Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([NH:16][S:17]([C:20]2[S:21][C:22](Br)=[CH:23][CH:24]=2)(=[O:19])=[O:18])[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([NH:16][S:17]([C:20]2[S:21][C:22]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[CH:23][CH:24]=2)(=[O:19])=[O:18])[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C1[C@H](NS(=O)(=O)c2ccc(Br)s2)CC=CCN1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)N[C@@H]3CC=CCN(OCc4ccccc4)C3=O)s2)cc1
Yield: 51.6 %

Procedure:
(R)-5-Bromo-thiophene-2-sulfonic acid (1-benzyloxy-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl)-amide (100 mg, 0.28 mmol) from example 16 was dissolved in THF (3 mL). (4-Methoxyphenyl) boronic acid (64 mg, 0.42 mmol), potassium carbonate (80 mg, 0.56 mmol) and tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol) were added at room temperature. The mixture in a sealed vessel was irradiated in microwave oven at 150° C. for 20 min. The resulting reaction mixture was filtered. The solids were washed with water and 1:1 Ether-hexane, then dried under vacuum to give the desired product (70 mg, 51% yield). MS: 485, 487 (M+H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][C@H:14]([CH3:21])[CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:12])=[CH:7][CH:6]=1)(=O)C.CN>C1(C)C=CC=CC=1.CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13][C@H:14]([CH3:21])[CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:12])=[CH:9][CH:10]=1
Reactant: CCC(CC)C[C@@H](C)OC(=O)c1ccc(OC(C)=O)cc1
Agent: CN
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC(CC)C[C@@H](C)OC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
63 Grams (0.215 mol) of (R)-4-acetoxy-1-(3-ethyl-1-methylpentyloxycarbonyl)benzene was dissolved in 900 ml of dehydrated toluene, 25 g of a solution of 40% methylamine in methanol was dropwise added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was washed with 2N hydrochloric acid and washed with water. The resultant organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was distilled off, to give 49 g (0.195 moll yield 91%) of an end compound.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:24][CH2:25][CH2:26][Cl:27]>O1CCCC1>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCN(CCCCl)CC1)c1ccccc1

Procedure:
A mixture of 4-benzamidopiperidine (3.2 g; preparation I11), triethylamine (5.67 ml) and 1-bromo-3-chloropropane (2.31 ml) in 150 ml of tetrahydrofuran was refluxed overnight, then concentrated to a small volume and treated with 100 ml of chloroform. The solution was washed with 50 ml of aqueous saturated solution of potassium carbonate, dried over sodium sulfate and concentrated to dryness. The residue (6 g) was purified by silica gel chromatography (eluent chloroform/methanol 9:1) to give, after recrystallization from 20 ml of diethyl ether, 1.63 g of the product, m.p. 145-147° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:15][N:14]([C:16]3[N:17]([CH3:29])[C:18](=[O:28])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)[N:21]=3)[CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[O:30]1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].OO>C(O)C>[CH3:29][N:17]1[C:18](=[O:28])[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[N:21]=[C:16]1[N:14]1[CH2:13][CH2:12][CH2:11][O:10][C@@H:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]([NH2:2])=[O:30])[CH2:15]1
Reactant: Cn1c(N2CCCO[C@@H](c3cccc(C#N)c3)C2)nc(-c2ccncn2)cc1=O
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: Cn1c(N2CCCO[C@@H](c3cccc(C(N)=O)c3)C2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-[2-(3-cyano-phenyl)-[1,4]oxazepan-4-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (A039) (300 mg, 0.772 mmol), tetrahydrofuran (1.90 ml) and 3.0N-sodium carbonate (1.90 ml) in ethanol (1.90 ml) was added 30%-hydrogen peroxide (1.90 ml) at room temperature. The mixture was stirred at room temperature for 2 hours and partitioned between water and chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was washed with diethyl ether to afford (S)-3-[4-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-[1,4]oxazepan-2-yl]-benzamide (A015) as pale yellow solid (293 mg, 93%).
Reaction SMILES: [CH:1]([CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:5]([OH:7])=O)([CH3:3])[CH3:2].[C:22](Cl)(=[O:26])[C:23](Cl)=O>>[CH:1]([CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:5]([N:19]1[CH2:16][CH2:15][CH2:14][C@H:23]1[CH2:22][OH:26])=[O:7])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)C(CCCCCc1ccc([N+](=O)[O-])cc1)C(=O)O
Product: CC(C)C(CCCCCc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC[C@H]1CO
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (10 ml) was added to 2-isopropyl-7-(p-nitrophenyl)heptanoic acid (200 mg; prepared in reference example 6). The solution was stirred for 10 mins, and concentrated to dryness. Methylene chloride (10 ml) was added to this residue followed by the addition of 2-hydroxymethylpyrrolidine (0.087 ml). The solution was cooled with ice. Triethylamine (0.143 ml) was added to this reaction solution. The solution was stirred for 30 mins. Subsequently, the reaction solution was evaporated. The residue was purified by column chromatography on silica gel to give the title compound (150 mg) having the following physical data:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16]([O:19][CH2:20]C)(=[O:18])C.ClCCl.[C]=O>CO.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(N(CC)CC)C>[CH3:20][O:19][C:16]([C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1)=[O:18]
Reactant: CCOC(C)=O
Reactant: Nc1ncc(Br)nc1-c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C]=O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N)c(-c2ccc(F)cc2)n1

Procedure:
To a solution of 1.87 g 5-bromo-3-(4-fluoro-phenyl)-pyrazin-2-ylamine in 35 ml methanol was added 15 ml ethyl acetate, 0.260 g [1,1′-bis(diphenylphosphino)ferrocen]palladium(II)chloride 1:1 complex with dichloromethane and 1.95 ml triethylamine and the mixture was stirred at 110° C. under 70 bar carbon monoxide for 18 h. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel with heptane:ethyl acetate=1:1 to yield 1.26 g of the title compound as white crystals. MS (ISP) (M+H+)=248.3.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[CH:10]=[CH:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([NH2:16])[CH:3]=1.[C:17](O)(=[O:21])[C:18](O)=[O:19].Cl>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[N:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH:10]=[CH:9]1)[NH:15][C:18](=[O:19])[C:17](=[O:21])[NH:16]2
Reactant: Nc1cc(F)c(-n2ccc(=O)cc2)cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2F)cc1
Yield: 73.7 %

Procedure:
First, 4.266 g of 4-fluoro-5-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine, and 1.927 g of oxalic acid were added to 48 ml of 4N hydrochloric acid. The mixture was refluxed by heating for 2.5 hours. After the reaction, precipitated crystals were filtered, washed with water, and dried to give 3.920 g of 6-fluoro-7-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]([C:31]#[N:32])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl.O.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:31]([C:23]1[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:25][C:20]([NH:19][C:17]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)=[C:11]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:18])=[N:21][CH:22]=1)#[N:32]
Reactant: OB(O)c1cccnc1
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(Br)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: COCCNc1cc(NC(=O)N2CCCc3cc(-c4cccnc4)c(C(OC)OC)nc32)ncc1C#N
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
A suspension of 6-bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 315, 49.9 mg, 0.099 mmol), 3-pyridineboronic acid (14 mg, 0.108 mmol), PdCl2(dppf) (7 mg, 9.57 μmol) and saturated aqueous Na2CO3 (160 μl) in DME (480 μl) was sealed in a vial and purged with argon. Then reaction mixture was stirred at 120° C. for 15 min in a microwave. The suspension was diluted with DCM and water, phases were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-5%) in DCM. Product fractions were combined, evaporated and dried to yield the title compound as a colorless film. (UPLC-MS 3) tR 0.97 min; ESI-MS 504.2 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.66-8.62 (m, 2H), 8.22 (s, 1H), 7.83 (dt, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.40 (d d, 1H), 5.34 (s, 1H), 5.24 (t, 1H), 4.11-4.06 (m, 2H), 3.63 (t, 2H), 3.48 (q, 2H), 3.42-3.36 (m, 9H), 2.90 (t, 2H), 2.04 (q, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH+]1C=CC=CC=1.Cl>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(C#N)cc2)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A mixture of 5.12 g (0.0187 mol) of 4-[(4-methoxyphenyl)sulfonyl]benzonitrile and 21.6 g of pyridinium hydrochloride is kept at 200° C. for 2 hours. After cooling, the reaction medium is hydrolyzed in a 1 N solution of hydrochloric acid. The precipitate formed is filtered off and rinsed with a 1 N solution of hydrochloric acid and then with water until the pH of the washings is neutral. 4.5 g (yield: 99%) of the expected product are thus obtained in the form of a gray solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:29]=[N+:30]=[N-:31].[Na+].[I-].[K+]>CN(C)C=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][N:29]=[N+:30]=[N-:31])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CCCOS(=O)(=O)c2ccc(C)cc2)cc1OC1CCCC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCCN=[N+]=[N-])cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 0.21 g (0.5 mmol) of 3-(3-cyclopentoxy-4-methoxyphenyl)-1-O-p-toluenesulfonyl-1-propanol in 10 mL of dry N,N-dimethylformamide under a nitrogen atmosphere was added 0.7 g (1.0 mmol) of sodium azide and 0.6 g (0.4 mmol) of potassium iodide in single portions. The mixture was stirred at room temperature for 16 hours at the end of which time the reaction was quenched with excess water and extracted with three, 25 mL portions of chloroform. The combined organic fractions were dried over magnesium sulfate and concentrated under high vacuum to dryness. The resulting oil was purified to an analytically pure oil using liquid chromatography over 50 g of silica gel and eluting with 10% ethyl acetate in hexane followed by drying in vacuo.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([OH:24])[CH:15]=[CH:16][C:17]=3[O:21][CH2:22][CH3:23])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:28])(=O)=O>ClCCl>[Cl:28][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[C:14]([OH:24])[CH:15]=[CH:16][C:17]=2[O:21][CH2:22][CH3:23])[S:10]1(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOc1ccc(O)c2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Solvent: ClCCl
Product: CCOc1ccc(O)c2c1C(=O)N(CCl)S2(=O)=O

Procedure:
By the methods of parts D and E of Example 45 debenzylation of 2-benzyl-4-ethoxy-7-hydroxysaccharin (part B of Example 50) with ammonium formate and palladium on carbon in methanol gave 4-ethoxy-7-hydroxysaccharin ammonium salt, phenylthiomethylation of which with chloromethyl phenyl sulfide in dimethylformamide gave 2-phenylthiomethyl-4-ethoxy-7-hydroxysaccharin, reaction of which with sulfuryl chloride in dichloromethane gave 2-chloromethyl-4-ethoxy-7-hydroxysaccharin.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:8][CH2:9][OH:10].[Cl:16][C:17]([Cl:21])([Cl:20])[C:18]#[N:19].O>C(Cl)Cl>[Cl:16][C:17]([Cl:21])([Cl:20])[C:18](=[NH:19])[O:10][CH2:9][CH2:8][C:7]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([O:4][CH3:3])[CH:6]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: COc1ccc(CCO)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CCOC(=N)C(Cl)(Cl)Cl)cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 74.7 %

Procedure:
A 500 mL 2-necked round bottom flask equipped with an argon inlet, rubber septum and magnetic stir bar was charged with NaH (80% dispersion, 5.2 g, 173.3 mmol). NaH was washed with anhydrous hexanes (15 mL) prior to the addition of 50 mL of anhydrous CH2Cl2 and of 3,4-dimethoxyphenethyl alcohol (20.0 g, 109.8 mmol) in anhydrous CH2Cl2 (30 mL). The solution was allowed to stir at r.t. for 75 min. The solution was then cooled to 0° C. prior to the dropwise addition of trichloroacetonitrile (16.5 mL, 23.8 g, 164.7 mmol) at 0° C. The solution was stirred for 15 min at 0° C. and 2 hr at room temperature. Distilled water (150 mL) was slowly added dropwise to quench the reaction. The aqueous layer was then extracted with CH2Cl2 (4×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous MgSO4 and concentrated by rotary evaporation to afford a brown syrup (26.8 g, 95%). The product was allowed to solidify overnight at −20° C. Rf 0.74 (EtOAc-hexanes, 1:2, v/v).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])=[C:5]([CH3:23])[CH:4]=1.[CH3:24][C:25]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:26]=1[C:27](Cl)=[O:28].ClC(Cl)C>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][N:19]([CH:20]([CH3:21])[CH3:22])[C:27]([C:26]2[C:25]([CH3:24])=[CH:33][C:32]([CH3:34])=[CH:31][C:30]=2[CH3:35])=[O:28])=[C:5]([CH3:23])[CH:4]=1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: COc1ccc(-n2c(CNC(C)C)nc3ccccc32)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(-n2c(CN(C(=O)c3c(C)cc(C)cc3C)C(C)C)nc3ccccc32)c(C)c1
Yield: 92 %

Procedure:
A solution of 3 g (10.5 mmole) 1-[2-(chloromethyl)benzimidazolyl]-4-methoxy-2-methylbenzene in 20 mL of dry acetonitrile is treated with 5 mL of isopropylamine for 1 hour in a sealed reaction vessel at 50° C. The solvent is removed in vacuo and the residue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. The ethyl acetate layer is dried over anhydrous Na2SO4 and solvent removed in vacuo to afford 3.1 g (98%) {[1-(4-methoxy-2-methylphenyl)benzimidazol-2-yl]methyl}(methylethyl)amine. The latter amine is then vigorously stirred with 2.6 mL of 2,4,6-trimethylbenzoylchloride in a 1:1 mixture of dichloroethane and saturated aqueous sodium carbonate (30 mL) at room temperature for 1 hour. The mixture is partitioned, the organic layer is dried with Na2SO4 and the solvent removed in vacuo. The crystallized product is triturated in ethyl ether, filtered and dried to afford 4.4 g (92%) of white solid N-{[1-(4-methoxy-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: Mass Spec. 456 (M+H); (Compound 1).
Reaction SMILES: [N:1]1[NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:18][OH:19])=[C:7]3[CH2:13][CH2:12][C:11]4[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=4[C:9]=1[C:8]=23>[O-2].[O-2].[Mn+4]>[N:1]1[NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH:18]=[O:19])=[C:7]3[CH2:13][CH2:12][C:11]4[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=4[C:9]=1[C:8]=23
Reactant: OCc1ccc2[nH]nc3c2c1CCc1ccccc1-3
Agent: [Mn+4]
Agent: [O-2]
Product: O=Cc1ccc2[nH]nc3c2c1CCc1ccccc1-3
Yield: 100.8 %

Procedure:
120 mg of 6,7-dihydro-2H-benzo[6,7]cyclohepta[cd]indazol-5-ylmethanol prepared in Example 1-h was treated by the procedure of Example 1-f using 500 mg of manganese dioxide, to give 120 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:17])[C:8]([F:16])=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[CH:11]=[CH:10]2)=[O:4].O.[H][H]>C(O)(=O)C.[Pt]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:17])[C:8]([F:16])=[C:9]2[C:14]=1[NH:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cc(F)c(F)c2ccc(C)nc12
Agent: [Pt]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(F)c(F)c2c1NC(C)CC2
Yield: 68.9 %

Procedure:
A solution of 8.0 g (33.7 mmol) of 5,6-difluoro-2-methylquinoline-8-carboxylic acid methyl ester (Example 33) in 100 mL of glacial acetic acid is treated with 2.15 g of platinum on carbon (0.8 g of active catalyst+62.8% water) and then shaken in a hydrogen atmosphere at temperatures of 24° C. to 29° C. and pressures of 23.9 to 46.6 psi for 3 hours. The catalyst is removed by filtration and the solvent is removed in vacuo at 50° C. The residue is triturated with water (50 mL) and extracted with dichloromethane (2×200 mL). The combined organic layers are stirred with 5% sodium bicarbonate solution, washed with water, dried (MgSO4), filtered and evaporated in vacuo. The residue is chromatographed over flash grade silica gel (230-400 mesh) eluting with dichloromethane to give 5.6 g of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3): 7.66 (bs, 1H), 7.49 (m, 1H), 3.82 (s, 3H), 3.46 (m, 1H), 2.88 (m, 1H), 2.67 (m, 1H), 1.97 (m, 1H), 1.27 (d, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[O:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])[CH3:26].CCN=C=NCCCN(C)C>>[OH:24][C:13]1([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:14][CH2:15][CH:10]([N:8]2[CH2:9][CH:6]([NH:5][C:3]([CH2:2][NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([O:25][CH3:26])[CH:28]=3)=[O:4])[CH2:7]2)[CH2:11][CH2:12]1
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Reactant: COc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Product: COc1cccc(C(=O)NCC(=O)NC2CN(C3CCC(O)(c4ccc(OC)nc4)CC3)C2)c1

Procedure:
The title compound was prepared as yellow solid from 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, and 3-methoxylbenzoic acid (Aldrich) by EDCI coupling using the procedure described in Step C of Example 16.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C([N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:42]3[CH:43]=[N:39][NH:40][CH:41]=3)[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cn[nH]c2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 11.3 %

Procedure:
To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (5.3 ml), ethanol (2.7 ml) and water (2.7 ml), N-Boc-pyrazole-4-boronic acid pinacol ester (0.334 g, 1.137 mmoles) and sodium carbonate (0.401 g, 3.79 mmoles) were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.172 g, 0.149 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.040 g, 11% yield). MP: 223-226° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.2 (s,1H), 8.03(m,2H), 7.85(m, 2H),7.68(d, J=8.3Hz, 1H), 7.52(t, J=7.7Hz, 1H), 7.25(m,1H), 7.07-6.93(m, 3H), 5.92(q, J=6.9Hz, 1H), 1.87(d, J=7.0Hz, 3H). Mass: 467.84(M+).
Reaction SMILES: [NH3:1].Br[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:5]>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:1]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[C:8]=2[CH:9]=1
Reactant: N
Reactant: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1
Product: O=C1CN=C(c2ccc(O)cc2)c2cc(Cl)ccc2N1
Yield: 67 %

Procedure:
To 350 ml of liquid ammonia was added 60 g (0.163 mole) of 2-bromo-4'-chloro-2'-(4-hydroxybenzoyl)acetanilide. After refluxing for 3 hr, the ammonia was allowed to evaporate. The residue was heated to reflux in 400 ml of ethanol for 3 hr. Ethanol was evaproated, and 800 ml of acetone was added. This suspension was heated and filtered to remove inorganic salts. Concentration of acetone filtrate gave 31.5 g (67%) of product, mp 271°-272°.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][N:16]([CH:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][C:24]([N+:30]([O-])=O)=[CH:25][CH:26]=4)[CH2:21]3)[CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[NH2:30][C:24]1[CH:23]=[C:22]2[C:27]([CH2:28][CH2:29][CH:20]([N:16]([CH2:15][CH:12]3[CH2:11][CH2:10][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:14][CH2:13]3)[CH2:17][CH2:18][CH3:19])[CH2:21]2)=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(N)cc2C1
Yield: 86.8 %

Procedure:
To a solution of morpholin-4-yl-(4-{[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidin-1-yl)-methanone (540 mg, 1.2 mmol) in ethanol (30 mL) was added 10% palladium on charcoal (50 mg). The solution was shaken on a Parr shaker for 24 h at 55 psi of hydrogen. The solution was filtered through Celite® and concentrated to afford (4-{[(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidin-1-yl)-morpholin-4-yl-methanone (432 mg) 95, [M+H]+=415; which was used directly.