Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16]([NH2:18])=[O:17].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16](=[NH:18])[O:17][CH2:6][CH3:7]
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1c(F)cccc1F
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=N)c1c(F)cccc1F
Temperature: 20 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
A mixture of triethyloxonium tetrafluoroborate (8.0 g, 0.042M), 2,6-difluorobenzamide (5.62 g, 0.036M) and methylene chloride was stirred at 20° C. for 18 hours, after which an excess of aqueous sodium bicarbonate solution was added. The methylene chloride phase was separated and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure yielded ethyl 2,6-difluorobenzimidate as a pale yellow oil (6.0 g) which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(O)[CH2:12][CH2:11]2)=[C:6]([F:22])[C:5]=1[F:23])[CH3:2].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH2:11]2)=[C:6]([F:22])[C:5]=1[F:23])[CH3:2]
Reactant: CCCCCC1(O)CCC(c2ccc(OCC)c(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1=CCC(c2ccc(OCC)c(F)c2F)CC1

Procedure:
A solution of 128.0 g of 4-(4-ethoxy-2,3-difluoro-phenyl)-1-pentylcyclohexanol in 11 of toluene was refluxed in a water separator with addition of 5.0 g of toluene-4-sulphonic acid monohydrate. When all the water had been removed, the mixture was subjected to conventional work-up, giving 1-ethoxy-2,3-difluoro-4-(4-pentylcyclohex-3-enyl)benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][C:11]([OH:28])([CH3:27])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH2:44].[Cl-].[Na+].[OH2:47]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([CH2:10][C:11]([OH:28])([CH3:27])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[O:13])(=[O:47])=[O:44])[CH:6]=[CH:7][CH:8]=1
Reactant: O
Reactant: COc1cccc(SCC(C)(O)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c1
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)CC(C)(O)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3-methoxyphenylthio)-N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (29 mg, 0.07 mmol) in dichloromethane (0.18 mL) at −78° C. was added 30% hydrogen peroxide (16 μL, 0.57 mmol) followed by the slow addition of trifluoroacetic anhydride (60 μL, 0.45 mmol). The reaction was stirred at room temperature for 16 h. The reaction was diluted with dichloromethane. Cold water and brine were added, and the reaction was stirred for 20 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography (hexane:EtOAc 50:50) yielded 19 mg of desired product. Production of PLM5 was confirmed by 1-H NMR, 13-C NMR, and mass spectral analysis.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][N:19]([CH2:2][CH:3]([C:5]2[CH:14]=[CH:13][C:8]3[NH:9][C:10](=[O:12])[O:11][C:7]=3[CH:6]=2)[OH:4])[CH2:18][CH2:17]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C(CCl)c1ccc2[nH]c(=O)oc2c1
Product: O=c1[nH]c2ccc(C(O)CN3CCC(O)(c4ccccc4)CC3)cc2o1
Yield: 25 %

Procedure:
By the procedures of Examples 8 and 2, 6-(2-chloroacetyl)-2(1H)-benzoxazolone and 4-hydroxy-4-phenylpiperidine were converted to present title product in 25% yield after recrystallization from ethanol/ether; m.p. 175°-177° C. NMR (methanol-d4) 7.51 (dd, J=1.5, 8.5 Hz, 2H), 7.35-7.29 (m, 3H), 7.24-7.19 (m, 2H), 7.05 (d, J=8 Hz, 1H), 4.94-4.90 (m, 1H--becomes dd J=3, 8.5 Hz with D2O wash), 2.96-2.90 (m, 2H), 2.80-2.57 (m, 4H), 2.19 (dq, J=4.5, 13 Hz, 2H), 1.74 (br d, J=14.5 Hz, 2H). IR(KBr) 3320, 3115, 2920, 2830, 1785, 1750.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=5[CH:32]=[O:33])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[BH4-].[Na+].Cl.C(OCC)(=O)C>CO>[F:38][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=5[CH2:32][OH:33])[O:27][N:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: O=Cc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4CO)C3)cs2)CC1

Procedure:
To a solution of 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde (1.9 g) in methanol (50 ml) was added, at 0° C., sodium borohydride (0.16 g), and then the mixture was stirred at room temperature for 2 hours. Subsequently, the reaction mixture was admixed at 0° C. with 0.1 molar hydrochloric acid and ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(hydroxymethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-ethanone (1.1 g).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([NH:9][C:10]2[CH:29]=[CH:28][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][N:16]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.CN(C)C=O>O>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([NH:9][C:10]2[CH:29]=[CH:28][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:40][CH2:41][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][N:16]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCN1CCOCC1
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ncnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
4-{4-[4-(Tert-butyl)anilino]phenoxy}-6-methoxy-7-quinazolinol (starting compound 11) (100 mg), potassium carbonate (50 mg), and 4-(2-chloroethyl)morpholine hydrochloride (67 mg) were added to N,N-dimethylformamide (2 ml), and the mixture was stirred at 80° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and was dried over sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude thus obtained was purified by thin-layer chromatography on silica gel using chloroform/methanol for development to give the title compound (120 mg, yield 94%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]5[CH2:28][CH2:29][N:30]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Temperature: 85 °C
Yield: 99.4 %

Procedure:
Seal tube containing 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperidin-4-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (product of step-iii of example 82) (125 mg, 0.194 mmol), (S)-2-methyloxirane (23 mg, 0.389 mmol), DIPEA (100 mg, 0.778 mmol) and ethanol were heated at 85° C. for 3 hours and distilled the solvent on rotavapor to get 128 mg (99% yield) of the titled compound. MS: m/z=664.4 (M+1).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[C:2]=[S:3].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH2:30])=[CH:18][CH:17]=1>O1CCCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:30][C:2]([NH:1][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]2)=[S:3])=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CCC(N=C=S)CC1
Reactant: Nc1cnccc1NCc1ccc(F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(=S)Nc2cnccc2NCc2ccc(F)cc2)CC1
Yield: 52 %

Procedure:
A mixture of 84.7 parts of ethyl 4-isothiocyanato-1-piperidinecarboxylate, 86.8 parts of N4 -[(4-fluorophenyl)-methyl]-3,4-pyridinediamine and 450 parts of tetrahydrofuran was stirred and refluxed for 3 hours. The reaction mixture was evaporated and the residue was crystallized from acetonitrile, yielding 90 parts (52%) of ethyl 4-[[[[4-[[(4-fluorophenyl)methyl]amino]-3-pyridinyl]-amino]thioxomethyl]amino]-1-piperidinecarboxylate; mp. 166° C. (15).
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[N:6]([CH3:11])[C:7](=[O:10])[CH2:8]Br)(=[O:3])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[C:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[N:6]([CH3:11])[C:7](=[O:10])[CH2:8][N:16]=[N+:17]=[N-:18])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1ccccc1N(C)C(=O)CBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1N(C)C(=O)CN=[N+]=[N-]
Yield: 51.6 %

Procedure:
2.05 g (7.59 mmol) of 2′-acetyl-2-bromo-N-methylacetanilide and 2 g (30.77 mmol) of sodium azide were stirred in 20 ml of dimethylformamide at room temperature for 4 hours. The resulting mixture was diluted with water and extracted with diethyl ether. The organic phase was washed twice with water, dried over magnesium sulphate, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate/petrol 5:3 for the elution. There was obtained 910 mg of 2′-acetyl-2-azido-N-methylacetanilide as a colorless gum. MS: m/e 233 [M+H]+.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].Br[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[N:11]=1>O1CCCC1>[C:17]1([CH3:24])[CH:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[C:16]=1[C:12]1[N:11]=[C:10]([CH2:7][C:6]#[N:8])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(C)c(-c2cccc(Br)n2)c(C)c1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2cccc(CC#N)n2)c(C)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 40.9 %

Procedure:
n-Butyllithium (2.5M, 19.1 mL, 47.8 mmol) was added to tetrahydrofuran (135 mL) and the solution was cooled to −78° C. Acetonitrile (2.5 mL, 47.8 mmol) was then added dropwise and the reaction stirred for 45 min. 2-Bromo-6-mesitylpyridine (2.00 g, 7.24 mmol) was added as a solution in 10 mL of tetrahydrofuran. The reaction continued to stir at −78° C. for 0.5 hr and was then warmed to room temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate, dried, and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave 0.70 g (41% yield) of the desired product as an orange oil.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][C:8]([O:12][CH3:13])([O:10][CH3:11])[CH2:7]1)=[O:5].[CH2:15]([Mg]Br)[CH2:16][CH:17]=[CH2:18]>C1COCC1>[CH3:13][O:12][C:8]1([O:10][CH3:11])[CH2:7][CH:6]([C:4](=[O:5])[CH2:18][CH2:17][CH:16]=[CH2:15])[CH2:9]1
Reactant: CON(C)C(=O)C1CC(OC)(OC)C1
Reactant: C=CCC[Mg]Br
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CC(OC)(OC)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
N,3,3-trimethoxy-N-methylcyclobutanecarboxamide (12.19 g, 60.0 mmol) was dissolved in THF (130 mL), cooled to 0° C. and treated with 3-butenylmagnesium bromide (168 mL, 0.5 M/THF, 84 mmol). After stirring for 1.5 h at room temperature, the reaction was re-cooled to 0° C. and quenched with 1 N citric acid (30 mL), diluted with ethyl acetate, washed successively with water, saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5-40% ethyl acetate in heptane to afford the desired product 10.98 g (92%). Rf 0.77 (50% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 5.87-5.72 (m, 1H), 5.06-4.95 (m, 2H), 3.17 (s, 3H), 3.13 (s, 3H), 3.06-2.88 (m, 1H), 2.54-2.48 (m, 2H), 2.38-2.28 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]([NH:26][S:27]([C:30]1[S:31][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:34]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[S:31][C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:21])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:33][CH:34]=1)(=[O:28])=[O:29])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.44) (0.36 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.14 g), which was subsequently deprotected.
Reaction SMILES: Cl[C:2]1([CH3:12])[CH:11]2[CH:3]1[CH2:4][CH2:5][C:6]12[O:10][CH2:9][CH2:8][O:7]1.CC([O-])(C)C.[K+]>CS(C)=O>[CH2:12]=[C:2]1[CH:11]2[CH:3]1[CH2:4][CH2:5][C:6]12[O:7][CH2:8][CH2:9][O:10]1
Reactant: CC1(Cl)C2CCC3(OCCO3)C21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C1C2CCC3(OCCO3)C12
Temperature: 60 °C

Procedure:
To a solution of (±)-6-chloro-6-methyl-spiro[bicyclo[3.1.0]hexane-2,2′-[1,3]dioxolane] (2.50 g, 13.25 mmol) in DMSO (40 mL) was added a solution of KOtBu (15.9 mL of 1.0M in THF). The solution heated at 60 ° C. overnight. After cooling down the reaction mixture to rt, the product was extracted into n-Hexane. Solvent was removed under reduced pressure. SiO2 column chromatography (14-25% EtOAc/n-hexane) gave the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 5.55 (s, 1H), 5.42 (t, 1H, J=1.0 Hz), 4.08-3.91 (m, 4H), 2.07-1.97 (m, 2H), 1.90-1.84 (m, 2H), 1.65-1.54 (m, 2H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=3[F:32])[C:13]([NH:17][S:18]([CH:21]3[CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:32][C:26]1[CH:27]=[C:28]([I:31])[CH:29]=[CH:30][C:25]=1[NH:24][C:12]1[C:13]([NH:17][S:18]([CH:21]2[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][NH:8]2
Reactant: CC(C)(C)OC(=O)n1ncc2c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3CC3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc2[nH]ncc2c1Nc1ccc(I)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a solution of 5-cyclopropanesulfonylamino-4-(2-fluoro-4-iodo-phenylamino)-indazole-1-carboxylic acid tert-butyl ester (206 mg, 0.36 mmol) in DCM (8 mL) was added TFA (1 mL) and the reaction mixture stirred at room temperature for 2 hours. Additional TFA (1 mL) was added and stirring continued for a further 1 hour before the reaction mixture was concentrated in vacuo and the residue azeotroped with DCM, methanol and then DCM again. The resultant residue was triturated with diethyl ether, the solid filtered off and dried under vacuum at 40° C. to give the title compound as a yellow solid (83 mg, 49%). LCMS (Method A): RT=10.03 [M+H]+=437, 1H NMR (DMSO-d6, 400 MHz): 13.14 (1 H, s), 9.07 (1 H, s), 7.80 (1 H, s), 7.57 (1 H, dd, J=10.84, 1.96 Hz), 7.39 (1 H, s), 7.31 (1 H, d, J=8.74 Hz), 7.25-7.20 (2 H, m), 6.45 (1 H, t, J=8.84 Hz), 2.40-2.32 (1 H, m), 0.75-0.62 (4 H, m), −0.05 (1 H, t, J=3.33 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[N:3]=1.[OH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: Cc1coc(-c2nc(N)nc(S(C)=O)c2C#N)c1
Reactant: OCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1coc(-c2nc(N)nc(OCCc3ccccn3)c2C#N)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-(4-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH3:11])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].CN(C=O)C.[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[NH:1]([C:23]([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:24])[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:20]([O:22][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH3:11])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
The Fmoc-Met-Ala-Leu is added into a round bottom flask with DMF and a magnetic stirrer. After the tripeptide is dissolved, benzyl bromide, followed by cesium carbonate, is added to the solution with stirring. The reaction mixture is stirred at room temperature for 1.5 hrs. Then, the reaction mixture is slowly poured into a flask with iced water. The precipitate is collected by suction filtration. The product, Fmoc-Met-Ala-Leu-OBn, is washed with water and placed in a vacuum desiccator.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[F:8].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.C(O)C.[OH-].[Na+]>CC(O)C.Cl>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)c(F)c2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)O
Product: CCOC(=O)C1=C(Nc2ccc(F)c(F)c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 44.3 %

Procedure:
To a solution of ethyl 2-[(3,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.084 g, 0.30 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.041 g, 0.28 mmol) in 2-propanol (2.0 mL), 2M hydrochloric acid in ethanol (0.14 mL, 0.28 mmol) was added at ambient temperature. The mixture was refluxed for 18 h. Cooled with ice bath, aqueous 2M sodium hydroxide solution (0.13 mL, 0.26 mmol) was added dropwise to neutralize, ethanol (5.0 mL) was added and the mixture was refluxed for 1.5 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.051 g, y. 44%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.CC(O)=O.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:31]([CH3:32])[CH:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: CNC1CCN(C)CC1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(CN(C)C2CCN(C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reaction time: 0.25 h
Yield: 88 %

Procedure:
2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (0.5 g) was dissolved in 10 mL of 1,2-DCE and 1.0 eq. AcOH and 1.3 eq. of 1-methyl-4-(methylamino)piperidine was added and the reaction was stirred 15 minutes followed by the addition of sodium triacetoxyborohydride. The reaction was stirred for 24 hours and product formation was confirmed by LCMS. The reaction was diluted with sat. NaHCO3, extracted with dichloromethane, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/hexanes) to give 0.61 g N-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,1-dimethylpiperidin-4-amine (88% yield). MS (Q1) 411 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(Cl)cc3)nc3ccccc13)C2
Yield: 11 %

Procedure:
Reaction of 2-(4-chlorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 27 (11% yield) as off-white oil. 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.90 (2t, 2H), 3.48 and 4.03 (2t, 2H), 3.74-3.80 (2s, 3H), 4.39 and 4.92 (2s, 2H), 6.31 and 6.77 (2d, 1H), 6.71 and 6.91 (2d, 1H), 7.62-7.81 (m, 3H), 7.87-7.98 (2d, 1H), 8.07-8.19 (m, 2H), 8.50-8.56 (m, 2H), 8.67 and 8.72 (2s, 1H); MS (ESI) m/z 446 ([M+H]+).