Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][C@H:13]([CH3:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:11]([CH3:23])[CH2:10]2)=[CH:4][CH:3]=1.[BH4-].[Na+].[CH2:26]=O.C[O-].[Na+]>>[CH3:23][C@@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:26])=[CH:3][CH:4]=2)[CH2:14][C@H:13]([CH3:15])[N:12]1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17]
Reactant: C[C@@H]1CN(Cc2ccc(N)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2R,6S)-4-[(4-aminophenyl)methyl]-2,6-dimethyl-1-piperazinecarboxylate (D28) using a method similar to that described for D23 in Description 23A although the reaction was heated at 50° C. for 48 h prior to addition of sodium borohydride then for 1 h after addition. Further paraformaldehyde (1 eq) and sodium methoxide (1 eq) were added; the reaction was heated at 50° C. for 12 h; further sodium borohydride (1 eq) was added and the reaction heated at 50° C. for 1 h. δH (CDCl3, 400 MHz) 7.16 (2H, d), 6.57 (2H, d), 4.05 (2H, m), 3.70 (1H, br s), 3.36 (2H, s), 2.82 (3H, s), 2.59 (2H, d), 2.06 (2H, dd), 1.49 (9H, s), 1.27 (6H, d). MS (ES): 356.3, (MNa+), 234.3, no molecular ion (MH+) observed.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.CC(O)=O.[BH3-]C#N.[Na+].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:23]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(Cc2ccccc2)C1
Yield: 104 %

Procedure:
To a solution of (R)-tert-butyl piperidin-3-ylcarbamate (500 mg, 2.4 mmol) in MeOH (15 mL), AcOH (0.75 mL, 12.4 mmol) and NaCNBH3 (310 mg, 4.8 mmol) were added sequentially. To this stirred solution was added benzaldehyde (0.25 mL, 2.4 mmol) drop-wise. The reaction mixture was stirred at rt for 60 h before saturated K2CO3(aq) solution was added to neutralize it. The reaction mixture was concentrated in vacuo to give a residue which was dissolved in water and extracted with EtOAc (30 mL×3). The combined EtOAc layer was dried over Na2SO4 and concentrated in vacuo to afford the titled intermediate (725 mg, 48%) that was used in the next step without further purification. LC-MS: m/z [M+1]=291.
Reaction SMILES: Cl.Cl.[C:3]1([C:9]2[C:10]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([C@@H:35]2[CH2:39][CH2:38][C:37]([CH3:41])([CH3:40])[N:36]2[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:32](O)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([C@@H:31]([C@H:35]2[N:36]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:37]([CH3:41])([CH3:40])[CH2:38][CH2:39]2)[C:32](=[O:33])[N:21]2[CH2:20][CH2:19][N:18]([C:10]3[C:9]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:14][N:13]=[C:12]4[NH:15][CH:16]=[CH:17][C:11]=34)[CH2:23][CH2:22]2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Br)cc2)CCC1(C)C
Reactant: c1ccc(-c2cnc3[nH]ccc3c2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2CCN(c3c(-c4ccccc4)cnc4[nH]ccc34)CC2)c2ccc(Br)cc2)CCC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyri dine dihydrochloride (0.0159 g, 0.0454 mmol, see Example 19), (S)-2-(4-bromophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.017 g, 0.0412 mmol, see Example C) and TBTU (0.0159 g, 0.0495 mmol) in DCM (1 mL) were added to DIEA (0.0287 mL, 0.165 mmol) and stirred at room temperature for 1 hour. The mixture was directly loaded to column and purified by chromatography (1:1 hexane:ethyl acetate) to give (S)-tert-butyl 5-((S)-1-(4-bromophenyl)-2-oxo-2-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)ethyl)-2,2-dimethylpyrrolidine-1-carboxylate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (0.5 mL) and 2M HCl in ether (1 mL) was added. The resulting solid was collected by filtration to give (S)-2-(4-bromophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)ethanone dihydrochloride (0.025 g, 95%). MS APCI (+) m/z 574 detected.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[C:14]([CH3:21])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.C(#N)C.O.FC(F)(F)C(O)=O>CN(C)C=O>[CH:22]1([NH:25][C:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[C:14]([CH3:21])[CH:13]=3)[CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: Cc1cc(-c2cc3ncccc3c(Cl)n2)ccc1N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc3ncccc3c(NC3CC3)n2)ccc1N(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
100 mg (0.34 mmol) 6.1, 75 μL (1.07 mmol) cyclopropylamine were dissolved in 500 μl dimethylformamide and stirred overnight at 100° C. The mixture was combined with acetonitrile/water and trifluoroacetic acid and purified by chromatography (RP-HPLC). The corresponding fractions were freeze-dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9](Cl)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH2:12])=[O:5])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH2:12])=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1N
Solvent: CCN(CC)CC
Product: CCCCNc1nc(C)c(C(=O)OCC)c(N)c1[N+](=O)[O-]

Procedure:
26 g. of 4-amino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol.) in 300 ml. of alcohol and 15 g. of triethylamine are treated with 7.3 g. of butylamine for 30 minutes at reflux temperature. After this time, the solution is evaporated to dryness and 100 ml. of ethyl acetate are added to the residue. The triethylammonium chloride is filtered off, the solvent is evaporated and the remaining oil recrystallized from methanol. The yield of 4-amino-6-butylamino-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester is 25 g. (84%), m.p. 74°-76° (methanol).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[N:7]([CH3:16])[C:6]=1[CH3:17])=[O:4].B(Br)(Br)Br>>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[N:7]([CH3:16])[C:6]=1[CH3:17])=[O:4]
Reactant: CNC(=O)c1c(C)n(C)c2cc(OC)ccc12
Agent: BrB(Br)Br
Product: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Yield: 72.5 %

Procedure:
Example 16(e) was prepared from 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16d (560 mg, 2.4 mmole) by treatment with BBr3 in a manner as previously described for example 1d to obtain 380 mg (73%) of white solid. 1H NMR (DMSO-d6) δ 9.05 (1H, s), 7.50 (1H, d, J=8.59 Hz), 7.35–7.28 (1H, m), 6.73 (1H,d, J=1.77 Hz), 6.60 (1H, dd, J=8.5, 2.27 Hz), 3.54 (3H, s), 2.75 (3H, d, J=4.55 Hz), 2.53 (3H, s). Anal. Calcd. for C12H14N2O2.0.3H2O: C, 64.44; H, 6.58; N, 12.53. Found: C, 64.55; H, 6.49; N, 12.35.
Reaction SMILES: [Cl:1][C:2]1[C:19]([O:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH:10]([CH3:11])[C:4]=2[C:3]=1[Cl:22].C([O-])([O-])=O.[K+].[K+].CO>O>[Cl:1][C:2]1[C:19]([O:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([CH3:11])[C:4]=2[C:3]=1[Cl:22]
Reactant: COc1nc2c(c(Cl)c1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1nc2c(c(Cl)c1Cl)C(C)CNCC2
Temperature: 57.5 °C
Yield: 90.1 %

Procedure:
To a solution of CuCl2 (87 mg, 0.65 mmol) and nBuNO2 (950 μl, 0.81 mmol) in MeCN (18 ml) was added a solution of 4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (182 mg, 0.54 mmol) in MeCN (9 ml) at room temperature. After heating the mixture at 50° C. for 4 h, it was quenched with sat. aq. NaHCO3 and extracted with EtOAc The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to provide 62 mg (32%) of 3,4-dichloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 4.30 (0.5H), 4.00 (0.5H), 3.92 (3H), 3.83 (1H), 3.74 (1H), 3.38 (1H), 3.25 (2H), 3.10 (1H), 1.16 (3H) ppm. A mixture of 3,4-dichloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (61 mg, 0.17 mmol), K2CO3 (70 mg, 0.51 mmol), MeOH (2.4 ml) and H2O (0.5 ml) was heated at 55-60° C. for 30 minutes. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to give 40 mg (90%) of 3,4-dichloro-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 3.91 (s, 3H), 3.55 (m, 1H), 3.20 (m, 2H), 3.10 (dd, 1H), 2.93 (m, 2H), 2.71 (dd, 1H), 1.25 (d, 3H) ppm.
Reaction SMILES: Br[C:2]1(Br)[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12.CC(C)=[O:25]>O.[N+]([O-])([O-])=O.[Ag+]>[I:13][C:11]1[CH:10]=[CH:9][C:6]2[O:7][CH2:8][C:2](=[O:25])[C:3]3[N:4]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=3)[C:5]=2[CH:12]=1
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(Br)Br
Reactant: CC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A solution of ethyl 4,4-dibromo-9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (0.93 g, 1.71 mmol) in acetone (40 ml) and water (10 ml) was treated with silver(I) nitrate (0.78 g, 4.59 mmol) and then stirred at room temperature for 2 hours. The solids were removed by filtration through celite and carefully washed with acetone (3×50 ml). The filtrate and washings were combined and concentrated in vacuo before the residue was distributed between ethyl acetate (300 ml) and brine (100 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified by FCC (silica, 0-20% ethyl acetate in heptane) to give 0.54 g (79%) of the title compound as crystalline solid. 1H-NMR (500 MHz, CDCl3) 8 ppm 1.45 (3H, t, J=7.10 Hz), 4.48 (2H, q, J=7.17 Hz), 4.78 (2H, s), 7.06 (1H, d, J=8.39 Hz), 7.67 (1H, s), 7.70 (1H, dd, J=8.54, 2.14 Hz), 8.44 (1H, d, J=2.14 Hz); M+1=399.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[N:24]1([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:34][C:33]4[CH:32]=[CH:31][C:30]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:36][CH:35]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(N4CCOCC4)cc3)(CC1)CC2
Yield: 44.1 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-morpholinylaniline (61.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-morpholinylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (33.0 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].CN(C)N>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:11]1[C:10](=[O:15])[CH:11]=[C:12]([CH3:13])[O:14][C:12]=1[CH3:13])=[O:15]
Reactant: CC(=O)CC(=O)Nc1c(C)cccc1C
Agent: CN(C)N
Product: Cc1cc(=O)c(C(=O)Nc2c(C)cccc2C)c(C)o1
Yield: 63 %

Procedure:
The title compound was prepared from N-(2,6-dimethylphenyl)-3-oxo-butanamide and N,N-dimethylhydrazine as the raw materials in a similar manner to the method described in Example 2. (Yield: 63%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.FC(F)(F)C(O)=O.[C:30]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[CH:42]=1)[C:37](O)=[O:38])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[CH:42]=1)[C:37]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:38])([CH3:33])([CH3:31])[CH3:32]
Reactant: CN1CCN(c2cc(C(=O)O)cc(C(C)(C)C)c2)CC1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(N3CCN(C)CC3)cc(C(C)(C)C)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
35 mg (0.12 mmol) of the compound of Example 6A and 47 mg (0.12 mmol) of the compound of Example 21A were reacted and worked up analogously to the procedure of Example 16. This gave 25 mg (95% pure, 38% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:32]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:18]([C:19]([F:32])=[O:20])=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1C(=O)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a suspension of 4.91 g (14.85 mmol) of the product prepared in step 11.1 in 75 mL of dichloromethane are added 2.07 g (14.85 mmol) of triethylamine and then 1.88 mL (22.28 mmol) of cyanuric fluoride. The mixture is stirred at room temperature for 2 hours and the solution is diluted with 100 mL of dichloromethane. The organic phase is washed three times with 100 mL of ice-cold aqueous NaHCO3, dried over MgSO4, filtered and concentrated under vacuum. 4.56 g of the expected product are obtained, and are used directly in the following step. Yield=98%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH2:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.O.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl>[Na].C(O)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: CC(=O)Cc1ccc2c(c1)Cc1cccnc1O2
Reactant: CN(C)CCCl
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)C(CCN(C)C)c1ccc2c(c1)Cc1cccnc1O2
Yield: 56.4 %

Procedure:
4.1 g of 5H-[1]benzopyrano[2,3-b]pyridin-7-yl-acetone is dissolved in a solution of 0.44 g of metallic sodium in 20 ml of absolute isopropyl alcohol by warming to 50°-60°C. The solution is water-cooled, 2.3 g of 2-dimethylaminoethyl chloride is added, and the mixture is stirred under reflux for 1 hour. The reaction mixture is concentrated, chloroform and water are added to the residue, and the mixture is shaken. The chloroform layer is separated and extracted with dilute hydrochloric acid, and the extract is neutralized with 10% sodium hydroxide and then extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous magnesium sulfate and concentrated to give 3 g of crude 3-(5H-[1]benzopyrano[2,3-b]-pyridin-7-yl)-5-dimethylamino-2-pentanone as a pale yellowish brown transparent oil. The product is treated with maleic acid in acetone in a conventional manner, and the crystalline precipitate is recrystallized from isopropyl alcohol to give 3-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-5-dimethylamino-2-pentanone maleate as white needles melting at 145°-146°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](Br)[CH:12]=2)[NH:7][N:6]=1)=[O:4].[CH:15](O[Na])=[O:16]>CN(C=O)C.CCOC(C)=O.O.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>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:15]=[O:16])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]c2ccc(Br)cc12
Reactant: O=CO[Na]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1n[nH]c2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.7 %

Procedure:
A mixture of 5-bromo-1H-indazole-3-carboxylic acid methyl ester (1 g, 3.92 mmol), HCOONa (400 mg, 5.88 mmol), and PdCl2(PPh3)2 (138 mg, 0.2 mmol) in DMF (10 mL) was put under vacuum, and charged with CO. This process was repeated three times, and the mixture was kept at 110° C. for 6 hr. The reaction mixture was cooled to rt, diluted with EtOAc and water, and extracted. The organic phase was dried and concentrated. Purification via flash chromatography afforded 5-formyl-1H-indazole-3-carboxylic acid methyl ester (430 mg, 54%).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[CH:8]([NH:18]C(=O)C)[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[O:16][CH3:17])(C)(C)C.Cl.[OH-].[Na+]>>[NH2:18][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[O:16][CH3:17])[CH2:7][OH:6]
Reactant: COc1cnccc1CC(NC(C)=O)C(C)(C)O[SiH2]C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cnccc1CC(N)CO
Temperature: 100 °C
Yield: 46.4 %

Procedure:
A mixture of 1.2 g of N-[1-(tert-butyl-dimethyl-silanyloxymethyl)-2-(3-methoxy-pyridin-4-yl)ethyl]-acetamide in 60 mL of aqueous solution of 6N hydrochloric acid is heated at a temperature of about 100° C. for 30 minutes. After cooling at a temperature of about 20° C., an adequate volume of an aqueous 30% sodium hydroxide solution is added dropwise to obtain a pH of about 10. The mixture is extracted with 3 times 100 mL of ethyl acetate and the organic extracts are combined, dried over magnesium sulfate then concentrated under reduced pressure (2 kPa) at a temperature of about 40° C. About 0.3 g of 2-amino-3-(3-methoxy-pyridin-4-yl)-1-propanol is obtained in the form of an yellow-colored oil. [Infrared spectrum CH2Cl2: 3628; 3335; 2948; 1614; 1561; 1400; 1319; 1162; 1044 et 815 cm−1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:18]([OH:20])=[O:19])[S:17][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]2[CH2:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:18]([O:20][CH2:31][CH3:32])=[O:19])[S:17][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(C(=O)O)cc1C(c1ccccc1Cl)=NC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Reaction time: 8 h

Procedure:
The obtained (4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-2-yl)carboxylic acid was dissolved in dimethylformamide. Potassium carbonate and ethyl iodide were added, and the mixture was stirred overnight to give ethyl (4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-2-yl)carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][OH:19])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[O:20]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][OH:19])=[C:8]2[C:13]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:33][CH:32]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CO
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1CO
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of compound 16B (84 mg, 0.30 mmol), 4-phenoxyaniline (72 mg, 0.39 mmol) and triethylamine (0.083 mL, 0.60 mmol) in THF (2.5 mL) was heated at 70° C. for 30 min. After cooled to room temperature, the reaction was concentrated to about 0.5 mL, diluted with MeOH (2 mL) and filtered. The solid was washed with MeOH and dried to give compound 16C as yellow solid (118 mg, 92%). HPLC: 92% at 2.12 min (retention time) (Prime Sphere 5u C18-HC column. 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). MS (ES): m/z 429.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:6][C:7]=1[CH2:8][OH:9].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(OC([NH:57][C@H:58]([C:62](O)=[O:63])[CH:59]([CH3:61])[CH3:60])=O)(C)(C)C.C(N(CC)CC)C>>[CH3:1][C:2]1[C:3]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:6][C:7]=1[CH2:8][O:9][C:62](=[O:63])[C@H:58]([CH:59]([CH3:61])[CH3:60])[NH2:57]
Reactant: Cc1c(CO)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1c(COC(=O)[C@@H](N)C(C)C)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C

Procedure:
The same procedures as in Example 167 were repeated using 5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (32.9 mg, 0.171 mmol), N-t-butyloxycarbonyl-valine (34.4 mg, 0.158 mmol), and triethylamine(23.9 μl, 0.171 mmol) to afford the titled compound.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.Br[N:20]1[C:24]2[CH:25]=[C:26]([N+:33]([O-:35])=[O:34])[C:27]([N+:30]([O-:32])=[O:31])=[C:28](Br)[C:23]=2[NH:22][S:21]1>C1COCC1.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>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[N:20]1[C:24]2[CH:25]=[C:26]([N+:33]([O-:35])=[O:34])[C:27]([N+:30]([O-:32])=[O:31])=[C:28]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)[C:23]=2[NH:22][S:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: O=[N+]([O-])c1cc2c(c(Br)c1[N+](=O)[O-])NSN2Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(c(-c3cccs3)c1[N+](=O)[O-])NSN2c1cccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Tributylstannylthiophene (9.06 g, 24.3 mmol) and 1,4-dibromo-5,6-dinitro-2,1,3-benzothiadiazole (3.80 g, 9.90 mmol) were dissolved in anhydrous THF (150 mL). After adding Pd(PPh3)2Cl2 (338 mg, 0.48 mmol), reflux was performed for 16 hours. After the reaction was terminated, the temperature was raised to room temperature and the solvent was removed. The product was extracted with dichloromethane and distilled water, dried, subjected to column chromatography (neutral alumina, hexane) and recrystallized in toluene to obtain yellow solid. 1H NMR (500 MHz, CDCl3, ppm): δ 7.75 (dd, 2H, J=5.0 Hz, J=1.0 Hz), 7.52 (dd, 2H, J=3.5 Hz, J=1.0 Hz), 7.24 (dd, 2H, J=5.0 Hz, J=3.5 Hz).