Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([OH:12])=O)[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH2:18][CH2:17]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[O:12])[CH:3]=1
Reactant: COc1cc(Cl)cc(C(=O)O)n1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1

Procedure:
0.55 g (2.9 mmol) 4-chloro-6-methoxy-pyridine-2-carboxylic acid, 0.41 g (3.0 mmol) 5-fluoroindoline, 1.1 g (3.3 mmol) TBTU and 0.93 mL (6.6 mmol) triethylamine in 5.0 mL DMF were stirred for 3 h at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and evaporated down using the rotary evaporator.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=3)=[CH:14][C:13]([C:25]([O:27]CC)=[O:26])=[N:12]2)[CH:8]=[CH:9][CH:10]=1.Cl>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=3)=[CH:14][C:13]([C:25]([OH:27])=[O:26])=[N:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)n(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.0 ml of water and 453 mg (18.9 mmol) of lithium hydroxide are added to 700 mg (1.89 mmol) of the carboxylic ester of Example 130A in 60.0 ml of THF. The mixture is stirred at RT overnight and a 1N aqueous hydrogen chloride solution is subsequently added to the reaction solution. The mixture is extracted with dichloromethane, and the combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 712 mg (89% of theory) of the title compound are obtained in 81% purity.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:8](=[O:10])[CH3:9])[S:6][CH:7]=1.[C:11]([OH:14])(=[O:13])[CH3:12].C([O-])(=O)C.[K+]>C(OCC)(=O)C>[C:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][O:14][C:11](=[O:13])[CH3:12])[N:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)O
Reactant: CC(=O)c1nc(CBr)cs1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1csc(C(C)=O)n1
Yield: 70 %

Procedure:
Bromide 3a (4.95 g, 0.0224 mol) was heated with acetic acid (50 mL) and potassium acetate (2.64 g, 0.0269 mol) at 100° C. for 16 h. Diluted with ethyl acetate and washed with water 3 times. The organic layer was dried (Na2SO4) and concentrated in vacuo to give a crude oil that was subjected to flash chromatography (20% ethyl acetate/80% hexanes) to give 2.48 g (70%) of the desired product 4a. 1H NMR (CDCl3) δ 7.8 (s, 1H), 5.2 (s, 2H), 2.8 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[NH2:3].[C:20](Cl)(Cl)=[S:21].C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[S:21])[NH:3]1
Reactant: CN(N)C(=O)Nc1ccccc1Oc1ccccc1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1[nH]c(=S)n(-c2ccccc2Oc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.54 g of 1-methyl-N-(2-phenoxyphenyl)hydrazinecarboxamide in 50 mL of tetrahydrofuran, cooled in an ice bath, was treated with 0.46 mL of thiophosgene, and then 1.68 mL of triethylamine. A precipitate formed and the mixture was stirred at ambient temperature overnight. The precipitate was removed by filtration and washed with tetrahydrofuran. The combined filtrate and washings were concentrated under reduced pressure to afford 1.8 g of an amber glassy oil. The crude material was used in the next step without further purification. 1H NMR (CDCl3): δ6.8-7.4 (m, 9H), 3.57 (s,3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H][H].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17]Br)[CH3:14]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])=[CH:6][CH:5]=1
Reactant: CCOC(CBr)OCC
Reactant: [H][H]
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(Cl)cc1)OCC
Temperature: 120 °C
Yield: 78.6 %

Procedure:
To a suspension of sodium hydride (11.24 g, 281 mmol) in anhydrous N,N-dimethylformamide (500 mL) was added 4-chlorophenol (30 g, 234 mmol) at 0° C. After hydrogen evolution had ceased, bromo-acetaldehyde diethyl acetal (55 g, 281 mmol) was added. The reaction was heated at 120° C. overnight. The mixture was poured into ice-water, extracted with ethyl acetate (3×150 ml), washed with 1N sodium hydroxide (3×100 ml), and brine (3×100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. The residue was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford 1-chloro-4-(2,2-diethoxyethoxy)benzene as oil (45 g, 75%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[S:11][C:10]2[CH:12]=C(C#N)[CH:14]=[CH:15][C:9]=2[C:8]=1[CH3:18].[OH-:19].[Na+].[CH2:21]([OH:23])[CH3:22]>O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[S:11][C:10]2[CH:12]=[C:22]([C:21]([OH:19])=[O:23])[CH:14]=[CH:15][C:9]=2[C:8]=1[CH3:18]
Reactant: Cc1c(Cc2ncc[nH]2)sc2cc(C#N)ccc12
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: Cc1c(Cc2ncc[nH]2)sc2cc(C(=O)O)ccc12

Procedure:
A mixture of 2-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-6-carbonitrile (0.40 g), sodium hydroxide (0.20 g), ethanol (2 ml) and water (20 ml) was heated under reflux for 24 hours. The solution was evaporated and the residue was dissolved in water and the solution was acidified with acetic acid. The solid was filtered off and purified by redissolving in dilute sodium hydroxide solution, filtering and acidifying the filtrate with acetic acid. The solid was filtered off, washed with water and dried to give 2-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-6-carboxylic acid (0.35 g), m.p. 254°-255°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[N:9]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=2)[CH2:8][C:7]1=[O:23].[CH3:30][S:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][OH:37])=[CH:34][CH:33]=1>C(Cl)Cl>[CH3:30][S:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][O:37][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([CH2:13][N:9]3[CH2:8][C:7](=[O:23])[N:6]([CH2:5][C:4]4[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=4[O:2][CH3:1])[S:10]3(=[O:12])=[O:11])=[CH:15][CH:16]=2)=[CH:34][CH:33]=1
Reactant: CSc1ccc(CO)cc1
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)Cl)cc3)S2(=O)=O)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)OCc4ccc(SC)cc4)cc3)S2(=O)=O)c(OC)c1

Procedure:
400 mg (911 μmol) of the title B compound, 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoyl chloride, 140 μL (1.0 mmol) of TEA and 141 mg (914 μmol) of 4-(methylthio)benzyl alcohol in 10 mL of CH2Cl2 are stirred at RT for 18 h. The solvent is removed under reduced pressure and the residue is chromatographed on a Biotage 40M column with 98/2 —CH2Cl2/EtOAc to give 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid 4-methylsulfanyl-benzyl ester: [M+NH4]+=574.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:18]1([CH:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[NH2:22])[CH2:20][CH2:19]1>>[CH:18]1([CH:21]([NH:22][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:19][CH2:20]1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(N)C2CC2)no1
Product: Cc1nc(C(NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and α-cyclopropyl-5-methyl-1,2,4-oxadiazole-3-methanamine (CAN 1291557-80-6) as starting materials, and isolated (95 mg, 86%) as light yellow solid; LC-MS (UV peak area, ESI) 100%, 370.1876 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[F:14])[CH3:5].CS(O[CH:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)(=O)=O.O>CN(C=O)C>[CH3:5][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:20]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]2)=[CH:9][C:8]=1[F:14])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: CN(C)Cc1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(OC2CN(C(=O)OC(C)(C)C)C2)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.31 g, 7.7 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 26A (1.0 g, 5.9 mmol) in DMF (10 mL) was added drop-wise over 10 minutes. The mixture was stirred for 30 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.63 g, 6.5 mmol) in DMF (10 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (100 mL) was added and the mixture was extracted three times with EtOAc (50 mL). The combined organic phases were filtered through a phase separator and the solvent was removed by evaporation. The residue was purified by preparative chromatography on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-50% acetonitrile in water/acetonitrile/formic acid (95/5/0.2), 100 mL/min. Fractions were collected, pooled and concentrated in vacuo. DCM was added and the solution was filtered through a phase separator and concentrated by evaporation. There was obtained 1.2 g (55%) of 26B as a solid. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.58 (s, 6H), 3.90 (s, 2H), 3.95-4.05 (m, 2H), 4.25-4.35 (m, 2H), 4.81-4.92 (m, 1H), 6.45-6.65 (m, 2H), 7.35-7.45 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[OH:9])C=C.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18].O>CC1OCCC1>[C:17]([O:9][CH:5]1[CH2:6][CH:7]1[CH2:8][CH:4]=[CH2:1])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: C=CCC1CCCC1O
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCC1CC1OC(C)=O
Temperature: 0 °C

Procedure:
Into a reaction vessel was added 2-allylcyclopentanol M (1 equivalent) in MeTHF (10 volumes). The vessel was purged with nitrogen and the solution was then cooled to 0° C. Triethylamine (3.0 equivalents) was then slowly added to the solution over about 30 minutes. The mixture was allowed to stir for about 30 minutes after which acetyl chloride (2.5 equivalents) was added maintaining the internal temperature about below 20° C. The reaction was then allowed to stir for at least 12 hours at about 21° C. After the allotted time, water (6 volumes) was slowly charged to the reactor and the phases were separated. The organic layer was then washed with 2M hydrochloric acid (6 volumes), 10 wt. % sodium bicarbonate (6 volumes) and then brine (6 volumes). The organic layer is concentrated under reduced pressure at about 0° C. to obtain crude racemic 2-allylcyclopropyl acetate N. 1H NMR (400 MHz, CDCl3): δ 5.85-5.73 (m, 1H), 5.10-5.04 (m, 1H), 5.00-4.97 (m, 1H), 3.85-3.82 (m, 1H), 2.13-2.07 (m, 1H), 1.99 (s, 3H), 2.01-1.89 (m, 1H), 1.14-1.03 (m, 1H), 0.87-0.76 (m, 1H), 0.64-0.57 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([OH:17])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:16][CH:15]([OH:17])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CC(O)C5)sc34)ccc12

Procedure:
This material was prepared by the reaction of (7-chloro-thieno [3,2-b]pyridin-2-yl)-(3-hydroxy-azetidin-1-yl)-methanone 9d with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ8.41 (1H, d, J=5.5 Hz), 7.78-7.74 (2H, m), 7.29 (1H, d, J=2.1 Hz), 6.95 (1H, dd, J=2.1, 8.6 Hz), 6.62 (1H, d, J=5.5 Hz), 4.76-4.73 (2H, m), 4.63 (1H, bs), 4.35-4.32 (2H, m), 3.97-3.94 (1H, m), 3.62 (3H, s), 2.89 (3H, s), 2.57 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 451, found 451.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[OH-].[NH4+:15]>>[NH2:15][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: [NH4+]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: [OH-]
Product: NS(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
To ice-cold solution of ammonium hydroxide (25%, 250 ml) is added 3-(chlorosulfonyl)benzoic acid (25 g, commercially available, Aldrich) portionwise and the mixture is stirred at room temperature for 15 h. The solvent is removed under vacuum to about 50 ml and the mixture is acidified with conc. HCl. The precipitate is collected by filtration and dried under vacuum to afford 22 g (96%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 13.44 (br s, 1H), 8.38 (s, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.49 (s, 2H), HPLC (max plot) 97%; Rt 0.68 min. LC/MS: (ES−): 199.8.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([N:15](CC)CC)C.[CH3:20][C:21]([CH3:32])([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[CH2:22]N>C1C=CC=CC=1>[Cl:1][C:2]1[N:11]=[C:10]([CH2:32][C:21]([CH3:22])([CH3:20])[O:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH2:15])[N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(OC(C)(C)CN)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: c1ccccc1
Product: Cc1ccc(OC(C)(C)Cc2nc(Cl)nc3cccc(N)c23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
To a solution of 2.0 g (0.01 mol) of 2,4-dichloroquinazoline in 50 ml of benzene were added 1.0 g (0.01 mol) of triethylamine and 1.8 g (0.01 mol) of 2,2-dimethyl-2-(4-methylphenoxy)-ethylamine and the mixture was stirred at an ambient temperature for 4 hours. After completion of the reaction, the benzene was evaporated under reduced pressure, and the residue was dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate. The chloroform was removed by evaporation under reduced pressure to leave crystals, which were recrystallized from benzene/hexane, affording 2.3 g of 2-chloro-4-[2,2-dimethyl-2-(4-methylphenoxy)ethyl]-aminoquinazoline in the form of a colorless fine powder.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]([OH:10])=[N:2]1.[CH2:11]([Br:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)=O>CN1C(=O)CCC1>[Br-:18].[CH2:11]([N+:7]1[CH:6]=[C:5]2[O:1][N:2]=[C:3]([OH:10])[C:4]2=[CH:9][CH:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Oc1noc2cnccc12
Solvent: CN1CCCC1=O
Solvent: CC(C)=O
Product: Oc1noc2c[n+](Cc3ccccc3)ccc12
Product: [Br-]
Reaction time: 24 h
Yield: 83.5 %

Procedure:
To a stirred solution of isoxazolo[5,4-c]pyridin-3-ol (50.0 g, 367 mmol) in NMP (100 ml) was added benzyl bromide (75.4 g, 441 mmol) dropwise rapidly. The thick solution was stirred for 24 h. The mixture was then added slowly to acetone (1.5 L) with stirring, and the solution was seeded. Stirring was continued at room temperature for 30 min, and then for a further 1 h in an ice/water bath. The mixture was filtered, the residue was washed with acetone and then dried under vacuum to give 6-benzyl-3-hydroxy-isoxazolo[5,4-c]pyridin-6-ium bromide (94.1 g, 83%; HPLC: 91% pure) as a white crystalline solid.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.O.[OH-].[Na+]>CO>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)(=[O:19])=[O:20])=[CH:16][CH:17]=2)[C:4]([OH:28])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)O)cc2)CC1

Procedure:
A solution of the title D compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester (14 g, 0.034 mol) in methanol:water (30 mL:10 mL) and sodium hydroxide (4.11 g, 0.10 mol) is stirred at 60° C. for 8 h in an oil bath. The methanol is then removed in vacuo at 45-50° C. The residue is diluted with water (25 mL) and extracted with ether (1×40 mL). The aqueous layer is acidified to pH 5 with 3 N aqueous hydrochloric acid solution. The precipitated solid is collected by vacuum filtration, washed with water (20 mL), followed by isopropyl alcohol (20 mL). Finally, solid cake is washed with 100 mL of hexane and dried under vacuum at 40° C. for 6 h to give 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.1-2.0 (m, 11H), 2.4 (s, 3H), 2.7 (br s, 4H), 3.1 (br s, 4H), 3.6 (m, 1H), 7.5 (d, J=8.3, 2H), 7.6 (d, J=8.3, 2H); MS 381 [M+l]+.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1>C(O)C>[CH3:1][S:2][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [Na+]
Solvent: CCO
Product: CSCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
Sodium methanethiolate (13.5 g; 192 mmol) was added in two portions to a stirred solution of 1-(chloromethyl)-3-nitrobenzene (30.0 g; 175 mmol; Aldrich Chemical Company Inc.) in ethanol (360 mL) at −15° C. The cold bath was removed and the batch was stirred at room temperature for 3 hours. The batch was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2×). The combined organic phases were washed with water, dried (sodium sulfate), filtered and concentrated to give the desired product (32.2 g) that was used without further purification.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][C:19]=1[F:28]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:26])=[CH:20][C:19]=1[F:28]
Reactant: O=C(Cl)Cc1ccc(Cl)c(F)c1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)c(F)c1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 11B and 2-(4-chloro-3-fluorophenyl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.92-11.95 (bs, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.11-8.17 (m, 1H), 7.99-8.08 (m, 2H), 7.58 (t, J=8.1 Hz, 1H), 7.43 (dd, J=10.5, 1.9 Hz, 1H), 7.25 (dd, J=8.3, 1.9 Hz, 1H), 3.79 (s, 2H); MS (ESI) m/z 400 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:35]1[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4ccc(Cl)cc4nc3OC)CC2)cc(OC)c1OC
Yield: 83 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 83%). 1H NMR (300 MHz, CDCl3): 3.24 (s, 4H), 3.81-3.86 (m, 12H), 4.15 (s, 3H), 6.21 (s, 2H), 7.36-7.45 (m, 1H), 7.27 (s, 1H), 7.36-7.45 (m, 1H), 7.64-7.75 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:21]=[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[N:11]3[N:10]=2)=[CH:5][CH:4]=1.[OH2:22].[OH-].[Na+].Cl>CO>[C:19]([C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:12]1[CH:21]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:10][N:11]=1)([OH:22])=[O:20]
Reactant: O
Reactant: COc1ccc(-c2cc3n(n2)C(=O)c2ccccc2-3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2cc(-c3ccccc3C(=O)O)n[nH]2)cc1
Reaction time: 0.08 h

Procedure:
A mixture of 2 -(4-methoxyphenyl)-8H-pyrazolo[5,1-a]isoindol-8-one (100 mg), water (5 ml) and methanol (5ml) was stirred for one hour with sodium hydroxide (0.5 g). Within 5 minutes, a colorless solution has been produced. The mixture was then acidified to pH 3 with concentrated hydrochloric acid, cooled to 0° and filtered. The colorless crystalline residue was rinsed with water and air-dried. It was recrystallized from 33% aqueous ethanol (15 ml), recovery 80.7 mg (79%) of colorless crystals, mp 223°-225° dec, of 3-(2-carboxyphenyl)-5-(4-methoxyphenyl)pyrazole.
Reaction SMILES: [CH2:1](Br)/[CH:2]=[C:3](\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])/[CH3:4].OC/C=C(/C)\CCC=C(C)C.[CH2:23]([O:25][CH:26]([O:35][CH2:36][CH3:37])[C:27](=[O:34])[CH2:28]C(OCC)=O)[CH3:24]>>[CH2:23]([O:25][CH:26]([O:35][CH2:36][CH3:37])[C:27](=[O:34])[CH2:28][CH2:1]/[CH:2]=[C:3](/[CH3:4])\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:24]
Reactant: CC(C)=CCC/C(C)=C\CBr
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Agent: CC(C)=CCC/C(C)=C\CO
Product: CCOC(OCC)C(=O)CC/C=C(/C)CCC=C(C)C

Procedure:
Reaction of neryl bromide which had been prepared from 31 g of nerol with 41.5 g of ethyl 4,4-diethoxyacetoacetate was carried out in the same manner as in Referential example 1 to yield 20 g of the desired product, b.p. 122° C./0.02 mmHg.
Reaction SMILES: [OH-].[K+].[C:3](=[N:16][OH:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[C@H:23]1[CH2:27][CH2:26][N:25](OC(C)(C)C)[C:24]1=C=O)(=O)=O.O>CS(C)=O>[NH:25]1[CH2:26][CH2:27][C@@H:23]([O:17][N:16]=[C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:24]1
Reactant: ON=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)ON1CC[C@H](OS(C)(=O)=O)C1=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(C(=NO[C@@H]2CCNC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of KOH powder (4.86 g) in DMSO (250 ml) under vigorous stirring, benzophenone oxime (7.86 g) was added. After stirring at RT for 30 min, a solution of N-tert-butoxy-carbonyl-3-(S)-pyrrolidinyl methanesulfonate (10.0 g) in DMSO (70 ml) was added. After 18 h at RT the reaction was poured into iced water (900 ml) and extracted with Et2O. The combined organic layers were washed with water, brine, dried and the solvent was evaporated. Benzophenone O-[(R)-3-pyrrolidinyl]oxime was obtained (13.0 g, 96%) as a white solid and used without any further purification in the next step.