Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:17]([C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].Cl>N1C=CC=CC=1>[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH:16][S:26]([C:24]3[S:25][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=3)(=[O:27])=[O:28])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)s1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.43 g of 5-tert-butyl-thiophene-2-sulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted three times with 30 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. The residue was chromatographed on 50 g of Kieselgel 60 with ethyl acetate/hexane (1:2) as the eluent. The product-containing fractions were concentrated and the residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.20 g of 5-tert-butyl-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide separated as yellowish crystals after neutralization with concentrated hydrochloric acid and repeated boiling.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](/[C:21]([OH:23])=[O:22])\[CH3:20])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]([CH3:29])[NH:8][C:7]=1[CH3:30])=[O:5])[CH3:2].[CH2:31](Br)[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](\[CH3:20])/[C:21]([O:23][CH2:31][CH3:32])=[O:22])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]([CH3:29])[NH:8][C:7]=1[CH3:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1/C=C(\C)C(=O)O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1/C=C(\C)C(=O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
A suspension of Compound A (4 g), ethyl bromide (1 g) and potassium carbonate (30 g) in dimethylformamide (60 ml) was stirred at room temperature for 6 h. The mixture was poured into water and extracted with ethyl acetate, then washed thoroughly with water and dried over Na2SO4. Evaporation of the solvent gave an oil which was triturated with petrol and recrystallized from petrol ether to give the title compound as a white solid (3.2 g). M.p. 105°-106°.
Reaction SMILES: [CH2:1]([N:8]([C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C=O)C>[CH2:1]([N:8]([C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[O:26][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1OCC(=O)OC(C)(C)C
Temperature: 75 °C

Procedure:
A solution of Example 20C (300 mg, 0.68 mmol) in DMF (5.0 mL) was treated with K2CO3 (189 mg, 1.36 mmol) and t-butyl bromoacetate (121 μL, 0.82 mmol), heated at 75° C. for 1.5 hours, quenched with water, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel 4:1 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]=[S:27]>CS(C)=O.O>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:28](=[O:29])[O:30][CH2:31][CH3:32])=[S:27])=[N:7][CH:6]=2)=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)n(C)n1
Reactant: CCOC(=O)N=C=S
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cc(C)nn3C)c2)cn1
Reaction time: 15 h
Yield: 103.6 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (184 mg, 0.569 mmol) in DMSO (4 mL) was added ethyl isothiocyanatoformate (89.6 mg, 0.682 mmol), and the mixture was stirred for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (268 mg, 99%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:19][C@H:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[CH3:21])=[O:18])[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:19][C@H:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[CH3:21])=[O:18])[CH2:10][CH2:9][CH2:8]2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3c2N(Cc2ccc(Cl)cc2)CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1cccc2c1N(Cc1ccc(Cl)cc1)CCC2)c1ccc(C(=O)O)cc1
Reaction time: 48 h
Yield: 143.4 %

Procedure:
To a solution of methyl 4-[(1S)-1-({[1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-yl]carbonyl}amino)ethyl]benzoate (129 mg) in THF (2.0 mL) and methanol (1.0 mL) was added a 1 M aqueous sodium hydroxide solution (1.0 mL) at room temperature, followed by stirring for 2 days. The reaction mixture was neutralized by adding 1 M hydrochloric acid (1.0 mL) at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate). The resulting product was dissolved in ethyl acetate (2.0 mL), and to the solution was added a 4 M hydrogen chloride ethyl acetate solution (2.0 mL) at room temperature, followed by stirring for 1 day. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate, collected by filtration, and dried under reduced pressure to obtain 4-[(1S)-1-({[1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-yl]carbonyl}amino)ethyl]benzoic acid hydrochloride (97 mg).
Reaction SMILES: O[Li].O.[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[C:10]2[CH:17]=[C:16]([C:18]([O:20]CC)=[O:19])[NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.Cl>O.CO>[C:18]([C:16]1[NH:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:7]3[CH:23]=[CH:24][CH:25]=[C:5]([Cl:4])[CH:6]=3)[C:10]=2[CH:17]=1)([OH:20])=[O:19]
Reactant: CCOC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reaction time: 4.5 h

Procedure:
A solution of 25 mg (0.6 mmol) of LiOH.H2O in 0.4 ml of H2O is added dropwise to a suspension of 95 mg (0.30 mmol) of 4-(3-chloro-anilino)-6-ethoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine in 0.7 ml of methanol. The reaction mixture is heated at boiling for 4.5 hours, then cooled in an ice-bath and acidified with 0.6 ml of 1 N HCl solution. Filtering and washing with water yield the title compound; HPLC: tRet (Grad20)=8.7; FAB-MS: (M+H)+ =289.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:11])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: CCC(O)c1ccnc(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)c1ccnc(Br)c1
Reaction time: 30 h

Procedure:
To a solution of 1-(2-bromo-pyridin-4-yl)-propan-1-ol (2.20 g 10.2 mmol) in dichloromethane (55 mL) was added Dess-Martin periodinane (5.6 g, 13 mmol). After 30 hours, and was diluted with saturated aqueous sodium carbonate (40 mL) and partially concentrated to remove the dichloromethane. The crude material was filtered through diatomaceous earth and washed with EtOAc (100 mL). The aqueous layer was separated and extracted with EtOAc (40 mL). The combined organic layers were washed with saturated aqueous sodium carbonate (40 mL) and brine (40 mL). The material was dried over magnesium sulfate, filtered and concentrated to afford 1-(2-bromo-pyridin-4-yl)-propan-1-one as a clear oil which was used without further purification.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:30]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:29])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:28])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21]C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[N:6]=1.[C:38]1(B2OC(C)(C)C(C)(C)O2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=1>>[NH2:30][C:4]1[S:3][C:2]([C:38]2=[CH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:28])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH2:21])[CH2:16][CH2:15]1)=[O:29]
Reactant: CC1(C)OB(C2=CCCCCC2)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Product: Cn1ncc(NC(=O)c2nc(C3=CCCCCC3)sc2N)c1N1CCC[C@@H](N)CC1
Yield: 14 %

Procedure:
Following the procedure for Example 350 starting with (R)-tert-butyl 2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate and 1-cycloheptenylboronic acid pinacol ester gave 339 as an orange solid (7.0 mg, 14%). 1H NMR (400 MHz, d4-MeOD) δ 7.57 (s, 1H), 6.46 (t, J=6.7 Hz, 1H), 3.74 (s, 3H), 3.31-3.22 (m, 4H), 3.14-3.06 (m, 1H), 2.88-2.82 (m, 2H), 2.39-2.32 (m, 2H), 2.05-1.56 (m, 12H). LCMS (ES+) m/z 430 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:28].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:24]=[CH:23][C:22]([C:25]([OH:28])=[O:26])=[CH:21][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formyl-N-3-pyridinylbenzamide (may be prepared as described in Example 82; 100 mg, 0.29 mmol) in acetone (10 ml) was added potassium permanganate (67.7 mg, 0.43 mmol) as a solution in 10 ml of water. The mixture was stirred at room temperature overnight. The mixture was quenched by adding 10 ml of 5% sodium sulfite solution. The solution was filtered through celite and mixed with 1 ml of acetic acid. The mixture was evaporated to a third volume, water (20 ml) was added and the mixture was filtered to yield the title compound as a white solid. This contains about 10% starting material and was used directly without further purification. 63 mg.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:20]2[C:11](=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>C(OCC)C.O1CCCC1>[F:31][C:7]1[C:20]2[C:11](=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=1
Reactant: Brc1cccc2cc3ccccc3cc12
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1cccc2cc3ccccc3cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
1.2 millimoles n-butyl lithium were dropped into a solution of 1 millimole bromoanthracene in 5 milliliters diethyl ether at 5° C. The solution was cooled to 0° C, was stirred for 1 hour, and then was cooled further to -78° C.; 1.2 millimoles N-fluorobenzenesulfonimide prepared according to Example 1 above in 5 milliliters tetrahydrofuran were dropped into the mixture which was stirred for 1 hour. The temperature was allowed to rise to 20° C. while stirring was continued. The reaction mixture was quenched by pouring into saturated ammonium chloride solution and extracted with diethyl ether. Fluoroanthracene was obtained in 76% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:23]=2[O:22][CH2:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29]([C:27]1[CH:26]=[CH:25][C:24]2[O:20][CH2:21][O:22][C:23]=2[CH:28]=1)=[O:30]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)OCO2

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with benzo[1,3]-dioxole-5-carboxylic acid. MS: 408.4 (M+H).
Reaction SMILES: [H-].[Na+].[P:3]([O-:20])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27]Br)[CH3:22]>CN(C=O)C>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][P:3]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:20])[CH3:22]
Reactant: CCOC(=O)CCCBr
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCP(=O)(OCc1ccccc1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60%, 2.52 g, 63 mmol) in DMF (60 mL) was added dibenzyl phosphite (12 mL, 48.45 mmol). After 15 minutes of stirring, ethyl-4-bromobutyrate was added and the mixture was stirred for 48 h at room temperature. The DMF was removed by evaporation. The residue was partitioned between brine, ammonium chloride and ether. The water phase was extracted several times with ether. The recombined organic layer was extracted with brine, dried over sodium sulfate, filtered and evaporated. The residue was flashed using 50% ethyl acetate in hexanes to afford the product as a colorless oil. 1H-NMR(CDCl3, 400 MH: 1.23(t, J=7.2 Hz, 3H); 1.77–2.04(m, 4H); 2.37(m, 2H); 4.10(q, J=7.2 Hz, 2H), 5.03(m, 4H); 7.31(m, 10H). 31P-NMR(CDCl3, 400 MHz): 32.78.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][S+:9]([O-:19])[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:18]=2)=[N:6][CH:5]=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25].[OH-].[Na+:27].C>C1COCC1>[CH3:1][C:2]1[C:7]([CH2:8][S+:9]([O-:19])[C:10]2[N-:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:18]=2)=[N:6][CH:5]=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25].[Na+:27]
Reactant: COCCCOc1ccnc(C[S+]([O-])c2nc3ccccc3[nH]2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCCOc1ccnc(C[S+]([O-])c2nc3ccccc3[n-]2)c1C
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
Rabeprazole (10 g) was suspended in 30 ml THF and added sodium hydroxide solution (1.11 g sodium hydroxide dissolved in 1 ml water) at 25-30° C. Reaction mass was stirred for 30 minutes at 25-30° C. Added activated charcoal (1.0 g) and stirred for 30 minutes at 25-30° C. Filter and washed charcoal bed with THF (20 ml). Distilled out THF under reduced pressure at 30-35° C. completely. Dissolved residue in THF (20 ml). In a separate R B flask charged diisopropyl ether (100 ml) at 25° C. Added slowly above reaction mass in 15-20 minutes at 25-30° C. Stirred at 25-30° C. for 2 hours. The product was filtered off under nitrogen atmosphere and wet cake was washed with diisopropyl ether (2×20 ml). Dried under vacuum at 50° C. for 20-24 hours to obtain amorphous Rabeprazole sodium.
Reaction SMILES: CO.[OH:3][C:4]1[CH:27]=[C:26]([O:28]COC)[CH:25]=[C:24]([O:32]COC)[C:5]=1[C:6](=[O:23])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]COC)=[C:11]([O:19]COC)[CH:10]=1.Cl.CO>O>[OH:3][C:4]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([OH:32])[C:5]=1[C:6](=[O:23])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:19])[CH:10]=1
Reactant: COCOc1cc(O)c(C(=O)C=Cc2ccc(OCOC)c(OCOC)c2)c(OCOC)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C(C=Cc1ccc(O)c(O)c1)c1c(O)cc(O)cc1O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 32.9 %

Procedure:
Then, 20 ml of methanol was added to 5.19 g of the so-obtained 2'-hydroxy-3,4,4',6'-tetrakis(methoxymethoxy)chalcone, and 40 ml of a hydrochloric acid/methanol reagent was added to the formed suspension and the mixture was stirred at 60° C. for 15 minutes. After the reaction, the reaction liquid was poured into water, and the precipitated crystal was recovered by filtration, washed with water and dried to obtain 2.81 g (yield=87.2%) of a crude crystal. The crude crystal was subjected to the column chromatography (200 g of 240-400 mesh Kieselgel 60; 0.3 kg/cm2 : eluting solvent: hexane/ethyl acetate=2/1, 2700 ml, hexane/ethyl acetate=1/1). Fractions of 50 ml were collected and the 92nd to 149th fractions were combined and concentrated to dryness to obtain 1.06 g (yield=32.9%) of 2',3,4,4',6'-pentahydroxychalcone.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[S:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:10]I>[H-].[Na+]>[CH3:10][S:9][C:3]1[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[N:4]=1
Reactant: O=c1[nH]cc(Cl)c(=S)[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CSc1nc(=O)[nH]cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
5-Chloro-4-thiouracil (0.0027 mol) was dissolved in 1 M sodium hydride (3 ml) and methyl iodide (0.007 mol) added. The solution was stirred at room temperature for 3 hr. and the solid precipitate collected and recrystallised from water; yield 21%, m.p. 254° C.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7]>O.CC#N>[C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#CCC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 118.6 %

Procedure:
To a solution of 105 mg (1.6 mmol) of KCN in 1 mL of water, 220 mg (0.8 mmol) of 2-bromo-4′-phenylacetophenone in 3 mL of MeCN was added. The mixture was warmed in a 50° C. bath to dissolve some of the halide. After ˜20 min the solids dissolved. The reaction was stirred for 30 min, then partitioned between 1.2 N HCl and EtOAc. The organic layer was washed with brine, dried and concentrated leaving 210 mg of the title compound which was used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([F:9])[CH:3]=1.[Li]CCCC.CN(C)[C:17](=[O:19])[CH3:18].[Cl-].[NH4+]>C(OCC)C>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([F:9])[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)N(C)C
Reactant: Fc1cc(Br)ccc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-bromo-4-chloro-3-fluorobenzene (2.09 g, 10 mmol) in dry diethyl ether (12.0 ml) was added a solution of n-BuLi (1.55M in hexane, 6.77ml, 10.5 mmol) at −78° C. under nitrogen atmosphere. The mixture was allowed to warm to −20_C stirred for 45 min. A solution of N,N-dimethylacetamide (1.04 ml, 11.2 mmol) in diethyl ether (1.5 ml) was added and the mixture stirred for an additional 1 h. The mixture was then allowed to warm to room temperature. After stirring for 3 h, the reaction mixture was poured into saturated aqueous ammonium chloride (20 ml) and extracted with diethyl ether (30 ml×3). The combined organic layers were washed with 2N aqueous HCl (20 ml), saturated aqueous sodium bicarbonate (20 ml), brine (20 ml), and dried (MgSO4). Removal of solvent gave the title compound as a yellow oil (quant.).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:22])=[CH:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=1)=O.CO.[NH3:25]>>[Cl:22][C:8]1[N:7]=[N:6][C:5]([C:3]([NH2:25])=[O:2])=[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[CH:9]=1
Reactant: COC(=O)c1nnc(Cl)cc1Nc1ccc(OC)c(OC)n1
Reactant: N
Solvent: CO
Product: COc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
6-Chloro-4-(5,6-dimethoxy-pyridin-2-ylamino)-pyridazine-3-carboxylic acid methyl ester (1.7 g, 5.2 mmol) was suspended in ammonia in methanol (7N, 30.0 mL, 210 mmol) and the flask sealed. After stirring for 6 h at room temperature the mixture was concentrated in vacuo to give 6-chloro-4-(5,6-dimethoxy-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (1.55 g, 96%) as a yellow powder. LC-MS: 310.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:4]=2[N:3]=1.[Br-].[CH:19]1([CH2:22][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][CH2:16][C:14]2[CH:13]=[CH:12][C:5]3=[C:6]4[C:11](=[C:2]([NH2:1])[N:3]=[C:4]3[CH:15]=2)[N:10]=[CH:9][CH:8]=[CH:7]4)[CH2:21][CH2:20]1
Reactant: Nc1nc2cc(C=O)ccc2c2cccnc12
Reactant: c1ccc([P+](CC2CC2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: Nc1nc2cc(CCC3CC3)ccc2c2cccnc12

Procedure:
8-(2-Cyclopropylethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 87) with (cyclopropylmethyl)triphenylphosphonium bromide following the procedures described for Example 91 (wittig reaction) and Example 92 (reduction). 1H NMR (acetone-d6): δ 8.99 (dd, 1H), 8.88 (dd, 1H), 8.35 (d, 1H), 7.83 (dd, 1H), 7.47 (d, 1H), 7.23 (dd, 1H), 6.64 (br s, 2H), 1.60 (q, 2H), 1.34-1.25 (m, 1H), 0.91-0.72 (m, 2H), 0.45-0.41 (m, 2H), 0.11-0.07 (m, 2H). LRMS [M+H]=264.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5](O)=[O:6].C[CH2:13][N:14](C(C)C)[CH:15](C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([N:14]([CH3:15])[CH3:13])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)N(C)C)cc(Cl)n1
Reaction time: 0.08 h

Procedure:
To a solution of 2-Chloro-6-methyl-isonicotinic acid (1 g) in DMF (200 ml) at 25° C. was added DIPEA (2.9 mL) and TBTU (1.8 ml). After 5 min, dimethylamine (0.75 g) was added dropwise. This was stirred overnight. The reaction was added to water and extracted with EtOAc. The organic layer was separated, dried and concentrated in vacuum. Flash:chromatography (9:1 to 2:8 gradient cyclohexane:EtOAc) afforded the title compound (320 mg). Rf=0.56 (1:1 cyclohexane:EtOAc)