Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OCCCO2)=[C:18]([F:28])[C:17]=1[O:29][CH3:30].[F-].[K+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([O:29][CH3:30])[C:18]=2[F:28])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl
Temperature: 70 °C
Yield: 76 %

Procedure:
A 250 mL three-neck flask with a reflux condenser, a nitrogen inlet and a thermocouple was charged with methyl 4-amino-3,6-dichloro-5-fluoropicolinate (9.965 g, 41.7 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (12.74 g, 52.1 mmol) and KF (4.84 g, 83 mmol). Acetonitrile (78 mL) and water (26 mL) were added. The reaction mixture was purged with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh3)2Cl2; 1.477 g, 2.10 mmol, 5 mol %) was added, and the solution was heated to 70° C. under nitrogen for 2 h. Upon cooling to room temperature, a precipitate formed which was filtered and washed with water. The precipitate was dissolved in EtOAc (ca 500 mL) and washed with water and then brine. The organic layer was dried (MgSO4) and the solvent was removed using a rotary evaporator to give an orange solid, which was dried in vacuum oven at 50° C. (11.46 g, 76% yield): mp 169-170.5° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.4 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.15 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 164.85 (s), 153.11 (d, J=252.5 Hz), 146.29 (s), 144.52 (d, J=4.3 Hz), 143.74 (s), 142.75 (dd, J=227.1, 14.0 Hz), 136.38 (d, J=13.4 Hz), 128.58 (d, J=3.2 Hz), 125.87 (s), 125.54 (d, J=3.5 Hz), 122.89 (dd, J=13.8, 4.0 Hz), 113.01 (d, J=3.0 Hz), 61.61 (d, J=4.2 Hz), 52.70 (s); ESIMS m/z 364 ([M+H]+). Anal. Calcd for C14H10Cl2F2N2O3: C, 46.30; H, 2.78; N, 7.71. Found: C, 46.60; H, 2.68; N, 7.51.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=2)=[CH:19][CH:18]=1>ClCCl.CN(C)C=O>[N:29]([C:25]1[CH:24]=[C:23]([C:20]2[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=2)[N:28]=[CH:27][N:26]=1)=[C:1]=[S:2]
Reactant: Nc1cc(-c2ccncc2)ncn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: S=C=Nc1cc(-c2ccncc2)ncn1
Temperature: 60 °C

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.601 g, 2.59 mmol) in dichloromethane/N,N-dimethylformamide at room temperature was added 6-(pyridin-4-yl)pyrimidin-4-amine (0.297 g, 1.725 mmol). The orange mixture was heated at 60° C. for 18 hours. LC/MS showed the desired product peak as the major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-(pyridin-4-yl)pyrimidine (0.055 g, 0.257 mmol, 15% yield) as an orange solid. LCMS R.T.=1.46; [M+H]+=215.09.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C@H:24]([CH2:26][OH:27])[NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:25][C@H:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:26][OH:27])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(Cl)c1cccc(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](CO)c1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 3-benzyloxybenzoic acid (22 g, 96 mmol) in toluene (200 ml) was added dropwise thionyl chloride (14.1 ml, 19 mmol). The reaction mixture was heated at 90° C. for 2 hours, cooled to ambient temperature and volatiles removed under reduced pressure to afford crude 3-benzyloxybenzoyl chloride (32 g, quant.). The crude 3-benzyloxybenzoyl chloride was dissolved in CH2Cl2 and added dropwise over 30 min., to a vigorously stirred solution of (R)-(-)-2-phenylglycinol (15.8 g, 115 mmol) and triethylamine (16 ml, 15 mmol) in CH2Cl2 (200 ml) cooled to 0° C. The reaction mixture was allowed to warm ambient temperature and stirred for overnight. Solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (1 L) and water (1 L). The aqueous layer was separated, extracted with ethyl acetate (2×500ml) and the combined organic phase washed with 1N HCl (500 ml), aqueous 4% NaHCO3 solution (500 ml) and brine (500 ml), dried over MgSO4 and concentrated under reduced pressure to give 2-(3-benzyloxybenzamido)-2(R)-phenylethan-1-ol (29 g, 88%) as pale yellow solids.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:8]([O:10][C:11](=[O:33])[CH:12]([O:30][CH2:31][CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:16][CH:15]=1)[CH3:9].CCCCCCC>C1(C)C=CC=CC=1>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([O:30][CH2:31][CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:27][CH:28]=2)=[CH:16][CH:15]=1)[CH3:9]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Reactant: CC(C)(C)N=C=O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OC(=O)NC(C)(C)C)cc2)cc1)OCC
Yield: 20.3 %

Procedure:
tert-Butyl isocyanate (0.14 g; 1.4 mmole) was slowly added to a solution of 2-ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 26b) (0.5 g; 1.4 mmole) in toluene (5 ml) and thereafter the reaction mixture was stirred over night. The crude mixture was purified by chromatography on silica gel using ethyl acetate:heptane (gradient 1.25-80% ethyl acetate) as eluant to give 0.13 g (yield 20%) of 3-{4-[2-(4-tert-butylcarbamoyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]([C:21]([F:24])([F:23])[F:22])=[N:6][N:7]([CH2:9][C:10]2[NH:11][C:12](=[O:20])[C:13]3[CH:18]=[C:17]([CH3:19])[S:16][C:14]=3[N:15]=2)[CH:8]=1.N1C=CC=CC=1.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>O>[CH3:34][S:31]([O:1][CH2:2][CH2:3][C:4]1[C:5]([C:21]([F:23])([F:22])[F:24])=[N:6][N:7]([CH2:9][C:10]2[NH:11][C:12](=[O:20])[C:13]3[CH:18]=[C:17]([CH3:19])[S:16][C:14]=3[N:15]=2)[CH:8]=1)(=[O:33])=[O:32]
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(CCO)c(C(F)(F)F)n3)nc2s1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc2c(=O)[nH]c(Cn3cc(CCOS(C)(=O)=O)c(C(F)(F)F)n3)nc2s1
Temperature: -10 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2-((4-(2-Hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (1.99 g, 5.55 mmol) was completely dissolved in pyridine (0.44 g, 20 mL, 5.55 mmol) and cooled in an acetone/sodium chloride/ice bath. Internal temperature was maintained at −10° C. Mesyl chloride (2.07 g, 1.40 mL, 18.1 mmol) was added portionwise and the temperature exothermed to 0° C. The mixture was stirred for 1 h at 0° C. and deionised water was added until solid precipitated out. The reaction was filtered, washed with water, and concentrated in vacuo to give the title compound as a pale yellow solid (2.11 g, 4.83 mmol, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:19]([NH:21][NH:22][C:23](=[O:32])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:43](Cl)(=[O:47])[C:44](Cl)=[O:45]>ClCCl>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:19]([NH:21][N:22]1[C:44](=[O:45])[C:43](=[O:47])[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]1=[O:32])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NNC(=O)NCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.94 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-(benzyl)carbamoyl-4-methylvalerohydrazide in 10 ml of dichloromethane was cooled to 0° C. under a nitrogen atmosphere and treated with 0.4 ml of pyridine and 0.174 ml of oxalyl chloride. The mixture was stirred at 0° C. for 2 hours and then allowed to warm to room temperature overnight. The mixture was washed in sequence with 2M aqueous hydrogen chloride, water, 5% aqueous sodium hydrogen carbonate, and saturated aqueous sodium chloride. The organic fraction was dried over anhydrous magnesium sulphate and evaporated. The solid residue was recrystallized from ethyl acetate to give 0.69 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1)#[N:9].[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:9][CH2:8][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)=[O:21]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
Add triethylamine (0.3 mL, 2.12 mmol) to a solution of 4-cyano-benzylamine (1.0 g, 7.58 mmol) in DCM (11 mL) and cool the mixture at 0° C. Add 2,2-dimethyl-propionyl chloride (0.93 mL, 7.58 mmol) dropwise and allow to stir the mixture at 0° C. for 15 min and at room temperature for 2 h. Add water, separate the organic phase and extract the aqueous phase twice with DCM. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (1.23 g, 75%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:15]2[O:14][CH2:13][C:12](=[O:16])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:17]I.O>CN(C)C=O>[CH3:17][N:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[C:15]=2[O:14][CH2:13][C:12]1=[O:16]
Reactant: CI
Reactant: O=C1COc2c(cccc2[N+](=O)[O-])N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)COc2c1cccc2[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
Sodium hydride (60%) (300 mg, 7.50 mmol) was added to a solution of 8-nitro-2 H-1,4-benzoxazin-3(4 H)-one (971 mg, 5.00 mmol) in N,N-dimethylformamide (15 mL) at room temperature, the mixture was stirred for 10 min, and then methyl iodide (374 μL, 6.00 mmol) was added dropwise thereto. The mixture was stirred at room temperature for 3 hr and water was added to the reaction mixture. The resulting precipitate was collected by filtration, washed with ethyl acetate and water, and then dried at 60° C. under reduced pressure to afford 4-methyl-8-nitro-2 H-1,4-benzoxazin-3(4 H)-one as a pale yellow amorphous substance (453 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=1)(=[O:17])=[O:16])(=[O:6])=[O:5].CCN(CC)CC.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH2:3][CH2:2][NH:1][C:36](=[O:38])[CH3:37])(=[O:5])=[O:6])=[C:8]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=2)(=[O:17])=[O:16])[CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCS(=O)(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCS(=O)(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-{2-[(2-aminoethyl)sulfonyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide (23 mg, 0.048 mmol) in CH2Cl2 (2 ml) was added Et3N (14 μl, 0.10 mmol), acetic anhydride (5 μl, 0.053 mmol), and catalytic amount of DMAP. The reaction was stirred at room temperature for 1 h and was concentrated. The crude product was purified by column chromatography on silica gel (0→10% MeOH in ethyl acetate), followed by PTLC (10% MeOH in ethyl acetate) to give the title compound.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:6][N:7]=[C:8]([C:11]1[C:12](=[O:27])[CH2:13][C:14]([CH3:26])([CH3:25])[CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C:16]=1[OH:17])[CH2:9][CH3:10])[CH:4]=[CH2:5].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[CH2:3]([O:6][N:7]=[C:8]([C:11]1[C:12](=[O:27])[CH2:13][C:14]([CH3:26])([CH3:25])[CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C:16]=1[O:17][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH3:10])[CH:4]=[CH2:5]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCON=C(CC)C1=C(O)C(c2cccc(Cl)c2)C(C)(C)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCON=C(CC)C1=C(OC(=O)c2ccccc2)C(c2cccc(Cl)c2)C(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
Aqueous 1% sodium hydroxide (30 ml) was added to a stirred solution of 2-[1-(allyloxyimino)propyl-3-hydroxy-4-(3-chlorophenyl)-5,5-dimethyl-cyclohex-2-en-1-one (2.5 g) in acetone (200 ml). The mixture was stirred at ambient temperature for 5 minutes and then benzoyl chloride (1 g) in acetone (25 ml) was added dropwise. After 30 minutes the mixture was evaporated in vacuo and the residue purified on a silica gel column using methylene chloride as eluant to give the title compound (3.0 g) as a colourless oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][N:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]3[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccnc(N2CCN(C3CCCC3)CC2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccnc(N2CCN(C3CCCC3)CC2)c1
Yield: 95 %

Procedure:
A mixture of 2.85 g (10 mmol) 1-cyclopentyl-4-(4-nitro-pyridin-2-yl)-piperazine and 0.285 g Pd/C (10%) in 25 ml methanol was treated with 1 bar hydrogen at room temperature for 3 h. After filtration the mixture was evaporated to dryness to yield 2.34 g (92%) of the title compound as brownish solid. (m/e): 247.4 (MH+; 100%).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH2:30](I)[CH3:31]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:30][CH3:31]
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: CCI
Product: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3OCC)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 363 and ethyl iodide, white powdery 3-[2-(3-difluoromethoxy-4-ethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[N:5][C:6]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)=[C:7]([Cl:18])[N:8]=2)[N:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:18][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[N:19]1[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]1)[N:3]=[C:2]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc3nc(Cl)nc(N4CCOCC4)c3nc2Cl)CC1
Product: O=S1CCN(c2nc3nc(N4CCNCC4)nc(N4CCOCC4)c3nc2Cl)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-4-morpholino-7-(1-oxido-thiomorpholino)pteridine and piperazine.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:9]2[C:8]([O:3][CH2:2][CH2:1][OH:4])=[N:13][CH:12]=[C:11]([CH:10]=2)[C:14]([OH:16])=[O:15])=[CH:22][CH:21]=1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(OCCO)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.8 %

Procedure:
To a solution of ethane-1,2-diol (301 mg, 270 μA, 4.84 mmol) in dried DMF (6 mL) was added sodium hydride (232 mg, 4.84 mmol) and the reaction mixture was stirred at room temperature for 15 minutes. The resulting solution was added slowly to a solution of 6-chloro-5-(4-chlorophenyl)-3-pyridinecarboxylic acid (CAN 1012792-56-1; 0.590 g, 2.2 mmol) in dried DMF (6 mL) and stirred at 80° C. for 4 h. More sodium hydride (106 mg, 2.2 mmol) was added and at room temperature and stirring at 80° C. commenced for another 2 h. Water was added and DMF was evaporated. The residue was dissolved in water; acidified with 3M HCl to pH 3. The suspension was filtered; the filter cake was washed with water and dried under high vacuo. The crude material was purified by flash chromatography (ReproFlash Acidosil-S, 50 g, 50% to 100% ethylacetate in heptane) to give 0.27 g (41%) of the title compound as a white solid; MS (ESI): 292.1 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=1.CS(O[C@@H:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)[CH3:23])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([O:16][C@H:22]([CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:34])[CH3:35])=[O:31])[CH2:28][CH2:29]2)[CH3:23])=[N:14][CH:15]=1
Reactant: CSc1ccc(-c2cnc(O)cn2)c(F)c1
Reactant: CC(C)OC(=O)N1CCC([C@@H](C)OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(-c2cnc(O[C@@H](C)C3CCN(C(=O)OC(C)C)CC3)cn2)c(F)c1
Yield: 45 %

Procedure:
1-Methylethyl 4-[(1S)-1-({5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinyl}oxy)ethyl]-1-piperidinecarboxylate (0.334 g, 45%) was prepared as a yellow oil from 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 161, Alternative synthesis, Step 4, 0.405 g, 1.71 mmol), crude 1-methylethyl 4-{(1R)-1-[(methylsulfonyl)oxy]ethyl}-1-piperidinecarboxylate (0.70 g, 2.32 mmol) and K2CO3 (0.48 g, 3.43 mmol) in DMF (15 mL) in a manner similar to Example 166, Step 2. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 25% EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.22 (d, 1H, J=1.3 Hz), 7.85 (t, 1H, J=8.3 Hz), 7.10 (dd, 1H, Ja=8.3 Hz, Jb=1.7 Hz), 7.01 (dd, 1H, Ja=12.1 Hz, Jb=1.8 Hz), 5.15-5.05 (m, 1H), 4.89 (septet, 1H, J=6.2 Hz), 4.19 (bs, 2H), 2.80-2.65 (m, 2H), 2.50 (s, 3H), 1.85-1.65 (m, 3H), 1.40-1.15 (m, 11H); LRMS (ESI), m/z 434 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:22][CH2:23][CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:22][CH2:23][CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: [H][H]
Reactant: CCCC(NC(=O)Cc1ccc(C=CC(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCCC(NC(=O)Cc1ccc(CCC(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
A solution of ethyl 2-ethoxy-4-[N-(1-(2-piperidinophenyl)-1-butyl)-aminocarbonylmethyl]-cinnamate (0.54 g, 1.1 mmol) in ethanol (15 ml) is hydrogenated for 1 hour at ambient temperature and under 3 bars of hydrogen on 10% palladium/charcoal (0.1 g). The mixture is filtered, concentrated by evaporation in vacuo and the evaporation residue is crystallized from petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.[NH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: CC=C(CC)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(C)(N)CO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC=C(CC)C1N(CC(=O)NC(C)(C)CO)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 68.6 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-fluorocarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.24 mmol) prepared in example 82a was reacted with 2-amino-2-methyl-propan-1-ol (73 mg, 0.82 mmol), N-methylmorpholine (0.2 g, 1.98 mmol) and 4-dimethylaminopyridine (2 mg, 0.016 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-[(2-hydroxy-1,1-dimethylethyl)aminocarbonylmethyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 92 mg, 67%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13])=O.[NH2:14][C:15]([NH2:17])=[S:16]>C(O)C>[C:6]1([CH3:13])[CH:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:14]=[C:15]([NH2:17])[S:16][CH:2]=1
Reactant: Cc1cc(C)c(C(=O)CBr)c(C)c1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 107 %

Procedure:
2-Bromo-1-mesitylethanone (2.43 g, 10.1 mmol) and thiourea (0.810 g, 10.6 mmol) were dissolved in 95% ethanol (20 mL). The reaction mixture was heated at reflux for 2.0 h. The solution was concentrated under reduced pressure, and the residue was recrystallized from 2-propanol to give the desired 4-mesitylthiazol-2-amine (2.36 g) as white solids: 1H NMR (500 MHz, CD3OD) δ 7.00 (s, 2 H), 6.67 (s, 1 H), 2.31 (s, 3 H), 2.19 (s, 6 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1[C:19]2([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:18]1>O1CCCC1.[Cu]I>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:18][C:19]1([OH:17])[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: Br[Mg]c1ccccc1OCc1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccccc2OCc2ccccc2)CC1

Procedure:
(2-(Benzyloxy)phenyl)magnesium bromide (33.8 mL, 1M) was added to a solution of EXAMPLE 263A (6.0 g) and CuI (1.07 g) in tetrahydrofuran (220 mL) at 0° C. over 10 minutes. The reaction was quenched with pH 7 buffer (20 mL), extracted twice with ether, and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed on silica gel using 2-20% ethyl acetate in hexanes to provide the title compound.