Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[C:3]1[CH:8]=[N:7][N:6]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5](=[O:19])[C:4]=1[CH:20]=O.[NH2:23]N.O>CCO>[CH3:18][C:11]1([CH3:17])[CH2:12][C:13]([CH3:15])([CH3:16])[CH2:14][CH:9]([N:6]2[C:5](=[O:19])[C:4]3[CH:20]=[N:23][NH:2][C:3]=3[CH:8]=[N:7]2)[CH2:10]1
Reactant: NN
Reactant: CN(C)c1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1C=O
Solvent: O
Solvent: CCO
Product: CC1(C)CC(n2ncc3[nH]ncc3c2=O)CC(C)(C)C1
Yield: 46.3 %

Procedure:
A solution of 5-dimethylamino-3-oxo-2-(3,3,5,5-tetramethyl-cyclohexyl)-2,3-dihydro-pyridazine-4-carbaldehyde (1.19 g, 3.903 mmol) in EtOH (30 mL) was treated with H2NNH2.H2O (1.2 mL, 39.03 mmol). After stirring at reflux for 20 h, the volatiles were removed in vacuo and the solid residue was extracted with EtOAc. The organics were then washed with brine, dried (Na2SO4). After evaporation of volatiles, the residue was purified by flash chromatography (50 g (solute SiO2 cartridge, continuous gradient 100% hexanes→hexanes/EtOAc, 1:1) to provide 5-(3,3,5,5-tetramethyl-cyclohexyl)-1,5-dihydro-pyrazolo[3,4-d]pyridazin-4-one (495.3 mg, 46%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.36 (1H, s), 8.31 (1H, s), 5.45 (1H, app heptet, J=4.6 Hz), 1.71-1.57 (4H, m), 1.40-1.22 (2H, m), 1.19 (6H, s), 1.00 (6H, s).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:21])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][NH:13]2)=[CH:8][CH:7]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:21])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:13]2[CH3:22])=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2cc(C3OCCO3)ccc2c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2cc(C3OCCO3)ccc2c1=O
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Compound 8 was dissolved in anhydrous DMF (Aldrich) in a 500 mL 1-neck round bottom flask. Anhydrous potassium carbonate (EM Science) was added and the mixture was stirred for 15 min. After addition of iodomethane (Aldrich), the mixture was stirred at room temperature overnight, after which it was concentrated and partitioned between CH2Cl2 and aq. sodium thiosulfate. The CH2Cl2 layer was rinsed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to 19.30 g crude 9 (brownish solid). 1H NMR spectrum was satisfactory; however, TLC (MeOH:DCM 1:9) shows small amounts of lower polarity impurities and some high polarity impurities (possibly largely inorganic). Attempts to purify via re-precipitation from THF/water or CH2Cl2/hexane were unsatisfactory. Chromatography on a silica gel plug (gradient 1-2-4-6-10% methanol in CH2Cl2) provided purified product (17.93 g, 95% yield).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([O:24][CH3:23])[CH:26]=3)=[O:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)c1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-methoxyaniline (30 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-methoxyphenyl)benzamide as a white solid. Yield: 13 mg (13%). 1H-NMR: 10.41 (s, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.43-7.41 (m, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.24-7.18 (m, 1H), 7.12-7.08 (m, 2H), 6.70 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 3.85-3.79 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.67-1.59 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][OH:28])[O:24][C:23]2=[O:29])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(Cl)Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][O:28][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[O:24][C:23]2=[O:29])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(N3CC(CO)OC3=O)cc2F)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CN(c3cc(F)c(N4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)C(=O)O2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
The [3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methanol (24.2 g, 59 mmol) was dissolved in pyridine (110 mL) and then cooled to 0° C. (ice bath). Freshly recrystalized p-toluenesulfonyl chloride (13.4 g, 70 mmol) of was added and the reaction was allowed to stir at 0° C. for 2.5 hours under N2. The flask was then stoppered and stored in the refrigeratior (5° C.) overnight. The reaction mixture became a pale pink slurry. TLC revealed that some alcohol still remained. The reaction mixture was treated with additional p-toluenesulfonyl chloride (1.12 g, 5.85 mmol), catalytic 4-(dimethylamino)pyridine, and 20 mL of dry CH2Cl2 to facilitate stirring. After 4 hours at 0° C., the reaction was found to be complete by TLC (5% MeOH/CH2Cl3, UV short wave). The mixture was added to 750 mL ice water and the precipitated product isolated via suction filtration, washing it with both water (1 L) and ether (500 mL). After drying in vacuo, 29.921 g (90%) of the title compound was obtained as white solid with mp 150.5°-151.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26]>C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 70 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
3.59 g (19.08 mmol) of N-(tert-butoxycarbonyl)-1,4-diaminobutane was dissolved in 70 ml of triethylamine and 3.79 g (18.17 mmol) of 4-chloro-3-nitroquinoline was added thereto. The resulting mixture was heated at 70° C. and stirred for 4 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with water, and dried (MgSO4). The solvent was distilled off under reduced pressure. The resulting residue was triturated with diethel ether and collected by filtration to obtain 5.77 g (16.01 mmol) of 4-[4-(tert-butoxycarbonylamino)butylamino]-3-nitroquinoline shown below as a yellow solid.
Reaction SMILES: [O:1]=[C:2]=[N:3][S:4]([Cl:7])(=[O:6])=[O:5].[CH3:8][C:9]([OH:12])([CH3:11])[CH3:10].CCCCCC>C1C=CC=CC=1>[Cl:7][S:4]([NH:3][C:2](=[O:1])[O:12][C:9]([CH3:11])([CH3:10])[CH3:8])(=[O:6])=[O:5]
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(oxomethylene)sulfamoyl chloride (13.4 mmol) was dissolved in dry benzene (5 mL) and dropwise added t-BuOH (13.4 mmol) while the temperature was kept below 25° C. The reaction mixture was stirred at 25° C. for 2 h, added hexane (5 mL) and cooled to 0° C. Precipitate was collected by filtration, washed with hexane affording tert-butyl N-chlorosulfonylcarbamate as white crystals. 4-(4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (4.6 mmol) (intermediate 21) was suspended in dry DCM (25 mL) and added triethylamine (6.9 mmol). To this suspension was slowly added tert-butyl N-chlorosulfonylcarbamate (4.6 mmol) at rt. After 15 min all starting material has been consumed. The obtained reaction mixture was concentrated in vacuo on celite. The product was purified by flash chromatography on silica using EtOAc:MeOH in heptane as eluent.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18].C(O)(=O)C.[K+].[Br-]>C(O)C>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:23]([C:22]3[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:6])[CH2:15][CH3:16]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(C#N)cc3)nc2n(CCC)c1=O
Temperature: 0 °C

Procedure:
1,3-Dipropyl-8-(4-cyanophenyl)xanthine was prepared by treatment of 1,3-dipropyl-5,6-diaminouracil (6.37 g, 28.15 mmol) with 4-cyanobenzaldehyde (3.72 g, 28.37 mmol) in absolute ethanol (175 ml) with acetic acid (5 ml) heated at reflux for 2 hours. The reaction mixture was then cooled to 0° C., and the resulting precipitate collected, and recrystallized from ethanol yielding a white solid (8.1 g, 24.0 mmol, 85%) IR (KBr) 3142 (N--H), 2965 (C--H), 2232 (C=N), 1695 (C=O), 1651 (C=O) cm-1 ; 1H NMR (DMSO d6) δ8.2 (d,J=8 Hz, 6H). Anal. Calcd. for C18H19N4O21, MW. 337.38: C, 64.08; H, 5.68; N, 20.76. Found: C, 64.15, H, 5.69; N, 20.72.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.C(N(CC)CC)C.[Cl:13][CH:14]([Cl:31])[C:15]([NH:17][CH:18]1[C:29](=[O:30])[N:20]2[C:21]([C:26]([OH:28])=[O:27])=[C:22]([CH3:25])[CH2:23][S:24][C@H:19]12)=[O:16]>C(Cl)(Cl)Cl>[CH3:1][Si:2]([O:28][C:26]([C:21]1[N:20]2[C:29](=[O:30])[CH:18]([NH:17][C:15](=[O:16])[CH:14]([Cl:31])[Cl:13])[C@H:19]2[S:24][CH2:23][C:22]=1[CH3:25])=[O:27])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
Trimethylchlorosilane(0.5 ml) and triethylamine (0.17 ml) were added to a solution of 7-dichloroacetamido-3-methyl-3-cephem-4-carboxylic acid(325 mg) in chloroform (12 ml). The reaction mixture was stirred at 10°C. overnight to afford a chloroform solution of 7-dichloroacetamido-3-methyl-3-cephem-4-carboxylic acid trimethylsilyl ester. The resulting solution was added dropwise at -50°C. to a mixture prepared from phosphorus pentachloride(220 mg), quinoline(0.15 ml) and chloroform (15 ml). The reaction mixture was stirred at -50°C. for 3 hours and diluted with dry tetrahydrofuran(20 ml). To this solution was added a methanol solution of lithium methoxide prepared from lithium(150 mg) and methanol(15 ml) a -78°C. The mixture was stirred at -78°C. for 30 minutes and treated with acetic acid(1.5 ml). The solution was poured into water and extracted with chloroform. The extracts were washed with water, dried(Na2SO4) and evaporated under reduced pressure. The residue was dissolved in a small amount of chloroform, to which was added excess hexane to precipitate the desired substance. This process was repeated three times to give 240 mg of 7β-(2'-chloro-1'-methoxyethylidenimino)-7α-methoxy-3-methyl-3-cephem-4-carboxylic acid. NMR(CDCl3) δ ppm: 2.05(3H, singlet), 3.03 and 3.43(2H, AB-quartet, J=18 Hz), 3.40(3H, singlet), 3.75(3H, singlet), 4.18 and 4.53(2H, AB-quartet, J=12 Hz), 5.00(1H, singlet).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[C:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]>CN(C=O)C>[C:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:38]=[CH:39][C:40]([CH:43]3[CH2:48][CH2:47][N:46]([C:11]4[CH:12]=[CH:13][C:14]5[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=5)[N:16]=4)[CH2:45][CH2:44]3)=[CH:41][CH:42]=2)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCN(CCCOc2ccc(C3CCNCC3)cc2)CC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(CCCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
DIPEA (5.21 mL, 29.93 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (6.06 g, 27.21 mmol) and 4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidine (9.40 g, 27.21 mmol) in DMF (200 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature then evaporated to dryness. Water (600 mL) was then added and the mixture extracted with DCM (2×600 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 6-[4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (13.80 g, 95%) as an orange solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:11][CH2:12][OH:13])[CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20]>N1C=CC=CC=1.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:19]([O:1][CH2:2][CH2:3][N:4]([CH2:11][CH2:12][O:13][C:19](=[O:20])[C:18]1[CH:17]=[C:16]([O:15][CH3:14])[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:5][CH2:6][S:7]([OH:10])(=[O:8])=[O:9])=[O:20]
Reactant: O=S(=O)(O)CCN(CCO)CCO
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cc(C(=O)OCCN(CCOC(=O)c2cc(OC)c(OC)c(OC)c2)CCS(=O)(=O)O)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
8.5 G of the product obtained in Example 2 (a) was suspended in 25 ml of anhydrous pyridine, and 18.4 g of 3,4,5-trimethoxybenzoyl chloride added slowly under agitation. After being left for one hour at ambient temperature the mixture was heated to 80° C. for a further hour. It was then cooled to ambient temperature, diluted with 50 ml of ethanol and left to stand in a refrigerator. A colourless crystalline compound precipitated which milted at 174°-178° C. After recrystallisation from methanol, the melting point was 180°-183° C. The yield was 11.5 g of pure product.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:6](I)[N:5]=[C:4]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH3:2].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([N:3]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:6]([C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)[N:5]=[C:4]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH3:2]
Reactant: CCn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1ccncc1
Product: CCn1c(-c2cccc(C(F)(F)F)c2)nc(-c2ccncc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [3-ethyl-5-iodo-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 69) was reacted with pyridine-4-yl-boronic acid to give the title compound as light yellow solid. MS: 498.1 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[N:27][NH:28]2)=[CH:24][CH:23]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:2]3[N:3]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Clc1nc(NCCCN2CCOCC2)c2cc[nH]c2n1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: c1cc2c(NCCCN3CCOCC3)nc(Nc3ccc4cn[nH]c4c3)nc2[nH]1
Temperature: 116 °C
Yield: 18.5 %

Procedure:
A mixture of 2-chloro-N-(3-morpholinopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (65 mg, 0.22 mmol), 6-aminoindazole (80 mg, 0.60 mmol) and trimethylsilyl chloride (0.100 mL, 0.72 mmol) in nBuOH (3 mL) was heated at 116° C. overnight. It was then purified by HPLC to give the titled compound (16 mg). MS 393.5 (M+H); UV 217.9, 239.1, 309.1 nm.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:30][S:31](O)(=[O:33])=[O:32].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[C:4]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:22])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:18])[CH3:19])[NH:13][N:12]=1
Reactant: CS(=O)(=O)O
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CNS(C)(=O)=O)cc2F)n[nH]1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)-N6-(5-isopropoxy-1H-pyrazol-3-yl)pyridine-2,6-diamine (Example 18; 0.10 g, 0.25 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.25 mmol), DIEA (0.064 g, 0.50 mmol), DMAP (0.033 g, 0.27 mmol), and THF (5 ml). The resulting suspension was shaken vigorously at 60° C. for 8 hrs and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give (0.82 g, 67%). 1H NMR (400 MHz, CD3OD) δ 7.44-7.41 (m, 2H), 7.17 (d, J=10.7 Hz, 1H), 7.02-6.97 (m, 2H), 5.26 (s, 1H), 5.01-4.99 (m, 1H), 4.56-4.53 (m, 1H), 4.16-4.08 (m, 1H), 3.01 (s, 3H), 1.52 (d, J=7.0 Hz, 3H), 1.31 (d, J=6.0 Hz, 6H). MS: Calcd.: 480. Found: [M+H]+ 481.
Reaction SMILES: Cl.[CH3:2][NH2:3].[CH3:4][C:5]1[CH:6]=[C:7]2[C:16](=[O:17])[O:15][C:14]([C:22]3[NH:26][C:25]4[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:24]=4[N:23]=3)([C:18]([F:21])([F:20])[F:19])[C:8]2=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2>C1COCC1.C([Mg]Cl)(C)C>[C:31]([C:29]1[CH:28]=[CH:27][C:25]2[NH:26][C:22]([C:14]([C:8]3[C:7]([C:16]([NH:3][CH3:2])=[O:17])=[CH:6][C:5]([CH3:4])=[C:13]4[C:9]=3[CH:10]=[CH:11][NH:12]4)([OH:15])[C:18]([F:19])([F:21])[F:20])=[N:23][C:24]=2[CH:30]=1)#[N:32]
Reactant: Cc1cc2c(c3cc[nH]c13)C(c1nc3cc(C#N)ccc3[nH]1)(C(F)(F)F)OC2=O
Reactant: CN
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C)c2[nH]ccc2c1C(O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of methylamine hydrochloride (102 mg, 1.51 mmol) in THF (0.5 mL), 2N isopropylmagnesium chloride in THF (1.51 mL, 3.03 mmol) was added. The reaction was stirred at room temperature for 3 hr, then a solution of (±)-2-(5-methyl-3-oxo-1-(trifluoromethyl)-3,6-dihydro-1H-furo[3,4-e]indol-1-yl)-1H-benzo[d]imidazole-5-carbonitrile (30 mg, 0.076 mmol) in THF (0.5 mL) was added. The reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was quenched with 1N HCl aqueous solution and then neutralized by adding NaHCO3. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4. After concentration under reduced pressure, the residue was separated via silica gel flash column chromatography (CH2Cl2/EtOAc=0 to 100%) to give the title compound. 1H NMR (400 MHz, DMSO-d6, with about 3% METHANOL-d4) δ ppm 7.85 (d, J=2.0 Hz, 1H), 7.41-7.46 (m, 2H), 7.39 (d, J=0.8 Hz, 1H), 7.19 (dd, J=8.3, 1.8 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H), 2.96 (s, 3H), 2.58 (s, 3H). HRMS calcd. for C21H16F3N5O2 (M+H)+ 428.1329. found 428.1333.
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8])#[N:2].N.[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOC(OCC)P(=O)(CCC#N)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CCCN)OCC

Procedure:
A solution of 9.6 g of ethyl 2-cyanoethyl(diethoxymethyl)phosphinate in 450 ml of ethanol is added to 82 g of an 8% solution of ammonia in ethanol. To this is added 5 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered, the filtrate is concentrated under reduced pressure and the crude product is distilled to give ethyl 3-aminopropyl(diethoxymethyl)phosphinate, b.p. 150° C./0.01 mbar, 31 p=+46.4 ppm (CDCl3).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CCOCC.[C:10]([N:14]1[C:19](=[O:20])[C:18](Cl)=[C:17]([Cl:22])[CH:16]=[N:15]1)([CH3:13])([CH3:12])[CH3:11].ClC1C=NNC(=O)C=1Cl>C1(C)C=CC=CC=1>[CH2:1]([C:18]1[C:19](=[O:20])[N:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:15]=[CH:16][C:17]=1[Cl:22])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CC[Mg]Br
Agent: O=c1[nH]ncc(Cl)c1Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCc1c(Cl)cnn(C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
Into a four-necked flask of 1 liter, 43 g of ethylmagnesium bromide (3 mol/liter of an ether solution) and 200 ml of dehydrated toluene were charged. While thoroughly stirring the mixture at room temperature, 22.1 g (0.1 mol) of 2-t-butyl-4,5-dichloro-3(2H)pyridazinone was added in three portions. The reaction temperature was raised to a level of about 60° C., and the stirring was continued for about 30 minutes. The disappearance of the starting dichloropyridazinone was confirmed by thin layer chromatography (developer; hexane:acetone =20:1, v/v), whereupon the reaction was terminated. After the addition of about 300 ml of chilled water, the mixture was stirred vigorously, and transferred to a separating funnel, and then the aqueous layer was removed. The organic layer was washed with about 200 ml of water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The pale brown oily substance thereby obtained was purified by silica gel column chromatography (developer; benzene) to obtain pale yellow crystals. 1.45 g (yield: 67.6%).