Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([NH:9][C@H:10]([C:12]2[N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14](=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH3:11])=[O:8])=[CH:5][N:6]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1.CN(C)C1C=CN=CC=1>[C:37]([NH:1][C:2]1[S:3][C:4]([C:7]([NH:9][C@H:10]([C:12]2[N:13]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:14](=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH3:11])=[O:8])=[CH:5][N:6]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: C[C@H](NC(=O)c1cnc(N)s1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(C(=O)N[C@@H](C)c2cc3cccc(Cl)c3c(=O)n2-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-2-amino-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)thiazole-5-carboxamide (2) (100 mg, 0.24 mmol) and triethylamine (0.07 mL, 0.48 mmol) in anhydrous THF (5 mL), acetyl chloride (0.025 mL, 0.35 mmol) and 4-(dimethylamino)pyridine (2.5 mg, 0.02 mmol) were added and the resulting mixture was stirred at RT for 4 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)-2-acetamido-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)thiazole-5-carboxamide (compound 50). ESI-MS m/z: 467.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([OH:9])[N:3]=1.NC1N=C(Cl)N=C(Cl)N=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23]>>[NH2:1][C:2]1[NH:3][C:4](=[O:9])[N:5]=[C:6]([NH:23][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])[N:7]=1
Reactant: Nc1nc(O)nc(Cl)n1
Reactant: COC(CN)OC
Agent: Nc1nc(Cl)nc(Cl)n1
Product: COC(CNc1nc(N)[nH]c(=O)n1)OC

Procedure:
2-Amino-4-chloro-6-hydroxy-s-triazine (hereinafter referred to as COMPOUND II) is described in Chem. Abst., 77, 165133y (1972). This compound in turn can be prepared from 2-amino-4,6-dichloro-s-triazine (hereinafter referred to as COMPOUND I) by controlled hydrolysis of one of the halogens of COMPOUND I. Condensation of COMPOUND II with aminoacetaldehyde dimethyl acetal in aqueous basic media at reflux temperatures gave crystalline 2-amino-4-(2,2-dimethoxyethylamino)-s-triazin-6-one (hereinafter referred to as COMPOUND III) in a good yield. Hydrolysis of the acetal groups of COMPOUND III was achieved by heating COMPOUND III in 6 N hydrochloric acid on a steambath under a nitrogen atmosphere to give the hydrochloride salt of 2-amino-4(2-hydroxyvinyleneamino)-s-triazin-4-one. The free-base of this compound, hereinafter referred to as COMPOUND IV, was obtained by careful neutralization of an aqueous solution of the hydrochloride salt. Ring annulation of either COMPOUND IV or its hydrochloride salt in concentrated sulfuric acid at 95° C. for 1.5 hours gave crystalline 2-aminoimidazo[1,2-a]-s-triazin-4-one (hereinafter referred to as COMPOUND V) in a good yield.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.[NH+]1C=CC=C[CH:23]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.C(N(CC)CC)C>COC(OC)(C)C.C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9](=[CH:10][CH2:11]2)[CH:8]=[C:7]([O:21][CH3:23])[CH2:6][CH2:5]1
Reactant: c1cc[nH+]cc1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: COC1=CC2=CC[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1

Procedure:
7.8 g of 11β-fluoro-estr-4-ene-3,17-dione (A′) was stirred in 40 ml of 2,2-dimethoxypropane with 780 mg of pyridinium-toluene-4-sulfonate for 5 hours at 80° C. Then, 1.5 ml of triethylamine was added. Then, it was diluted with ethyl acetate and washed with saturated sodium chloride solution. After crystallization from methanol, 5.3 g of 11β-fluoro-3-methoxy-estra-3,5-dien-17-one (A″) with a melting point of 173° C. was obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1([CH2:23][Cl:24])[C:11]2=[N:12][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:14]([OH:17])[C:15](=[O:16])[N:10]2[CH2:9][CH2:8][O:7]1)(=[O:3])[CH3:2].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:4][CH2:5][C:6]1([CH2:23][Cl:24])[C:11]2=[N:12][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:14]([O:17][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:16])[N:10]2[CH2:9][CH2:8][O:7]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2(CCl)COC(C)=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(CCl)COC(C)=O
Reaction time: 16 h

Procedure:
A solution of ethyl 9-(acetoxymethyl)-9-(chloromethyl)-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate (2.05 g, 5.68 mmol) in dimethylfomamide (60 mL) was treated with benzyl bromide (1.46 g, 8.5 mmol, Aldrich) and K2CO3 (1.26 g, 9.1 mmol) and stirred for 16 hrs. Solvent was removed in-vacuo and the crude material was dissolved in ethyl acetate (30 mL) and washed with water (30 mL) and brine (30 mL). The organic solution was dried (Na2SO4), filtered, and concentrated to give an amber oil. This was purified by flash column chromatography, eluting with 5% Et2O in CH2Cl2. Product fractions were pooled and concentrated in-vacuo to give the title compound as a colorless oil: 1H NMR (500 MHz, CDCl3) δ ppm 7.45 (2H, d, J=7.32 Hz), 7.29-7.39 (3H, m), 4.68 (1H, d, J=1 1.90 Hz), 4.37 (1H, d, J=1 1.90 Hz), 4.31 (2H, q, J=7.22 Hz), 4.16-4.24 (2H, m), 4.09-4.16 (1H, m), 4.06 (1H, d, J=11.29 Hz), 3.95-4.03 (1H, m), 3.89 (1H, d, J=1 1.29 Hz), 2.06 (3H, s), 1.56 (2H, s), 1.29 (3H, t, J=7.17 Hz); 13C NMR (126 MHz, CDCl3) δ ppm 170.16, 164.04, 158.67, 150.65, 141.94, 141.67, 136.51, 128.59 128.52, 128.45, 79.57, 74.51, 65.90, 62.11, 60.59, 49.08, 42.16, 20.83, 14.16; HRMS (ESI) calcd for C21H24N2O7Cl (M+H) 451.1272; found 451.1274.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].Br[C:21]1[CH:22]=[C:23]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:28][NH:27][C:24]2=[N:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-2](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[CH:28][NH:27][C:24]3=[N:25][CH:26]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCOc1ccc(B(O)O)cc1OCCOC
Reactant: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCCOc1ccc(-c2cnc3[nH]cc(-c4ccccc4OC)c3c2)cc1OCCOC
Yield: 63.5 %

Procedure:
A vial is charged with 81.0 mg (0.300 mmol) of 3,4-bis(2-methoxyethoxy)phenylboronic acid, 60.6 mg (0.200 mmol) of 5-bromo-3-(2-methoxyphenyl)-1H-pyrrolo [2,3-b]pyridine and 8.3 mg (5 mol %) of bis(triphenylphosphino)palladium(II)-dichloride. 1.5 ml of acetonitrile and 1.5 ml of a 2 M aqueous solution of sodium carbonate were added and the mixture irradiated in a Personal Chemistry® microwave reactor to 150° C. for 15 minutes. The mixture was extracted with three times with 15 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The dark brown residue (187 mg) was purified by flash chromatography on silicon using a gradient of ethyl acetate in hexane to give 57 mg of 5-[3,4-bis-(2-methoxy-ethoxy)-phenyl]-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as a colorless powder. 1H-NMR (d4-methanol) δ: 8.41 [1H] d (2.0 Hz), 8.17 [1H] d (2.0 Hz), 7.63 [1H] s, 7.56 [1H] dd (1.5 Hz, 7.5 Hz), 7.30 [1H] m, 7.26 [1H] d (2.5 Hz), 7.20 [1H] dd (2.3 Hz, 8.3 Hz), 7.11 [1H] d (8 Hz), 7.08 [1H] (8.5 Hz), 7.05 [1H] dt (1 Hz, 7.5 Hz) 4.24 [2H] m, 4.19 [2H] m, 3.77 [4H] m, 3.44 [3H] s, 3.43 [3H] s. MS m/z: 449.2 [MH+], 471.1.1 [MNa+].
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.B(O)(O)[C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1>>[C:16]1([C:3]2[C:2]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: Cc1ccc(B(O)O)cc1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(C)cc3)nc2c1
Yield: 74.7 %

Procedure:
The ester product was obtained via a Suzuki coupling reaction using the method previously shown in Example 13, Step 6. Methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.34 mmol, 1.00 equiv) and p-tolylboronic acid (54 mg, 0.4 mmol, 1.10 equiv) were used as starting materials and chromatography was performed with ethyl acetate/petroleum ether (1:20) as the eluent, affording 90 mg (76%) of methyl 2-phenyl-3-p-tolylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [OH:1]O.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]([CH3:22])[CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>C(O)(C)C.[Pt]>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]([CH3:22])[CH2:15][N+:16]2([O-:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: OO
Reactant: CC(=Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1
Agent: [Pt]
Solvent: CC(C)O
Product: CC(=Cc1ccc(C(C)(C)C)cc1)C[N+]1([O-])CCCCC1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
5.4 g of 30% hydrogen peroxide are added dropwise at 40° C. to a solution of 5.4 g of 1-[3-(p-tert.butyl-phenyl)-2-methyl-2-propenyl]-piperidine in 40 ml of isopropanol, this addition being repeated after 24 hours. After stirring at 40° C. for 60 hours, the mixture is cooled and the excess hydrogen peroxide is decomposed by the addition of platinum sponge. The solution is filtered, the filtrate is evaporated, the residue is taken up in 50 ml of water and extracted with hexane. The aqueous solution is subsequently evaporated and the residue is crystallised from pentane. There is obtained pure 1-[3-(p-tert.butyl-phenyl)-2-methyl-2-propenyl]-piperidine-1-oxide of melting point 82°-88° C. (hydrate).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.Cl[C:10]([F:14])([F:13])[CH2:11][Cl:12].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[Cl:12][CH2:11][C:10]([F:14])([F:13])[O:8][C:3]1[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=1
Reactant: FC(F)(Cl)CCl
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Nc1ccc(OC(F)(F)CCl)cc1

Procedure:
2.5 g (22.9 mmol) of p-aminophenol, 3.09 g (22.9 mmol) of 1,2-dichloro-1,1-difluoroethane, 5.48 g (39.6 mmol) of K2CO3 and 40 ml of dry acetonitrile were stirred together at room temperature for 5 days. The mixture was poured into water and extracted two times into ether. The combined ether extracts were washed with water, dried over MgSO4 and filtered: HCl gas was bubbled into the ether solution causing the above-named aniline to precipitate as the hydrochloride salt, which was collected by filtration and recrystallized twice from CH3CN to give 0.9 g (16 percent of theoretical d 245°-250° C.) of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=O)[CH:6]([Cl:10])[C:7](=O)[CH3:8])[CH3:2].[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.N1CCCCC1>CC#N.CCO>[CH2:1]([O:3][C:4]([C:5]1[C:6]([Cl:10])=[C:7]([CH3:8])[N:15]2[N:16]=[CH:17][CH:18]=[C:14]2[N:13]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)C(=O)C(Cl)C(C)=O
Reactant: Nc1cc[nH]n1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)c1nc2ccnn2c(C)c1Cl
Temperature: 90 °C
Yield: 19.8 %

Procedure:
3-Chloro-2,4-dioxo-pentanoic ethyl ester (0.325 g, 1.685 mmol) is added to a solution of 3-aminopyrazole (0.14 g, 1.685 mmol) and piperidine (0.18 mL, 1.85 mmol) in MeCN (15 mL), and the reaction mixture heated at 90° C. for 17 hours. After cooling to room temperature, the reaction mixture is diluted with EtOH and concentrated. Purification by flash chromatography (0.5% MeOH in methylene chloride) gives 80 mg (20%) desired product. 1H NMR (400 mHz, CD3OD) δ 8.27 (d, 1H), 6.84 (d, 1H), 4.48 (q, 2H), 2.97 (s, 3H), 1.42 (t, 3H).
Reaction SMILES: C(O)=O.[C:4]1([C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[N:22][N:23]=[C:13]3[CH:12]([NH2:24])[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1.C(N(CC)CC)C>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:24][CH:12]2[N:11]=[C:10]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[N:22][N:23]=[C:13]23)=[O:34])=[CH:28][CH:27]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2-n2cnnc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2-n2cnnc21
Reaction time: 8 h

Procedure:
6-Phenyl-4H-[1,2,4]triazolo-[4,3-a][1,4]benzodiazepin-4-ylamine formate salt (200 mg, 0.38 mmole) was combined with 4-chlorophenylisocyanate (57 mg, 0.37 mmole) and triethylamine (57 μL) in 10 mL of dry tetrahydrofuran. The mixture was allowed to stand at room temperature overnight. The analytically pure product, which crystallized from solution was collected and dried: m.p. 294°-296° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[CH3:15][O:16][C:17](=[O:27])[C@@H:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][O:16][C:17](=[O:27])[C@@H:18]([NH:26][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:19][C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1
Reactant: COC(=O)[C@@H](N)Cc1ccncc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccncc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 185 mg, 0.94 mmol) in DMF (7 mL) was added 2-(S)-amino-3-pyridin-4-yl propionic acid methyl ester hydrochloride (Preparation 93, 204 mg, 0.94 mmol) followed by TBTU (333 mg, 1.04 mmol) and DIPEA (740 μL, 4.24 mmol), and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the residue partitioned between ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with water (2×30 mL), NaHCO3 solution (3×40 mL) then brine (3×50 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography (SiO2, EtOAc) gave the title compound as a pink powder. m/z (ES+)=359.11 [M+H]+; RT=2.42 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][OH:22])=[N:6][CH:7]=1.[NH:23]1[C:31]2[C:26](=[CH:27][C:28](O)=[CH:29][CH:30]=2)[CH:25]=[N:24]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][O:22][C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[NH:23][N:24]=[CH:25]3)=[N:6][CH:7]=1
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(-c2nc(COc3ccc4[nH]ncc4c3)c(Sc3ccc(Cl)cn3)o2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol (intermediate B1.1, 0.12 g, 0.36 mmol) in THF (3 ml) was added 1H-indazole-5-ol (0.1 g, 0.71 mmol), Ph3P (0.19 g, 0.71 mmol) and DIAD (0.14 ml, 0.71 mmol). The reaction was stirred at rt for 3 h, concentrated and purified by flash chromatography (silica, 30-60% EtOAc/hexanes) to give 5-({5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methoxy)-1H-indazole as white solid. 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.32 (d, J=2.5 Hz, 1H), 8.10 (m, 2H), 7.89 (s, 1H), 7.32 (m, 2H), 7.23 (d, J=2.2 Hz, 1H), 7.15 (t, J=8.6 Hz, 2H), 7.09 (m, 1H), 5.17 (s, 2H); HRMS exact mass talc for C22H14ClFN4O2S [M+H]+: 453.0583; observed: 453.0584.
Reaction SMILES: BrC1C=C(C=CC=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[NH:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]1C(O)=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:55]3[NH:54][C:62]4[C:57]([CH:56]=3)=[CH:58][CH:59]=[CH:60][CH:61]=4)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:18]=[C:19]([O:27][CH3:28])[C:20]=1[O:25][CH3:26]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cc4ccccc4[nH]3)nn2)cc(OC)c1OC
Yield: 79 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 1H-indole-2-carboxylic acid (136 mg, 0.85 mmol), diisopropylethyl-amine (0.33 mL, 1.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (360 mg, 0.94 mmol) in dimethylformamide (5 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-indole-2-carboxamide (232 mg, 79%) as a yellow solid. MS m/z 448 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2=[N:12][N:13]([CH2:25][CH2:26][CH3:27])[C:14]([N:15]([CH2:23][CH3:24])C(=O)OC(C)(C)C)=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:28]>>[CH2:23]([NH:15][C:14]1[N:13]([CH2:25][CH2:26][CH3:27])[N:12]=[C:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:3]=[C:2]2[NH2:28])[CH3:24]
Reactant: CCCn1nc2c(Cl)nc3ccccc3c2c1N(CC)C(=O)OC(C)(C)C
Reactant: N
Product: CCCn1nc2c(N)nc3ccccc3c2c1NCC

Procedure:
tert-Butyl 4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl(ethyl)carbamate (718 mg, 1.85 mmol) and methanolic ammonia (25 mL of a 7 M solution) were heated in a steel Parr vessel in a 150° C. oven for 17 h. The reaction mixture was concentrated, treated with 2 M sodium carbonate and extracted with chloroform. The combined organic layers were dried (magnesium sulfate), filtered, concentrated, and purified by prep HPLC (silica cartridge, eluting with CMA in chloroform). The product was recrystallized from acetonitrile to afford 272 mg of N1-ethyl-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine as white crystals, mp 193-194° C. MS (APCI) m/z 270 (M+1)+; Anal. Calcd for C15H19N5: C, 66.89; H, 7.11; N, 26.00. Found: C, 66.65; H, 7.20; N, 26.19.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=[C:19]2[NH:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[Br:37]NC(=O)CCC(N)=O.C(=O)(O)[O-].[Na+].O>C(Cl)(Cl)Cl.ClCCl>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[C:27]([Br:37])=[C:19]2[NH:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3c2cc2c(c3Br)COC2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 73, Step 7) (2.64 mmol) in chloroform (20 mL), add N-bromosuccinamide (2.9 mmol) along with sodium bicarbonate (5.28 mmol). After stirring the mixture at room temperature for 20 minutes, add water (20 mL) and dilute the mixture with dichloromethane (20 mL). Separate the organics and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the crude intermediate over silica gel eluting with ethyl acetate/hexane to obtain the title compound as an off white solid. MS (ES+): 593 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[C:14]([O:18][C:19]([NH:21][C:22]([CH3:28])([CH3:27])[CH2:23][C:24](O)=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[C:14]([O:18][C:19]([NH:21][C:22]([CH3:28])([CH3:27])[CH2:23][C:24]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A solution of 8.70 g (49.4 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step E) in 100 mL of methylene chloride was treated with 10.73 g (49.4 mmol) of 3-t-butoxycarbonylamino-3-methylbutanoic acid (Step H) and 13.8 mL of triethylamine (10.0 g, 99 mmol, 2 eq.). The reaction flask was immersed in an ambient temperature water bath then 26 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (59 mmol, 1.2 eq) was added all at once and the mixture stirred at room temperature for 2 hours. The reaction mixture was added to 300 mL of ethyl acetate and washed three times with 5% aqueous citric acid, twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (4:1), to afford 17.42 g (46.4 mmol, 94%) of the product as a white solid. 1H NMR (200 MHz,CDCl3): 1.37 (s,6H), 1.44 (s,9H), 1.95 (m,1H), 2.46 (d,15 Hz,1H), 2.59 (d,15 Hz,1H), 2.6-3.0, (m,3H), 4.53 (m,1H), 5.30 (br s,1H), 6.72 (d,7 Hz,1H), 6.98 (d,8 Hz,1H), 7.1-7.3 (m,3H), 7.82 (br s,1H). FAB-MS: calculated for C20H29N3O4 375; found 376 (M+H,70%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=[O:18])[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>C1COCC1>[C:17]([C:14]1[C:15]([O:16][C:27](=[O:29])[CH3:28])=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=2)[S:12][CH:13]=1)(=[O:18])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(C(C)=O)csc1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 2-(4-tert-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (137 mg, 0.5 mmol) in THF (2 mL) were added triethylamine (105 μL, 0.75 mmol) and acetyl chloride (53.3 μL, 0.75 mmol). The reaction mixture was stirred at room temperature for 0.5 h. After removing solvent, the residue was diluted with AcOEt, washed with a saturated aqueous NH4Cl solution, dried over MgSO4 and concentrated to give product as a brown oil (146 mg, yield 92%).