Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[H-].[Na+].[C:27]([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([N:5]([CH3:27])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(C)NC(=O)c1ccc(C#Cc2ccnc(Cl)c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(C#Cc2ccnc(Cl)c2)cn1)C(C)(C)C
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
(180 mg, 574 μmol) 5-(2-Chloro-pyridin-4-ylethynyl)-pyridine-2-carboxylic acid tert-butylamide (Example 1, step 2) was dissolved in DMF (3 ml) and cooled to 0-5° C. Iodomethane (54 μl, 860 μmol, 1.5 equiv.) and NaH (55%) (41 mg, 860 μmol, 1.5 equiv.) were added and the mixture was stirred for 2 hours without cooling bath. The reaction mixture was treated with sat. NaHCO3 solution and extracted twice with EtOAc. The organic layers were extracted with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (20 g, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 5-(2-chloro-pyridin-4-ylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide (78 mg, 42% yield) was obtained as a yellow solid, MS: m/e=328.4/330.4 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C.O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1ccccc1
Reaction time: 0.67 h
Yield: 87.7 %

Procedure:
4-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole (530 mg, 2.2 mmol) was added to 88 mg (2.2 mmol) of 60% NaH/mineral oil in 20 mL of DMF and the mixture stirred for 0.67 hours. Then, 0.21 mL (2.2 mmol) of methyl bromoacetate was added and stirring maintained for 17 hours. The mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4), and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 597 mg (88% yield) of [[2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester, 140-143° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f21) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][C:36]1=[O:41]>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[C:36](=[O:41])[CH2:37]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: CN1CCNCC1=O
Solvent: COCCO
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)C(=O)C4)c(OC)cc23)c2c1OCO2
Yield: 79 %

Procedure:
This was prepared using the method described in example 13 using N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (250 mg, 0.51 mmol) and 1-methylpiperazin-2-one (290 mg, 2.54 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (229 mg, 79%) as a pale brown solid; NMR Spectrum: ()MSOd6) 1.98 (quintet, 2H), 2.56 (t, 2H), 2.69 (t, 2H), 2.82 (s, 3H), 3.01 (s, 2H), 3.30 (t, 2H), 3.35 (s, 3H), 3.93 (s, 3H), 4.19 (t, 2H), 4.37 (s, 2H), 6.16 (s, 2H), 7.15 (s, 1H), 7.18 (s, 1H), 7.81 (s, 1H), 8.32 (s, 1H), 9.52 (s, 1H); Mass Spectrum: M+H+ 566/568.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[F:22].[F:23][C:24]1[C:33]2[N:28]([C:29](=[O:51])[N:30]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37](B4OC(C)(C)C(C)(C)O4)[C:36]=3[CH3:50])[C:31](=[O:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C1COCC1>[F:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([N:30]2[C:31](=[O:34])[CH:32]=[C:33]4[C:24]([F:23])=[CH:25][CH:26]=[CH:27][N:28]4[C:29]2=[O:51])[C:36]=1[CH3:50])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(F)c(Br)c12
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2c(F)cccn2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: Cc1c(-c2c(F)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)cc2c(F)cccn2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 27] (6.00 g, 16.4 mmol), 5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione (single enantiomer) [Intermediate 38] (7.81 g, 19.7 mmol), 2 M aqueous K3PO4 (24.6 mL, 49.3 mmol), and THF (70 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with 1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (0.535 g, 0.821 mmol), and subjected to two more evacuate-fill cycles with nitrogen. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed sequentially with water and brine, and dried. The aqueous layer was filtered and the collected solid was added to the organic layer. The organic layer was concentrated, and the residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 50%, 62%, 75%, 85% and 100%), to provide 3-fluoro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of two atropisomers) as a yellow solid (8.55 g, 94% yield). A sample of this material (combined with other batches of the same material) was separated by chiral super-critical fluid chromatography as follows: column. CHIRALPAK® IC (3×25 cm, 5 μm); Mobile Phase: CO2-MeOH (50:50) at 165 mL/min, 45° C., 100 bar; sample preparation: 55 mg/mL in MeOH-THF-DMSO (2:1:1); injection: 3 mL. The first peak eluting from the column provided a single atropisomer of 3-fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Example 41].
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1(O)[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]1>Cl>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH:13]=1
Reactant: CCN1CCC(O)(c2cccc(C(F)(F)F)c2F)CC1
Agent: Cl
Product: CCN1CC=C(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to preparation 4: 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1-ethylpiperidin-4-ol (3.3 g, 11.3 mmol), hydrochloric acid (10 ml, conc). Yield: 3.1 g. MS m/z (rel. intensity, 70 eV) 273 (M+, 65), 272 (32), 258 (bp), 147 (24), 110 (22).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]1[CH2:11][NH:10][C:9](=O)[CH2:8][O:7]1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1>>[CH:23]1([C:2]2[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=2[O:4][C@@H:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:6]2[O:7][CH2:8][CH2:9][NH:10][CH2:11]2)[CH2:25][CH2:24]1
Reactant: OB(O)C1CC1
Reactant: O=C1COC(C(Oc2ccccc2Br)c2ccccc2)CN1
Product: c1ccc([C@H](Oc2ccccc2C2CC2)[C@@H]2CNCCO2)cc1

Procedure:
(S)-2-[(S)-(2-Cyclopropyl-phenoxy)-phenyl-methyl]-morpholine was synthesized from 6-[(2-Bromo-phenoxy)-phenyl-methyl]-morpholin-3-one and cyclopropyl boronic acid according to general procedures A and B and was isolated as a viscous colorless oil. 1H NMR (CDCl3): δ 7.40-7.24 (m, 5H), 6.91 (m, 1H), 6.80 (m, 2H), 6.66 (d, 1H), 5.15 (d, 1H), 3.94 (m, 2H), 3.65 (dt, 1H), 2.85-2.59 (m, 4H), 2.32 (m, 1H), 0.99-0.89 (m, 2H), 0.74-0.59 (m, 2H); MS (ES) 310.1 [C20H23NO2+H]+; HPLC purity (98.6%); Analysis: Calc'd for C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 76.61; H, 7.58; N, 4.37.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:16]([O-])=O)=[CH:7][C:6]=2[N:5]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:4]1>C1C=CC=CC=1.O=[Pt]=O>[NH2:16][C:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:3]([CH2:2][Cl:1])[CH2:4][N:5]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[C:6]=2[CH:7]=1
Reactant: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21)C(F)(F)F
Agent: O=[Pt]=O
Solvent: c1ccccc1
Product: Nc1cc2c(c3ccccc13)C(CCl)CN2C(=O)C(F)(F)F
Yield: 88.8 %

Procedure:
A solution of the above nitro compound (175 mg, 0.49 mmol) in benzene (30 mL) was hydrogenated over PtO2 (45 mg) at 50 psi for 1 h. Removal of the catalyst and solvent provided a solid which was recrystallised from i-Pr2O/petroleum ether to give 5-amino-1-(chloromethyl)-3-trifluoroacetyl-1,2-dihydro-3H-benz[e]indole (143 mg, 89%), mp 177° C. 1H NMR [(CD3)2SO] δ 8.11 (d, J=8.4 Hz, 1 H, H-6), 7.80 (d, J=8.3 Hz, 1 H, H-9), 7.60 (s, 1 H, H-4), 7.50 (t, J=7.7 Hz, 1 H, H-8), 7.35 (t, J=7.7 Hz, 1 H, H-7), 6.14 (s, 2 H, NH2), 4.45 (dd, J=11.0, 8.7 Hz, 1 H, H-2), 4.33 (d, J 11.2 Hz, 1 H, H-2), 4.24-4.16 (m, 1 H, H-1), 4.03 (dd, J=11.0, 3.0 Hz, 1 H, CHHCl), 3.84 (dd, J=11.0, 7.1 Hz, 1 H, CHHCl). Anal. Calculated for C15H12ClF3N2O: C, 54.8; H, 3.7; N, 8.5; Cl, 10.8. Found: C, 55.1; H, 3.4; N, 8.6; Cl, 10.7%.
Reaction SMILES: C[N:2]1C(=O)CCC1.N.Br[C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([C:20]3([CH3:24])[CH2:23][CH2:22][CH2:21]3)[N:15]=2)[CH:11]=1>C(OCC)(=O)C.[Cu](I)I>[CH3:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([C:20]3([CH3:24])[CH2:23][CH2:22][CH2:21]3)[N:15]=2)[CH:11]=[C:10]([NH2:2])[CH:18]=1
Reactant: CN1CCCC1=O
Reactant: Cc1cc(Br)cc2cn(C3(C)CCC3)nc12
Agent: I[Cu]I
Agent: N
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc2cn(C3(C)CCC3)nc12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Copper oxide (I) (50 mg), NMP (2.5 mL), and concentrated aqueous ammonia (2.5 mL) were added to 5-bromo-7-methyl-2-(1-methylcyclobutyl)-2H-indazole obtained in the above-described Step 1 (536 mg), and the reaction solution was stirred in a microwave reactor at 100° C. for 5 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and then washed successively with water three times and then with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum, and the resultant was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 7-methyl-2-(1-methylcyclobutyl)-2H-indazol-5-amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:16]=[C:15]([C:28]([OH:30])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:50]([N:52]3[CH2:56][C:55](=[O:57])[NH:54][CH2:53]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)[N:16]=[C:15]([C:28]([N:52]3[CH2:50][CH2:53][NH:54][C:55](=[O:57])[CH2:56]3)=[O:30])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:10])[F:12])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccnc(C(F)(F)F)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3ccnc(C(F)(F)F)c3)n2)CCN1

Procedure:
75 mg (0.15 mmol) of the compound of Example 47A is reacted analogously to the synthesis of the compound of Example 1 with 17 mg (0.17 mmol) of 2-oxopiperazine. 74 mg (84% of theory) of the title compound is obtained.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[O:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]([NH2:33])[CH2:25][CH2:24]1>>[O:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]([NH:33][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:25][CH2:24]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NC1CCOc2ccccc21
Product: Cc1nc(NCc2ccccn2)nc(NC2CCOc3ccccc32)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 3,4-dihydro-2H-chromen-4-ylamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.89 (s, 3H), 2.10 (bs, 1H), 2.42 (s, 3H), 4.11 (bs, 1H), 4.27 (bs, 1H), 4.93 (bs, 1H), 5.04 (bs, 1H), 5.31 (bs, 1H), 5.48 (bs, 1H), 6.75-6.88 (m, 3H), 7.20 (bs, 1H), 7.27 (bs, 1H), 7.42 (bs, 1H), 7.74 (bs, 1H), 8.02 (bs, 1H), 8.59 (bs, 1H), 10.63 (bs, 1H); MS (ESI) m/z 362.9 (M+1)+.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([Cl:23])[C:16]([Cl:24])=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[C:25](OCC)(=[O:29])/[CH:26]=[CH:27]/[CH3:28].[CH3:33][S:34]([OH:37])(=[O:36])=[O:35]>>[S:34]([OH:37])(=[O:36])(=[O:35])[CH3:33].[Cl:23][C:17]1[C:16]([Cl:24])=[C:15]2[C:14]3=[C:19]([C:20]4[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C:12]=4[N:13]3[CH:27]([CH3:28])[CH2:26][C:25]2=[O:29])[CH:18]=1
Reactant: C/C=C/C(=O)OCC
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cc(Cl)c(Cl)cc3c2CC1
Agent: CS(=O)(=O)O
Product: CC1CC(=O)c2c(Cl)c(Cl)cc3c4c(n1c23)CCNCC4

Procedure:
Following the general procedure of Example 41, making non-critical variations but starting with 3-benzoyl-8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, using ethyl crotonate in step 7, and using methanesulfonic acid for the salt formation, the title compound was obtained (mp 225-230° C. [dec.]). 1H NMR (d-DMSO) δ 8.94, 8.12, 4.97, 3.48-3.20, 3.13, 2.77, 2.30, 1.20; IR (drift) 3029, 2979, 2849, 2792, 1683, 1481, 1410, 1312, 1214, 1196, 1184, 1161, 1145,1040, 775 cm−1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:23]=1.[CH3:24][N:25]([CH2:27]N(C)C)[CH3:26]>C(Cl)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][CH2:24][N:25]([CH3:27])[CH3:26])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[CH:23]=1
Reactant: CN(C)CN(C)C
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(C)n1-2
Solvent: CC(=O)Cl
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCN(C)C)n1-2

Procedure:
In the manner given in Example 1, a solution of 8-methylthio-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide N,N,N',N',-tetramethyldiaminomethane and acetyl chloride (in 0.1 molar excess compared to the N,N,N',N',-tetramethyldiaminomethane) are reacted together to give 8-methylthio-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:16]3[O:17][C:18]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[N:19][N:20]=3)[C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:29]I>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:16]3[O:17][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:29])[CH2:23][CH2:22]4)=[N:19][N:20]=3)[C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: COc1cccc(-c2cnc(N)c(-c3nnc(C4CCNCC4)o3)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-c2cnc(N)c(-c3nnc(C4CCN(C)CC4)o3)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 19.3 %

Procedure:
To a solution of 5-(3-methoxyphenyl)-3-[5-(4-piperidyl)-1,3,4-oxadiazol-2-yl]pyridin-2-amine (150 mg, 0.42 mmol) in THF (20 mL) was added 60% NaH (25.0 mg, 064 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 10 min. Then MeI (54.5 mg, 0.38 mmol) was added at 0° C. and stirred the reaction mixture at 0° C. for 2 h. The reaction mixture was poured into ice-water (30 mL), extracted with ethyl acetate (3×20 mL), organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude product was purified by preparative TLC to afford the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15](F)[C:14]([F:18])=[CH:13][C:3]=1[C:4]([NH:6][C@@H:7]([CH3:12])[C:8]([F:11])([F:10])[F:9])=[O:5].Cl.[NH:20]1[CH2:23][CH:22]([OH:24])[CH2:21]1.N12CCCN=C1CCCCC2>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:16]=[C:15]([N:20]2[CH2:23][CH:22]([OH:24])[CH2:21]2)[C:14]([F:18])=[CH:13][C:3]=1[C:4]([NH:6][C@@H:7]([CH3:12])[C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: C[C@H](NC(=O)c1cc(F)c(F)cc1F)C(F)(F)F
Reactant: OC1CNC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(O)C2)cc1F)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of 2,4,5-trifluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (6.39 g, 23.6 mmol), azetidin-3-ol hydrochloride (3.19 g, 28.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (8.81 mL, 58.9 mmol) in acetonitrile (25 mL) was stirred at 80° C. for 2 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with 1N HCl (50 mL), 1N NaHCO3 (60 mL), 20% brine (50 mL) and water (75 mL). The aqueous layers were extracted with EtOAc (100 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to yield the desired product (7.59 g, 91.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.38 (dd, J=8.9, 1.9 Hz, 1H), 7.27 (dd, J=12.8, 6.5 Hz, 1H), 6.38 (dd, J=12.3, 7.5 Hz, 1H), 5.71 (d, J=6.4 Hz, 1H), 4.74 (dp, J=15.3, 7.6 Hz, 1H), 4.62-4.46 (m, 1H), 4.30-4.15 (m, 2H), 3.71 (m, 2H), 1.29 (d, J=7.1 Hz, 3H) ppm. LCMS cacld. for C13H14F5N2O2 (M+1)+: m/z=325.1. Found: 325.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([N:11]=[C:12]2[S:16][CH2:15][C:14]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:13]2)[N:3]=1.[CH2:21](Br)[CH:22]([CH3:24])[CH3:23].[H-].[Na+].CO>CN(C=O)C>[CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([N:11]=[C:12]2[S:16][CH2:15][C:14]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[N:13]2[CH2:21][CH:22]([CH3:24])[CH3:23])[N:3]=1
Reactant: CC(C)CBr
Reactant: Cc1cc(N=C2NC3(CCCC3)CS2)nc(C)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(N=C2SCC3(CCCC3)N2CC(C)C)nc(C)c1C#N
Temperature: 50 °C
Yield: 17 %

Procedure:
To a solution of 2-(2,4-dimethyl-3-cyano-6-pyridylimino)-3-thia-1-azaspiro[4.4]nonane (Method C1e; 0.192 g, 0.669 mmol) and isobutyl bromide (0.5 mL) in anh. DMF (0.5 mL) was added NaH (95%; 0.62 g, 6.69 mmol) portionwise. The resulting mixture was heated at 50° C. for 3 h, then treated with MeOH (approximately 0.5 mL) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from 20% EtOAc/hex to 100% CH2Cl2) to give 2-(2,4-dimethyl-3-cyano-6-pyridylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane (0.04 g, 17%): CI-MS m/z 343 ((M+H)+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:12])[C:10]=1[CH3:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:24]=[CH:25][CH:26]=[N:27]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:12][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[CH3:11])[C:5]([NH:27][CH:26]1[CH2:24][CH2:25]1)=[O:7]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(Br)cc(C(=O)O)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cc(C(=O)NC2CC2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3,5-dibromo-4-methylbenzoic acid (1 eq.) in DMF (0.4 M) was added HATU (1.3 eq.), cyclopropylamine (1.1 eq.) and Hunig's base (3 eq.). The resulting yellow mixture was stirred at RT for 18 h. The reaction was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Trituration of the crude product thus obtained in a mixture of ether and hexanes afforded the title compound as an off-white solid.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC(F)(F)S(O[C:35]1[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([CH3:42])[CH:36]=1)(=O)=O>>[CH3:42][C:37]1[CH:36]=[C:35]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH:18]=2)[CH2:16][NH:15][CH:12]2[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]2)[CH:40]=[C:39]([CH3:41])[N:38]=1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C)n1
Product: COc1ccc(-c2cc(C)nc(C)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (400 mg, 1.02 mmol) is coupled to pyridyl triflate 91 (260 mg, 1.02 mmol) using Method B to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][N:12]=2)=[N:3]1>[Pt]=O.CO>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]2[NH:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[N:3]1
Reactant: Cn1ccc(-c2cnccn2)n1
Agent: O=[Pt]
Solvent: CO
Product: Cn1ccc(C2CNCCN2)n1

Procedure:
A 1.76 g portion of 3-(1-methyl-1H-pyrazol-3-yl)pyrazine and 0.5 g of platinum oxide catalyst in 75 ml of methanol was hydrogenated for 18 hours. The catalyst was removed and the filtrate evaporated, giving 1.8 g of 3-(1-methyl-1H-pyrazol-3-yl)piperazine.