Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19](=[O:20])[O:18]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([O:14][CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19](=[O:20])[O:18]2)=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1ccc(C(C)C(=O)OC2OC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
To a solution of 6.2 g of 2-(4-isobutylphenyl)propionic acid in 30 ml of chloroform and 3.4 g of triethylamine, a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform is added. The solution thus obtained is stirred 24 hours at room temperature (about +22° C.), the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness. The residue, crystallized from petroleum ether, yields 8.1 g of phthalidyl 2-(4-isobutylphenyl)propionate; m.p. 62°-65° C. IR: 1795 and 1780 cm1
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[C:20]([F:21])=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])OC(C)(C)C)[CH3:25])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[C:8]([F:34])[C:7]=2[F:35])[CH2:3][CH2:2]1.Cl.[C:37](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[C:20]([F:21])=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[CH3:37])[CH3:25])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[C:8]([F:34])[C:7]=2[F:35])[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3F)oc2c1F)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3F)oc2c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-2,3-difluorophenyl)-7-fluoro-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (1.18 g) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (902 mg). 1H NMR (300 MHz, CDCl3) δ 0.35-0.46 (2H, m), 0.66-0.77 (2H, m), 1.24-1.41 (4H, m), 2.02 (3H, s), 4.00 (2H, d, J=6.8 Hz), 4.05-4.18 (2H, m), 4.34-4.49 (1H, m), 5.86 (1H, d, J=7.9 Hz), 6.86 (1H, ddd, J=9.1, 7.2, 1.9 Hz), 7.05 (1H, dd, J=8.7, 7.2 Hz), 7.48 (1H, dd, J=8.7, 1.1 Hz), 7.89 (1H, td, J=8.1, 2.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[C:13]=2[O:20][CH3:21])[CH:3]=1.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:25][CH3:24])[C:13]=2[O:20][CH3:21])[CH:3]=1
Reactant: COc1c(C=O)cccc1Oc1cc(Cl)c(F)cc1C#N
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(Cl)c(F)cc2C#N)c1OC
Yield: 58.5 %

Procedure:
4-Chloro-5-fluoro-2-(3-formyl-2-methoxyphenoxy)benzonitrile (0.29 g, 0.95 mmol), methylamine (33% in ethanol, 1.0 mL, 8.0 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 44 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (65 mg, 0.56 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-5-fluoro-2-(2-methoxy-3-methylaminomethylphenoxy)benzonitrile fumarate (143 mg, 35%) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:24]4[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.COC(OC)OC>C(O)=O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([C:22]4[NH:30][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: COC(OC)OC
Solvent: O=CO
Product: c1ccc2[nH]c(C3(c4ccc(OCCCN5CCCC5)cc4)CCOCC3)nc2c1
Yield: 30.3 %

Procedure:
N-({4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)benzene-1,2-diamine (500 mg, 1.22 mmol), trimethylorthoformate (5 ml) and formic acid (0.5 ml) were stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between aqueous sodium carbonate (50 ml) and ethyl acetate (100 ml). The layers were separated and the organic phase washed with water (50 ml), dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:2:0.2 to 92:8:1 by volume). The relevant fractions were evaporated and the residue taken up in diethyl ether (20 ml). The unsoluble material was filtered off and the filtrate concentrated in vacuo to provide the title compound (150 mg, 29%). 1H NMR (400 MHz, CD3OD) δ 1.83-1.85 (m, 4H), 1.98-2.06 (m, 4H), 2.23 (d, 2H), 2.62 (s, 4H), 2.69 (t, 2H), 3.42 (t, 2H), 3.82 (d, 2H), 4.00 (t, 2H), 4.33 (s, 2H), 6.84 (d, 2H), 7.06 (d, 2H), 7.14-7.18 (m, 3H), 7.26 (s, 1H), 7.55 (d, 1H). HRMS ESI+ m/z 420.2637 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)Cc1cc(F)c([N+](=O)[O-])c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1cc(F)c([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
To a solution of tert-butyl (3,5-difluoro-4-nitrophenyl)acetate (4.34 g, 15.88 mmol) in DCM (10 ml), at 0° C., was added TFA (10 ml). The reaction was warmed to room temperature and stirred for 1.5 hours. The reaction was concentrated in vacuo, slurried in heptane (10 ml), filtered and dried to provide the title compound as an orange solid (2.95 g, 86% yield).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=1.[CH2:16]1[CH:21]2[C:22]3[C:27]([CH2:28][CH2:29][N:20]2[CH2:19][CH2:18][NH:17]1)=[CH:26][CH:25]=[CH:24][CH:23]=3.C(N(CC)CC)C>CN(C)C=O>[CH2:16]1[CH:21]2[C:22]3[C:27]([CH2:28][CH2:29][N:20]2[CH2:19][CH2:18][N:17]1[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=1)=[CH:26][CH:25]=[CH:24][CH:23]=3
Reactant: c1ccc2c(c1)CCN1CCNCC21
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(N2CCN3CCc4ccccc4C3C2)nc(-c2ccncc2)cc1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 94.6 %

Procedure:
2-Chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (332 mg, 1.5 mmol) was added to the solution of 1,3,4,6,7,11b-hexahydro-2H-pyrazino[2,1-a]isoquinoline (292 mg, 1.55 mmol), triethylamine (0.223 ml, 1.6 mmol) in N,N-dimethylformamide (8 ml) and the mixture was stirred for 6 hours and stood overnight ice-water. After addition of ice-water the solution was partitioned between water and ethyl acetate, and the organic layer was washed with brine and dried with magnesium sulfate. The solvents were removed under reduced pressure and purification by silica gel column chromatography (eluent; dichloromethane/methanol=95/5) afforded title compound (530 mg, 95%). Treatment with 4N hydrogen chloride in ethyl acetate yielded corresponding hydrogen chloride salt (495 mg).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][SH:26])[C:5]1=[O:30])[CH:2]=[CH2:3].Br[CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35].[H-].[Na+]>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][S:26][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CS)C2CC2)C1=O
Reactant: CCC(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CSC(CC)CC)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-mercaptoethyl)-3-methylpiperidin-2-one (49 mg, 0.10 mmol; Example 366, Step A) and 3-bromopentane (51 μl, 0.41 mmol) in DMF (0.52 mL) was added 60% sodium hydride in mineral oil (17 mg, 0.41 mmol) at 25° C. The reaction was stirred at 25° C. for 1 h and then heated to 60° C. After being stirred at 60° C. overnight, the reaction was quenched (10% aq. citric acid), extracted (2×EtOAc), and washed (3×brine). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 9% and 18% EtOAc/hex) provided the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:21]=[CH:20][C:11]([C:12]([CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([OH:25])(=[S:24])[CH3:23]>C(OCC)C>[C:22]([S:24][CH:15]([CH2:14][C:12](=[O:13])[C:11]1[CH:20]=[CH:21][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[C:16]([O:18][CH3:19])=[O:17])(=[O:25])[CH3:23]
Reactant: COC(=O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(O)=S
Solvent: CCOCC
Product: COC(=O)C(CC(=O)c1ccc(Oc2ccccc2)cc1)SC(C)=O
Reaction time: 3 h

Procedure:
2.82 g of methyl 3-(4-phenoxybenzoyl)acrylate were dissolved in 30 ml of diethyl ether, then 1.5 ml of thioacetic acid were added. The mixture was stirred for 3 hours. The reaction mixture was washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water and then dried over magnesium sulfate. The diethyl ether was removed by distillation under reduced pressure. The residue was purified first by silica gel column chromatography, eluted with a mixture of hexane and diethyl ether, then by recrystallization from a mixture of hexane and diethyl ether to give 2.91 g of methyl 2-acetylthio-3-(4-phenoxybenzoyl)-propionate.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:27])=[C:22]([C:25]#[N:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[NH:28][C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30].C(=O)([O-])[O-].[K+].[K+].O.[C:42]([O:45][CH2:46][CH3:47])(=O)C>>[C:25]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH2:47][C@H:46]1[CH2:42][O:45]1)[N:18]=[CH:17][CH:16]=[C:15]2[O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:28][C:29]([NH:31][CH:32]2[CH2:33][CH2:34]2)=[O:30])=[C:7]([CH3:6])[C:12]=1[CH3:13])#[N:26]
Reactant: CCOC(C)=O
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(O)c(C#N)cc23)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)c1C
Temperature: 50 °C

Procedure:
Dimethylformamide (4 ml) was added to N-(2,3-dimethyl-4-(6-cyano-7-hydroxy-quinolin-4-yloxy)-phenyl)-N′-cyclopropylurea (476 mg), and then p-toluenesulfonic acid (2R)-glycidyl ester (365 mg) and potassium carbonate (340 mg) were further added and the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was washed with ethyl acetate to obtain the title compound (270 mg) as light yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:45][C@@H:46]1[NH:51][CH2:50][CH2:49][N:48]([S:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:47]1>CN(C=O)C>[CH3:1][C:2]1[C:7]([C:8]([N:51]2[CH2:50][CH2:49][N:48]([S:52]([C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=3)(=[O:53])=[O:54])[CH2:47][C@@H:46]2[CH3:45])=[O:10])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: Cc1ccc(C(=O)O)c(C)n1
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: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)c(C)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 65.1 %

Procedure:
2,6-Dimethyl-3-pyridinecarboxylic acid (GSK1770624A, Atlantic) (98 mg, 0.65 mmol) and HATU (247 mg, 0.65 mmol) were suspended in DMF (2 ml) and DIPEA (0.170 ml, 0.97 mmol) was added. This mixture was stirred for 40 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (100 mg, 0.32 mmol) was added and stirring continued for 3 h. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (10 ml each). The layers were separated and the aqueous was washed with further DCM (2×5 ml). The combined organic layers were concentrated to leave a brown oil. This was purified by MDAP to give the title compound (92 mg) as an orange solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=2[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C.O>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=2[N:21]=1
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: CNc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CN(c1ccc(O)cc1)c1nc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the sulfate salt of 4-(N-methylamino)phenol (0.008 mol, 2.76 g) in methyl ethyl ketone (25 ml) containing pure potassium carbonate (0.008 mol, 1.1 g) was warmed to reflux and a solution of 2,5-dichlorobenzoxazole (0.016 mol, 3.0 g) in methyl ethyl ketone (25 ml) was added dropwise over 2 hours. The resulting mixture was heated at reflux for a further hour, stood overnight, then stirred at room temperature for a further 8 hours. The solvent was then evaporated leaving a white solid. This was treated with a mixture of water (25 ml) and saturated aqueous sodium carbonate solution (25 ml). The solid was collected, washed with water, dried by suction and recrystallised three times from boiling toluene. Yield 1.4 g, mp 216°-217° C.; ir and pmr spectra and analysis consistent with assigned structure.
Reaction SMILES: [C:1]([N:9]1[C@@H:13]([CH:14]([CH3:16])[CH3:15])[C:12](=[O:17])OC1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1.CN1CCOCC1.Cl>C(OCC)(=O)C>[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:12](=[O:17])[C@H:13]([CH:14]([CH3:15])[CH3:16])[NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:26])=[CH:21][CH:20]=1
Reactant: CC(C)[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Reactant: Cc1ccc([C@H](C)N)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1ccc([C@H](C)NC(=O)[C@@H](NC(=O)c2ccccc2)C(C)C)cc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
(S)-3-Benzoyl-4-isopropyl-2,5-oxazolidinedione (N-benzoyl-L-valine-NCA) (100 mg, 0.40 mmol) was dissolved in ethyl acetate (2.0 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (55 mg, 0.40 mmol) and N-methylmorpholine (61 mg, 0.60 mmol) in ethyl acetate (2.0 mL) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (134 mg, 98%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:31]([F:34])([F:33])[F:32])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH:69]1[CH2:73][C:72](=[O:74])[NH:71][CH2:70]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:31]([F:34])([F:32])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:69]4[CH2:73][C:72](=[O:74])[NH:71][CH2:70]4)=[O:22])=[C:19]([CH2:26][C:27]([F:28])([F:30])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1CC(F)(F)F
Reactant: O=C1CNCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2CC(F)(F)F)CN1
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)benzoic acid (200 mg, 0.38 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), HATU (292 mg, 0.77 mmol, 2.00 equiv), DIEA (99 mg, 0.77 mmol, 1.94 equiv), imidazolidin-4-one hydrochloride (94 mg, 0.77 mmol, 1.98 equiv). The resulting solution was stirred for 2 h at r t. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC plate with ethyl acetate/petroleum ether (2:1). This resulted in 150 mg (60%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)phenyl)carbonyl]imidazolidin-4-one as yellow oil.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCI)cc1
Reactant: C1CCNCC1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCN2CCCCC2)cc1

Procedure:
In a manner similar to that described in Example 207, 3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and piperidine are converted to the named compound.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([CH:28]4[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([CH:28]4[CH2:33][CH2:32][CH2:31][N:30]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(C3CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 22.7 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.22 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (19 μL, 0.24 mmol) and N,N-diisopropylethylamine (114 μL, 0.65 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 20% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 25 mg (23%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.93 (s, 1 H), 7.80 (d, 1 H), 7.58 (s, 1 H), 7.27-7.37 (m, 5 H), 7.13 (dd, 1 H), 6.70 (s, 1 H), 5.64 (s, 2 H), 3.82-3.88 (m, 1 H), 3.55 (d, 1 H), 3.34-3.46 (m, 1 H), 2.86 (s, 3 H), 2.74-2.85 (m, 2 H), 2.03-2.13 (m, 1 H), 1.78-1.89 (m, 1 H), 1.57-1.77 (m, 2 H); ES-MS m/z 502.47 [M+H]+, HPLC RT (min) 3.04.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([O-:5])=[O:4].S(OC)(O[CH3:27])(=O)=O.O>CN(C=O)C>[CH3:27][N:8]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a suspension of sodium hydride (60%, 0.15 g (3.75 mmol)) in 3.0 ml of DMF, 2′-nitro-p-toluenesulfonanilide (1.00 g (3.42 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (0.4 ml (4.22 mmol)) was added dropwise. After 2 hour's stirring, water was added to bring about separation of crystals. The resulting crystals were filtered, washed with water, dried and subjected to silica gel column chromatography with ethyl acetate-hexane (1:2 to 1:1) as eluent to give 0.93 g (89%) of N-methyl-2′-nitro-p-toluenesulfonanilide (Compound No.38) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[O:8][C:9](/[CH:12]=[CH:13]/[N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.CS(C)=O.[BH4-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[O:8][C:9]([CH2:12][CH2:13][N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Cc2ccc(F)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(Cc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a solution of 2-(4-fluoro-benzyl)-5-((E)-2-nitro-vinyl)-furan (1.21 g, 4.89 mmol) described in Manufacturing Example 208-1-3 in acetic acid (0.6 mL) and dimethyl sulfoxide (10 mL) was added sodium borohydride (296 mg, 7.82 mmol), which was stirred for 30 minutes at room temperature. The mixture was cooled with ice water and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.14 g). The title compound was used in the following reaction without any further purification.