Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Br[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>O1CCCC1>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:14][CH:13]=1
Reactant: BrCCOc1ccc(-c2ccccc2)cc1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: c1ccc(-c2ccc(OCCNC3CC3)cc2)cc1
Temperature: 50 °C
Yield: 96.3 %

Procedure:
To a mixture of 5.15 g (90.2 mmol) of cyclopropylamine and 2.5 ml (18.04 mmol) of thiethylamine in 50 ml of tetrahydrofurane is added 5 g (18.04 mmol) of 4-(2-bromoethoxy)biphenyl. The reaction mixture is heated at 50° C. for 5 hrs. The solvent and the excess of cyclopropylamine are then removed under vacuum and the residue is dissolved in ethyl acetate. The organic solution is acidified to pH=4 by adding a 1N solution of HCl. The abundant obtained white precipate is filtered, washed by water and to diisopropyl ether and dried under vacuum to yield 4.4 g (96% yield) of N-[2-(biphenyl-4-yloxy)ethyl]cyclo-propanamine as its hydrochloride salt. mp (melting point)=252° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[Na].[CH3:11][OH:12]>>[NH2:1][C:2]1[C:7]([O:12][CH3:11])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: CO
Reactant: Nc1ncc(Br)nc1Br
Agent: [Na]
Product: COc1nc(Br)cnc1N

Procedure:
2-Amino-3,5-dibromopyrazine (7 g.) is boiled for about 9 hours with 0.65 g. sodium in 18.5 ml. methanol to give 2-amino-3-methoxy-5-bromopyrazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([CH3:19])[N:13]=[C:12]([NH:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[N:11]=2)=[C:4]([CH3:29])[CH:3]=1.C(O[CH:35](N(C)C)[N:36]([CH3:38])[CH3:37])(C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[C:14](/[CH:19]=[CH:35]/[N:36]([CH3:38])[CH3:37])[N:13]=[C:12]([NH:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[N:11]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc(Br)cc(C)c1Sc1nc(Nc2ccc(C#N)cc2)nc(C)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1Sc1nc(Nc2ccc(C#N)cc2)nc(/C=C/N(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(4-(4-bromo-2,6-dimethylphenylthio)-6-methyl-5-nitropyrimidin-2-ylamino)benzonitrile (50 mmol) in DMF (300 ml) is added tert-butoxybis (dimethylamino) methane (60 mmol) over 15 minutes. The mixture is stirred at room temperature overnight. DMF is partially removed. The residue is washed with water and extracted with ethyl acetate (×3). The combined organic layers are washed with brine, dried (MgSO4) and concentrated to dryness to give the desired product which is used in next step without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][NH:20][CH2:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1>C(#N)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:24]3[CH2:25][CH2:26][CH:22]([CH2:21][NH:20][CH3:19])[CH2:23]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CNCC1CCNC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNC)C3)nc21
Yield: 44.4 %

Procedure:
1.00 g (3.69 mmole) 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-napthyridine-3-carboxylic acid, 40 ml acetonitrile, and 1.27 g (11.08 mmole) N-methyl-3-pyrrolidinemethanamine are stirred at room temperature for three days. The reaction was filtered and the precipitate dissolved in aqueous ammonium hydroxide at pH 11. The solution was filtered and the solvent removed at reduced pressure. The product was washed with 5 ml of water, 10 ml ethanol/ether (1:1), and finally with ether until dry to give 0.571 g of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-[(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 251°-253° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17][C@@H:18]2[CH2:22][CH2:21][N:20](CC3C=CC=CC=3)[CH2:19]2)=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([NH:17][C@@H:18]2[CH2:22][CH2:21][NH:20][CH2:19]2)=[O:16])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)N[C@@H]2CCNC2)CC1
Reaction time: 8 h

Procedure:
To a solution of {4-[3-((R)-1-benzyl-pyrrolidin-3-yl)-ureido]-cyclohexyl}-carbamic acid tert-butyl ester in ethanol under an inert atmosphere of argon is added palladium hydroxide on carbon. The reaction mixture is purged with argon and placed under an atmosphere of hydrogen overnight. The mixture is filtered and the catalyst washed with ethanol. The organic portions are combined and concentrated in vacuo to yield the title compound.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[Cl:18])[C@@H:14]([C:19]([OH:21])=O)[CH2:13][CH2:12]2.[N:22]1([CH2:27][C@@H:28]2[CH2:33][S:32][CH2:31][CH2:30][NH:29]2)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(P(=O)(OCC)OCC)#N>O1CCCC1>[N:22]1([CH2:27][C@@H:28]2[CH2:33][S:32][CH2:31][CH2:30][N:29]2[C:19]([C@@H:14]2[C:15]3[C:11](=[CH:10][C:9]([Cl:8])=[C:17]([Cl:18])[CH:16]=3)[CH2:12][CH2:13]2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: C1CCN(C[C@@H]2CSCCN2)C1
Reactant: O=C(O)[C@H]1CCc2cc(Cl)c(Cl)cc21
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C([C@H]1CCc2cc(Cl)c(Cl)cc21)N1CCSC[C@H]1CN1CCCC1
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
9.0 ml of triethylamine were added dropwise to a solution of 14.7 g of (S)-5,6-dichloroindanecarboxylic acid in 200 ml of tetrahydrofuran at -25° to -20° C. under a stream of nitrogen and then a solution of 10.9 g of (R)-3-(1-pyrrolidinylmethyl)thiomorpholine in 50 ml of tetrahydrofuran was added dropwise thereto at the same temperature. After the solution was stirred for 10 minutes, a solution of 10.5 g of diethyl cyanophosphonate in 50 ml of tetrahydrofuran was added dropwise to the above solution and stirred at the same temperature for 30 minutes and then at 0° to 5° C. for an hour. After the tetrahydrofuran was distilled off, an aqueous solution of sodium hydrogencarbonate was added to the residue and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. After the organic solvent was distilled off, the residue was recrystallized from a mixture of ethyl acetate and hexane to give 13.1 g of the title compound. m.p.: 123°-124° C.
Reaction SMILES: [Na].C(O[CH:5](OCC)[C:6](=[CH:9]O)[C:7]#[N:8])C.Cl.[CH2:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[NH:23])=[CH:20][CH:19]=1)[CH2:16][CH3:17].Cl>O>[C:7]([C:6]1[CH:5]=[N:23][C:22]([C:21]2[CH:25]=[CH:26][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=2)=[N:24][CH:9]=1)#[N:8]
Reactant: CCOC(OCC)C(C#N)=CO
Reactant: CCCc1ccc(C(=N)N)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Product: CCCc1ccc(-c2ncc(C#N)cn2)cc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
3.26 G. of the crude sodium salt of hydroxymethylene-cyanacetaldehyde diethylacetal are dissolved in 20 ml. of water with stirring. 4.51 G. of p-n-propylbenzamidine hydrochloride are added and the resulting solution, which reacts alkaline, is adjusted to pH 4-5 with 1 ml. of 3-N hydrochloric acid. After stirring for 5 minutes, the mixture is concentrated to dryness at 50° C. in vacuo and the residue is left to stand at room temperature with 50 ml. of acetic anhydride for 16 hours. Then, the mixture is heated to 100° C. for 1 hour, evaporated in vacuo and the residue (brown oil, partly crystalline) is taken up in methylene chloride and chromatographed on silica gel. Elution with methylene chloride and methylene chloride/2% acetone yields 5-cyano-2-(4-n-propylphenyl)-pyrimidine, which is recrystallized from acetone/hexane to a constant melting point and then sublimed in a high vacuum at 120° C, whereby there are obtained colorless crystals of said pyrimidine having a melting point of 125.9°-126.0° C, which on cooling are liquid crystalline (monotropic) at 106.4° C.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[OH:20][C@@H:17]1[CH2:18][CH2:19][N:15]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@@H](O)C2)cc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a solution of t-butyl 4-fluorobenzoate (2.17 g, 11.0 mmol) and (R)-(+)-3-pyrrolidinol (1.00 g, 11.5 mmol) in DMSO (8 mL) was added potassium carbonate (1.53 g, 11.0 mmol). The mixture was stirred at 130° C. for 18 h and poured into stirring water (100 mL) while still hot. The resulting beige precipitate was collected by filtration and dried at 120° C. for 1.5 h to afford the title compound (2.64 g, 91% yield). 1H NMR (Acetone-d6) δ (ppm): 7.78 (d, J=9.0 Hz, 2H), 6.54 (d, J=8.8 Hz, 2H), 4.58 (bs, 1H), 4.15 (bs, 1H), 3.55 (dd, J=10.36, 4.7 Hz, 1H), 3.49 (t, J=6.8 Hz, 1H), 3.42 (td, J=9.2, 2.3 Hz, 1H), 3.28 (d, J=10.8 Hz, 1H), 2.21-2.10 (m, 1H), 2.09-2.03 (m, 1H), 1.56 (s, 9H). m/z: 520.3 (MH+).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:18][O:19][C:20]([CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26])=[O:21]>>[CH2:1]([N:6]([C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:20]([O:19][CH3:18])=[O:21])[CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: CCCCCNCCc1c[nH]c2ccccc12
Product: CCCCCN(CCc1c[nH]c2ccccc12)C(=O)CCCC(=O)OC
Yield: 71.5 %

Procedure:
13.4 g of N-pentyl-tryptamine and 10.5 g of 4-methoxycarbonylbutyryl chloride were treated in the same manner as described in Example 1. 14.9 g of N-pentyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-pentyl-4-methoxycarbonylbutanamido)ethyl]-indole) were thereby obtained. Yield: 71.9%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=2[CH3:32])[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=4[CH3:32])[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(F)cc3)CCCC2)CC1

Procedure:
Example 93 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.43–7.37 (m, 3H), 7.29–7.27 (m, 2H), 7.09 (d, 1H, J=8.4 Hz), 7.04–7.00 (m, 2H), 6.47 (br s, 1H), 3.29 (dd, 2H, J=5.6, 12.0 Hz), 2.94 (d, 2H, J=12.0 Hz), 2.66 (m; 1H), 2.54–2.48 (m, 3H), 2.33–2.30 (m, 2H), 2.29 (s, 3H), 2.03–1.95 (m, 4H), 1.84–1.60 (m, 10H), 1.26 (d, 6H, J=6.8 Hz); ESMS m/e: 508.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:19]=[C:18]([CH2:20][NH:21][CH3:22])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([CH:28]1[O:30]C1)[Cl:27]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:19]=[C:18]([CH2:20][NH:21][CH2:22][CH:28]([OH:30])[CH2:26][Cl:27])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: ClCC1CO1
Reactant: CNCc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1
Solvent: CCO
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CNCC(O)CCl)oc21
Temperature: 80 °C

Procedure:
A sealed tube was charged with a mixture of N-(4-chlorobenzyl)-7-methyl-2-((methylamino)methyl)-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 62, 3.21 g), epi-chlorohydrin (0.90 mL), and ethanol (80 mL). The mixture was heated to 80° C. overnight and then concentrated. The crude product was purified by column chromatography (acetone/CHCl3/NH4OH, 1/1/0.5%) to yield 1.62 g of the title compound as a white solid. Physical characteristics. 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.55, 7.39, 7.33, 5.08, 4.54, 3.93, 3.84, 3.75-3.65, 3.56, 2.53, 2.39, 2.28.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[NH2:16][NH2:17]>>[NH:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[NH2:17]
Reactant: COc1ccc(-c2ccc(Cl)nc2)cc1
Reactant: NN
Product: COc1ccc(-c2ccc(NN)nc2)cc1

Procedure:
Compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2. Coupling of a 2,5-dihalopyridine, such as 5-bromo-2-chloropyridine, with a substituted phenylboronic acid, such as 4-methoxyphenylboronic acid, in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium, produced 2-chloro-5-(4-methoxyphenyl)pyridine. Reaction of 2-chloro-5-(4-methoxyphenyl)pyridine with hydrazine produced 2-hydrazinyl-5-(4-methoxyphenyl)pyridine. Reaction of 2-hydrazinyl-5-(4-methoxyphenyl)pyridine with a substituted benzoic acid, such as 4-chloro-2-methoxybenzoic acid, in the presence of coupling agents, such as BOP (benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate) and NMM (N-methylmorpholine), produced 4-chloro-2-methoxy-N-(5-(4-methoxyphenyl)pyridin-2-yl)-benzohydrazide. Treatment of 4-chloro-2-methoxy-N-(5-(4-methoxyphenyl)pyridin-2-yl)-benzohydrazide with phosphorus oxychloride produced the cyclized product 3-(4-chloro-2-methoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine, which can be converted into a salt by treatment with HCl in ethyl acetate.
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[C:5](Cl)=[O:6])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:13]([O:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.Cl>N1C=CC=CC=1>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[C:5]([N:25]1[C:26]([CH3:28])=[CH:27][C:23]([O:22][C:13]2[C:12]([Cl:11])=[CH:17][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:15][N:14]=2)=[N:24]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CC(C)N(C(=O)Cl)C(C)C
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)nn1C(=O)N(C(C)C)C(C)C
Temperature: 80 °C
Yield: 86.5 %

Procedure:
A solution of diisopropylcarbamoyl chloride (1.47 g, 9.0 mmol) in pyridine (5 ml) was added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole (1.67 g, 6.0 mmol) in pyridine (10 ml), and the mixture was stirred under heating at 80° C. for 20 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid, and the mixture was extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a white solid of N,N-diisopropyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (2.1 g, yield: 86.7%). mp: 58-60° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.28 (d, J=7.5 Hz, 12H), 2.29 (s, 3H), 3.50-4.10 (m, 2H), 6.00 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 8.31 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([NH:1][CH2:2][CH:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:26])=[O:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(S(=O)(=O)NCc3ccccc3)cc2)CC1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(S(=O)(=O)NCc4ccccc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-(2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 70, N-benzyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid. 1H NMR (DMSO) δ 1.33 (m, 2H), 1.86 (m, 2H), 2.67(m, 3H), 2.89(s, 3H), 2.99(m, 2H), 3.69(m, 2H), 3.85(s, 2H), 4.49(m, 1H), 6.83 (d, 1H, J=6.0 Hz), 7.00(m, 2H), 7.19 (s, 1H), 7.24 (m, 6H), 7.56 (d, 2H, J=6.6 Hz); MS (ES) m/z: 575.1 (MH+); HRMS for C27H34N4O6S2: 575.2015 (MH+)
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16](=[S:18])[NH2:17])=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12.[Cl:21][CH2:22][C:23](=O)[CH2:24]Cl>O1CCOCC1>[Cl:21][CH2:22][C:23]1[N:17]=[C:16]([C:15]2[N:14]=[CH:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:2](=[O:1])[N:3]4[CH2:20][CH2:19][C@H:4]4[C:5]=23)[S:18][CH:24]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Solvent: C1COCCO1
Product: O=C1c2ccccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCN12
Yield: 41.6 %

Procedure:
A yellow suspension of 4.86 g (0.0171 mol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[l,5-a][1,4]benzodiazepine-1-thiocarboxamide in 120 ml of dioxan was treated with 2.38 g (0.0188 mol) of 1,3-dichloro-2-propanone. The suspension was boiled at reflux for 48 hrs. The solution obtained was cooled and completely freed from the solvents. The product was chromatographed over silica gel with dichloromethane/ethyl acetate 1:1 as the eluent and recrystallized from hot ethyl acetate. There were obtained 2.54 g (42%) of (S)-1-(4-chloromethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepin-9-one as white crystals; m.p. 248°-249° and [α]D20 =-186.1° (DMF, c=1%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Br)[CH3:23]>CS(C)=O>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][N:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]([CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Solvent: CS(C)=O
Product: CCOC(=O)Cn1c(C(=O)OCC)c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 30.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 300 ml. of dimethylsulfoxide is treated with 66.8 g. of bromoacetic acid ethyl ester and 27.6 g. of finely triturated, dry potassium carbonate and intensively stirred at room temperature for 17 hours. The mixture is poured into 750 ml. of ice-water and the separated product, after the addition of 50 g. of sodium chloride, is removed by filtration under suction, washed with water and then dissolved in methylene chloride. The aqueous layer is separated, the organic phase dried over sodium sulfate, filtered and concentrated to dryness. The resulting oil crystallizes on trituration with ether and pentane, and there is obtained 1-ethoxycarbonyl-5-chloro-3-phenylisoindole-2-acetic acid ethyl ester; melting point 100°-101° C. Recrystallization from ethanol increases the melting point to 103°-104° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.I[C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[CH3:41])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=1)=[O:18]>>[CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[C:12][C:39]3[CH:38]=[C:16]([CH:15]=[CH:14][C:40]=3[CH3:41])[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=3)=[O:18])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1ccc(NC2CC2)nn1
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1ccc(NC2CC2)nn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (as prepared above) in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 68-69° C.; 1H NMR (300 MHz, CDCl3) δ: 8.84 (1H, s), 7.99-8.01 (2H, d, J=6.0 Hz), 7.95-7.98 (1H, d, J=9.0 Hz), 7.82-7.85 (1H, d, J=9.0 Hz), 7.71-7.73 (1H, d, J=6.0 Hz), 7.40-7.43 (1H, d, J=9.0 Hz), 7.29-7.32 (1H, d, J=9.0 Hz), 6.99-7.02 (1H, d, J=9.0 Hz), 5.85 (1H, s), 3.63 (2H, s), 2.53 (8H, brs), 2.34 (3H, s), 2.03 (3H, s), 1.43 (1H, m), 0.86-0.88 (2H, m), 0.61-0.63 (2H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C30H32F3N6O: 549.2584. found: 549.2568.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH2:19]([S:21]([C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1)(=[O:23])=[O:22])[CH3:20]>>[CH2:19]([S:21]([C:24]1[S:28][C:27]([N:29]2[CH2:30][CH2:31][N:32]([C:7]([C:6]3[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=3[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:33][CH2:34]2)=[N:26][CH:25]=1)(=[O:23])=[O:22])[CH3:20]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CCS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)s1
Yield: 71 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-ethanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 32(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 71%). MS (m/e): 502.3 (M+H+, 100%), 519.3 (M+NH4+, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11]C)=[O:9].C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:21])C>>[NH:1]1[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8](=[O:9])[O:10][C:11]1=[O:21]
Reactant: CCOC(=O)C1=C(N)CCCC1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Product: O=c1[nH]c2c(c(=O)o1)CCCC2

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting ethyl 2-aminocyclohex-1-ene-1-carboxylate for the product of Example 3A (0.960 g, 97%). MS (ESI−) m/z 166 (M−H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17]>CO>[NH2:18][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[N:15]=1
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(N)=S
Solvent: CO
Product: COC(=O)c1ccc(-c2csc(N)n2)cc1

Procedure:
Methyl 4-(bromoacetyl)benzoate (300 mg, 1.17 mmol) and thiourea 110 mg, 1.40 mmol) were taken in MeOH (5 ml) and refluxed for 2 hours. The precipitated product was collected by filtration, washed with MeOH and dried (260 g). MS (ESP): 235 (M+H+) for C11H10N2O2S; NMR: 3.87 (s, 3H), 7.38 (s, 1H), 7.90 (d, 2H), 8.01 (d, 2H).