Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[OH:30].C(=O)([O-])[O-].[K+].[K+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Br>O>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:30][CH2:37][CH:39]1[CH2:40][O:41]1
Reactant: BrCC1CO1
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
N,N-Dimethylformamide (6 ml) was added to 7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-6-ol (189 mg), potassium carbonate (236 mg), and epibromohydrin (234 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give 7-methoxy-4-(2-methyl-quinolin-3-yloxy)-6-oxiranylmethoxy-quinoline (59 mg, yield 27%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N:13]([CH2:18][CH3:19])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][N:10]2[N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]([C:23](=[O:26])[NH:24][CH3:25])=[C:9]2[CH:8]=1)(=O)=O.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1([NH:45][C:46](=[O:62])[C:47]2[CH:52]=[CH:51][CH:50]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)[CH2:44][CH2:43]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[CH2:18]([N:13]([C:12]1[C:7]([C:51]2[CH:50]=[CH:49][CH:48]=[C:47]([C:46](=[O:62])[NH:45][C:42]3([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)[CH2:43][CH2:44]3)[CH:52]=2)=[CH:8][C:9]2[N:10]([N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]=2[C:23]([NH:24][CH3:25])=[O:26])[CH:11]=1)[S:14]([CH3:17])(=[O:15])=[O:16])[CH3:19]
Reactant: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1OS(=O)(=O)C(F)(F)F)S(C)(=O)=O
Reactant: CC1(C)OB(c2cccc(C(=O)NC3(c4ccccn4)CC3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)NC2(c3ccccn3)CC2)c1)S(C)(=O)=O

Procedure:
6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl trifluoromethanesulfonate (0.1 g, 0.17 mmol, 1 eq), N-(1-(pyridin-2-yl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.0.65 g, 0.18 mmol, 1.1 eq), tetrakistriphenylphosphine palladium (0.0058 g, 0.0051 mmol, 0.03 eq) and cesium carbonate (0.165 g, 0.51 mmol, 3 eq) were dissolved in 1,4-dioxane (10 ml) and water (2 ml) and the reaction was heated at 90° C. for 14 hours. The solution was filtered through celiete. Water was added to the filtrate which was then extracted with ethyl acetate. The organic layer was concentrated and the residue obtained purified by Preparative HPLC. Yield: 22 mg (26%) 1HNMR (400 MHz, CD3OD): δ 1.05 (t, J=8 Hz, 3H), 1.65-1.66 (m, 2H), 1.78-1.82 (m, 2H), 2.89 (s, 3H), 3.20 (s, 3H), 3.62 (br s, 2H), 7.28-7.30 (t, J=7.76 Hz, 2H), 7.57 (br s, 1H), 7.67 (t, J=7.72 Hz, 1H), 7.75 (d, J=8.20 Hz, 1H), 7.86-7.88 (m, 3H), 7.96 (s, 1H), 8.02 (d, J=2.09 Hz, 1H), 8.18 (br, 1H), 8.23 (s, 1H), 8.55 (d, J=5.32 Hz, 1H), 8.98 (s, 1H). LCMS: (ES+) m/z=627.2 (M+H); Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm); Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH; Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH; Flow: 1 mL/Min; RT min: 1.768;
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:9]([O:11][CH3:12])=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1)=[CH2:2]>[Pd].C(O)C>[CH2:1]([C:3]1[C:4]([C:9]([O:11][CH3:12])=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1cccnc1C(=O)OC
Agent: [Pd]
Solvent: CCO
Product: CCc1cccnc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Palladium on carbon (10%, 25 mg) was added to a solution of methyl 3-vinylpicolinate (120 mg, 0.74 mmol) in ethanol (10 mL). The suspension was stirred at room temperature under an atmosphere of hydrogen for 1 h before it was filtered through CELITE® and the pad of CELITE® was washed with methanol. The filtrate was concentrated down to dryness to yield methyl 3-ethylpicolinate (i.e., Cap-175, step b) which was taken directly into the next reaction. Rt=1.15 min (Cond.-MD1); LC/MS: Anal. Calcd. for [M+H]+ C9H12NO2: 166.09; found: 166.09.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH4+].[OH-]>CO.C1COCC1.[Ni]>[NH2:20][CH2:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH2:5][CH2:6]3)[S:11][C:12]=2[CH:18]=1
Reactant: N#Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carbonitrile (1 g, 3.52 mmol) in MeOH-THF (120 mL, 5:3) was added NH4OH (15 mL) and Raney Ni (200 mg). The mixture was stirred for 12 h at rt under 50 psi H2 atmosphere. After filtration, the mixture was concentrated to give 6-aminomethyl-2-(4-cyclopropylpiperazin-1-yl)benzothiazole (500 mg, 49.3%), which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:32]=1[C:33]([NH:35][CH3:36])=[O:34].C(O)(C(F)(F)F)=O>>[F:41][C:38]1[CH:39]=[CH:40][C:31]([NH:30][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=3[O:28][CH3:29])[N:3]=2)=[C:32]([C:33](=[O:34])[NH:35][CH3:36])[CH:37]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1cc(F)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 33 %

Procedure:
A solution of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (50.0 mg, 0.110 mmol) and 2-amino-5-fluoro-N-methylbenzamide (Compound 102A, 22.24 mg, 0.1322 mmol) in TFE (1.00 mL) was charged with TFA (37.7 mg, 0.330 mmol). The reaction mixture was irradiated on the microwave at 105° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to yield a yellow oil. The material was purified by silica gel chromatography on an ISCO Combi-flash Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid, 21.4 mg (33% yield). The material still contained impurities, therefore was submitted for mass directed purification. The fractions containing product were combined and dried on the freeze dryer to yield a white solid, 10.9 mg (17% yield). 1H NMR (DMSO-d6, 400 MHz): δ=1.19 (t, J=7.07 Hz, 6 H), 2.76 (d, J=4.55 Hz, 3 H), 3.21-3.28 (m, 2 H), 3.76 (s, 3 H), 3.92-4.04 (m, 4 H), 6.84 (d, J=6.57 Hz, 1 H), 7.01 (br. s., 1 H), 7.24 (br. s., 1 H), 7.38-7.65 (m, 2 H), 8.24-8.55 (m, 2 H), 8.79 (br. s., 2 H), 11.25 (br. s., 1 H). MS (ES+): m/z 586.19 [MH+] (TOF, polar).
Reaction SMILES: [Na].[C:2](OCC)(=O)CC(OCC)=O.Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>>[CH3:2][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Na]
Product: Cc1ncccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Add sodium metal (3.5 g) portion-wise over 1 hour to a 3 neck flask containing 79 mL of diethyl malonate heated to 90° C. under nitrogen. Lower the temperature to 60° C. and add 2-chloro-3-nitropyridine (1a-1, 25.0 g) portion-wise over 15 min. The reaction color turns to dark red. Keep the solution for 3 h at 60° C. and then allow to stand at rt overnight. Tlc indicates remaining starting material. Heat the solution to 80° C. for an additional 3 h (completion of the reaction). Remove the diethyl malonate under reduced pressure and take-up the dark brown residue in a mixture of conc. H2SO4 (18 mL) and H2O (32 mL). Heat the mixture for 7 h at 105° C. (decarboxylation) and then allow to stand at rt overnight. Wash the mixture with 3×150 mL of Et2O and 2×200 mL of EtOAc, and discard the washings. Basify the aqueous phase to pH 8-9 with NaOH and extract with 3×200 mL EtOAc. Filter the combined organic extracts over Celite® (diatomaceous earth) (Celite Corporation, 137 West Central Avenue, Lompor, Calif. 93436) and remove the solvent under reduced pressure. The residue crystallizes to give 2a-1 (15.0 g, 68%), mp 29-31° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[O:21])[CH:14]=2)[C:9]2[N:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1)([OH:3])=O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>O1CCOCC1.C(OCC)(=O)C>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[NH:19][C:15]1[CH:14]=[C:13]([N:10]2[C:11](=[O:12])[C:6]([CH2:5][CH2:4][C:1]([N:60]3[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]3)=[O:3])=[N:7][C:8]3[CH:34]=[CH:33][CH:32]=[N:31][C:9]2=3)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)O)nc3cccnc32)c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)N3CCN(C)CC3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of 2-(2-carboxyethyl)-3-oxo-4-(3-[3-(2-methoxyphenyl)ureido]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine (115 mg) and 1-hydroxybenzotriazole (40 mg) in dry dioxane (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (47 mg) and N-methylpiperazine (30 mg). The mixture was stirred at room temperature for 4 hours, diluted with ethyl acetate, washed with water. After evaporation of the solvents, crude residue was crystallized from ethanol to give 4-[3-[3-(2-methoxyphenyl)ureido]phenyl]-2-[2-(4-methylpiperazin-1-yl)carbonylethyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH3:13])([O-:12])=[O:11].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
A mixture of 4-bromobenzaldehyde (16.8 g, 91 mmol), nitromethane (24.6 mL, 455 mmol), ammonium acetate (14 g, 182 mmol), and acetic acid (160 mL) was stirred for 4 hours at 100° C. This mixture was cooled to room temperature and poured into water. The precipitate thus produced was collected, washed with water, and dried under a reduced pressure to obtain the title compound (17.4 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)C.[F:9][C:10]([F:14])([F:13])[S:11]Cl>ClCCl>[F:9][C:10]([F:14])([F:13])[S:11][C:2]([CH3:4])([CH3:3])[CH:1]=[O:5]
Reactant: FC(F)(F)SCl
Reactant: CC(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C=O)SC(F)(F)F
Temperature: -78 °C

Procedure:
A mixture of isobutyraldehyde (0.25 mole), ethanol (0.4 g) and dichloromethane (75 ml) was placed in a three-necked flask fitted with a gas inlet tube, a Dry Ice condenser and a gas outlet tube connected to a gas trap cooled to -78°C. Trifluoromethanesulfenyl chloride (0.22 mole) was added to the cold solution which was maintained under a nitrogen atmosphere. (Caution: It should be noted that trifluoromethanesulfenyl chloride is a highly hazardous material which must be handled with care to avoid inhalation or contact with the skin.) The reaction mixture was then allowed to warm to about 25°C and stirred magnetically until the orange colored solution had become nearly colorless (about 6 hours). The reaction mixture was then distilled. The distillation assembly was connected to a -78°C gas trap to trap any unreacted trifluoromethylsulfenyl chloride. The 2-trifluoromethylthio-2-methylpropionaldehyde, b.p. 108°-116°C was identified by spectral and elemental analyses of a purified sample, b.p. 116°C.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.N1C=CC=CC=1.[C:15]([C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[F:23])#[N:16].Cl>ClCCl>[Cl:8][C:5]1[S:4][C:3]([NH:2][S:24]([C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([C:15]#[N:16])[CH:18]=2)(=[O:25])=[O:26])=[N:7][CH:6]=1
Reactant: Nc1ncc(Cl)s1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of 2-amino-5-chlorothiazole-hydrochloride (3.76 g, 22.0 mmol) in dichloromethane (20 ml) was added pyridine (8.09 ml, 100 mmol). 3-cyano-4-fluorobenzenesulfonyl chloride (4.39 g, 20 mmol) dissolved in dichloromethane (5 mL) and was added to the reaction mixture dropwise at room temperature. After stirring for 48 hours at room temperature, 1 N HCl (100 mL) was poured into the reaction and the mixture was extracted with dichloromethane/methanol (v/v=95/5, 100 ml) three times. The collected organic layer was evaporated in vacuo and dried over MgSO4 to obtain the crude residue. The crude residue was washed with dichloromethane (10 mL) and filtered to afford pale yellow solid as the title compound. LCMS Rt=1.39 minutes MS m/z 318 [M35ClH]+, 320 [M37ClH]+ 1HNMR (d6-DMSO): δ 7.59 (s, 1H), 7.66-7.73 (m, 1H), 8.15-8.21 (m, 1H), 8.33-8.37 (m, 1H).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[O:14]=[CH:15][CH2:16][C@H:17]1[O:22][CH2:21][O:20][C@@H:19]([CH2:23][C:24]#[N:25])[CH2:18]1.C(OCC)C>CC(C)=O>[C:24]([CH2:23][C@H:19]1[O:20][CH2:21][O:22][C@@H:17]([CH2:16][C:15]([OH:3])=[O:14])[CH2:18]1)#[N:25]
Reactant: CC(C)=O
Reactant: N#CC[C@H]1C[C@@H](CC=O)OCO1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: N#CC[C@@H]1C[C@H](CC(=O)O)OCO1
Reaction time: 0.25 h

Procedure:
Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 mL (97.6 mmol), is added dropwise to a 0° C. solution of (±)-cis-6-(2-oxoethyl)-1,3-dioxane-4-acetonitrile, 1.29 g of (7.6 mmol), dissolved in 50 mL of acetone until the orange color is not discharged. After stirring a further 15 minutes, the mixture is poured into 300 mL of diethyl ether and washed with brine until the aqueous washes are colorless. The diethyl ether layer is dried (magnesium sulfate), filtered, and concentrated to provide 1.2 g of (±)-cis-6-(cyanomethyl)-1,3-dioxane-4-acetic acid as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH2:20][C:17]2[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:28])[N:22]([CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1
Yield: 65.5 %

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.35 g, 0.926 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.19 g, 1.02 mmol) gave 4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester as a white solid (0.333 g, 60%). The material is used directly in the next step. MS (ESI) m/z 549.3 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([N+:9]#[C-:10])[CH2:7][CH3:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][CH2:23]Cl)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[CH2:7]([C:6]([N+:9]#[C-:10])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:23][CH2:22][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=1)[CH3:8]
Reactant: [C-]#[N+]C(CC)c1cccs1
Reactant: COc1ccc(CCCCl)cc1OC
Product: [C-]#[N+]C(CC)(CCCc1ccc(OC)c(OC)c1)c1cccs1
Yield: 68.3 %

Procedure:
4.84 g of 1-(2-thienyl)propyl isocyanide and 6.87 g of 3-(3,4-dimethoxyphenyl)propyl chloride are treated in the same manner as described in Example 1-(1) to give 7.2 g of 1-ethyl-4-(3,4-dimethoxyphenyl)-1-(2-thienyl)butyl isocyanide as a colorless oil. Yield; 68.3%
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2].[NH2:20][NH:21][C:22]([NH2:24])=S>C(O)C>[CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:22]([NH2:24])=[N:21][N:20]=3)[N:14]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: NNC(N)=S
Solvent: CCO
Product: CCN(C(C)=O)c1cccc(-c2ccc3nnc(N)n3n2)c1

Procedure:
A solution of 2.0 g of N-ethyl-N-[3-(6-chloro-3pyridazinyl)phenyl]acetamide and 1.32 g of thiosemicarbazide in 100 ml of ethanol was refluxed for 8 hours, then evaporated in vacuo. To the residue was added 100 ml of glacial acetic acid. This mixture was refluxed overnight, then the solvent was removed in vacuo, 150 ml of water added and aqueous sodium bicarbonate added to neutralize the solution. This mixture was extracted with dichloromethane:methanol (9:1). The extracts were dried and evaporated. The residue was chromatographed on a silica gel column eluting with dichloromethane:methanol (9:1). The fractions containing product were combined and evaporated.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:17]C(=O)C)[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1>C(O)C.Cl>[NH2:17][C:4]1[S:5][C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(C(C)(C)C)c2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccnc(C(C)(C)C)c1

Procedure:
N-[4-methyl-5-(2-tert-butyl-4-pyridyl)-1,3-thiazol-2-yl]acetamide (90 mg) in ethanol (4.5 ml) and 6N hydrochloric acid (0.5 ml) is heated in a Emrys Optimiser personal chemistry microwave at 100° C. for 90 minutes. Cooling of the reaction mixture and filtration gives the title compound.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]([F:22])([F:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([CH2:19]O)[CH:16]=[N:15]2)=[CH:10][CH:9]=1>CCOCC>[Br:2][CH2:19][C:17]1[CH:16]=[N:15][N:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]([F:22])([F:21])[F:5])=[CH:9][CH:10]=2)[CH:18]=1
Reactant: BrP(Br)Br
Reactant: OCc1cnn(-c2ccc(OC(F)(F)F)cc2)c1
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc(-n2cc(CBr)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
PBr3 (76 μL, 0.81 mmol) was added to a solution of alcohol 117 (0.210 g, 0.813 mmol) in ether (10 mL) at 0° C. The mixture was stirred at room temperature for 2 h, then cooled to 0° C., quenched with ice, and partitioned between Et2O and water. Column chromatography of the organic portion on silica gel (eluting with CH2Cl2) gave 4-(bromomethyl)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole (118) (0.212 g, 81%) as a white solid: mp 50-51° C.; 1H NMR (CDCl3) δ 7.94 (d, J=0.5 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J=9.1 Hz, 2H), 7.31 (d, J=9.1 Hz, 2H), 4.50 (s, 2H). APCI MS m/z 321, 323 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][N:11]([Si](C(C)C)(C(C)C)C(C)C)[C:8]=3[N:9]=[CH:10][C:5]2=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[N:3]=1.C1C(=O)N([Br:41])C(=O)C1>C(Cl)Cl>[Br:41][C:12]1[NH:11][C:8]2[N:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][C:4]=3[C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[C:7]=2[CH:13]=1
Reactant: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)n12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3[nH]c(Br)cc3n12
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
To a solution of 2-(4-(1-methyl-6-(triisopropylsilyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.755 g, 1.63 mmol, Preparation #AX.1) in DCM (16.3 ml) at about −20° C. was added NBS (0.462 g, 2.59 mmol). The resulting suspension was allowed to stir at about −20° C. for about 15 min. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (40 g silica gel column; gradient elution with 0 to 50% EtOAc/heptane) to give 2-(4-(7-bromo-1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.11 g, 18%). LC/MS (Table 2, Method a) Rt=2.41 min; MS m/z 385 (M+H)+. Syk IC50=B.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([SH:17])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br>C(O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][S:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Sc1nnc(-c2ccccc2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Clc1cccc(CSc2nnc(-c3ccccc3)c3ccccc23)c1
Reaction time: 0.17 h
Yield: 11 %

Procedure:
To a suspension of 4-phenylphthalazine-1-thiol (1 mmol; from Example 1B) in ethanol (20 ml) is added aqueous KOH (1 molar;1 ml), and the mixture is stirred for 10 minutes to give a clear solution. 3-Chlorobenzylbromide (0.13 ml, 1 mmol) is added at room temperature, and the solution is stirred overnight. Work-up yields the title compound as a white solid (40 mg).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=2[CH3:24])[CH:9]=1.[CH:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[C:28](B(O)O)=[CH:27][CH:26]=1>>[CH:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[C:28]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[CH3:24])[CH:9]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(-c2cccc3c2oc2ccccc23)ncn1
Temperature: 80 °C

Procedure:
An aqueous Na2CO3-solution (11.0 g, 104 mmol carbonate in 104 mL of water) is stirred with (6-chloropyrimidin-4-yl)-(2-methyl-5-nitro-phenyl)-amine (compound C3) (2.80 g, 10.6 mmol), 4-dibenzofuranboronic acid (3.36 g, 15.9 mmol) and bistriphenylphosphinpalladiumdichloride (0.74 g, 1.1 mmol) in ethylenglycoledimethylether (168 mL). The mixture is heated to 80° C. After 1 h the mixture is cooled and filtered. The product is purified by flash silica gel chromatography.