Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Product: COc1c(N2CCN(C)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 5 h
Yield: 19.7 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), N-methylpiperazine (140 mg) and anhydrous DMSO (3 ml) was stirred for 5 hours at 70° to 95° C. on an oil bath. The reacting mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with chloroform-methanol-concentrated aqueous ammonia (20:6:1), the residue was recrystallized from methanol to give the title compound (50 mg) as colorless needles, mp 221°-222° C. (decompd.).
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]2[N:5]([C:9](=[S:21])[NH:10][C:11]=2[C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:7][N:8]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:22]([S:21][C:9]1[N:5]2[CH:6]=[CH:7][N:8]=[C:3]([NH2:2])[C:4]2=[C:11]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nccn2c(=S)[nH]c(-c3cc4ccccc4[nH]3)c12
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccn2c(SCc3ccccc3)nc(-c3cc4ccccc4[nH]3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
A solution of 8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazine-3(2H)-thione hydrobromide (10 mg, 0.04 mmol) and benzyl bromide (5.1 uL, 0.043 mmol) in DMF (1.0 mL) was charged with N,N-diisopropylethylamine (18 uL, 0.11 mmol) and stirred at rt for 2 h. The solvent was then removed in vacuo and the crude product was dissolved in purified by preparative TLC eluting with 3% NH3/MeOH in DCM to afford 2.5 mg 3-(benzylthio)-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine. 1H NMR (400 MHz, MeOD) δ ppm 4.25 (s, 2H), 6.76 (s, 1H), 6.92 (d, J=5.05 Hz, 1H), 7.06-7.14 (m, 3H), 7.14-7.23 (m, 4H), 7.28 (d, J=5.05 Hz, 1H), 7.48(d, J=8.08 Hz, 1H), 7.63 (d, J=8.08 Hz, 1H); MS (ES+): m/z 373.35 [MH+].
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.O1CCCC1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[O:24])=[CH:18][CH:17]=1
Reactant: NCCCn1ccnc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCCn1ccnc1)Nc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A 2.5 g. portion of 1H-imidazole-1-propanamine was added to 20 ml. of toluene and then 7 ml. of tetrahydrofuran was added to produce solution. A solution of 3.1 g. of distilled p-chlorophenyl isocyanate in 20 ml. of toluene was added, the mixture was stirred overnight and then evaporated to a waxy solid. This solid was triturated with ether and the resulting crystals recrystallized from chilled acetone, giving 2.3 g. of the desired product as colorless crystals, mp. 123°-125° C.
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH2:22][CH3:23])=[C:4]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]#[N:9].[CH3:24][S:25]([C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([C:32]2[CH:31]=[N:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=2)[C:3]([O:21][CH2:22][CH3:23])=[C:4]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:5]=1
Reactant: CC1(C)OB(c2cncc(S(C)(=O)=O)c2)OC1(C)C
Reactant: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1Br
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 100 °C
Yield: 62.5 %

Procedure:
To tert-butyl [-1-(3-bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl]carbamate (50 mg, 0.1 mmol, from Example 179, Step 3) and 3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (30. mg, 0.11 mmol, Peptech, catalog #BE358) in 1,4-dioxane (4 mL) was added potassium carbonate (30 mg, 0.2 mmol) in water (2 mL). The reaction was degassed with N2. Tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.04 mmol) was added and degassed again with N2. The reaction was heated at 100° C. overnight. The reaction was allowed to cool to room temperature and was partitioned between EtOAc and water. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give crude product. The product was purified by chromatography on silica gel eluting with a hexane:EtOAc gradient to give tert-butyl (1-{5-chloro-4-cyano-2-ethoxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate as a yellow oil (0.030 g, 60%). LCMS calculated for C22H27ClN3O5S (M+H)+: m/z=480.1. found: 480.1.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:24][CH3:25])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C1COCC1>[C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH:23][C:26](=[O:28])[CH3:27])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:24][CH3:25])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)Nc2ccccc2)c2c1oc1ccc(N)cc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N1-phenyl-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (69 mg, 0.207 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF (10 ml) containing pyridine (1.1 eq) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 2 h. THF was evaporated and the residue was washed ethanol to obtain 40 mg of N1-phenyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 252° C.
Reaction SMILES: I.[CH3:2][NH:3][C:4](=[NH:7])[S:5][CH3:6].[CH3:8][N:9]([C:13](Cl)=[O:14])[C:10](Cl)=[O:11].[OH-].[Na+]>C1C=CC=CC=1.O>[CH3:8][N:9]1[C:13](=[O:14])[NH:7][CH:4]([S:5][CH3:6])[N:3]([CH3:2])[C:10]1=[O:11]
Reactant: CNC(=N)SC
Reactant: CN(C(=O)Cl)C(=O)Cl
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CSC1NC(=O)N(C)C(=O)N1C
Yield: 75 %

Procedure:
23.2 g (0.1 mole) of N,S-dimethyl-isothiourea hydroiodide were initially introduced into 100 ml of water and 250 ml of benzene. 15.6 (0.1 mole) of N-methyl-bis-(chlorocarbonyl)-amine in 100 ml of dry benzene and 12 g (0.3 mole) of sodium hydroxide dissolved in 100 ml of water were simultaneously slowly added dropwise from two dropping funnels with vigorous stirring. The reaction took place strongly exothermically. The mixture was stirred for a further hour, any product which precipitated was filtered off, and the benzene phase was separated off, dried over calcium chloride and evaporated in vacuo. The residue, together with the filter residue, was recrystallized from isopropanol. 14 g (75%) of 1,3-dimethyl-4-methylmercapto tetrahydro-1,3,5-triazine-2,6-dione were obtained as a colorless powder of melting point 137°-139° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[C:28]([OH:30])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:32]1[C:36](=O)CC[C:33]1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.CNC>O1CCOCC1.C(N(CC)CC)C>[CH3:33][N:32]([CH3:36])[C:28]([CH:9]1[CH2:10][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:30]
Reactant: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C(=O)O)C2)cc(OC)c1OC
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C(=O)N(C)C)C2)cc(OC)c1OC
Reaction time: 5 h
Yield: 65.8 %

Procedure:
To a mixture of 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylic acid (3.0 g), N-hydroxysuccinimide (1.2 g) and dioxane (30 ml) is added, at room temperature, dicyclohexyl carbodiimide (2.6 g). The mixture is stirred for 5 hours. To a mixture of dimethylamine hydrochloride (8.0 g), triethylamine (10.0g) and dioxane (30 ml) is added dropwise at 0° C the solution of active ester prepared above. The reaction mixture is concentrated, and the concentrate is dissolved in dichloromethane. The solution is washed with a 5% aqueous solution of citric acid and a saturated aqueous solution of sodium hydrogencarbonate, which is then dried and further concentrated. The crude product is subjected to a silica gel column chromatography (ethyl acetate-methanol=9:1) to afford N,N-dimethyl 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2carboxamide (2.1 g) as colorless crystals, m.p. 146-147° C.
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[N:4][N:5]([CH3:7])[CH:6]=1.[Li]CCCC.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:3]1[C:2]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:6][N:5]([CH3:7])[N:4]=1
Reactant: Cn1cc(Br)c(-c2ccccc2F)n1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.9 %

Procedure:
To a solution of 4-bromo-3-(2-fluorophenyl)-1-methyl-1H-pyrazole (3.03 g, 11.9 mmol, 1.0 eq.) in THF (40 mL) under nitrogen at −78° C. was added nBuLi (hexane, 2.5 M, 5.3 mL, 13.2 mmol, 1.1 eq.) over 10 min. After 45 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.7 mL, 13.2 mmol, 1.1 eq.) was added. After 1 h 45 min, saturated aqueous NH4Cl and EtOAc were added. The cold bath was removed, and the reaction mixture was stirred to room temperature. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography using hexanes:EtOAc (3:1) as eluent afforded 3-(2-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid (1.83 g, 51% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C(N(CC)CC)C.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>C1C=CC=CC=1>[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)[C:18](=[O:19])[O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CSc1ccc(N(C)C(=O)Cl)cc1
Reactant: OCc1cccnc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ccc(N(C)C(=O)OCc2cccnc2)cc1
Yield: 40.5 %

Procedure:
A solution of 3-pyridylcarbinol (2.4 g., 0.0222 mole) in triethylamine (2.24 g., 0.0222 mole) was added dropwise to a solution of N-methyl-(4-methylthiophenyl)carbamoyl chloride in 150 ml. of benzene. The reaction mixture was heated to reflux temperature for about 1 hr. then allowed to stand over night at room temperature. The reaction mixture was washed with water and the benzene layer separated, dried over magnesium sulfate and concentrated in vacuo to give an oil which solidified. The product was recrystallized from methylcyclohexane to give 2.6 g. of solid melting at 100°-102° C. This was a 40.5% yield of 3-pyridylmethyl N-methyl-N-(4-methylthiophenyl)carbamate.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].O.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH:2]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:6]=1)#[N:9]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
4-Acetylbenzonitrile (44al, 1.00 g, 6.9 mmol), sodium hydroxide (0.40 g, 10.0 mmol) and water (20 ml) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. Benzaldehyde (1b, 0.70 ml, 6.9 mmol) was added and the mixture stirred for 2 hr at room temperature. The resulting mixture was filtered and recrystallized from ethanol to give 1.46 g (91%) of a yellow solid: mp 120° C. [expected mp 119-120° C.]; 1H NMR: δ 7.34 (m, 3H), 7.62 (m, 2H), 7.80 (m, 4H), 8.06 (d, 2H, J=8.1 Hz); 13C NMR: δ 115.9, 117.9, 121.1, 128.6, 128.8, 129.0, 131.0, 132.4, 134.3, 141.4, 146.4, 188.9.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A solution of 2-chloro-4-methyl-5-nitropyridine (10 g, 0.058 mol), in DMF (100 mL) was treated with phenol (6.6 g, 0.07 mol) and potassium carbonate (9.6 g, 0.07 mol) and the reaction mixture was stirred at 110° C. for 4 hr and then cooled. To the reaction mixture was then added water. The reaction mixture was extracted into EtOAc, dried and concentrated to a syrup, which was purified via column chromatography (4:2:0.5; CHCl3:hexanes:EtOAc, v/v) to yield 4-methyl-5-nitro-2-phenoxy-pyridine as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:18][C:9]2=[N:10][C:11]([Cl:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:25]([O:29][C:30]([N:32]1[CH2:36][C@H:35]([CH3:37])OS1(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[N:18]([C@H:35]([CH3:37])[CH2:36][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:9]2=[N:10][C:11]([Cl:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCC)c(Cl)nc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCC)c(Cl)nc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to example 3, intermediate j) from 6-chloro-5-ethoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, potassium tert-butoxide and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[S:4]1)[OH:2].[CH3:15][N:16]=[C:17]=[O:18]>>[CH3:15][NH:16][C:17]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[S:4]1)=[O:18]
Reactant: CCCCCC1(C)SC(=NO)N=C1C
Reactant: CN=C=O
Product: CCCCCC1(C)SC(=NOC(=O)NC)N=C1C

Procedure:
2-oxo-4,5-dimethyl-5-pentyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4,5-dimethyl-5-pentyl-3-thiazoline-O-(methylcarbamoyl)-oxime as a viscous oil; nD44.5 =1.5256. The 2-oxo-4,5-dimethyl-5-pentyl-3-thiazoline-oxime starting material melts at 104°-106° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:17]2[CH:26]=[CH:25][C:20]3[C:21](=[O:24])[O:22][CH2:23][C:19]=3[C:18]=2[CH3:27])[CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:27][C:18]1[C:19]2[CH2:23][O:22][C:21](=[O:24])[C:20]=2[CH:25]=[CH:26][C:17]=1[CH:15]([CH3:16])[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1c(C(C)CN2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1COC2=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(C)CN2CCNCC2)ccc2c1COC2=O

Procedure:
tert-Butyl-4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propyl]piperazine-1-carboxylate (160 mg, 0.43 mmol) was stirred in TFA (3 mL) at r.t for 3 hr. The reaction was concentrated and pumped over high vacuum pump overnight to give the desired product, which could be converted to its freebase by partitioning between an organic solvent and saturated NaHCO3 solution. LC-MS (IE, m/z): 275.38 [M+1]+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[N:26]=[CH:25][N:24]=[C:23]([S:27][CH2:28]C(O)=O)[C:22]=2[C:32]#[N:33])[CH:16]=[CH:17][C:18]=1[F:19]>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:22]3[C:32]([NH2:33])=[CH:28][S:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: N#Cc1c(Nc2ccc(F)c(Cl)c2)ncnc1SCC(=O)O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1csc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 25 °C

Procedure:
DBU (0.88 mL, 5.9 mmol) was added to a solution of [6-(3-chloro-4-fluoro-phenylamino)-5-cyano-pyrimidin-4-ylsulfanyl]-acetic acid Compound 1h (2.0 g, 5.9 mmol) in THF (50 mL). The solution was heated to reflux for 24 hrs and then cooled to room temperature. The mixture was partitioned between EtOAc and 1 N NH4Cl. The organic layer washed twice with 1 N NH4Cl and once with brine. The organic solution was dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography using gradient elution (20% EtOAc/80% Hexanes to 50% EtOAc/50% Hexanes) to yield N-(3-chloro-4-fluoro-phenyl)-thieno[2,3-d]pyrimidine-4,5-diamine Compound 84a (606 mg, 32%). MS 295 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=[C:9]1[C@H:17]([NH:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=[C:9]1[C@H:17]([N:21]([CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)N[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Reactant: ClCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N(CCN2CCCC2)[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To N—[(R)-1-(1-benzyl-4,5-dimethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-2-methyl-propyl]-4-methyl-benzamide (50 mg, 0.123 Mmol) in DMF was added sodium hydride (5 mg, 0.147 Mmol). The reaction stirred for 15 at RT then 1-(2-chloro-ethyl)-pyrrolidine (20 mg, 0.135 mmol) (Tilford et al.; J. Am. Chem. Soc.; 70; 1948; 4001). was added. The reaction was stirred at RT for 24 h, quenched with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (1×20 ml), brine (1×20 mL), dried (Na2SO4), filtered, and evaporated to yield the title compound (30 mg, 49%) as a colorless oil: MS (ES) m/e 501.4 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[CH:16]([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24]>>[CH2:1]([S:8][C:9]1[C:10]([CH:16]([F:18])[F:17])=[C:11]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)c1c(Br)cccc1SCc1ccccc1
Reactant: O=C1CCCN1
Product: O=C1CCCN1c1cccc(SCc2ccccc2)c1C(F)F
Reaction time: 8 h

Procedure:
Intermediate 55 (2.008 g, 6.1 mmol) was coupled with pyrrolidin-2-one (0.623 g, 7.32 mmol) in close analogy to the procedure described in step 1.6). After workup the crude oil crystallized upon standing overnight and was then triturated with MTBE.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:25][N:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:7]([C:21]([NH:23][CH3:24])=[O:22])=[CH:6]2.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[CH3:1][O:2][C:3]1[C:4]([CH2:25][N:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:7]([C:21]([NH:23][CH3:24])=[O:22])=[CH:6]2
Reactant: CNC(=O)c1cc2c(CN3CCN(C(=O)OC(C)(C)C)CC3)c(OC)ccc2n1S(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc2c(CN3CCNCC3)c(OC)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-{[5-methoxy-2-[(methylamino)carbonyl]-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (3.4 mg, 0.063 mmol, Intermediate 58) was dissolved in DCM (2 mL) before TFA (1 mL) was added. The reaction mixture was stirred for 2 h at RT before completed. The solvent was evaporated and the obtained oil was dissolved in methanol and the solvent was evaporated. The obtained brown solid was stored under vacuum for 24 h. Quantitative yield was obtained. MS (ESI+) for C22H26N4O4S m/z 443 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C=O)C>[CH3:19][N:20]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:16](=[O:18])/[CH:15]=[CH:14]/[C:10]2[CH:11]=[N:12][CH:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH:9]=2)=[CH:33][CH:34]=1)[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(-c2cncc(/C=C/C(=O)O)c2)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cncc(/C=C/C(=O)Nc3ccc(CN(C)C4CCOCC4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.7 %

Procedure:
To a solution of (E)-3-[5-(4-methylphenyl)pyridin-3-yl]acrylic acid (150 mg), 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (168 mg) and triethylamine (0.10 ml) in DMF (10 ml) was added diethyl cyanophosphate (0.12 ml) at 0° C., and the mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. To the residue was added water, the mixture was extracted with chloroform. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:2) to give (E)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]-phenyl]-3-[5-(4-methylphenyl)pyridin-3-yl]acrylic amide (Compound 215) (24 mg) as yellow solid.