Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][OH:25])[N:18]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:28][C:29](Cl)=[O:30].[OH-].[K+]>O.C1COCC1>[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:28][C:29]3=[O:30])[N:18]=2)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCCNCCO)cs1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCCN2CCOCC2=O)cs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.8 %

Procedure:
To a solution of EXAMPLE 208B (187 mg, 0.44 mmol) in H2O (2 mL)/THF (1 mL) was chloroacetyl chloride (110 mg, 0.97 mmol) in THF (3 mL) dropwise added under a period of 40 min. The temperature was kept at 8° C. and 2 M KOH was added continuously to adjust the pH to around 6-8. Aqueous potassium hydroxide (6 M, 0.38 mL, 1.41 mmol) was added and the mixture was stirred at room temperature for 20 min. The pH was adjusted to 8 and the mixture was extracted with ethyl acetate. The organic phase was separated and the solvent was evaporated. The residue was flash chromatographed on silica gel eluting with 30% acetone in DCM, yielding 98 mg (52 %) of the title compound: MS (Ionspray, [M+H]+) m/z 429. Anal. Calcd. (found) for C17H20ClN3O4S2: C, 47.5 (47.4)%; H, 4.7 (4.9)%; N, 9.8 (9.5)%.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=1>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)NC(=O)c3cccnc3)cc1)n2C)c1ccccn1
Yield: 56 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and nicotinic acid chloride. Yield: 56% of theory, C34H33N7O4 (603.7) Rf value: 0.52 (silica gel; dichloromethane/methanol=9:1) ##EQU97##
Reaction SMILES: CN([CH:4]=[C:5]1[C:13](=O)[C:12]2[N:11]([CH3:15])[N:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]=2[CH2:7][CH2:6]1)C.C(=O)(O)O.[NH2:25][C:26]([NH2:28])=[NH:27].O>CN(C=O)C>[NH2:27][C:26]1[N:28]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10][N:11]([CH3:15])[C:12]=3[C:13]=2[N:25]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCC(=CN(C)C)C2=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(C)c2c1ccc1cnc(N)nc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 164.8 %

Procedure:
To a solution of 16.62 g (60 mmol) of ethyl 6-[(dimethylamino)methylene]-7-oxo-1-methyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate in 0.5 L of DMF, 27 g (150 mmol) of guanidine carbonate was added. The mixture was stirred at 110° C. overnight. After cooling the mixture was poured into water (2.5 L) and stirred for 30 minutes. The precipitate was filtered, washed with water and dried to yield 26.83 g of title compound (91%).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:17])[CH:6]=[C:7]([CH2:15][CH3:16])[CH:8]([CH3:14])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH3:3].[CH2:18](O)[CH2:19]CC>C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:17])[CH:6]=[C:7]([CH2:15][CH3:16])[CH:8]([CH3:14])[CH2:9][CH:10]=[C:11]([CH3:12])[CH3:13])[CH2:3][CH2:18][CH3:19]
Reactant: CCOC(=O)C=C(CC)C(C)CC=C(C)C
Reactant: CCCCO
Agent: [Na]
Solvent: CC(=O)O
Product: CCCCOC(=O)C=C(CC)C(C)CC=C(C)C
Temperature: 100 °C
Yield: 73 %

Procedure:
A solution of 100 mg of sodium in 85 ml of n-butanol is placed in a flask filled with nitrogen and cooled to ca 5° C. At this temperature, 20 g (0.09 mol) of 3-ethyl-4,7-dimethyl-2,6-octadienoic acid ethyl ester are added. The mixture is then warmed to 60° C for 5 hours and to 100° C for 3 hours. For the working-up, the mixture is acidified with a few drops of glacial acetic acid and then the major part of the n-butanol is distilled off on a rotary evaporator. The residue is taken up in n-hexane, washed twice with sodium bicarbonate solution and three times with water, dried over sodium over sodium sulphate and evaporated. The crude product (19.3 g) is fractionally distilled. There are obtained 16.4 g (73%) of pure 3-ethyl-4,7-dimethyl-2,6-octadienoic acid n-butyl ester of boiling point 90°-92° C/0.04 mm Hg; nD 20 = 1.4677.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2)C1C=CC=CC=1.CO.[H][H]>[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[CH3:19][O:18][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][C:9]=1[OH:8]
Reactant: [H][H]
Reactant: COc1cc2[nH]ccc2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2[nH]ccc2cc1O

Procedure:
5-(benzyloxy)-6-methoxy-1H-indole (3.00 g) was added to methanol (100 mL) and ethyl acetate (100 mL) in a pressure bottle. Palladium hydroxide on carbon (0.832 g) was added and the solution was shaken under 30 psi of hydrogen at room temperature for 40 minutes. The mixture was filtered through a nylon membrane, the solvent removed under vacuum, the residue taken up in ethyl acetate, the solution was filtered over a pad of silica gel, and the solvent was removed from the filtrate under vacuum.
Reaction SMILES: [F:1][C:2]1[C:6](=[O:7])S[C:4](=[O:8])[C:3]=1[F:9].FC1(F)SC(=[O:16])C(F)=C1F.FC1(F)SC(F)(F)C(F)=C1F>>[F:1][C:2]1=[C:3]([F:9])[C:4]([O:7][C:6]1=[O:16])=[O:8]
Reactant: O=C1SC(=O)C(F)=C1F
Reactant: O=C1SC(F)(F)C(F)=C1F
Agent: FC1=C(F)C(F)(F)SC1(F)F
Product: O=C1OC(=O)C(F)=C1F

Procedure:
Both difluoro-2,5-dihydrothiophene-2,5-dione and tetrafluoro-2,5-dihydrothiophene-2-one are made by the reaction of SO3 with hexafluoro-2,5-dihyrothiophene (Example 3, infra). Thus reaction of the hexafluoro-2,5-dihydrothiophene with SO3 under reaction conditions less vigorous than those reported herein that produce difluoromaleic anhydride will produce difluoro-2,5-dihydrothiophene-2,5-dione and/or tetrafluoro-2,5-dihydrothiophene-2-one. Less vigorous conditions include one or more of lower reaction temperatures, shorter reaction times, lesser amounts of SO3 and the absence of catalysts. Since difluoro-2,5-dihydrothiophene-2,5-dione and tetrafluoro-2,5-dihydrothiophene-2-one are both intermediates in the reaction of hexafluoro-2,5-dihydrothiophene with SO3 to produce difluoromaleic anhydride, reaction of either difluoro-2,5-dihydrothiophene-2,5-dione or tetrafluoro-2,5-dihydrothiophene-2-one with SO3 under conditions described herein will yield difluoromaleic anhydride.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:19]=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(NCc2ccccc2)nc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(NCc2ccccc2)nc1)C(=O)OCC
Temperature: 130 °C
Yield: 84.1 %

Procedure:
A mixture of 2-benzylamino-5-aminopyridine (1.76 g) and diethyl ethoxymethylenemalonate (1.78 mL, 8.82 mmol) was heated at 130° C. for 2 h. While warm, the mixture was evacuated. After cooling, the product was triturated with 2:1 hexanes/ether and collected to give 2.74 g of diethyl (2-benzylamino-5-pyridylaminomethylene)malonate as a gold solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:3]1[CH2:4][CH2:5]2)=O.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1.C1(C)C(C)=CC=CC=1>O>[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[N:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:7](=[O:9])[CH:6]3[C:2]([CH3:1])([CH3:12])[CH:3]([CH2:4][CH2:5]3)[C:10]2=[O:11])[CH2:19][CH2:20]1
Reactant: CC1(C)C2CCC1C(=O)OC2=O
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1(C)C2CCC1C(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O

Procedure:
2,2-Dimethylcyclopentane-1,3-dicarboxylic anhydride (1.68 g., 10 mmole) and 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (2.55 g., 11 mmole) were combined in 500 ml. of xylene and refluxed for 48 hours with water removal via a Dean-Stark trap. The solvent was removed in vacuo and the residue column chromatographed on 100 g. of silica gel using a gradient elution from straight chloroform to 5% ethanol/chloroform. Concentration of the product in vacuum and recrystallization from isopropanol with addition of 4N isopropanolic HCl and acetone gave 600 mg. of the title compound as the dihydrochloride, monohydrate; m.p. 227°-229° C. (d).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:9]1[CH:14]=[C:13]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-methylpiperazine (119.3 mg, 132.6 μL, 1.191 mmol) in THF (1.5 mL) was added to a stirred solution of 2,4-dichloro-5-nitro-pyridine (200 mg, 1.036 mmol) and DIPEA (160.6 mg, 216.4 μL, 1.243 mmol) in THF (3.000 mL) at 0° C. under an atmosphere of nitrogen. The reaction was allowed to stir at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and NaHCO3 (sat. aq. soln). The combined organics was washed with brine, dried over MgSO4 and concentrated under reduced pressure to yield 1-(2-chloro-5-nitro-4-pyridyl)-4-methyl-piperazine. (100%) MS (ES+) 257.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=O)=[CH:4][CH:3]=1.B.C1COCC1.Cl.O>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][C:12]3[C:13](=[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: CCCCCOc1cccc2c1C(=O)N(CCc1ccc(O)cc1)C2=O
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCOc1cccc2c1C(=O)N(CCc1ccc(O)cc1)C2
Yield: 58.1 %

Procedure:
N-2-(4-Hydroxyphenyl)ethyl-3-pentyloxyphthalimide (412 mg, 1.17 mmol) was dissolved in THF (1 ml), and a 1.0M THF solution (4 ml) of BH3·THF (4.0 mmol) was added to this solution. The mixture was stirred with refluxing under heating for 8 hours. A 3N aqueous hydrochloric acid solution (10 ml) was added to the reaction mixture. The mixture was further stirred for 0.5 hour at the same temperature, and water (20 ml) was added. The mixture was extracted with ethyl acetate (20 ml×3), and washed with a saturated aqueous sodium hydrogencarbonate solution (20 ml) and saturated brine (30 ml). The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give N-2-(4-hydroxyphenyl)ethyl-7-pentyloxyisoindol-1-one (232 mg, 0.68 mmol, 59%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=1N)([O-:3])=[O:2].[I:14]CI>>[I:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:10][CH:9]=[CH:8][C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: ICI
Reactant: Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a dispersion of 2,6-dinitroaniline (4.00 g, 0.021 mol) in diiodomethane (24 mL, 0.297 mol) isoamylnitrite (15 mL, 0.112 mol) was added (Smith et al., 1990, which is incorporated herein by reference). The mixture was stirred at room temperature for one hour, and then heated at 105° C. for eight hours. The excess of diiodomethane was removed in high vacuo. The residue was diluted with acetyl acetate (10 mL). Silica (ca 30 mL, mesh 230-400 Å) was added; the mixture was concentrated in vacuo and purified by column chromatography to yield 1-iodo-2,6-dinitrobenzene (3.21 g, 52%). 1H NMR (400 MHz, CDCl3): δ 7.84 (d, 2 H, J=8.0 Hz), 7.67 (t, 1 H, J=8.0 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[H-].[Li+].Br[CH2:16][CH:17]=[CH2:18]>CN(C)C=O>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:18][CH:17]=[CH2:16])[C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Reactant: C=CCBr
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCn1c2c(ccc1=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (20.0 g), lithium hydride (1.57 g), and dimethylformamide (800 ml) was stirred for 3 hrs at 25° C., under nitrogen. 3-Bromopropene (15.5 g) was added and the mixture was stirred for an additional eighteen hrs. The redaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with petroleum ether to afford 15.7 g (63%) of 5,6,7,8-tetrahydro-5-oxo-1-(2-propenyl)-2(1H)-quinolinone.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([CH2:11][S:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]2=3)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Br[CH2:26][CH2:27][CH2:28][CH:29]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[CH2:30][N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:48][C:44]1[CH:43]=[C:42]([CH:29]([CH2:28][CH2:27][CH2:26][N:2]2[CH2:7][CH2:6][C:5]3([CH2:11][S:10][C:9]4[CH:12]=[CH:13][CH:14]=[CH:15][C:8]3=4)[CH2:4][CH2:3]2)[CH2:30][N:31]([CH3:41])[S:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH:47]=[CH:46][CH:45]=1
Reactant: c1ccc2c(c1)SCC21CCNCC1
Reactant: CN(CC(CCCBr)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(CCCN1CCC2(CC1)CSc1ccccc12)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Temperature: 52 °C
Reaction time: 48 h
Yield: 42.7 %

Procedure:
Spiro(benzo[b] thiophene-3(2H),4'-piperidine) hydrochloride (16.5 mg, 0.068 mmol) and N,N-diisopropylethylamine (0.036 mL, 27 mg, 0.21 mmol) were added to a solution of N-(5-bromo-2-(3-chlorophenyl)pentyl)-N-methylbenzenesulfonamide (24.6 mg, 0.057 mmol) in 0.30 mL of acetonitrile, and the mixture was heated in an oil bath at 52° C. After 2 days, tetrabutylammonium iodide (5.5 mg, 0.011 mmol) was added and the reaction was continued for an additional 24 h. Without work-up, the reaction mixture was purified by preparative TLC. Elution with 30% ethyl acetate in dichloromethane gave 13.5 mg the title compound. 1NMR (400 MHz, CD3OD): δ 7.74 (d, 2H, J=8 Hz), 7.64 (tt, 1H, J=8, 1 Hz), 7.57 (t, 2H, J=8 Hz), 7.33-7.22 (m, 3H), 7.18 (d, 1H, J=8 Hz), 7.13-7.01 (m, 4H), 3.32-3.25 (m, 3H), 3.11 (dd, 1H, J=13, 8 Hz), 3.00-2.84 (m, 3H), 2.61 (s, 3H), 2.48-2.35 (m, 2H), 2.21 (bq, 2H, J=12 Hz), 1.99 (tt, 2H, J=13, 4 Hz), 1.84-1.75 (m, 3H), 1.67-1.56 (m, 1H), 1.52-1.34 (m, 2H). Mass spectrum (ESI): m/z=555 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([F:42])[CH:35]=1.[H-].[Na+].O>CC#N>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([NH:33][C:19]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:8][CH:7]=2)=[O:20])=[CH:35][C:36]=1[F:42])#[N:39]
Reactant: N#Cc1ccc(N)cc1F
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 158 μmol, example 88) in MeCN (0.5 mL) was added 4-amino-2-fluorobenzonitrile (65 mg, 475 μmol). The resulting mixture was then subjected to a microwave irradiation at 180° C. for 15 min. Then, sodium hydride, 60% dispersion in mineral oil (22 μL, 475 μmol) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added and the solvents were removed. The residue was then dissolved in a solution of MeOH and DMSO (1:1, 1.0 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was then dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 440 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:10](=[O:12])[CH:11]=1)=O)C.O.[NH2:22][NH2:23]>C(O)C>[O:12]=[C:10]1[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[CH:7][C:6]([C:4]([NH:22][NH2:23])=[O:3])=[CH:11]1
Reactant: CCOC(=O)c1cnn(COCC[Si](C)(C)C)c(=O)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ncc(C(=O)NN)cc1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
The title compound from Example 19.2 (0.85 g, 2.8 mmol) was stirred in ethanol. Hydrazine hydrate (0.720 g, 14.2 mmol) was added to the solution and the reaction was stirred at 50° C. for 1 hour. The reaction was concentrated and triturated with methanol and diethyl ether to produce a precipitate which was collected by vacuum filtration as the title compound (0.56 g, 57%).
Reaction SMILES: C([Li])(CC)C.C1CCCCC1.[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[CH3:28])=[O:18])([CH3:15])([CH3:14])[CH3:13].CON(C)[C:32](=[O:35])[CH2:33][CH3:34]>C1COCC1>[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[CH2:28][C:32](=[O:35])[CH2:33][CH3:34])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Reactant: CCC(=O)N(C)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCC(=O)Cc1cc(OC)ccc1NC(=O)OC(C)(C)C
Temperature: -60 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A solution of 1.3M sec-butyl lithium/cyclohexane (81 mL, 0.105 mol) was added slowly to 11.85 g (0.05 mol) of N-tert-butoxycarbonyl-4-methoxy-2-methylaniline in 80 mL of THF while keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to -20° C. and then the bath was replaced. After the temperature had cooled to -60° C., 6.1 g (0.052 mol) of N-methoxy-N-methylpropanamide in an equal volulme of THF was added dropwise. The reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 1 hour. It was then poured into a mixture of 200 mL of ether and 200 mL of 1N HCl. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated at reduced pressure to give 10.9 g (74% yield) of 1-(2-(tert-butoxycarbonylamino)-5-methoxyphenyl]-2-butanone, melting at 80°-81° C., after chromatography on silica eluting with 5% EtOAc/toluene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2]1.[N:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:21]=[O:22].CCN(C(C)C)C(C)C>C1COCC1>[CH2:23]([NH:20][C:21]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2]1)=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=NCc1ccccc1
Reactant: NC(=O)c1cnc2[nH]ccc2c1NC1CCCNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc2[nH]ccc2c1NC1CCCN(C(=O)NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
To a solution of 4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (62 mg, 0.24 mmol, 1.0 eq) and (isocyanatomethyl)benzene (35 mg, 0.26 mmol, 1.1 eq) in THF (2 mL) were added DIPEA (93 mg, 0.72 mmol, 3.0 eq). The mixture was stirred at rt for 3 h and the solvent was removed in vacuo to afford a residue which was purified by prep-HPLC (MeOH/H2O with 0.05% NH3.H2O) to give the title compound as a light brown solid (23 mg, yield: 11%). 1H NMR (400 MHz, CD3OD) δ: 8.32 (s, 1H), 7.15-7.09 (m, 6H), 6.91 (d, J=3.6 Hz, 1H), 4.23-4.20 (m, 3H), 3.87-3.83 (m, 1H), 3.46-3.34 (m, 3H), 2.09-2.05 (m, 1H), 1.81-1.80 (m, 2H), 1.62-1.59 (m, 1H). ESI-MS (M+H)+: 393.20.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[S:23]1[C:27]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)=[CH:26][N:25]=[CH:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:32][C:31]4[CH:30]=[CH:29][C:28]([C:27]5[S:23][CH:24]=[N:25][CH:26]=5)=[CH:35][CH:34]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(-c2cncs2)cc1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccc(-c5cncs5)cc4)c23)c1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 567 mg (3.0 mmol) of 4-(thiazol-5-yl)-benzaldehyde to form 4-(3-chloro-phenylamino)-3-[{4-(thiazol-5yl)-phenyl}-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H, analogous working-up and digestion in diethyl ether yield 4-(3-chloro-phenylamino)-3-[4-(thiazol-5-yl)-benzylamino]-1H-pyrazolo[3,4-d]pyrimidine; m.p. 235° C.; TLC: Rf=0.42 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=8.5; FABMS: (M+H)+=434.