Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+]>ClCCl.CCCCCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:17][CH2:16][N:15]([C:33](=[O:35])[CH3:34])[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.5 %

Procedure:
The 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidine hydrochloride (90 mg, 0.22 mmol) obtained in Example 260 and triethylamine (0.092 ml, 0.66 mmol) were dissolved in dichloromethane (4 ml), followed by the addition of acetyl chloride (0.024 ml, 0.34 mmol) at room temperature. After stirring at room temperature for 14 hours, a saturated aqueous solution of sodium bicarbonate (0.5 ml) was added. The residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure to give a white solid. The solid thus obtained was washed with hexane, whereby the title compound (48 mg, 0.12 mmol, 53%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[S:26][C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1)[CH3:2].Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:26][C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:8](=[O:10])[N:9]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: CCc1cc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(s1)n(Cc1ccc(-c3ccccc3C#N)cc1)c(=O)n2CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a mixture of 4′-[(5-ethyl-2-oxo-1,2-dihydro-3H-thieno[2,3-d]imidazol-3-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (2-bromoethyl)benzene (0.23 mL) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.066 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.58 g, 87%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)O.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:14][C:13](=[O:15])[CH2:12][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:16])([F:1])[F:17])[CH:11]=2)[CH:7]=[CH:8]1
Reactant: O=C(O)Cn1ccc2ccc(C(F)(F)F)cc21
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cn1ccc2ccc(C(F)(F)F)cc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A mixture of 2-(6-(trifluoromethyl)-1H-indol-1-yl)acetic acid (90 mg, 0.370 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (130 mg, 0.308 mmol), EDC (83 mg, 0.432 mmol) and DMAP (75 mg, 0.617 mmol) in dry DCM (5 ml) was stirred at room temperature overnight. Aqueous 1N HCl was added to the reaction mixture and the organic phase was separated, washed with brine and dried over sodium sulfate. The solvent was removed under vacuum, and the crude was purified by flash chromatography on silica gel column (DCM/MeOH 96/4) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(trifluoromethyl)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (95 mg, 0.147 mmol, 48% yield). MS/ESI+ 645.03 [MH]+; [αD]=−2.157, c=0.510; DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.45 (s, 2H), 7.67-7.85 (m, 2H), 7.51 (d, 1H), 7.32 (dd, 1H), 7.12 (d, 1H), 6.97 (d, 1H), 6.87 (dd, 1H), 7.03 (t, 1H), 6.61 (dd, 1H), 5.98 (dd, 1H), 5.38 (d, 1H), 5.25 (d, 1H), 3.82 (d, 2H), 3.39 (dd, 1H), 3.19 (dd, 1H), 1.10-1.22 (m, 1H), 0.46-0.70 (m, 2H), 0.15-0.46 (m, 2H)
Reaction SMILES: C(O)(C(F)(F)F)=[O:2].[N:8]([CH2:11][C@H:12]1[O:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C(C)(C)C)=[O:24])=[C:19]([F:30])[CH:18]=2)[CH2:13]1)=[N+:9]=[N-:10]>C(Cl)Cl>[N:8]([CH2:11][C@H:12]1[O:16][C:15](=[O:2])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([F:30])[CH:18]=2)[CH2:13]1)=[N+:9]=[N-:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1ccc(N2CO[C@H](CN=[N+]=[N-])C2)cc1F
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
60% TFA in DCM (5 mL) was added to 5-(S)-azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine (0.336 g, 1 mmol), and the solution kept at r.t. for 1 h. Solvents were removed in vacuo to afford 5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl-]oxazolidine-2-one dried (0.280 g, 99%). N-Trimethylsilyl-N,N-diethylamine (0.23 mL, 1.2 mmol) was added to above product in dry dichloromethane (3 mL) under nitrogen atmosphere, and the solution stirred for 15 min. Solvents and excess reagent were removed in vacuo, and residue dissolved in dichloromethane (4 mL). The solution was cooled to about 0° C., and oxalyl chloride (1.5 mmol, 0.13 mL) was added dropwise, followed by catalytic N,N-dimethylformamide (about 0.01 mL). The mixture was allowed to warm up to r.t. (room temperature), and stirred at r.t. for another 2 h. Solvents were removed in vacuo to afford the product as a white solid. Yield 0.292 g (98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18](O)=O)=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[F:15])=[C:4]([F:21])[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:44][NH:45][C:46]([NH2:48])=[S:47].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)Cl>CN(C=O)C.[NH4+].[Cl-].C(OCC)(=O)C.CC#N.C(Cl)Cl>[NH2:48][C:46]1[S:47][C:18]([C:10]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:21])=[C:14]([F:15])[C:13](=[O:16])[N:12]([CH3:17])[CH:11]=2)=[N:44][N:45]=1
Reactant: NNC(N)=S
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)c(F)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1cc(-c2nnc(N)s2)c(Nc2ccc(Br)cc2F)c(F)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 4.3 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (200 mg, 0.557 mmol), EDCl (214 mg, 1.11 mmol) and HOBt (151 mg, 1.11 mol) were stirred in DMF (10 mL) for 30 minutes. Thiosemicarbazide (51 mg, 0.562 mmol) and Et3N (0.116 mL, 1.5 mmol) were added. After 1 hour, the reaction mixture was diluted with saturated aqueous NH4Cl, and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (5% to 10% MeOH in methylene chloride) gave 70 mg partially pure intermediate adduct. PPh3 (78 mg, 0.30 mmol), Et3N (0.10 mL, 0.74 mmol), and CCl4 (0.029 mL, 0.30 mmol) were added to a stirred suspension of intermediate adduct (40 mg, 0.093 mmol) in 1:1 methylene chloride:MeCN (4 mL). The reaction mixture was heated to 50° C. for 5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (twice) (4% MeOH in methylene chloride) gave clean desired product (10 mg, 33%): MS APCI (+) m/z 414, 416 (M+, Br pattern) detected; 1H NMR (400 mHz. CD3OD) δ 7.80 (s, 1H), 7.31 (dd, t H), 7.25 (d, 1H), 7.02 (td, 1H), 3.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[OH:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][OH:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:34]([CH2:35][CH2:36][OH:37])[CH2:33][CH2:32][OH:31])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: OCCNCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(CCO)CCO

Procedure:
In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and bis-(2-hydroxy-ethyl) amine was converted to 22.2 mg of the title compound (free base), mass spectrum (electrospray, m/e): M+H 514.0 and 60.7 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electrospray, m/e): M+H 514.0.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.[OH-].[Na+].Cl[CH2:35][CH:36]([OH:39])[CH2:37][OH:38]>O.CCOCC>[O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:35][CH:36]([OH:39])[CH2:37][OH:38])=[O:17])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(O)CCl
Reactant: O=C(O)c1ccc(NCCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: O
Product: O=C(OCC(O)CO)c1ccc(NCCCOc2ccccc2)cc1

Procedure:
A solution of 5.5 g. of 4-(3-phenoxypropylamino)benzoic acid in 50 ml. of hexamethylphosphoramide is treated with 4.80 g. of 25% aqueous sodium hydroxide followed by 11.0 g. of 3-chloro-1,2-propanediol and then is heated at 140° C. for 6 hours. The mixture is diluted with water and ether and filtered to yield a white solid. Recrystallization from acetonitrile affords pure 2,3-dihydroxypropyl 4-(3-phenoxypropylamino)benzoate as a white crystalline solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:26])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[C:7]=1[C:27]([O:29]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:28])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:26])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:19]=2)[C:7]=1[C:27]([OH:29])=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(-c4ccccc4)cs3)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](Nc3nc(-c4ccccc4)cs3)[C@H]2SC1
Yield: 70 %

Procedure:
A mixture of 182 mg of (6R-trans)-3-[(acetyloxy)methyl]-8-oxo-7-[(4-phenyl-2-thiazolyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 0.5 ml of trifluoroacetic acid, 3 drops of anisole and 3 ml of dichloromethane was reacted as described in Example 2, giving 92 mg of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11](Cl)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([NH:28][CH:25]3[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH2:26]3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1cccc2nc(Cl)oc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)oc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.4 %

Procedure:
To a solution of 2-chloro-benzooxazole-7-carboxylic acid methyl ester (1.50 g, 7.08 mmol, 1.0 equiv; example 252/step 3) in acetonitrile (23 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.42 g, 7.08 mmol, 1.0 equiv) and triethylamine (0.79 g, 7.79 mmol, 1.1 equiv). After stirring for 48 h at rt, the reaction mixture was poured on ice, the solution extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with water (2×100 mL) and a conc. solution of sodium chloride (100 mL). The organic phase was dried over MgSO4, concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with hexane/ethyl acetate (1:1) providing 2.27 g (85%) of the title compound. MS (ISP): 376.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]>>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:8](=[O:9])[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1nccs1
Product: O=C(Nc1nccs1)Oc1ccccc1

Procedure:
Using analogous procedures to those described in Example 49, the appropriate 2-amino-1,3-thiazole was reacted with phenyl chloroformate and the phenyl N-(1,3-thiazol-2-yl)carbamate so obtained was reacted with the appropriate alkylamine to give the compounds described in Table II.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:49][CH2:50][CH2:51][O:52][C:53](=[O:62])[N:54]([CH3:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH2:49][CH2:50][CH2:51][O:52][C:53](=[O:62])[N:54]([CH3:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C(=O)OCCCBr)c1ccccc1
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nn(CCCOC(=O)N(C)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 86 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with 3-bromopropyl-N-methyl-N-phenylcarbamate was carried out as described in Example 3, Step A, except that only 2.4 equivalents of the alkylating agent was used. After work-up, the residue was flash chromatographed over silica gel (35 mL for 0.162 mmole, gradient elution using 0.75-2.5% MeOH/CH2Cl2) to give the desired material as a white foam in 86% yield, mass spectrum (FAB) 809 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4]([C:13]2[C:18]([O:19]C)=[CH:17][CH:16]=[CH:15][C:14]=2[F:21])[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:6](=[CH:11][C:10]([CH3:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[C:14]([F:21])=[CH:15][CH:16]=[CH:17][C:18]=2[OH:19])[N:3]=1
Reactant: COc1cccc(F)c1-c1nc(Cl)c2c(C)cccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 65.5 %

Procedure:
Under an N2 atmosphere, 4-chloro-2-(2-fluoro-6-methoxyphenyl)-methylquinazolin (7.0 g, 23.12 mmol) was dissolved in CH2Cl2 (110 mL) and cooled to −50° C. internal temperature using a dry ice/acetone bath. A 1.0 M solution of BBr3 in CH2Cl2 (115.6 mL, 115.6 mmol) was added dropwise via an addition funnel while maintaining the internal temperature at −50° C. The reaction mixture was allowed to warm to 0° C., and the reaction was complete after 1.5 h. It was then slowly quenched with saturated aqueous NaHCO3 solution to pH 7. After partitioning between CH2Cl2 and H2O, the mixture was separated and the aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a brown solid. Purification via silica gel chromatography using 75% CH2Cl2/25% hexanes gave 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol as a yellow solid (4.37 g, 66%). LC/MS: m/z 289.1 (M+H)+ at 3.71 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) d 8.22 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J=8.6, 1.5 Hz, 1H), 7.42-7.36 (m, 1H), 6.86-6.82 (m, 2H), 3.81 (s, 3H), 2.64 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[C:12]([N:19]1[CH2:23][CH2:22][C@@H:21](O)[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@H:22]1[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:23]1)[N:6]=[C:5]2[I:11]
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](n2nc(I)c3cc(F)ccc32)C1
Yield: 32 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and BOC—(R)-3-pyrrolidinol in 32% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 1.43 (9H, s), 2.38-2.40 (1H, m), 2.56-2.66 (1H, m), 3.51-3.57 (1H, m), 3.74-3.78 (2H, m), 3.85-3.94 (1H, m), 5.12-5.15 (1H, m), 7.13 (1H, d, J=8.0 Hz), 7.23-7.27 (1H, m), 7.35-7.37 (1H, m).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([F:24])=[C:19]([Cl:25])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO.COC(C)(C)C>ClCCCl.O>[Cl:25][C:19]1[CH:18]=[C:17]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:22]=[C:21]([Cl:23])[C:20]=1[F:24]
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CCN(Cc3ccccc3)C2)cc1Cl
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Solvent: COC(C)(C)C
Product: Fc1c(Cl)cc(C2(C(F)(F)F)CCNC2)cc1Cl
Yield: 91.2 %

Procedure:
1-Benzyl-3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)pyrrolidine (3.7 g) was dissolved in 1,2-dichloroethane (20 ml), added with 1-chloroethyl chloroformate (2.7 g) at room temperature, and then refluxed under heating for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was added with methanol (30 ml) and further refluxed under heating for 2 hours. The reaction solution was concentrated under reduced pressure and the residue obtained was added with t-butyl methyl ether and water to separate the aqueous layer. After that, the organic layer was again washed with a 1 M aqueous solution of hydrochloric acid, and the aqueous layers were combined, added with a saturated aqueous solution of potassium carbonate to make the liquid alkaline, and extracted with t-butyl methyl ether. The aqueous phase was extracted again with t-butyl methyl ether, and the organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)pyrrolidine (2.6 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:22][C@@H:23]2[CH2:25][O:24]2)(=O)=O)C=CC=1)([O-])=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:22][CH:23]2[CH2:25][O:24]2)=[CH:6][N:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Product: Cc1ccc(OCC2CO2)cn1

Procedure:
The title compound was prepared from 6-methyl-3-pyridinol and (2S)-oxiranylmethyl 3-nitrobenzenesulfonate in substantially the same manner as described in Example 123. The product was obtained as a brown oil; 1H NMR (400 MHz, DMSO-d6) δ 2.38 (s, 2.38, 1H), 2.68-2.70 (m, 1H), 2.81-2.84 (m, 1H), 3.30-3.34 (m, 1H), 3.83-3.87 (m, 1H), 4.34-4.38 (m, 1H), 7.15-7.17 (m, 1H), 7.28-7.31 (m, 1H), 8.15-8.16m (m, 1H); MS (ES) m/z: 165 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1>[Pd].CCO>[F:1][C:2]1[CH:3]=[C:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 97 %

Procedure:
A mixture of ethyl (2E)-3-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-2-propenoate (205 mg, 0.68 mmol) and 10% Pd/C catalyst (40 mg) in EtOH (4 mL) was stirred under an atmosphere of hydrogen at ambient temperature for 16.5 h. The mixture was then filtered through celite placed directly on the top of a SPE (silica, 5 g cartridge) eluting with EtOH. The filtrate was reduced under vacuum and the residue purified further by SPE (silica, 5 g cartridge) eluting with cyclohexane:EtOAc (gradient 25:1 to 3:1) to afford the title compound (140 mg).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[OH:9][C:10]1[C:19]2[C:14](=[C:15]([CH3:24])[C:16]([O:20][CH2:21][O:22][CH3:23])=[CH:17][CH:18]=2)[O:13][C:12](=[S:25])[C:11]=1[CH3:26].O>CC(C)=O>[CH3:23][O:22][CH2:21][O:20][C:16]1[C:15]([CH3:24])=[C:14]2[C:19]([C:10](=[O:9])[C:11]([CH3:26])=[C:12]([S:25][CH3:1])[O:13]2)=[CH:18][CH:17]=1
Reactant: COCOc1ccc2c(O)c(C)c(=S)oc2c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: COCOc1ccc2c(=O)c(C)c(SC)oc2c1C
Temperature: 25 °C
Yield: 79.7 %

Procedure:
Potassium carbonate (995 mg, 7.20 mmol) and methyl iodide (1.50 mL, 24.0 mmol) were added to a solution of 4-hydroxy-7-(methoxymethoxy)-3,8-dimethyl-2H-chromene-2-thione (1.60 g, 6.00 mmol) obtained in Example 37-1 in acetone (16 mL), and the mixture was refluxed for 45 minutes. After cooling to room temperature, water (15 mL) was added to the reaction solution, followed by extraction with ethyl acetate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=95/5→60/40) to obtain 1.34 g of the title compound (yield: 80%).