Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>C(Cl)Cl>[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)C(C)C)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.40 mmol) in CH2Cl2 (10 mL) was added Et3N (0.08 mL, 0.60 mmol) and isobutyryl chloride (0.03 mL, 0.36 mmol). The resulting solution was stirred at room temperature for 1 hour. The solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with 2% to 10% of MeOH/CH2Cl2. The solid was further purified by flash chromatography on silica gel, eluting with 0% to 5% of MeOH/EtOAc, to afford the title compound (0.080 g, 50%): 1H NMR (300 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.11 (d, J=9.0 Hz, 2H), 7.03 (d, J=9.1 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.76-3.92 (m, 6H), 3.52-3.71 (m, 4H), 3.16-3.44 (m, 4H), 2.83-3.00 (m, 1H), 1.02 (d, J=6.8 Hz, 6H); APCI MS m/z 437 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH:23][C:24]([CH3:29])([CH3:28])[C:25](O)=O>>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]2[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:25]([C:24]([OH:23])([CH3:29])[CH3:28])=[N:22][C:16]=2[CH:17]=1
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Reactant: CC(C)(O)C(=O)O
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCNCC1

Procedure:
2-(5-Methyl-1-piperidin-4-yl-1H-benzoimidazol-2-yl)-propan-2-ol was prepared from 4-(2-amino-4-methyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester and 2-hydroxyisobutyric acid according to the procedure described by Skolnik et. al. J. Amer. Chem. Soc., 1943, 65, 1854-1858. The yields of the product after washing with water and drying varied from 78-87% as an off-white solid. 1H NMR (DMSO-d6, 300 MHz) δ 7.60, 7.36, 6.99, 5.63 (s, 1H), 5.30 (m, 1H), 3.10 (br m, 2H), 2.54 (br m, 2H), 2.37 (s, 3H), 2.22-2.36 (m, 3H), 1.74 (brd, 2H), 1.61 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:5]([NH2:7])=O.[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:16][C:12]1[N:11]([C:10]2[CH:9]=[CH:8][C:4]([C:5]#[N:7])=[CH:3][C:2]=2[CH3:1])[CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(N)=O)ccc1-n1cccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C#N)ccc1-n1cccc1Br
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 36 %

Procedure:
To a solution of 3-methyl-4-(1H-pyrrol-1-yl)benzamide (6A, see first step of Scheme 6 for synthesis) in DMF (5 mL) was added N-bromosuccinimide (177 mg, 1 mmol) portionwise at 0° C., after the addition was completed, the mixture was stirred at room temperature for 35 min. The reaction mixture was poured into water, and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (25 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5:1) to afford 50B (100 mg, yield 36%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[S:23]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:25]4[CH:26]=[CH:27][S:23][CH:24]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccsc1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccsc4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 168 mg (1.5 mmol) of thiophene-3-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(thien-3-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of that intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in DIPE yield 4-(3-chlorophenylamino)-3-[(thien-3-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=11.4; FAB-MS: (M+H)+=357.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:20]1([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:3]=[C:4]([C:8]3([C:14]#[N:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCCN1CCCC1
Reactant: N#CC1(c2cccc(O)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(OCCCN3CCCC3)c2)CCOCC1
Yield: 31.2 %

Procedure:
4-(3-Hydroxy-phenyl)-tetrahydro-2H-pyran-4-carbonitrile (1.03 g, 5.10 mmol), 1-(3-chloro-propyl)-pyrrolidine (600 mg, 4.08 mmol), DMF (6.8 ml) and K2CO3 (2.82 g, 20.4 mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3×50 ml), brine (3×50 ml), dried over MgSO4, fitered and concentrated in vacuo at 35° C. The crude mixture was slurried in TBME:heptane (1:20, 10 ml). The solid was filtered, washed with heptane (10 ml) and dried on the filter for 2 hours to give the title compound (0.4 g, 31%). 1H NMR (400 MHz, CDCl3) δ 7.32 (t, 1H), 7.07-6.99 (m, 2H), 6.87 (dd, 1H), 4.11-4.04 (m, 2H), 4.05 (t, 2H), 3.90 (td, 2H), 2.63 (t, 2H), 2.57-2.49 (m, 4H), 2.18-1.97 (m, 6H), 1.84-1.75 (m, 4H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19]2)=[O:17])=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:19]2)=[O:17])=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)N2CCOC(c3ccccc3)C2)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(NCc2ccccc2)cc1)N1CCOC(c2ccccc2)C1
Temperature: 45 °C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
Benzaldehyde (0.1 ml, 1 mmol) was added to a stirred solution of (4-amino-phenyl)-(2-phenyl-morpholin-4-yl)-methanone (240 mg, 0.84 mmol) in dichloromethane (20 ml) and the resulting mixture was heated to 45° C. for 2 hours. The reaction mixture was cooled to room temperature then sodium triacetoxyborohydride (250 mg, 1.2 mmol) was added and the reaction was stirred at room temperature for 48 hours. The reaction was diluted with dichloromethane (10 ml) and quenched by the addition of water (10 ml). The aqueous was washed with dichloromethane (2×10 ml), the organics combined and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue purified by flash chromatography to afford the title compound as a colourless oil (0.22 g, 70% yield). HPLC retention time 6.18 min. Mass spectrum (ES+) m/z 373 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29](O)=[O:30])[C:22]3=[O:32])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:33])=[CH:7][CH:8]=2)[N:3]=1.[NH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29]([NH:34][C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)=[O:30])[C:22]3=[O:32])=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:33])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccncc1
Reactant: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC(=O)O)C3=O)CC2)c2ccc(Cl)cc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC(=O)Nc4ccncc4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described as example 208, (3S)-[[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-acetic acid, 4-aminopyridine, HATU, and diisopropylethylamine are reacted to afford the product. LC-MS: 551 (M++1). 1H NMR (CD3OD) δ 1.60–1.80 (m, 4H), 1.90 (m, 2H), 3.10 (m, 4H), 3.30 (m, 1H), 3.60 (m, 4H), 4.20 (m, 2H), 4.60 (d, 1H), 6.24 (s, 1H), 7.08 (d, 1H), 7.39 (s, 1H), 7.55 (m, 2H), 7.75 (d, 2H), 8.30 (m, 2H).
Reaction SMILES: [OH:1]O.[NH2:3][C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=[CH:6][C:5]=1[C:15]#[N:16]>C(O)C.N>[NH2:3][C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=[CH:6][C:5]=1[C:15]([NH2:16])=[O:1]
Reactant: OO
Reactant: N#Cc1cnn(C2CCCCC2)c1N
Agent: N
Solvent: CCO
Product: NC(=O)c1cnn(C2CCCCC2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18 ml of 30% strength hydrogen peroxide solution are added to a solution of 5-amino-1-cyclohexyl-1H-pyrazole-4-carbonitrile (1.86 g, 9.81 mmol) in a mixture of 73 ml of ethanol and 90 ml of concentrated aqueous ammonia solution at room temperature, and the mixture is stirred at room temperature for 1 h. The nonaqueous solvents are then stripped off in a rotary evaporator. The product precipitates as solids from the remaining mixture and is filtered off with suction, washed with a little water and dried under high vacuum.
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.[CH3:16]S(O)(=O)=O>CO>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:5][C:6]([O:8][CH3:16])=[O:7])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)O
Reactant: O=C(O)CC(c1ccc(O)cc1)C1CC1
Solvent: CO
Product: COC(=O)CC(c1ccc(O)cc1)C1CC1
Temperature: 65 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer and reflux condenser was charged with 5 mL of Methanol. To the stirred solvent was added 3-cyclopropyl-3-(4-hydroxyphenyl)propanoic acid (160 mg, 0.7759 mmol) followed by the addition of Methane sulfonic acid (74.56 mg, 0.7759 mmol). The resulting mixture was stirred at 65° C. for 2 h. After completion of the reaction (reaction monitored by TLC), solvent from the reaction mass was removed under reduced pressure and the resulting crude mass was taken in ethyl acetate (50 mL) and was washed with water (100 mL×3), sodium bicarbonate solution (100 mL×3), saturated brine solution (100 mL). Then the organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The product was obtained as brown syrup. yield: 98.0% (0.23 g, crude) (300 MHz, DMSO-d6): δ 9.16 (s, 1H), 7.01-7.04 (d, 2H), 6.64-6.67 (d, 2H), 3.49 (s, 3H), 2.63-2.68 (m, 2H), 2.14-2.22 (m, 1H), 0.93-0.97 (m, 1H), 0.45-0.49 (m, 1H), 0.26-0.33 (m, 1H), 0.13-0.17 (m, 1H), 0.04-0.07 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[Br:9][C:10]1[CH:11]=[C:12]([SH:19])[C:13](=[CH:17][CH:18]=1)[C:14](O)=[O:15]>N1C=CC=CC=1>[Br:9][C:10]1[CH:18]=[CH:17][C:13]2[C:14](=[O:15])[N:2]=[C:1]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[S:19][C:12]=2[CH:11]=1
Reactant: O=C(O)c1ccc(Br)cc1S
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2cc(Br)ccc12
Yield: 36.9 %

Procedure:
2-Cyanopyridine (0.29 g, 2.8 mmol) and 4-bromothiosalicylic acid (0.8 g, 3.4 mmol) were dissolved in pyridine (6 ml), and the mixture was refluxed for 8 hrs. The solvent was evaporated, and the residue was subjected to silica gel column chromatography. The fractions eluted with chloroform-ethyl acetate (5:1, v/v) were collected, concentrated and recrystallized from hexane-chloroform to give the titled compound (0.33 g, 36%) as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][CH:8]=[C:7]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[CH:6]=1)[CH3:3].CS[C:17]1[N:22]=[C:21]([OH:23])[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1>C(O)C>[N+:24]([C:20]1[C:21](=[O:23])[NH:22][C:17]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:7]2[CH:6]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:9][CH:8]=2)=[N:18][CH:19]=1)([O-:26])=[O:25]
Reactant: CSc1ncc([N+](=O)[O-])c(O)n1
Reactant: CN(C)Cc1cc(CSCCN)cs1
Solvent: CCO
Product: CN(C)Cc1cc(CSCCNc2ncc([N+](=O)[O-])c(=O)[nH]2)cs1
Yield: 63.5 %

Procedure:
A mixture containing 2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamine (2.88 g; 12.5 mmoles) and 2-methylthio-5-nitro-4-hydroxypyrimidine (2.33 g; 12.44 mmoles) in 10 ml of ethanol was heated at reflux temperature for 13 hours. The reaction mixture was evaporated under reduced pressure, and the residue was placed on 150 g of silica gel and chromatographed by flash chromatography using a gradient elution of methanol-methylene chloride. The appropriate fractions gave 2.92 g of product which was recrystallized from tetrahydrofuran to give the title compound, mp 150°-153° C.
Reaction SMILES: C([O:4][CH:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[CH:6]1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(=O)C.[Li+].[OH-]>C1COCC1.O>[OH:4][CH:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[CH:6]1[C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OC1NC(=O)C=C(c2cccc(C)c2)C1c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C2=CC(=O)NC(O)C2c2ccncc2)c1
Reaction time: 0.17 h

Procedure:
To a solution of 6-acetoxy-4-m-tolyl-5,6-dihydro-1H-[5,4′]bipyridinyl-2-one (200 mg, 0.6 mmole) in THF (2 mL) and water (2 mL) at r.t. was added LiOH (51 mg, 1.2 mmole) in one portion. The reaction mixture was stirred at that temperature for 10 min before quenching the mixture with aqueous NH4Cl. The reaction was quenched with 1.45 mL of 1N HCl the resulting white precipitate was filtered, rinsed with water and dried to give the title compound as a white solid.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[C@H:10]([CH2:11][C:12]([O:14]C)=[O:13])[CH2:9][C:8]2[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:19][C:7]=2[CH2:6][N:5]1[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.O>[O:3]=[C:4]1[C@H:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:9][C:8]2[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:19][C:7]=2[CH2:6][N:5]1[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)C[C@@H]1Cc2ccc(OCCCNc3ccccn3)cc2CN(CCc2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@@H]1Cc2ccc(OCCCNc3ccccn3)cc2CN(CCc2ccccc2)C1=O
Temperature: 25 °C
Yield: 48.5 %

Procedure:
1.0 N LiOH (0.3 mL, 0.3 mmole) was added to a solution of methyl (S)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (133 mg, 0.27 mmole) in THF (1.5 mL) and H2O (1.2 mL) at 0° C. The mixture was allowed to warm to RT over 18 hr. The mixture was washed with Et2O (2×5 mL) then a mild vacuum was applied to remove residual organic solvents. The aqueous layer was passed through a 0.45 μm Acrodisk filter, then was carefully acidified to pH 6 using 10% HCl in H2O at 0° C. The precipitate was collected, washed with H2O, and dried under vacuum at 50° C. to give the title compound as a white solid (62 mg, 48%): MS (ES) m/e 474 (M+H)+. Anal. Calcd for C28H31N3O4.0.75 H2O: C, 69.05; H, 6.75; N, 8.63. Found: C, 69.05; H, 6.66; N, 8.55.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:10][CH:9]2[CH2:11][CH:5]([CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8]2)[CH2:4]1.[ClH:19].C(OCC)(=O)C>CO>[ClH:19].[CH:9]12[CH2:11][CH:5]([CH2:4][CH:3]([CH2:2][OH:1])[CH2:10]1)[CH2:6][NH:7][CH2:8]2
Reactant: CC(C)(C)OC(=O)N1CC2CC(CO)CC(C2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: OCC1CC2CNCC(C1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-tert-butyl 7-hydroxymethyl-3-azabicyclo[3.3.1]nonane-3-carboxylate (7.78 g) in methanol (76 mL) was added 4M hydrogen chloride/ethyl acetate solution (76 mL). The reaction mixture was stirred at room temperature for 4 hr, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (50 mL), and Amberlyst A-21 was added. The mixture was stirred at room temperature for 20 min, and the solid was removed by filtration. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/ethyl acetate to give the title compound (5.22 g).
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:38])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:39][S:40](O)(=[O:42])=[O:41]>C(Cl)Cl>[C:1]1([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:38])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([S:40]([Cl:39])(=[O:42])=[O:41])=[CH:18][C:17]=2[O:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])=[O:25])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(COc1ccccc1OCC(=O)OCCS(=O)(=O)c1ccccc1)OCCS(=O)(=O)c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=C(COc1ccc(S(=O)(=O)Cl)cc1OCC(=O)OCCS(=O)(=O)c1ccccc1)OCCS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
To a solution of [2-(2-benzenesulfonyl-ethoxycarbonylmethoxy)phenoxy]acetic acid 2-benzenesulfonyl-ethyl ester (Intermediate 28, 7.4 g, 13.2 mmol) in 10 mL of CH2Cl2 was added drop-wise ClSO3H (5.0 mL, 8.8 g, 75.8 mmol, 5.7 eq) at 0° C. with vigorous stirring. The mixture was stirred at 0° C. for 1.5 h. and then poured onto crushed ice with vigorous stirring, resulting in a thick mass. This was extracted with CH2Cl2. The organic layers were dried and concentrated under reduced pressure. The residual oil was dried under vacuum overnight to give Intermediate 29 (8.0 g, 92%) as an off-white foam.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([CH3:41])[CH3:40]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:46][CH2:47][N:42]([CH:39]([CH3:41])[CH3:40])[CH2:43][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)N1CCNCC1
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)C)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-isopropyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H49N4O2Cl2 [(M+H)+] 663.3227, observed 663.3228.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].N.S(=O)(=O)(O)[OH:17]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:14])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnn(-c2ccccc2)c1N
Agent: N
Product: NC(=O)c1cnn(-c2ccccc2)c1N
Temperature: 0 °C

Procedure:
9 g of 5-amino-1-phenyl-4-pyrazolecarbonitrile were stirred at 10°-15° C. with 40 ml of concentrated sulphuric acid until all of the solid had dissolved. The mixture was poured on to 150 g of crushed ice and made basic with concentrated ammonia solution. The precipitated product was filtered off and purified by chromatography on silica gel using 5% methanol in ethyl acetate for the elution. There were obtained 5.8 g of 5-amino-1-phenyl-4-pyrazolecarboxamide. A sample recrystallized from water melted at 163°-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:21]#[C:22][Si](C(C)C)(C(C)C)C(C)C)[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].[F-].[Cs+]>CC#N.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6]
Reactant: COCCOCCOCCNC(=O)c1cc(N)cc(C#C[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CC#N
Product: C#Cc1cc(N)cc(C(=O)NCCOCCOCCOC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product from step (iii) above (1200 g, 2.59 mol) in MeCN (8.8 L) was added CsF (433.6 g, 2.85 mol). The reaction was stirred at RT overnight, after which HPLC analysis showed 1.7% product, 97.4% starting material. Additional CsF (420 g, 2.76 mol) was charged and the reaction stirred at RT overnight, whereupon HPLC analysis revealed 91.0% product, 4.4% starting material. The mixture was filtered and the filtrate concentrated in vacuo to give material which was 92.5% product, 0.7% starting material by HPLC. The residue was dissolved in DCM (3 L) and EtOAc (3 L), before being split into two equal portions. Each portion was passed through a silica pad (1.6 kg), eluting with EtOAc (50 L). The filtrates were combined and concentrated in vacuo. The crude material was washed with heptane (2×4 L) to remove silyl impurities. A total of 719 g of sub-title compound was isolated (83% assay by 1H NMR, 75% active yield, 597 g active).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12]([O:17][C@@H:18]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]3[OH:20])=[N:13][NH:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1)[CH3:2].[C:29](O)(=[O:31])[CH3:30].C(OC(=O)C)(=O)C>O1CCCC1>[C:29]([N:14]1[C:15]([CH3:16])=[C:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([S:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:12]([O:17][C@@H:18]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]2[OH:20])=[N:13]1)(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(C(C)=O)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[(4-ethylthiophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole (0.41 g) in tetrahydrofuran (10 mL) were added acetic acid (0.11 mL) and acetic anhydride (0.18 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. The resulting precipitated crystal was collected by filtration to give 1-acetyl-4-[(4-ethylthiophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methylpyrazole (0.36 g).