]1
Reactant: CCCCCc1cnc(Cl)nc1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Product: CCCCCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of the first step of Example 2 and Example 38 were performed except for using 2-chloro-5-pentyl pyrimidine instead of 5-bromo-2-chloropyrimidine, and from 100 mg (0.148 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 95 mg of the title compound was obtained as a white solid (yield: 91%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].O>C(O)C.[Fe]>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)NCCc1cccc(N)c1
Yield: 95.9 %

Procedure:
N-Acetyl-N-(3-nitrophenethyl)amine (2.1 g, Production Example 28b) was dissolved in ethanol (40 ml). To the mixture were added an iron powder (2.25 g), ammonium acetate (4.3 g) and water (20 ml), followed by heating under reflux for 1.5 hours. Solid was filtered off and washed with ethanol, and then the filtrate was partially evaporated. The residue was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (1.723 g, 96%) as a yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1>CO.C(Cl)Cl.[Pt](=O)=O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccnc(-c2ccc(Cl)cc2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(Cl)cc2)C1
Reaction time: 1 h
Yield: 78.6 %

Procedure:
Methyl 2-(4-chlorophenyl)isonicotinate hydrochloride (4.46 g, 15.69 mmol) was dissolved in MeOH (40 mL) and platinum(IV) oxide (0.356 g, 1.57 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 1 h. The catalyst was filtered off and washed with MeOH and the eluate evaporated leaving a brown solid. The solid was dissolved in DCM and washed with 1 M K2CO3 and brine. The organic layer was dried through a phase-separator and evaporated. The residue was dissolved in DCM and added onto SCX-2 cation exchange columns (4*10 g columns. Each column was washed with DCM, MeOH and then eluted with NH3/MeOH (1 CV each). The NH3/MeOH layer was evaporated yielding methyl 2-(4-chlorophenyl)piperidine-4-carboxylate (3.13 g, 79%). MS m/z 254 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[C:14]([C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=4)=[C:15]4[C:20](=[CH:21][C:12]=3[S:11][C:10]=2[CH:29]=1)[CH:19]=[CH:18][CH:17]=[CH:16]4.O[C@@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([O:35]C)=[O:34]>>[C:3]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[C:14]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH:32]([CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:33]([OH:35])=[O:34])=[CH:26][CH:27]=4)=[C:15]4[C:20](=[CH:21][C:12]=3[S:11][C:10]=2[CH:29]=1)[CH:19]=[CH:18][CH:17]=[CH:16]4)([OH:2])=[O:30]
Reactant: COC(=O)COc1ccc2c(c1)sc1cc3ccccc3c(-c3ccc(O)cc3)c12
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Product: O=C(O)COc1ccc2c(c1)sc1cc3ccccc3c(-c3ccc(OC(Cc4ccccc4)C(=O)O)cc3)c12

Procedure:
Prepared from of [11 -(4-hydroxy-phenyl)-benzo[b]naphtho[2,3-d]thiophen-3-yloxy ]-acetic acid methyl ester (Example 72) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: mp: 191-201° C.: NMR (DMSO-d6); δ13.1 (broad s, 2 H), 8.45 (s, 1 H), 8.01 (d, J=8 Hz, 1 H), 7.55-7.25 (m, 11H), 7.16 (d, J =9 Hz, 2 H), 6.67 (dd, J=9, 2Hz, 1 H), 6.49 (d, J=9 Hz, 1 H), 5.18 (dd, J=7,4Hz, 1 H), 4.74 (s, 2 H), 3.28 (dd, J=7, 4 Hz, 1 H), 3.21 (dd, J=14, 7 Hz, 1 H); MS (EI): 458 (80%, M+); Anal. Calc. for C33H24O6S: C, 72.25, H, 4.41, N, 0.00. Found: C, 69.57, H, 4.15, N, 0.32; Analytical HPLC :92% purity.
Reaction SMILES: Cl.[S:2]1[C:6]2=[CH:7][N+:8]([O-])=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:14])=O>O1CCOCC1>[Cl:14][C:7]1[N:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3][S:2][C:6]=12
Reactant: [O-][n+]1ccc2ccsc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Product: Clc1nccc2ccsc12

Procedure:
adb) 671.5 g of thieno[2,3-c]pyridine 6-oxide hydrochloride were suspended in 4000 ml of dioxane under argon and 655 ml of phosphorus oxychloride are added. The mixture was heated on an oil-bath until the exothermic reaction set in. After the exothermic reaction faded away, the mixture was heated to reflux for an additional 10 minutes. The mixture was concentrated in vacuo and the residue was taken up in 2000 ml of toluene. The solution was then treated with 300 ml of water while cooling slowly. The mixture was neutralized by the portionwise addition of sodium carbonate. The organic phase was separated and the aqueous phase was extracted with 1000 ml of toluene. After washing with water, the combined organic solutions were dried over sodium sulfate, filtered and evaporated, whereby crude 7-chloro-thieno[2,3-c]pyridine was obtained as a brown oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]([C:23]([F:26])([F:25])[F:24])=[N:13]2)=[CH:8][CH:7]=1)=[N+]=[N-]>CC#N>[C:17]1([C:16]2[N:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][NH2:1])=[CH:7][CH:8]=3)[N:13]=[C:14]([C:23]([F:25])([F:26])[F:24])[CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [N-]=[N+]=NCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1
Solvent: CC#N
Product: NCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 14 from 1-[4-(2-azidoethyl)phenyl]-5-phenyl-3-(trifluoromethyl)-1H-pyrazole (step 2): MS (ESI) m/z 332 [M+H]+, 373 [M+H+CH3CN]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)[C:16]1=[O:27]>CC(C)=O.[I-].[Cs+]>[CH3:26][O:25][C:19]1[CH:18]=[C:17]2[C:22]([CH2:23][CH2:24][CH:15]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:16]2=[O:27])=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)C(=O)C(Br)CC2
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)C(=O)C(Oc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
A mixture of 2.95 g (31.4 mmol) of phenol, 25.5 g (78.2 mmol) of cesium carbonate and 320 mg (1.23 mmol) of cesium iodide in 64 ml of acetone was heated at reflux for 40 minutes and then cooled to 0° C. To this 0° C. mixture was added 8.00 g (31.4 mmol) of 2-bromo-3,4-dihydro-7-methoxy-1(2H)-naphthalenone. The resultant reaction mixture was stirred 3 hours at 0° C. and 15 hours at 25° C., then filtrated. The filtrate was evaporated to an oil which was purified via column chromatography on 400 g of silica gel, eluting with 25% ether-hexane, to give 5.14 g (61%) of present title product as an oil, crystallized from ether-hexane, m.p. 94.5°-96.5° C.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=O)[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[F:21]>C(O)(=O)C>[O:9]=[C:7]1[CH:2]2[CH:1]([CH2:6][CH2:5][CH2:4][CH2:3]2)[C:10](=[O:11])[N:12]1[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[F:21]
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: N#Cc1ccc(N)c(F)c1
Solvent: CC(=O)O
Product: N#Cc1ccc(N2C(=O)C3CCCCC3C2=O)c(F)c1

Procedure:
To a solution of 5 parts of cis-1,2-cyclohexane dicarboxylic anhydride in 75 parts of glacial acetic acid was added 4.8 parts of 4-amino-3-fluorobenzonitrile in one portion. The mixture was refluxed for 4 hours, poured over 200 parts of ice and filtered. The crude crystalline product was recrystallized from methanol to yield 4.4 parts of beige 4-(1,3-dioxo-2,3,3a,4,5,6,7,7a-octahydro-1H-isoindol-2-yl)-3-fluorobenzonitrile melting 120°-123°.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]1([C:9]2[O:13][C:12]([C:14]3[C:15](O)=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=3)=[N:11][N:10]=2)[CH2:8][CH2:7]1.C(=O)([O-])O.[Na+]>>[Cl:3][C:15]1[C:14]([C:12]2[O:13][C:9]([CH:6]3[CH2:8][CH2:7]3)=[N:10][N:11]=2)=[CH:19][N:18]=[C:17]([S:20][CH3:21])[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(-c2nnc(C3CC3)o2)c(O)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CSc1ncc(-c2nnc(C3CC3)o2)c(Cl)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Phosphorus oxychloride (15 mL) was added to 5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-4-hydroxy-2-methylthiopyrimidine (6.26 g) obtained in Step 6, and the mixture was stirred at 60° C. for 30 minutes. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue to precipitate crystals. The resulting crystals were collected by filtration and dried thoroughly under reduced pressure to give 4-chloro-5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-2-methylthiopyrimidine (5.31 g, yield 79%).
Reaction SMILES: [SH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl.Cl[CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[CH:19]=[N:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:21]([N:20]1[CH:19]=[N:18][N:17]=[C:16]1[CH2:15][S:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12])[CH2:22][CH3:23]
Reactant: CCCn1cnnc1CCl
Reactant: Nc1ccc(S)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cnnc1CSc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
4-mercapto-3-trifluoromethylaniline (1.0 g), 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (1.1 g) and potassium carbonate (1.4 g) were added to N,N-dimethylformamide (35 ml), and the mixture was stirred overnight at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was evaporated. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate) to give 4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylthio]-3-trifluoromethylaniline (1.4 g) as pale brown oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20]3[C:23]([C:37]([F:40])([F:39])[F:38])=[N:24][N:25]([C:26]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:27]=4[C:28](Cl)=[O:29])[C:19]=3[C:18]2=[O:41])=[CH:13][CH:12]=1)(=[O:4])=[O:3].[NH3:42]>ClCCl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20]3[C:23]([C:37]([F:40])([F:39])[F:38])=[N:24][N:25]([C:26]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:27]=4[C:28]([NH2:42])=[O:29])[C:19]=3[C:18]2=[O:41])=[CH:13][CH:12]=1)(=[O:4])=[O:3]
Reactant: N
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(-c4ccccc4S(C)(=O)=O)cc2)CC3)c(C(=O)Cl)c1
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(-c4ccccc4S(C)(=O)=O)cc2)CC3)c(C(N)=O)c1

Procedure:
Part C: 2-[6-(2′-Methanesulfonyl-biphenyl-4-yl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoyl chloride (0.10 mmol) was dissolved in dry dichloromethane (1 mL) under a nitrogen atmosphere, and a stream of ammonia gas was introduced for 30 sec. The solvent was evaporated, and the residue was purified by reverse phase HPLC to give the title compound as a colorless solid. MS (ES+) 607.1 (M+Na)+(100%); 1H NMR (DMSO-d6) δ 8.08 (d, 1H, J=6.6 Hz), 7.79-7.34 (m, 10H), 7.16 (d, 1H, J=2.9 Hz), 7.09 (dd, 1H, J=8.5, 2.6), 4.11 (t, 2H, J=6.4 Hz), 3.84 (s, 3H), 3.11 (t, 2H, J=6.4), 2.81 (s, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3].[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O)c1C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a solution of 15 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid allyl ester in 0.12 l of N,N-dimethylformamide were added 13.8 g of tert-butyl-dimethylchlorosilane and 12.0 g of triethylamine. The mixture was stirred for 3 h at room temperature and then evaporated in vacuo. The residue was taken up in 0.4 l of ethyl acetate and the solution was washed successively with 1N hydrochloric acid, water and brine. The organic layer was dried over sodium sulfate. The solvent was evaporated in vacuo and the solid residue was recrystallized from hexane to give 20.5 g of 2-formyl-3-(tert-butyldimethylsilanyloxy)-5-methoxy-6-methylbenzoic acid allyl ester as white crystals of m.p. 94°-95° C.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][CH:31]([CH2:33][NH2:34])[O:30][C:29]2=[O:35])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][CH:31]([CH2:33][NH:34][C:43](=[O:45])[CH3:44])[O:30][C:29]2=[O:35])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CC(=O)OC(C)=O
Reactant: NCC1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Yield: 85 %

Procedure:
To a reaction flask were added 6.53 mmol of dihydrochloride of 3-(3-fluoro-4-morpholinylphenyl-5-aminomethyl-1,3-oxazolidin-2-one (5a), 100 ml of dichloromethane and 2.95 ml (21.2 mmol) of triethylamine. Then 0.8 ml (8.45 mmol) of acetic anhydride was added while being stirred in an ice-bath. The mixture was then allowed to react at room temperature for 2 hours before being washed successively with 5% aqueous NaOH solution and saturated aqueous NaCl solution. The organic layer was then dried by anhydrous sodium sulfate and filtered, and subsequently put under reduced pressure for solvent removal. The residue was then subjected to recrystallization using ethyl acetate to give white needle crystals at a yield of 85%, HR-TOF-MS (+Q) m/z: 338.1520 (Calculated [C16H20FN3O4+H]+: 338.1516).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(Cl)c1ccccc1Cl

Procedure:
As described for Reference Example 26, 3.13 g of 2-chlorobenzoic acid is reacted with 40 ml of thionyl chloride to give 3.32 of product as an off-white semi solid.