Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C:10]3=[C:9]([C:23](OC)=[O:24])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:28][NH:29][O:30][CH3:31].C([Mg]Cl)(C)C>C1COCC1>[CH3:31][O:30][N:29]([CH3:28])[C:23]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]2[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:15][C:10]=12)=[O:24]
Reactant: COC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
Under a nitrogen atmosphere 7-tert-butyl 1-methyl 3-phenyl-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate (Intermediate 3A) (1.50 g, 4.20 mmol) was dissolved in THF (6 mL) and N,O-dimethyl-hydroxylamine hydrochloride (1.23 g, 12.59 mmol) was added. The resulting suspension was cooled to −20° C. and a solution of iPrMgCl (2M, 6.3 mL, 12.59 mmol) in THF was added dropwise over 10 min. The mixture was stirred for 20 min at −10° C. and then was quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated to provide Intermediate 26A as a white solid (1.35 g, 83%). 1H-NMR (400 MHz, CDCl3) δ: 1.52 (s, 9H), 3.63 (s, 3H), 3.80 (m, 2H), 3.90 (s, 3H), 4.12 (t, 2H), 5.02 (s, 2H), 7.46 (m, 3H), 7.65 (m, 2H); LCMS (+ESI) m/z 387.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][NH:20][CH2:21][CH3:22])[CH:8]=[CH:9][CH:10]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)=[O:26]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[C:31]([F:36])[CH:32]=[C:33]([F:35])[CH:34]=2)=[O:26])[CH2:21][CH3:22])[CH:8]=[CH:9][CH:10]=1
Reactant: CCNCc1cccc(OC)c1-c1cccc(CC(=O)OC)c1
Reactant: O=C(Cl)OCc1cc(F)cc(F)c1
Product: CCN(Cc1cccc(OC)c1-c1cccc(CC(=O)OC)c1)C(=O)OCc1cc(F)cc(F)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and 3,5-difluorobenzyl chloroformate.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[C:25](N1C=CN=C1)(N1C=CN=C1)=[S:26]>O1CCCC1>[S:26]=[C:25]1[N:12]2[C:13]3[N:14]([C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:4]=4)=[CH:10][CH2:11]2)[N:15]=[CH:16][C:17]=3[C:18](=[O:19])[NH:20]1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a stirred solution of 1.00 g of 4,5-dihydro-7-(3-(trifluoromethyl)phenyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (prepared as described in Example 8) in 30 ml of dry tetrahydrofuran cooled to -78° C. is added 286 mg of 60 percent sodium hydride (dispersion in mineral oil). The reaction mixture is stirred at -78° C. for 30 minutes then 637 mg of 1,1'-thiocarbonyldiimidazole is added and the mixture is allowed to slowly warm to room temperature and then is stirred for 36 hours. The mixture is quenched with water, neutralized with 5 percent aqueous hydrochloric acid and extracted with chloroform. Evaporation of the extract in vacuo gives 934 mg of the desired product.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:16]([O-:18])=[O:17])=[C:7]([C:12](Br)=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:44]([O:48][CH3:49])(=[O:47])[CH:45]=[CH2:46]>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([NH:4][C:5]1[C:6]([N+:16]([O-:18])=[O:17])=[C:7]([C:12](/[CH:46]=[CH:45]/[C:44]([O:48][CH3:49])=[O:47])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: COC(=O)c1c(Br)ccc(NC(C)=O)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(NC(C)=O)c([N+](=O)[O-])c1C(=O)OC
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A suspension of methyl 3-(acetylamino)-6-bromo-2-nitrobenzoate (500 mg, 1.58 mmol), palladium acetate (36.0 mg, 0.16 mmol), triphenylphosphine (84.0 mg, 0.32 mmol), potassium carbonate (328 mg, 2.37 mmol) and methyl acrylate (213 μL, 2.37 mmol) in N,N-dimethylformamide (15 mL) was stirred under a nitrogen atmosphere at 110° C. for 30 min with heating. The reaction solution was diluted with water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=25/75→55/45) to give the title compound (303 mg, yield 60%).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([N:15]=[C:16]=[O:17])=[O:14].C([O-])(=O)/C=C/C([O-])=O>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:16]([NH:15][C:13](=[O:14])[C:12]1[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=1[CH3:10])=[O:17])[CH2:3]2
Reactant: NC1CN2CCC1CC2
Reactant: Cc1ccccc1C(=O)N=C=O
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: Cc1ccccc1C(=O)NC(=O)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine (0.63 g, 5 mmol) and crude 2-methylbenzoyl isocyanate (1.35 g, ca 7 mmol). The product (1.23 g) was converted to the 1:1 fumarate, mp 216°-217° C.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].[NH2:22][CH2:23][CH:24]([OH:26])[CH3:25]>>[OH:26][CH:24]([CH3:25])[CH2:23][NH:22][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4]
Reactant: CC(O)CN
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)NCC(C)O)s1
Yield: 69 %

Procedure:
As described for example 58, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (90 mg, 0.29 mmol) was converted, using rac-1-amino-2-propanol instead of rac-2-amino-1-propanol, to the title compound (50 mg, 69%) which was obtained as a light yellow oil. MS: m/e=352.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[CH3:10].[OH:11]O>C(O)=O.O>[Cl:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([C:8]([OH:11])=[O:9])=[CH:6][N:7]=1
Reactant: OO
Reactant: Cc1cc(C=O)cnc1Cl
Solvent: O=CO
Solvent: O
Product: Cc1cc(C(=O)O)cnc1Cl
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A solution of 6-chloro-3-formyl-5-methyl-pyridine (10 g, 64 mmol) in formic acid (200 mL) is cooled at 0° C. and an aq. 50% wt solution of H2O2 in water (9.6 mL, 360 mmol) is added at this temperature. The mixture is stirred at 0° C. for 15 h, carefully diluted with water (200 mL) and extracted with DCM (8×100 mL). The combined org. extracts are washed with 1M aq. HCl (100 mL) (check for remaining peroxide), dried (MgSO4), filtered and evaporated. The residue is dried to give 6-chloro-5-methyl-nicotinic acid (9.56 g); LC-MS: tR=0.72 min, [M+1]+=172.0.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:22][C:21]=3[CH:32]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33].[BH4-].[Na+]>>[CH2:13]([C:12]([C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:22][C:21]=2[CH:32]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:34])[C:2]([CH3:35])([CH3:36])[CH3:1])=[C:7]([CH3:33])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)NCC(=O)O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)NCC(=O)O)cc2c1
Yield: 86.5 %

Procedure:
[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carbonyl)-amino]-acetic acid (52 mg, 0.105 mmol) is reduced with NaBH4 (12 mg, 0.316 mmol) analogous to Example 3 to give the title product (45 mg, 86%).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([C:26]1[CH:45]=[CH:44][C:29]([CH2:30][N:31]([CH2:33][C:34]2[CH:35]=[C:36]([CH:40]([OH:43])[CH2:41][CH3:42])[CH:37]=[CH:38][CH:39]=2)[CH3:32])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C(OCC)C.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[C:22]([C:26]1[CH:45]=[CH:44][C:29]([CH2:30][N:31]([CH2:33][C:34]2[CH:35]=[C:36]([C:40](=[O:43])[CH2:41][CH3:42])[CH:37]=[CH:38][CH:39]=2)[CH3:32])=[CH:28][CH:27]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CCC(O)c1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(=O)c1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 38.1 %

Procedure:
Pyridinium dichromate (2.89 g; 7.68 mmol) was suspended in methylene chloride (30 ml). While the suspension was stirred at room temperature, Compound 92 (0.50 g; 1.54 mmol) in methylene chloride (5 ml) was added dropwise. The mixture was stirred for 4 hours, and diethyl ether (30 ml) and magnesium sulfate (3 g) were added thereto, followed by stirring for 10 minutes. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.19 g of the target compound as colorless transparent oily matter (yield: 38.1%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([NH:18][CH2:19][CH2:20][S:21][CH2:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[CH3:28])=[N:13][CH2:14]CCC.C(N)CCC.CN>C(O)C>[CH3:28][C:27]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:22][S:21][CH2:20][CH2:19][NH:18][C:12]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])=[N:13][CH3:14]
Reactant: CCCCN=C(NCCSCc1nc[nH]c1C)NCCSCc1nc[nH]c1C
Agent: CN
Solvent: CCCCN
Solvent: CCO
Product: CN=C(NCCSCc1nc[nH]c1C)NCCSCc1nc[nH]c1C

Procedure:
In a similar manner N,N'-bis-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]-N"-butylguanidine may be prepared using butylamine in ethanol in place of ethanolic methylamine.
Reaction SMILES: [CH:1]1([N:4]([CH3:27])[C:5]2[C:6]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][N:22]=[CH:21]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O-:17])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([N:4]([CH3:27])[C:5]2[C:6]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][N:22]=[CH:21]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1
Reactant: CN(c1nc2cc(C(=O)[O-])ccc2nc1-c1ccc2[nH]ncc2c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 3-(cyclopropyl(methyl)amino)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylate (40.0 mg, 0.11 mmol,) in methanol (15 mL) and water (1 mL) was added a solution of NaOH (20 mg, 0.50 mmol). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (5 mL) and adjusted to pH 6 with hydrochloric acid (3N). The solids were collected by filtration to afford 3-(cyclopropyl(methyl)amino)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (18.2 mg, 47%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31]([C:26]1[NH:27][C:28]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:21][CH3:20])=[CH:30][CH:29]=2)=[O:32]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Product: COc1ccc2[nH]c(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)cc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 5-methoxy-1H-indole-2-carboxylic acid. MS: 433.2 (M+H).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCc1c(-c2ccccc2)nc2ncnn2c1O
Product: CCCCCCCCc1c(-c2ccccc2)nc2ncnn2c1Cl

Procedure:
A mixture of 17 g (0.05 mol) of 7-hydroxy-6-octyl-5-phenyl-[1,2,4]-triazolo-[1,5-α]-pyrimidine (cf. Ex. 7) and 50 ml of phosphorus oxychloride was heated under reflux for 8 h. Work-up was carried out analogously to Ex. 2. This gave 16 g (0.046 mol) of the title compound.
Reaction SMILES: [ClH:1].Cl.N[C@@H]1CCN([CH2:9][CH:10]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)C1.C(OC(=O)[NH:35][C@@H:36]1[CH2:40][CH2:39][N:38](C(=O)C(C2(O)CCCCC2)C2C=CC=C(OC(F)(F)F)C=2)[CH2:37]1)(C)(C)C>>[ClH:1].[ClH:1].[NH2:35][C@@H:36]1[CH2:40][CH2:39][N:38]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]2([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH3:9])[OH:28])[CH2:37]1
Reactant: N[C@@H]1CCN(CC(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)C(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CC(c1cccc(OC(F)(F)F)c1)C1(O)CCCCC1N1CC[C@@H](N)C1

Procedure:
In an analogous manner to Example 1, step 2, 1-{2-[(3R)-3-aminopyrrolidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl((3R)-1-{(1-hydroxycyclohexyl)[3-(trifluoromethoxy)phenyl]acetyl}pyrrolidin-3-yl)carbamate. MS (ESI) m/z 373; HRMS: calcd for C19H27F3N2O2+H+, 373.20974; found (ESI, [M+H]+), 373.2097.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:10][C@@H:9]([NH2:8])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](COc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)COc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
Dissolve (R)-2-(tert-butoxycarbonylamino)-3-phenoxy-propane (340 mg, 1.35 mmol) in DCM (80 mL), add trifluoroacetic acid (35 mL), and stir at 0° C. for 2 h. Evaporate and purify by SCX chromatography to give the title compound as a colorless oil (186 mg, 91%). MS (ES+) m/z: 151 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([NH:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:28]3[CH:29]=[C:24]([CH2:23][NH:22][S:19]([CH3:18])(=[O:20])=[O:21])[CH:25]=[CH:26][CH:27]=3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Reactant: CS(=O)(=O)NCc1cccc(B(O)O)c1
Product: CS(=O)(=O)NCc1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1

Procedure:
4-(5-Chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 was reacted with 3-((methylsulfonylamino)methyl)phenylboronic acid via General Procedure A to give crude (3-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)phenyl)-N-methylsulfonylmethanamine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 126 after purification by reverse HPLC. MS (Q1) 499 (M+)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:12][C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Cl:12][C:13]1[CH:14]=[N:15][N:16]([C:2]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH:17]=1
Reactant: Clc1cn[nH]c1
Reactant: COc1ccc(F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-n2cc(Cl)cn2)c(C=O)c1
Temperature: 100 °C

Procedure:
To a solution of 2-fluoro-5-methoxybenzaldehyde (450 mg, 2.92 mmol) in DMSO (13 mL) are added 4-chloro-1H-pyrazole (450 mg, 4.39 mmol) and K2CO3 (810 mg, 5.84 mmol) at room temperature. The solution is heated to 100° C. for 1.5 hours. The solution is cooled down and is diluted with H2O (150 mL) and extracted with EtOAc (3×). The combined organic layers are dried with MgSO4 and filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 5-25% EtOAc in heptane as the eluent to afford 2-(4-chloro-pyrazol-1-yl)-5-methoxy-benzaldehyde which is used without further purification
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl.O>[C:34](=[O:35])([O:36][CH2:37][CH3:38])[O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:2]([NH2:1])=[N:3][C:4]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:5]=4[C:6]=3[CH:7]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) (1.0 equiv.) and triethyl amine (2 equiv.) in dichloromethane (0.10 M) at 0° C. was added ethyl chloroformate (1.2 equiv.). The resulting mixture was allowed to stir for 30 minutes at 0° C., after which it was diluted with water and dichloromethane. The biphasic layers were separated and the aqueous layer was washed twice with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexanes to provide 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl ethyl carbonate as a solid. 1H NMR (Acetone-d6): δ 8.78 (s, 1H), 8.73 (s, 1H), 8.28 (d, 1H), 7.43 (s, 1H), 7.33 (d, 2H), 7.10-7.17 (m, 3H), 6.64 (br, 2H), 4.18 (t, 2H), 3.25 (t, 2H), 3.14 (t, 2H), 2.45 (s, 3H), 1.68-1.77 (m, 2H), 0.97 (t, 3H). LRMS [M+H]=416.2
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][NH2:14])=[CH:8][CH2:9][O:10]2)=[CH:5][CH:4]=1>[Ni].CO.CC(O)=O>[ClH:2].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:13][NH2:14])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: NCC1=CCOc2cc(Cl)ccc21
Agent: [Ni]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: NCC1CCOc2cc(Cl)ccc21
Yield: 92 %

Procedure:
Hydrogenation of 1-(7-chloro-2H-chromen-4-yl)methanamine hydrochloride (500 mg, 2.6 mmol) was carried out in the presence of Raney Nickel (300 mg) in 2:1 MeOH/HOAc under 50 psi of H2 for 16 h at 30° C. The reaction was filtered through Celite and concentrated in vacuo. Precipitation from EtOAc and filtration gave 280 mg (56%) of the title compound as a white solid. [M+H] calc'd for C10H12ClNO, 198. found 198.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.[F:18][C:19]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>>[F:18][C:19]1[CH:26]=[C:25]([C:2]2[N:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)[N:3]=2)[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Reactant: CC1(C)OB(c2ccc(C=O)c(F)c2)OC1(C)C
Product: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1F

Procedure:
The title compound was prepared as described in Example 86 using 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (CB5) and isolated as a white solid (0.569 g, 47%): 1H NMR (400 MHz, CDCl3) δ 10.42 (d, J=0.7 Hz, 1H), 8.61 (s, 1H), 8.12 (ddd, J=8.1, 1.5, 0.8 Hz, 1H), 8.05-7.95 (m, 1H), 7.81 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 1H), 7.45-7.39 (m, 2H); ESIMS m/z 352 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Br:11]Br>[Fe].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Br:11]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Fe]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
Iron (0.35 g) was added to 1chloro-4-nitrobenzene (15.8 g) at 140° C., bromine (2.8 ml) was added dropwise and the mixture heated to 140° C. for 1 hour. Two further additions of iron and bromine were made at 1 hour intervals followed by a final addition of iron (0.07 g) and heating to 140° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, added to sodium metabisulfite solution (200 ml) and stirred for 30 min. The solution was extracted with dichioromethane (×4), washed with aqueous sodium metabisulfite and water then dried (MgSO4) to give an oil which was used in the next step without further purification.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCOCC1.Cl>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(S(=O)(=O)c3ccccc3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)c1cccc(N2CCNCC2)c1
Yield: 99.2 %

Procedure:
A solution of 1-(3-phenylsulfonylphenyl)-4-tert-butyloxycarbonyl piperazine (D3) (96 mg, 0.23 mmol) in 1,4-dioxane (3 ml) and 4M HCl (3 ml) was refluxed at 60° C. for 1 h. The solvents were then evaporated in vacuo and the product dried under high vacuum to give a yellow solid (69 mg, 96%)
Reaction SMILES: [OH:1]O.O.[CH3:4][O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:7]>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].[O-2].[Mn+2].CO>[CH3:4][O:5][C:6]([C:8]1[CH:9]=[N+:10]([O-:1])[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:7]
Reactant: COC(=O)c1ccc(C)nc1
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Mn+2]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C)[n+]([O-])c1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 98 %

Procedure:
30% Hydrogen peroxide in water (5.7 mL, 50 mmol) and sodium tungstate dihydrate (270 mg, 0.80 mmol) were added to 6-methylpyridine-3-carboxylic acid methyl ester (3.0 g, 20 mmol). The reaction mixture was stirred at 60° C. for 70 minutes and at 80° C. for 4.5 hours. Under ice cooling, methanol (10 mL) and manganese oxide (0.51 g, 6.0 mmol) were added thereto, and then the reaction mixture was stirred at room temperature for 16 hours. After the insoluble was filtered off with celite, the filtrate was concentrated to give 3.2 g of the title reference compound as a pale brown solid. (Yield 98%)