Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([CH3:19])([O:13]C1CCCO1)[C:8]#[C:9][CH:10]1[CH2:12][CH2:11]1)[CH3:3].C(O)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C[O-].[Na+]>O>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([CH3:19])([OH:13])[C:8]#[C:9][CH:10]1[CH2:12][CH2:11]1)[CH3:1]
Reactant: CC(C)CCCC(C)(C#CC1CC1)OC1CCCO1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)CCCC(C)(O)C#CC1CC1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
In a dried flask (300 ml volume), the inside of which had been flushed with nitrogen, were placed 2,6-dimethyl-6-tetrahydrofuranoxy-8-cyclopropyl-7-octyne (10.72 g, purity 98.5%, 0.04 mol.) prepared in Example 2, ethanol (100 ml) and pyridinium p-toluenesulfonate (5.4 mg). The resulting mixture was heated at 50° C. to 60° C. for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and to the mixture was added 10 mg of sodium methoxide (25% methanol solution). Ethanol was removed by distillation through a rotary evaporator. To the concentrate obtained was added 100 ml of water and the resulting mixture was subjected to extraction with two 100 ml portions of ethyl acetate. The extract was washed with an aqueous saturated sodium bicarbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated by distillation of the solvent through a rotary evaporator to give 10.1 g of a crude product. The crude product was purified by distillation under reduced pressure to give 2,6-dimethyl-6-hydroxy-8-cyclopropyl-7-octyne (7.33 g, purity 99.0%, yield 93.5%) having the following physical data:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:15]([F:18])([F:17])[CH2:14]2)[CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]2([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][C:15]([F:18])([F:17])[CH2:16]2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(F)(F)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C2CCN(Cc3ccccc3)C2)CC(F)(F)C1
Temperature: 0 °C
Yield: 56 %

Procedure:
Under an atmosphere of nitrogen, 927 mg (2.44 mmol) of 1-benzyl-4-[3-(tert-butoxycarbonylamino)-1,1-difluorocyclobutan-3-yl]-2-pyrrolidone (Isomer F1) was dissolved in 20 ml of tetrahydrofuran to which, while cooling in an ice bath with stirring, was subsequently added 7.31 ml of 1 N borane-tetrahydrofuran complex tetrahydrofuran solution. Ten minutes thereafter, the ice bath was detached and the reaction mixture was stirred at room temperature for 18 hours. After evaporation of the solvent under a reduced pressure, the thus obtained residue was mixed with 30 ml of 80% ethanol and 3 ml of triethylamine and heated under reflux for 2 hours. After evaporation of the solvent under a reduced pressure, the thus obtained residue was mixed with ethyl acetate and saturated sodium bicarbonate aqueous solution to effect separation of layers. The organic layer was washed with saturated brine, the aqueous layer was extracted with ethyl acetate and then the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography to give 501 mg (56.1%) of the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]([F:16])([F:15])[F:14])(=O)=O)=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=1[OH:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=1[O:26][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: OCc1ccc(Cl)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccc(Cl)c(OCC(F)(F)F)c1
Temperature: 100 °C
Yield: 71.1 %

Procedure:
A mixture of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (1.34 g, 5.28 mmol), 2-chloro-5-(hydroxymethyl)phenol (837 mg, 5.28 mmol), K2CO3 (1.46 g, 10.56 mmol) and DMF (9 mL) was heated to 100° C. overnight. It was then poured into ice-water and extracted with ethyl acetate twice. Organic phase washed with water twice, brine and dried with Na2SO4, concentrated to a residue which was purified by flash column chromatograph to give the title compound (903 mg, 75%). 1H NMR (400 MHz, CDCl3): δ 1.77 (1H, t, J=5.6 Hz), 4.42 (2H, q, J=8.0 Hz), 4.68 (2H, d, J=5.2 Hz), 6.99 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.02 (1H, s), 7.37 (1H, d, J=8.0 Hz).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([F:29])[CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[C:22]([F:29])[CH:21]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(Cl)cc1F
Product: N#Cc1cc(-c2ccc(Cl)cc2F)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (83 mg, 94%), MS (ISP) m/z=354.4 [(M+H)+], mp 217.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH3:13][O:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:15]([O:14][CH3:13])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccc(C(F)(F)F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(C(F)(F)F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with O-methyl-N-(4-trifluoromethyl-benzyl)-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (97% yield): mp 110° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 3.71 (3H, s, OCH3), 4.87 (2H, s, NCH2), 6.40 (1H, s, CH), 7.47 (2H, m, aromatics), 7.59 (2H, m, aromatics). Anal. calcd for C16H16F3NO5: C, 53.49; H, 4.49; N, 3.90. Found: C, 53.48; H, 4.53; N, 3.83.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=2[C:10]([CH3:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:25][NH2:26])[CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([Cl:20])[N:14]=[CH:15][C:16]([C:17](=[O:19])[NH:26][CH2:25][CH:22]3[CH2:24][CH2:23]3)=[C:11]2[C:10]([CH3:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC1CC1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12
Product: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)NCC3CC3)c12

Procedure:
Prepared in a similar manner to Example 11 (b) from 7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1,4-dicarboxylic acid 1-tert-butyl ester using cyclopropylmethylamine (167 μl) instead of morpholine to give the title compound as a pale brown foam (389 mg).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[CH:7][C:6]=12.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26]>>[F:14][C:11]([F:12])([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:26]#[C:25][C:27]3[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=3)=[C:6]2[CH:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(I)c3c2)cc1
Reactant: C#Cc1ccc(N)nc1
Product: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cc23)cn1

Procedure:
The title compound was prepared from 3-iodo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyridine (example C.22 step 9) (300 mg, 0.7 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (93 mg, 0.8 mmol) according to general procedure II. Obtained as a yellow solid (230 mg, 78%). MS (ISP) 447.2 [(M+H)+]; mp 243-245° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[CH:12]([CH3:14])[CH3:13])(=[O:4])=[O:3].[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[CH:15]([NH:18][CH2:7][CH:8]([OH:11])[CH2:9][O:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([CH:12]([CH3:14])[CH3:13])[CH:7]=1)([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: CC(C)c1cc(O)ccc1S(C)(=O)=O
Product: CC(C)NCC(O)COc1ccc(S(C)(=O)=O)c(C(C)C)c1

Procedure:
Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-3-isopropylphenol with isopropylamine according to the procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-[4-(METHYLSULFONYL)-3-ISOPROPYLPHENOXY]-2-PROPANOL.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]23[O:16][C:15](=[O:17])[CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10]3)=[O:8])=[CH:5][CH:4]=1.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>COC(C)(C)C>[CH2:20]([NH:24][C:15]([CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1([C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[OH:16])=[O:17])[CH2:21][CH2:22][CH3:23]
Reactant: COc1ccc(C(=O)C23CCCCC2C(=O)O3)cc1
Reactant: CCCCN
Solvent: COC(C)(C)C
Product: CCCCNC(=O)C1CCCCC1(O)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
20.8 g (0.08 mol) of 6-(4-methoxy-benzoyl)-7-oxa-bicyclo[4.2.0]octan-8-one (example 10) are dissolved in 200 ml of tert-butyl methyl ether. 10.46 g (0.143 mol) of n-butylamine are slowly added to this solution over one hour. The reaction mixture is stirred overnight at room temperature and the solvent is subsequently distilled off under vacuum. The yellowish oil thus obtained crystallizes upon standing and is purified by recrystallization from heptane. 22.5 g (85%) 2-(4-methoxybenzoyl)-2-hydroxy-cyclohexanecarboxylic acid butyl-amide are thus obtained as white solid with a melting point of 94-95° C.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]([NH:30][NH2:31])=O>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:28]([C:24]5[O:23][CH:27]=[CH:26][CH:25]=5)=[N:30][N:31]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: NNC(=O)c1ccco1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nnc(-c5ccco5)[nH]4)cc23)cc1
Yield: 14.9 %

Procedure:
The procedure described in example 119 using ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (200 mg, 0.62 mmol), triethylainine (0.25 mL, 1.86 mmol) and 2-furoic acid hydrazide (157.6 mg, 1.25 mmol) was followed to yield the title compound (32 mg, 15% yield). 1H NMR (DMSO-d6) δ 14.8 (br s, 1H), 13.5 (s, 1H), 8.7 (s, 1H), 8.0–8.15 (m, 3H), 7.78 (s, 1H), 7.75 (d, 1H), 7.4 (t, 2H), 7.0 (br s, 7.0), 6.65 (s, 1H), ES-MS (m/z) 346 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][CH:8]3[C:13]4[C:18]([CH2:19][CH:7]3[C:6]=2[CH:5]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH3:3])[CH3:2].[CH2:20]([Li])CCC.IC>O1CCCC1>[CH3:20][C@@:8]12[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][C@@H:7]1[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:12]=[CH:11][C:10]=1[NH:9]2
Reactant: CC(C)c1ccc2c(c1)C1Cc3ccccc3C1N2
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)c1ccc2c(c1)[C@H]1Cc3ccccc3[C@@]1(C)N2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under an inert atmosphere, a flame-dried flash was charged with 4b,5,9b,10-tetrahydro-8-isopropylindeno[1,2-b]indole (1.49 g 5.98 mmol) and dry tetrahydrofuran (THF, 20 cm3). The solution was cooled to -78° C., and a solution of n-butyllithium in hexanes (4.0 cm3 of 1.6M solution) added dropwise. The reaction was warmed to room temperature, and dry CO2 gas bubbled through until the colour of the anion had dispersed. The solvent and excess CO2 were carefully removed at a vacuum pump, the resulting solid re-dissolved in dry THF (20 cm3) and cooled to -78° C. A further equivalent of n-butyllithium was added, and the reaction stirred at -20° C. for 30 minutes. Iodomethane (0.4 cm3, 1 eq) was added at -78° C., and the reaction warmed to room temperature and stirred for 3 hours. The solvents were removed at the water pump, and 2N HCl solution (20 cm3) added. After 20 minutes, the solution was basified with solid sodium carbonate, and extracted into ethyl acetate. The organic extract was washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by flash chromatography as an unstable pale yellow oil. Yield: 1.01 g, 64%. 1H NMR (CDCl3) δ: 7.30-7.15 (4H, m), 7.00 (1H, s), 6.85 (1H, d, J=7.9 Hz), 6.49 (1H, d, J=7.9 Hz), 4.0 (1H, br), 3.73 (1H, d, J=8.1 Hz), 3.49 (1H, dd, J=16.1, 8.2 Hz), 3.16 (1H, d, J=16.1 Hz), 2.79 (1H, septet, J=6.8 Hz), 1.61 (3H, s), 1.19 (6H, d, J=6.8 Hz).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:6][C:5]=1[OH:17])[CH2:2][CH3:3].Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH:27]([OH:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1>>[CH2:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:6][C:5]=1[O:17][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH:27]([OH:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)C(O)c1ccc(OCCCBr)cc1
Reactant: CCCc1cc(Oc2cnccn2)ccc1O
Product: CCCc1cc(Oc2cnccn2)ccc1OCCCOc1ccc(C(O)C(=O)OCC)cc1

Procedure:
The title compound was prepared according to the method described in Example 22, Step C using 2-propyl-4-pyrazinyloxyphenol (19.0 g, 62.0 m-mol) and ethyl 4-(3-bromopropoxy)mandelate (19.5 g, 58.9 mmol) (as prepared in Example 22, Step C) as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:23]=[CH2:24])[CH:22]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][CH2:23][C:21]3[CH:20]=[N:19][CH:18]=[C:17]([F:16])[CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cncc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cncc(F)c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 3-fluoro-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17](=O)[CH3:18])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH3:18])[N:1]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5](=[O:6])[NH2:7])[CH:3]=2)[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:28])[CH3:12]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: NC(=O)c1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(C(N)=O)c2)c1-c1ccccc1

Procedure:
3-Aminobenzamide (5 mmol, 1.0 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting precipitate was filtered from the reaction mixture, then washed with ethanol. The tan solid product was used without further purification (m.p. 208.9° C.-210.3° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[CH:5]=[C:4]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:3]=1.N1C=CC=CC=1.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([O:10][C:6]1[CH:5]=[C:4]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH:8]=[O:9])(=[O:26])=[O:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1c(Cl)cc(OC2CCCCO2)cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a mixture of 6-chloro-2-hydroxy-4-(tetrahydro-pyran-2-yloxy)benzaldehyde (10.5 g, 40.9 mmol) and pyridine (14.6 mL, 0.20 mol) in DCM (150 mL) cooled at −10˜0° C. was added Tf2O (10.3 mL, 61.2 mmol) dropwise. The reaction mixture was stirred at 0° C. for an additional 2 h and quenched with cold brine (40 mL). The resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc: PE=1:200) to give the title compound as a yellow oil (10.5 g. Yield: 66%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[CH2:9]([N:11]([CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:12]1[C:17]([NH:18][CH2:19][CH3:20])=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:10]>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:11]([CH2:9][CH3:10])[C:12]2[C:17]([NH:18][CH2:19][CH3:20])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:27][CH2:26]1)=[O:8]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CCNc1cccnc1N(CC)CC1CCNCC1
Product: CCNc1cccnc1N(CC)CC1CCN(C(=O)c2ccc[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 149 and making non-critical variations, but using pyrrole-2-carboxylic acid (823 mg, 7.40 mmol) and 4-[N-ethyl-N-(3-ethylamino-2-pyridinyl)aminomethyl]piperidine (970 mg, 3.70 mmol), a crude product is obtained. Chromatography [with 40-100% ethyl acetate/hexane], followed by crystallization from ether/hexane gives the title compound, mp=109°-110°.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=4[S:10][C:9]=3[NH:8][C:7]=2[CH:21]=1.[CH3:22][O:23][CH2:24][CH2:25][C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1.C(N(C(C)C)CC)(C)C>CS(C)=O.C1(C)C=CC=CC=1.C(Cl)Cl>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:31]3)[C:13]3[C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=4[S:10][C:9]=3[NH:8][C:7]=2[CH:21]=1
Reactant: COCC[C@H]1CNCCN1
Reactant: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)CCN1
Temperature: 110 °C
Reaction time: 55 h

Procedure:
Combine 9-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrogen chloride (510.2 mg, 1.6 mmol, (S)-2-(2-methoxy-ethyl) piperazine (460.8 mg, 3.2 mmol) and diisopropylethyl amine (206 mg, 1.6 mmol) in DMSO (0.75 mL) and toluene (3.0 mL), stir and heat to 110° C. After 55 hours, cool the reaction to RT, dilute with CH2Cl2, wash with H2O and Brine. Dry the organic layer with by Na2SO4. The crude material pass through a 5 g SCX column, collect the 0.2 N NH3/MeOH eluent, concentrate to a residue, which purified by chromatography on silica gel, gradient (100% CH2Cl2 to 100% CH2Cl2: 2N NH3/MeOH=15:1), give 410 mg of title compound. Mass spectrum: ACPI (m/e): 411.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17]O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(CO)cc2C1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccc(CN3CCCC3)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.25 g 5-hydroxymethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (5.01 mmol) in 14 ml dichloromethane was slowly added 0.781 ml methanesulfonyl chloride (10.03 mmol) at room temperature. Subsequently the mixture was heated for 4 hours at reflux. LCMS control indicted a near complete formation of the corresponding mesylate, which was not isolated. After cooling to room temperature, 1.244 ml pyrrolidine (15.04 mmol) were added and the mixture was stirred at room temperature overnight. The reaction was complete according to LCMS. Water was added to the reaction mixture, the acidic aqueous phase was extracted two times with dichloromethane, and the water phase was basified and extracted three times with ethyl acetate. The combined ethyl acetate solutions were extracted with brine, dried over Na2SO4, filtered, and the organic solvent was removed under reduced pressure to provide the title compound. The dichloromethane phase was extracted two times with diluted NaOH, once with brine and then dried over Na2SO4. Filtration and removal of the organic solvent under reduced pressure provided additional title compound. Both fractions were combined and used in the next step without further purification. LCMS: m/z 303.2 (M+H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])=[CH:6][C:5]=1[CH:22]=[N:23][O:24][CH3:25].[N+:26](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:26][N:12]1[C:13]([C:17]([F:18])([F:19])[F:20])=[CH:14][C:15](=[O:16])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[C:5]([CH:22]=[N:23][O:24][CH3:25])[CH:6]=2)[C:11]1=[O:21]
Reactant: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)ccc1Cl
Temperature: 50 °C
Reaction time: 6 h
Yield: 29.5 %

Procedure:
0.38 g (16 mmol) of sodium hydride in 50 ml of anhydrous dimethylformamide was treated dropwise at 0°-5° C. with a solution of 5.0 g (14 mmol) of 3-(4-chloro-3-methoxyiminomethylphenyl)-2,4-dioxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 50 ml of anhydrous dimethylformamide. A solution of 2.8 g (14 mmol) of 2,4-dinitrophenoxyamine in 50 ml of anhydrous dimethylformamide was added dropwise to this mixture after 10 minutes, after which it was stirred for 60 hours at 20°-25° C. and for 6 hours at 50° C. For working up, the cooled reaction mixture was poured into 800 ml of ice water. The aqueous phase was extracted three times with 200 ml of ethyl acetate each time. The ethyl acetate extracts were then dried over sodium sulfate and concentrated. After chromatographic purification of the crude product on silica gel (eluent: cyclohexane/ethyl acetate/triethylamine 79:20:1), 1.5 g (29%) of a colorless oil were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[NH2:10].[C:11](=S)=[S:12]>C(O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:11]([SH:12])[NH:10][C:3]=2[C:4]=1[F:9]
Reactant: S=C=S
Reactant: Nc1ccc(F)c(F)c1N
Solvent: CCO
Product: Fc1ccc2nc(S)[nH]c2c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.2 %

Procedure:
To a solution of 1,2-diamino-3,4-difluoro-benzene (996 mg, 6.9 mmol) in 20 mL of ethanol in a 25 mL microwave tube, are added 2.0 mL (33.3 mmol) of carbon disulfide. The tube is capped and the reaction mixture is heated under microwaves at 120° C. twice for 20 minutes, upon which 1.0 mL (16.6 mmol) of carbon disulfide is added and heating under microwaves is pursued for 20 minutes. Carbon disulfide 2.0 mL (33.3 mmol) is added and heating is pursued for 30 minutes under microwaves at 150° C. The reaction mixture is then cooled to room temperature and concentrated to dryness under reduced pressure. The residue is dissolved into ethyl acetate and concentrated to dryness under reduced pressure. The residue is triturated into diisopropylether, filtered and washed once with diisopropylether. The solid is dried under reduced pressure. 0.35 g of 6,7-difluoro-1H-benzimidazole-2-thiol is obtained as mauve solid. LCMS-DAD-ELSD: 185(−): [M−H]−; 186(+): [M+H]+.