Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:33]=[CH:32][C:27]3[C:28](=[O:31])[O:29][CH2:30][C:26]=3[CH:25]=2)[CH2:18][CH2:17]1)=[O:15].[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[N:8]1([C:6]2[CH:5]=[CH:4][C:3]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]4[CH:33]=[CH:32][C:27]5[C:28](=[O:31])[O:29][CH2:30][C:26]=5[CH:25]=4)[CH2:18][CH2:17]3)=[O:15])=[C:2]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:7]=2)[CH:12]=[N:11][N:10]=[N:9]1
Reactant: O=C1OCc2cc(CCN3CCN(C(=O)Cc4ccc(-n5cnnn5)cc4Br)CC3)ccc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1OCc2cc(CCN3CCN(C(=O)Cc4ccc(-n5cnnn5)cc4-c4ccccc4)CC3)ccc21
Temperature: 80 °C

Procedure:
A mixture of 5-[2-(4-{[2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (40 mg, 0.08 mmol), PhB(OH)2(24 mg, 0.2 mmol), Na2CO3 (42 mg, 0.4 mmol) and Pd(PPh)4(10 mg) in 3 mL of toluene and 3 mL of ethanol was heated to 80° C. under N2 overnight. The solution was concentrated to get the crude product, which was purified via prep-TLC to afford 5-[2-(4-{[5-(1H-tetrazol-1-yl)biphenyl-2-yl]acetyl}piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one. 1H-NMR (300 MHz, CDCl3) δ ppm 9.0 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.67˜7.70 (m, 1H), 7.53˜7.63 (m, 2H), 7.44˜7.49 (m, 3H), 7.30˜7.37 (m, 4H), 5.28 (s, 2H), 3.58˜3.74 (m, 4H), 3.17˜3.30 (m, 2H), 2.87˜2.98 (m, 2H), 2.39˜2.69 (m, 4H), 2.22˜2.36 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1([C:12](=[O:14])[CH3:13])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[CH2:2].[Br:15]Br>C(Cl)Cl>[Br:15][CH2:13][C:12]([C:3]1([CH:1]=[CH2:2])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[O:14]
Reactant: C=CC1(C(C)=O)Cc2ccccc2C1
Reactant: BrBr
Solvent: ClCCl
Product: C=CC1(C(=O)CBr)Cc2ccccc2C1

Procedure:
1-(2,3-Dihydro-2-vinyl-1H-inden-2-yl)-ethanone (5.0 g) was dissolved in methylene chloride (50 ml) and to the solution bromine (4.3 g) in methylene chloride (45 ml) was added dropwise at room temperature. When a gas chromatogram indicated that the starting material had reacted, the methylene chloride solution was washed with a dilute NaHCO3 -solution and then with water. The organic layer was dried with Na2SO4 and the solvent was evaporated at reduced pressure to give the desired product.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH:23]1([NH:26][C:27](=[O:44])[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:27]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([C:2]3[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:29]=2)=[O:44])[CH2:24][CH2:25]1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-(3-methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.71 min, MH+479. NMR: δH [2H6]-DMSO 9.33, (1H, t), 9.15, (1H, s), 8.48-8.33, (3H, m), 7.89, (1H, s), 7.81, (1H, d), 7.73, (1H d), 7.41, (1H, d), 7.31, (1H, t), 7.21, (1H, s), 7.10, (2H, m), 4.51, (2H, d), 2.99, (3H, s), 2.86, (1H, m), 2.38, (3H, s), 0.69, (2H, m), 0.57, (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5](=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:6]([OH:8])=[O:7].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.Cl>[OH-].[Na+]>[CH2:16]([NH:15][C:4]1[CH:3]=[C:2]([Cl:1])[C:10]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(N)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)c(NCc2ccccc2)cc1Cl

Procedure:
A solution of 4-chloro-5-methylsulfonylanthranilic acid (250 mg.) and benzyl bromide (180 mg.) in 5% aqueous sodium hydroxide is heated on a water bath at 50° C. for four hours during which time 5% aqueous sodium hydroxide is added a few drops at a time to maintain a basic reaction medium. The reaction mixture is poured into water and acidified with hydrochloric acid to give 2-benzylamino-4-chloro-5-methylsulfonylbenzoic acid, m.p. 179° C. after recrystallization from ethanol and water.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[C:13]1(C)C=CC(S(OC)(=O)=O)=CC=1>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[CH:7]2
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(Br)ccc21
Yield: 98.5 %

Procedure:
Sodium hydride (440 mg of a 60% dispersion in paraffin wax) was added to a stirred solution of 5-bromoindole (1.96 g, 10 mmol) in dimethylformamide (20 ml) at ambient temperature under a nitrogen atmosphere. After 30 minutes methyl p-toluenesulphonate (2.05 g, 11 mmol) was added. After 20 hours the mixture was partitioned between diethyl ether and water. The organic layer was separated and washed twice with water. The organic layer was dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was purified by flash column chromatography (using 50% hexane, 50% dichloromethane as eluant) to give 2.07 g of product as a waxy solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:26][CH2:25]1.O>CS(C)=O>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([O:13][CH3:14])=[CH:3][C:2]=1[N:33]1[CH2:32][CH2:31][CH:30]([N:27]2[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][F:21])[CH2:29][CH2:28]2)[CH2:35][CH2:34]1
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1Cl
Reactant: FCCN1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])c(OC)cc1N1CCC(N2CCN(CCF)CC2)CC1
Temperature: 80 °C
Reaction time: 60 h
Yield: 74.6 %

Procedure:
4-Chloro-2,5-dimethoxynitrobenzene (1.0 g, 4.6 mmol) was dissolved in DMSO (10 mL). K2CO3 (0.953 g, 6.9 mmol) and 1-(2-fluoroethyl)-4-(4-piperidinyl)piperazine (0.989 g, 4.6 mmol) were added and the reaction mixture was heated to 80° C. and allowed to stir for 60 h. The mixture was then poured into H2O and extracted with EtOAc (2×). The combined organics were dried with MgSO4, filtered, and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step E (1.36 g, 75%). MS (M+H, ES+) 397.
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=O)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([OH:14])=[N:10][CH:11]=[N:12][CH:13]=1.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[F:1][C:2]1[C:3](/[C:15](/[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:25]\[OH:26])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([OH:14])=[N:10][CH:11]=[N:12][CH:13]=1
Reactant: NO
Reactant: O=C(c1ccc(F)cc1)c1nccc(-c2cncnc2O)c1F
Agent: Cl
Solvent: c1ccncc1
Product: O/N=C(/c1ccc(F)cc1)c1nccc(-c2cncnc2O)c1F
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A solution of (3-fluoro-4-(4-hydroxypyrimidin-5-yl)pyridin-2-yl)(4-fluorophenyl)methanone (0.168 g, 0.536 mmol) and hydroxylamine hydrochloride (0.039 g, 0.563 mmol) in Pyridine (Volume: 2.68 ml) was refluxed for 1.5 hr, allowed to cool to room temperature, and then concentrated in vacuo. Solvent was evaporated. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 1-25% MeOH in CH2Cl2 over 19 min, tr=12 min) gave the title compound (0.123 g, 0.371 mmol, 69.2% yield) as a tan solid. ESI MS (M+H)+=329.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14](=O)[CH3:15])=[O:5])[CH3:2].B.CSC.Cl.N.O>O1CCCC1>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4]([O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH3:15])=[O:5])[CH3:18]
Reactant: CCN(CC)C(=O)Oc1cnccc1NC(C)=O
Agent: B
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Solvent: CSC
Product: CCNc1ccncc1OC(=O)N(CC)CC
Reaction time: 0.5 h

Procedure:
4-Acetylamino-3-pyridinol N,N-diethylcarbamate (3.43 g) was dissolved in tetrahydrofuran (75 mL) and then the reaction mixture was chilled in an ice-water bath. Borane/methyl sulfide (BMS) was added (3.25 mL, 2.60 g) and the reaction mixture was stirred in the cold bath for 30 minutes. At the end of this time an additional 3.0 mL of BMS was added and stirring was continued for 3 hours. The reaction mixture was then poured into ice/conc. HCl, stirred for 30 minutes, basified with NH3 /water and then extracted with ethyl acetate. The organic phase was then dried, concentrated and purified by flash chromatography to give 0.86 g of chromatographically pure product. This product was combined with a crop obtained from another run and recrystallized from hexane to give an analytically pure material, mp. 107°-108° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:13].[Br:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:13][CH2:16][CH2:15][Br:14]
Reactant: Oc1ccc2cc(Br)ccc2c1Br
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: BrCCOc1ccc2cc(Br)ccc2c1Br
Temperature: 0 °C
Reaction time: 48 h
Yield: 69.9 %

Procedure:
1,6-Dibromo-2-naphthol (15.0 g, 49.67 mmol) and 1,2-dibromoethane (46.7 g, 248.37 mmol) were added to a suspension of potassium carbonate (84.8 g, 74.51 mmol) in acetonitrile (500 mL) at rt. The reaction mixture was stirred for 48 h. Additional 1,2-dibromoethane (21.5 mL, 248.37 mmol) was added and the reaction mixture was stirred for 96 h at rt. The reaction mixture was cooled to 0° C. with an ice bath and filtered through a fritted glass funnel. The resulting filtrate was concentrated under reduced pressure to give the title compound (14.2 g, 69.9% yield) as a brown solid. GC/MS m/z 406 (M)+, RT 10.25 min; 1H NMR (400 MHz, acetone-d6) δ 14-8.09 (m, 2H), 7.96 (d, 1H), 7.71 (d, 1H), 7.54 (d, 1H), 4.64-4.60 (m, 2H), 3.90-3.86 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[OH:27]>O>[Br:1][CH2:2][CH2:3][CH2:4][O:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[Cl:17]
Reactant: BrCCCBr
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(OCCCBr)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-dibromo propane (1.3 mL, 12.65 mmol) and cesium carbonate (4.1 g, 12.65 mmol) was added to the DMF (18 mL) solution of 2-chloro-5-nitro phenol (2.0 g, 11.5 mmol) and the reaction mixture stirred overnight at room temperature. Water (20 mL) was added to the mixture, extracted with DCM (3×25 mL) and combined extracts were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography to get the title compound 26a in 64% (2.176 g) yield as colorless oil.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:14].CC(C)(C)CN[C:19](=[O:43])[C:20]1[CH:25]=[C:24]([CH:26]([OH:41])[CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:30][CH2:29]2)[CH:23]=[CH:22][C:21]=1[OH:42]>>[ClH:14].[CH2:1]([NH:13][C:19](=[O:43])[C:20]1[CH:25]=[C:24]([CH:26]([OH:41])[CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:32][CH2:33]2)[CH:23]=[CH:22][C:21]=1[OH:42])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Cc1ccccc1N1CCN(CC(O)c2ccc(O)c(C(=O)NCC(C)(C)C)c2)CC1
Reactant: CCCCCCCCCCCCN
Agent: Cl
Product: CCCCCCCCCCCCNC(=O)c1cc(C(O)CN2CCN(c3ccccc3C)CC2)ccc1O

Procedure:
Following essentially the same procedure but substituting dodecylamine for the neopentylamine above results in the preparation of N-dodecyl-2-hydroxy-5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]ethyl]benzamide hydrochloride.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])C.[C:12]([NH2:18])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].[O-]CC.[Na+:22]>CCO>[C:14]([C:13]1[C:12]([O-:17])=[N:18][C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][CH:4]=1)(=[O:15])[CH3:16].[Na+:22]
Reactant: CC(=O)CC(N)=O
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1ccc(C(F)(F)F)nc1[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
A solution of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (4.21 g, 22.5 mmol), EtOH (42 mL), acetoacetamide (2.28 g, 22.5 mmol), and sodium ethoxide (21 weight % in EtOH, 8.41 mL, 22.5 mmol) was heated to 75° C. After 12 hours, the mixture was cooled to room temperature over 30 minutes, stirred for 4 hours, then cooled to <5° C. After 10 minutes, the white slurry was filtered, washing with cold EtOH (5 mL). The white solid was dried in a vacuum oven at 60° C. to provide the title compound (4.39 g, 19.3 mmol, 86% yield).
Reaction SMILES: [CH2:1]=[C:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[C:3](O)=[O:4].[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1>>[CH2:1]=[C:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[C:3]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: C=C(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: C=C(C(=O)Nc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to Example 4(c), by reaction of 4.6 g (18 mmol) of α-methylene-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid with 2.7 g (18 mmol) of methyl 4-aminobenzoate, 2.4 g (34%) of the expected ester are obtained in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:22]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:22][C:4]1[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=1[O:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1
Reactant: CCN(CC)C(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: CCN(CC)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Yield: 84.4 %

Procedure:
The product from Example 129a (1.0 g, 2.87 mmol) was reduced with SnCl2 following the procedure from Example 1f giving the title compound as a clear oil (772 mg, 85%).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:15])=[N:9][C:10]3[N:11]([N:12]=[CH:13][CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH3:21]>>[NH2:21][C:2]1[C:7]2[C:8]([CH3:15])=[N:9][C:10]3[N:11]([N:12]=[CH:13][CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: N
Reactant: CCOC(=O)c1cnc2c(c(C)nc3ccnn32)c1Cl
Product: CCOC(=O)c1cnc2c(c(C)nc3ccnn32)c1N

Procedure:
By treating the product of Example 10 with ammonia according to the procedure of Example 5, 6-amino-5-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester is obtained. Treatment of this product with ethanolic hydrochloric acid yields the hydrochloride salt.
Reaction SMILES: CN(C)C.[CH2:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH2:14][CH3:15])[C:8]=1[C:16]1[C:17](=[O:30])[CH:18]2[CH:22]([C:23]=1[OH:24])[CH2:21][CH:20]([CH:25]([O:28][CH3:29])[O:26][CH3:27])[CH2:19]2)[CH3:6].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>ClCCl>[C:32](=[O:33])([O:34][CH2:35][CH3:36])[O:30][C:17]1[CH:18]2[CH:22]([CH2:21][CH:20]([CH:25]([O:26][CH3:27])[O:28][CH3:29])[CH2:19]2)[C:23](=[O:24])[C:16]=1[C:8]1[C:9]([CH2:14][CH3:15])=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[CH2:5][CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CCc1cc(C)cc(CC)c1C1=C(O)C2CC(C(OC)OC)CC2C1=O
Agent: CN(C)C
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2c(CC)cc(C)cc2CC)C(=O)C2CC(C(OC)OC)CC12
Reaction time: 1 h

Procedure:
At room temperature, 80 mg (0.80 mmol) of trimethylamine are added dropwise to 0.090 g (0.25 mmol) of 2-(2,6-diethyl-4-methylphenyl)-5-(dimethoxymethyl)-3-hydroxy-4,5,6,6a-tetrahydropentalen-1(3aH)-one (compound I-a-9 according to the invention) and 30 mg (0.28 mmol) of ethyl chloroformate in 15 ml of dichloromethane, and the mixture is stirred for another 1 h. The mixture is poured onto ice-water, taken up in dichloromethane, washed with water, dried (magnesium sulphate), and the solvent is distilled off.
Reaction SMILES: O.[OH-].[Li+].[O:4]1[C:8]2([CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[NH:22][C:23]3[C:24]4[C:31]([CH3:32])=[C:30]([C:33]([O:35]C)=[O:34])[S:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1>C1COCC1.O>[O:4]1[C:8]2([CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[NH:22][C:23]3[C:24]4[C:31]([CH3:32])=[C:30]([C:33]([OH:35])=[O:34])[S:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCC4(CC3)OCCO4)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC4(CC3)OCCO4)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.065 g lithium hydroxide monohydrate was added to 2.003 g methyl 4-(2-(1,4-dioxaspiro[4.5]decan-8-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (cpd.19.1) in 100 ml THF and 60 ml water. After stirring at rt overnight the reaction mixture was quenched by 2 M aq. HCl and concentrated in vacuo. The resulting aq. layer was filtered. The filtercake was dried and triturated with MeOH:Et2O 20:1 to give the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[C:3]=1[N+:17]([O-])=O.C(OC([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH2:36])[CH:34]=2)[C:29](=[O:37])[NH:28]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C>C1COCC1>[NH2:17][C:3]1[C:2]([NH:36][C:33]2[CH:34]=[C:35]3[C:30]([C:29](=[O:37])[NH:28][NH:27]3)=[CH:31][CH:32]=2)=[N:7][CH:6]=[N:5][C:4]=1[NH:8][C:9]1[NH:10][N:11]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Nc1cc(C2CC2)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Nc2ccc3c(=O)[nH][nH]c3c2)ncnc1Nc1cc(C2CC2)n[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 33.6 %

Procedure:
To a solution of (6-chloro-5-nitro-pyrimidin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (50 mg, 0.18 mmol) in anhydrous THF (2 mL) was added 6-amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (67 mg, 0.27 mmol) and diisopropylethylamine (23 mg, 0.18 mmol). The mixture was stirred at RT for 14 hrs and the solvents were removed under vacuum. The residue was dissolved in CH2Cl2 (3 mL) and treated with TFA (2 mL) at RT for 2 hrs. After removal of the solvents via evaporation, the residue was reduced by hydrogen (50 psi) in MeOH (10 mL) in the presence of Pd/C (10%, 50 mg) for 3 hrs. The solution was filtered via celite, the filtrate was evaporated under vacuum, and the residue was purified by HPLC to give the desired product as white solid (22 mg). NMR (500 MHz, DMSO-d6) δ11.16 (br, 1H), 9.92 (br, 1H), 8.98 (s, 1H), 8.27 (s, 1H), 7.67 (s, 1H), 7.55 (d, 1H), 7.08 (d, 1H), 5.95 (s, 1H), 2.00 (m, 1H), 1.06 (m, 2H), 0.81 (m, 2H) ppm. MS (ES+): m/e=364.3 (M+H); LC/Method A/2.45 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[C:20]([C:35]([F:36])([F:37])[F:38])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: Cc1ccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 13-3 (790 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (540 mg) as a white powder.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1COCC1>[F:1][C:2]([F:21])([F:20])/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[S:31]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccnc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)c1
Solvent: C1CCOC1
Product: Cc1ccnc(N2CCN(C(=S)/C=C/C(F)(F)F)CC2)c1
Temperature: 110 °C
Yield: 20 %

Procedure:
The residue of step A was dissolved in anhydrous THF (2 ml), Lawesson's reagent (40 mg, 0.2 mmol) was added and the mixture was stirred at 110° C. in closed vial under microwave heating. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Waters X-Bridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 12 mg of a solid (0.039 mmol, yield 20% for two steps).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[CH:28]\[C:29]([NH:31][NH2:32])=[O:30])/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:35](OC(OCC)OCC)C>>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[CH:28]\[C:29]5[O:30][CH:35]=[N:32][N:31]=5)/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C/C(=O)NN
Reactant: CCOC(OCC)OCC
Product: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C/c1nnco1
Temperature: 120 °C
Reaction time: 5 h
Yield: 16 %

Procedure:
To (E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]acetohydrazide (118 mg, 0.25 mmol) obtained in Example 106, step 1 was added triethoxymethane (2.1 mL), and the mixture was stirred at 120° C. for 5 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 10/90) to give the title compound (compound 107) (18 mg, 16%).