Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NCC)C.[CH2:6]([OH:9])[C:7]#[CH:8].I[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>O1CCCC1.O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]#[C:7][CH2:6][OH:9])=[CH:12][CH:13]=1
Reactant: C#CCO
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCNCC
Solvent: O
Product: COc1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
Diethylamine (80 mL, propargyl alcohol (6.4 mL, 0.11 mol), copper(I)iodide (0.7 g), tetrahydrofuran (25 mL), and tetrakis(triphenylphosphine)palladium(o) (1.2 g) were placed in a 250-mL flask under nitrogen. A solution of p-iodoanisole (23.4 g, 0.1 mol) in 40 mL of tetrahydrofuran was added to the reaction dropwise over 30 minutes. The reaction was stirred for 16 hours at room temperature, then evaporated in vacuo to give a dark brown residue. The residue was dissolved in 200 mL of water and extracted four times with diethyl ether (200 mL). The combined extracts were dried over anhydrous sodium sulfate and evaporated to give a dark brown solid that was purified by column chromatography (silica gel), eluting with 9:1 hexane-ethyl acetate to give 15.38 g of the title product.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[F-:17]>CC(C)=O>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][S:12]([F:17])(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CCCCOc1ccccc1
Reactant: [F-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=S(=O)(F)CCCCOc1ccccc1
Yield: 90.9 %

Procedure:
4-Phenoxybutylsulfonyl fluoride (17) was synthesized as in 13.1 using 16 (0.4 g, 1.6 mmol) and NH4F (0.118 g, 3.2 mmol) in dry acetone (20 mL). Purification by flash column chromatography on silica gel gave 17 (0.338 g, 91% yield) as a white solid (m p 74-76° C.) 1H NMR (500 MHz, CDCl3) δ 7.29 (t, J=7.5 Hz, 2H), 6.97 (t, J=7.5 Hz, 1H), 6.89 (d, J=7.5 Hz, 2H), 4.03 (t, J=5.5 Hz, 2H), 3.52-3.48 (m, 2H), 2.20 (quintet, J=7.7 Hz, 2H), 2.00 (quintet, J=8.0 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[F:23][C:24]([F:36])([F:35])[S:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C(#N)C.O.C(OCC)(=O)C>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([S:25][C:24]([F:36])([F:23])[F:35])=[CH:27][CH:28]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(SC(F)(F)F)cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccc(SC(F)(F)F)cc4)cc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
TEA was added to a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) and 4-(trifluoromethylthio)benzoyl chloride (0.75 g, 3.1 mmol) in acetonitrile (30 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (100 mL) and ethyl acetate (100 mL). The organic phase was separated and concentrated in vacuo. The residue was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting 1.2 g of the product at 60-70% ethyl acetate, in 76% yield as a white solid; mp 171-173° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.72 (97.94%); 1H NMR (DMSO-d6) δ 2.02-2.10 (m, 1H), 2.46-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4.66 (d, J=5.8 Hz, 2H), 5.15 (dd, J=12.8 Hz, J=5.3 Hz, 1H), 7.81-7.92 (m, 5H), 8.00-8.03 (m, 2H), 9.41 (t, J=5.8 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 42.7, 49.0, 122.0, 123.6, 126.4, 128.7, 129.5 (q, J=306 Hz), 129.9, 131.6, 133.5, 135.9, 136.5, 147.2, 165.5, 167.0, 167.1, 169.8, 172.7; Anal. Calcd for C22H16N3O5F3S: C, 53.77; H, 3.28; N, 8.55. Found: C, 53.55; H, 3.14; N, 8.37.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>C(N(CC)CC)C.[Cu]I>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1cccnc1Br
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ncccc2C=O)cc1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a solution of 2-bromo-3-pyridinecarboxaldehyde (1.86 g, 10 mmol) and 4′-methoxy phenylacetylene (1.58 g, 12 mmol) in triethylamine (40 mL) were added dichlorobis(triphenylphosphine) palladium (II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h, then cooled to room temperature. The ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure leaving 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.35 g, 99%) as a yellow solid. 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.28 g, 9.60 mmol) and tert-butylamine (3.83 g, 60 mmol) were stirred under nitrogen for 24 h at room temperature. The resulting mixture was extracted with ether and dried over anhydrous Na2SO4. Removal of solvent gave the expected imine (2.72 g, 97%), which was used in next step without further purification. To a solution of the above imine (2.7 g, 9.23 mmol) in anhydrous DMF (50 mL) was added copper (I) iodide (0.190 g, 0.1 mmol). The reaction mixture was heated at 100° C. for 4 h, then cooled to room temperature and diluted with ether (200 mL). The organic layer was washed with a saturated aqueous ammonium chloride solution (3×100 mL). The organic layer was dried over anhydrous Na2SO4. Removal of solvent gave the crude compound as a dark-colored solid. Purification by column chromatography (silica gel 230-400 mesh; 30% ethyl acetate in hexanes as eluent) afforded 7-(4-methoxy phenyl) [1,6]naphthridine (0.730 g, 33%) as a brown solid. To a solution of 7-(4-methoxy phenyl) [1,6]naphthridine (0.485 g, 2.05 mmol) in anhydrous N-methyl-2-pyrrolidinone (5 mL) was added thiophenol (0.25 g, 2.26 mmol) and potassium carbonate (0.028 g, 0.205 mmol). The reaction mixture was stirred at 190° C. for 1 h under nitrogen. The reaction mixture was cooled to room temperature. The compound was purified by column chromatography to give 4-(1,6-naphthyridin-7-yl)phenol (0.33 g, 71%) as a pale yellow solid. Selected data: MS (ES) m/z: 223.95, 222.95; MP 219-221° C.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([CH2:11][NH:12][C:13]([C:15]1[N:16]=[C:17]([C:33]#[N:34])[C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]=2)=[O:14])([CH3:10])[CH2:8][CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:33]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:19]=2)[C:24]([OH:25])=[C:15]([C:13]([NH:12][CH2:11][C:7]([CH3:10])([CH2:8][CH3:9])[C:6]([OH:35])=[O:5])=[O:14])[N:16]=1)#[N:34]
Reactant: CCC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-{[(1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-methyl}-2-methyl-butyric acid tert-butyl ester (45 mg, 0.10 mmol) was dissolved in TFA (1.7 mL) and CH2Cl2 (1.7 mL). The resulting mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was dissolved again in CH2Cl2 (4 mL). The volatiles were removed again in vacuo to give the title compound in 36 mg. MS: (−) m/z 418.14 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(C)C.CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CC(=O)O)cc1Br
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CCO)cc1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of [3-bromo-4-(methyloxy)phenyl]acetic acid (10.0 g, 40.8 mmol) in anhydrous THF (50 mL) was added BH3.(CH3)2S (5.3 mL, 53 mmol) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 3 h. The mixture was then treated with MeOH until gas evolution subsided, and then concentrated under reduced pressure. The residue was then partitioned between water and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to give crude 2-[3-bromo-4-(methyloxy)phenyl]ethanol, which was used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1Br.[OH-].[Na+].[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17](B(O)O)[CH:18]=1>COCCOC.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:15]1[CH:14]=[C:13]([F:12])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Clc1cccc(Cl)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(F)cc1-c1c(Cl)cccc1Cl
Temperature: 90 °C
Yield: 61.6 %

Procedure:
To a solution of 2,6-dichlorobromobenzene (3.5 g, 15.7 mmol) and sodium hydroxide (3.14 g, 78.5 mmol) in DME-water (2:1) was added 5-fluoro-2-methoxybenzene boronic acid (4.0 g, 23.5 mmol) at 90° C., followed by tetrakis(triphenylphosphine)palladium (0) (0.9 g, 0.78 mmol). The reaction mixture was heated at 90° C. overnight and cooled to room temperature. The mixture was extracted with methylene chloride and washed with water. The organic solvent was removed under vacuum. Chromatography with 5% ethyl acetate in hexanes afforded 2.62 g (87%) of 2′,6′-dichloro-5-fluoro-2-methoxybiphenyl as a colorless oil. MS (EI) m/z 270 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22][CH3:23])=[O:21])[CH3:24])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1sccc1N(C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 65 °C
Yield: 83.6 %

Procedure:
To a solution of 55 (0.15 g; 0.42 mmol) in N,N-dimethylformamide (2 mL) at room temperature was added potassium carbonate (0.282 g; 2.12 mmol) followed by iodomethane (0.053 mL; 0.85 mmol). The reaction mixture was heated at 65° C. for 12 hours, cooled to room temperature, diluted with aqueous hydrochloric acid (50 mL; 2M) and extracted with dichloromethane (3×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a crude residue that was purified by chromatography on silica gel eluting with a 0 to 10% ethyl acetate/hexanes gradient to give the title product (0.129 g).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.C(=O)(O)[O-].[Na+].[CH2:29]([OH:32])[CH2:30][CH3:31]>S(=O)(=O)(O)O>[CH2:29]([O:32][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])[CH2:30][CH3:31]
Reactant: CCCO
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
2α,3α-Epoxy-5α-pregnan-20-one (360 mg) was dissolved in 80 mL of propanol and cooled to °C. and added to a cold 1.0 mL propanol solution containing 5-drops of concentrated sulfuric acid. This reaction mixture was stirred for 30 minutes at this temperature and additional 30 minutes at room temperature, poured into a 20% sodium bicarbonate solution and washed several times with chloroform. The combined organic phase was dried over potassium carbonate and concentrated. Purification of the crude product on a silica gel column eluting with hexane/ethyl acetate (70:30) gave the titled compound (206 mg, 50% yield) as white crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:51])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:38][CH:39]=[C:40]([CH2:42][O:43]C3CCCCO3)[N:41]=2)[CH:32]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[O:38][CH:39]=[C:40]([CH2:42][OH:43])[N:41]=4)[CH:32]=3)[CH2:29][C:28](=[O:51])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.23 g) (Example J27) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.31 g) (Example K11) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.18 g).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].CCCCCC>C(#N)C>[Cl:8][C:7]1[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CN1CCNCC1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Product: CN1CCN(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
A mixture of 2,3-dichloropyrazine (5.0 g, 34 mmol), N-methylpiperazine (5.1 g, 51 mmol) and potassium carbonate (7.0 g, 51 mmol) in acetonitrile (100 mL) was stirred at ambient temperature for 2 h. Addition of hexane, followed by filtration and concentration of the filtrate gave 7.3 g of the crude product as an orange liquid. Purification by filtration through silica using heptane/EtOAc (3:1) followed by EtOAc/acetone (1:1) gave 4.1 g (57%) of the title compound as a yellow oil which solidified upon cooling. HPLC purity: 100%. MS m/z 213 (M+H)+. *Reported in WO 00/76984, Example 169, Step 1.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30]C3CCOC3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[O:36]1[CH2:40][CH2:39][CH2:38][CH:37]1CC(NN)=O.O1CCC(CC(NN)=O)C1>>[CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30][CH:37]3[CH2:38][CH2:39][CH2:40][O:36]3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: NNC(=O)CC1CCCO1
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: NNC(=O)CC1CCOC1
Product: Cc1cc(C)c(-c2nnc(CC3CCCO3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using 2-(tetrahydrofuran-2-yl)acetohydrazide (compound 138.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 470 (M+H)+.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:28][C:24]1[CH:23]=[C:22]([NH:21][C:15]2[N:14]=[C:13]([C:11]3[CH:10]=[N:9][N:8]([CH:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:5][C:6]#[N:7])[CH:12]=3)[C:18]([O:19][CH3:20])=[CH:17][N:16]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: COc1cnc(Nc2cccc([N+](=O)[O-])c2)nc1-c1cnn(C(CC#N)C2CC2)c1
Agent: [Pd]
Solvent: CO
Product: COc1cnc(Nc2cccc(N)c2)nc1-c1cnn(C(CC#N)C2CC2)c1

Procedure:
A mixture of 3-cyclopropyl-3-(4-{5-methoxy-2-[(3-nitrophenyl)amino]pyrimidin-4-yl}-1H-pyrazol-1-yl)propanenitrile (from example 321, 0.010 g, 0.000025 mol) in 2 mL of MeOH was hydrogenated in the presence of 10% Pd/C, under balloon pressure of hydrogen, for 2 h. After filtering off the catalyst, the filtrate was evaporated to dryness to provide the desired product as a racemic mixture (8 mg, 86.39%). LCMS (M+H) 376.1.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:16])=[S:15].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1>[NH2:16][C:14]1[S:15][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=2[N:13]=1
Reactant: NC(=S)Nc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: Nc1nc2c(Cl)cccc2s1
Temperature: 20 °C

Procedure:
210 Parts of sulfuryl chloride were added within about 2 hours at a temperature of 35°-40° C. to a stirred mixture of 186.5 parts of 2-chlorophenylthiourea, 500 parts of toluene, 300 parts of chlorobenzene and 11 parts of sodium carbonate. The gas development being terminated, 250 parts of water were added, the solvent mixture was distilled off with steam, and the remaining aqueous phase was combined with 500 parts of 30% hydrochloric acid. Filtration from the undissolved matter was carried out at about 90° C., the filtrate was cooled to about 20° C., and the free amine was precipitated from the 2-amino-4-chlorobenzothiazole dissolved as hydrochloride by adding excess sodium hydroxide solution until a final pH of 8.5-9.0 was adjusted. The product was suction-filtered, washed to neutral with water, and dried. 170 Parts of 2-amino-4-chlorobenzothiazole having a melting point of 199°-200° C. (92.4% of th.) were obtained.
Reaction SMILES: CN(C)C(=O)[O:4][CH:5]([C:9]1[N:10]([CH3:30])[C:11]([C:20]2[S:21][C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH2:29])[C:27]=3[N:28]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)[CH:6]1[CH2:8][CH2:7]1.CN(C)C(=O)OC(C1N(C)C(C2SC3N=CN=C(N)C=3N=2)=C(C2C=CC=CC=2)N=1)C1C=CC=CC=1>>[NH2:29][C:26]1[C:27]2[N:28]=[C:20]([C:11]3[N:10]([CH3:30])[C:9]([CH:5]([CH:6]4[CH2:7][CH2:8]4)[OH:4])=[N:13][C:12]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:21][C:22]=2[N:23]=[CH:24][N:25]=1
Reactant: CN(C)C(=O)OC(c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C)C1CC1
Agent: CN(C)C(=O)OC(c1ccccc1)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Product: Cn1c(C(O)C2CC2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 104 but using [5-(7-amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazol-2-yl](cyclopropyl)methyl dimethylcarbamate. (Intermediate 98) in place of [5-(7-amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazol-2-yl](phenyl)methyl dimethylcarbamate (Intermediate 97). Colourless solid (6 mg, 66%);
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C@@H:4]([NH:9]C(=O)OC(C)(C)C)[C:5]([CH3:8])([CH3:7])[CH3:6].Cl.CCN(CC)CC.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([N:39]=[C:40]=[S:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>O1CCOCC1>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:32]=[C:31]([NH:39][C:40](=[S:41])[NH:9][C@@H:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]([N:2]([CH3:18])[CH3:1])=[O:17])[CH:30]=[C:29]([C:28]([F:42])([F:27])[F:43])[CH:34]=1
Reactant: CN(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@@H](NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
A 50-mL round-bottomed flask was charged with (S)-tert-butyl 1-(dimethylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (6c) (860 mg, 2.0 mmol, 1.0 equiv) and 4N HCl in dioxane (5.0 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure and maintained at ˜1 torr for 1 h. The resulting white, foamy solid was dissolved in CH2Cl2 (10 mL). Et3N (562 μL, 4.0 mmol, 2.0 equiv) and 3,5-bis(trifluoromethyl)phenylisothiocyanate (596 mg, 2.2 mmol, 1.1 equiv) were added sequentially via syringe. The flask was capped with a plastic stopper, and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to purification by flash column chromatography on silica gel (gradient elution, 3:1 hexanes/Et2O→1:1 hexanes/Et2O) to provide the product (4a) as a white solid (613 mg, 1.43 mmol, 71% yield over two steps). [α]D25=−32.8° (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 9.06 (1H, s), 7.90 (2H, s), 7.77 (1H, d, J=9 Hz), 7.56 (1H, s), 5.68 (1H, d, J=9 Hz), 3.35 (3H, s), 2.97 (3H, s), 1.12 (9H, s). 13C {1H}NMR (100 MHz, CDCl3): δ 181.8, 174.0, 140.3, 131.7 (q, JC-F=33 Hz), 123.7 (m), 123.3 (q, JC-F=272 Hz), 118.1 (m), 60.9, 39.1, 36.2, 36.0, 27.2. IR (cm−1): 3322 (br m), 2972 (m), 1611 (m), 1532 (s), 1474 (m), 1385 (m), 1274 (s), 1174 (m), 1126 (s), 963 (m), 883 (m), 848 (w), 700 (m), 680 (m). LRMS (ESI): 452.1 (60%) [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2Cl)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccccc2Cl)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 48.3 %

Procedure:
To a solution of ethyl 2[(2-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.14 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.073 g, 0.50 mmol) in ethanol (2.0 mL), piperidine (0.054 mL, 0.55 mmol) was added at ambient temperature. The mixture was refluxed for 12 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.099 g, y. 48%).