Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12]OC(=O)N1C(=O)CC1C=CC(C(F)(F)F)=C(F)C=1)[C:2]1C=CC=[CH:4][CH:3]=1.[CH:28](N(C(C)C)CC)(C)C.COC1CCCN1[C:44]([O:46][C:47]([CH3:50])(C)C)=[O:45]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:12][CH2:8][CH2:1][CH2:2][CH2:3][CH3:4].[C:44]([O:46][CH2:47][CH3:50])(=[O:45])[CH3:28]
Reactant: COC1CCCN1C(=O)OC(C)(C)C
Reactant: O=C(Cc1ccc(C(F)(F)F)c(F)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCC
Product: CCOC(C)=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 196.7 %

Procedure:
A solution of (R)-4-benzyl-3-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetyl)oxazolidin-2-one (1.6 g, 4.20 mmol) was dissolved in dichloromethane (40 mL), cooled to −78° C. and treated slowly with titanium (IV) chloride (4.4 mL, 4.40 mmol). This was followed by treatment with diisopropylethylamine (0.76 mL, 4.36 mmol). The mixture was stirred at −78° C. for 15 minutes, and tert-butyl 2-methoxypyrrolidine-1-carboxylate (1.0 g, 4.97 mmol) was added. After 15 minutes, the reaction was allowed to warm to ambient temperature for one hour. The reaction was quenched with saturated NH4Cl (20 mL) and extracted with dichloromethane (3×100 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography, eluting with hexane/ethyl acetate (4:1), (1.44 g, 62.3% yield). 7.55 (t, J=8.2, 1H), 7.38-7.18 (m, 7H), 5.61-5.51 (m, 1H), 4.72-4.56 (m, 2H), 4.16-4.02 (m, 2H), 3.43-3.34 (m, 1H), 3.28-3.15 (m, 1H), 2.77-2.61 (m, 1H), 1.96-1.80 (m, 1H), 1.75-1.56 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: I[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].[F:7][C:8]1([F:52])[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[CH:22]([OH:24])[CH2:21][C:20]([CH3:26])([CH3:25])[CH2:19][C:18]=3[N:17]=[C:16]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:38]=[CH:37][C:36]([OH:39])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)[C:15]=2[CH:40]([F:51])[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH2:10][CH2:9]1>>[F:52][C:8]1([F:7])[CH2:9][CH2:10][CH:11]([C:14]2[C:23]3[CH:22]([OH:24])[CH2:21][C:20]([CH3:25])([CH3:26])[CH2:19][C:18]=3[N:17]=[C:16]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]4[N:38]=[CH:37][C:36]([O:39][CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:35][N:34]=4)[CH2:31][CH2:32]3)[C:15]=2[CH:40]([F:51])[C:41]2[CH:42]=[CH:43][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:45][CH:46]=2)[CH2:12][CH2:13]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: CC(C)CCI
Product: CC(C)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Example 21 were performed except for using 62 (0.47 mmol) of 1-iodo-3-methylbutane instead of 1-iodo-2-methylpropane, and from 55 mg (0.085 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 40 mg of the title compound was obtained as a white solid (yield: 65%).
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=O)=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(Cl)Cl.S(Cl)(Cl)=O.N[CH2:37][CH:38]([OH:41])[CH2:39][OH:40].[N:42]1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(COC)OC>[OH:41][CH:38]([CH2:39][OH:40])[CH2:37][CH:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:24][CH:23]=1)[C:26]([NH2:42])=[O:28]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)O)cc1
Reactant: NCC(O)CO
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(CC(O)CO)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A slurry of 8.0 g. of 4-(hexadecylamino)phenylacetic acid hydrochloride in 175 ml. of methylene chloride and 50 ml. of glyme containing 10 ml. of thionyl chloride is heated at reflux for 2 hours. The clear solution is concentrated in vacuo giving 9.5 g. of an amber oil. This oil is dilutd with 50 ml. of pyridine containing 0.1 g. of 4-dimethylaminopyridine and 9.1 g. of 3-amino-1,2-propanediol. The reaction is stirred for two days at room temperature. The solution is partitioned between ether and water. The water phase is extracted twice more with 100 ml. of chloroform and ether. The combined organic layer is extracted with water, dried over magnesium sulfate and evaporated to a tacky solid. The solid is recrystallized from acetone-water and then from benzene.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:11]=[C:10]([C:24]2[CH:29]=[CH:28][C:27]([NH:30]C(=O)OC(C)(C)C)=[CH:26][CH:25]=2)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[N:11]=[C:10]([C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(-c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Tert-butyl (4-{4-[(3S)-3-methylmorpholin-4-yl]-6-[(phenylsulfonyl)methyl]pyrimidin-2-yl}phenyl)carbamate (3.1 g, 5.91 mmol) was dissolved in DCM (20 mL) and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours then diluted with DCM (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). Organic phase collected, dried over magnesium sulphate, filtered and concentrated in vacuo to give the desired material as a beige solid (2.5 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.S([CH2:19][N+:20]#[C-:21])(C1C=CC(C)=CC=1)(=O)=O.[C-]#[N:23].[K+]>C(O)C>[NH:20]1[CH:21]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:23]=[CH:19]1
Reactant: O=Cc1ccccn1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Product: c1ccc(-c2c[nH]cn2)nc1
Temperature: 125 °C
Reaction time: 0.75 h

Procedure:
2-Pyridinecarboxaldehyde (4.76 mL, 50 mmol) and tosylmethyl isocyanide (9.76 g, 50 mmol) were suspended in ethanol (150 mL) at room temperature. A catalytic amount of potassium cyanide (0.33 g) was added and the resulting mixture was stirred for 45 min. The mixture became homogeneous after 5 min. of stirring and then a white suspension appeared. The solid material was collected by filtration and rinsed with diethyl ether. After drying under vacuum the solid was transferred to a sealed tube. A 2M solution of ammonia in methanol (20 mL) was added and the tube was sealed and heated at 125° C. for 24 h. The dark reaction mixture was cooled to room temperature and the solvents removed in vacuo. The residue was purified by silica gel chromatography (20-100% EtOAc/Hexane then 0%-50% MeOH/CH2Cl2) to afford 2-(1H-imidazol-4-yl)pyridine as a dark oil. 1H NMR (500 MHz, CD3OD) δ 8.31 (d, 1H), 7.92 (s, 1H), 7.72-7.63 (m, 3H), 7.54 (s, 1H), 7.07 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10](=O)[CH2:11]Br)[CH:7]=[CH:6][C:5]=1[Cl:14].[C:16]([NH2:19])(=[S:18])[CH3:17]>C(O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]2[N:19]=[C:16]([CH3:17])[S:18][CH:11]=2)[CH:7]=[CH:6][C:5]=1[Cl:14]
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CC(N)=S
Solvent: CCO
Product: COC(=O)c1cc(-c2csc(C)n2)ccc1Cl
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
A mixture of 5-(2-bromo-acetyl)-2-chloro-benzoic acid methyl ester (25 mg, 0.09 mmol) and thioacetamide (6.5 mg, 0.08 mmol) in ethanol (2 mL) and stirred at 50° C. for 15 minutes. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (10 mg).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:9]([N:16]([CH2:20][Si](C)(C)C)[CH2:17]OC)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:7]([O:6][C:1]([CH:2]1[CH:3]([CH3:4])[CH2:17][N:16]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:20]1)=[O:5])[CH3:8]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C/C=C/C(=O)OCC
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1C

Procedure:
102.1 In analogy to example 101.1 ethyl crotonate and N-benzyl-N-(methoxymethyl)tri-methylsilylmethylamine (CAS 93102-05-7) were reacted to give (3RS,4RS)-1-benzyl-4-methyl-pyrrolidine-3-carboxylic acid ethyl ester. Light yellow solid. MS 248.3 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[N+:16]([C:4]1[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:5]=1[CH2:6][N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=1)([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CNCc1ccc(Br)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccc(Br)cc1[N+](=O)[O-])C(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
4.2 g (13.1 mmol) of ethyl (4-bromo-2-nitrobenzyl)aminoacetate was dissolved in 30 ml of dichloromethane. 2.2 ml (17.7 mmol) of 4-chlorobenzoyl chloride and 2.9 ml (19.6 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the crude product.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:9]=[CH:10][C:11]=2[O:15][CH2:16][CH3:17])[S:4]1(=[O:6])=[O:5].[Na].[C:28]1([N:34]2[C:38]([SH:39])=[N:37][N:36]=[N:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([N:34]2[C:38]([S:39][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[C:8]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:9]=[CH:10][C:11]=4[O:15][CH2:16][CH3:17])[S:4]3(=[O:6])=[O:5])=[N:37][N:36]=[N:35]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(CCl)S2(=O)=O
Agent: [Na]
Product: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Yield: 71 %

Procedure:
By the method of part F of Example 45 condensation of 2-chloromethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin (1.42 g) and 1-phenyltetrazol-5-thiol sodium salt (0.70 g initially and a small amount more after 6 hours reaction time, total reaction time 8 hours) and isolation of the product (1.20 g) by extraction with dichloromethane and purification of part (0.42 g) thereof by column chromatography on silica gel using dichloromethane-acetone (up to 98:2) as eluant afforded 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin, 300 mg, 71% yield, mp 110°-112° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:40])([CH3:39])[CH2:4][NH:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[CH2:23][CH2:22]3)[N:17]=[C:16]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])[N:15]=2)=[C:9]([F:37])[CH:8]=1.[CH3:41][N:42]([CH3:48])[C:43](=[O:47])[C:44](O)=[O:45].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2([NH:20][C:18]3[N:17]=[C:16]([O:31][CH2:32][C:33]([F:35])([F:36])[F:34])[N:15]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][C:3]([CH3:40])([CH3:39])[CH2:2][NH:1][C:44](=[O:45])[C:43]([N:42]([CH3:48])[CH3:41])=[O:47])=[O:38])=[CH:8][C:9]=4[F:37])[N:19]=3)[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: CC(C)(CN)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Reactant: CN(C)C(=O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=O)NCC(C)(C)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamide (20 mg, 0.034 mmol) and 2-(dimethylamino)-2-oxoacetic acid (4.83 mg, 0.041 mmol) in DMF (1 mL) were added O-(benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (16.5 mg, 0.052 mmol) and iPr2NEt (0.012 ml, 0.069 mmol). After stirring at rt for 16 hs, the mixture was purified by preparative HPLC to give N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamido)-2,2-dimethylpropyl)-N2,N2-dimethyloxalamide (13.8 mg, 56%) as product. 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.03 (6H, s), 1.31-1.53 (4H, m), 3.06 (3H, s), 3.10-3.21 (2H, m), 3.29 (2H, d, J=6.0 Hz), 3.39 (3H, s), 4.75 (2H, m), 7.14-7.29 (3H, m), 7.33-7.48 (1H, m), 7.70-7.81 (1H, m), 7.92-8.04 (1H, m), 8.07-8.15 (1H, m).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:22][OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[NH:25][CH:26]1[C:34]2[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=2)[CH2:28][CH:27]1[O:36][CH3:37].C(O)CCC.C(N(CC)CC)C>>[Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[C:19]([NH:25][C@@H:26]3[C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[CH2:28][C@@H:27]3[O:36][CH3:37])[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:22][OH:23])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC1Cc2cc(Cl)ccc2C1NCl
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](Oc2cc(Cl)ncn2)C[C@H]1CO
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Temperature: 148 °C
Reaction time: 72 h
Yield: 70.9 %

Procedure:
To a solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-chloropyrimidin-4-yl)oxy]cyclopentyl}methanol (15) (11.2 g, 0.0312 mol) and N,5-dichloro-2-methoxy-2,3-dihydro-1H-inden-1-amine (9.00 g, 0.0384 mol) in 1-butanol (99.2 mL, 1.09 mol), in a 350 mL sealable reaction vessel, was added triethylamine (21.7 mL, 0.156 mol). The vessel was sealed and then heated with stirring to 148° C. in an oil bath for 72 hours. The vessel was cooled to room temperature and the volatiles were removed in vacuo and Et2O (200 mL) was added to the resulting residue. The solids were homogenized by sonication, filtered, and rinsed with Et2O (50 mL). To the filtrate was added Celite® (100 mL) and the volatiles were removed in vacuo. The product adsorbed onto Celite® was added to a dry load cartridge and purified via column chromatography (400 g column, eluent 0-80% EtOAc:hexanes over 80 min) to afford {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methanol (11.5 g, 71%). LCMS: (FA) ES+ 520; 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.24-7.13 (m, 3H), 5.75 (s, 1H), 5.56 (s, 1H), 5.45 (dt, J=2.9, 5.8, 2H), 4.57 (dd, J=5.9, 11.2, 1H), 4.19 (td, J=1.3, 4.7, 1H), 3.84-3.77 (m, 1H), 3.75-3.65 (m, 1H), 3.37 (s, 3H), 3.10 (d, J=16.6, 1H), 2.97 (dd, J=4.5, 16.7, 1H), 2.58 (dd, J=4.8, 7.4, 1H), 2.43-2.32 (m, 1H), 2.23-2.06 (m, 3H), 1.90 (dd, J=8.0, 14.2, 1H), 0.91 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:8](=S)=[S:9].C(N(CC)CC)C.C(Cl)(=O)OCC>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[S:9]
Reactant: S=C=S
Reactant: NCCCCCO
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: OCCCCCN=C=S

Procedure:
The synthesis method of Example 45-(1) was applied. 5-Hydroxypentylamine (6.00 g), carbon disulfide (40 ml), triethylamine (8.3 ml), ethyl chlorocarbonate (5.4 ml), triethylamine (8.3 ml) and chloroform (20 ml) were used as reagents. After the reaction, a yellow liquid was quantitatively obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:33])([CH3:32])[CH2:3][N:4]([CH:9]([C:13]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[O:30])[C:20]2[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=2)[N:14]=1)[CH:10]([CH3:12])[CH3:11])[C:5](=[O:8])[CH:6]=[CH2:7].C(OC(=O)NC(C)(C)C(C(=O)C=C)(C(C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C)N)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:23]([N:22]1[C:21](=[O:30])[C:20]2[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=2)[N:14]=[C:13]1[CH:9]([N:4]1[C:5](=[O:8])[CH2:6][CH2:7][NH:1][C:2]([CH3:32])([CH3:33])[CH2:3]1)[CH:10]([CH3:12])[CH3:11])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=CC(=O)N(CC(C)(C)N)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Agent: C=CC(=O)C(N)(C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)C(C)(C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CC(C)(C)NCCC1=O

Procedure:
N-(2-Amino-2-methyl-propyl)—N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl propyl]-acrylamide: According to the procedure of Example 1d above, ({acryloyl-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-amino-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester (730 mg, 1.29 mmol) was treated with 50% TFA in CH2Cl2 (10 mL) to give the title compound: MS (ES) m/e 467.2 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:16]=[C:15]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=1[NH:23][CH2:24][CH:25]1[CH2:27][CH2:26]1>>[CH:1]1([CH2:6][C:7]2[N:23]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:12]3[CH:13]=[CH:14][C:15]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:16][C:11]=3[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Reactant: O=C(Cl)CC1CCCC1
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(CC1CCCC1)n2CC1CC1

Procedure:
The title compound was prepared according to the procedure described in Step C of Example 5 from cyclopentylacetyl chloride (Step B) and 2-amino-1-(N-cyclopropylmethylamino)-4-(isopropylsulfonyl)benzene (Step E of Example 1).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:4].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:13][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[Cl:12]
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1ccccc1)Nc1ccc(Cl)c(Cl)c1
Yield: 1000.4 %

Procedure:
To 2-bromo-N-(3,4-dichloro-phenyl)-acetamide (2 g) in THF (80 mL) was added aniline (41 mg) and N-ethyldiisopropylamine and the reaction mixture was stirred over night at reflux. The precipitated salt was then filtered off and the filtrate was then concentrated in vacuo. The residue was then purified by column chromatography to give the title compound as a light brown solid (1.3 g, mp=110-112° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25](Cl)(=O)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[C:28]1([CH2:27][CH:26]=[CH:25][NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC=CCc3ccccc3)cc2)c2ccc3ccccc3c2N1
Yield: 908.1 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.158 mmol) obtained in Example 1, (3), and cinnamoyl chloride (32 mg, 0.19 mmol), the title compound (622 mg, yield 31%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[N:14][NH:13][C:12](=[O:21])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[N:14][N:13]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[N:31][CH:30]=4)[C:12](=[O:21])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: COc1ccc(Br)cn1
Reactant: CN(C)C(=O)c1n[nH]c(=O)c2c1c1ccc(F)cc1n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(=O)N(C)C)c3c4ccc(F)cc4n(C)c3c2=O)cn1

Procedure:
A solution of 0.3 g (1.04 mmol) of 7-fluoro-N,N,5-trimethyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-carboxamide (obtained in stage 3.2.), 0.120 g (0.63 mmol) of cuprous iodide, 0.20 g (1.45 mmol) of potassium carbonate and 0.60 g (3.19 mmol) of 3-bromo-6-methoxypyridine in 50 ml of N,N-dimethylformamide is heated at 150° C. for 20 h. The reaction mixture is cooled and concentrated under reduced pressure. Dichloromethane, water and a sodium hydroxide solution (1M) are added. The organic phase is separated by settling, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: dichloromethane/ethyl acetate: 100/0 to 0/100; then ethyl acetate/methanol: 95/5). The white solid obtained is recrystallized from a dichloromethane/ethyl acetate mixture and washed with diethyl ether. A white solid (0.26 g; 0.66 mmol) is isolated.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1.N1C=CC=CC=1.O>C1COCC1>[CH:14]1([C:17]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)=[O:18])[CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(O)c1ccc(OCCO)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc(OCCOC(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To 3.7 g (20.3 mmol) of 4-(hydroxyethoxy)benzoic acid, 100 ml of dry THF and 5.3 g (50.75 mmol) of cyclopropylcarboxylic acid chloride, at 0°, is added 6.6 ml (81.2 mmol) of pyridine. The mixture is allowed to warm to RT and is stirred at RT for 6 days, after which it is filtered. The filtrate is stirred, at RT, with 0.7 ml (~40.6 mmol) of water for 6 days. Solvent is removed by rotoevaporation, and 150 ml of ethyl acetate, 150 ml of water and 40 ml of aqueous 3 N sulfuric acid are added to the residue. The aqueous layer is separated and extracted once with 50 ml of ethyl acetate. The combined organic layers are washed with water (100 ml), with aqueous saturated cupric sulfate (50 ml), again with water (100 ml) and with aqueous saturated sodium chloride (50 ml) and are then dried over calcium sulfate. Solvent is removed by rotoevaporation, and the crude product is washed with 20 ml hexane (3X) and dried to yield 4-(2-cyclopropylcarbonyloxyethoxy)benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[CH3:24][N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]=O>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:30]([C:26]3[N:25]([CH3:24])[CH:29]=[CH:28][CH:27]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Cn1cccc1C=O
Reactant: Nc1cc(Br)cc(N)n1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Product: Cn1cccc1-c1nc2cc(Br)cc(N)n2n1

Procedure:
The title compound, MS m/e (%): 294 (M++2, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 1-methylpyrrole-2-carboxaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.