Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:16][CH:17]([C:19]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:20])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CNC1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Pyrrolidine (271 μL, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(pyrrolidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (550 mg, 72%). 1H NMR (CD3OD, 400 MHz) δ 3.93-3.65 (m, 5 H); 3.43-3.28 (m, 4 H) and 2.00-1.81 (m, 4 H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:22][CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24]([O:30][CH2:31]Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[N:16]([CH2:31][O:30][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:17]=[N:18]2)=[CH:13][C:12]=1[O:22][CH3:23])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
Sodium hydride (1.44 g of a 60% suspension in mineral oil, 36 mmol) was added in portions over 20 minutes to a solution of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.46 g, 30 mmol), in DMF (70 ml) and the mixture was stirred for 1.5 hours. Chloromethyl pivalate (5.65 g, 37.5 mmol) was added dropwise and the mixture stirred for 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (100 ml) and poured onto ice/water (400 ml) and 2M hydrochloric acid (4 ml). The organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined extracts were washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with a mixture of ether and petroleum ether, the solid was collected by filtration and dried under vacuum to give 7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10 g, 84%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.[F-].[Cs+]>C(COC)OC.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1[C:30]1[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Reactant: OB(O)c1cccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2cccnc2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (1.0 g, 2.4 mmol) was dissolved in dimethoxyethane (15 mL) and ethanol (1.5 mL). Pyridin-3-ylboronic acid (0.33 g, 2.65 mmol) was added and argon was bubbled in the mixture for 15 minutes. Cesium fluoride (0.8 g, 5.3 mmol) and tetrakistriphenylphosphine palladium (0.14 g, 0.1 mmol) were added and the mixture was brought to reflux under an argon atmosphere for 4 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate/water (15 mL/15 mL). The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 9/1) to yield 0.45 g (55%) of the desired product as a yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:59])[C:7]([O:10]/[N:11]=[C:12](/[C:46]1[N:47]=[C:48]([NH:51]C(OC(C)(C)C)=O)[S:49][CH:50]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:51][C:48]1[S:49][CH:50]=[C:46](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:59])=[O:5])/[C:13](=[O:14])[NH:15][C@H:16]2[C@@H:17]([CH2:25][N:26]3[CH:30]=[C:29]([CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]4)[N:28]=[N:27]3)[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C:19]2=[O:20])[N:47]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)nn2)cs1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cc(CCN2CCNCC2)nn1)c1csc(N)n1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
To a solution of (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (120 mg, 0.138 mmol) in DCM (1.4 mL) at 0° C. added TFA: DCM (1:1, 4.2 mL) followed by triethylsilane (65 μL, 0.411 mmol). The reaction mixture was stirred at 0° C. for 30 min and slowly warmed to room temperature. After 2 h at rt it was concentrated in vacuo and triturated with MTBE: Heptane (1:2) whereupon a solid was observed. The crude solid was purified by reverse phase prep HPLC (C18 column, acetonitrile: water solvent system with 0.1% formic acid modifier) to afford the title compound (9.3 mg, 11%); LCMS: m/z=612.8 (M−1); 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.99 (s, 1H), 7.30 (s, 2H), 6.66 (s, 1H), 5.27 (dd, J=8.8, 5.5 Hz, 1H), 4.82 (dd, J=14.7, 4.0 Hz, 1H), 4.68 (dd, J=14.7, 6.6 Hz, 1H), 4.24 (td, J=5.9, 4.2 Hz, 1H), 3.10 (t, J=5.2 Hz, 4H), 2.76 (t, J=7.0 Hz, 2H), 2.64-2.54 (m, 6H), 1.37 (s, 3H), 1.30 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[Cl:9].[N+:10]([O-])([OH:12])=[O:11]>>[Cl:9][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([Cl:8])=[CH:7][C:2]=1[Br:1]
Reactant: Clc1ccc(Cl)c(Br)c1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(Cl)c(Br)cc1Cl
Temperature: 0 °C

Procedure:
A solution of 2-bromo-1,4-dichlorobenzene (1.000 g, 4.443 mmol, Aldrich, used as received) in fuming HNO3 (7.0 mL) was stirred at 50° C. for 1.5 h and poured into ice (80 g). Yellowish white solid was filtered, washed with water (10 mL), and dried under vacuum to obtain 1.14 g (95%) of pure (1H NMR) title compound as a yellowish white powder; m.p. 50-53° C. (lit m.p. 57-58° C.; Fox, D. L. and Turner, E. E., J. Chem. Soc. 1859 (1930)); 1H NMR (CDCl3): δ 7.863 (s, 1H), 8.030 (s, 1H). This material was used as such for the next reaction.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>C(OCC)C>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18]1)[N:6]=[CH:5][N:4]=[C:3]2[NH:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCCN(C)C1
Agent: Cl
Solvent: CCOCC
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCC1CCCN(C)C1
Yield: 34 %

Procedure:
Using an analogous procedure to that described in Example 26 except that 3 equivalents of the 1M solution of hydrogen chloride in diethyl ether were used, 4-chloro-6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)quinazoline was reacted with N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide. The reaction product was purified by column chromatography on silica using an 89:10:1 mixture of methylene chloride, methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound in 34% yield; NMR: 1.12 (m, 1H), 1.52 (m, 1H), 1.65-2.05 (broad, 3H), 2.15 (s, 3H), 2.2 (s, 3H), 2.7 (m, 2H), 2.90 (m, 2H), 3.53 (m, 4H), 3.73 (m, 4H), 3.95 (s, 3H), 4.04 (d, 2H), 7.1 (m, 1H), 7.16 (s, 1H), 7.24 (m, 1H), 7.31 (m, 1H), 7.59 (m, 1H), 7.78 (m, 1H), 7.84 (s, 1H), 8.27 (m, 2H), 9.4 (s, 1H), 10.3 (s, 1H); m/s: M+H+ 598.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7](O)=[O:8].O=S(Cl)[Cl:16]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7]([Cl:16])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)cc(OCC(=O)O)c1
Solvent: c1ccccc1
Product: Cc1cc(C)cc(OCC(=O)Cl)c1

Procedure:
A mixture of the 3,5-dimethylphenoxyacetic acid (prepared as described above, 9.3 g, 51.6 mmol) and SOCl2 (11.3 mL, 18.5 g, 156 mmol, 3.0 eq) in 10 mL of benzene was refluxed for 2 h. Then volatile materials were removed by vacuum distillation to give 3,5-dimethylphenoxyacetic acid chloride as a light brown oil. To an ice-bath cooled solution of 6-amino-n-caproic acid (13.5 g, 103 mmol, 2.0 eq) and NaOH (4.2 g, 105 mmol) in 100 mL of H2O and 130 mL of CH3CN were added drop-wise a solution of the acid chloride (prepared in previous step) in 100 mL of CH3CN and a solution of NaHCO3 (6.5 g, 77.0 mmol, 1.5 eq) in 80 mL of H2O. The mixture was stirred vigorously overnight. Then most of the CH3CN was removed under reduced pressure and the mixture was acidified to pH 2 at room temperature with conc-HCl. The resulting white precipitates were collected by filtration, washed with H2O, followed by hexane, and thereafter dried under high vacuum to yield Intermediate 15 (14.5 g, 95%) as a white solid.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][NH:10][CH2:11][C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:55]1([C:61](O)=[O:62])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:30][C:2]1([F:1])[CH2:3][CH2:4][N:5]([CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][N:10]([CH2:11][C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:61]([CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)=[O:62])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CCCCC1
Reactant: Cn1c(=O)c(CNCC(c2ccccc2)N2CCC(F)(F)CC2)cc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(=O)c(CN(CC(c2ccccc2)N2CCC(F)(F)CC2)C(=O)C2CCCCC2)cc2ccccc21
Temperature: 50 °C

Procedure:
3-({[2-(4,4-difluoropiperidin-1-yl)-2-phenylethyl]amino}methyl)-1-methylquinolin-2(1H)-one (52 mg, 0.126 mmol), HATU (57.7 mg, 0.152 mmol), cyclohexanecarboxylic acid (0.019 ml, 0.152 mmol), and DIEA (0.026 ml, 0.152 mmol) were combined in DMF (1.5 ml) and the reaction heated at 50° C. for 0.75 hours. The mixture was purified directly by reversed-phase chromatography (15-95% ACN in water (with 0.5 ml/l NH4OH) over 20 min at 20 ml/min, 20×100 mm Phenomenex Gemini C18 column). Fractions containing desired material were concentrated in vacuo and repurified by reversed-phase chromatography (5-50% ACN (with 0.1% TFA) in water (with 0.1% TFA) over 20 min at 20 ml/min, 20×100 mm Phenomenex Gemini C18 column). Desired fractions were free-based via Phenomenex Strata X-C cartridge. HRMS [M+H] 1+ 522.2936. 1H NMR (400 MHz, CDCl3): δ 7.60-7.55 (m, 1 H), 7.53-7.49 (m, 1 H), 7.39 (d, J=8.52 Hz, 1 H), 7.35-7.28 (m, 4 H), 7.25-7.19 (m, 3 H), 4.50-4.35 (m, 2 H), 4.16-4.07 (m, 1 H), 3.88 (t, J=7.6 Hz, 1 H), 3.76 (s, 3 H), 3.31 (dd, J=7.38 Hz, 13.42 Hz, 1 H), 2.69-2.65 (m, 2 H), 2.53-2.43 (m, 2 H), 2.28-2.20 (m, 1 H), 2.01-1.88 (m, 4 H), 1.74-1.34 (m, 7 H), 1.25-1.05 (m, 3 H). 29.8 mg, 45%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7](CCS)=[N:6][S:5](=[O:12])(=[O:11])[N:4]=1.Cl.Cl[CH2:15][C:16]1[N:17]=[C:18]([NH:21][C:22]([NH2:24])=[NH:23])[S:19][CH:20]=1>>[NH:21]([C:18]1[S:19][CH:20]=[C:16]([CH2:15][S:19][CH2:20][CH2:16][NH:17][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:11])(=[O:12])[N:6]=2)[N:17]=1)[C:22]([NH2:24])=[NH:23]
Reactant: CNC1=NS(=O)(=O)N=C1CCS
Reactant: N=C(N)Nc1nc(CCl)cs1
Agent: Cl
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1

Procedure:
When a solution of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1,1-dioxide [prepared in Example 25, Step A] is reacted with 4-chloromethyl-2-guanidinothiazole hydrochloride and a strong base, the title compound is thereby produced, which is identical to the product obtained in Example 31.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][N:14]([CH3:31])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1>>[CH3:13][N:14]([CH3:31])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=2)[C:10]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:12])=[CH:19][CH:20]=1
Reactant: CCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCc2ccccc21
Product: CCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCc3ccccc32)cc1
Yield: 16 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using indan-1-carboxylic acid (0.46 g) and [(4-dimethylaminophenyl)methyl](4-ethylphenyl)amine (0.6 g) as starting materials, N-[(4-dimethylaminophenyl) methyl]-N-(4-ethylphenyl)indan-1-carboxamide (0.15 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[N:18]([CH3:22])[CH:19]=[N:20][CH:21]=2)=[N:10][S:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[F:23])#[N:2].[CH3:24][Mg+].[Br-]>C1COCC1.CCOCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:10][S:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])([C:17]2[N:18]([CH3:22])[CH:19]=[N:20][CH:21]=2)[CH3:24])=[CH:5][C:4]=1[F:23])#[N:2]
Reactant: C[Mg+]
Reactant: CC(C)CS(=O)N=C(c1ccc(C#N)c(F)c1)c1cncn1C
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CS(=O)NC(C)(c1ccc(C#N)c(F)c1)c1cncn1C

Procedure:
N-[(4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methylene]-2-methylpropanesulfinamide (as described above in Step B) (1.50 g, 4.51 mmol) was dissolved in anhydrous THF (30 mL) at 0° C. to which a 3.0M solution of MeMgBr (4.50 mL, 13.5 mmol) in Et2O was added. The reaction was quenched with aq. NH4Cl solution, diluted with saturated NaHCO3 solution and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, concentrated, and recrystallized from 95% EtOAc/Hexane to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:18][C:19](=O)[NH:20][C:21]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:22]=4[C:23]=3[N:24]=2)[C:9]([CH3:12])=[N:10][CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:18][C:19](=[S:36])[NH:20][C:21]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:22]=4[C:23]=3[N:24]=2)[C:9]([CH3:12])=[N:10][CH:11]=1
Reactant: Cc1ncc(CCCN(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1ncc(CCCN(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=S)C2
Temperature: 50 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of 2-({5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (175 g, 372 mmol), phosphorus pentasulfide (82.7 g, 372 mmol) and pyridine (1.35 L) was heated at 50° C. for 18 hours. HPLC analysis showed completion of the reaction. After the reaction mixture was cooled below room temperature, a solution of sodium carbonate (525 g, 4.95 mol) in 5.1 L of water was slowly added while the temperature was kept at below room temperature. The resulting biphasic solution was separated and the organic layer was washed with the same amount of sodium carbonate solution two times. The organic phase was then reduced to ca. 1.1 L in volume. The solution was diluted with water (1.0 L) and stirred at room temperature overnight resulting in a yellow suspension. The solid was filtered and washed with 200 mL EtOH/water (1 vol/2 vol), and water 200 mL. After drying overnight under vacuo at 40° C., the crude product was dissolved in 1.2 L of EtOH at reflux. Water (2.0 L) was slowly added at 75° C. to induce crystallization. The suspension was then slowly cooled to room temperature and stirred overnight. The solid 2-({5-[3-(Dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-thione was filtered and dried under vac at 40° C. to a constant weight (140.0 g, HPLC purity>98%, 77% yield). LCMS (FA): Rt=6.26 min, m/z=485.2 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1.Br[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Cn1nccc1-c1cc(N)ccc1O
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 29.1 %

Procedure:
4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (3.02 g, 15.96 mmol), tert-butyl 2-bromoethylcarbamate (7.153 g, 2.0 eq) and potassium carbonate (4.412 g, 2.0 eq) were dissolved in 100 mL acetone and refluxed at 60° C. for 24 h. After reaction, the potassium carbonate was filtered and acetone was evaporated. The residue was dissolved in 100 mL DCM and extracted with 3×100 mL 1N NaOH. Purified by column chromatography (50-100% ethyl acetate in hexane) to afford the title compound as a yellow oil in 29.10% yield. LCMS m/z (%)=333 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9 H), 3.33 (q, J=5.05 Hz, 2 H), 3.75 (s, 3 H), 3.91 (t, J=5.05 Hz, 2 H), 4.45-4.51 (m, 1 H), 6.23 (d, J=2.02 Hz, 1 H), 6.62 (d, J=3.03 Hz, 1 H), 6.73 (dd, J=8.59, 3.03 Hz, 1 H), 6.85 (d, 1 H), 7.52 (d, J=2.02 Hz, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([NH2:11])=[O:10].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O>CC(C)=O>[C:16]1([C:14]2[C:7]([CH2:8][C:9]([NH2:11])=[O:10])=[C:2]3[N:1]([CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=O)CCc1ccccn1
Solvent: CC(C)=O
Product: NC(=O)Cc1c(-c2ccccc2)cn2ccccc12
Reaction time: 48 h

Procedure:
2-Pyridinepropaneamide (8.0 g, 53 mmol) was dissolved in warm acetone (500 mL). 2-Bromoacetophenone (12.0 g, 60 mmol) was added and the reaction mixture was heated under reflux overnight. After standing at room temperature for 2 days, the solvent was decanted from the tan precipitate, which was dissolved in ethanol and heated under reflux for 6 h. After standing overnight at ambient temperature, the ethanol was removed under reduced pressure to give a residue which was recrystallized from heptane (500 mL) to give 2-(2-phenyl-indolizin-1-yl)acetamide. 2-(2-Phenylindolizin-1-yl)acetamide (450 mg, 1.8 mmol) was suspended in ethyl ether. To the suspension was added lithium aluminum hydride (360 mg) and the reaction mixture was heated under reflux overnight under a nitrogen atmosphere. After cooling to room temperature, an aqueous solution of Rochelle salt was cautiously added with stirring until a solution was observed. The phases were separated and the aqueous phase was extracted 3 times with ether. The combined organic layers were extracted with 0.1 N HCl, and the aqueous layer was made basic with 2.5 N NaOH. The aqueous phase was extracted with methylene chloride three times and the organic phase was evaporated under reduced pressure to give crude product. The product was purified by chromatography on silica gel eluting with 5-11% methanol in methylene chloride containing 1% ammonium hydroxide. A 53% yield of the title compound was obtained, mp 212-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:29][CH2:30][CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:29][CH2:30][CH:31]=[C:32]3[C:38]4[CH:39]=[CH:40][CH:41]=[N:42][C:37]=4[CH2:36][O:35][C:34]4[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]3=4)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C2(O)CCNCC2)ccc1Cl
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)c([N+](=O)[O-])c3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 14 h
Yield: 30.3 %

Procedure:
To a solution of the 4-(4-Chloro-3-nitro-phenyl)-piperidin-4-ol (0.295 g, 1.2 mmol) in isopropanol was added 2,6-lutidine (0.225 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.224 g, 0.6 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.100 g, 30%). 1H-NMR (CDCl3): δ 1.53 (s, 6H), 1.70 (d, 2H), 1.81–2.18 (m, 4H), 2.3–2.44 (m, 4H), 2.56 (t, 2H), 2.69 (d, 2H), 5.32 (bs, 2H), 6.16 (t, 1H), 6.81 (d, 1H), 7.28 (t, 2H), 7.48 (t, 2H), 7.58 (t, 2H), 8.06 (s, 1H). ESI-MS m/z: 550 (M+1), retention time 1.51.