Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:35])[NH:31][CH2:32][CH2:33][F:34])=[O:24])[N:18]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.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.[CH2:76]([O:78][C:79]([N:81]1[CH2:86][CH2:85][NH:84][CH2:83][C@H:82]1[CH3:87])=[O:80])[CH3:77]>CN(C=O)C>[CH2:76]([O:78][C:79]([N:81]1[CH2:86][CH2:85][N:84]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:35])[NH:31][CH2:32][CH2:33][F:34])=[O:24])[N:18]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:42])=[O:5])[CH2:83][C@H:82]1[CH3:87])=[O:80])[CH3:77]
Reactant: CCOC(=O)N1CCNC[C@H]1C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NCCF)n(-c3ccccc3)n2)C[C@H]1C
Reaction time: 24 h

Procedure:
To a solution of 81 mg (S)-2-({5-[2-((S)-2-(2-Fluoroethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 22 μl DIPEA, 52 mg HATU and 24 mg (R)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 24 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 300 μl TFA. After stirring for 16 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:13][CH2:14][C:15](Cl)=[O:16]>C(Cl)Cl>[C:1]([NH:5][C:15](=[O:16])[CH2:14][Cl:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a cooled (0° C.) solution of tert-butyl amine (5.25 mL, 50 mmol) in DCM (40 mL) was added triethylamine (14 mL, 101 mmol) followed by chloro acetylchloride (3.98 mL, 50.3 mmol). The reaction was warmed to RT and stirred for 2 h. The reaction mixture was concentrated, redissolved in EtOAc (20 mL) and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to yield 5.39 g of crude product which was further purified by flash column chromatography using 7:3 Pet. Ether: EtOAc as the eluant. Pure N-tert-butyl-2-chloroacetamide (3.65 g) was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[CH2:26][C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[Cl:18])[CH2:7]1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1ccc(Cl)cc1Cl)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1

Procedure:
Example 18 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (2,4-dichlorophenyl)acetic acid (0.0.41 g) to give the title compound (0.019 g).
Reaction SMILES: C(O)C=C.BrCC1C=CC(C(O)=O)=CC=1.[H-].[Na+].[CH2:18]([O:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)[CH2:19][CH:20]=C>>[CH2:18]([O:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)[CH:19]=[CH2:20]
Reactant: C=CCCOCc1ccc(C(=O)O)cc1
Agent: O=C(O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C=CCO
Product: C=CCOCc1ccc(C(=O)O)cc1

Procedure:
The reaction of allyl alcohol and 4-Bromomethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 4-Allyloxymethyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.91 (d, J=8.3, 2 arom. H); 7.42 (d, J=8.3, 2 arom.H); 5.90 (m, —CHCH2); 5.30, 5.18 (2 d-like, —CH═CH2); 4.54 (s, —OCH2—C6H4); 4.01 (2 d-like, CH2═CHCH2O). 13C-NMR (100 MHz, d6-DMSO): 161.18 (—C═O); 143.48; 134.97; 129.95; 129.31 (2 arom.C); 127.11 (2 arom.C); 116.63; 70.64 (2 C).
Reaction SMILES: [CH2:1]([C:8]1([OH:32])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33]>CO.[Pd]>[ClH:33].[CH2:1]([C:8]1([OH:32])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(Cc2ccccc2)CCN(CCCOc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Oc1ccc(OCCCN2CCC(O)(Cc3ccccc3)CC2)cc1
Yield: 88 %

Procedure:
4-Benzyl-1-[3-(4-benzyloxy-phenoxy)-propyl]-piperidin-4-ol (0.432 g, 1 mmol) was dissolved in MeOH (50 ml) and hydrogenated in the presence of Pd on C at room temperature and atmospheric pressure. After filtration and evaporation of the solvent, the residue was dissolved in tetrahydrofuran (THF) (3 ml) and ether (10 ml). 1.1 equivalent of etheric HCl were added to give 4-benzyl-1-[3-(4-hydroxy-phenoxy)-propyl]-piperidin-4-ol hydrochloride (0.30 g, 88%) as colorless solid, m.p. 64° C. and MS: m/e=342.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]([CH3:20])=[C:12]3[C:21]#[N:22])[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=1.[CH2:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:31][CH3:32].C(N(CC)CC)C>ClCCl>[C:21]([C:12]1[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=[C:2]3[NH:1][S:33]([CH2:30][CH2:31][CH3:32])(=[O:35])=[O:34])[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])#[N:22]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 200 mg (0.512 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) in dichloromethane (4 ml) were added 219 mg (1.54 mmol) propane-1-sulfonyl chloride and 0.21 ml (1.54 mmol) triethylamine. The mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 28 mg (11% of th.) of the title compound.
Reaction SMILES: O=[C:2]([CH2:8][C:9]([O:11]C)=O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[OH:11][C:9]1[N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:20]=[C:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH:8]=1
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: NNc1ccccc1
Solvent: c1ccccc1
Product: COC(=O)Cc1cc(O)n(-c2ccccc2)n1
Yield: 80 %

Procedure:
The mixture of dimethyl 3-oxopentanedioate (10 mmol, 1.74 g) and phenylhydrazine (10 mmol, 1.08 g) in dry benzene (50 ml) was refluxed for 8 h, then solvent was removed in vacuo and the title compound was separated by recrystallization from i-PrOH (20 ml). Yield: 80%. 1HNMR (500 MHz, DMSO-d6, ppm): 3.49 (2H, s), 3.68 (3H, s), 5.43 (1H, s), 7.12 (1H, t, 7.4 Hz), 7.35 (2H, t, 7.6 Hz), 7.78 (2H, d, 7.9 Hz), 11.1 (1H, bs)
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([O:35][CH3:36])[N:28]=3)[CH2:12]1)[C:8](=[O:37])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO>[CH3:36][O:35][C:29]1[N:28]=[C:27]([O:26][CH:11]2[CH2:10][CH:9]3[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]4[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]3=[O:37])[CH2:23]4)[CH2:12]2)[CH:32]=[C:31]([O:33][CH3:34])[N:30]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(OC)nc(OC)n3)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)nc(OC)n1
Yield: 99.1 %

Procedure:
A solution of the ethyl ester 18f (0.33 g, 0.64 mmol) in THF/MeOH 1:1 (20 ml) was treated with a 1M solution of LiOH (10 ml) as described in Example 13 step d. Purification by column chromatography on silica gel eluted with DCM-MeOH gave the title compound, (0.31 g, 99%), (M+H)+489.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([O:8]CC)=O)(=[O:3])[CH3:2].[CH2:11]([NH2:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(OCC)(=O)C>[CH2:11]([NH:33][C:6](=[O:8])[CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCCCCCN
Reactant: CCOC(=O)CNC(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCCCCCNC(=O)CNC(C)=O
Temperature: 150 °C

Procedure:
A mixture consisting of 1.13 gm (0.01 mol) of ethyl N-acetyl-glycinate and 2.50 gm (0.0078 mol) of n-docosyl-amine was heated for 90 minutes at 150°C., while stirring. Thereafter, ethyl acetate was added to the hot reaction mixture, and upon cooling of the mixture a crystalline substance separated out which was collected and again recrystallized from ethyl acetate in the presence of activated charcoal and silicagel. 1.5 gm (55% of theory) of the compound of the formula ##EQU6## having a melting point of 135°-137°C. were obtained.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[O:24][N:23]=[C:22]([NH2:25])[CH:21]=1>O1CCCC1>[CH3:19][C:20]1[O:24][N:23]=[C:22]([NH:25][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH:21]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Cc1cc(N)no1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1cc(NC=C2C(=O)Nc3ccccc32)no1

Procedure:
The named compound is prepared by substituting 5-methyl-isoxazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1228 gms. 5-methyl-isoxazol-3-ylamine by refluxing in tetrahydrofuran (2.7 mL).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].[Br:13][C:14]1[NH:15][CH:16]=[C:17]([CH3:19])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:13][C:14]1[N:15]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH:16]=[C:17]([CH3:19])[N:18]=1
Reactant: Cc1c[nH]c(Br)n1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(F)cc(F)c2[N+](=O)[O-])c(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A mixture of 1,3,5-trifluoro-2-nitrobenzene (2.2 mL, 18.6 mmol), 2-bromo-4-methylimidazole (3 g, 18.6 mmol) and K2CO3 (5.66 g, 41 mmol) in 80 mL DMF was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water. Standard work up procedure followed by column purification using 10% ethyl acetate in dichloromethane as eluent provided 3.18 g (54% yield) of the product as a yellow powder. EIMS 317.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]O)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[OH-].[Na+].S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][Cl:24])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Agent: [Na+]
Agent: [OH-]
Product: ClCCC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To 6-chloro-2-[4-(2-hydroxyethyl)piperidine-1-yl]benzothiazole (1.20 g; 4.03 mmol) was added thionyl chloride (10 ml). The mixture was stirred at 60° C. for 1 hour. The reaction solution was poured into ice water. 5N aqueous sodium hydroxide was added thereto to neutralize and the precipitate was collected. The precipitate was washed with diisopropyl ether to give 6-chloro-2-[4-(2-chloroethyl)piperidine-1-yl]benzothiazole as colorless crystal (0.98 g; 77%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>C(#N)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Sc1ccc2ccccc2n1
Solvent: CC#N
Product: COc1cc2nccc(Sc3ccc4ccccc4n3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
2-Quinolinethiol (87 mg) and 4-chloro-6,7-dimethoxyquinoline (100 mg) were suspended in acetonitrile (3 ml), and the suspension was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was neutralized with sodium hydrogencarbonate and was then extracted with chloroform. The chloroform layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (15 mg, yield 10%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:27])[C:21]=2[CH:20]=[C:19]([CH3:28])[N:18]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:16][C:17]1[C:26]2[C:21](=[C:22]([NH:27][C:10]([NH:9][CH2:8][C:6]3[CH:5]=[CH:4][C:3]([C:12]([F:13])([F:14])[F:15])=[C:2]([F:1])[CH:7]=3)=[O:11])[CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([CH3:28])[N:18]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1cc2c(N)cccc2c(C)n1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2c(C)n1
Temperature: 25 °C

Procedure:
The product from Example 205A (4.4 mmol) in toluene (10 mL) was treated with 1,3-dimethyl-5-isoquinolinamine (375 mg, 2.18 mmol) and DIEA (3.5 mL) The mixture was heated at 80° overnight. After cooling to room temperature, the precipitated solids were collected by filtration and chromatographed on silica gel (98:2 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.13 (d, 1H, J=7.8 Hz), 7.75-7.83 (m, 2H), 7.61 (s, 1H), 7.38-7.51 (m, 3H), 7.18 (t, 1H, J=6.1 Hz), 4.46 (d, 2H, J=5.8 Hz), 2.84 (s, 3H), 2.59 (s, 3H); MS (ESI+) m/z 392 (M+H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][C:28]([O:31]CC4C=CC=CC=4)=[CH:27][CH:26]=3)[O:22][C:23]=1[CH3:24])[C:13]([CH3:39])=[CH:12]2)([OH:8])[C:4]([F:7])([F:6])[F:5]>CO.[Pd]>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)=[N:20][C:19]=1[CH2:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:41])([F:40])[F:1])[C:4]([F:5])([F:6])[F:7])=[CH:17][CH:16]=2)[CH:12]=[C:13]1[CH3:39]
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Agent: [Pd]
Solvent: CO
Product: Cc1oc(-c2ccc(O)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Reaction time: 6 h
Yield: 87.6 %

Procedure:
A solution of 80 mg (0.139 mmol) of 2-{1-[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-1H-indol-5-yl}-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 98) in 1 mL of methanol was treated with 20 mg Pd/C (10% Pd) and stirred under H2 at atmospheric pressure for 6 hrs. Filtration and evaporation of the solvent yielded 59 mg (87%) of 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazol-2-yl}-phenol, light green foam, MS: 485 (MH+).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([Br:11])=[C:8]([CH3:10])[CH:9]=1)=[O:4].[OH-].[Na+].BrC1SC(C(O)=O)=CC=1C.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CCO.O.CN(C=O)C.CCOC(C)=O>[Br:11][C:7]1[S:6][C:5]([C:3]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:4])=[CH:9][C:8]=1[CH3:10]
Reactant: COC(=O)c1cc(C)c(Br)s1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1cc(C(=O)O)sc1Br
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCOCC2)sc1Br
Temperature: 80 °C

Procedure:
5-Bromo-4-methyl-thiophene-2-carboxylic acid methyl ester (8.51 mmol) was dissolved in EtOH (100 ml) and NaOH (42.5 mmol) added, as a 1M solution in water. Reaction was heated to 80° C. for 2 h, after which time all starting material had been consumed. Reaction was then concentrated in vacuo and the residue taken up in DCM and shaken with 1M HCl. The resulting biphasic mixture was then filtered and the filtrant washed with hexane and dried under vacuum. This gave 5-Bromo-4-methyl-thiophene-2-carboxylic acid as off white solid: m/z in MS AP−=219, 221 [M−H]−, 6.79 mmol, 80%. 5-Bromo-4-methyl-thiophene-2-carboxylic acid (6.79 mmol) was taken up in 30 ml DMF and morpholine (7.47 mmol), WSC.HCl (7.47 mmol) and HOBt (7.47 mmol) were added. Reaction was stirred at room temperature for 17 h and then diluted with EtOAc, washed with 1M HCl and brine, dried over Na2SO4 and concentrated in vacuo. Flash chromatography of the residue (silica, 33-50% EtOAc in hexane) gave (5-Bromo-4-methyl-thiophen-2-yl)-morpholin-4-yl-methanone as a pale golden oil: m/z in MS ES+=290, 292 [M+H]+, 4.67 mmol, 69%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][S-:10].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([S:10][CH3:9])=[N:6][CH:7]=1
Reactant: C[S-]
Reactant: Clc1ncc(Br)cn1
Agent: [Na+]
Solvent: CCO
Product: CSc1ncc(Br)cn1
Reaction time: 8 h
Yield: 103.2 %

Procedure:
The subtitle compound was prepared following a method by Takahashi et al., Chem. Pharm. Bull., 1958, 6, 334-337. To a solution of 5-bromo-2-chloropyrimidine (1.0 g, 5.2 mmol) in EtOH was added sodium methanethiolate (0.36 g, 5.2 mmol) at room temperature and the reaction mixture was stirred overnight. The mixture was partitioned between EtOAc (15 mL) and water (10 mL). The aqueous layer was extracted twice with EtOAc and washed with brine. The combined organic layers were dried and concentrated to give the subtitle compound as a white solid (1.1 g).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:18][F:19])([CH2:16][F:17])[CH:3]=1.C([Li])CCC.[CH3:25][O:26][C:27](=[S:30])OC.[Cl-].[NH4+]>COC(C)(C)C>[F:17][CH2:16][C:4]1([CH2:18][F:19])[CH:3]=[C:2]([C:27](=[S:30])[O:26][CH3:25])[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: COC(=S)OC
Reactant: FCC1(CF)C=C(Br)c2cc(C(F)(F)F)ccc2O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COC(C)(C)C
Product: COC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
An amount (65 mg) of 4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran was dissolved in t-butyl methyl ether (2 ml); to the solution, 1.69 M n-butyllithium (0.11 ml) was added at −70° C. under a nitrogen atmosphere and the mixture was stirred for 10 minutes. Then, dimethoxycarbon sulfide (39 mg) was slowly added dropwise to the reaction mixture, which was stirred for 30 minutes at −70° C. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added, followed by extraction with hexane/ethyl acetate (3/1). The resulting organic layers were washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=2/1) to give the titled compound (36 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@H:7]([CH:9]([CH3:11])[CH3:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15]>CO>[C:1]([O:5][C:6](=[O:12])[C@H:7]([CH:9]([CH3:10])[CH3:11])[NH:8][CH2:15][CH2:14][C:13]([O:17][CH3:18])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN[C@H](C(=O)OC(C)(C)C)C(C)C
Yield: 93.9 %

Procedure:
To a solution of 1.73 g of L-Valine t-butyl ester in 10 ml of methanol was added 9.0 ml of methyl acrylate. The solution was heated to reflux overnight. Another 9.0 ml of methyl acrylate was added and continued the reflux for 24 h. The solvent was evaporated in vacuo and the crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane) to provide 2.435 g of desired compound (93.9%). 300 MHz 1H NMR (CDCl3) δ 0.91 (d, J=3.5 Hz, 3H), 0.93 (d, J=3.5 Hz, 3H), 1.47 (s, 9H), 1.85 (m, 1H), 2.47 (t, J=7 Hz, 2H), 2.68 (m, 1H), 2.81 (d, J=6 Hz, 1H), 2.95 (m, 1H), 3.68 (s, 3H). Mass spectrum: (M+H)+=260.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[CH:4][C:3]=1[O:21][CH3:22].S(=O)(=O)(O)O.[N+:28]([O-])([OH:30])=[O:29]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([N+:28]([O-:30])=[O:29])[C:3]=1[O:21][CH3:22]
Reactant: COc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4-Chloro-6-fluoro-3-methoxyphenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (10.0 g, 29.5 mmol) was slowly added to a stirred mixture of con. sulfuric acid (36 ml) and con. nitric acid (4 ml) with stirring at −15° C. The solution was then slowly warmed to room temperature and allowed to stir for 2 hr. Addition of the solution to ice-water resulted in a light yellow precipitate which was separated by filtration to afford the title compound (9.1 g). NMR data for the compound are listed in Table XVIII.