Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]2[C:7]([O:9][C:10](=[O:11])[C:3]=2[CH:2]=1)=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.FC1C=CC(F)=CC=1C(C1C(C(O)=O)=CN=CC=1)=O>[N+](C1C=CC=CC=1)([O-])=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:10]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[C:7]([OH:9])=[O:8])=[O:11]
Reactant: O=C1OC(=O)c2cnccc21
Reactant: Fc1ccc(F)cc1
Agent: O=C(O)c1cnccc1C(=O)c1cc(F)ccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccncc1C(=O)c1cc(F)ccc1F
Reaction time: 3 h
Yield: 84 %

Procedure:
3,4-Pyridine dicarboxylic acid anhydride (95.7 g, 0.67 mol) and AlCl3 (367.3 g, 2.67 mol) were simultaneously, but separately, added in five portions (one every 15') to boiling 1,4-difluorobenzene (650 mL, 90° C.). After about 1 hour from the last addition, the majority of the 1,4-difluorobenzene was removed by distillation at normal pressure until a thick mass was obtained. The temperature was lowered to 80° C. and nitrobenzene (150 mL) was added in order to dissolve the residual mass. While still hot, the resulting solution was cautiously quenched into ice-cooled and stirred water (1000 g of ice and 530 g of demineralized water) (i.e., slowly drop the solution into the ice water). Then concentrated HCl (37%, 160 mL) was added to the poured mixture at 0°-5° C. and stirring was continued for about 3 hours. A greasy beige precipitate (about 150 g wet) was collected by filtration while the aqueous layer was separated from nitrobenzene and extracted with AcOEt (6×500 mL). Nitrobenzene layer was diluted with petroleum ether (400 mL) and the resulting little amount of precipitate was collected by filtration (about 2 g). Combined extracts were concentrated under vacuum, and the residual crude solid (about 45 g), together with the previously collected precipitates, was suspended into a mixture of AcOEt/petroleum ether (1/1) (600 mL). After about 2 hours at room temperature the suspension was filtered and dried in vacuum to give the mixture of 4-(2',5'-difluorobenzoyl)nicotinic acid and 3-(2',5'-difluorobenzoyl)isonicotinic acid (147.3 g, 84% yield) as a pale beige solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]>ClCCl>[N+:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][C:18](=[O:19])[NH:10][C:8]2[O:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=2)=[CH:26][CH:25]=1)([O-:29])=[O:28]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1cc(N)on1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A solution of 3-tert-butyl-isoxazol-5-ylamine (2.50 g, 17.83 mmol) in dichloromethane was treated with pyridine (2 mL, 26.7 mmol) followed by p-nitrophenyl chloroformate (3.77 g, 18.73 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 1N HCl, filtered, and concentrated under reduced pressure. The residue was triturated with ether and collected by filtration to afford 2.2 g of product (41% yield).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH:15]=O)[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[S:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:22]([C:24](=[O:31])[CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1)[NH2:23].[OH-].[K+]>CO>[C:1]1([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH:15]=[N:23][NH:22][C:24]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:31])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[S:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(N)C(=O)C1CCCNC1
Reactant: O=Cc1c(-c2ccccc2)nc2sc3ccccc3n12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(NN=Cc1c(-c2ccccc2)nc2sc3ccccc3n12)c1cccnc1
Yield: 68 %

Procedure:
0.28 g of 2-phenyl-3-formylimidazo[2,1-b]benzothiazole, 0.15 g of N-methylnipecotohydrazide, and 0.1 g of potassium hydroxide were heated and stirred in 20 ml of methanol at 90° C. for 6 hours. After cooling, the desired substance was obtained in an amount of 0.27 g (yield of 68.0%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:28]1(C(=O)CC=C)[C:32]2C=C[CH:35]=[CH:36][C:31]=2N=[N:29]1.O.NN>C1COCC1.CCO>[CH2:31]([C:32]1[NH:28][N:29]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:36]=[CH2:35]
Reactant: C=CCC(=O)n1nnc2ccccc21
Reactant: Cc1ccc(C(=O)Cc2ccccc2)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: NN
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C=CCc1[nH]nc(-c2ccc(C)cc2F)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a solution of 1-(2-fluoro-4-methylphenyl)-2-phenylethanone (1.0 g, 4.38 mmol) in THF (10 mL) was added LiHMDS (1.0 M in THF) (8.76 mL, 8.76 mmol) slowly via syringe at 0° C. After stirring for 10 min, 1-(1H-benzo[d][1,2,3]triazol-1-yl)but-3-en-1-one (0.984 g, 5.26 mmol) was added in one portion. The reaction was stirred at 0° C. for 30 min before quenched with AcOH (2 mL). To the reaction were added EtOH (30 mL), hydrazine hydrate (0.658 g, 13.14 mmol), and heated to reflux for 1 h. After cooled to room temperature, the reaction was concentrated and extracted with EtOAc/H2O, washed with brine, dried over MgSO4, and purified by column chromatography to give the title compound as clear oil (0.50 g). LCMS m/z=293.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H), 3.40 (d, J=5.94 Hz, 2H), 4.94-5.08 (m, 2H), 5.88-6.00 (m, 1H), 6.92-7.31 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=2[N:7]=1.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=2[N:7]=1
Reactant: NC1CCC1
Reactant: Cc1cc2c(Cl)nc(Cl)nc2[nH]1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1cc2c(NC3CCC3)nc(Cl)nc2[nH]1
Yield: 44.9 %

Procedure:
A solution of 2,4-dichloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (190 mg, 0.94 mmol), cyclobutylamine (0.160 mL, 1.88 mmol) and triethylamine (0.200 mL, 1.44 mmol) in nBuOH (6 mL) was stirred at 70° C. overnight. It was then purified by HPLC to give 2-chloro-N-cyclobutyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg).
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19](C4C=CC=CN=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:28])[CH2:12][CH2:11]2)[N:6]=[CH:5]1.C([Sn](CCCC)(CCCC)[C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)CCC>>[ClH:1].[ClH:1].[ClH:1].[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:44]4[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:28])[CH2:12][CH2:11]2)[N:6]=[CH:5]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccccn3)cc2C1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3cccnc3)cc2C1
Yield: 8 %

Procedure:
Example 67 was prepared as a yellow solid in 8% yield from Compound A of Example 37 and 3-(tributylstannyl)pyridine as described for Compound B of Example 37.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.[CH3:21][O:22][CH2:23]Cl>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH2:21][O:22][CH3:23])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(O)cc1OC
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(OC)c(OC)c1
Reaction time: 17 h

Procedure:
To a stirred solution of 3,4-bis(methyloxy)phenol (Commercial eg Alfa Aesar) (1.0 g) and DIPEA (2.28 ml) in DCM (15 ml) was added chloromethyl methyl ether (0.74 ml) at 0 C. After stirring at 25-30 C for 17 h, the reaction was washed with dilute hydrochloric acid and saturated aqueous sodium bicarbonate. This was dried over sodium sulphate and purified through silica eluting with 0-5% ethyl acetate in hexane, to give the title compound, 0.80 g
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:16])([CH3:15])[C:5](=[O:14])[NH:6]2.[CH:17]1(O)[CH2:20][CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH:17]1([N:6]2[C:7]3[C:3](=[C:2]([F:1])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=3)[C:4]([CH3:16])([CH3:15])[C:5]2=[O:14])[CH2:20][CH2:19][CH2:18]1
Reactant: CC1(C)C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Reactant: OC1CCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(=O)N(C2CCC2)c2ccc([N+](=O)[O-])c(F)c21
Reaction time: 5 h

Procedure:
To a solution of 4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (300 mg), cyclobutanol (0.136 mL) and triphenylphosphine (702 mg) in THF (15 mL) was added dropwise diethyl azocarboxylate (40% toluene solution, 1.48 mL) at 0° C., and the mixture was stirred for 5 hr under a nitrogen atmosphere. To the reaction mixture was added water at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:22]1[CH2:23][CH2:24][CH2:25][C:20]([OH:26])([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:21]1)=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3c(F)cccc3F)C2)c1

Procedure:
The compound of Example 23 was prepared according to the general preparation protocol A from 2,6-diflourobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: CS(O[CH2:6][C@H:7]([CH3:15])[CH2:8][CH2:9]OS(C)(=O)=O)(=O)=O.[NH2:16][C@@H:17]([CH3:20])[CH2:18][OH:19]>C(Cl)Cl.C([O-])([O-])=O.[K+].[K+].O>[CH3:15][C@@H:7]1[CH2:8][CH2:9][N:16]([C@@H:17]([CH3:20])[CH2:18][OH:19])[CH2:6]1
Reactant: C[C@H](CCOS(C)(=O)=O)COS(C)(=O)=O
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CCN([C@@H](C)CO)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
(R)-2-Methylbutane-1,4-diyl dimethanesulfonate (37.5 g, 0.144 mol) was added to neat (S)-2-aminopropan-1-ol (54.8 g, 0.730 mol). The mixture was stirred in a room temperature water bath to minimize the exotherm. After 24 h, the reaction was diluted with DCM (150 mL), sat'd K2CO3 solution (150 mL), and just enough water (60 mL) to dissolve the resulting ppt. The organic layer was separated, and the aqueous layer was extracted with DCM (150 mL). The organic layers were combined, dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (10:7; ethyl acetate:hexanes→10:7:2:1; ethyl acetate:hexanes:methanol:triethylamine) to give (S)-2-((R)-3-methylpyrrolidin-1-yl)propan-1-ol (17.9 g) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 4.33 (t, 1H), 3.48 (m, 1H), 3.18 (m, 1H), 2.79 (dd, 1H), 2.58 (m, 1H), 2.48 (m, 1H), 2.26 (m, 1H), 2.08 (m, 1H), 2.01 (dd, 1H), 1.88 (m, 1H), 1.20 (m, 1H), 0.98 (d, 3H), 0.96 (d, 3H); LCMS: 144.3 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH:18]([CH3:20])[CH3:19])[S:5](=[O:17])(=[O:16])[C:6]2[S:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][C:7]=2[CH:8]=1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:39]([NH2:42])[C:40]#[CH:41]>C1COCC1>[CH3:19][CH:18]([N:4]1[C:3]([CH2:2][NH:42][CH2:39][C:40]#[CH:41])=[CH:8][C:7]2[CH:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:6]=2[S:5]1(=[O:17])=[O:16])[CH3:20]
Reactant: CC(C)N1C(CO)=Cc2cc(S(N)(=O)=O)sc2S1(=O)=O
Reactant: C#CCN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCNCC1=Cc2cc(S(N)(=O)=O)sc2S(=O)(=O)N1C(C)C
Reaction time: 18 h
Yield: 39 %

Procedure:
To a solution of the product from Example 15, Step E (1.40 g, 4.14 mmol) and triethylamine (1.26 g, 12.4 mmol) in anhydrous THF (80 mL) at 0° C. was added p-toluenesulfonyl chloride (1.18 g, 6.21 mmol) and the mixture was maintained at this temperature for 20 h. Propargylamine (3 mL) was added to the reaction mixture which was stirred for an additional 18 h. The reaction mixture was evaporated to a residue which was mixed with 2N HCl (60 mL) and this mixture was extracted with ethyl acetate (2×50 mL). The aqueous layer was separated and adjusted to pH 7.5 by the addition of a saturated aqueous solution of sodium bicarbonate (100 mL) followed by extraction with ethyl acetate (2×60 mL). The combined extracts were dried (MgSO4), filtered, and evaporated to a residue which was purified by column chromatography (silica, 50% to 75% ethyl acetate/hexane) to give an oil which crystallized from methylene chloride/hexane to provided an off-white solid (0.61 g, 39%): mp 133°-135° C. Analysis: Calculated for C13H17N3O4S3 : C, 41.58; H, 4.60; N, 11.11. Found: C, 41.42; H, 4.60;0N, 11.11.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[BH:15]1C2CCCC1CCC2.Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[C:28]2[C:34]1[N:35]=[N:36][N:37]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[O:46])=[CH:41][CH:40]=2)[CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C=O)C.O>[BH3:15].[N:47]1([C:45]([C:42]2[CH:41]=[CH:40][C:39]([N:37]3[CH:38]=[C:34]([C:28]4[C:27]5[C:31](=[CH:32][CH:33]=[C:25]([CH2:14][CH:11]6[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]6)[CH:26]=5)[NH:30][N:29]=4)[N:35]=[N:36]3)=[CH:44][CH:43]=2)=[O:46])[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1
Reactant: B1C2CCCC1CCC2
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Br)cc34)nn2)cc1)N1CCOCC1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: B
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)CC1
Temperature: 25 °C
Yield: 87 %

Procedure:
A degassed solution of 1-N-Boc-4-methylene-piperidine (48 mg; 0.24 mmol; 1.1 eq.) and 9-BBN (0.5 M 0.44 mL of a 0.5 M solution in THF; 0.22 mmol; 1.0 eq.) in THF (0.5 mL) was heated at 800 for 1 h in a sealed tube. This solution was allowed to cool to RT and cannulated to a degassed mixture of 5-bromo-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole (100 mg; 0.22 mmol; 1.0 eq.), PdCl2dppf (1 mg; 0.001 mmol; 0.01 eq.) and potassium carbonate (76 mg; 0.55 mmol; 2.5 eq.) in DMF (1 mL) and water (0.1 mL). The resulting mixture was heated at 65° C. O/N. As the reaction was not complete, a second solution of borane was prepared (from 0.24 mmol of 1-N-Boc-4-methylene-piperidine) and added to the reaction mixture which was heated at 65° C. for one more night. The reaction mixture was poured into water and extracted twice with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 90:10) gave the title compound as a yellow powder (110 mg, 87%). 1H NMR (300 MHz, DMSO-d6) δ 13.29 (brs, 1H), 9.36 (s, 1H), 8.21-8.08 (m, 3H), 7.74-7.65 (m, 2H), 7.56-7.48 (m, 1H), 7.32-7.23 (m, 1H), 4.04-3.81 (m, 2H), 3.79-3.36 (m, 8H), 2.83-2.56 (m, 3H), 1.84-1.50 (m, 3H), 1.49-1.39 (m, 1H), 1.37 (s, 9H), 1.21-0.91 (m, 2H). HPLC (max plot) 86.0%; Rt 4.36 min. UPLC/MS: (MS−) 470.2 (M-tBuOCO).
Reaction SMILES: COC1C=C(NC2N=CC3CC(=O)NC4C=C(I)C=CC=4C=3N=2)C=CC=1OC.CNCC#C.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([NH:44][C:45]2[N:46]=[CH:47][C:48]3[CH2:54][C:53](=[O:55])[NH:52][C:51]4[CH:56]=[C:57]([C:60]#[C:61][CH2:62][NH:63][CH3:64])[CH:58]=[CH:59][C:50]=4[C:49]=3[N:65]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH3:43].Cl>>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([NH:44][C:45]2[N:46]=[CH:47][C:48]3[CH2:54][C:53](=[O:55])[NH:52][C:51]4[CH:56]=[C:57]([CH2:60][CH2:61][CH2:62][NH:63][CH3:64])[CH:58]=[CH:59][C:50]=4[C:49]=3[N:65]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH3:43]
Reactant: CNCC#Cc1ccc2c(c1)NC(=O)Cc1cnc(Nc3ccc(OC)c(OC)c3)nc1-2
Agent: C#CCNC
Agent: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Agent: Cl
Product: CNCCCc1ccc2c(c1)NC(=O)Cc1cnc(Nc3ccc(OC)c(OC)c3)nc1-2

Procedure:
In a manner similar to that described for Method O, 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) and N-methylprop-2-yn-1-amine were converted to 2-(3,4-dimethoxy-phenylamino)-9-(3-methylamino-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one. The crude product (unstable) was carried on in a similar manner to that described for Method P to give I-87, which was converted to the HCl salt (40%): MS Rt═0.98 min, m/z═434 (M+H).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].[CH3:7][C:8]1[CH:17]=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH2:18]=O.Cl>C(O)C.O.C(N(CC)CC)C>[NH3:4].[CH2:2]([N:4]([CH2:5][CH3:6])[CH2:18][CH2:7][C:8]1[CH:17]=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH3:3]
Reactant: Cc1cnc2ccccc2n1
Reactant: CCNCC
Reactant: C=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)CCc1cnc2ccccc2n1
Product: N
Temperature: 60 °C
Yield: 0.1 %
Yield: 66.5 %

Procedure:
A solution of diethylamine hydrochloride (3.82 g, 35 mmol) and triethylamine (0.23 ml) in ethanol (1.75 ml) and water (1.75 ml) was added dropwise, at 60° C., to a mixture of 2-methyl-quinoxaline (5.0 g, 35 mmol), formaldehyde (2.81 g of 37% solution, 35 mmol), triethylamine (0.17 ml) and ethanol (4.6 ml). The pH was adjusted to 7–7.5 by mean of dilute aqueous hydrochloric acid. Stirring was maintained 16 hours at 60° C. The solvent was concentrated, the residue was diluted with water and extracted with diethyl ether to remove the unreacted quinoxaline. The aqueous phase was basified with 20% aqueous sodium hydroxide (10 ml) and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with dichloromethane-methanol (first 95-5 then 90-10 and finally 90-10 plus 0.1% of ammonia) to give diethyl-(2-quinoxalin-2-yl-ethyl)-amine (2.67 g, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12](I)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32]([N:34]1[CH:38]=[C:37]([CH3:39])[C:36]([CH3:40])=[C:35]1[CH:41]([OH:44])[C:42]#[CH:43])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(N(CC)CC)C.[Cu]I.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>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([C:43]#[C:42][CH:41]([C:35]3[N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH:38]=[C:37]([CH3:39])[C:36]=3[CH3:40])[OH:44])[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Oc1cc2c(I)c(F)ccc2n1C(=O)OC(C)(C)C
Reactant: C#CC(O)c1c(C)c(C)cn1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cn(C(=O)OC(C)(C)C)c(C(O)C#Cc2c(F)ccc3c2cc(OC(=O)OC(C)(C)C)n3C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-tert-butoxycarbonyloxy-5-fluoro-4-iodo-indole-1-carboxylic acid tert-butyl ester (from Example 2 above) (1 g, 2.22 mmol), and 3,4-dimethyl-2-(1-hydroxy-prop-2-ynyl)-pyrrole-1-carboxylic acid tert-butyl ester (from Example 45 above) (1.38 g, 5.54 mmol) in dry THF(12 mL) and triethylamine(Aldrich, 12 mL) was degassed by bubbling argon through the solution for 10 minutes. At this time copper(I) iodide (Aldrich, 84.4 mg, 0.44 mmol) and (Ph3P)4Pd (0.25 g, 0.22 mmol) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo. Flash chromatography (silica gel, 85:15 hexanes/ethyl acetate) afforded 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-3,4-dimethyl-1H-pyrrol-2-yl)-3-hydroxy-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester as an orange oil. (Yield 0.76 g, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:9]3[CH2:12][C:11](=O)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:16][C@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.N1C=CC=CC=1.B>ClCCl.C(O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@@H:11]([N:18]4[CH2:19][CH2:20][CH2:21][C@@H:17]4[CH3:16])[CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: C[C@H]1CCCN1
Reactant: O=C1CC(c2nc3ccc(Br)cc3s2)C1
Agent: B
Solvent: CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CCCN1[C@H]1C[C@@H](c2nc3ccc(Br)cc3s2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
The product of Example 1C (500 mg, 1.77 mmole) was dissolved in 6 ml dichloromethane and 4 ml ethanol. 2-(S)-methylpyrrolidine (1.04 g, 4.43 mmole, toluene extract from 50% sodium hydroxide) was then added and the solution was stirred at room temperature for 30 minutes. Borane-pyridine (358 μl, 3.54 mmole) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the crude product which was purified by column chromatography (0.4% ammonium hydroxide and 4% methanol in dichloromethane) to give 98 mg (16% yield) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.98 (d, J=2.14 Hz, 1H) 7.80 (d, J=8.85 Hz, 1H) 7.54 (dd, J=8.54, 1.83 Hz, 1H) 3.54-3.65 (m, 1H) 3.15-3.29 (m, 1H) 3.00-3.12 (m, 1H) 2.74-2.85 (m, 1H) 2.58-2.68 (m, 1H) 2.43-2.56 (m, 3H) 2.30-2.39 (m, 1H) 1.92-2.02 (m, 1H) 1.78-1.89 (m, 1H) 1.70-1.76 (m, 1H) 1.44-1.59 (m, 1H) 1.16 (s, 3H). MS: (M+H)+=351/353.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:39])[N:3]=1.C(N(CC)CC)C.[C:47](OC(=O)C)(=[O:49])[CH3:48]>ClCCl>[C:47]([NH:39][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:23]=1[C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=1)(=[O:49])[CH3:48]
Reactant: COc1ccc(COc2cccc(N)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(N)n2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COc2cccc(NC(C)=O)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
To a cooled (0° C.), stirred solution of tert-butyl 3-(2-amino-6-{2-amino-6-[(4-methoxybenzyl)oxy]phenyl}-3-cyano-4-pyridinyl)-1-piperidinecarboxylate (0.10 g, 0.189 mmol) obtained in the step (1) of Example 1-11 in dichloromethane (10 mL) including triethylamine (0.02 g, 0.227 mmol) was added acetic anhydride (0.08 g, 0.889 mmol).The stirring was continued at 0° C. for 5 hrs. The mixture was allowed to warm to room temperature, and the stirring was continued for 30 min. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/1-1/2) to give tert-butyl 3-(6-{2-(acetylamino)-6-[(4-methoxybenzyl)oxy]phenyl}-2-amino-3-cyano-4-pyridinyl)-1-piperidine-carboxylate as a pale yellow oil (0.102 g, yield; 94.5%).