Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccco1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccco4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.068 mMol) 2-furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 337(M+1)
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1C)#[CH:2].BrC1C2C(=CC=CC=2)C=CC=1C.Br[C:27]1C2C(=CC=CC=2)C=C[C:28]=1[N:37](CC)[CH2:38][CH3:39]>>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[N:37]([CH2:38][CH3:39])[CH2:28][CH3:27])#[CH:2]
Reactant: C#Cc1c(C)ccc2ccccc12
Reactant: CCN(CC)c1ccc2ccccc2c1Br
Agent: Cc1ccc2ccccc2c1Br
Product: C#Cc1c(N(CC)CC)ccc2ccccc12

Procedure:
1-Ethynyl-2-diethylaminonaphthalene was prepared in a similar manner to 1-ethynyl-2-methylnaphthalene, except that 1-bromo-2-methylnaphthalene was replaced by 1-bromo-2-diethylaminonaphthalene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][C:18]#[N:19])[C:9]([CH3:15])([C:11]([O:13]C)=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(Cl)Cl.CCO>O1CCOCC1>[C:18]([C:17]1[CH2:16][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]([CH3:10])([CH3:15])[C:11]=1[OH:13])#[N:19]
Reactant: COC(=O)C(C)(C)N(CCC#N)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(C#N)=C(O)C1(C)C
Temperature: 120 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
45 g of methyl N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalaninate were dissolved in dioxane (240 ml) under nitrogen and 7.9 g of sodium hydride were added. The mixture was refluxed for 6 hours (120° C. internal temperature), and then left to stand overnight at room temperature (TLC: CH2Cl2/EtOH 90/10). The solvent was evaporated, water was added (1000 ml) and the mixture was brought to pH 3-4 with citric acid. The aqueous layer was extracted 4 times with ethyl acetate, the extracts washed with a limited amount of water and evaporated. Then the residue was taken up with hexane, evaporated and crystallized from hexane. 33.1 g of tert-butyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate were thus obtained (yield: 85%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][C:6](/[CH:20]=[CH:21]/[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:7][CH:8]=2)[N:3]=1.C(Cl)(Cl)Cl>[Pd].C(O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][C:6]([CH2:20][CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[C@H]1COCc2nc3c(N)nc4cc(/C=C/C(=O)N(C)C)ccc4c3n21
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C[C@H]1COCc2nc3c(N)nc4cc(CCC(=O)N(C)C)ccc4c3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A 250-mL, glass Parr bottle was charged with palladium on carbon (10%, 0.05 g) and 2 mL of ethanol. A solution of (2E)-3-[(11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-yl]-N,N-dimethylprop-2-enamide (210 mg, 0.60 mmol) dissolved in 50 mL of ethanol was then added. The reaction mixture was placed on Parr apparatus and shaken under H2 at 50 PSI (3.4×105 Pa) overnight at ambient temperature. The reaction mixture was treated with additional palladium on carbon (10%, 0.05 g) and shaken under H2 at 50 PSI (3.4×105 Pa) for 24 hours. The reaction mixture was then filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were concentrated under reduced pressure to give a white solid. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid that was crystallized from acetonitrile to give 120 mg of 3-[(11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-yl]-N,N-dimethylpropanamide as white crystals, mp 235-237° C.
Reaction SMILES: CC([O-])(C)C.[K+].[Br-].[C:8]([O:12][C:13](=[O:20])[CH2:14][S+]1CCCC1)([CH3:11])([CH3:10])[CH3:9].C(O)C(F)(F)F.[C:27]([O:31][C:32]([NH:34][C@:35]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:39]=[CH:38][C:37](=[O:40])[CH2:36]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(#N)C.CC(OC)(C)C>[C:44]([O:43][C:41]([C@:35]1([NH:34][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:36][C:37](=[O:40])[C@@H:38]2[C@H:39]1[C@H:14]2[C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:20])=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)C[S+]1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)C=CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: OCC(F)(F)F
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 4 °C
Reaction time: 1.5 h

Procedure:
Add KOtBu (42 mL, 42 mmol, 1 M solution in THF, 2.5 equiv) to a 0° C. solution of 1-(2-tert-butoxy-2-oxoethyl)tetrahydrothiophenium bromide (11.9 g, 42 mmol, 2.5 equiv., Preparation 48) in acetonitrile (30 mL) under N2 over 10 minutes keeping the temperature below 5° C. Stir the milky solution cold for 1.5 hours. Add trifluoroethanol (6.9 g, 69 mmol, 4.1 equiv) dropwise. Add a solution of (1S)-1-(tert-butoxycarbonylamino)-1-(tert-butoxycarbonyl)-cyclopent-4-en-3-one (5 g, 16.8 mmol, Preparation 47) and trifluoroethanol (13.3 g, 132 mmol, 7.9 equiv) in acetonitrile (20 mL), over 5 minutes, maintaining the temperature at 3-5° C. Stir the solution for 4.5 hours at 0-5° C. Add MTBE (155 mL) and 120 (80 mL) to the cold reaction mixture. Separate the layers and wash the organic layer with H2O (50 mL), then 20% brine (50 mL). Concentrate the organic layer via atmospheric pressure distillation to approximately 30 mL. Add heptane (100 mL) and concentrate the solution. Add additional heptane as needed until the vapor temperature of the distillate reaches 93° C. Add THF (65 mL) to yield a solution of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-trifluoromethyl-phenoxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (78%, white crystals). HPLC-MS m/z=388.0 (M+1), Rt: 5.59 min.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[S:32][CH3:33])=[O:11])=CC=1)([O-])=O.O1CCCC1.C(O)C>[Pd].O1CCCC1.C(O)C>[CH3:33][S:32][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[N:17]2[C:12]=1[C:10]([OH:11])=[O:9]
Reactant: CSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CSC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 2.6 g (5 mmols) of 3-methylthio-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 75 ml of a warm 5:1 mixture of tetrahydrofurane and ethanol is added to a mixture, which has been pre-hydrogenated for 30 minutes in a hydrogenation apparatus, of 2.5 g of 5% strength palladium-on-charcoal catalyst in 10 ml of tetrahydrofurane/ethanol, 1:1, and the mixture is hydrogenated for 4 hours whilst stirring. The solution is filtered, the catalyst is washed with ethyl acetate and the filtrate and washing liquor are combined, washed successively with an aqueous citric acid solution and water and then extracted several times with 5% strength aqueous sodium bicarbonate solution. The bicarbonate extracts are combined, washed with methylene chloride, cooled to 0° C., slowly acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The residue is recrystallised from methylene chloride/diethyl ether and gives 3-methylthio-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid of melting point 164°-166° C. (decomposition); [α]D20 =+109°±1° (c=1; dioxane); thin layer chromatogram: silica gel (toluene/ethyl acetate/water, 5:5:1) Rf=0.16; UV spectrum (ethanol); λmax =269 nm (ε=4800), 276 nm (ε=5200) and 308 nm (ε=7700); IR spectrum (KBr): characteristic bands at 3.00; 3.40; 5.63; 5.91; 6.25; 6.53; 6.68; 8.20; 8.55; 8.90; 9.25; 9.43; 13.20 and 14.45μ.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH:19]([C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:25][CH:24]=1)=[O:22])[NH2:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[C:7]([C:8]([NH:20][NH:19][C:21]([C:23]2[CH:24]=[CH:25][C:26]([CH2:29][N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:27][CH:28]=2)=[O:22])=[O:10])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CN(Cc1ccc(C(=O)NN)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CN(Cc1ccc(C(=O)NNC(=O)c2cc(Br)cnc2N)cc1)C(=O)OC(C)(C)C
Reaction time: 60 h
Yield: 58 %

Procedure:
2-amino-5-bromo-pyridine-3-carboxylic acid (776.9 mg, 3.580 mmol) and triethylamine (724.5 mg, 997.9 μL 7.160 mmol) were added to a stirred solution of tert-butyl N-[[4-(hydrazinecarbonyl)phenyl]methyl]-N-methyl-carbamate (1 g, 3.580 mmol in DMF (8 mL). To the stirred slurry was added TBTU (1.724 g, 5.370 mmol) and the mixture stirred at ambient for 60 hours. The mixture was diluted with EtOAc/water and the layers separated. The mixture was extracted with ethyl acetate (×3) and the combined extracts washed with saturated aqueous NaHCO3 (×1) and brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/Petroleum ether) and the product containing fractions concentrated in vacuo. The residue was triturated from acetonitrile to give the desired sub-title product as a cream solid (992 mg, 58% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.39-1.45 (m, 9H), 2.80 (s, 3H), 4.45 (s, 2H), 7.28 (s, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.90 (d, J=7.8 Hz, 2H), 8.20 (d, J=2.4 Hz, 1H), 8.24 (d, J=2.2 Hz, 1H), 10.50 (s, 1H) and 10.54 (s, 1H) ppm; MS (ES+) 480.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:28])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(Cl)C1CCCCC1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C1CCCCC1
Yield: 76.2 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with cyclohexanecarbonyl chloride (0.55 mL, 4.1 mmol) to provide 1.07 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclohexanecarboxamide as an off white solid, m.p. 191.6-192.6° C. Analysis: Calculated for C22H29N5O.0.25 H2O: % C, 68.81; % H, 7.74; % N, 18.24. Found: % C, 68.85; % H, 7.75; % N, 17.95.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(O)(=O)C.[CH2:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:34].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH2:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:28][CH:27]=2)[CH2:37][CH2:36]1)[CH3:34]
Reactant: CCN1CCNCC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.54 mmol) in dichloromethane (30 mL) was added acetic acid (1 mL) followed by the addition of 1-ethylpiperazine (121 mg, 1.63 mmol). After the addition, the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. NaBH(OAc)3 (173 mg, 0.81 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. dichloromethane was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by prep-HPLC to give 8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (135 mg, yield 47%) as white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.22 (t, 3H), 2.36-2.44 (m, 1H), 2.74-3.11 (m, 8H), 4.01-4.10 (m, 3H), 4.33 (dd, 1H), 4.78 (dd, 1H), 7.13-7.31 (m, 10H), 7.37 (d, 1H), 7.47 (s, 1H), 7.58 (t, 3H); LC-MS (ESI) m/z: 452(M+1)+.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([CH3:16])[CH:14]=[O:15])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Ca+2].[OH-].[H][H]>[Pd]>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]([CH3:16])[CH:14]=[O:15])=[CH:10][CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccc(C=C(C)C=O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Ca+2]
Agent: [OH-]
Product: CCC(C)(C)c1ccc(CC(C)C=O)cc1

Procedure:
A mixture of 110 g of 3-(p-tert.amyl-phenyl)-2-methyl-acrolein, 4.75 g of 5% palladium/carbon and 0.390 g of calcium hydroxide is flushed with nitrogen and a solution of 7.6 ml of water in 285 ml of methanol is added. The mixture is hydrogenated at room temperature until 1 mol of hydrogen has been taken up. The catalyst is filtered the filtrate is evaporated and the residue is distilled. There is obtained pure 3-(p-tert.amyl-phenyl)-2-methyl-propionaldehyde of boiling point 109°-111° C./0.06 Torr.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]4)[C:24]([N:26]4[CH2:30][C@H:29]([O:31][CH3:32])[CH2:28][C@H:27]4[CH:33]([CH3:35])[CH3:34])=[N:25][C:21]=3[CH:20]=[C:19]([C:44]#[N:45])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:36][C@H:37]4[CH2:38][CH2:39][C@H:40]([CH3:43])[CH2:41][CH2:42]4)[C:24]([N:26]4[CH2:30][C@H:29]([O:31][CH3:32])[CH2:28][C@H:27]4[CH:33]([CH3:35])[CH3:34])=[N:25][C:21]=3[CH:20]=[C:19]([C:44](=[N:2][OH:3])[NH2:45])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(C#N)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (20.2 mg, 0.29 mmol), sodium bicarbonate (36.6 mg, 0.44 mmol), and water (0.436 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (73.7 mg, 0.145 mmol) dissolved in ethanol (1 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-N′-hydroxy-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C28H38ClN7O2 [M+H]+ 540. found 540.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[Cl:7].S(Cl)(Cl)=O.C1C=CC=CC=1.[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:8]([C:4]1[NH:5][C:6]([Cl:7])=[C:2]([Cl:1])[CH:3]=1)=[O:10]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1cc(Cl)c(Cl)[nH]1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1Cl)c1cc(Cl)c(Cl)[nH]1

Procedure:
4,5-Dichloropyrrole-2-carboxylic acid (10 g., 0.056 mole) was converted to the corresponding acid chloride by reaction with 15 ml. of thionyl chloride, and the acid chloride dissolved in 25 ml. of benzene was reacted with 9.2 g. (0.057 mole) of 2,4-dichloroaniline in 50 ml. of pyridine using the procedure described above in Example 3. The product was recrystallized from an ethyl acetate/ethanol mixture to give 10.0 of 2',4,4',5-tetrachloropyrrole-2-carboxanilide, m.p. 262°-264° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12]O)[CH:6]=[CH:5]2.P(Br)(Br)[Br:15]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][Br:15])[CH:8]=2)[CH:3]=1
Reactant: OCc1ccc2cc(Br)ccc2c1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: BrCc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58 %

Procedure:
To a three-necked flask (2 L) was added (6-bromonaphthalen-2-yl)methanol (47.7 g, 0.201 mol) and chloroform (600 ml). The mixture was then cooled with an ethanol-liquid nitrogen bath to −35□. To the suspension was added phosphorus tribromide (28.6 ml, 0.603 mol) dropwise slowly over 25 minutes. The cooling bath was removed and the reaction mixture was kept under stirring for additional 2.5 hours at room temperature. The mixture was cooled again and to it was added methanol (250 mL) dropwise slowly and released quickly was hydrogen bromide, which was absorbed with a potassium hydrate solution. The mixture was warmed to room temperature and the resulting precipitate was collected by filtering under reduced pressure. The filter cake was washed with ethanol and dried to afford a white solid, 2-bromo-6-(bromomethyl)naphthalene (35 g).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[CH2:2][S:1][C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)CS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a mixture of methyl mercaptoacetate (5.30 g, 50 mmol) and triphenylmethanol (13.0 g, 50 mmol) in chloroform (20 mL) was added trifloroacetic acid (5 mL) in 5 min. After stirring at room temperature for 1 h, the volatiles were removed in vacuo. The crude product was purified by recrystallization (dichloromethane/Hexane=1/2) to provide Tritylsulfanyl-acetic acid methyl ester (15.9 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.44-7.38 (m, 6H), 7.34-7.18 (m, 9H), 3.58 (s, 3H), 2.98 (s, 2H).
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.P(Cl)(Cl)(Cl)=O.[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>CN(C)C1C=CC=CC=1>[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH:17]1[NH:16][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12
Reactant: Oc1ncnc2[nH]ncc12
Reactant: NC1Cc2ccccc2C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: c1ccc2c(c1)CC(Nc1ncnc3[nH]ncc13)C2
Yield: 56 %

Procedure:
Using 4-hydroxypyrazolo[3,4-d]pyrimidine (140 mg, 1.0 mmol), phosphorus oxichloride (3.0 ml), and dimethylaniline (0.39 ml, 3.1 μmol), and then 2-aminoindan (400 mg, 3.0 mmol), a similar procedure to Preparation Example 5 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=5:2) to obtain the title compound (150 mg, 0.56 mmol) having the following physical properties:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:18]1([N:13]2[C:12]([C:36]3[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 44.6 %

Procedure:
The title compound (60.2 mg) was prepared as in Example 177, Steps C and D, using 203.8 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 181.6 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C20H27N3, 309.45; found, m/z 310.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37 (d, J=7.7 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 3.97-3.89 (m, 1H), 3.44-3.39 (m, 2H), 3.31-3.26 (m, 2H), 3.20-3.15 (m, 2H), 2.80-2.75 (m, 2H), 1.96-1.78 (m, 6H), 1.70-1.62 (m, 1H), 1.28-1.18 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:16][CH:17]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:30])[N:7]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1C>>[C:18]([N:15]1[CH2:14][CH2:13][CH:12]([C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[CH:5][C:6](=[O:30])[N:7]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[CH:11]=2)[CH2:17][CH2:16]1)([CH3:19])([CH3:21])[CH3:20]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: CC(C)(C)N1CC=C(c2cc(Br)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Product: CC(C)(C)N1CCC(c2cc(-c3ccc(F)cc3)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
The title compound was prepared from 5-bromo-7-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,6-dichlorophenyl)quinolin-2(1H)-one (INTERMEDIATE ABA5) and using 4-fluoro-3-methylphenylboronic acid as described in EXAMPLE ABA11. 1H NMR (CD3OD, 500 MHz): δ 1.252 (s, 9H), 1.734 (bs, 2H), 1.955 (bs, 2H), 2.084 (s, 3H), 2.665 (bs, 4H), 3.307 (m, 1H), 3.394 (bs, 2H), 6.471 (s, 1H), 6.650 (d, J=9.9 Hz, 1H), 7.064 (t, J=5.7 Hz, 1H), 7.123 (s, 1H), 7.146 (dd, J=2.7, 9.9 Hz, 1H), 7.243 (dd, J=5.7, 8.5 Hz, 1H), 7.570 (d, J=9.9 Hz, 1H), 7.616 (t, J=8.5 Hz, 1H), 7.737 (m, 2H). Mass spectrum (ESI): 537.2 (M+1).