Azzindani/Open_Reaction_Data huggingface dataset:
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](O)=[O:17])=[C:5]2[C@@H:4]2[CH2:19][CH2:20][CH2:21][N:3]12.[CH:22]1([C:25](=[N:27]O)[NH2:26])[CH2:24][CH2:23]1>CN(C)C=O>[CH:22]1([C:25]2[N:27]=[C:16]([C:15]3[N:14]=[CH:13][N:6]4[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[C:2](=[O:1])[N:3]5[CH2:21][CH2:20][CH2:19][C@H:4]5[C:5]=34)[O:17][N:26]=2)[CH2:24][CH2:23]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2cnc(-c3nc(C4CC4)no3)c2[C@@H]2CCCN12

Procedure:
7.70 g (2.72 mmol) of (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid in 40 ml of N,N-dimethylformamide are stirred at room temperature for 10 minutes and at 85° for 20 minutes with 4.41 g (27.2 mmol) of N,N'-carbonyldiimidazole. 2.72 g (27.2 mmol) of cyclopropanecarboxamidoxime are subsequently added thereto and the mixture is stirred at 110° for a further hour. After removing the N,N-dimethylformamide the residue is stirred in 30 ml of acetic acid at 120° for 4 hours. The solution is evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated. By recrystallization from ethyl acetate there is obtained (S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 211°-212°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1>C(O)C>[F:14][C:15]([F:25])([F:26])[O:16][C:17]1[CH:22]=[C:21]2[C:20](=[CH:19][CH:18]=1)[NH:23][C:9]1[CH2:10][CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][C:8]2=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Yield: 147.7 %

Procedure:
A mixture of 4-oxocyclohexane carboxylic acid ethyl ester (3.75 g, 0.022 mol), 4-trifluoromethoxy phenylhydrazine hydrochloride (5 g, 0.0218 mol) and anhydrous ethanol (68 mL) was refluxed overnight under nitrogen. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic extracts were washed with 1:1 water/brine and dried over anhydrous magnesium sulfate. Removal of the solvent provided a yellow solid that was dried in vacuo (7.15 g). The material from two runs (11.64 g) was chromatographed on silica gel Merck 60 using a 5 to 15% gradient of ethyl acetate in hexane to yield the title compound as a pale tan solid (10.54 g, 92%), m.p. 131-132° C. MS [(+)ES, m/z}: 328.1 [M+H]+. MS [(−)ES, m/z]: 326.1 {M−H]−. HPLC: Chromolith Monolith column, 0.46×10 cm, gradient of acetonitrile in water (0.01% TFA), 4 mL/min, detection at 280 nm; Rt 2.45 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](C#N)=[N:6][CH:7]=1.C[Mg+].[Br-].[CH2:13]1[CH2:17][O:16]CC1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:17](=[O:16])[CH3:13])=[N:6][CH:7]=1
Reactant: C1CCOC1
Reactant: N#Cc1ncc(Br)cn1
Agent: C[Mg+]
Agent: [Br-]
Product: CC(=O)c1ncc(Br)cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 30.2 %

Procedure:
To a solution of 5-bromopyrimidine-2-carbonitrile (300 mg, 1.63 mmol) in THF (20 mL) was added MeMgBr (5.43 mL, 16.3 mmol) at −78° C. under nitrogen. The solution was stirred at −78° C. for 20 min., quenched with satd aq NH4Cl, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give an oil, which was purified by prep TLC (3:1 PE/EtOAc) to give 1-(5-bromopyrimidin-2-yl)ethanone (99 mg, yield 30.2%). 1H NMR (CDCl3): δ2.70 (s, 3H), 8.90 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[N+:20]([C:23]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26])([O-:22])=[O:21].[N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.O=S(Cl)Cl>C(Cl)(Cl)Cl>[N+:20]([C:23]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=1[C:25]([NH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:26])([O-:22])=[O:21]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: NCC(=O)OCc1ccccc1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])OCc1ccccc1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of benzyl glycinate.PTS salt (1.589 g, 4.716 mmol) in chloroform (20 mL) was added triethylamine (1.95 mL, 14. 148 mmol) at ice cold temperature. A solution of 2,4-dinitrobenzoyl chloride (prepared from 2,4-dinitrobenzoic acid, 1.0 g and SOCl2, 10 mL, refluxed for 2 h and evaporated the solvents) in chloroform (5 mL) was added to the above solution for 10 min and stirred for 1 h. After completion of the reaction, it was diluted with chloroform (100 mL). The chloroform layer was washed with water (2×50 mL), brine (50 mL) and dried over anhyd Na2SO4. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform:methanol (98:02) as eluents to give the product as an off-white color solid (1.55 g, 92%), mp 116-118° C. 1H NMR (400 MHz, CDCl3): δ 8.91 (1H, d, J=2.0 Hz), 8.52 (1H, dd, J=8.2, 2.2 Hz), 7.77 (1H, d, J=8.4 Hz), 7.38 (5H, s), 6.52-6.55 (1H, m), 5.24 (2H, s), 4.31 (2H, d, J=5.2 Hz); LC-MS (negative ion mode): m/z 358 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]1[C:7](C)(C)[S:6][C@H:5]2[CH2:10][CH2:11][CH2:12][CH2:13][N:4]2[C:3]1=[O:14].C1C2C(COC(N[C@@H](CSC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C(O)=O)=O)C3C(=CC=CC=3)C=2C=CC=1>>[NH2:1][C@H:2]1[CH2:7][S:6][C@H:5]2[CH2:10][CH2:11][CH2:12][CH2:13][N:4]2[C:3]1=[O:14]
Reactant: CC1(C)S[C@H]2CCCCN2C(=O)[C@H]1N
Agent: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: N[C@H]1CS[C@H]2CCCCN2C1=O

Procedure:
(3R,9aS)-3-Aminohexahydropyrido[2,1-b][1,3]thiazin-4(6H)-one (350 mg, 1.879 mmol) was synthesized as described for the preparation of Intermediate 30 using (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(tritylthio)propanoic acid in step A. 1H NMR (500 MHz, CD3OD) δ ppm 4.66-4.58 (m, 1H), 4.51 (dd, J=11.55, 2.75 Hz, 1H), 4.20 (dd, J=11.27, 5.22 Hz, 1H), 3.28-3.22 (m, 1H), 3.01 (dd, J=13.20, 4.95 Hz, 1H), 2.81 (td, J=12.65, 2.75 Hz, 1H), 2.10-1.99 (m, 1H), 1.95 (d, J=7.15 Hz, 2H), 1.82-1.71 (m, 1H), 1.67 (d, J=13.75 Hz, 1H), 1.53-1.41 (m, 1H); 13C NMR (126 MHz, CD3OD) δ ppm 165.13, 60.06, 52.13, 47.02, 35.88, 25.73, 25.18, 24.71.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:23](=[O:24])[CH2:22][C:21]([CH3:20])=[O:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)NCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
2-{[4-(2-Aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.0 g) synthesized in Example 7 was dissolved in N,N-dimethylformamide (50 mL), and diketene (0.88 g) was added dropwise under ice-cooling. After raising to room temperature, the mixture was stirred for one hour. The mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2-({4-[2-(acetoacetylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (3.4 g) as a colorless oil. This compound was used in the next step without particular purification. [4-(Trifluoromethoxy)phenyl]hydrazine hydrochloride (390 mg) was dissolved in ethanol (8 mL), pulverized sodium hydroxide (65 mg) was added at room temperature. The insoluble material was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was dissolved again in ethanol (8 mL), 2-({4-[2-(acetoacetylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (600 mg) obtained earlier was added at room temperature, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (8 mL), diphosphorus pentasulfide (345 mg) and sodium carbonate (329 mg) were added, and the mixture was heated under reflux for 2 hr. The solvent was evaporated, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (690 mg) as a colorless oil.
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([CH2:32][O:33][CH3:34])[C:17]2[C:22]([C:23]=1[O:24]CC1C=CC=CC=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])C1C=CC=CC=1.CCOC(C)=O>[Pd].CO>[OH:24][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:32][O:33][CH3:34])=[N:15][C:14]=1[C:12]([NH:11][CH2:10][C:9]([OH:35])=[O:8])=[O:13]
Reactant: COCc1nc(C(=O)NCC(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1nc(C(=O)NCC(=O)O)c(O)c2ccccc12
Reaction time: 18 h
Yield: 89.5 %

Procedure:
A mixture of [(4-benzyloxy-1-methoxymethyl-isoquinoline-3-carbonyl)-amino]-acetic acid benzyl ester (134 mg, 0.285 mmol), Pd/C (100 mg, 10 wt % Pd), EtOAc (10 ml) and MeOH (50 ml) was stirred under a H2-atmosphere at ambient pressure and temperature for 18 h. Then the mixture was filtered through a pad of celite. Celite and filter cake were washed thoroughly with EtOAc and the combined organic phases were concentrated in vacuo to give the title compound as a tan solid (74 mg); MS-(−)-ion: M−1=289.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](N)[CH:16]=1)[CH2:6][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].OS(C(F)(F)F)(=O)=O.[C:31]([O:35][C:36]([NH:38][C:39]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[NH:40])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:40][C:39]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[N:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:6][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(CP(=O)(OCC)OCC)c1cccc(N)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CP(=O)(OCC)OCC)c1ccccc1NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 27 h
Yield: 19.5 %

Procedure:
2-(3-aminophenyl)-3-di(ethoxy)phosphinoylpropanoic acid ethyl ester (350.0 mg, 0.96 mmol), N,N′-di(t-butoxycarbonyl)guanidine triflate (375 mg, 0.96 mmol), chloroform (10 mL) and triethylamine (133.4 mL, 0.96 mmol) were combined in a 25 ml flask and stirred at 50° C. for 27 hours. The solvents were evaporated. The resulting residue was dissolved in acetonitrile/water (8 mL) and purified by preparative chromatography. The fractions were combined and evaporated to an oil, which was dried under high vacuum for 48 hours to give 107 mg of 2-(3-N,N′-di(t-butoxycarbonyl)-guanidinophenyl)-3-di(ethoxy)phosphinoylpropanoic acid ethyl ester, which was used in the next step.
Reaction SMILES: [OH:1]S(O)(=O)=O.[CH2:6]1[O:14][CH:7]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[C:8]1([CH:7]([OH:1])[CH2:6][OH:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: O=S(=O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: CCOCC
Product: OCC(O)c1ccccc1
Reaction time: 2 h
Yield: 91 %

Procedure:
A 2 l stirrer fitted with reflux condenser, thermometer and dropping funnel was charged with 600 g of 0.1% strength H2SO4 and 2 g of tetrabutylammonium hydrogensulfate, and then, at 20° C. to 25° C., 200 g (1.67 mol) of styrene oxide (2) were added over the course of 1 h. When the dropwise addition was complete, the mixture was then stirred for 2 h and then worked up. 200 ml of diethyl ether were added to the reaction mixture, and the organic phase was washed until neutral with sodium carbonate solution and water, and dried over Na2SO4, and the solvent was distilled off under reduced pressure, leaving 223 g of crude product (91% pure according to GC).
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:19][N:20]1[CH:24]=[C:23](Br)[CH:22]=[C:21]1[CH:26]=[O:27]>>[CH3:19][N:20]1[CH:24]=[C:23]([C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)[CH:22]=[C:21]1[CH:26]=[O:27]
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: Cn1cc(Br)cc1C=O
Product: Cc1cc2c(cc1-c1cc(C=O)n(C)c1)C(C)(C)CCC2(C)C
Yield: 59.2 %

Procedure:
In a similar manner to Example 3(b), by reaction of 3 g (12.1 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid with 1.9 g (10.1 mmol) of N-methyl-4-bromo-2-pyrrolecarboxaldehyde, 1.85 g (59%) of the expected product are obtained in the form of a pale yellow oil.
Reaction SMILES: [CH2:1]([S:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O-])([O-])=O.[Na+].[Na+].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[CH3:32]>C(O)C>[CH2:1]([S:9][C:10]1[N:11]=[C:12]([Cl:17])[CH:13]=[C:14]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=2[CH3:32])[N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCSc1nc(Cl)cc(Cl)n1
Reactant: Cc1cccc(N)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCSc1nc(Cl)cc(Nc2cccc(C)c2C)n1

Procedure:
To a solution of 2-octylthio-4,6-dichloropyrimidine (3 g) in ethanol (25 ml), 2,3-xylidine (1,5 ml) and anhydrous Na2CO3 (1.25 g) are added; the mixture is refluxed for 20 hours. The residue is hot filtered and the solvent is evaporated. The residue is purified by chromathography on silica gel, yielding 1.9 g of 2-octylthio-4-chloro-6-(2,3-xylidino)-pyrimidine (III, 35).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][N:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:26]=[N:27][CH:28]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1cncc2ccccc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cncc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and isoquinoline-4-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM/Methanol=97:3) to yield the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[N:5]2[CH2:13][CH2:14][N:15]([C:17]([O:19]C(C)(C)C)=O)[CH2:16][CH:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:31][C:32]1[CH:40]=[CH:39][C:35](C(Cl)=O)=[CH:34][CH:33]=1>C(Cl)Cl>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:17]([N:15]2[CH2:14][CH2:13][N:5]3[C:6]4[N:12]=[CH:11][CH:10]=[CH:9][C:7]=4[NH:8][C:2](=[O:1])[CH2:3][CH:4]3[CH2:16]2)=[O:19])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncccc3NC(=O)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC2CN(C(=O)c3ccc(F)cc3)CCN2c2ncccc2N1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A solution of the product of Example 64A (0.50 g, 1.570 mmol) in CH2Cl2 (3 mL) was stirred with ice cooling as trifluoroacetic acid (2 mL) was added over 1 minute. The resulting solution was stirred at 0° C. for 50 minutes and then allowed to warm to room temperature for 1 hour. The mixture was concentrated under vacuum, and the residue was taken up in 6% NaOH (12 mL) and CH2Cl2 (5 mL), and p-fluorobenzoyl chloride (0.45 g, 2.8 mmol) was added. The mixture was stirred at room temperature for 13 hours and then filtered through diatomaceous earth with a CHCl3 (25 mL) rinse. The aqueous layer was extracted with CHCl3 (2×25 mL) and the combined extract was dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography (SiO2, CH2Cl2-methanol-15 M NH4OH, 95:5:0.5) to provide the title compound: MS (DCI) m/z 341 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[S:9]2(=[O:15])=[O:14])=[CH:5][CH:4]=1.[N:18]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[O:14]=[S:9]1(=[O:15])[N:10]([CH3:13])[CH2:11][CH2:12][N:8]1[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([NH:2][NH2:18])=[CH:17][CH:16]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)S1(=O)=O
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CN1CCN(Cc2ccc(NN)cc2)S1(=O)=O
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 35.2 %

Procedure:
To a cooled (-10° C.) and stirred suspension of the product from Step 2 (20 g, 72.0 mmol) in concentrated hydrochloric acid (100 ml) and water (10 ml) was added dropwise a solution of sodium nitrite (5.22 g, 75.6 mmol) in water (40 ml) at such a rate as to maintain the temperature below -5° C. (ca 20 minutes). After a further 10 minutes, the mixture was quickly filtered to remove solids and the filtrate was added portionwise to a cooled (-15° C.) and stirred solution of tin (II) chloride dihydrate (81.2 g, 360 mmol) in concentrated hydrochloric acid (60 ml) at such a rate as to maintain the temperature below -10° C. (ca 15 minutes). The mixture was allowed to warm to 0° C. and it was concentrated to 50% of the volume under vacuum. The remaining acid aqueous solution was basified with 10N potassium hydroxide (temperature maintained below 30° C.) and the resulting mixture was shaken with ethyl acetate (500 ml) and filtered through Hyflo supercel filter aid. The organic phase was decanted off and the basic aqueous solution was extracted with ethyl acetate (3×250 ml). The combined organic phases were washed with brine (1×100 ml), dried (Na2SO4) and concentrated. Crystallization of the remaining residue from ethyl acetate followed by flash chromatography purification of the mother liquors (silica gel, ethyl acetate-methanol, 98:2; and dichloromethane-methanol, 95:5) gave 6.5 g (35%) of the required title compound as a yellow solid; δH (250 MHz, DMSO-d6) 7.07 (2H, d, J=8.5 Hz, Ar--H), 6.74 (2H, d, J=8.5 Hz, Ar--H), 6.70 (1H, br s, --NH--), 3.94 (2H, s, Ar--CH2 --N), 3.91 (2H, br s, --NH2), 3.23--3.05 (4H, m, N--CH2CH2 --N), 2.60 (3H, s, --NMe); m/z (EI) 256 (M+).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:21]=[CH:20][C:11]3[N:12]=[C:13]([C:15]4[S:16][CH:17]=[CH:18][CH:19]=4)[O:14][C:10]=3[CH:9]=2)=[N:6][NH:5][C:4](=[O:22])[CH2:3]1>[O-2].[Mn+4].[O-2].O1CCOCC1>[CH3:1][C:2]1[C:7]([C:8]2[CH:21]=[CH:20][C:11]3[N:12]=[C:13]([C:15]4[S:16][CH:17]=[CH:18][CH:19]=4)[O:14][C:10]=3[CH:9]=2)=[N:6][NH:5][C:4](=[O:22])[CH:3]=1
Reactant: CC1CC(=O)NN=C1c1ccc2nc(-c3cccs3)oc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cc1cc(=O)[nH]nc1-c1ccc2nc(-c3cccs3)oc2c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
100 mg (321 μmol) 5-methyl-6-(2-thiophen-2-yl-benzoxazol-6-yl)-4,5-dihydro-2H-pyridazin-3-one, 0.08 mg (964 μmol) activated manganese(IV)oxide and 10 ml dioxane are combined and stirred overnight at 120° C. The reaction mixture is filtered through Celite, washed with DCM and EA and the solv. of the filtrate is eliminated i.V. The residue is recrystallised with DMF.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:25])[CH3:26])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:32]2[CH:33]=[C:28]([Cl:27])[C:29]([OH:44])=[C:30]([Cl:43])[CH:31]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F, {6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (45 mg, 0.110 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38 mg, 0.135 mmol) to afford the desired product (32 mg, 58%) as a light yellow solid: NMR (500 MHz, CD3OD) δ 9.30 (s, 1H), 8.50 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.78 (s, 2H), 4.47 (s, 1H), 3.45 (s, 1H), 2.91 (s, 6H), 2.85 (s, 1H), 2.51 (s, 2H), 2.31 (s, 2H), 1.91-1.74 (m, 4H), 1.31-1.18 (m, 4H); ESI MS m/z 498 [C27H29Cl2N3O2+H]+; HPLC 96.9% (AUC), tR=11.50 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[C:24]1([N:30]=[C:31]=[S:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:31](=[S:32])[NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Reactant: S=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2SCCC1(CO)COC(=S)Nc1ccccc1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (252 mg, 1.06 mmol) in 13 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.16 ml, 1.16 mmol) and phenyl isothiocyanate (277 μl, 2.3 mmol). The mixture was stirred at 80° C. for 36 hours, concentrated and purified by column chromatography on silica gel (eluent: 4:1 diisopropyl ether/hexane). The product was obtained in a yield of 48 mg (12%).
Reaction SMILES: Cl.Cl.[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[NH2:22].C([O:25]CC)C>>[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12]([CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[NH2:22])=[O:25]
Reactant: CCOCC
Reactant: COc1ccc(N)c(CSc2nc3ccccc3[nH]2)c1
Agent: Cl
Product: COc1ccc(N)c(CS(=O)c2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared by the method of Example 3 using 2.20 g of the free base of the title product of Example 19 instead of the title product of Example 2. Trituration with diethyl ether gave 900 mg of the title compound: m.p. 152-153° C. Anal. Calc'd. for C15H5N3O2S: C, 59.78; H, 5.02; N, 13.94; S, 10.64. Found: C, 59.01; H, 4.97; N, 13.65; S, 10.65.