Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CCBr)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2CCc2ccc(F)cc2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(2-bromoethyl)-4-fluorobenzene. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.46 (d, J=1.6 Hz, 1 H), 7.18-7.07 (m, 3 H), 6.99-6.89 (m, 4 H), 6.31 (dd, J=3.5, 7.6 Hz, 1 H), 5.52 (d, J=6.0 Hz, 1 H), 4.82-4.73 (m, 1 H), 4.68-4.58 (m, 1 H), 4.30 (t, J=5.1 Hz, 2 H), 3.16 (tq, J=7.0, 14.3 Hz, 2 H), 2.94-2.77 (m, 5 H), 2.15-2.04 (m, 2 H), 0.99-0.89 (s, 9 H); LC/MS (m/z) ES+=517.4 (M+1).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+].CCCCCC.CCOCC>O1CCCC1>[C:9]1([S:15]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C#CC(O)(CF)CF
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(CF)(CF)OS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol and benzenesulfonyl chloride (1.8 g) were dissolved in tetrahydrofuran (10 ml); to the solution under cooling with ice, 60% oily sodium hydride (0.48 g) was added in a nitrogen atmosphere. After the end of the addition, the mixture was stirred for 4 hours while its temperature was raised to room temperature. A hexane/ether mixed solvent (1/1) was added to the reaction mixture, which was then washed with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane/methylene chloride=1/1) to give the titled compound (2.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)cc1

Procedure:
51.1 mg of pale yellow solid 3-{4-[3-(4-methoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-methoxyphenyl isocyanate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([N+:16]([O-])=O)[C:10]=1[NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C.O.NN>CO.[Fe](Cl)(Cl)Cl>[NH2:16][C:11]1[CH:12]=[C:13]([Br:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)C(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)C(=O)Nc1c(N)cc(Br)cc1OCc1ccccc1
Temperature: 70 °C
Yield: 55.7 %

Procedure:
A suspension of 25.2 g (64.3 mmol) N-(2benzyloxy-4-bromo-6-nitro-phenyl)-isobutyramide, 6.3 g (38.5 mmol) iron(III) chloride and 15.7 g activated charcoal in 600 ml methanol was heated to 70° C. 31.3 ml (643 mmol). Hydrazine hydrate were added dropwise and the reaction mixture was refluxed for 90 min. After cooling to room temperature the reaction was filtered through celite, the filter cake washed with dichloromethane/methanol and the filtrate concentrated in vacuo. The residue was dried in vacuo at 40° C. to afford 13.0 g (56%) of the title compound as a white solid. m.p. 214°-215° C.
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13]CCN(C)C)[N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC.Br[C:34]1[N:39]=[C:38]2[C:40]([C:43]([NH:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[CH:41][NH:42][C:37]2=[N:36][CH:35]=1>CN(C=O)C.[Cu]I.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>[F:32][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:34]1[N:39]=[C:38]2[C:40]([C:43]([NH:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[CH:41][NH:42][C:37]2=[N:36][CH:35]=1
Reactant: CC(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CCCN(C)C)c2ccc(OC(F)F)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(OC(F)F)cc34)nc12
Temperature: 80 °C
Reaction time: 0.15 h
Yield: 9 %

Procedure:
To a solution of 3-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (200 mg, 0.36 mmol) and 2-bromo-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (180 mg, 0.43 mmol) in DMF (10 mL) were added CuI (18 mg, 0.08 mmol) and Pd(PPh3)4 (14 mg, 0.014 mmol), Then the reaction mixture was degassed by bubbling nitrogen for 3 minutes and refilled with nitrogen. The mixture was heated to 80° C. for 5 hours under nitrogen, after cooling to room temperature, water (50 mL) was added and product extracted with EtOAc (3×40 mL), the combined organic layers were dried over Na2SO4, concentrated under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide as yellow solid (13 mg, 9%). LCMS: (M+H)+=472; 1H NMR (300 MHz, CD3OD): δ 9.11 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.69 (d, 1H, J=9.0 Hz), 7.38 (d, 1H, J=8.7 Hz), 6.85 (t, 1H, J=74.1 Hz), 4.85-4.78 (m, 2H), 4.65-4.60 (m, 1H), 3.34-3.32 (m, 2H), 2.89 (s, 6H), 2.50-2.40 (m, 2H), 1.43 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[Cl:25][C:26]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][C:27]=1[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:25][C:26]1[CH:40]=[C:39]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:22]5[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=5)[N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:7]=2)[CH:38]=[CH:37][C:27]=1[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35]
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(CNC(=O)OC(C)(C)C)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (200 mg, 585 μmol), tert-butyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (323 mg, 878 μmol), dichloro[1,1 bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (86 mg, 117 μmol), cesium carbonate (763 mg, 2341 μmol) in dioxane (3 mL) and water (0.3 mL) was sparged with argon for 10 min then heated to 100° C. for 18 h. Reaction then partitioned between 9:1 CHCl3/IPA (50 mL) and 5% NaHCO3 (25 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×10 mL). Combined organics then dried over MgSO4, concentrated, and purified on silica (40 g) eluting with 0>6% 2M NH3 in MeOH/DCM. Product isolated as an off white solid. 84024-19-2 MS (ESI pos. ion) m/z: 547 (MH+). Calc'd exact mass for C28H27ClN6O4: 546.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl>[Si:27]([O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=1[C:14]([F:15])([F:16])[F:17])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(CO)Cc1ccc(N)cc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.7 %

Procedure:
To a mixture of 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol (300 mg, 1.213 mmol) in DCM (150 mL) was added imidazole (124 mg, 1.820 mmol) and TBSCl (219 mg, 1.456 mmol). Then the mixture was stirred at 25° C. for 5 h. The mixture was filtered and the filtrate was concentrated. The crude material was purified by preparative TLC (PE/EA=2:1, Rf=0.5) to yield a light yellow solid of 4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline (350 mg, 0.930 mmol, 77% yield): 1H NMR (400 MHz, CDCl3) δ: 7.14 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 6.70 (dd, J=2.8, 8.4 Hz, 1H), 3.20 (s, 2H), 2.62 (d, J=1.2 Hz, 2H), 0.87 (s, 9H), 0.73 (s, 6H), 0.00 (s, 6H); ES-LCMS m/z 362 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[NH2:12][CH2:13][C:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:25][C:19]1[CH:18]=[C:17]2[C:22]([C:23](=[O:24])[C:14]([CH2:13][NH:12][C:5](=[O:6])[C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=3)=[CH:15][N:16]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
A 10 mL round bottom flask was charged with 3,5-difluorobenzoyl chloride (78.0 mg, 0.442 mmol) and anhydrous methylene chloride (5 mL) and was treated with 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (49.8 mg, 0.175 mmol), triethylamine (87.1 mg, 0.12 mL, 0.861 mmol), and catalytic N,N-(dimethylamino)pyridine (DMAP) (one spatula tip). The flask was capped with a glass stopper and the reaction stirred at room temperature over the weekend. The reaction was partitioned between methylene chloride (25 mL) and water (25 mL). The organic portions were dried over magnesium sulfate, filtered and rinsed with methylene chloride, concentrated on a rotary evaporator, and briefly dried on a vacuum pump. The material was then purified via Analogix Intelliflash 280 chromatography using a 12 g silica gel column and a 1%-5% MeOH/CH2Cl2 gradient elution. Two columns were required to isolate the desired product from the bis-acylation side product. Fractions containing the two products were separately combined and concentrated. The second product to elute was the desired product N-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3,5-difluoro-benzamide, isolated as an off-white solid (44 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (t, J=5.14 Hz, 1H) 8.27 (d, J=8.66 Hz, 1H) 8.03 (s, 1H) 7.38-7.73 (m, 9H) 6.90 (d, J=1.81 Hz, 1H) 4.37 (d, J=5.24 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10]C(C)(O)C)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[K+].O>C1(C)C=CC=CC=1.CCOCC>[C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH:3]=1)[NH2:1])#[CH:10]
Reactant: Cc1ccc(C#CC(C)(C)O)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C#Cc1ccc(C)c(N)c1
Temperature: 25 °C

Procedure:
A solution of 4-(3-amino-4-methylphenyl)-2-methylbut-3-yn-2-ol (509 mg, 2.7 mmol) in toluene (2 mL) was treated with potassium hydroxide (1.0 g, 18 mmol) at reflux for 20 min. After cooling to rt, water and ether were added, and the layers were partitioned. The organic phase was acidified with 4 N hydrochloric acid in dioxane (700 μL). The volatile materials were removed in vacuo providing a yellow/brown solid. The solid was taken up in ether and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated carefully to avoid loss of the moderately volatile product. Desired 5-ethynyl-2-methylaniline was isolated as an oil in quantitative yield, contaminated with 10% ether by mass. 1H NMR (400 MHz, CDCl3): 6.99 (d, 1H), 6.85 (dd, 1H), 6.81 (d, 1H), 3.61 (br s, 2H), 2.98 (s, 1H), 2.16 (s, 3H); GCMS for C9H9N: 131 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=2[N:9]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)#[CH:25]>>[CH:14]1([CH2:13][N:12]2[C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=3[N:9]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:25]#[C:24][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Brc1ccccc1-c1nc2ccccc2n1CC1CCCCC1
Product: COc1ccc(C#Cc2ccccc2-c2nc3ccccc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 72, intermediate a, from 2-(2-bromo-phenyl)-1-cyclohexylmethyl-1H-benzoimidazole and 1-ethynyl-4-methoxy-benzene (CAS Reg. No. 768-60-5). Yellow sticky solid (24%). MS (Turbo Spray): m/z=421.4 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=1.N>C(O)C>[F:25][C:17]1[CH:16]=[C:15]([NH:14][C:2]2[N:7]3[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]3[N:5]=[C:4]([CH3:13])[CH:3]=2)[CH:20]=[CH:19][C:18]=1[C:21]([F:23])([F:24])[F:22]
Reactant: CSc1nc2nc(C)cc(Cl)n2n1
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Agent: N
Solvent: CCO
Product: CSc1nc2nc(C)cc(Nc3ccc(C(F)(F)F)c(F)c3)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 7-chloro-5-methyl-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine (Intermediate 8 (0.3 g, 1.397 mmol)) in ethanol (5 mL), 4-amino-2-fluorobenzotrifluoride (ALFAAESAR, 0.25 g, 1.397 mmol) was added and the mixture was stirred at room temperature for 2 h. Anhydrous ammonia (0.2 mL, 1.397 mmol) was added and solvent was removed in vacuo. The residue was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures form 95:5 to 40:60%) to yield the title compound as a white solid.
Reaction SMILES: C(OC([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>CCO.O>[C:19]1([N:16]2[C:12]3[C:13]4[CH2:14][CH2:15][NH:6][CH2:7][CH2:8][C:9]=4[S:10][C:11]=3[CH:18]=[CH:17]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)N1CCc2sc3ccn(-c4ccccc4)c3c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(-n2ccc3sc4c(c32)CCNCC4)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of the product from step (a) (0.066 g, 0.19 mmol) in EtOH (2 ml) was added 40% aqueous KOH (2 ml). The reaction mixture was heated to 100° C. until LCMS that the reaction was complete (usually 16-32 hours). The reaction mixture was cooled to RT, diluted with water (30 ml), and extracted with DCM (3×). The combined DCM extracts were dried (MgSO4), filtered, and solvent evaporated in vacuo to give the crude product. Purification by preparative HPLC gave the title compound as a tan solid. 1HNMR (CD3)2CO™ 7.52-7.50 (m, 2H), 7.44-7.41 (m, 3H), 6.97 (d, J=3 Hz, 1H), 6.42 (d, J=3 Hz, 1H), 2.92-2.89 (m, 4H), 2.74-2.71 (m, 2H), 2.52-2.49 (m, 2H), 2.06-2.04 (m, 1H); MS: ESI (positive): 269 (M+H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[CH:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[CH2:24].C(=O)([O-])[O-].[Cs+].[Cs+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:25]1(/[CH:23]=[CH:24]/[C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: C=CC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(/C=C/C2CCCCC2)cc1Nc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.20 g were added vinylcyclohexane 0.15 mL, cesium carbonate 0.36 g, tetrabutylammonium bromide 53 mg and polymer-carried bis(acetato)triphenylphosphine palladium(II) 86 mg at room temperature, and it was stirred at 110° C. for 22 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 4-((E)-2-cyclohexylvinyl)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([C@@H:26]2[C@H:30]([CH2:31][CH3:32])[CH2:29][C@H:28]([NH:33][S:34]([CH:37]3[CH2:39][CH2:38]3)(=[O:36])=[O:35])[CH2:27]2)[N:7]2[C:12]3[CH:13]=[CH:14][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]=3[N:10]=[CH:9][C:8]=12)C=C.I([O-])(=O)(=O)=[O:41].[Na+].[BH4-].[Na+].Cl.[OH-].[Na+]>O1CCOCC1.O.CCOC(C)=O.[NH4+].[Cl-].[Os](=O)(=O)(=O)=O>[CH2:31]([C@H:30]1[C@@H:26]([C:6]2[N:7]3[C:12]4[CH:13]=[CH:14][NH:15][C:11]=4[N:10]=[CH:9][C:8]3=[C:4]([CH2:1][OH:41])[N:5]=2)[CH2:27][C@@H:28]([NH:33][S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:35])=[O:36])[CH2:29]1)[CH3:32]
Reactant: C=CCc1nc([C@H]2C[C@@H](NS(=O)(=O)C3CC3)C[C@H]2CC)n2c1cnc1c2ccn1S(=O)(=O)c1ccc(C)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Agent: [BH4-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nc(CO)c2cnc3[nH]ccc3n12
Temperature: 80 °C
Reaction time: 48 h
Yield: 5.8 %

Procedure:
To a solution of N-((1S,3S,4R)-3-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.17 g, 0.299 mmol, prepared using H with Preparation #12, Preparation #Z.1, HATU and DIEA, and Q with Lawesson's reagent and mercury (II) trifluoroacetate) in 1,4-dioxane (5 mL) and water (1.7 mL) was added sodium periodate (0.26 g, 1.2 mmol) followed by osmium tetroxide (4 wt % in water, 0.117 mL, 0.015 mmol). After about 48 h at ambient temperature, the reaction mixture was diluted with water (about 50 mL) and EtOAc (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concd in vacuo. The crude aldehyde was dissolved in EtOH (10 mL) and NaBH4 (0.023 g, 0.599 mmol) was added to the reaction mixture. After about 2 h at ambient temperature, HCl (1 N aqueous, about 3 mL) was added. After stirring for about 30 min, the reaction mixture was concd in vacuo. The residue was partitioned between EtOAc (30 mL) and saturated aqueous NaHCO3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concd in vacuo. The crude alcohol was dissolved in 1,4-dioxane (10 mL) and NaOH (2 N aqueous, 1.5 mL, 2.99 mmol) was added. The reaction mixture was heated to about 80° C. After about 4 h, the reaction mixture was cooled to ambient temperature and diluted with EtOAc (30 mL) and saturated aqueous NH4Cl (30 mL). The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel eluting with 10-50% MeCN in DCM to provide N-((1S,3R,4S)-3-ethyl-4-(3-(hydroxymethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.007 g, 6%) as a yellow solid: LC/MS (Table 1, Method a) Rt=1.59 min; MS m/z: 404 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][OH:10].Cl[CH2:12][CH2:13][N:14]([CH2:25][CH2:26]Cl)S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH2:26][CH2:25][NH:14][CH2:13][CH2:12]2)=[C:3]([CH2:9][OH:10])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: Cc1ccc(N)c(CO)c1
Product: Cc1ccc(N2CCNCC2)c(CO)c1
Yield: 55.4 %

Procedure:
Using (2-amino-5-methylphenyl)methanol (1 g) and N,N-bis(2-chloroethyl)-p-toluenesulfonamide (2.1 g) and by the reaction and treatment in the same manner as in Preparation Example 95, the title compound (810 mg) was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS([O:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)(=O)=O.[OH:22][C:23]1[CH:32]=[C:31](O)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].[I-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.CN(C)C(=O)C>[OH:22][C:23]1[CH:32]=[C:31]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: CS(=O)(=O)OC1CCN(S(C)(=O)=O)CC1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC2CCN(S(C)(=O)=O)CC2)cc1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
Potassium carbonate (0.31 g) and 1-(methylsulfonyl)piperidin-4-yl methanesulfonate (0.46 g) were added to an N,N-dimethylacetamide (5 mL) solution of methyl 2,4-dihydroxybenzoate (0.25 g), followed by stirring at 90° C. for 1 hour. The reaction mixture was cooled to room temperature, and then sodium iodide (0.045 g) was added thereto, followed by stirring at 90° C. for 1 hour. The reaction mixture was cooled to room temperature, and then potassium carbonate (0.10 g) and 1-(methylsulfonyl)piperidin-4-yl methanesulfonate (0.12 g) were added thereto, followed by stirring at 90° C. for 1 hour. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a 10% aqueous solution of citric acid and saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-60% hexane/ethyl acetate] to obtain 0.19 g of methyl 2-hydroxy-4-((1-(methylsulfonyl)piperidin-4-yl)oxy)benzoate as a white solid.