Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:16][CH2:15][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11](N)=[CH:10][C:9]=3[C:5]=2[CH2:4]1.N([O-])=[O:19].[Na+].S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>Cl.O>[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:16][CH2:15][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([OH:19])=[CH:10][C:9]=3[C:5]=2[CH2:4]1
Reactant: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CN(C)C1CCc2oc3ccc(O)cc3c2C1
Reaction time: 1 h
Yield: 36.3 %

Procedure:
A solution of 0.332 gm (1.44 mMol) N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine in 5 mL concentrated hydrochloric acid and 5 mL water was cooled to -10° C. To this solution was added a solution of 0.109 gm (1.58 mMol) sodium nitrite in 10 mL water dropwise. The resulting solution was stirred for 1 hour and was then added to 10 mL concentrated sulfuric acid. This mixture was stirred at reflux for 4 hours. The reaction mixture was poured over ice and the solution made basic by the addition of aqueous potassium carbonate. The solution was then extracted well with chloroform containing 10% isopropanol. The organic extracts were combined, dried over potassium carbonate and concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 2 mm). Fractions containing product were combined and concentrated under reduced pressure to provide 0.121 gm (36%) of the title compound as an off-white foam.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([CH3:25])[CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][OH:20])=[C:17]([CH3:25])[CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)ccc1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A suspension of 0.11 g (2.93 mmol) of lithium aluminum hydride in 20 ml of tetrahydrofuran was cooled to 0° C. A solution of 0.75 g (2.93 mmol) of methyl 4-benzyloxy-2-methylbenzoate in 20 ml of tetrahydrofuran was added dropwise to the suspension at 0° C. After stirring at 0° C. for 2 hours, the reaction mixture was treated in a conventional manner to give 0.66 g of 4-benzyloxy-2-methylbenzyl alcohol.
Reaction SMILES: [SH:1][CH2:2][CH:3]([SH:6])[CH2:4][SH:5].O=[CH:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].B(F)(F)F.CCOCC>C(Cl)Cl>[SH:1][CH2:2][CH:3]1[CH2:4][S:5][CH:8]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[S:6]1
Reactant: SCC(S)CS
Reactant: COC(=O)CCC=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCC1SCC(CS)S1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 1,2,3-trimercaptopropane (4.21 g, 0.03 mol), methyl 4-oxobutanoate from Example 73 (3.5 g, 0.03 mol) and boron trifluoride etherate (1 ml) in methylene chloride (75 ml). The crude product was chromatographed on silica gel using 5% ethyl acetate/hexane as eluent to give 2.5 g (35%) of product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1S(N)(=O)=O.[Cl:15]C1C=CC(O)=CC=1.C1(=O)OCCO1.OCCOC1C=CC=CC=1Cl.C(Cl)(Cl)=O>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:15]
Reactant: Oc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccccc1OCCCl
Agent: O=C(Cl)Cl
Agent: OCCOc1ccccc1Cl
Solvent: O=C1OCCO1
Product: ClCCOc1ccccc1Cl

Procedure:
A process for the preparation of 2-(2-chloroethoxy)-benzenesulfonamide of formula I ##STR15## which process comprises the etherification of 4-chlorophenol of formula II ##STR16## with ethylene carbonate at a temperature between +130° C. and +150° C. and chlorination of the resulting 2-(2-hydroxyethoxy)-chlorobenzene of formula III ##STR17## with phosgene at a temperature between +70° C. and +90° C. to give 2-(2-chloroethoxy)-chlorobenzene of formula IV ##STR18## which is converted with chlorosulfonic acid, at a temperature between +20° C. and +60° C. and subsequent neutralization with sodium hydroxide to the sulfonic acid sodium salt of formula V ##STR19## which is hydrogenated at a temperature between +20° C. and +70° C. to the compound formula VI ##STR20## which is subsequently reacted with phosgene at a temperature between +60° C. and +120° C. to the sulfonic acid chloride of formula VII ##STR21## which is reacted with ammonia at a temperature between 0° C. and +100° C. to the sulfonamide of formula I.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[N:5]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]([C:20](Cl)=[O:21])[C@@H:8]([CH3:23])[CH2:7]1)[CH3:2].[N:32]1[CH:37]=CC=C[CH:33]=1.Cl.CNC.[OH-].[K+]>ClCCl.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:31])[N:5]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]([C:20](=[O:21])[N:32]([CH3:37])[CH3:33])[C@@H:8]([CH3:23])[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)Cl)c2cc(OC)c(OC)cc21
Reactant: c1ccncc1
Agent: CNC
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)N(C)C)c2cc(OC)c(OC)cc21
Yield: 24 %

Procedure:
A solution of cis-4-benzyl-(1-chlorocarbonyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid ethyl ester (Example 107A) (38 mg, 0.085 mmol), pyridine (0.5 mL), and dimethylamine hydrochloride (12 mg, 0.14 mmol) in anhydrous dichloromethane (1 mL) was stirred at room temperature overnight. Then, 10 mL water and 10 mL 2N KOH were added followed by extration with ethyl acetate (3×10 mL). The combined organic phases were washed with 1N HCl (2×10 mL), 10 mL of a saturated sodium bicarbonate solution, and 10 ml of brine. The combined washed organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 0-75% ethyl acetate/hexanes as eluent afforded cis-benzyl-(1-dimethylcarbamoyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid ethyl ester (Example 108A) (10 mg, 24%) MS m/z 455 (M+), 277 (M+ -178); 1H NMR (CDCl3) δ 3.79 (C6/7, s, 3H), 3.70 (C6/7, s, 3H), 2.79 (N1, s, 6H); and cis-benzyl-[6,7-dimethoxy-2-methyl-1-(5-oxo-penta-1,3-dienylcarbamoyl)-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic acid ethyl ester (Example 108B) (7 mg, 15%): MS m/z 508 (M+ +1), 329 (M+ -178); 1H NMR (CDCl3) δ 9.46 (aldehyde, d, 1H), 3.85 (C6/7, s, 3H), 3.79 (C6/7, s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:28]5[CH2:29][CH2:30][NH:31][CH2:32][C:27]5=[N:26][CH:25]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=2)[N:4]=1)[CH3:2].[BH-](OC(C)=O)(OC(C)=O)O[C:43](C)=O.[Na+].C=O>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:28]5[CH2:29][CH2:30][N:31]([CH3:43])[CH2:32][C:27]5=[N:26][CH:25]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=2)[N:4]=1)[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5cnc6n5CCNC6)ccn34)c12
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5cnc6n5CCN(C)C6)ccn34)c12
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (5 mg, 0.0094 mmol; prepared as in Example 59) in MeOH (4 mL) was added NaBH(OAc)3 (8.0 mg, 0.038 mmol), and HCHO (as a 35% aqueous solution) (15 mg, 0.19 mmol). The reaction mixture was stirred for 30 minutes then concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to provide the final product (3.2 mg). MS (ES+APCI) m/z=546 (M+H).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:11][C:12]([C:14]1[N:15]([CH2:30][CH3:31])[C:16]2[C:21]([C:22]=1[C:23](=O)[C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:19]([F:29])=[CH:18][CH:17]=2)=O)C.O>C(O)(=O)C>[CH2:30]([N:15]1[C:16]2[CH:17]=[CH:18][C:19]([F:29])=[CH:20][C:21]=2[C:22]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12](=[O:11])[C:14]1=2)[CH3:31]
Reactant: CCOC(=O)c1c(C(=O)C(=O)OC)c2cc(F)ccc2n1CC
Reactant: NNc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCn1c2ccc(F)cc2c2c(C(=O)OC)nn(-c3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
18.4 ml (187.2 mmol) of phenylhydrazine are added, at room temperature, to a solution of 14 g (43.6 mmol) of methyl 2-(ethoxycarbonyl)-1-ethyl-5-fluoro-α-oxo-1H-indole-3-acetate in 150 ml of acetic acid and the reaction mixture is stirred for 30 min at room temperature and then for 2 h at reflux. The mixture is cooled, 100 ml of water are added and an insoluble material is separated by filtration, the insoluble material being washed on sintered glass with a 70/30 mixture of water and acetone. 10.5 g (28.6 mmol) of white solid are thus isolated, which solid is used as is in the following stage.
Reaction SMILES: [N:1]([CH:4]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[C@H:5]([OH:16])[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.CO>O1CCCC1.O>[NH2:1][CH:4]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[C@H:5]([OH:16])[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H](O)C(N=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)C(N)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
10.00 g (25.6 mmole) of 1-azido-4-t-butyldimethylsilyloxy-(2R)-(3,4-dichlorophenyl)-2-butanol [prepared as described in step (d) above] were dissolved in 100 ml of tetrahydrofuran and 0.6 ml of water, and 7.39 g (28.2 mmole) of triphenylphosphine were added to the resulting solution. The mixture was then stirred under a nitrogen atmosphere at 80° C. for 4 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, hexane was added to the resulting residue and the deposited crystals were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography, using a gradient elution method, with mixtures of methylene chloride and methanol ranging from 30:1 to 10:1 by volume as the eluent, to obtain 3.83 g (yield 41%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.CCN(CC)CC.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CN[C@@H](C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a 0° C. solution of (S)-(−)-1-(4-methoxyphenyl)ethylamine (25 g, 165 mmol) and Et3N (46 mL, 330 mmol) in THF (350 mL) was added a solution of ethyl bromoacetate (27.5 mL, 248 mmol) in THF (50 mL) dropwise over 30 min. The reaction mixture was allowed to warm to room temperature, stirred overnight, then diluted with EtOAc and washed with water and a saturated NaCl solution. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give ethyl 2-{[(1S)-1-(4-methoxyphenyl)ethyl]amino}acetate (40 g, 100%) as a colorless oil: TLC (40% EtOAc/hex) Rf 0.4; 1H NMR (CDCl3) δ 1.25 (t, J=7.2 Hz, 3H), 1.37 (d, J=6.6 Hz, 3H), 2.03 (br s, 1H), 3.21 (d, J=17.6 Hz, 1H), 3.29 (d, J=17.6 Hz, 1H),), 3.76 (q, J=6.6 Hz, 1H), 3.81 (s, 3H), 4.16 (q, J=7.2 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 7.23 (d, J=8.7 Hz, 2H); 13C NMR (CDCl3) δ 14.1, 24.2, 48.8, 55.2, 57.0, 60.6, 113.8, 127.8, 136.6, 158.7, 172.6; HPLC ES-MS m/z (rel abundance) 238 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:38]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[C:42]([CH:38]4[CH2:41][CH2:40][CH2:39]4)=[O:43])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: O=C(Cl)C1CCC1
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)C1CCC1)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by cyclobutanecarbonyl chloride (42 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 154 mg, 85%; 1H NMR (mix of rotomers, 400 MHz, DMSO-D6) δ ppm 8.52 (2 H, d, J=6.06 Hz), 7.66 (2 H, d, J=6.06 Hz), 7.30 (2 H, dd, J=8.46, 5.68 Hz), 7.15 (2 H, t, J=8.97 Hz), 6.52 (1 H, s), 5.08-5.33 (2 H, m), 4.42-4.57 (0.5 H, m), 4.38 (1 H, d, J=13.39 Hz), 3.95 (3 H, s), 3.64-3.79 (0.5 H, m), 3.36-3.48 (0.5 H, m), 3.24-3.34 (0.5 H, m), 3.03-3.20 (1 H, m), 2.55-2.76 (4 H, m), 2.01-2.28 (4 H, m), 1.39-1.99 (6 H, m); m/z (APCI+) for C28H32N5O2F 490.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]2[O:8][CH2:9][CH:10]([NH2:11])[CH:6]2[O:5][CH2:4]1.C(N(CC)CC)C.[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([Cl:27])=[CH:22][N:21]=1>CCO>[Cl:19][C:20]1[N:25]=[C:24]([NH:11][CH:10]2[CH2:9][O:8][CH:7]3[CH:3]([O:2][CH3:1])[CH2:4][O:5][CH:6]23)[C:23]([Cl:27])=[CH:22][N:21]=1
Reactant: COC1COC2C(N)COC12
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC1COC2C(Nc3nc(Cl)ncc3Cl)COC12
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To a solution of 6-methoxyhexahydrofuro[3,2-b]furan-3-amine (380 mg, 2.3872 mmol) in EtOH (25 mL) were added N,N-diethylethanamine (967.4 mg, 9.560 mmol) and 2,4,5-trichloropyrimidine (526.2 mg, 2.869 mmol). The reaction was stirred at rt for 4 h, then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give a white solid (490 mg, 67.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:24]([O-])=O)=[C:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:24][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]2[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][C:13]=1[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: COc1ccc(COc2ccc([N+](=O)[O-])c(CNC(=O)OC(C)(C)C)c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(COc2ccc(N)c(CNC(=O)OC(C)(C)C)c2)cc1
Yield: 100.1 %

Procedure:
A solution of tert-butyl {5-[(4-methoxybenzyl)oxy]-2-nitrophenyl}methylcarbamate produced in Example (1a) (209 g, 538 mmol), iron powder (150 g, 2.69 mol) and ammonium chloride (15.0 g, 280 mmol) in ethanol (1.2 L) and water (1 L) was stirred with heating under reflux for five hours. After leaving to cool, the reaction mixture was filtered through celite. The filtrate was concentrated to about half volume under reduced pressure, and the concentrated residue was extracted with toluene (1 L) twice. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (193 g, 99%) as a brown oil.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH:30]=[CH:31][C:32]3[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=3)=[N:20][N:21]2C2CCCCO2)=[CH:17][CH:16]=1.C([Si](C)(C)OCC#CCNC(=O)C1C=CC=CC=1NC1C=C2C(C(C=CC3C=C(C)C=CN=3)=NN2C2CCCCO2)=CC=1)(C)(C)C>>[CH3:38][C:36]1[CH:35]=[CH:34][N:33]=[C:32](/[CH:31]=[CH:30]/[C:19]2[C:18]3[C:22](=[CH:23][C:15]([NH:14][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:7]([NH:6][CH2:5][C:4]#[C:3][CH2:2][OH:1])=[O:39])=[CH:16][CH:17]=3)[NH:21][N:20]=2)[CH:37]=1
Reactant: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)NCC#CCO)ccc23)c1
Agent: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)NCC#CCO[Si](C)(C)C(C)(C)C)ccc23)c1
Product: Cc1ccnc(/C=C/c2n[nH]c3cc(Nc4ccccc4C(=O)NCC#CCO)ccc23)c1

Procedure:
Prepared in a similar manner to that described for Example 7 except using a mixture of N-(4-Hydroxy-but-2-ynyl)-2-[3-[2-(4-methyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzamide and N-[4-(tert-butyl-dimethyl-silanyloxy)-but-2-ynyl)-2-[3-[2-(4-methyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzamide instead of N-[4-(tert-butyl-dimethyl-silanyloxy)-but-2-ynyl)-2-[3-[2-(4,6-dimethyl -pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzamide. 1H NMR (DMSO -d6): δ 12.92 (1H, s), 9.83 (1H, s), 9.00 (1H, t, J=5.3 Hz), 8.44 (1H, d, J=4.9 Hz), 8.06 (1H, d, J=9.0 Hz), 7.87 (1H, d, J=16.6 Hz), 7.68 (1H, d, J=7.9 Hz), 7.50–7.38 (4H, m), 7.26 (1H, s), 7.09 (1H, d, J=5.3 Hz), 7.01 (1H, dd, J=8.7, 1.5 Hz), 6.88 (1H,dt, J=6.8, 1.5 Hz), 5.11 (1H, t, J=3.0 Hz), 4.10–4.04 (4H, m), 2.34 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:21])=[N:13][C:14]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[C:10]3[CH2:9][N+:8]([O-])=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:6]=2[CH:30]=1.Cl[Si](Cl)(Cl)[Si](Cl)(Cl)Cl.C(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:21])=[N:13][C:14]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[C:10]3[CH2:9][N:8]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:6]=2[CH:30]=1
Reactant: Cc1nc(N2CCOCC2)c2n1-c1ccc(Cl)cc1C(c1ccccc1F)=[N+]([O-])C2
Agent: Cl[Si](Cl)(Cl)[Si](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1nc(N2CCOCC2)c2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 48 h

Procedure:
A mixture of 0.2 g of 8-chloro-6-(2-fluorophenyl)-1-methyl-3-morpholino-4H-imidazo[1,5-a][1,4]-benzodiazepine 5-oxide, 0.2 ml of hexachlorodisilane and 10 ml of methylene chloride was allowed to sit for two days. It was then diluted with toluene and washed with 1 N sodium hydroxide solution. The organic phase was dried and evaporated. Crystallization of the residue from ether/hexane gave end product with mp 172°-174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[Cl-].[Al+3].[Cl-].[Cl-].[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(Cl)Cl>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([S:11]([NH2:12])(=[O:14])=[O:13])[CH:4]=1)(=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.9 %

Procedure:
To a well stirred solution of 4-chloro-3-sulfamoyl-benzoyl chloride (0.5 g, 1.97 mmol) in 5 mL methylene chloride is added aluminum chloride (0.485 g, 1.85 mmol). After 30 min, benzene (1 mL, 5.72 mmol) is added and the reaction is stirred for 2 h at room temperature. The reaction mixture is then poured over ice, acidified with 6 N HCl and extracted three times with diethyl ether. The organic layers were combined, dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is purified via silica gel chromatography to yield 40 mg (69%) of the title compound as a tan solid. MS (m/z): 294 (M−1). Analytics calculated for C13H10ClNO3S: C, 52.8; H, 3.41; N, 4.74. Found: C, 52.62; H, 3.21; N, 4.72.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.Cl.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:9]3[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:7]([O:21][CH3:22])[CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: COc1cc2nc(Cl)nc(-c3cccc([N+](=O)[O-])c3)c2cc1OC
Agent: Cl
Product: COc1cc2nc(NC3CC3)nc(-c3cccc([N+](=O)[O-])c3)c2cc1OC
Yield: 25.3 %

Procedure:
Starting from 500 mg 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline and 414 mg cyclopropylamine hydrochloride, 134 mg of the title compound was obtained in the same manner as in Production Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[N:32]1([C@H:37]2[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][N:34]=[CH:33]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C@H:11]([C:27]([N:39]3[CH2:40][CH2:41][C@H:37]([N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH2:38]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: c1cn([C@H]2CCNC2)cn1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](n4ccnc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
1.09 g of N,N'-carbonyldiimidazole were added to a solution of 2.5 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 25 ml of dry acetonitrile, and the resulting mixture stirred at room temperature for 30 minutes. A solution of 850 mg of (3S)-3-(imidazol-1-yl)pyrrolidine in 5 ml of dry acetonitrile was then added, and the mixture was stirred at room temperature for 2 hours and then at 40° C. for a further 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was purified by reverse phase column chromatography through 200 ml of Cosmo Sil 75C18 -PREP (a trade mark for a product of Nacalai Tesque), using a gradient elution method, with mixtures of acetonitrile and water ranging from 50:50 to 55:45 by volume as the eluent. Those fractions containing the title compound were combined and concentrated by evaporation under reduced pressure, to give 2.54 g of the title compound, as a powder.