Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.ClCCl.Cl.CN(C)CCCN=C=NCC.[CH:27]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH:27]1([CH2:32][CH2:33][NH:34][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCCC1CCCC1
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCC2CCCC2)cc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a round-bottomed flask was charged 3-iodo-4-methylbenzoic acid (1.4 g, 5.4 mmol), dicloromethane (4 ml), and DMF (2 ml). This mixture was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.3 mmol) was added. The reaction mixture was stirred for 10 min before 2-cyclopentylethanamine (0.47 g, 4.2 mmol) was introduced. The reaction mixture was stirred at 0° C. for 1 h, then at RT under N2 for 16 h. The reaction was partitioned between DCM (60 ml) and brine (50 mL). The aqueous layer was back exacted with DCM (4×20 mL) and the combined DCM layer was dried (Na2SO4) and concentrated. The crude product was dissolved in DCM and purified by chromatography through a Redi-sep pre-packed silica gel column (330 g), eluting with a gradient of 5% to 15% EtOAc in hexane, to provide N-(2-cyclopentylethyl)-3-iodo-4-methylbenzamide as a white solid. MS (ESI, pos. ion) m/z: 358.1 (M+1).
Reaction SMILES: NOS(O)(=O)=O.[C:7]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl-].[NH4+:17].O>C(O)=O>[C:7]1(=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:17]1
Reactant: O=C1CCCCCCC1
Reactant: [NH4+]
Agent: NOS(=O)(=O)O
Agent: [Cl-]
Solvent: O=CO
Solvent: O
Product: O=C1CCCCCCCN1
Temperature: 105 °C
Yield: 65 %

Procedure:
A 5 L three-neck round bottom flask was fitted with a heating mantle, an overhead mechanical stirrer, an addition funnel, and a thermometer. The reaction was performed under an argon atmosphere. Hydroxylamine-O-sulfonic acid (196.7 g, 1.74 moles, 1.10 equiv.) and formic acid (1 L) were charged into the round bottom flask and stirred to form a white slurry. A solution of cyclooctanone (200.0 g 1.58 moles, 1.0 equiv.) in formic acid (600 mL) was added dropwise to the white slurry via the addition funnel. After the addition, the addition funnel was replaced by a reflux condenser, and the reaction was heated to reflux (internal temperature about 105° C.) for 1 hour to give a brown solution. After the solution was cooled to room temperature, it was poured into a mixture of saturated aqueous ammonium chloride (1.5 L) and water (1.5 L). The aqueous mixture was extracted with chloroform (3×1200 mL). The combined chloroform layers were transferred into a beaker, and saturated sodium bicarbonate (2 L) was added slowly. The chloroform layer was then separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to afford a brown oil. The oil was placed in a 500 mL round bottom flask with a magnetic stirrer. The round bottom flask was placed in a silicon oil bath and was fitted with a short path vacuum distillation head equipped with a thermometer. A Cow-type receiver was connected to three 250 mL flasks. 2-Azacyclononanone (145 g, 65%, mp 64-69° C.) was obtained by vacuum distillation (fraction with head temperature range from 80 to 120° C. at pressures between 3.0 and 3.4 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C:29]1([CH2:34]O)([CH2:32][OH:33])[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:34][C:29]3([CH2:32][OH:33])[CH2:31][CH2:30]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: OCC1(CO)CC1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Product: O=C1c2ccccc2C(OCC2(CO)CC2)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 63.1 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cyclopropane dimethanol (516 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as an off-white solid (305 mg, 63%). 1H NMR (300 MHz, CDCl3): 8.01-7.98 (m, 2H, O2N—C—CH), 7.92-7.89 (m, 1H, C(O)═C═CH), 7.55-7.52 (m, 2H, Ar—H), 7.32-7.29 (m, 2H, Ar—H), 7.19-7.12 (m, 5 H, Ar—H), 4.49 (s, 2H, N—CH2), 3.51-3.43 (m, 2H, HOCH2), 2.81 (s, 2H, OCH2), 0.43-0.40 (m, 2H, CH2), 0.22-0.12 (m, 2H, CH2). 13C NMR (75 MHz, CDCl3): 168.54, 145.52, 144.95, 137.47, 135.29, 133.45, 131.87, 130.50, 130.21, 128.98, 128.30, 124.16, 123.60, 123.48, 94.96, 67.84, 42.75, 22.68, 8.94, 8.90 Anal.: calc. for C26H23ClN2O5: C, 65.20; H, 4.84; N, 5.85, Found: C, 64.83; H, 4.92; N, 5.63.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: OCc1ccccc1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCc5ccccc5)cc4CCC3C2C2CCCC2)cc1Cl

Procedure:
The title compound was prepared according to Method E from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and benzyl alcohol. Yellow solid, 193 mg. ES-MS m/z 510 (M+H).
Reaction SMILES: C([O:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[CH3:26][C@@H:19]([O:18][C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]([OH:27])=[O:8])=[CH:15][CH:14]=1)=[O:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC[C@@H](C)OC(=O)c1ccc(C(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(C(=O)O)cc1
Yield: 99.6 %

Procedure:
Then, 0.12 g of 5% palladium/carbon and 30 ml of a tetrahydrofuran solution containing 1.21 g of 4-((R)-1-methylheptyloxycarbonyl)benzoic acid benzyl ester were stirred overnight at room temperature in a stream of hydrogen to decompose a benzyl protective group by hydrogenation. 5% palladium/carbon was removed using Celite as a filter aid, and the filtrate was concentrated. The concentrate obtained was purified by column chromatography to obtain 0.91 g of 4-((R)-1-methylheptyloxycarbonyl) benzoic acid as a colorless liquid (gradually crystallized) (isolated yield: 99%).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[N:12](S(C1C=CC=CC=1)(=O)=O)[CH:11]=[CH:10]3.[OH-].[Na+]>CCO>[CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[NH:12][CH:11]=[CH:10]3
Reactant: CC1c2c(ccc3c2ccn3S(=O)(=O)c2ccccc2)OCCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 95.3 %

Procedure:
To tert-butyl 1-methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 41, 1.5 g, 3.4 mmol) dissolved in EtOH (50 mL), 2 M NaOH (10 mL, 20 mmol) was added and the reaction mixture was heated at 70° C. for 2 hours. The EtOH was removed under reduced pressure and the water phase was extracted with DCM (2×100 mL). The organic layer was collected, dried (MgSO4) and evaporated to afford the title compound (0.98 g) as a yellow solid. MS m/z 303 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](O)=[O:20])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:22]([O:24][C:25]([C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29])=[O:26])[CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](=[O:20])[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[C:25]([O:24][CH2:22][CH3:23])=[O:26])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CCOC(=O)c1ccccc1N
Reactant: C[C@@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)O
Product: CCOC(=O)c1ccccc1NC(=O)C[C@H]1[C@H](C)Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 34.3 %

Procedure:
A procedure similar to that described in Example 52 was carried out with trans-9-bromo-5-carboxymethyl-6-methyl-6,7-dihydro- 1H, 5 H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0,849 mmol) and o-ethoxycarbonylaniline (147 mg, 0.891 mmol) to give 153 mg of the title compound (36%): mp 238°~248° C.; 1H NMR (270 MHz, DMSO-d6) δ11.39 (s, 1H), 11.31 (s, 1H), 8.66 (d, 2H, J=8.4 Hz), 8.04 (dd, 1H, J=8.4, 1.7 Hz), 7.55 (td, 1H, J=8.4, 1.7 Hz), 7.35 (d, 1H, J=1.9 Hz), 7.19 (d, 1H, J=1.9 Hz), 7.11 (td, 1H, J=8.4, 1.7 Hz), 5.19~5.29 (m, 1H), 4.37 (q, 2H, J=7.3 Hz), 3.29 (dd, 1H, J=17.0, 5.1 Hz), 2.97 (dd, 1H, J=14.5, 4.6 Hz), 2.55~2.70 (m, 3H), 1.40 (t, 3H, J=7.3 Hz), 0.88 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[C].[Ru]>[CH:1]1[C:6]2[C:1]3([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1CCCCC1
Agent: [Ru]
Product: c1ccc2c(c1)-c1ccccc1C21CCCCC1

Procedure:
110 g of spiro[cyclohexane-1,9'-fluorene] obtained in the above (1), 100 ml of cyclohexane solvent and 20 g of 5% ruthenium-carbon catalyst (manufactured by Japan Engelhard Co.) were charged in an autoclave of 1 liter and hydrogenation was effected with a hydrogen pressure of 80 kg/cm2G at 170° C. for 5 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[CH2:12]1N2CCN(CC2)C1.CN(C=O)C>CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[CH:6]2
Reactant: C1CN2CCN1CC2
Reactant: COc1ccc2[nH]ccc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(ccn2C)c1
Temperature: 92.5 °C
Yield: 967 %

Procedure:
To a solution of 5-methoxyindole (1.0 g, 6.79 mmol) in DMC (10 mL), DABCO (0.076 g, 0.68 mmol) is added followed by DMF (2 mL). The resulting solution is heated to 90-95° C. for 7 h. The reaction is cooled to RT, and diluted with EtOAc (40 mL) and H2O (40 mL). The organic layer is separated and washed in sequence with H2O (50 mL), 10% aqueous citric acid (2×40 mL) and H2O (4×40 mL). The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 5-methoxy-1-methylindole (about 1.06 g, 97%) as a solid: 1H NMR (CDCl3) δ7.21 (d, 1H), 7.09 (d, 1H), 7.00 (d, 1H), 6.87 (dd, 1H) 6.39 (d, 1H), 3.84 (s, 3H), 3.73 (s, 3H); 13C NMR (CDCl3) δ153.9, 132.1, 129.3, 128.7, 111.8, 109.9, 102.4, 100.3, 55.9, 32.9; MS m/z 161 [M+1]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:3]1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[N:26]([CH2:14][C@@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[N+:27]=[N-:28]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CN=[N+]=[N-]
Temperature: 55 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a solution of Example 220A (365 mg, 1.021 mmol) in N,N-dimethylformamide (5 mL) was added sodium azide (531 mg, 8.17 mmol). The reaction mixture was stirred at 55° C. for 8 hours. Chromatography on a 12 g silica gel column eluted with 5% ethyl acetate/hexanes for 3 minutes followed by a gradient to 100% ethyl acetate over 20 minutes provided the title compound (135 mg, 0.557 mmol, 54.6% yield) as an oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.65 (d, J=3.5 Hz, 1H), 4.24 (d, J=3.5 Hz, 1H), 3.97 (ddd, J=10.2, 7.6, 3.1 Hz, 1H), 3.64 (dd, J=12.3, 5.5 Hz, 1H), 3.39-3.22 (m, 3H), 2.01-1.80 (m, 2H), 1.42 (s, 9H); MS (DCI) m/z 243 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:14])[C:12](=[O:15])[O:11][CH2:10][CH2:9][C:8]=2[CH:16]=1)([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:14])[C:12](=[O:15])[O:11][CH2:10][CH2:9][C:8]=2[CH:16]=1
Reactant: CN1C(=O)OCCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Solvent: CCO
Product: CN1C(=O)OCCc2cc(N)ccc21
Reaction time: 3 h

Procedure:
A mixture of 2-nitro-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (0.7 g) and 50% Raney Ni (1 mL) in ethanol (25 mL) was hydrogenated at 30 psi for 3 hours. The reaction mixture was filtered through celite and concentrated to yield 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one: 1H NMR (300 MHz, CDCl3) δ 6.94 (d, 1H), 6.60 (dd, 1H), 6.53 (d, 1H), 4.45 (t, 2H), 3.67 (bs, 1H), 3.33 (s, 3H), 2.87 (t, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:10]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](F)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1>>[Cl:8][C:9]1[C:10]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: CN1CCNCC1
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 120 °C

Procedure:
1-Methylpiperazine (492 μL, 4.44 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 76, 612 mg, 1.48 mmol). The mixture was heated at 120° C. for 1 h and was then concentrated in vacuo. The residue was dissolved in CH2Cl2 (25 mL) and washed with water (2×25 mL) and sat. brine (25 mL), then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-10% CH3OH in CH2Cl2 gave the title compound as an orange gum. This gum was dissolved in ethanol (25 mL) and a solid precipitated. This solid was collected by filtration and washed with ethanol and diethyl ether to give the title compound (365 mg, 50%) as a yellow/orange solid; 1H NMR: 2.26 (3H, s), 2.47-2.55 (4H, m), 3.07-3.13 (4H, m), 3.93 (3H, s), 6.85 (1H, s), 6.99 (1H, t), 7.16-7.22 (1H, m), 7.48 (1H, d), 8.26 (1H, d), 8.36 (1H, s), 8.42 (1H, d), 8.51 (1H, s), 8.54 (1H, s), 11.88 (1H, s); m/z: ES+ MH+ 494.46.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:3][CH2:2]1.[O:22]1[CH2:25][C:24](=O)[CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([N:4]([CH:24]2[CH2:25][O:22][CH2:23]2)[CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:3][CH2:2]1
Reactant: O=C1COC1
Reactant: NS(=O)(=O)c1ccc(NCCCNC2CC2)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NCCCN(C2CC2)C2COC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 308A (314 mg) in dichloromethane (5 mL) was added oxetan-3-one (72 mg) followed by sodium triacetoxyborohydride (318 mg). The mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water and brine and dried over Na2SO4. After filtration, evaporation of the solvent gave the crude title compound.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][Br:10])=[CH:5][CH:4]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: BrCCCCCCBr
Agent: [K]
Product: Clc1ccc(OCCCCCCBr)cc1

Procedure:
The intermediate 6-(4-chlorophenoxy)hexyl bromide was prepared from the potassium salt of 4-chlorophenol and 1,6-dibromohexane.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[C:4]2[C:11]([C:12]3[CH:13]=[C:14]([CH2:18]O)[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:9]([CH2:20][O:21]CC[Si](C)(C)C)[C:5]=2[N:6]=[CH:7][N:8]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>>[F:29][C:30]([F:35])([F:34])[C:31]([O:33][CH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]2[C:4]3[C:3]([N:2]([CH3:1])[CH3:28])=[N:8][CH:7]=[N:6][C:5]=3[N:9]([CH2:20][OH:21])[CH:10]=2)[CH:13]=1)=[O:32]
Reactant: CN(C)c1ncnc2c1c(-c1cccc(CO)c1)cn2COCC[Si](C)(C)C
Reactant: O=C(O)C(F)(F)F
Product: CN(C)c1ncnc2c1c(-c1cccc(COC(=O)C(F)(F)F)c1)cn2CO

Procedure:
A solution of {3-[4-(dimethylamino)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}methanol (C26) (397 mg, 0.996 mmol) in trifluoroacetic acid (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to provide the product (400 mg) as a brown oil. This material was taken directly into the following step. LCMS m/z 395.1 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[C:13]3[O:20]C)[CH:7]=1.Cl>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][NH:14][C:13]3=[O:20])[CH:7]=1
Reactant: COc1ccc(O)cc1CCc1ccc2ncnc(OC)c2c1
Agent: Cl
Solvent: CO
Product: COc1ccc(O)cc1CCc1ccc2nc[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
90 mg of 6-[2-(5-hydroxy-2-methoxyphenyl)ethyl]-4-methoxyquinazoline are dissolved in 8 ml of methanol and treated with 1 ml of 4 N aqueous hydrochloric acid. The mixture is stirred for 16 hours at room temperature, then poured onto 2 M aqueous pH 7 buffer and extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol=9/1) to yield the title compound as colourless crystals. mp: 221-224°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:9][O-:10].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:10][CH3:9])[N:3]=1
Reactant: C[O-]
Reactant: Clc1cncc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1cncc(Cl)n1

Procedure:
2,6-Dichloropyrazine (0.067 mole) is treated with a solution of sodium methoxide (0.067 mole) in 100 ml. dry methanol for 1 hour at 25°. The solvent is removed in vacuo and the residue is extracted with boiling hexane extract. 2-Chloro-6-methoxypyrazine crystallizes from the hexane extract. Another recrystallization from isopropanol at -70° gives 2-chloro-6-methoxypyrazine as an oil at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:22]=1)=[CH:5]2.C(N(C(C)C)CC)(C)C.O=C1CCC(=O)N1[O:47][C:48](=O)[CH2:49][C:50]([F:53])([F:52])[F:51].O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([C:48](=[O:47])[CH2:49][C:50]([F:53])([F:52])[F:51])[CH2:27][CH2:26]3)[N:22]=1)=[CH:5]2
Reactant: O=C(CC(F)(F)F)ON1C(=O)CCC1=O
Reactant: Clc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(F)(F)F)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.3 %

Procedure:
The compound (66 mg, 0.15 mmol) prepared in Example 117 was dissolved in dichloromethane (10 ml). Diisopropylethylamine (0.08 ml, 0.44 mmol) and 3,3,3-trifluoropropionic acid 2,5-dioxo-pyrrolidin-1-yl ester (29 mg, 0.13 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (6 mg, Yield 9%).
Reaction SMILES: [Sn](Cl)[Cl:2].[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([C:18](=[O:21])[NH:19][N:20]=3)[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)([O-])=O>Cl>[ClH:2].[NH2:4][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([C:18](=[O:21])[NH:19][N:20]=3)[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1
Reactant: Cl[Sn]Cl
Reactant: O=c1[nH]nc2c3ccc([N+](=O)[O-])cc3[nH]c(=O)n12
Agent: Cl
Product: Nc1ccc2c(c1)[nH]c(=O)n1c(=O)[nH]nc21
Yield: 62.1 %

Procedure:
1.98 g (8.8 mmol) of tin dichloride were dissolved in 10 ml of conc. hydrochloric acid at 80° C. 494 mg (2 mmol) of 8-nitro-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione were added portionwise thereto. After heating at reflux for 2 hrs. the precipitate was filtered off, washed with water and dried in a vacuum. 315 mg (62%) of 8-amino-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione hydrochloride were obtained as white crystals;
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]2[CH:13]=[CH:14][C:15]([CH2:17][OH:18])=[CH:16][C:4]=2[N:3]=1.CN(C=O)C.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH2:26]([O:18][CH2:17][C:15]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:2]([Cl:1])=[N:3][C:4]=2[CH:16]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COCCOCn1c(Cl)nc2cc(CO)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCn1c(Cl)nc2cc(COCc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of [2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-5-yl]-methanol (100 mg, 0.370 mmol) and DMF (3 mL) was added NaH (30.0 mg, 0.740 mmol, 60% suspension in mineral oil) at 0° C. The reaction mixture was stirred for 1 h at 0° C., then treated with benzyl bromide (52.0 μL, 0.440 mmol). The reaction mixture was stirred for 16 h. Water (5 mL) was added and the product was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-50% EtOAc/hexanes) to provide the titled compound (100 mg, 75%). MS (ESI/CI): mass calcd. for C19H21ClN2O3, 360.1; m/z found, 361.1 [M+H]+
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]([CH2:20][CH:21]2[CH2:23][CH2:22]2)(=[O:19])=[O:18])[CH2:14][NH:13]1)=[O:11].[C:24](OC(C)(C)C)(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27]>C(N(CC)CC)C>[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]([CH2:20][CH:21]2[CH2:23][CH2:22]2)(=[O:18])=[O:19])[CH2:14][N:13]1[C:24](=[O:29])[CH2:25][C:26](=[O:27])[CH3:28])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-cyclopropylmethanesulfonyl-pyrrolidine-2-carboxylic acid methyl ester trifluoroacetate was reacted with tert-butyl acetoacetate in the presence of triethylamine to give the title compound as brown solid. MS (ESI): m/z=332.2 [M+H]+.