Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)(=[O:25])=[O:24])=[C:16]([O:34][CH3:35])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:37]1C=C(S(Cl)(=O)=O)C=C(Cl)C=1>>[CH3:37][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=3)(=[O:24])=[O:25])=[C:16]([O:34][CH3:35])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(Cl)c2)cc2c1CCN2S(=O)(=O)c1cc(Cl)cc(Cl)c1
Product: COC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(Cl)cc(Cl)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3,5-dichloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 555.25 (M+H+.), was prepared in analogy to example 21, steps 1 to 6. Step 5 was performed using 3,5-dichloro-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3,5-dichloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:18])=[N:14][CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:18])=[N:14][CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1cn[n+]([O-])c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1cn[n+]([O-])c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 170.7 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one-1-oxide (173 mg) and aminoguanidine hydrochloride (73 mg) were added ethanol (4 ml) and concentrated hydrochloric acid (0.07 ml), and the mixture was stirred at 90° C. (bath temperature) for 3.5 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnolin-1-oxide hydrochloride (Compound 159) (195 mg) as colorless crystals.
Reaction SMILES: CO.[ClH:3].Cl.Cl.[CH3:6][O:7][C:8]1[CH:33]=[CH:32][C:11]([CH2:12][CH2:13][NH:14][C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[NH:19])=[NH:16])=[CH:10][CH:9]=1.[CH3:34][C:35]([CH3:37])=O>>[ClH:3].[CH2:21]([NH:20][C:18]1[NH:17][C:15]([NH:14][CH2:13][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:33][CH:32]=2)=[N:16][C:35]([CH3:37])([CH3:34])[N:19]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCNC(=N)NC(=N)NCCc1ccc(OC)cc1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCNC1=NC(C)(C)N=C(NCCc2ccc(OC)cc2)N1

Procedure:
100 ml of methanol, 40 ml of acetone and 0.2 ml of concentrated hydrochloric acid were added to 2.0 g (4.3 mmol) of N1-(4-methoxyphenethyl)-N5-undecyl-biguanide dihydrochloride, and the mixture was refluxed for 16 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform/methanol/acetic acid (8:0.5:0.5)), and dissolved in hydrous ethanol. The solvent was distilled off under reduced pressure, followed by sufficient drying under reduced pressure to obtain 16 g of a colorless resinous solid.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([NH:19][C:20]([C:22]1[NH:31][C:25]2=[CH:26][N:27]=[C:28]([Cl:30])[CH:29]=[C:24]2[CH:23]=1)=[O:21])[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1.O>[OH:8][CH2:9][C@H:10]([NH:19][C:20]([C:22]1[NH:31][C:25]2=[CH:26][N:27]=[C:28]([Cl:30])[CH:29]=[C:24]2[CH:23]=1)=[O:21])[C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](NC(=O)c1cc2cc(Cl)ncc2[nH]1)C(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](CO)C(=O)c1ccccc1)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [1-(S) -(tert-butyldimethylsilanyloxymethyl)-2-oxo-2-phenylethyl]amide (Preparation 101, 220 mg, 0.48 mmol) in THF (10 mL) was added acetic acid (60 μL) and tetrabutylammonium fluoride solution (1 ml, 1M in THF) at rt. After stirring for 3 h the reaction mixture was distributed between ethyl acetate (100 mL) and water (30 mL). The organic layer was separated, then washed with brine (50 ml), dried (MgSO4) and concentrated to a solid residue. Recrystallisation from THF gave the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[S:22][C:23]4[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.ClC(OCC)=O.C(N(C(C)C)CC)(C)C.C(Cl)Cl>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:30][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([C:18]3[CH:19]=[N:20][C:15]([N:12]4[CH2:11][CH2:10][N:9]([CH3:8])[CH2:14][CH2:13]4)=[CH:16][CH:17]=3)[S:22][C:23]=2[CH:29]=1)=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CN1CCN(c2ccc(-c3nc4ccc(N)cc4s3)cn2)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3nc4ccc(NC(=O)C(F)(F)F)cc4s3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of 2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazol-6-amine trifluoroacetate (0.12 g, 0.27 mmol), ethyl chloroformate (36 μL, 0.38 mmol) and diisopropylethylamine (0.238 mL, 1.44 mmol) in DCM/THF (1:1, 7 mL) was stirred at r.t. overnight. Additional DCM was added before washing the sol. with sat. sodium hydrogencarbonate and then brine. The sol. was then dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by prep. HPLC, to give intermediate 2,2,2-trifluoro-N-{2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazol-6-yl}acetamide (43 mg). MS m/z (M+H) 422, (M−H) 420. To this intermediate (43 mg) in THF (5 mL) was added lithium aluminium hydride (12 mg, 0.3 mmol). The r.m. was refluxed for 1.5 h then allowed to come to r.t. Two drops of sat. Na2SO4, followed by ethyl acetate was added and the mixture was stirred for a few minutes. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by prep. HPLC to yield the title compound (25 mg) as a pale yellow solid. 1H NMR (MeOH-D4) δ 8.59 (d, 1H) 7.97 (dd, 1H) 7.60 (d, 1H) 7.11 (d, 1H) 6.75-6.87 (m, 2H) 3.80 (q, 2H) 3.55-3.70 (m, 4H) 2.50-2.61 (m, 4H) 2.33 (s, 3H); MS m/z (M+H) 408, (M−H) 406.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[N:11][OH:12].[CH3:13][N:14]=[C:15]=[O:16]>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[N:11][O:12][C:15](=[O:16])[NH:14][CH3:13]
Reactant: CN=C=O
Reactant: COCCN1C(=O)CSC1=NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C1SCC(=O)N1CCOC

Procedure:
A solution of 5.4 g 3-(2-methoxyethyl)-2-oximino-4-thiazolidinone in 50 ml methylene chloride, 4.0 g of methylisocyanate and 4 drops of triethylamine was kept in a pressure bottle for 16 hours at ambient temperature. On concentration under reduced pressure the reddish brown liquid was dissolved in methanol, decolorized with charcoal and concentrated. The desired produced was crystallized from methanol. Weight 5.5 g., m.p. 153°-155°C.
Reaction SMILES: C(OC(=O)NCCCNC(C1N(CC2C=CC=CC=2)C(=O)C2C=CC=NC=2N=1)C(C)C)(C)(C)C.CCN(C(C)C)C(C)C.C1(C)C=CC(C(Cl)=O)=CC=1.C(OC(=O)[NH:60][CH2:61][CH2:62][CH2:63][N:64]([CH:74]([C:78]1[N:79]([CH2:89][C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[C:80](=[O:88])[C:81]2[CH:87]=[CH:86][CH:85]=[N:84][C:82]=2[N:83]=1)[CH:75]([CH3:77])[CH3:76])[C:65](=[O:73])[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:60][CH2:61][CH2:62][CH2:63][N:64]([CH:74]([C:78]1[N:79]([CH2:89][C:90]2[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=2)[C:80](=[O:88])[C:81]2[CH:87]=[CH:86][CH:85]=[N:84][C:82]=2[N:83]=1)[CH:75]([CH3:76])[CH3:77])[C:65](=[O:73])[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3ncccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: CC(C)C(NCCCNC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1Cc1ccccc1
Agent: Cc1ccc(C(=O)Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3ncccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-{3-[1-(3-benzyl-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2-methyl-proplyamino]-propyl}-carbamic acid tert butyl ester (110 mg, 0.236 mmol), DIEA (82 μL, 0.473 mmol) and dichloromethane (2 mL) was added p-toluoyl chloride (47 μL, 0.354 mmol) dropwise. The reaction mixture was stirred at room temperature overnight, and then diluted with dichloromethane and washed with saturated sodium bicarbonate, water and brine. After concentration, the residue was subjected to flash silica gel chromatography using hexane-EtOAc (1:2) and EtOAc-MeOH (20:1) as eluent to give the corresponding crude acylated product, {3-[[1-(3-benzyl-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2-methyl-proply]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester, which was then treated with 30% TFA in dichloromethane (3 mL) for 15 minutes, diluted with dichloromethane, washed with saturated sodium bicarbonate, water, and brine, and dried (Na2SO4). Concentration of the dichloromethane solution gave the title product, N-(3-amino-propyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2-methyl-propyl]-4-methyl-benzamide, as a white solid (89 mg, 78%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:9]2[N:10]([CH3:17])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:25]([O:29][C:30](ON=C(C1C=CC=CC=1)C#N)=[O:31])([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[CH3:1][N:2]([CH2:3][CH:4]1[C:9]2[N:10]([CH3:17])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1)[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: CNCC1CCSc2c1n(C)c1ccccc21
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CC1CCSc2c1n(C)c1ccccc21)C(=O)OC(C)(C)C
Yield: 87 %

Procedure:
A solution of 4-methylaminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (3.2 g) in dry tetrahydrofuran (30 ml) is allowed to react with triethylamine and 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile in the same manner as in Example 6(a) to give 4-(N-methyl-N-t-butoxycarbonylaminomethyl)-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole: Yield 87.0%. Mp. 111.5°-114° C. (decomp.) (b) The above product is treated in the same procedure as in Example 12 to give 4-(N-methyl-N-t-butoxycarbonylaminomethyl)-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole 1-oxide. Mp. 218°-220.5° C. (decomp.). The product is dissolved in methylene chloride (20 ml) and trifluoroacetic acid (4 ml) is added thereto. The mixture is kept at room temperature for 2 hours and then treated in the usual manner to give the title compound (1.13 g): Yield 89.7%.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH2:11][C@H:12]([CH3:14])[N:13]=2)=[CH:5][C:4]=1[N+:15]([O-])=O>CO.[Ni]>[ClH:1].[NH2:15][C:4]1[CH:5]=[C:6]([C:9]2[NH:10][CH2:11][C@H:12]([CH3:14])[N:13]=2)[CH:7]=[CH:8][C:3]=1[NH2:2]
Reactant: C[C@H]1CNC(c2ccc(N)c([N+](=O)[O-])c2)=N1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: C[C@H]1CNC(c2ccc(N)c(N)c2)=N1

Procedure:
51 g of 2-(4-amino-3-nitrophenyl)-4(5)-methyl-2-imidazoline-hydrochloride are hydrogenated in 1 l of methanol with Raney-nickel at room temperature. After termination of the hydrogen absorption, the catalyst is filtered off with suction and the filtrate is brought to dryness under reduced pressure. The remaining oil is recrystallized from isopropanol. Yield: 42.6 g (corresponding to 94% of theor. yield),
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>ClCCl>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:31])=[CH:24][CH:25]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccccc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
A vigorously stirring solution of N-phenyl-1,2-phenylenediamine (20.15 g) in dichloromethane (325 ml) and triethylamine (11.07 g) was cooled in an ice/acetone bath under nitrogen. p-Anisoyl chloride (18.66 g) dissolved in dichloromethane (100 ml) was added dropwise over a 20 minute period while maintaining a temperature of <5° C. The reaction mixture was allowed to warm to ambient temperature and stirred for two hours. The organic solution was washed successively with water (200 ml), 2N aqueous HCl (80 ml), and saturated brine solution (160 ml), then dried over sodium sulfate and passed through a pad of silica (150 g). The silica was eluted with ethyl acetate (1 L) and the eluent was evaporated in vacuo to a pink solid. The solid was triturated overnight with ethyl ether (350 ml), cooled in an ice bath, filtered, and dried in vacuo to give the title compound as a light pink solid (21.67 g). 1H (300 MHz, CDCl3): d 3.82 (s, 3H), 5.75 (br s, 1H), 6.80-6.91(m, 5H), 7.12-7.29 (m, 5H), 7.62 (d, J=8.8 Hz, 2H), 8.15 (dd, J=1.7, 7.8 Hz, 1H), 8.36 (s, 1H); TLC (EtOAc/Hex, 1:4): Rf =0.24; m.p.: 148°-150° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH3:14])[C:9]=2[C:8](=[O:15])[NH:7][C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].BrCCCC=C.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]1[CH:35]=CC=[C:32]([C:36]([O:38]O)=O)[CH:31]=1>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH3:14])[C:9]=2[C:8](=[O:15])[N:7]([CH2:35][CH2:30][CH2:31][CH:32]2[O:38][CH2:36]2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1ncn2C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C=CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCC2CO2)c(=O)c2c1ncn2C
Temperature: 100 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
33.3 g (0.15 mole) of 3-butyl-7-methylxanthine, 24.3 g (0.16 mole) of 1-bromo-4-pentene and 22.1 g (0.16 mole) of potassium carbonate in 500 ml of dimethylformamide were heated with stirring at 100° C. for 15 hours. After cooling down, the reaction mixture was evaporated under reduced pressure, the residue was taken up in methylene chloride, filtered and the filtrate was extracted by shaking with 1N sodium hydroxide solution, the organic phase was washed with water to neutrality, dried over sodium sulfate and solvent was removed in a rotary evaporator. This produced 42.2 g (97% of theory) of crude, crystalline 3-butyl-7-methyl-1-(4-pentenyl)xanthine ##STR32## which was dissolved in 550 ml of chloroform, 35.6 g (0.175 mole) of 3-chloroperbenzoic acid (85% pure) were added and the mixture, after covering with an atmosphere of nitrogen, was stirred at room temperature for 67 hours. Extraction by shaking with 10% strength sodium dithionite solution until disappearance of the iodine-starch reaction, washing, initially with 10% strength sodium bicarbonate solution and then with water, drying over sodium sulfate and evaporation under reduced pressure provided 37.7 g (84.7% of theory) of crude 3-butyl-1-(4,5-epoxypentyl)-7-methylxanthine, ##STR33## which was subjected to hydrolytic opening of the oxirane ring without intermediate purification. For this purpose, the 37.7 g of epoxide was dissolved in a mixture of 200 ml of tetrahydrofuran and 135 ml of water, and 0.61 ml of perchloric acid (70% strength) was added dropwise with stirring within about 10 minutes at room temperature. After stirring at room temperature for 14 hours, the mixture was neutralized with saturated sodium bicarbonate solution and evaporated under reduced pressure. The remaining oily crude product (100% of theory) could be purified by column chromatography on silica gel with chloroform/methanol (volume ratio 10/1) as the eluting agent and subsequent recrystallization from ethyl acetate with the addition of petroleum ether at the boiling point until cloudy.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[N:10]([CH2:14][CH:15]=O)[CH2:11][CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]1([NH2:22])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH2:1]([O:8][C:9]([N:10]1[CH2:14][CH2:15][N:22]([C:19]2([CH3:18])[CH2:21][CH2:20]2)[CH2:12][CH2:11]1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCN(CC=O)C(=O)OCc1ccccc1
Reactant: CC1(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC1(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 48.7 %

Procedure:
Bis-(2-oxoethyl)carbamicacidbenzylester (0.90 g, 3.81 mmol) and 1-methyl-cyclopropylamine (0.41 g, 3.81 mmol) were dissolved in dichloroethane (20 mL), and sodium triacetoxyborohydride (3.23 g, 15.24 mmol) was added thereto. The mixture was stirred for 4 days at room temperature. A saturated aqueous solution of sodium hydrogen carbonate (20 mL) was added to the reaction liquor, and the mixture was stirred for 20 minutes, and then extracted with methylene chloride. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 25S, n-hexane/ethyl acetate=5/1 to ethyl acetate), to obtain the title compound (509 mg, 49%) as an oily matter.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:14][S:15]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([S:15]([CH3:14])(=[O:17])=[O:16])[CH2:3]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCNC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a dichloromethane (200 mL) solution of (S)-3-hydroxypyrrolidine (5.0 g, 57 mmol) and triethylamine (24.0 mL, 172 mmol) at 0° C. was added methanesulfonyl chloride (7.23 g, 63.1 mmol). 4-(Dimethylamino)pyridine (0.70 g, 5.7 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. It was diluted with dichloromethane (50 mL), and the combined organic layers were washed with aqueous 1 M hydrochloric acid (30 mL), water (30 mL), brine (30 mL), dried (magnesium sulfate), filtered and concentrated in vacuo to afford the title compound. The crude product was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 5.28 (t, J=4.5 Hz, 1H), 3.71 (d, J=12.9 Hz, 1H), 3.64 (dd, J=12.7, 4.0 Hz, 1H), 3.59 (td, J=9.2, 2.3 Hz, 1H), 3.46 (td, J=10.1, 6.7 Hz, 1H), 3.07 (s, 3H), 2.89 (s, 3H), 2.39-2.33 (m, 1H), 2.29-2.19 (m, 1H); LC-MS: m/z 244.1 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:30]([F:33])([F:32])[F:31])[N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21](=O)[O:22]C4C=CC=CC=4)=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([S:41]([NH:44][C:21]([NH:20][CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([N:10]3[CH:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]3[C:30]([F:31])([F:32])[F:33])=[CH:17][CH:16]=2)=[O:22])(=[O:42])=[O:43])=[CH:39][CH:40]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(NCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1)Oc1ccccc1
Product: O=C(NCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[4-phenyl-2-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 549 [M+H]+, 547 [M−H]−, 1 H-NMR (CDCl3) δ 2.92 (2H, t, J=7.3 Hz), 3.40-3.60 (2H, m), 6.60 (1H, br), 7.24-7.45 (7H, m), 7.51 (2H, d, J=9.0 Hz), 7.77 (2H, d, J=9.0 Hz), 7.82 (2H, d, J=6.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)=[CH:4][C:3]=1[C:20]([N:22]1[CH2:27][CH2:26][N:25]2[C:28]([C:33]([F:36])([F:35])[F:34])=[N:29][C:30]([CH2:31]O)=[C:24]2[CH2:23]1)=[O:21].S(Cl)([Cl:39])=O>>[Cl:39][CH2:31][C:30]1[N:29]=[C:28]([C:33]([F:36])([F:35])[F:34])[N:25]2[CH2:26][CH2:27][N:22]([C:20]([C:3]3[CH:4]=[C:5]([CH2:8][C:9]4[C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:12](=[O:19])[NH:11][N:10]=4)[CH:6]=[CH:7][C:2]=3[F:1])=[O:21])[CH2:23][C:24]=12
Reactant: O=S(Cl)Cl
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(CO)c2C1
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(CCl)c2C1
Yield: 96.6 %

Procedure:
4-[[4-Fluoro-3-[1-(hydroxymethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 6 (200 mg, 0.40 mmol) was dissolved in 5 mL of thionyl chloride. The reaction mixture was heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 10 mL of H2O, extracted with dichloromethane (10 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 4-[[3-[1-(chloromethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 9a (200 mg, yield 96.6%) as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])[CH2:20][CH:19]4[O:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]5[O:44][CH2:43][CH2:42][N:41]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]=5[CH:50]=4)=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CI.[H-].[Na+].[C:55](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:49][O:48][CH2:47][CH2:46][CH2:45][N:41]1[C:40]2[CH:50]=[C:36]([CH2:35][O:34][CH:19]3[CH:18]([C:15]4[CH:14]=[CH:13][C:12]([CH:11]([O:10][C:5]5[CH:6]=[CH:7][CH:8]=[C:9]6[C:4]=5[CH:3]=[CH:2][NH:1]6)[CH3:55])=[CH:17][CH:16]=4)[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:20]3)[CH:37]=[CH:38][C:39]=2[O:44][CH2:43][CH2:42]1
Reactant: O=C([O-])O
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COc4cccc5[nH]ccc45)cc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(C)Oc4cccc5[nH]ccc45)cc3)cc21
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
The solution of 0.100 g of benzyl 4-[4-(1H-indol-4-yloxymethyl)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 346a), 0.0424 g of methyl iodide and 1.5 ml of N,N-dimethylformamide is admixed with stirring at −10° C. with 0.012 g of sodium hydride dispersion (60%). The reaction mixture is stirred at −10° C. for 1.5 hours, then poured onto saturated aqueous sodium hydrogencarbonate solution (45 ml) and extracted with tert-butyl methyl ether (2×75 ml). The combined organic phases are washed with 75 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a violet oil from the residue. Rt=5.90.