Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7](=[N:16]O)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+].C([BH3-])#N.[Na+]>[Cl-].[Cl-].[Cl-].[Ti+3]>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]([NH2:16])[C:6]2[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C(=NO)c2ccc(OC)cc2)cc1
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Product: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Yield: 80.8 %

Procedure:
Following a procedure similar to that described in Preparation 12, but using 10.7 g of 4,4'-dimethoxybenzophenone oxime, 33.9 g of ammonium acetate, 7.46 g of sodium cyanoborohydride, and 79 ml of a 17-19% by volume aqueous solution of titanium trichloride, 8.18 g of the title compound were obtained, as an oily substance.
Reaction SMILES: Cl[N:2]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:4]([CH3:16])[CH2:3]1.Br[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=1>>[C:12]([O:11][C:9]([N:5]1[CH2:6][C@H:7]([CH3:8])[N:2]([C:18]2[CH:23]=[N:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:3][C@H:4]1[CH3:16])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: C[C@@H]1CN(Cl)[C@@H](C)CN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])nc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Yield: 74.3 %

Procedure:
Following the procedures as described for compound 108a, (2R,5S)-tert-butyl 4-chloro-2,5-dimethylpiperazine-1-carboxylate (1.5 g, 6.0 mmol) and 5-bromo-2-nitropyridine (1212 mg, 6.0 mol) were reacted to give 104a as a yellow solid (1500 mg, 75%). LCMS: [M+H]+ 337. See FIG. 4.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:19][CH3:20])=[CH:7][C:8]([CH:17]=[O:18])=[C:9]([CH:16]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2].N1C=CN=C1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl.CCOCC.O>[C:1]([O:4][C:5]1[C:6]([O:19][CH3:20])=[CH:7][C:8]([CH2:17][O:18][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31])=[C:9]([CH:16]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CCc1cc(OC(C)=O)c(OC)cc1C=O
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCc1cc(OC(C)=O)c(OC)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-acetoxy-2-formyl-4-methoxyhydrocinnamate (3.31 g) and imidazole (2.42 g) in methylene chloride (25 ml) is added a solution of tert-butylchlorodimethylsilane (2.73 g) in methylene chloride (25 ml). The mixture is stirred at room temperature for about 60 minutes, diluted with ether and water, and the organic layer washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([NH:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]([O:29]C)=[O:28])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:33])[C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]([OH:29])=[O:28])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N[C@@H](C)c3ccccc3)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
To a solution of (S)-methyl 2-(4-fluorophenyl)-3-(1-phenylethylamino)quinoxaline-6-carboxylate (100 mg, 0.25 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (30 mg, 0.75 mmol), and the reaction mixture was stirred for 10 minutes. CH3I (106 mg, 0.75 mmol) was added, and the resulting mixture was stirred overnight. The reaction was then quenched by the addition of NH4Cl solution (50 mL) and adjusted pH to 5 with hydrochloric acid (3N). The solids were collected by filtration to afford (S)-2-(4-fluorophenyl)-3-(methyl(1-phenylethyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (47.5 mg, 48%).
Reaction SMILES: [ClH:1].[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:35]CC2C=CC=CC=2)=[C:26]([NH:28][S:29]([N:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH:27]=1)[OH:21].CO.C(OCC)(=O)C>CO.[Pd]>[ClH:1].[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:35])=[C:26]([NH:28][S:29]([N:32]([CH3:33])[CH3:34])(=[O:30])=[O:31])[CH:27]=1)[OH:21]
Reactant: CN(C)S(=O)(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)S(=O)(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1O

Procedure:
According to the procedures as given in Example 2, the compound of Example 24 (in a solution of 40 mg of the compound in 5.1 ml of methanol) was subjected to a hydrogenolysis using 10% palladium/carbon black (24 mg), whereby the above-identified compound (38.3 mg) was obtained. Rf=0.38 (methanol/ethyl acetate of 1/3).
Reaction SMILES: Cl[S:2]([NH:5][CH2:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])(=[O:4])=[O:3].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[CH2:23][N:22]([CH3:28])[CH2:21][CH:20]2[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[CH2:23][N:22]([CH3:28])[CH2:21][CH:20]2[C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:2]([NH:5][CH2:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])(=[O:4])=[O:3])=[CH:31][CH:30]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Reactant: CCOP(=O)(CCNS(=O)(=O)Cl)OCC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CCNS(=O)(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1)OCC
Temperature: 60 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed diethyl 2-(chlorosulfonylamino)ethylphosphonate (intermediate 30.8) (670 mg, 2.40 mmol, 1.47 equiv), 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenamine (intermediate 30.7) (500 mg, 1.63 mmol, 1.00 equiv), N-ethyl-N-isopropylpropan-2-amine (400 mg, 3.10 mmol, 1.91 equiv) in acetonitrile (20 mL). The resulting solution was stirred for 3 h at 60° C. The resulting mixture was concentrated under vacuum and the residue was applied to a silica gel column and eluted with dichloromethane/methanol (20:1). This resulted in 150 mg (16%) of the title compound as a light yellow solid.
Reaction SMILES: [N+]([C:4]([CH3:16])=[CH:5][C:6]1[S:7][CH:8]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:10]=1)([O-])=O.[OH2:17].Cl>[Fe].CO>[N:11]1([C:9]2[CH:10]=[C:6]([CH2:5][C:4](=[O:17])[CH3:16])[S:7][CH:8]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O
Reactant: CC(=Cc1cc(-n2ccnc2)cs1)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CC(=O)Cc1cc(-n2ccnc2)cs1

Procedure:
A mixture of 34 g (1-[2-(2-nitro-1-propenyl)-4-thienyl]-imidazole, 65 g iron powder, 0.9 ferrichloride hexahydrate, 51 ml methanol and 100 ml water are heated to reflux temperature while stirring. At this temperature, 65 ml concentrated hydrochloric acid are added dropwise within 1 hour. Subsequently, stirring is continued for 11/2 hours under reflux. After cooling, the mixture is stirred into 4 times the amount of methanol. Then, it is filtrated. The filtrate is evaporated to about 1/5 of its volume and filled up with water to 500 ml. The precipitated brown deposit is sucked off, then the filtrate is extracted several times with dichloromethane. The united dichloromethane phases are dried and evaporated. The residual crude product is used in the following reaction steps without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:16][C:15]([F:18])([F:17])[CH2:14]3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:17][C:15]1([F:18])[CH2:16][CH:13]([N:10]2[C:4]3[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:27]4[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=4)[C:3]=3[CH2:12][CH2:11]2)[CH2:14]1
Reactant: CSc1nc(Cl)c2c(n1)N(C1CC(F)(F)C1)CC2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CSc1nc(-c2cnc(N)nc2)c2c(n1)N(C1CC(F)(F)C1)CC2
Temperature: 120 °C
Yield: 24.7 %

Procedure:
To a suspension of 4-chloro-7-(3,3-difluorocyclobutyl)-2-(methylsulfanyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (844 mg, 2.89 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (920 mg, 4.20 mmol) in 1,4-dioxane (24 mL), was added 1 M aqueous solution of Na2CO3 (9 mL, 8.68 mmol) at room temperature. The reaction was purged with nitrogen for a few minutes before adding PdCl2(dppf)-DCM (354 mg, 0.434 mmol). The reaction was heated at 120° C. for 1 h in a microwave reactor. The mixture was cooled to room temperature and filtered through Celite® rinsing with EtOAc. The filtrate was concentrated and DCM was added, resulting in precipitation that was filtered to give a crude title compound (768 mg, ˜80% purity). The mother liquor was purified via silica gel chromatography using a gradient of EtOAc/heptane to afford an additional 250 mg of the title compound as a white solid (95% purity). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 2 H), 7.08 (s, 2 H), 4.51-4.36 (m, 1 H), 3.71 (t, J=8.2 Hz, 2 H), 3.22 (t, J=8.2 Hz, 2 H), 3.13-2.94 (m, 2 H), 2.94-2.80 (m, 2 H), 2.47 (s, 3 H). m/z (APCI+) for C15H16F2N6S 351.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[N:30]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:33]3[CH2:34][CH2:35][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:32]3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.39 mmol), tert-butyl piperazine-1-carboxylate (218 mg, 1.17 mmol), and acetic acid (117 mg, 1.95 mmol) in dichloromethane (20 mL) was stirred at room temperature overnight. Then the mixture was cooled to 0° C. and sodium triacetoxyborohydride (124 mg, 0.58 mmol) was added. After the addition, the mixture was stirred at room temperature for 5 h. Dichloromethane was removed under reduced pressure. The crude product was purified by flash chromatography to give the title compound (70 mg, yield 32%). LC-MS (ESI) m/z: 556 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C:13](=[CH:15][CH3:16])[CH2:12][N:11]([C:17](OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.ClC1[CH:42]=[CH:41][N:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44]>C(O)C.CCOC(C)=O.[Pd]>[CH2:15]([C@H:13]1[CH2:12][N:11]([C:17]2[CH:42]=[CH:41][N:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])[CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14]1)[CH3:16]
Reactant: CC=C1C[C@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91 %

Procedure:
To a solution of (S)-benzyl 3-(tert-butoxycarbonylamino)-5-ethylidenepiperidine-1-carboxylate (1 eq) in 5.5 mL of ethanol and 5.5 mL of EtOAc was added 10% Pd/C (0.1 eq). The resulting suspension was stirred at H2 atmosphere for 45 minutes. The crude solids were filtered through a pad of Celite on a paper lined Buchner funnel, washed with MeOH, then concentrated in vacuo. The residue was dissolved in 1.4 mL of isopropanol and DIPEA (2.5 eq) and 4-chloro-3-nitropyridine (1.5 eq) were added. The reaction mixture was stirred at 80° C. overnight, at which point the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with 120 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to yield tert-butyl(3S,5R)-5-ethyl-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate (91%). LC/MS (m/z): 351.2 (MH+), Rt: 0.75 min.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:33][CH2:32][C:18]2([N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[NH:20][C:19]2=[O:31])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl.C(Cl)Cl.CCCCCC>[ClH:29].[ClH:1].[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:21]1[NH:20][C:19](=[O:31])[C:18]2([CH2:32][CH2:33][NH:15][CH2:16][CH2:17]2)[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1ccc(Cl)cc1Cl)NC2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=C1NC(c2ccc(Cl)cc2Cl)=NC12CCNCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 219.4 %

Procedure:
4 N HCl-dioxane (20 ml, 80 mmol) was added to a solution of 2-(2,4-dichloro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (3.11 g, 7.81 mmol) in CH2Cl2 (60 mL), and the mixture was stirred at room temperature for four hours. The reaction mixture was diluted with CH2Cl2-hexane, and the precipitated solid was then filtered. The resulting solid was washed with ethyl acetate and then dried under reduced pressure to give 2-(2,4-dichloro-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one dihydrochloride (3.18 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1/[CH:34]=[CH:35]/[CH:36]=[CH:37]/[CH:38]=O)[C:29]#[N:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:29]([C:28]1[CH:31]=[CH:32][C:33](/[CH:34]=[CH:35]/[CH:36]=[CH:37]/[C@H:38]2[O:21][CH2:20][C@H:19]([S:18][C@H:16]([CH3:17])[C@:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])([OH:24])[CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:22][O:23]2)=[C:26]([F:25])[CH:27]=1)#[N:30]
Reactant: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Yield: 66.8 %

Procedure:
In the same manner as that described in Example 1(iii) above, a reaction was carried out using 1.02 g (2.84 mmol) of (2R,3R)-2-(2,5-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(IH-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Step 8(vi) above], 571.6 mg (2.84 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile and 594.5 mg (3.13 mmol) of p-toluenesulfonic acid monohydrate and the reaction product was purified by chromatography on a silica gel (75 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to give 1.03 g (yield 66%) of the title compound as a colorless non-crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH:22]=O)[C:19]([C:24](OC)=[O:25])=[C:18]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=1[CH2:44][NH2:45].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[CH3:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=1[CH2:44][N:45]1[C:24](=[O:25])[C:19]2[C:18]([C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)=[N:17][C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[N:21][C:20]=2[CH2:22]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1c(C=O)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2Cc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Reaction time: 1 h
Yield: 3 %

Procedure:
Methyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-formyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (0.175 g, 0.382 mmol) was dissolved in DCM (2 mL) and MeOH (1 mL). To this mixture was added (2,4-dimethoxyphenyl)methanamine (0.057 mL, 0.382 mmol) and sodium acetate (0.094 g, 1.145 mmol). The mixture was stirred in a capped 20 mL vial for 1 h, after which sodium cyanoborohydride (0.060 g, 0.954 mmol) was added. The reaction mixture was stirred at RT overnight. After the solvent was removed under reduced pressure, the residue was dissolved in DMSO/MeOH (1/1) solution. An off-white solid precipitate was initially formed, which was isolated by vacuum filtration, rinsed with MeOH, and air dried to give a first batch of the title compound (6.7 mg). The mother liquor was purified via preparative HPLC. The fractions were concentrated under reduced pressure until an off-white solid precipitate was formed, which was collected by vacuum filtration and air dried to give a second batch (46 mg) of the title compound (total 62.5 mg, 28%). [M+H] calc'd for C30H39N7O5, 578. found, 578.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH3:11])[C:6]([C:9]#[N:10])=[N:7][CH:8]=1>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]([CH3:11])[C:6]([C:9]#[N:10])=[N:7][CH:8]=1)=[O:1]
Reactant: Cc1cc(CO)cnc1C#N
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cc(C=O)cnc1C#N
Reaction time: 8 h
Yield: 72.7 %

Procedure:
MnO2 (165 mg, 1.903 mmol) was added to a solution of 5-(hydroxymethyl)-3-methyl-2-pyridinecarbonitrile (28.2 mg, 0.190 mmol) in DCM (2 ml) at rt and the mixture was stirred at that temperature overnight. LCMS showed the starting material was gone. The solids were filtered off and the solvent evaporated. 5-Formyl-3-methyl-2-pyridinecarbonitrile (20.2 mg) was obtained impure. It was used in the next step without prior purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:16])(=O)=O.C([O-])(O)=O.[Na+]>ClC1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:16][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cccc1C
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COC(=O)c1c(C)cccc1CCl
Reaction time: 2 h
Yield: 128.4 %

Procedure:
11.9 g of methyl 2,6-dimethylbenzoate are initially charged in 50 ml of chlorobenzene admixed at room temperature with 8.2 g of sulfuryl chloride and 40 mg of AIBN. The mixture is stirred at 60–90° C. for 2 h. Afterwards, the mixture is admixed with 80 ml of saturated NaHCO3 solution. After the phase separation, the organic phase is washed with 100 ml of 10% Na2SO3 solution, the organic phase is dried over magnesium sulfate and the chlorobenzene is distilled off in vacuo. 15.5 g of colorless liquid are obtained. The product is distilled under high vacuum (0.1 mbar, 66–77° C.). Yield: 10.2 g (71% of theory; 95.2 area %).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C(#N)C.[Pt]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)OCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CC#N
Product: CC(C)OCCCNc1c(N)cnc2cc(Br)ccc12
Reaction time: 4 h
Yield: 96.1 %

Procedure:
(7-Bromo-3-nitroquinolin-4-yl)-(3-isopropoxypropyl)amine (51 g) was slurried in acetonitrile (750 mL) and added to a Parr flask containing 5% platinum on carbon (5 g). The flask was degassed three times, then charged with hydrogen (30 psi) and shaken for 4 hours with replenishment of the hydrogen as necessary. The platinum catalyst was removed by filtration through a bed of CELITE filter agent. The filtrate was evaporated to afford 7-bromo-N4-(3-isopropoxypropyl)quinoline-3,4-diamine as a yellow oil (45 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][NH:29][CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:13][CH2:12]1>>[NH2:33][C:19]1[N:20]=[C:21]([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])[CH2:30]3)=[CH:25][CH:24]=2)[CH:22]=[C:17]([N:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]2)[N:18]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Product: CC(C)COC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared from isobutyl chloroformate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=425.4.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([NH2:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(-n2nc(C(C)C)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(C)C)cc2NC(=O)Oc2ccccc2)cc1
Yield: 98.1 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (333 mg, 1.45 mmol) and potassium carbonate (261 mg, 1.89 mmol) in anhydrous DCM (5.3 ml) was added dropwise phenyl chloroformate (0.55 ml, 4.34 mmol) as a solution in DCM (3.5 ml). The crude was purified by silica gel chromatography (DCM/MeOH 0-10%) to afford phenyl 3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate (500 mg, 98%). 1H NMR (300 MHz, CDCl3) δ 1.30 (d, J=7 Hz, 6H), 2.99 (m, 1H), 3.87 (s, 3H), 6.41 (s, 1H), 7.03 (d, J=9 Hz, 2H), 7.11-7.14 (m, 2H), 7.23-7.26 (m, 2H), 7.35-7.42 (m, 4H); LC-MS (ESI) m/z 352 (M+H)+.