Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:9]2[N:10]([CH2:17][CH3:18])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1.C[OH:20]>C(Cl)Cl>[CH3:1][NH:2][CH2:3][CH:4]1[C:9]2[N:10]([CH2:17][CH3:18])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7](=[O:20])[CH2:6][CH2:5]1
Reactant: CCn1c2c(c3ccccc31)SCCC2CNC
Reactant: CO
Solvent: ClCCl
Product: CCn1c2c(c3ccccc31)S(=O)CCC2CNC
Reaction time: 5 h
Yield: 92.8 %

Procedure:
A solution of 4-methylaminomethyl-5-ethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (1.3 g) in methanol (30 ml) is mixed with an aqueous solution (10 ml) of sodium periodide (1.12 g) and kept at room temperature for 5 hours. The precipitate is filtered off and the filtrate is condensed. The residue is dissolved in methylene chloride, washed with water, dried and evaporated to give the title compound (1.28 g) as an oil: Yield 92.8%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(N)c1
Solvent: CC(=O)O
Product: COc1cccc(NC(C)=O)c1
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
m-Anisidine (50 g, 0.406 mol) was added to acetic acid (25 mL)and cooled in an ice bath. Acetic anhydride (45.6 g, 0.447 mol) was added dropwise with stirring over 10 min. The resulting mixture was stirred and allowed to come to room temperature. After 1.5 hr the mixture was concentrated under reduced pressure until crystallization commenced. The crystals were collected and allowed to air dry in the hood overnight and finally in a desiccator to afford 66.5 g (99%) of N-(3-methoxyphenyl)acetamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([F:34])[C:13]([N:21]3[CH2:25][CH2:24][C@H:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[C:14]([F:20])[C:15]=2F)[N:10]([CH:35]2[CH2:37][CH2:36]2)[C:9]1=[O:38])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CS(C)=O>[C:1]([O:5][C:6](=[O:39])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([F:34])[C:13]([N:21]3[CH2:25][CH2:24][C@H:23]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:22]3)=[C:14]([F:20])[C:15]=2[NH:54][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:10]([CH:35]2[CH2:36][CH2:37]2)[C:9]1=[O:38])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(F)c3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2F)C1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(NCc3ccccc3)c3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2F)C1
Yield: 86.8 %

Procedure:
A solution of {7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-1,4-dihydro-2,4-dioxo-5,6,8-trifluoro-2H-quinazolin-3-yl}carbamic acid tert-butyl ester from Example 8 (0.51 g, 0.914 mmol), triethylamine (1.3 mL, 9.3 mmol), and benzylamine (0.50 mL, 4.6 mmol) in dimethyl sulfoxide (7.5 mL) is heated at 100° C. for 16 hours in a sealed glass tube. The mixture is concentrated under high vacuum and the residue purified by column chromatography (1:2 ethyl acetate/hexanes) to afford {7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-benzylamino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamic acid tert-butyl ester as a solid (0.51 g). 1H NMR (CDCl3): δ 8.50 (bs, 1H), 7.37-7.18 (m, 5H), 6.56 (bs, 1H), 4.76-4.62 (bd, 1H), 4.59-4.48 (m, 2H), 4.34-4.18 (m, 1H), 3.93-3.49 (m, 3H), 3.48-3.20 (m, 2H), 2.24-2.04 (m, 1H), 1.96-1.74 (m, 1H), 1.49 (s, 9H), 1.46 (s, 9H), 1.13-1.00 (m, 2H), 0.75-0.61 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26].CO>>[ClH:26].[C:20]1([C:19]2[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[CH:17][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2-c2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(-c2nccnc2C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 4-(3-Phenyl-pyrazin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (89) (128 mg, 0.38 mmol) in 4 M HCl/MeOH solution (10 mL) was stirred at RT. for 30 min. Then the solvent was evaporated at 40° C. to give 2-phenyl-3-piperidin-4-yl-pyrazine hydrochloride (90) (105 mg, 0.38 mmol, 100% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Br:17])=[CH:12][C:11]=2[Br:18])[CH:4]=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:19](OC(=O)C)(=[O:21])[CH3:20].O>C(O)(=O)C>[C:7]([C:6]1[C:5]([CH3:9])=[CH:4][N:3]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Br:17])=[CH:12][C:11]=2[Br:18])[C:2]=1[NH:1][C:19](=[O:21])[CH3:20])#[N:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn(-c2c(Cl)cc(Br)cc2Br)c(N)c1C#N
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C#N)c(C)cn1-c1c(Cl)cc(Br)cc1Br

Procedure:
In 5 ml of acetic acid, 1.9 g of 2-amino-4-methyl-1-(2,4-dibromo-6-chlorophenyl)pyrrole-3-carbonitrile and 1.48 g of acetic anhydride were dissolved. The reaction mixture was heated under reflux for 30 minutes. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. Subsequently, the extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to yield crude N-[3-cyano-4-methyl-1-(2,4-dibromo-6-chlorophenyl)-1H-pyrrol-2-yl]acetamide. To the obtained crude N-[3-cyano-4-methyl-1-(2,4-dibromo-6-chlorophenyl)-1H-pyrrol-2-yl]acetamide, 8 ml of 85% phosphoric acid were added. The reaction mixture was heated for 0.5 hours at 130° C., and subsequently, water was added thereto. The reaction mixture was extracted with chloroform, and subsequently, the extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) and was allowed to stand for crystallization. The precipitated crystals were washed with ethyl acetate to yield 1.1 g of 2,5-dimethyl-7-(2,4-dibromo-6-chlorophenyl)-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one.
Reaction SMILES: [C:1]1([CH:7]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]3[CH2:12][CH2:11][CH2:10][C:9](=O)[C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)C>N1C=CC=CC=1>[C:1]1([CH:7]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCC2=C1C(c1ccccc1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1CCCC2=C1C(c1ccccc1)C1=C(CCCC1)N2
Temperature: 70 °C
Yield: 63 %

Procedure:
A mixture of 9-phenyl-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (5.0 g), sodium borohydride (6.5 g), ethanol (150 mL) and pyridine (50 mL) was heated at 70° C. overnight and cooled to room temperature. The solvent was removed, the residue partitioned between water and ethyl acetate, the organic layer was dried and the solvent removed. Chromatography (methylene chloride/methanol; 98/2) provided the title compound (3.0 g) as a white solid. Recrystallization from ethanol/hexane returned analytically pure title compound, mp 252°-254° C., NMR: 1.41-1.51 (m,3, CH2), 1.60-1.88 (m,5, CH2), 2.03-2.13 (m,4, CH2), 2.38-2.44 (m,2, CH2), 4.14 (s,1, CH), 7.04-7.21 (m,5, Ar) 8.34 (s,1, NH); (CI, CH4) MS: m/z=280(M+1). Analysis for C19H21NO.0.2H2O: Calculated C, 80.64; H, 7.62; N, 4.95; Found: C, 80.84; H, 7.62; N, 4.80.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:24].CCOC(C)=O>C1COCC1>[ClH:24].[ClH:24].[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)Oc2cccnc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC1CCN(C(=O)Oc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pyridin-3-yl 4-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate (0.249 g) was dissolved in THF (5.0 ml), and under ice cooling, 4 M hydrogen chloride/EtOAc solution (2.10 ml) was added thereto, followed by stirring at room temperature for 24 hours. The reaction solution was concentrated to dryness to obtain pyridin-3-yl 4-aminopiperidine-1-carboxylate dihydrochloride (0.280 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:4]2([NH:8][CH:7]([C:9]3[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:28].[S:29](=[O:33])(=[O:32])([OH:31])[OH:30]>CC#N>[S:29](=[O:31])(=[O:30])([OH:33])[OH:32].[CH3:1][N:2]1[CH2:27][CH2:26][C@:4]2([NH:8][C@@H:7]([C:9]3[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=4)[N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:28]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C2CCC3(CCN(C)C3=O)N2)n1
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc([C@H]2CC[C@@]3(CCN(C)C3=O)N2)n1
Reaction time: 2 h

Procedure:
A similarly prepared sample was recrystallised from diethyl ether and isohexane to give the free base form of the title material as a colorless solid with a melting point of 66-67° C. Similarly prepared 7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one with a diastereomeric excess of approximately 92% (49 g, 125.51 mmol) in MeCN (700 mL) was suction filtered through a shallow pad of Hyflo to give a clear yellow solution. To this rapidly stirred solution at 50° C. was added 7.5M sulphuric acid (17.6 mL, 132 mmol) over 5 seconds to give a solution which quickly crystallized. The mixture was left to stand at ambient temperature for 2 h then filtered and washed with acetonitrile/Et2O (1:1) (200 ml) then Et2O (150 ml) and dried 50° C. to give the title material (E7a) in an 82:1 ratio of (2R,5S) and (2S,5S) isomers (50.6 g) assessed by NMR.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]([C:19]1[C:24]([O:25][CH3:26])=[N:23][C:22]([CH3:27])=[CH:21][N:20]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I)(=[O:11])=[O:10])=[O:7])[CH:2]([CH3:4])[CH3:3].[C:28]1([CH3:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:5][C:6]([N:8]([C:19]1[C:24]([O:25][CH3:26])=[N:23][C:22]([CH3:27])=[CH:21][N:20]=1)[S:9]([C:12]1[C:13]([C:31]2[CH:32]=[CH:33][C:28]([CH3:34])=[CH:29][CH:30]=2)=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1I
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(C)cc1

Procedure:
A mixture of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methyl-2-pyrazinyl)-2-iodobenzenesulphonamide (0.252 g) 4-methylbenzeneboronic acid (0.068 g), tetrakis(triphenylphosphine)palladium(0) (0.0115 g), toluene (2.5 ml), ethanol (1.25 ml) and 2H sodium carbonate solution (3.75 ml) was stirred vigorously and heated under reflux for 2 hours under an atmosphere of argon. Water (10 ml) was added and the mixture was extracted with ethyl acetate (2×10 ml). The combined extracts were washed with saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:4 v/v), to give N-(isobutoxycarbonyl)-N-(3-methoxy-5-methyl-2-pyrazinyl)-4'-methyl-2-biphenylsulphonamide (0.182 g); 1H NMR (DMSO-d6): 0.6 (d,6H), 1.55-1.75 (m,1H), 2.35 (s,3H), 2.5 (s,3H), 3.85 (d,2H), 3.95 (s,3H), 7.15-7.25 (m,4H), 7.35-7.45 (m,1H), 7.7-7.8 (m,2H), 8.15 (s,1H), 8.45-8.55 (m,1H); mass spectrum (+ve FAB, methanol/NBA): 470 (M+H)+.
Reaction SMILES: [Na].[CH3:2][C:3]([CH2:6][CH3:7])=[N:4][OH:5].[CH3:8][Si:9]([CH3:13])([CH3:12])[CH2:10]Cl>CN(C)C=O>[CH3:8][Si:9]([CH2:13][O:5][N:4]=[C:3]([CH2:6][CH3:7])[CH3:2])([CH3:12])[CH3:10]
Reactant: C[Si](C)(C)CCl
Reactant: CCC(C)=NO
Agent: [Na]
Solvent: CN(C)C=O
Product: CCC(C)=NOC[Si](C)(C)C
Yield: 70 %

Procedure:
To the above obtained dispersion of metallic sodium was added 34.8 g (0.4 mole) of methylethylketoxime and the reaction mixture was heated at 60° to 80° C. for about 180 minutes followed by removal of toluene under reduced pressure to give pasty sodium salt of methylethylketoxime. Then, this sodium salt of methylethylketoxime was dispersed in a mixture of 49.2 g (0.4 mole) of trimethylchloromethylsilane and 100 ml of N,N-dimethylformamide and heated at 70° to 80° C. for 3 hours with agitation. The reaction mixture after completion of the reaction was washed with water to remove sodium chloride formed as the by-product and N,N-dimethylformamide and the residue was extracted with diethyl ether followed by evaporation of the ether to give a crude product which was further distilled under reduced pressure to give 48.4 g of a liquid product boiling at 84° C. under 50 mmHg. This product is referred to as compound S-I hereinafter.
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].[N-:16]=[N+:17]=[N-:18].[Na+]>CS(C)=O>[N:16]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[NH:4][C:3]1=[O:15])=[N+:17]=[N-:18]
Reactant: COc1ccc2c(c1)NC(=O)C(Cl)CC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)NC(=O)C(N=[N+]=[N-])CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (12.5 g) and sodium azide (4.3 g) in dimethylsulfoxide (150 ml) was maintained at 80° under an atmosphere of nitrogen for 3 hours. The reaction mixture was poured into ice/water (300 ml) and the suspension was stirred for 30 minutes. The solid was filtered off, washed with water (50 ml) and dried to give 3-azido-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one, m.p. 136°-138°.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH:2]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([N:3]3[C:4]4[CH:5]=[N:6][CH:7]=[CH:8][C:9]=4[N:1]=[CH:2]3)=[CH:11][CH:12]=2)=[O:26])=[CH:20][C:19]=1[C:27]([F:28])([F:29])[F:30]
Reactant: Nc1ccc(-n2cnc3ccncc32)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(-n2cnc3ccncc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
The 4-(imidazo[4,5-c]pyridin-3-yl)aniline prepared in Step A was dissolved in 10 mL of dichloromethane, and 14.2 mg (0.064 mmol) of 4-chloro-3-(trifluoromethyl)phenyl isocyanate was added thereto and the mixture solution was stirred at room temperature for three hours. The solvent was distilled under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate to obtain 20.2 mg (73%) of 1-(4-chloro-3-(trifluoromethyl)-phenyl)-3-(4-imidazo[4,5-c]pyridin-3-ylphenyl)urea (Table 1, Compound No. 2) as a colorless crystal.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](B2OC(C)(C)C(C)(C)O2)=[N:22]1>>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[N:3]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Product: COc1cccc(Nc2nc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with indazole boronic acid pinacol ester using General Procedure A. Purification on silica yielded 122. NMR: (CDCl3): 3.88 (s, 3H, CH3), 4.19 (s, 3H, CH3), 6.88-6.91 (m, H, ArH), 7.16-7.18 (m, H, ArH), 7.31 (sbr, H, NH), 7.40 (t. H, ArH, J=8.1 Hz), 7.50 (s, H, ArH), 7.55 (t. H, ArH, J=4 Hz), 7.65 (d, H, ArH, J=8.3 Hz), 8.45 (d, H, ArH, J=7.49 Hz), 9.17 (s, H, ArH) 10.2 (sbr, H, NH). MS: (ESI+) MH+=372.25
Reaction SMILES: [CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35]([NH2:38])(=[O:37])=[O:36])=[CH:25][CH:24]=2)[C:8]2=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:39]1([CH:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46](Cl)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35]([NH:38][C:46](=[O:47])[CH:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)(=[O:37])=[O:36])=[CH:27][CH:28]=2)[C:8]2=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCCC(=O)Nc1cnc2c(nc(CCCC)n2Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c1C
Product: CCCCC(=O)Nc1cnc2c(nc(CCCC)n2Cc2ccc(-c3ccccc3S(=O)(=O)NC(=O)C(c3ccccc3)c3ccccc3)cc2)c1C

Procedure:
The title compound was prepared from 2-butyl-3-[[2'-[(amino)sulfonyl][1,1'-biphenyl]-4-yl]methyl]-7-methyl-6-[(1-oxopentyl)amino]-3H-imidazo[4,5-b]pyridine and diphenylacetyl chloride as described in Example 1, Step 5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:17].[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:17]=[C:5]1[C:4]2[C:14](=[CH:15][CH:16]=[C:2]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:18]#[N:19])[CH:3]=2)[O:13][C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:6]1
Reactant: O=C1CC2(CCOCC2)Oc2ccc(Br)cc21
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC2(CCOCC2)O3)c1
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 43.8 %

Procedure:
A mixture of 6-bromo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-one (300 mg, 1 mmol), 3-cyanophenylboronic acid (298 mg, 2 mmol), Cs2CO3 (2 M, 4 mL) and Pd(PPh3)2Cl2 (80 mg) in 1,4-dioxane (10 mL) under Ar was stirred under microwave at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 3-(4-oxo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-6-yl)benzonitrile (140 mg, 43%). 1H-NMR (CDCl3): 1.81-1.85 (m, 2H), 2.00-2.04 (d, 2H), 2.80 (s, 2H), 3.78-3.87 (m, 4H), 7.14 (d, 1H), 7.52-7.56 (t, 1H), 7.61-7.64 (d, 1H), 7.71-7.74 (d, 1H), 7.78 (d, 1H), 7.80 (s, 1H), 8.07 (s, 1H).
Reaction SMILES: [CH2:1]([Sn](Cl)(Cl)Cl)[CH2:2][CH2:3][CH3:4].[CH2:9]([Sn:13]([Br:16])(Br)Br)[CH2:10][CH2:11][CH3:12]>>[Sn:13]([Br:16])([CH2:9][CH2:10][CH2:11][CH3:12])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](Br)(Br)Br
Reactant: CCCC[Sn](Cl)(Cl)Cl
Product: CCCC[Sn](Br)(CCCC)CCCC

Procedure:
In place of the BuSnCl3 mentioned initially an equimolar amount of BuSnBr3 may be used to give Bu3SnBr in the same manner, but after 2.5 hours.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([N+:19]([O-])=O)=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.O>C(O)(=O)C.[Zn]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COCCOc1cc(Oc2ccccc2)cnc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1cc(Oc2ccccc2)cnc1N
Temperature: 100 °C
Yield: 76 %

Procedure:
3-(2-Methoxy-ethoxy)-2-nitro-5-phenoxy-pyridine (0.4 mmol) is dissolved in acetic acid (1.3 ml). After addition of water (1.3 ml), zinc powder (6 eq.) is added and the reaction suspension is heated to 100° C. for 3 h. The reaction suspension is cooled to room temperature and filtrated. The filtrate is pored into 3.5% NaOH (30 ml) and extracted with dichloromethane. The combined organic layers are extracted with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxyethoxy)-5-phenoxy-pyridine-2-ylamine is obtained as brown oil in a yield of 76%. HPLC (method C): 1.43 min; LC-MS (method A): 0.808 min, 261.15 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](Cl)=[O:31]>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[O:31])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccccn4)cc3C2=O)C(=O)N1
Yield: 49.3 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and pyridine-2-carbonyl chloride hydrochloride (0.64 g, 3.60 mmol) in THF (50 mL), was added TEA (1.46 mL, 10.50 mmol) at room temperature under nitrogen. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (100 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH/CH2Cl2). The product fractions were combined, concentrated and dried in vacuo to give pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.58 g, 49% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.17 min (99.35%); mp: 212-214° C.; 1H NMR (DMSO-d6) δ 2.02-2.06 (m, 1H, CHH), 2.43-2.62 (m, 2H, CHH, CHH), 2.81-2.96 (m, 1H, CHH), 4.66 (d, J=6.4 Hz, 2H, CH2), 5.14 (dd, J=5.3, 12.6 Hz, 1H, CH), 7.61-7.66 (m, 1H, Ar), 7.80-7.90 (m, 3H, Ar), 7.97-8.07 (m, 2H, Ar), 8.67-8.69 (m, 1H, Ar), 9.64 (t, J=6.4 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 42.37, 48.98, 122.07, 122.11, 123.52, 126.73, 129.79, 131.57, 133.58, 137.86, 147.49, 148.54, 149.71, 164.29, 166.99, 167.14, 169.81, 172.72; Anal Calcd for C20H16N4O5+0.05H2O: C, 61.08; H, 4.13; N, 14.25. Found: C, 60.81; H, 3.82; N, 14.15.