Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1(C)[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1.C1(=O)CCCCC1>C(O)C>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=C1CCCCC1
Solvent: CCO
Product: Fc1ccc2[nH]c3c(c2c1)CCCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.6 g of p-fluoroaniline was dissolved in 100 ml of ethanol and a catalytic amount of p-toluenesulfonic acid was added thereto. 9.8 g of cyclohexanone was then added dropwise to the mixture at room temperature. After completion of the addition, the mixture was stirred at room temperature for one hour and concentrated under reduced pressure. Dilute sulfuric acid prepared from 190 ml of water and 20 ml of concentrated sulfuric acid was added to the residue and the mixture was heated at 110° C. for 15 minutes on an oil bath to precipitate light orange crystals. The crystals thus formed were filtered, washed 3 times with water and dried to obtain 17.4 g of 6-fluoro-1,2,3,4-tetrahydrocarbazol which was identified by NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].Br[C:26]([C:28]([F:31])([F:30])[F:29])=[CH2:27]>C1COCC1.O.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>[Cl:9][C:6]1[CH:5]=[C:4]([C:26]([C:28]([F:31])([F:30])[F:29])=[CH2:27])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)c(C)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
The mixture of 2-(3,5-dichloro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (160 mg, 0.56 mmol), K2CO3 (232 mg, 1.68 mmol), compound 2-bromo-3,3,3-trifluoroprop-1-ene (146 mg, 0.84 mmol) and Pd(PPh3)2Cl2 (39 mg, 0.1 mmol) in THF/H2O (2/1 mL) was stirred in a sealed tube at 80° C. for 3 h. It was partitioned between EA and H2O. The organic layer was washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by column chromatography to give the desired product (78 mg, 55% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=O.Cl.[NH2:19][OH:20].O>CO>[OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[N:19][OH:20]
Reactant: Cc1cc2c(c(C)c1O)C(=O)CC1(CCC1)O2
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc2c(c(C)c1O)C(=NO)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 98.6 %

Procedure:
A mixture of 1 g of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one and 0.91 g of hydroxylamine hydrochloride was dissolved in 5 mL of MeOH by way of brief heating. After all solids had dissolved, the solution was sealed in a microwave reaction vial and placed in a microwave reactor for 25 min at 125° C. The reaction was cooled to room temperature, added to H2O and extracted with EtOAc, washed with brine and dried over Na2SO4. Evaporation of solvent yielded 1.05 g of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one oxime as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26]Br)=[CH:18][CH:17]=1)#[N:15]>CC(C)=O>[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][N:2]2[N:3]=[N:4][CH:5]=[N:1]2)=[CH:18][CH:17]=1)#[N:15]
Reactant: c1nnn[nH]1
Reactant: N#Cc1ccc(CBr)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cn2ncnn2)c2ccccc12
Reaction time: 3.5 h

Procedure:
420 mg of tetrazole, 553 mg of potassium carbonate and 53 mg of potassium iodide are added to a solution of 985 mg of 1-cyano-4-bromomethyl-naphthalene in 20 ml acetone, and the mixture is stirred for 3.5 hours at 45°. After the reaction mixture has cooled, the solvent is distilled off and the residue is dissolved in methylene chloride. The organic solution is washed with water and brine, then dried over sodium sulfate and concentrated. Separation by column chromatography yields first, by elution with toluene/ethyl acetate (9:1), 1-cyano-4-(2-tetrazolyl)methyl-naphthalene, m.p. 124°, [IR(CH2Cl2): 3052, 2225, 1592, 1516 cm-1, 1H-NMR (DMSO-d6): δ=6.62 (2H, s), 7.6 and 8.2 (2H, m), 7.83 (2H, m), 8.2 and 8.33 (2H, m), 9.02 (1H, s) ppm] and then, with toluene/ethyl acetate (3:1), 1-cyano- 4-(1-tetrazolyl)methylnaphthalene, m.p. 171° [IR(CH2Cl2): 3050, 2227, 1516, 1482 cm-1 ; 1H-NMR (DMSO-d6): δ=6.36 (2H, s), 7.5 and 8.2 (2H, m), 7.85 (2H, m), 8.2 and 8.37 (2H, m), 9.6 (1H, s) ppm.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=1)=[O:7].O>C(O)(=O)C>[I:15][C:11]1[CH:10]=[C:9]([N:8]2[CH:3]=[CH:4][NH:5][C:6]2=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: COC(CNC(=O)Nc1cccc(I)c1)OC
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]ccn1-c1cccc(I)c1
Temperature: 100 °C
Yield: 25.7 %

Procedure:
N(2,2-Dimethoxyethyl)-N′-(3-iodophenyl)urea (618 mg) was dissolved in acetic acid (10 ml) and water (1 ml) and the mixture was stirred at 20° C. for 17 h and then heated to 100° C. for 0.5 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with NaHCO3 solution, dried and purified by chromatography on 10 g silica Bond Elut cartridge eluting with EtOAc-petroleum ether (1:7 to 1:1) to give the title compound (130 mg) LCMS RT=2.66 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]([NH:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[OH:23])=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([NH:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[N:7]=[C:6]([NH:20][C:19]3[CH:21]=[CH:22][C:16]([NH:15][C:13]([O:12][CH2:10][CH3:11])=[O:14])=[C:17]([OH:23])[CH:18]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:18][C:17]=1[OH:23])=[O:14])[CH3:11]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)Nc1ccc(N)cc1O
Product: CCOC(=O)Nc1ccc(Nc2ncc(F)c(Nc3ccc(NC(=O)OCC)c(O)c3)n2)cc1O

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-ethoxycarbonylamino-3-hydroxyaniline were reacted to yield N2,N4-bis(4-ethoxycarbonylamino-3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.86 (d, 1H J=4 Hz), 7.67 (m, 2H), 7.20 (dd, 1H, J=8 Hz, J=4.1 Hz), 7.13 (d, 1H), 6.90 (m, 2H), 4.2 (m, 4H), 1.32 (m, 6H); LCMS: ret. time: 20.92 min.; purity: 98%; MS (m/e): 487 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](O)=[O:26]>CCCCCCC.CCOC(C)=O>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[C:25]([N:15]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][C:17]([F:18])([F:20])[F:19])=[O:26]
Reactant: COc1ncccc1-c1ccncc1NCC(F)(F)F
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ncccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from (2-methoxy-[3,4]bipyridinyl-3′-yl)-(2,2,2-trifluoro-ethyl)-amine (example 135, intermediate a) and 3-fluoro-5-(trifluoromethyl)benzoic acid (CAS RN 161622-05-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow solid (16%). MS (ESI): m/z=474.104 [M+H]+.
Reaction SMILES: C(O)(C)C.[OH-].[Na+].[C:7]1([C:13]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH:14]2[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[N:26]1([CH2:32][CH2:33]Cl)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O>[CH2:29]1[CH2:30][CH2:31][N:26]([CH2:32][CH2:33][O:17][C:16]([CH:14]2[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:15]2)=[O:18])[CH2:27][CH2:28]1
Reactant: ClCCN1CCCCC1
Reactant: O=C(O)C1CC1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(OCCN1CCCCC1)C1CC1(c1ccccc1)c1ccccc1

Procedure:
100 ml. of isopropanol and 0.21 mol of powdered sodium hydroxide are added to a mixture of 0.1 mol of 2,2-diphenyl-cyclopropane-carboxylic acid and 0.11 mol of piperidino-β-chloroethane hydrochloride. The mixture is heated under reflux for 8 hours, 300 ml. of water are added and the mixture extracted with diethyl ether. The ether phase is washed with water, dried over sodium sulphate, and the ether removed in vacuo to yield the base.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([NH:8][C:9](=O)[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[C:15]#[N:16].[ClH:17].[OH-:18].[Na+]>>[ClH:17].[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]2[C:3]=1[C:15](=[O:18])[NH:16][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[N:8]2
Reactant: [OH-]
Reactant: CC(C)CC(=O)Nc1nn(C)c(N)c1C#N
Agent: Cl
Agent: [Na+]
Product: CC(C)Cc1nc2nn(C)c(N)c2c(=O)[nH]1

Procedure:
5-Amino-4-cyano-1-methyl-3-(3-methylbutanoylamino)pyrazole (10 g), prepared as in Example 27 was heated with 1 M sodium hydroxide solution (90 ml) for 2 hours. The solution was adjusted to pH=7 with concentrated hydrochloric acid, and was evaporated to dryness. The residue was extracted with acetone containing 5% water (100 ml). The extracts were evaporated, and the residue was dissolved in a minimum of hot ethanol. Then the solution was cooled and a precipitate which formed was filtered off. The filtrate was mixed with concentrate hydrochloric acid (5 ml) and the precipitate was recrystallised from water to give the title compound, m.p. 292°-294° C. decomp.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([CH3:34])=[C:6]([CH2:12][C:13]2[C:14]([O:30]C(=O)C)=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([CH3:34])=[C:6]([CH2:12][C:13]2[C:14]([OH:30])=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(Cl)cc3Cl)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(Cl)cc3Cl)c2O)=C(C)C1=O
Yield: 50.7 %

Procedure:
N-[3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-2,4-dichloroaniline (0.075 g, 0.145 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 2 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.035 g, 0.0735 mmol, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[S:10])[CH2:8][O:9][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14].CI.[C:19](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([S:10][CH3:19])[CH2:8][O:9][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1c(N)ccc2c1OCC(=S)N2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1c(N)ccc2c1OCC(SC)=N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of methyl 7-amino-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylate (Intermediate 29, 0.795 g), methyl iodide (0.710 g) and potassium carbonate (1.38 g) in acetone (20 mL) was stirred at room temperature for 2 hours. The resultant mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25% to give methyl 7-amino-3-methylsulfanyl-2H-benzo[1,4]oxazine-8-carboxylate (0.648 g) as a sandy coloured solid.
Reaction SMILES: [CH2:1]([CH:5]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:15][C:16]([OH:18])=O)[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C:25]1([C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30]1)[CH2:24]2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([CH:5]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:15][C:16]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[CH2:26][C:25]2([C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30]2)[CH2:24]3)=[O:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Sc2ccccc2N(CC(=O)O)C1=O
Reactant: Nc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCC1Sc2ccccc2N(CC(=O)Nc2ccc3c(c2)CC2(C3)NC(=O)NC2=O)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-butyl-3-oxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)acetic acid (0.2 mmol, 56 mg), 5′-amino-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-2,5-dione (0.2 mmol, 43 mg) and DIPEA (0.6 mmol, 104.5 μl) in DMF (1 ml) was added HATU (0.2 mmol, 76 mg) and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=479.2; tR=3.18. H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.55 (d, 1H), 7.42 (q, 1H), 7.25-7.33 (m, 2H), 7.16 (d, 1H), 7.07-7.15 (m, 2H), 4.86 (d, 1H), 4.60 (d, 1H), 3.59 (t, 1H), 3.27-3.34 (m, 2H), 2.97-3.04 (m, 2H), 1.6 (m, 1H), 1.24-1.28 (m, 5H), 0.83 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8](Cl)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(B(CC)[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: CCB(CC)c1cccnc1
Reactant: COC(=O)c1sc2ncc(Cl)nc2c1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ncc(-c3cccnc3)nc2c1N
Temperature: 95 °C
Yield: 80 %

Procedure:
A solution of the methyl 7-amino-2-chloro-thieno[2,3-b]pyrazine-6carboxylate prepared as described in Example 10C (0.468 g), diethyl(3-pyridyl)borane (0.293 g), Pd(dppf)Cl2 (0.157 g), and K2CO3 (0.800 g) in degassed DMF (10 mL) was heated to 95° C. for 1.5 h, cooled, quenched in sat'd NH4Cl, the solid precipitate collected, washed with water and dried. Purification by silica gel column chromatographed provided 0.44 g (80%) of the title compound. 1H NMR (DMSO-d6) δ 3.87 (3H, s), 7.25 (2H, br s), 7.6 (1H, dd), 8.75 (2H, m), 9.49 (1H, s), 9.58 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]1[O:16][N:15]=[C:14]([CH2:17][N:18]2[C:26]3[C:21](=[C:22]([C:29]([F:32])([F:31])[F:30])[C:23]([C:27]#[N:28])=[CH:24][CH:25]=3)[CH:20]=[C:19]2[CH2:33][CH2:34][CH3:35])[N:13]=1.O[Li].O.O.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]1[O:16][N:15]=[C:14]([CH2:17][N:18]2[C:26]3[C:21](=[C:22]([C:29]([F:31])([F:30])[F:32])[C:23]([C:27]#[N:28])=[CH:24][CH:25]=3)[CH:20]=[C:19]2[CH2:33][CH2:34][CH3:35])[N:13]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)OC)ccc2Cl)n1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)O)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 70.9 %

Procedure:
To a solution of methyl 4-chloro-3-(3-{[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-1,2,4-oxadiazol-5-yl)benzoate (Example 293) (0.190 g, 0.378 mmol) in 1,4-dioxane (70 mL) was added LiOH—H2O (0.063 g, 1.50 mmol) and water (30 mL). The mixture was stirred at rt for 17 h followed by cooling to 0-5° C. The solution was made acidic using concentrated HCl, extracted into Et2O, dried (MgSO4) and concentrated to afford a pure solid (0.131 g, 71% yield): MS (ES) m/z 488 (M+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][C:7]2[S:9][CH:10]=[CH:11][C:6]=2[C:5]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:3][C:4]1[N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[C:7]2[S:9][CH:10]=[CH:11][C:6]=2[C:5]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cc1c(C)[nH]c2sccc12
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2)c2sccc12
Temperature: 25 °C
Yield: 59.6 %

Procedure:
Sodium hydride (0.014 g, 0.583 mmol) was added to a solution of methyl 2-(5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate (0.109 g, 0.52 mmol) in DMF (5 mL) at 0° C. The mixture was stirred 1 h at 0° C. before sequential addition of the 1-(chloromethyl)-4-(methylsulfonyl)benzene (0.156 g, 0.762 mmol) and sodium iodide (0.0935 g, 0.624 mmol). The reaction mixture was allowed to warm up to ambient temperature over 4 h. EtOAc was added and the resulting solution washed with water. The layers were separated and the organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (heptane/EtOAc: 80/20 to 50/50) to give the title compound (0.117 g, 59.6%): LC/MS (Table 1, Method b) Rt=2.45 min; MS m/z 395 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:46][NH2:47]>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:46][NH:47]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: NN
Reactant: CC1CCCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCO
Product: CC1CCCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)C1
Temperature: 110 °C
Yield: 17.8 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-(3-methylcyclohexyl)-3-piperidinecarboxamide (186.2 mg, 0.413 mmol), 5 mL of EtOH, Hunig's base (0.289 ml, 1.653 mmol), and hydrazine anhydrous (0.078 mL, 2.480 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid and the yellow solution were carefully separated due to the black solid is heavier than yellow solution. Water (20 mL) was added to the yellow solution, and a solid formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized using CH3CN, and the solid in the solvent was filtered, washed by EtOAc and CH3CN, and dried in vacuum to afford the light yellow title compound (34 mg). LC-MS (ES) m/z=463 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.67-0.94 (m, 6H), 0.97-1.33 (m, 6H), 1.36-1.87 (m, 7H), 2.13-2.42 (m, 1H), 2.90 (m, 1H), 3.45-3.63 (m, 1H), 4.67 (m, 2H), 5.38 (s, 2H), 6.07 (s, 2H), 6.57 (s, 1H), 7.57 (dd, J=8.6, 1.0 Hz, 1H), 7.70 (m, 2H), 7.94 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[CH:18]=[CH:17][N:16]=[C:15]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:14]3=[O:25])[CH:9]=[CH:8][C:6]=2[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[CH:18]=[CH:17][N:16]=[C:15]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:14]3=[O:25])[CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:34]
Reactant: CSc1nc2ccc(Cn3ccnc(N4CCOCC4)c3=O)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3ccnc(N4CCOCC4)c3=O)cc2s1
Yield: 55.1 %

Procedure:
A solution of 1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one (752 mg, 2.0 mmol) and m-CPBA (449 mg, 2.6 mmol) in DCM (20 mL) was stirred at 0° C. for 4 h. The reaction mixture was washed with aqueous Na2S2O3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:3 petroleum ether/ethyl acetate to give 1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one as a light yellow solid (430 mg, 55.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.59 (d, J=6.9 Hz, 1H), 7.29 (d, J=4.5 Hz, 1H), 6.96 (d, J=4.2 Hz, 1H), 5.20 (s, 2H), 3.65 (s, 8H), 3.07 (s, 3H). LCMS (ESI) m/z 391 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[N:10]=2)[CH:7]=1.[CH3:15][N:16](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:17].F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CNC>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([N:16]([CH3:17])[CH3:15])=[O:13])[N:10]=2)[CH:7]=1
Reactant: Cc1c(C(=O)O)nc2ccc(I)cn12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N(C)C)nc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a stirred solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (150 mg) in DMF (5 ml) were added HATU (283 mg) and N,N-diisopropylethylamine (0.17 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 30 min. Dimethylamine (2 M in THF, 0.2 ml) was added, and the resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo and the residue was diluted with DCM (100 ml). The DCM layer was successively washed with saturated aqueous NH4Cl solution (40 ml), saturated aqueous NaHCO3 solution (20 ml), water (30 ml) and brine (50 ml). The DCM layer was then dried m over Na2SO4, and concentrated in vacuo to give the title compound (150 mg) as a brown oil.