Azzindani/Open_Reaction_Data huggingface dataset:
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.[OH-].[K+].[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[CH2:19]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][CH2:18][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cncnc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cncnc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g, 0.68 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.19 g, 3.4 mmol) and allowed to stir for 10 min at RT. 5-vinyl pyrimidine (0.177 g, 1.7 mmol) was added and stirred for further 5 h at 60 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.030 g, 14% yield). 8-Chloro-2-methyl-5-(2-pyrimidin-5-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.025 g, 0.076 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.0096 g, 0.076 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.025 g, 78% yield).
Reaction SMILES: [CH:1]1([NH:4][C@@H:5]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]2)[CH2:3][CH2:2]1.Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([N:4]([CH:1]2[CH2:2][CH2:3]2)[C@@H:5]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]2)=[N:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC2CC2)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N(c2ccc(C#N)cn2)C2CC2)C1

Procedure:
The title compound was prepared according to the procedures of Intermediate 2 (A) using (R)-tert-butyl 3-(cyclopropylamino)pyrrolidine-1-carboxylate and 6-bromonicotinonitrile under similar conditions MS (m/z): 329 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:27]O>>[CH3:27][O:14][C:13](=[O:15])[CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(NC(=O)OCc1ccccc1)C1CC(=O)NC1=O
Reaction time: 4 h

Procedure:
In 300 ml of methanol was suspended 10 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine and, under cooling at -20° C. or below, 10 g of thionyl chloride was added dropwise. The mixture was stirred at 0°-5° C. for 4 hours and then at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-acetone (4:1). The eluate was concentrated under reduced pressure and to the residue was added ethyl ether to give crystals. Yield 5.8 g.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH:21](Br)[CH3:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>CS(C)=O>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: CC(Br)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)C(C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.8 %

Procedure:
1.18 g of sodium hydride (60% and oily) was suspended in 20 ml of dimethyl sulfoxide, and 3.9 g of dimethyl malonate was added dropwise thereto under ice cooling. After the addition, the temperature of the reaction solution was elevated to room temperature, and 3.4 g of 1-(4-nitrophenyl)ethyl bromide synthesized in the above-mentioned section (1) was added thereto, followed by stirring at room temperature for 20 hours in an atmosphere which was shielded from light. The resulting reaction mixture was poured into 1N hydrochloric acid slowly, and the solution was then extracted twice with 50 ml of ether. Extracts were joined together, washed with water and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The solution was then evaporated to dryness, thereby obtaining 3.9 g of dimethyl 1-(4-nitrophenyl)ethylmalonate in an oily state.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][C:43]=4[CH3:44])[C:24]([NH:26][C:27]4([C:30]([NH:32][NH:33]C(OC(C)(C)C)=O)=[O:31])[CH2:29][CH2:28]4)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:26][C:27]5([C:30]([NH:32][NH2:33])=[O:31])[CH2:28][CH2:29]5)[CH:41]=[CH:42][C:43]=4[CH3:44])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=O)NNC(=O)OC(C)(C)C)CC4)ccc3C)cc12
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=O)NN)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 2-(1-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)cyclopropanecarbonyl)hydrazinecarboxylate (33.1 mg, 0.055 mmol) in a round-bottom flask at r.t. under N2 was added HCl (1 ml, 4.00 mmol, 4 M in 1,4-dioxane). The mixture was stirred at r.t. for four hours. The mixture was evaporated, and the crude hydrochloride salt used without further purification. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: PHENOMENEX® Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=501.06, HPLC Rt=1.483 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:23]=[CH:22][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[CH3:24].C(Cl)Cl.CO.[NH4+].[OH-]>C(Cl)Cl>[OH:5][C:6]1[C:23]([N+:1]([O-:4])=[O:2])=[CH:22][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[CH3:24]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(O)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(O)c([N+](=O)[O-])cc2c1CCN(C(=O)OC(C)(C)C)CC2
Yield: 67 %

Procedure:
Nitric acid (65%, 0.370 ml) was added dropwise with vigorous stirring to 1,1-dimethylethyl 7-hydroxy-6-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (600 mg) and silica gel (1.67 g) in DCM (5.7 ml) at −15° C. After 30 min a mixture of DCM/MeOH/conc.NH4OH: 10/3/1.5 was added and silica gel was filtered off. The solvent was evaporated under reduced pressure and the residue was purified on silica gel (ethyl acetate/petroleum ether: 15/85) obtaining the desired compound (470 mg, 67% yield).
Reaction SMILES: [F:1][C:2]1[C:36]([C:37]([F:40])([F:39])[F:38])=[N:35][CH:34]=[CH:33][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:15][C:14]([CH2:30][C:31]#[N:32])([N:16]3[CH:20]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:18]=[N:17]3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5].Cl[C:42]1[C:43]2[CH:50]=[CH:49][NH:48][C:44]=2[N:45]=[CH:46][N:47]=1.C(=O)(O)[O-].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[N:45]1[C:44]2[NH:48][CH:49]=[CH:50][C:43]=2[C:42]([C:19]2[CH:18]=[N:17][N:16]([C:14]3([CH2:30][C:31]#[N:32])[CH2:13][N:12]([CH:9]4[CH2:8][CH2:7][N:6]([C:4](=[O:5])[C:3]5[CH:33]=[CH:34][N:35]=[C:36]([C:37]([F:40])([F:38])[F:39])[C:2]=5[F:1])[CH2:11][CH2:10]4)[CH2:15]3)[CH:20]=2)=[N:47][CH:46]=1
Reactant: CC1(C)OB(c2cnn(C3(CC#N)CN(C4CCN(C(=O)c5ccnc(C(F)(F)F)c5F)CC4)C3)c2)OC1(C)C
Reactant: Clc1ncnc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3ccnc(C(F)(F)F)c3F)CC2)C1
Temperature: 85 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a 25-mL flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a magnetic stirrer were added 2-(1-(1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (11, 307 mg, 0.546 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4, 84.8 mg, 0.548 mmol, 1.0 equiv), sodium bicarbonate (NaHCO3, 229 mg, 2.72 mmol, 5.0 equiv), water (1.6 mL), and 1,4-dioxane (1.6 mL) at ambient temperature. The mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (12.8 mg, 0.011 mmol, 0.02 equiv) at ambient temperature and the resulting reaction mixture was de-gassed and refilled with nitrogen for 3 times before being heated to 85° C. The reaction mixture was stirred at 85° C. under nitrogen for overnight. When the reaction was complete as monitored by HPLC, the reaction mixture was concentrated to dryness under reduced pressure and the desired product, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base, 135 mg, 302.2 mg theoretical, 44.6%), was obtained as off-white solids by direct silica gel (SiO2) column chromatography (0-10% of ethyl acetate in hexane gradient elution) purification of the dried reaction mixture. The compound obtained by this synthetic approach is identical in every comparable aspect to the compound 8 manufactured by the synthetic method as described above in Example 1.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[C:17]1([CH2:27][C:28]([OH:30])=O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[N:12]1([C@@H:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@H:3]2[N:2]([CH3:1])[C:28](=[O:30])[CH2:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN(C(=O)Cc1cccc2ccccc12)[C@@H]1c2ccccc2C[C@H]1N1CCCC1

Procedure:
Using the procedure of Step C of Example 1, 0.432 g of the product of the product of Step B of Example 1, 0.484 g of 1-naphthylacetic acid and 0.422 g of carbonyldiimidazole were reacted to obtain 0.718 g of trans (+) N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-1-naphthalene-acetamide melting at 127° C. and then 0.655 g of the base were reacted to obtain 0.533 g of its hydrochloride melting at ≃240° C.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([CH2:10][F:11])([CH2:8][F:9])[CH:6]=[CH2:7])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[F:9][CH2:8][C:5]([CH2:10][F:11])([CH:6]=[CH2:7])[C:4]([OH:12])=[O:3]
Reactant: C=CC(CF)(CF)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(CF)(CF)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 140.2 %

Procedure:
To a solution of 2,2-bis-hydroxymethyl-but-3-enoic acid ethyl ester (338 mg, 1.9 mmol) and 2,6-lutidine (813 mg, 0.88 mL, 7.6 mmol) in dichloromethane (10 mL) at −78° C. under nitrogen was added dropwise trifluoromethanesulfonic anhydride (1.07 g, 0.66 mL, 3.8 mmol) and the reaction mixture was warmed to room temperature and stirred at room temperature for 30 min. The solution was washed with ice-cold hydrochloric acid (1 M) and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude 2,2-bis-trifluoromethanesulfonyloxymethyl-but-3-enoic acid ethyl ester (1.9 mmol) as an orange oil which was used immediately in the next step. A solution of 2,2-bis-trifluoromethanesulfonyloxymethyl-but-3-enoic acid ethyl ester (1.9 mmol) in tetrahydrofuran (5 mL) was stirred at 0° C. under nitrogen. Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran, 4.75 mL, 4.75 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. The solvent was evaporated. The residue was dissolved in dichloromethane and the solution was washed with saturated sodium hydrogen carbonate solution, water and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 19:1 to 4:1 to afford 2,2-bis-fluoromethyl-but-3-enoic acid ethyl ester (1.9 mmol) contaminated with solvent as a clear oil. A solution of crude 2,2-bis-fluoromethyl-but-3-enoic acid ethyl ester (1.9 mmol) in tetrahydrofuran (10 mL) was stirred at 0° C. under nitrogen. A solution of lithium hydroxide monohydrate (240 mg, 5.7 mmol) in water (2.5 mL) was added and the reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 24 h. The reaction mixture was acidified to pH 2 with hydrochloric acid (2 M). Water was added and the mixture was extracted with diethyl ether. The organic extracts were combined, washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford the title compound (400 mg) as a clear oil. 1H NMR (300 MHz, d6-DMSO) δ 4.54-4.83 (m, 4H), 5.33 (d, J=17.8 Hz, 1H), 5.36 (d, J=10.7 Hz, 1H), 5.81 (dd, J=17.8, 10.7 Hz, 1H), 13.0-13.5 (br s, 1H). LCMS (m/z) 149.2 [M−H], Tr=1.45 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][CH2:32][CH2:33]Br>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:31][CH2:32][CH3:33])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OCC1CC1
Temperature: 70 °C
Yield: 22.2 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.740 mmol) and n-propyl bromide (91 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 22%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:29]([CH2:30][CH3:31])=[CH:28][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])=[CH:14][N:13](C4CCCCO4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[C:29]([CH2:30][CH3:31])=[CH:28][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH:16][C:17]([CH:19]4[CH2:20][CH2:21]4)=[O:18])=[CH:14][NH:13][N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3NC(=O)C3CC3)[nH]c2cc1CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc2nc(-c3n[nH]cc3NC(=O)C3CC3)[nH]c2cc1CC
Yield: 49.9 %

Procedure:
A solution of cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide [0.3 g, Reference Example 48(a)] and p-toluenesulfonic acid hydrate (1.2 g) in ethanol (25 mL) was heated in an 80° C. in an oil bath for 1 hour, then cooled, and then poured into aqueous sodium bicarbonate solution. The aqueous mixture was extracted twice with ethyl acetate (75 mL). The combined extracts were evaporated and the residue was redissolved in a mixture of methylene chloride (100 mL) and methanol (10 mL). This solution was washed with aqueous sodium bicarbonate, to remove some residual p-toluenesulfonic acid, then evaporated to give cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide (120 mg) as a white solid. LC-MS (Method E): RT=2.36 minutes, 340 (M+H)+. (b) 3-(1,5,6,7-Tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-ylamine
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.C(=S)=S>O>[CH2:6]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[C:17]=1[C:22]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:31])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(Cc2cc3ccccc3o2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: S=C=S
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)oc3ccccc23)cc1
Yield: 84.2 %

Procedure:
Tin tetrachloride (6.5 mL, 55.5 mmol) was added dropwise over a 30 minute period to a stirred solution of 2-benzyl-benzofuran (10.0 g, 48.01 mmol), anisoyl chloride (8.51 g, 49.93 mmol) and carbon disulfide (53 mL) at room temperature under a dry nitrogen atmosphere. After 15 h the reaction mixture was added to water and extracted with dichloromethane. Silica gel was added to the dichloromethane phase and the solvent was removed. The adsorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate as eluent) to provide the title compond as a white solid (13.84 g, 84%): mp 84-85° C.: NMR (CDCl3); δ7.87 (dm, J=9 Hz, 2 H), 7.46 (dm, 1 H), 7.36-7.12 (m, 8 H), 6.97 (dm, J=9 Hz, 2 H), 4.29 (s, 2 H), 3.90 (s, 3 H): MS (EI):
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:30](Br)[CH:31]([CH3:33])[CH3:32]>C(OCC)(=O)C>[CH2:30]([O:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=1)[CH:31]([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1cc(O)n(-c2ccccc2C)n1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(C)C)n(-c2ccccc2C)n1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a mixture of ethyl 5-hydroxy-1-(2-methylphenyl)-1H-pyrazole-3-carboxylate (1.0 g, 4.06 mmol), potassium carbonate (0.84 g, 6.09 mmol) and N,N-dimethylformamide (10 mL) was added isobutyl bromide (0.49 mL, 4.47 mmol) under stirring at room temperature, and the mixture was stirred at the same temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and 5% aqueous potassium hydrogensulfate solution, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-4/1) to give the title compound (1.07 g, yield 87%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH:21]=O)=[CH:15][N:14]=1)(=[O:11])=[O:10].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH2:21][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:15][N:14]=1)(=[O:10])=[O:11]
Reactant: C1COCCN1
Reactant: COc1nc(C=O)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Product: COc1nc(CN2CCOCC2)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared as for Example 107b using 2,3-dichloro-N-(5-formyl-3-methoxy-2-pyrazinyl)benzenesulphonamide (Example 186a) (0.26 g) and morpholine (3.7 mL). Yield 0.057 g.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7]=2[NH:6][CH:5]=1.F[C:17]1[C:26]([F:27])=[C:25]2[C:20]([C:21]([NH2:28])=[N:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>CN(C=O)C>[NH2:28][C:21]1[C:20]2[C:25](=[C:26]([F:27])[C:17]([N:6]3[C:7]4[CH2:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11](=[O:13])[C:12]=4[C:4]([CH3:3])=[CH:5]3)=[CH:18][CH:19]=2)[N:24]=[CH:23][N:22]=1
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: Nc1ncnc2c(F)c(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc3c(N)ncnc3c2F)c2c1C(=O)CC(C)(C)C2
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% suspension in mineral oil, 50 mg, 1.3 mmol) is added to a solution of 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (50 mg, 0.29 mmol) in anhydrous DMF (1 mL). This mixture is stirred at room temperature for 5 minutes before 7,8-Difluoro-quinazolin-4-ylamine (75 mg, 0.41 mmol) is added. After 10 minutes at room temperature, the reaction mixture is heated at 50° C. overnight. The cooled reaction mixture is partitioned between ethyl acetate and water to remove DMF, and the organic layer is concentrated to dryness via Rotovap. The resulting crude residue is further purified through two consecutive silica gel columns (0%-8% of methanol in DCM, gradient) to afford 1-(4-Amino-8-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (15 mg, not optimized) as white solid. LC/MS m/z=339 [M+H]+.