Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9]/[C:10](=[N:12]/[S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])/[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].C[Si]([C:25]#[N:26])(C)C>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])([C:25]#[N:26])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C(COCc1ccccc1)=N\S(=O)C(C)(C)C
Reactant: C[Si](C)(C)C#N
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C#N)(COCc1ccccc1)NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of (E)-N-(1-(benzyloxy)propan-2-ylidene)-2-methylpropane-2-sulfinamide (CAN 393536-49-7, 3.1 g, 11.6 mmol) in dry THF (55 ml) under an argon atmosphere was added cesium fluoride (1.94 g, 12.8 mmol) followed by addition of trimethylsilyl cyanide (1.27 g, 1.71 ml, 12.8 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and poured into a separatory funnel. Organic phase was extracted with a 1M aqueous solution of sodium bicarbonate and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (2.53 gr, 74%); MS (ESI, m/z): 295.6 (M+H+).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Nc1ccc(C(F)(F)F)cn1)c1ncccc1Cl
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cccnc1C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
0.33 g of sodium ethanethiolate was added to a mixture of 0.45 g of 3-chloro-N-(5-trifluoromethylpyridin-2-yl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. Water was poured to the reaction mixture cooled to room temperature, and the precipitated solid was taken by filtration and dried under reduced pressure to obtain 0.42 g of 3-ethylsulfanyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 2).
Reaction SMILES: [Si](Cl)(C(C)(C)C)(C)C.N1C=CN=C1.[Si:14]([O:21][CH2:22][CH2:23][C:24]1[CH:25]=[C:26]([CH2:29][C:30]#N)[S:27][CH:28]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(=O)([O-])[O-:33].[K+].[K+]>CN(C=O)C.C1COCC1.O>[Si:14]([O:21][CH2:22][CH2:23][C:24]1[CH:25]=[C:26]([CH2:29][CH2:30][OH:33])[S:27][CH:28]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(CC#N)c1
Reactant: O=C([O-])[O-]
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1csc(CCO)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
tert-Butyldimethylsilyl chloride (2.21 g) was added portionwise to a mixture of imidazole (1.00 g) and 2-(4-(2-hydroxyethyl)thiophen-2-yl)acetic acid [Aromatic Intermediate 20, step c] (1.3 g) in DMF (15 mL) at 20° C. over a period of 20 minutes. The resulting solution was stirred at 20° C. for 1 hour. The reaction mixture was diluted with THF (15 mL), cooled in ice-water, and treated with a solution of potassium carbonate (1.35 g) in water (15 mL). This mixture was stirred at 0° C. for 20 minutes. The mixture was partitioned between ethyl acetate and aqueous brine, and the phases separated. The organic layer was washed twice with aqueous brine, dried, filtered and the solvent removed under reduced pressure. The residue was dissolved in THF (40 mL), cooled in an ice bath and treated with borane tetrahydrofuran complex (1M in THF, 21 mL), added dropwise. The resultant solution was stirred at 20° C. for 2 hours. The reaction mixture was quenched by dropwise addition of methanol (10 mL) and the solvents were removed under reduced pressure. The crude product was purified by flash silica chromatography using 17% ethyl acetate in isohexane as solvent. Fractions containing the product were evaporated to dryness to afford the titled compound. Yield 1.25 g.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([N+]([O-])=O)[C:15]=1[C:16]#[N:17])([O-:13])=[O:12]>>[C:16]([C:15]1[C:14]([N+:11]([O-:13])=[O:12])=[CH:21][CH:20]=[CH:19][C:18]=1[O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1)#[N:17]
Reactant: O=C(O)C1CCC(O)CC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OC2CCC(C(=O)O)CC2)cccc1[N+](=O)[O-]

Procedure:
Prepared as in Example Ed from 4-hydroxycyclohexanecarboxylic acid and 2,6-dinitrobenzonitrile as a brown solid (50%). MS 291 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[NH:6][C:7]([CH:9]([CH:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)[NH:10][C:11](=[O:26])[C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:19])=[C:14]([CH3:25])[CH:13]=3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[C:37](Cl)(=[O:39])[CH3:38].O>O1CCCC1>[C:37]([N:29]1[CH2:30][CH2:31][CH2:32][CH:27]([CH:9]([C:7]2[NH:6][C:5]3[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][C:4]=3[N:8]=2)[NH:10][C:11](=[O:26])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[C:14]([CH3:25])[CH:13]=2)[CH2:28]1)(=[O:39])[CH3:38]
Reactant: Cc1cc(C(=O)NC(c2nc3cc(Cl)ccc3[nH]2)C2CCCNC2)ccc1C(=O)N1CCCC1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCCC(C(NC(=O)c2ccc(C(=O)N3CCCC3)c(C)c2)c2nc3cc(Cl)ccc3[nH]2)C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
90 mg (0.16 mmol) of rac.-N-[(5-chloro-1H-benzimidazol-2-yl)-(piperidin-3-yl)methyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is dissolved in 3 mL of tetrahydrofuran and, after the addition of 8.4 mg (0.17 mmol) of sodium hydride (50% solution in oil), stirred for one hour at 40° C. Then the mixture is cooled to ambient temperature and stirred for a further 16 hours with 11.4 μL (0.16 mmol) of acetyl chloride. Then water is added and the mixture is extracted with dichloromethane. The combined organic extracts are dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with dichloromethane/ethanol (100:0 and 90:10). The 4 possible stereoisomers were separated into one pair of enantiomers with a high Rf value (Example 189) and one pair of enantiomers with a low Rf value (Example 190). Yield: 30 mg (36% of theory); Rf value: 0.37 (silica gel; dichloromethane/ethanol=9:1); C28H32ClN5O3 (522.05); mass spectrum: (M+H)+=522/524 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:12])[CH3:11])[CH:5]=1.[BH4-].[Na+]>CCO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([OH:12])[CH3:11])[CH:5]=1
Reactant: COC(=O)c1cccc(C(C)=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cccc(C(C)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
General Procedure EE: Into the EtOH (70 ml) solution of methyl-3-acetylbenzoate (771 mg, 3.98 mmol) was added sodium borohydride (232 mg, 6.09 mmol). The mixture was stirred at rt under an atmosphere of nitrogen for one hour. After that time, the mixture was quenched with saturated NH4Cl followed by water, extracted with EtOAc (3×50 ml). The extracts were washed with water (50 ml), brine (50 ml), dried over MgSO4. After concentrated in vacuo, a beige oil (6269-42, 700 mg) was obtained. It was purified by chromatography on silica gel (25 g) eluting with 20% (200 ml), 30% (200 ml) and 40% EtOAc/hexane (200 ml) to give the title compound as a colorless oil (504 mg, 67% yield). TLC: Rf=0.41 (eluting with 30% EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ=1.52 (d, J=6.4 Hz, 3H), 1.89 (d, J=4.0 Hz, 1H), 3.92 (s, 3H), 4.93-5.01 (m, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.59 (md, J=8.0 Hz, 1H), 7.95 (td, J=1.6 & 8.0 Hz, 1H), 8.03-8.05 (m, 1H). MS (ES+): m/z 181.19 [MH+]. HPLC: tR=2.51 min (polar—5 min, ZQ3).
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[C:9]2=[O:20])=CC=1.Br.C([O-])([O-])=[O:25].[Na+].[Na+]>C(O)(=O)C>[OH:25][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH3:19])([CH3:18])[C:9](=[O:20])[NH:8]2)=[CH:12][C:13]=1[CH3:17]
Reactant: COc1ccc(CN2C(=O)C(C)(C)c3cc(C)ccc32)cc1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2c(cc1O)NC(=O)C2(C)C
Temperature: 0 °C
Yield: 74 %

Procedure:
6-Methoxy-1-(4-methoxy-benzyl-3,3,5-trimethyl-1,3-dihydro-indol-2-one (640 mg, 1.97 mmol) was mixed with acetic acid (0.7 mL)and 48% hydrobromic acid (7 mL) and heated to reflux 12 hours. The solution was cooled to 0° C. and aqueous Na2CO3 was added to adjust to pH=7 then extracted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: EtOAc/4:1 to 1:1) to give 280 mg of 6-Hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (74%). 1H NMR (300 MHz, DMSO-d6, ppm): δ: 1.15 (s, 6 H), 2.026.34 (s,1 H), 6.89 (s, 1 H), 9.21 (s,1 H), 10.01(s, 1 H).
Reaction SMILES: Cl.CC1(C)[O:7][CH:6]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]([C:24]3[CH:39]=[CH:38][C:27]4[N:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[N:29]=[N:30][C:26]=4[CH:25]=3)([OH:23])[C:19]([F:22])([F:21])[F:20])=[CH:10]2)[CH2:5][O:4]1>C(#N)C>[F:21][C:19]([F:20])([F:22])[C:18]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([CH2:8][CH:6]([OH:7])[CH2:5][OH:4])[CH:10]=1)([C:24]1[CH:39]=[CH:38][C:27]2[N:28]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[N:29]=[N:30][C:26]=2[CH:25]=1)[OH:23]
Reactant: CC1(C)OCC(Cn2cc(C(O)(c3ccc4c(c3)nnn4-c3ccc(F)cc3)C(F)(F)F)c3ccccc32)O1
Agent: Cl
Solvent: CC#N
Product: OCC(O)Cn1cc(C(O)(c2ccc3c(c2)nnn3-c2ccc(F)cc2)C(F)(F)F)c2ccccc21
Reaction time: 1.5 h

Procedure:
At room temperature, approximately 200 μL of concentrated HCl was added to 1-[1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-1H-indol-3-yl]-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-benzotriazol-5-yl]ethanol (100 mg) in aqueous acetonitrile. After 90 minutes, LCMS showed one peak MS m/z 501 (MH+) for the desired product. The mixture was then concentrated and the residue diluted with sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 95 mg of the title compound as an off-white solid.
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12]C)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].I>C(O)(=O)C.O>[OH:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cccc(C(=O)O)c1OC
Agent: I
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cccc(O)c1O
Temperature: 25 °C
Yield: 99.3 %

Procedure:
2,3-Dimethoxybenzoic acid (2 g, 10.98 mmol) was dissolved in acetic acid (25 mL). Hydroiodic acid solution (25 mL, 47% in water) was added and the reaction stirred under reflux overnight. The reaction was allowed to cool to room temperature and the solvent removed in vacuo. The yellow solid obtained was dissolved in a minimum amount of water and extracted with EtOAc (4×50 mL). Organic layers were combined, washed with Na2S2O3 (10% solution, 2×50 mL), water (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield 1.68 g (99%) 2,3-dihydroxybenzoic acid as a white solid. 1H NMR (CD3OD): 7.34 (d, J =8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.72 (t, J=8.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:42][CH2:41][C:36]4([CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:44]([O-:46])=[O:45])[CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O-:47][C:48]#[N:49].[K+].O>CO>[NH2:49][C:48]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26](=[O:43])[C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:34][CH2:35][C:36]4([CH2:37][CH2:38][CH2:39][CH2:40]4)[CH2:41][CH2:42]3)=[CH:31][CH:32]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:44]([O-:46])=[O:45])[CH2:7][S:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:47]
Reactant: N#C[O-]
Reactant: NCCCC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC4(CCCC4)CC3)cc2)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=O)NCCCC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC4(CCCC4)CC3)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of Example 287 (60 mg, 0.1 mmol) and potassium cyanate (20 mg, 0.25 mmol) in methanol (1 mL) was stirred at 55° C. for 1.5 hours, cooled to room temperature, treated with water, and extracted with dichloromethane. The combined extracts were washed with saturated sodium bicarbonate, dried (MgSO4), filtered, and concentrated. The concentrate was purified by reverse phase HPLC with 0-100% acetonitrile/water containing 0.1% TFA to provide the desired product. MS (ESI(+)) m/e 709 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.53 (d, 1H), 8.32 (d, 1H), 7.85 (dd, 1H), 7.73 (d, 2H), 7.25-7.10 (m, 6H), 6.93 (d, 2H), 5.90 (s, 1H), 4.10 (m, 1H), 3.34 (m, 6H), 2.91 (t, 2H), 1.75 (m, 1H), 1.59 (m, 4H), 1.42 (m, 8H), 1.34 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[O:22][CH2:21][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[NH:13][C:12]4=[O:20])[C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:46][C:47]1[O:48][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:50][CH:51]=1.ClCC1C=NC(OC)=NC=1>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[O:22][CH2:21][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]([CH2:46][C:47]5[O:48][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:50][CH:51]=5)[C:12]4=[O:20])[C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)Nc2ccccc21
Agent: COc1ncc(CCl)cn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using 3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 5-(chloromethyl)-2-methoxypyrimidine, 3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione was obtained (59%) as a colorless solid: mp 198-199° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 7.37-7.30 (m, 1H), 7.23-7.18 (m, 3H), 7.12-7.03 (m, 2H), 6.77 (s, 1H), 6.56 (s, 1H), 5.17-4.99 (m, 2H), 4.91-4.75 (m, 2H), 3.31 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.2, 156.8, 154.3, 152.9, 141.5, 136.1, 132.9, 131.4, 128.9, 123.6, 123.3, 121.5, 114.0 (2C), 109.8, 109.2, 104.2, 92.4, 79.3, 57.2, 36.4, 28.1; MS (ES+) m/z 456.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:27]([NH:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:27]([NH:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][N:23]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCCN(S(C)(=O)=O)C1
Reaction time: 1 h
Yield: 59 %

Procedure:
3-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methylpiperidine-3-carboxamide (Example 89.1, Isomer 1) (100 mg, 0.21 mmol) was dissolved in dichloromethane (2.5 ml) and diisopropylethylamine (54 μl, 0.31 mmol) added. Methanesulfonyl chloride (19 μl, 0.25 mmol) was added and the mixture stirred for 1 hour, absorbed onto an Isolute SCX column, washed with methanol and eluted with ammonia in methanol. The appropriate fractions were concentrated and the residues purified by column chromatography on silica, eluting with methanol/dichloromethane (2/98) to give the title product (Isomer 1) (70 mg, 60%) as a white solid; 1H NMR Spectrum: (DMSO d6) 1.67 (m, 1H); 1.92 (m, 2H); 2.07 (m, 1H); 2.21 (s, 3H); 2.66 (d, 3H); 2.88 (s, 3H); 3.03 (m, 1H); 3.21 (m, 1H); 3.34 (d, 1H); 3.52 (d, 1H); 3.62 (d, 1H); 3.79 (d, 1H); 3.96 (s, 3H); 7.20 (s, 1H); 7.30 (dt, 1H); 7.50 (m, 1H); 7.62 (m, 2H); 8.32 (s, 1H); 8.44 (s, 1H); 9.57 (s, 1H). Mass Spectrum: (M+H)+ 565.5
Reaction SMILES: C(O[C:9]([C:11]1[O:36][C:14]2=[CH:15][CH:16]=[C:17]3[C:21]([N:20]([CH2:22][C@@H:23]([NH:25][C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH3:24])[N:19]=[CH:18]3)=[C:13]2[CH:12]=1)=[O:10])C1C=CC=CC=1.[Cl-].[NH4+].[CH2:39]([CH2:41][NH2:42])[OH:40]>>[CH2:29]([O:28][C:26](=[O:27])[NH:25][C@@H:23]([CH3:24])[CH2:22][N:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]3[O:36][C:11]([C:9](=[O:10])[NH:42][CH2:41][CH2:39][OH:40])=[CH:12][C:13]3=2)[CH:18]=[N:19]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(C(=O)OCc4ccccc4)cc3c21)NC(=O)OCc1ccccc1
Reactant: NCCO
Agent: [Cl-]
Agent: [NH4+]
Product: C[C@@H](Cn1ncc2ccc3oc(C(=O)NCCO)cc3c21)NC(=O)OCc1ccccc1
Yield: 57 %

Procedure:
A stirred solution of the product from Step A, Example 2 (0.44 g, 0.91 mmol) in ethanolamine was heated at 80° C. for 8 h. A saturated aqueous solution of ammonium chloride (20 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried and evaporated to a residue, which was purified by chromatography (silica, 60% ethyl acetate in hexane) to give an oil (0.23 g, 57%): MS (ES) m/z 437 (M+); 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.69 (d, 1H, J=8.0 Hz), 7.22-7.30 (m, 7H), 5.30 (brs, 1H), 5.03 (m, 2H), 4.63 (m, 1H), 4.40 (m, 1H), 4.15 (m, 1H), 3.85 (m, 2H), 3.65 (m, 2H), 1.26 (d, 3H, J=8.0 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[C@H:9]2[CH3:20])[CH:5]=[N:4][C:3]=1[C:21]#[N:22].[CH:23]1([N:26]2[CH2:31][CH2:30][C:29]([C:33]3[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=3)([CH3:32])[CH2:28][CH2:27]2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[C@H:9]2[CH3:20])=[N:7][C:2]=1[NH:37][C:36]1[CH:38]=[CH:39][C:33]([C:29]2([CH3:32])[CH2:30][CH2:31][N:26]([CH:23]3[CH2:25][CH2:24]3)[CH2:27][CH2:28]2)=[CH:34][CH:35]=1)#[N:22]
Reactant: CC1(c2ccc(N)cc2)CCN(C2CC2)CC1
Reactant: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1c1cnc(C#N)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1c1cnc(C#N)c(Nc2ccc(C3(C)CCN(C4CC4)CC3)cc2)n1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
The mixture of 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (326) (75 mg, 0.23 mmol), 4-(1-cyclopropyl-4-methylpiperidin-4-yl)aniline (342) (65 mg, 0.28 mmol), fine-powder cesium carbonate (230 mg, 0.70 mmol), Pd(OAc)2 (16 mg, 0.07 mmol), BINAP (44 mg, 0.07 mmol) in 20 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered using ChemGlass OP-6602-12 disposable funnel. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 10% MeOH in DCM to isolate 3-((2R,3R)-1-(5-cyano-6-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (343). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added fine-powder cesium carbonate (50 mg), DIEA (60 μL), and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 30 min, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was acidified with TFA (0.5 mL) and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide (344) as HCl salt (68 mg, 55% overall yield for 2 steps). LC-MS (ESI): m/z (M+1) 535.9. UV: λ=268, 278, 306, 336, 372 nm. Proton NMR (CD3OD): δ 7.74-7.64 (3H, m), 7.38-7.33 (2H, m), 5.08 (1H, m), 4.33 (1H, m), 3.88 (1H, m), 3.62-3.47 (2H, m), 3.05 (2H, m), 2.96 (6H, s), 2.70-2.64 (2H, m), 2.20-2.12 (2H, m), 1.91-1.86 (4H, m), 1.75 (1H, m), 1.66 (1H, m), 1.45-1.26 (3H, s), 1.17 (3H, d, J=7.0 Hz), 1.02-0.89 (4H, m) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:19](=[O:20])[C:18]([CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[NH:17][C:16]2=[CH:35][C:36]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)=[O:37])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:20]=[C:19]1[N:15]([CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:16](=[CH:35][C:36]([C:38]2[CH:39]=[CH:40][C:41]([C:44]#[N:45])=[CH:42][CH:43]=2)=[O:37])[NH:17][C:18]1([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNCC2)cc1

Procedure:
Using the same procedure as described in Example 3, the title compound of 40A (0.958 g, 1.58 mmol) was treated with TFA (3 ml) in CH2Cl2 to give the title compound of 40B (0.621 g, 1.23 mmol, 78% yield).