Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[OH-].[K+].[CH2:41]1OCCOCCOCCOCCOCCOC1.IC>C1COCC1>[CH3:41][O:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CC(C)C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@H](CC(C)C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
In a 10 mL round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (73 mg, 0.135 mmol) was dissolved in THF (1.4 ml) to give a colorless solution. The reaction was cooled in an ice bath and crushed KOH (76 mg, 1.35 mmol), 18-crown-6 (36 mg, 0.135 mmol), and iodomethane (9 μl, 0.135 mmol) were added successively. The reaction mixture was stirred at 0° C. for 1 h after which the ice bath was removed. The reaction mixture was stirred at room temperature for 2 h then diluted with dichloromethane (10 mL) and washed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-70% EtOAc) to afford 38 mg (50%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methyl-butyl)-amide as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ: 9.18 (s, 1H), 8.64 (s, 1H), 8.52 (dd, J=9.1, 5.3 Hz, 1H), 8.15 (d, J=9.4 Hz, 1H), 7.72 (dd, J=9.6, 2.1 Hz, 1H), 7.13 (td, J=9.1, 1.9 Hz, 1H), 5.73 (s, 2H), 4.41 (td, J=9.0, 5.1 Hz, 1H), 4.17 (s, 3H), 3.60 (t, J=7.9 Hz, 2H), 3.44-3.55 (m, 2H), 3.27 (s, 3H), 1.48-1.72 (m, 3H), 0.91 (d, J=6.0 Hz, 3H), 0.86 (d, J=6.0 Hz, 3H), 0.85 (t, J=7.6 Hz, 2H), −0.08 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1)=O.[Cl-].[OH:27][NH3+:28].N1C=CC=CC=1>C(O)C>[F:1][C:2]([F:25])([F:24])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1)=[N:28][OH:27]
Reactant: [NH3+]O
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)C(F)(F)F)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(C(=NO)C(F)(F)F)cc1
Yield: 25.2 %

Procedure:
32 g (89.3 mmol) of 2,2,2-trifluoro-1-(4-dodecyloxyphenyl)-ethanone are dissolved in 200 ml of ethanol. To the solution are added 7.4 g (107 mmol) of hydroxylammonium chloride and 21.2 g (268 mmol) of pyridine. The reaction mixture is refluxed for 1.5 hours, and the solvent is distilled off by a rotary evaporator. The residue is poured into water, and extracted with ethyl acetate. The organic phase is washed with potassium hydrogen sulfate aqueous solution, water, and brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from hexane/toluene, yielding 8.4 g of 2,2,2-trifluoro-1-(4-dodecyloxyphenyl)-ethanone oxime as a white solid with a melting point of 70-72° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 0.89 (t, 3H), 1.20-1.40 (m, 16H), 1.40-1.50 (m, 2H), 1.79 (m, 2H), 3.86-4.03 (m, 2H), 6.93(E)/6.97(Z) (d, 2H), 7.44(E)/7.53(Z) (d, 2H), 8.59(Z)/8.61 (E) (br s, 1H). The signals are tentatively assigned to the E- and Z-conformations. The spectrum indicates that the compound is a mixture of E- and Z-isomers. The ratio of the mixture is estimated to be E:Z=1:4.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.[CH:20]1([CH2:26][C@H:27]([OH:36])[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCOCC1>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:36][C@H:27]([C:28]([N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1)=[O:29])[CH2:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C([C@@H](O)CC1CCCCC1)N1CCOCC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](CC1CCCCC1)C(=O)N1CCOCC1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
A solution of 4-nitrophenyl chloroformate (20.55 g, 102 mmol) in dioxane (150 mL) is treated with pyridine (50 mL) resulting in a suspension. This material is heated to 70° C. and a solution of 3 (12.30 g, 51.0 mmol) in dioxane (50 mL) is added via pressure equalizing dropping funnel over ˜5 minutes. After stirring for an additional 5 minutes, the reaction is allowed to cool to room temperature and the solvent is removed by rotary evaporation. The resulting mass is partitioned between ethyl acetate and water. The organic layer is collected and the aqueous phase is extracted once more with ethyl acetate and discarded. The combined organics are dried over MgSO4 and the solvent is removed. The resulting solid is dissolved in a minimal amount of hot dichloroethane and treated with dichloromethane. The mixture is then kept in a −4° C. refrigerator overnight and filtered. The mother liquor is concentrated and purified over 330 g of silica gel using a gradient of 0-100% ethyl acetate in hexane to afford 15.2 g (73% yield) of (S)-2-cyclohexyl-1-(morpholine-4-carbonyl)ethyl 4-nitro-phenyl carbonate (4) as a slightly yellow oil; 1H NMR (CDCl3, 400 MHz) δ 0.97-1.08 (m, 2H), 1.09-1.36 (m, 3H), 1.48-4.62 (m, 2H), 1.65-1.68 (m, 4H), 1.82-1.97 (m, 2H), 3.41-3.60 (m, 3H), 3.64-3.80 (m, 5H), 5.29-5.36 (m, 1H), 7.38-7.44 (m, 2H), 8.24-8.30 (m, 2H); HPLC-MS calculated for C20H26N2O7 (M+H+) 407.2, found 407.4.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[N+:8]=1[O-:9].N([O-])=O.[Na+].[N-:18]=[N+:19]=[N-].[Na+]>Cl>[N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[N+:8]=1[O-:9])=[N+:18]=[N-:19]
Reactant: COC(=O)c1cccc(N)[n+]1[O-]
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cccc(N=[N+]=[N-])[n+]1[O-]
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
Methyl 6-aminopyridine-2-carboxylate 1-oxide hydrochloride (Intermediate 122, 3.34 g, 16 mmol) was dissolved in 10% HCl (aqueous) and cooled to 5° C. An aqueous solution of NaNO2 (1.5 g, 21 mmol) was added dropwise maintaining temperature below 5° C. After 15 minutes of stirring, an aqueous solution of NaN3 (1.4 g, 21 mmol) was added dropwise maintaining temperature below 5° C. The reaction was stirred at 5° C. for 30 minutes and slowly warmed to room temperature. The product was extracted with DCM and then the aqueous layer was basified (with 50% NaOH to pH 13) and then extracted again with DCM. Drying (MgSO4) and removal of solvent yielded a yellow oil (2.6 g, 82%).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[CH3:23][CH:24]([CH3:33])[C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[Na].C(O)C>C(Cl)Cl>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([N:3]3[CH:2]([CH:26]([C:25](=[O:32])[CH:24]([CH3:33])[CH3:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:10]4[C:5](=[N:6][CH:7]=[CH:8][N:9]=4)[C:4]3=[O:11])=[N:13]2)=[CH:18][CH:17]=1
Reactant: O=C1c2nccnc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C(=O)C(C)C)C1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 43.9 %

Procedure:
Ethyl 2-{6-(7-chloro-1,8-naphthyridin-2-yl)-6, 7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl}-4-methyl-3oxopentanoate may be obtained as in Example 29, but starting with 5-chloro-6-(7-chloro-1,8-naphthyridin-2-yl)-6, 7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazine (13 g), ethyl 4-methyl-3-oxopentanoate (8.7 g), sodium (1.1 g), ethanol (400 cc) and methylene chloride (200 cc). After recrystallization in methanol, ethyl 2-{6-(7-chloro-1, 8-naphthyridin-2-yl)-6,7-dihydro-7-oxo-5H-pyrrolo[3, 4-b]pyrazin-5yl}-4-methyl-3-oxopentanoate (7.8 g), m.p. 214° C., is thereby obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:24]([CH3:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30]>CO.CCOCC>[ClH:30].[ClH:30].[CH3:25][N:24]1[C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[N:21]=[C:20]1[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:15]=1
Reactant: Cn1c(-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c(-c2cccc(N3CCNCC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (1.30 g, 3.32 mmol) in MeOH (4 mL) was added 2M HCl in Et2O (9 mL) and the resulting solution was stirred for 6 h at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:19]=4[CH3:34])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:35][C:36]([CH3:38])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C:20]2[C:19]([CH3:34])=[C:18]([C:7]3[C:6]4[C:5]5[C:13](=[CH:14][C:2]([NH:1][CH:36]([CH3:38])[CH3:35])=[CH:3][CH:4]=5)[NH:12][C:11]=4[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=3)[CH:23]=[CH:22][CH:21]=2)=[O:33])=[CH:31][CH:30]=1
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(N)ccc3c12
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(NC(C)C)ccc3c12
Temperature: 40 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
A suspension of 7-amino-4-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-1-carboxamide (Example 54-5, 1 g, 2.210 mmol), acetone (3.4 mL, 20 eq.), and acetic acid (0.443 mL, 7.74 mmol) in 1,2-dichloroethane (220 mL) was treated with sodium triacetoxyborohydride (1.639 g, 7.74 mmol) and stirred at 40° C. for 4 h. Additional sodium triacetoxyborohydride (520 mg, 1.1 eq) and acetic acid (0.19 mL, 1.5 eq) were added and the mixture was stirred overnight. The mixture was treated with NaHCO3 (aq) and the organic phase was separated, washed with brine, dried and concentrated. The residue was purified by preparative HPLC. The appropriate effluent fractions were made basic with NaHCO3 (aq) and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was triturated with methanol to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(isopropylamino)-9H-carbazole-1-carboxamide as an off-white solid (520 mg, 48%). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (1 H, s), 10.09 (1 H, s), 8.07 (3 H, dd, J=8.8, 5.3 Hz), 7.77 (1 H, d, J=7.9 Hz), 7.27-7.51 (5 H, m), 7.17 (1 H, d, J=6.2 Hz), 6.73-6.88 (2 H, m), 6.60 (1 H, d, J=8.3 Hz), 6.23 (1 H, dd, J=8.8, 2.2 Hz), 5.49 (1 H, d, J=7.9 Hz), 3.53 (1H, dd, J=13.8, 6.4 Hz), 1.90 (3 H, s), 1.04-1.21 (6 H, m). Mass spectrum m/z 495.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([S:11](=[O:14])(=[O:13])[NH2:12])=[C:4](F)[CH:3]=1.[CH2:16]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19]>O>[CH2:16]([N:20]1[CH2:25][CH2:24][N:23]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[S:11](=[O:14])(=[O:13])[NH2:12])[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN1CCNCC1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Solvent: O
Product: CCCCN1CCN(c2cc(Cl)c(C(=O)O)cc2S(N)(=O)=O)CC1
Reaction time: 8 h

Procedure:
126 Grams of 6-chloro-4-fluoro-3-sulfamoylbenzoic acid (0.5 mole) were stirred with 0.2 l of N-butylpiperazine for 2 hours at 110° C. Subsequently the reaction solution was poured into 2 l of water, a small amount of amorphous precipitate formed was separated, and the filtrate was adjusted to a pH of 7.5 with 2N HCl. After having stood overnight at room temperature, the crystalline precipitate was suction-filtered and was recrystallized from a mixture of ethanol and water.
Reaction SMILES: [F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:43]2[CH2:44][CH2:45][N:40]([C:32]3[N:31]([CH3:30])[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=3)[CH2:41][CH2:42]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Cn1c(N2CCNCC2)nc2ccccc21
Reactant: O=C(NCC(F)(F)C(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)C(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,3,3,3-pentafluoro-propyl)-amide and 1-methyl-2-piperazin-1-yl-1H-benzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1.[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C.S(OC)(OC)(=O)=O>CN(C=O)C>[CH3:29][O:16][C:7]1[N:8]=[C:9]([CH3:15])[C:10]2[C:5]([C:6]=1[CH2:17][C:18]1[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: COc1cc2c(C)nc(O)c(Cc3ccc4ccccc4c3)c2cc1OC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1cc2c(C)nc(OC)c(Cc3ccc4ccccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6,7-dimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol CCH 29038 free base (58 mg, 161 μmol) in dry DMF (6 mL) at 0° C. in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added LiHMDS (1.0 N in TBME, 175 μL, 175 μmol) and the mixture was stirred for 20 min at RT. Dimethyl sulphate (18 μL, 192 μmol) was then added at 0° C. and the mixture was stirred overnight at RT. The mixture was then concentrated to dryness at 40° C. under vacuum and the residue was taken up in CH2Cl2 (40 mL). The organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 86:14) provided 23 mg of 3,6,7-trimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinoline. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.50 M HCl solution in MeOH (0.4 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 3,6,7-trimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinoline hydrochloride 18 as a brown solid (25 mg, 38% yield).
Reaction SMILES: Br.[Br:2][CH2:3][C:4]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=1[NH2:6].[C:12](Cl)(Cl)=[O:13].C1C=CC=CC=1>C1C=CC=CC=1>[Br:2][CH2:3][C:4]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=1[N:6]=[C:12]=[O:13]
Reactant: Nc1cc(Cl)ccc1CBr
Reactant: O=C(Cl)Cl
Agent: Br
Solvent: c1ccccc1
Product: O=C=Nc1cc(Cl)ccc1CBr

Procedure:
6.32 g of 2-bromomethyl-5-chloroaniline hydrobromide is added to 30 ml of benzene containing 12.5% phosgene (w/v) and the mixture refluxed in a vessel equipped with a Dean-Stark trap and additional phosgene/benzene added for a total of 250 ml (over a period of 6 hrs; 1/2 ml of water collected in the trap). The reaction mixture is cooled to 20°, insolubles removed by filtration and the filtrate concentrated (solvent removed), then distilled under vacuum to obtain 2-bromomethyl-5-chlorophenylisocyanate (distills at 0.05 mm Hg/50°). Further distillation yields 2-bromomethyl 4-bromo-5-chlorophenyl isocyanate (which may be refined by crystallization from petroleum ether, m.p. 48°-50°) which is useful as an intermediate in Examples 4 and 5 in preparing 6-bromo-7-chloro-4H-1,3-benzoxazine analogs of the title product of this example.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[Mg]Br.Br[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CN(CCN(C)C)C.[Cl-].[NH4+]>>[CH:14]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: BrC1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Product: c1ccc2cc(C3CCCCC3)ccc2c1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
2-Naphthyl magnesium bromide (1.46 mL of 0.82 M-THF solution, 1.2 mmol) was added to a mixture of bromocyclohexane (163.1 mg, 1.0 mmol), FeCl3 (0.5 mL of 0.1 M-THF solution, 5 mol %) and TMEDA (181.1 μL, 1.2 mmol) at 25° C. over 20 minutes through an injection pump. After the addition of Grignard reagent mixture was completed, the reaction mixture was stirred for 10 minutes at this temperature. After treating with saturated aqueous ammonium chloride solution in a conventional manner, the reaction mixture was filtered through a pad of Florisil® and concentrated in vacuum. Using the internal standard (tetrachloroethane, 79 mg, 0.47 mmol), the crude product was analyzed by 1H NMR to give 2-cyclohexylnaphthalene in a yield of 96%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18]>C(O)C>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:14]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A mixture of tert-butyl(piperidin-4-ylmethyl)carbamate (3.0 g, 14 mmol) and ethyl acrylate (1.7 g, 17 mmol) in ethanol (30 mL) was refluxed for 1 h. After cooled to room temperature, the solution was concentrated to give clear colorless oil. The residue was chromatographed on a silica gel column eluting with CH2Cl2/methanol (14:1) to give 4.0 g (91%) of the title compound as clear colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Br:8])[N:3]=1.[N:9]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CCO>[Br:8][C:4]1[N:3]=[C:2]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]2)[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)n2)CC1
Temperature: 100 °C
Yield: 70 %

Procedure:
A mixture of 2,6-dibromopyrazine (0.47 g, 2 mmol), tert-butyl 1,4-diazepane-1-carboxylate (0.4 g, 2 mmol), and DIPEA (0.78 g, 6 mmol) in EtOH (10 mL) was heated at 100° C. for 15 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (5% to 50%) as eluting solvents to afford tert-butyl 4-(6-bromopyrazin-2-yl)-1,4-diazepane-1-carboxylate as colorless oil (0.5 g, 70%). MS (ESI) m/z: 357 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:19][C:10]3=[N:11][CH:12]=[C:13]4[C:17]([NH2:18])=[N:16][NH:15][C:14]4=[C:9]3[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>C1COCC1.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2[O:19][C:10]3=[N:11][CH:12]=[C:13]4[C:17]([NH:18][C:29]([NH:28][CH2:26][CH3:27])=[O:30])=[N:16][NH:15][C:14]4=[C:9]3[C:8]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1n[nH]c2c1cnc1oc(-c3ccccc3)c(-c3ccccc3)c12
Reactant: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1n[nH]c2c1cnc1oc(-c3ccccc3)c(-c3ccccc3)c12
Temperature: 50 °C

Procedure:
To a solution of 11 (22 mg, 0.068 mmol, 1.0 equiv) in THF (2 mL) was added 4-(Dimethylamino)pyridine (1 mg, 0.008 mmol, 0.1 equiv) and ethyl isocyanate (53 μL, 0.675 mmol, 10.0 equiv). After heating at 50° C. for 2 hrs, the solvent was removed in vacuo. The resulting yellow residue was purified by silica gel chromatography (5% MeOH:CH2Cl2) to afford urea 12a. MS (MH+) 398.4; Calculated 397.2 for C23H19N5O2.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[N:13][NH:14]2)=[CH:10][CH:9]=1.[CH3:27][Si:28]([CH3:35])([CH3:34])[CH2:29][CH2:30][O:31][CH2:32]Cl>O1CCCC1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)(=[O:19])=[O:18])=[N:13][N:14]2[CH2:32][O:31][CH2:30][CH2:29][Si:28]([CH3:35])([CH3:34])[CH3:27])=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=S(=O)(c1ccc(F)cc1)c1n[nH]c2cc(Br)ccc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(S(=O)(=O)c2ccc(F)cc2)c2ccc(Br)cc21
Temperature: 0 °C

Procedure:
Sodium tert-butoxide (0.035 g) was added to an ice-cold solution of 6-bromo-3-[(4-fluorophenyl)sulfonyl]-1H-indazole (Intermediate 69) (0.11 g) in tetrahydrofuran (1.5 ml). 2-(Trimethylsilyl)ethoxymethyl chloride (0.06 ml) was then added and the mixture was warmed to room temp. over 1 h. The reaction was quenched using 2M aqueous ammonia (1 ml) and methanol (1 ml) the solvent was evaporated and the residue was purified on a Varian Bond-Elut SPE cartridge, eluting with cyclohexane:dichloromethane (100:0 to 0: 100) to give the title compound (0.67 g).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][OH:15])[N:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:15][CH2:14][CH2:13][O:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[N:11][C:2]([CH3:1])=[N:3]2)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc2c(OCCO)cccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc2c(OCCOS(C)(=O)=O)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of 2-(2-methylquinazolin-5-yloxy)ethanol (0.330 g, 1.62 mmol) in dichloromethane (20 mL) and triethylamine (0.34 mL, 2.43 mmol) was added methane sulfonyl chloride (0.14 mL, 1.78 mmol) dropwise. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with further dichloromethane and partitioned with saturated NaHCO3 aq. The organic phase was washed with brine, dried (MgSO4) and evaporated in vacuo to give the title compound as a cream solid (0.452 g, 99%).