Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[NH2:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])=[O:19])[CH2:14][CH2:13]1.FC(F)(F)C([O-])=O.[OH-].[Na+]>CC#N.O>[Cl:10][C:4]1[CH:5]=[C:6]([NH:8][CH3:9])[N:7]=[C:2]([NH:11][C@@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:29])([F:30])[F:31])=[O:19])[CH2:16][CH2:17]2)[N:3]=1
Reactant: N[C@H]1CC[C@@H](C(=O)NCc2ccccc2C(F)(F)F)CC1
Reactant: CNc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CNc1cc(Cl)nc(N[C@H]2CC[C@@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)n1

Procedure:
To a solution of 2,6-dichloro-N-methyl-4-pyrimidinamine (360 mg, 2.0 mmol) and cis-4-amino-N-{[2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide (Intermediate 1) trifluoroacetate (829 mg, 2.0 mmol), in MeCN/H2O (1:1, 5 mL) was added 1N NaOH solution until a pH of 12 was achieved. The mixture was irradiated in the microwave for 4 hours at 170° C., at which time LCMS indicated the formation of the desired product. The reaction mixture was extracted with EtOAc (2×50 mL), washed with water (2×50 mL), dried (Na2SO4), and concentrated to afford a waxy solid. The crude material was purified by column chromatography (Gradient from 0-5% MeOH in CH2Cl2) to afford 300 mg (0.68 mmol, 34%) of a colorless wax MS (ES+) m/e 442 [M+H]+. Regiochemistry was verified by 2D NMR analysis.
Reaction SMILES: [CH:1]1([CH:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1>>[CH:9]1([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[O:8][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: OC(C1CCCCC1)C1CCCCC1
Reactant: CCOC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OC(C2CCCCC2)C2CCCCC2)cc1

Procedure:
Dicyclohexylmethanol (8-1) (4.91 g, 25 mmol) and ethyl 4-hydroxybenzoate (8-2) (4.15 g, 25 mmol) were reacted, as in Example 6, Step B, to obtain a colorless oil 8-3 after chromatography. 1H NMR (CDCl3): δ 0.98-1.3 (11H, m), 1.36 (3H, t), 1.58-1.86 (11H, m), 4.02 (1H, t), 4.33 (2H, q), 6.92 (2H, d), 7.94 (2H, d).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[C:13][Si](C)(C)C)[CH:8]=2)[N:3]1[CH2:18][C:19]([O:21]C)=[O:20].O[Li].O>>[C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:18][C:19]([OH:21])=[O:20])[C:2](=[O:1])[CH:11]=[CH:10]2)#[CH:13]
Reactant: COC(=O)Cn1c(=O)ccc2cc(C#C[Si](C)(C)C)ccc21
Agent: [Li]O
Solvent: O
Product: C#Cc1ccc2c(ccc(=O)n2CC(=O)O)c1

Procedure:
Methyl 2-(2-oxo-6-((trimethylsilyl)ethynyl)quinolin-1(2H)-yl)acetate (0.128 mmol) was subjected to the protocol in Example 1.53.4, except with LiOH.H2O instead of NaOH. Retention time (min)=1.435, method [1], MS (ESI) 228.1 (M+H).
Reaction SMILES: [C:1]1(=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCCC=C1CCCC1
Agent: [Pd]
Solvent: CO
Product: OCCCCCCC1CCCC1
Yield: 111.4 %

Procedure:
A solution of 6-cyclopentylidene-hexan-1-ol (1.15 g, 6.85 mmol) in MeOH (50 mL) was hydrogenated with Pd—C (0.25 g, 10% w/w) in a Parr apparatus at 50 psi of H2 overnight. The catalyst was removed by filtration, and the filtrate was evaporated under reduced pressure to give 6-cyclopentyl-hexan-1-ol (1.30 g, 100%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.63 (2H, t, J=6.6 Hz), 1.42–1.64 (6H, m), 1.20–1.40 (8H, m), 1.04(2H, m); 13C NMR (75 MHz, CDCl3) δ 63.28, 40.41, 36.43, 33.06, 33.00, 29.98, 29.04, 26.05, 25.47.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[N:12]([C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.O[NH:22][C:23](=[NH:34])[C:24]1[CH:29]=[CH:28][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[N:12]([C:14]([C:17]4[O:19][N:34]=[C:23]([C:24]5[CH:25]=[CH:26][C:27]([S:30]([NH2:31])(=[O:32])=[O:33])=[CH:28][CH:29]=5)[N:22]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2c(C(=O)O)cnc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(-c3nc(-c4ccc(S(N)(=O)=O)cc4)no3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.33) (143 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (MeOH) as an off-white solid (143 mg, 61%). MS (EI) 465.1 [(M)+]; mp 311° C.
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[N:10]1([C:19]2[CH:47]=[CH:46][C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][S:30][CH2:31][C@H:32]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]([OH:35])=[O:34])=[CH:25][CH:24]=3)=[CH:21][CH:20]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>C(O)(=O)C.C(OCC)(=O)C>[N:10]1([C:19]2[CH:20]=[CH:21][C:22]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][S:30]([CH2:31][C@H:32]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]([OH:35])=[O:34])=[O:5])=[CH:27][CH:28]=3)=[CH:46][CH:47]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: O
Reactant: O=C(Cc1ccccc1)N[C@@H](CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(Cc1ccccc1)N[C@@H](CS(=O)Cc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Sodium perborate tetrahydrate (97 mg, 0.63 mmol) was added as a solid to a stirred solution of (2R)-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-2-phenylacetylamino-propionic acid (300 mg, 0.58 mmol) in acetic acid (10 mL) at 40° C. This solution was stirred at 40° C. for 2 hours (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 15% methanol in dichloromethane as eluent, afforded the title compound has an off-white solid (261 mg g, 84%) as a 1:1 mixture of diasereomers; 1H NMR (DMSO-d6, 300 MHz) δ 12.98 (1H, s, COOH), 8.75 and 8.80 (both 0.5H, d, J=8 Hz, NH), 8.40 (1H, d, J=8 Hz, NH), 7.84 (2H, m, Ar—H), 7.60-7.78 (7H, m, Ar—H), 7.44 and 7.39 (both 1H, d, J=8 Hz, Ar—H), 7.12-7.28 (7H, m, Ar—H), 6.72 (1H, d, J=3 Hz, Ar—H), 4.68 and 4.48 (both 0.5H, m, CHN), 4.16 (2H, m, PhCH2CO) 3.52 and 3.32 (both 1H, s, PhCH2S), 3.09 (1H, m, CHHCHN), 2.96 (1H, m, CHHCHN); ESI-LCMS e/z calcd for C32H28N2O4S 536.649, found 537 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1>C(#N)C>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Nc1ccc(CCO)cc1
Solvent: CC#N
Product: O=C(Nc1ccc(CCO)cc1)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 2-(4-aminophenyl)ethanol (Fluka), the title compound was obtained as a white solid after trituration in acetonitrile.
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[N:11][C:10]([C:13]([O-:15])=[O:14])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].Cl>O>[CH2:1]([N:8]1[N:12]=[N:11][C:10]([C:13]([OH:15])=[O:14])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1nnn(Cc2ccccc2)n1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1nnn(Cc2ccccc2)n1
Yield: 71.6 %

Procedure:
Potassium 2-benzyl-2H-tetrazole-5-carboxylate (2.42 g) was suspended in water (10 ml) and the mixture was warmed until it dissolved. The solution was cooled in ice and strongly acidified by treatment with concentrated hydrochloric acid to give 2-benzyl-2H-tetrazole-5-carboxylic acid (1.46 g), m.p. 127°-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCC1.Cl>CO.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:12]1([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: O=C1CCCCCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl
Solvent: O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCCCCC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.7 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 46.7 mmol), cycloheptanone (11 mL, 93.5 mmol) and pyrrolidine (7.7 mL, 93.5 mmol) in MeOH (190 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo to give the residue, which was added water and HCl (36%) until pH=1. The mixture was extracted with EtOAc and then the organic layer was concentrated to give 6-bromospiro[chroman-2,1′-cycloheptan]-4-one (18.3 g, 100%). 1H-NMR (CDCl3): 1.34 (m, 1H), 1.49 (m, 1H), 1.62 (m, 10H), 1.71 (m, 1H), 2.02 (m, 1H), 6.78 (m, 1H), 7.47 (m, 1H), 7.86 (m, 1H).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[O:11][C:10](=[O:12])[CH:9]=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:23]([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36][C:9]1[C:10](=[O:12])[O:11][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH2:7][C:8]=1[OH:13])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C1C=C(O)CC(CCc2cccc(O)c2)(C2CCCC2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccc(O)c3)(C3CCCC3)OC2=O)c(C(C)(C)C)cc1CO
Yield: 81 %

Procedure:
The title compound was prepared as described in General Method 9 using 6-cyclopentyl-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (0.26 g, 0.9 mmol) from Example AAAAA, toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF; 0.35 g, 1.0 mmol), 0.54 g (3.9 mmol) of K2CO3 in DMF (10 mL). The product was purified by column chromatography on silica gel eluting with EtOAc:hexane:CH2Cl2 (1:1:1) to afford the product in 81% yield as a white solid (m.p. 172°-174° C.). 1H-NMR (DMSO-d6) δ 1.47 (s, 9 H), 1.4-1.7 (m, 8 H, 1.9 (s, 3 H), 1.95-2.1 (m, 2 H), 2.35 (t, 1 H), 2.5-2.6 (m, 2 H, partially obscured by DMSO), 2.7 (q, 2 H), 4.35 (s, 2 H), 4.95 (bs, 1 H), 6.55 (t, 3 H), 6.65 (s, 1 H), 7.05 (t, 1 H), 7.25 (s, 1 H), 9.25 (s, 1 H).
Reaction SMILES: Cl.CN.C([N:7]([CH2:11]C)[CH:8]([CH3:10])C)(C)C.BrCC[O:16][C:17]1[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:21][CH:22]=1>O1CCCC1>[CH3:11][NH:7][CH2:8][CH2:10][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1
Reactant: FC(F)(F)c1cccc(OCCBr)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNCCOc1cccc(C(F)(F)F)c1
Yield: 45.2 %

Procedure:
A mixture of methylamine hydrochloride salt (380 mg, 5.57 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (1.44 g, 11.15 mmol) and 3-(2-bromoethoxy)benzotrifluoride (300 mg, 1.11 mmol). The reaction mixture was allowed to stir at reflux for 2 d. At this time, the reaction was quenched by the addition of water. The aqueous layer was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 methylene chloride/methanol) afforded methyl-[2-(3-trifluoromethyl-phenoxy)-ethyl]-amine (110 mg, 45%) as yellow solid. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@@H:5]2[CH2:4]1.F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][N:9]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH2:10][C@@H:5]2[CH2:4]1
Reactant: OC[C@H]1C[C@H]2CNCCN2C1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCN3C[C@@H](CO)C[C@H]3C2)cc1
Temperature: 80 °C
Yield: 37.4 %

Procedure:
A mixture of 1.5 g (9.6 mmol) of (7S,8aS)-7-hydroxymethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 13, Step A), 1.75 g (14.4 mmol) of 4-fluorobenzonitrile and 2.04 g (19.2 mmol) of sodium carbonate in 10 mL of DMSO was heated at 80° C. for 16 h. The solution was cooled to room temperature, diluted with water and extracted with 1:1 ethyl acetate:diethyl ether (3×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 9:1 chloroform: methanol gave 0.925 g (37%) of the title compound. 13C NMR (CDCl3): δ 31.1, 37.2, 46.7, 51.0, 51.8, 57.6, 62.3, 67.3, 100.1, 114.3, 120.0, 133.5, 153.4. m/z (MH+) 258.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5](Br)[N:6]=1.C([Li])CCC.[CH2:13]([Sn:15](Br)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]>CCOCC>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([Sn:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:13][CH3:14])[N:6]=1
Reactant: CC[Sn](Br)(CC)CC
Reactant: Cc1nc(Br)cs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC[Sn](CC)(CC)c1csc(C)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6M, 3.3 mL, 5.35 mmol) was added to a solution of 2,4-dibromothiazole (1.0 g, 4.12 mmol) in anhydrous ether (10 mL) stirred at −78 ° C. under nitrogen. After 20 minutes, methyl trifluromethanesulfonate (878 mg, 5.35 mmol) was added, then the reaction mixture was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched and washed with water, washed with brine, dried through MgSO4, and then the solvent was evaporated to give a brown oily residue of 2-methyl-4-bromo-thiazole (900 mg). Under nitrogen, the 2-methyl-4-bromo-thiazole (430 mg, 2.42 mmol) dissolved in anhydrous ether (5 mL) then cooled to −78° C. under nitrogen. n-Butyllithium (1.6M, 1.7 mL, 2.66 mmol) was added, followed, after 10 min by triethylstannyl bromide (760 mg, 2.66 mmol). The solution was then warmed to room temperature, and stirred for another 1 h. The mixture was quenched, and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give the sub-title compound give as a brown oily residue (655 mg), which was used without further purification in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[C:22]#[N:23])[CH:13]=[C:12]([C:24](O)=[O:25])[CH:11]=1)#[N:2].Cl.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C@H:35]([NH2:37])[CH3:36])[CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[C:22]#[N:23])[CH:13]=[C:12]([C:24]([NH:37][C@H:35]([CH3:36])[CH2:34][N:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[O:25])[CH:11]=1)#[N:2]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3cnccc3C#N)c2)c(C#N)c1
Reactant: C[C@@H](N)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)CN3CCOCC3)cc(-c3cnccc3C#N)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 2′-cyano-5-(4-cyanopyridin-3-yl)-4′-methylbiphenyl-3-carboxylic acid (20 mg, 0.059 mmol), (R)-1-morpholinopropan-2-amine hydrochloride (112 mg, 0.62 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (49 mg, 0.13 mmol), N,N-diisopropylethylamine (360 μL, 2.1 mmol), N,N-dimethylformamide (0.555 mL) and the reaction was stirred overnight at room temperature. The mixture was purified by HPLC to get the title compound as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:24][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc2nc(-c3cc([N+](=O)[O-])ccc3F)oc2c1
Reactant: CCCN
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2ccc(C)cc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-6-methylbenzoxazole (250 mg, 0.9 mmol) and propylamine (400 μL, 5.0 mmol) the subtitle compound was obtained (262 mg, 94%). 1H NMR (DMSO) δ 9.21(t, 1H), 8.78(d, 1H), 8.19(dd, 1H), 7.70–7.66(m, 2H), 7.25(d, 1H), 7.03(d, 1H), 3.43(q, 2H), 2.47(s, 3H), 1.73(m, 2H), 1.01(t, 3H).
Reaction SMILES: N1C=CC=CC=1C=[O:8].[F:9][C:10]([Si](C)(C)C)([F:12])[F:11].[F-].C([N+:22]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28]CC)CCCC)CCC>O1CCCC1>[F:9][C:10]([F:12])([F:11])[CH:34]([C:33]1[CH:28]=[CH:27][N:22]=[CH:31][CH:32]=1)[OH:8]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccn1
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccncc1)C(F)(F)F

Procedure:
According to Reference Example 8-12, by use of 2-pyridinecarboxaldehyde (500 μL, 5.24 mmol), (trifluoromethyl)trimethylsilane (928 μL, 6.28 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 524 μL, 0.524 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 2 hours. Then, purification by silica gel column chromatography (chloroform/methanol=9/1) was performed to give 4-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound CO) (1.04 g, yield: quantitative).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[CH2:17][C:16]1=[O:24]>>[CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=[C:17]1[C:18]2[C:23](=[N:22][CH:21]=[CH:20][CH:19]=2)[NH:15][C:16]1=[O:24])([CH3:3])[CH3:2]
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Reactant: O=C1Cc2cccnc2N1
Product: COc1cc(C)c(C=C2C(=O)Nc3ncccc32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde condensed with 7-aza-2-oxindole to give 0.25 g of 3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)(Cl)Cl>[CH3:21][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:33]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CN(C)CCCNc1ccccc1N
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCc1nc2ccccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.85 ml) was added to a solution containing N-[3-(dimethylamino)propyl]-1,2-benzenediamine (1.06 g) in chloroform (11 ml) and then dodecanoyl chloride (1.28 ml) was added thereto while being cooled with ice. After being stirred for 3 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.6 ml) was added to a solution containing the residue (2.23 g) in ethanol (23 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.14 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=60:1), thereby yielding the entitled compound (1.33 g) as pale brown wax.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].[CH2:24](Br)[C:25]#[CH:26].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([O:21][CH2:26][C:25]#[CH:24])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1)[CH3:2]
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(OCC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5 -hydroxyphenyl) -4-trifluoromethyl-6(1H)-pyrimidinone and propargyl bromide with sodium carbonate in acetone there is obtained 2-ethoxy-1-[4-chloro-2-fluoro-5 -(2-propynyloxy)-phenyl]-4-trifluoromethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.34 ppm (d,1H), 6.97 ppm (d,1H), 6.60 ppm (s,1H), 4.76 ppm (m,2H), 4.50 ppm (m,2H), 2.57 ppm (t,1H), 1.29 ppm (t,3H);
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([C:10]2[N:14](C3C=CC(C#N)=CC=3)[N:13]=[CH:12][C:11]=2I)=[C:6]([CH3:24])[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[C:4]1=[O:35])C.C([N:39]([CH2:43][CH3:44])C(C)C)(C)C.[CH3:45][S-:46].[Na+]>CN(C)C=O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][N:3]1[C:8](=[O:9])[C:7]([C:10]2[C:11]([S:46][CH3:45])=[CH:12][N:13]([C:6]3[CH:7]=[CH:10][CH:11]=[C:44]([CH:24]=3)[C:43]#[N:39])[N:14]=2)=[C:6]([CH3:24])[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=2)[C:4]1=[O:35]
Reactant: C[S-]
Reactant: CCn1c(=O)c(-c2c(I)cnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CCN(C(C)C)C(C)C
Agent: [Fe+2]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cn(-c2cccc(C#N)c2)nc1-c1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-iodo-1H-pyrazol-1-yl)benzonitrile (prepared in Example 268) (98.1 mg) in N,N-dimethy formamide (1.0 ml) were added palladium dibenzylidene acetone complex (15.9 mg), 1,1′-bis(diphenylphosphino)ferrocene) (18.9 mg), N,N-diisopropylethylamine (33.8 μl) and sodium methanethiolate (13.4 mg) and the resulting mixture was stirred at 110° C. for four hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylthio)-1H-pyrazol-1-yl)benzonitrile (57.4 mg).