Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.FC(F)(F)C(O)=O.[C:19]([N:26]1[CH2:30][CH2:29][C:28](=O)[CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH:7]1[C:8]2[C:3](=[C:2]([NH:1][CH:29]3[CH2:28][CH2:27][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:30]3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Nc1cccc2cnccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cnccc23)C1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
A 5 L flask (Flask A) equipped with a mechanical stirrer, internal temperature probe and addition funnel was charged with 5-aminoisoquinoline (300 g, 2.08 mol) and 2.7 L of tetrahydrofuran. Trifluoroacetic acid (543 mL, 7.29 mol) was added slowly while maintaining an internal temperature of <32° C. 1-Boc-3-pyrrolidinone (462.5 g, 2.50 mol) was added and the mixture was stirred for 10-30 minutes. A separate 12 L flask (Flask B) equipped with an internal temperature probe, mechanical stirrer and nitrogen inlet was flushed with nitrogen and charged with sodium triacetoxyborohydride (662.5 g, 3.13 mol) and 1.5 L of tetrahydrofuran. The contents of Flask A were slowly transferred to Flask B while maintaining an internal temperature in Flask B of <32° C. The reaction was stirred at 20-32° C. for 6 hours and all 5-aminoisoquinoline was consumed. The reaction was quenched with 3 L of 5N NaOH maintaining a temperature of <45° C. After 20 minutes, the aqueous layer was separated. The organic phase was washed with 3 L of 2N NaOH at 40° C. (with external heating). The organic phase was diluted with isopropyl acetate (2.25 L), washed with 1.5 L of water at 40° C. (with external heating), and concentrated to ˜2 L by distillation. The resulting solution was cooled to ˜20° C. The resulting slurry was filtered, washed (3×200 mL of MTBE), and dried in a vacuum oven at ˜60° C. Approximately 536 g of tert-Butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylate was isolated as a solid (82% yield).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:17][CH:16]=2)[CH2:10][C:11]([NH:13]C)=[O:12])[CH:5]=[CH:6][C:7]=1F.[Cl:26]C1C=CC([Mg]Br)=CC=1>>[Cl:26][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:17][CH:16]=2)[CH2:10][C:11]([NH2:13])=[O:12])=[CH:3][CH:2]=1
Reactant: CNC(=O)CC(c1ccc(-c2cn[nH]c2)cc1)c1ccc(F)c(F)c1
Reactant: Clc1ccc([Mg]Br)cc1
Product: NC(=O)CC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
By following the procedure described in Example 9A and 9B but substituting 3,4-difluorophenylmagnesium bromide for 4-chlorophenylmagnesium bromide, the title compound was obtained. LC/MS: (PS-A2) Rt 2.54 [M+H]+ 326. 1H NMR (Me-d3-OD) δ 2.95 (2H, d), 4.53 (1H, t), 7.27 (6H, m), 7.50 (2H, d), 7.91 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[N:5]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:4](=[O:18])[CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[N:5]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:4](=[O:18])[C:3]=1[Br:19]
Reactant: CSc1ncc2c(N)cc(=O)n(C3CCC3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CSc1ncc2c(N)c(Br)c(=O)n(C3CCC3)c2n1
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a mixture of 5-amino-8-cyclobutyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.3 g, 4.46 mmol) in DCM (120 mL) at 0° C. was added N-bromosuccinimide (0.87 g, 4.9 mmol) in 5 portions over 5 min. After stirring for 30 min, the DCM was evaporated under reduced pressure and the residue treated with 100 mL water and 100 mL NaHCO3 (sat'd, aq). The crude product was extracted into EtOAc (2×100 mL). The combined organic layers were washed with NaHCO3 (4×60 mL) and water (2×50 mL) and evaporated under reduced pressure to give 1.3 g of 5-amino-6-bromo-8-cyclobutyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a brown solid.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:10][O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15]>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:17]([NH:16][C:14](=[O:15])[C:13]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[O:11][CH3:10])=[O:18])[CH2:3]2
Reactant: COc1ccccc1C(=O)N=C=O
Reactant: NC1CN2CCC1CC2
Product: COc1ccccc1C(=O)NC(=O)NC1CN2CCC1CC2
Yield: 105.5 %

Procedure:
This compound was prepared by the procedure of example 1, using 3-aminoquinuclidine (0.63 g, 5 mmol) and 2-methoxybenzoyl isocyanate (1.0 g, 5 mmol), giving crude title product (1.6 g) which was purified as its 1:1 fumarate mp 187°-188° C. (0.79 g)
Reaction SMILES: [C:1]([C:7]1[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=1[C:9](N(C)OC)=[O:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][Mg]Cl)=[CH:22][CH:21]=1>C1COCC1>[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][C:9]([C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:10])=[CH:22][CH:21]=1
Reactant: CCCCC#Cc1ccccc1C(=O)N(C)OC
Reactant: Fc1ccc(C[Mg]Cl)cc1
Solvent: C1CCOC1
Product: CCCCC#Cc1ccccc1C(=O)Cc1ccc(F)cc1
Yield: 61 %

Procedure:
2-(1-Hexyn-1-yl)-N-methyl-N-(methyloxy)benzamide (158) (0.50 g, 2.04 mmol) was treated with 4-fluorobenzylmagnesium chloride in THF at room temperature to give 0.37 g (61%) of compound (165) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.93 (t, J=7.2 Hz, 3H), 1.40-1.53 (m, 2H), 1.56-1.65 (m, 2H), 2.45 (t, J=7.1 Hz, 2H), 4.40 (s, 2H), 6.99 (t, J=8.6 Hz, 2H), 7.16-7.22 (m, 2H), 7.26-7.32 (m, 1H), 7.35-7.41 (m, 1H), 7.45-7.52 (m, 2H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[NH:20]1[CH:24]=[N:23][N:22]=[N:21]1>>[N:20]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=2)[CH:24]=[N:23][N:22]=[N:21]1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: c1nnn[nH]1
Product: CN(C(=O)Oc1ccc(Cn2cnnn2)cc1)c1ccccc1
Yield: 6 %

Procedure:
The title compound was prepared in 6% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and tetrazole. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.57 (s, 2H), 7.17 (br s, 2H), 7.26–7.42 (m, 7H), 8.52 (s, 1H); HPLC-MS: m/z=332.0 (M+23); Rt=3.24 min.
Reaction SMILES: [CH:1]1([P:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8]C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([S:24][CH3:25])[N:18]=1>ClC1C=CC=CC=1Cl>[CH:1]1([P:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)([C:17]2[CH:22]=[C:21]([P:7]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[N:20]=[C:19]([S:24][CH3:25])[N:18]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: COP(C1CCCCC1)C1CCCCC1
Solvent: Clc1ccccc1Cl
Product: CSc1nc(P(=O)(C2CCCCC2)C2CCCCC2)cc(P(=O)(C2CCCCC2)C2CCCCC2)n1
Yield: 5.3 %

Procedure:
A mixture of 2.50 g of methyl dicyclohexylphosphinite and 1.00 g of 4,6-dichloro-2-methylthiopyrimidine in 20 ml of o-dichlorobenzene was refluxed under nitrogen for 6.5 hours. Volatiles were removed from the mixture under vacuum, and the resulting oily residue was recrystallized twice from cyclohexane with decolorizing charcoal treatment and dried at 100° C./0.1 mm (13 Pa) to give 0.15 g of 4,6-bis(dicyclohexylphosphinyl)-2-methylthiopyrimidine as white crystals, mp 197°-198.5° C. Anal. Calcd for C29H48N2O2P2S: C, 63.25; H, 8.79; N, 5.07; S, 5.82. Found: C, 63.19; H, 8.81; N, 4.89; S, 6.04.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH3:13][Si](C=[N+]=[N-])(C)C>CO.ClCCl>[CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C(=O)O)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: CCCc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
To a 0° C. solution of 4-propylbenzoic acid (2 g, 12.18 mmol) in methanol (3.00 mL) and dichloromethane (10 mL) was added trimethylsilyldiazomethane (7.92 mL, 15.83 mmol), dropwise over a period of 5 min. Towards the end of the addition, the reaction mixture was pale yellow. The reaction was stirred at 0° C. for 30 min. and the excess diazo reagent was quenched by the slow addition of acetic acid at 0° C. (˜1.5 mL). The colorless solution was concentrated and partitioned between ether (20 mL) and sat. aq. sodium bicarbonate (10 mL). The ether layer was washed with brine (10 mL), dried over sodium sulfate and concentrated to yield methyl 4-propylbenzoate (2.1 g, 11.78 mmol, 97% yield) as a liquid. 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (d, J=8.28 Hz, 2H) 7.24 (d, J=8.53 Hz, 2H) 3.90 (s, 3H) 2.61-2.67 (m, 2H) 1.59-1.71 (m, 1H) 0.94 (t, J=7.40 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH:34]=[N:33][CH:32]=[N:31]5)=[CH:28][CH:29]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: BrCc1ccc(-n2cncn2)cc1
Product: Cc1nc(-c2ccn(Cc3ccc(-n4cncn4)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-(4-bromomethyl-phenyl)-1H-[1,2,4]-triazole as described in Example 49 and isolated as a white solid (76 mg, 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.53-8.57 (m, 1H), 8.54 (s, 1H), 8.10 (s, 1H), 7.66-7.71 (m, 3H), 7.45 (bs, 1H), 7.39 (d, J=8 Hz, 1H), 7.37-7.41 (m, 1H), 6.88 (s, 1H), 6.05-6.12 (m, 1H), 5.41 (s, 2H), 4.63 (d, J=4 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=457.2; Rt=1.08 min; HRMS (M+H)+=457.16.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH3:36])[C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][N:29]=2)[CH3:36])=[CH:25][CH:26]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: COc1ccnc(N(C)c2ccc(I)cc2)n1
Product: COC(=O)C(C/C=C/c1ccc(N(C)c2nccc(OC)n2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 43.6 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (43 mg) was reacted with N-(4-iodophenyl)-4-methoxy-N-methylpyrimidin-2-amine (51 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-methoxy-pyrimidin-2-yl)-methyl-amino)phenyl]pent-4-enoic acid methyl ester (32 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1) was used for purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl.O>C(O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(C)cccc1COCCCOCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(COCCCOCc2ccc3ccccc3n2)c1C(=O)O
Temperature: 90 °C

Procedure:
Methyl 2-methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoate (3.3 g, 8.7 mmol, EXAMPLE 35a) is dissolved in ethanol (81 mL). 10 N NaOH (9 mL, 90 mmol) is added and the contents are heated to 90° C. overnight. The reaction is cooled to r.t., and the volume reduced under vacuum. 2 N HCl (45 mL, 90 mmol) is added, and the pH is adjusted to ˜4. The contents are poured into water (400 mL) and extracted with dichloromethane (3×200 mL). The organic layers are combined, washed with brine (2×300 mL), dried over MgSO4, filtered and reduced under vacuum to dryness. The crude material is purified by flash chromatography (silica, 3% methanol in dichloromethane) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.27 (d, 2H), 7.86 (d, 1H), 7.73 (dd, 1H), 7.60-7.50 (m, 2H), 7.26-7.11 (m, 3H), 5.01 (s, 2H), 4.70 (s, 2H), 3.84 (t, 2H), 3.73 (t, 2H), 2.50 (s, 3H), 1.89 (quintet, 2H). MS (ESI) 366 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:20][CH2:21][O:22][CH3:23])[S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-])=O)[C:10]=1[OH:19])(=[O:8])=[O:7].[H][H]>[Pd]>[CH3:23][O:22][CH2:21][CH2:20][N:5]([CH2:4][CH2:3][O:2][CH3:1])[S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([NH2:16])[C:10]=1[OH:19])(=[O:7])=[O:8]
Reactant: [H][H]
Reactant: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Product: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 87.5 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N,N-di-(2-methoxyethyl)-6chloro-2-hydroxy-3-nitrobenzenesulfonamide (100 mg, 0.27mmol) was reduced with hydrogen and 10% Pd/C (50 mg) to form the desired product (80 mg, 87%). 1H NMR (MeOD-d4): δ 6.85 (m, 2H), 3.58 (t, 4H), 3.47 (t, 4H), 3.21 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C@@H:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])=[C:4]([NH:23][C:24]2[CH:25]=[N:26][C:27](F)=[CH:28][CH:29]=2)[CH:3]=1.CC(O)=[O:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([CH:10]([NH:12][C:13]3[N:21]=[CH:20][N:19]=[C:18]4[C:14]=3[N:15]=[CH:16][NH:17]4)[CH3:11])[N:23]([C:24]3[CH:29]=[CH:28][C:27](=[O:33])[NH:26][CH:25]=3)[C:4]=2[CH:3]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Reactant: CC(=O)O
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccc(=O)[nH]c1
Temperature: 100 °C
Yield: 16 %

Procedure:
A mixture of (S)—N-[4-fluoro-2-(6-fluoropyridin-3-ylamino)phenyl]-2-(9H-purin-6-ylamino)propionamide (255 mg, 0.62 mmol) in AcOH (10 mL) was heated at 100° C. for 24 h. After cooling to RT, the volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% 2M NH3/MeOH in DCM) to afford 382 as a pink solid (38 mg, 16%). LCMS (Method K): RT 2.40 min [M+H]+ 391.0. 1H NMR (DMSO-d6+TFA-D, 400 MHz, 80° C.): δ 8.58-8.49 (2H, m), 7.82 (1H, d, J=2.96 Hz), 7.75 (1H, dd, J=8.81, 4.70 Hz), 7.51 (1H, dd, J=9.59, 2.99 Hz), 7.21-7.07 (2H, m), 6.40 (1H, d, J=9.60 Hz), 5.86 (1H, br d), 1.79 (3H, d, J=6.82 Hz)
Reaction SMILES: C[Al](C)C.[CH3:5][CH:6]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22]C)=O)=[CH:16][N:15]=2)[CH2:9]1)[CH3:7].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH:41][C:20]([C:17]3[CH:18]=[N:19][C:14]([N:10]4[CH2:11][CH2:12][NH:13][C@@H:8]([CH:6]([CH3:5])[CH3:7])[CH2:9]4)=[N:15][CH:16]=3)=[O:22])[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCN[C@@H](C(C)C)C2)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN[C@@H](C(C)C)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
Trimethylaluminium (2M in toluene, 1.23 mL, 2.46 mmol) was added dropwise to a stirred suspension of (S)-methyl 2-(3-prop an-2-ylpiperazin-1-yl)pyrimidine-5-carboxylate (260 mg, 0.98 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (243 mg, 0.98 mmol) in toluene (8.38 mL) at room temperature. The reaction was then stirred at 60° C. for 18 h under a nitrogen atmosphere. The reaction mixture was quenched into methanol (100 mL) and treated with HCl (2N aqueous solution, until the pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (292 mg, 62%) as a white solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C@@H:11]([OH:13])[CH3:12].[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[N:18]=1>C1COCC1>[Cl:16][C:17]1[CH:22]=[C:21]([O:13][C@H:11]([C@H:2]2[CH2:3][O:4][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[O:1]2)[CH3:12])[N:20]=[C:19]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[N:18]=1
Reactant: C[C@H](O)[C@H]1COC2(CCCCC2)O1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (1S)-1-[(2R)-1,4-dioxaspiro[4.5]dec-2-yl]ethanol (prepared according to J. Org. Chem. 1995, 60, 585-587, 0.183 g of ˜2:1 mixture of diastereomers) in dry THF (5 ml) was cooled to 0° C. and to it was added (in portions) sodium hydride (46 mg as 60% dispersion in mineral oil) followed in portions by 4,6-dichloro-2-(2,3-difluoro-benzylsulfanyl)-pyrimidine (product of example 1 step ii, 0.252 g). The reaction mixture was stirred at room temperature for 24 h then quenched with saturated aqueous ammonium chloride (2 ml) and diluted with EtOAc. The layers were separated and the aqueous layer extracted with further EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated to leave a yellow oil which was purified by column chromatography on silica using a 0.5 to 4% mixture of EtOAc in iso-hexane as eluent to afford the subtitle compound as a white solid. Yield: 0.10 g
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([CH3:17])=[CH:12][C:13]([Br:16])=[C:14]([F:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Br:16][C:13]1[CH:12]=[C:11]([CH3:17])[C:9]2=[N:10][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=[C:8]2[C:14]=1[F:15]
Reactant: Cc1cc(Br)c(F)c2nn(CC(C)(N)C#N)nc12
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: Cc1cc(Br)c(F)c2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-bromo-4-fluoro-7-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile (120 mg, described in Example 50) and 4-trifluoromethylthiobenzoyl chloride (0.09 mL), the title compound was isolated as a white solid (175 mg, 88%). Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z [M+H]=516. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 2.41 (s, 3H), 5.41 (d, J=13.3 Hz, 1H), 5.56 (d, J=13.3 Hz, 1H), 7.45 (dd, J=5.9, 1.1 Hz, 1H), 7.85-7.90 (m, 4H), 8.90 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −122.4 (d, J=5.3 Hz, 1F), −42.0 (s, 3F).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:32]=1)[C:20](=[O:29])[CH2:21][C:22]([O:24][C:25](C)(C)C)=[O:23].Cl>CO.O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:32]=1)[C:20](=[O:29])[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CC(=O)OC(C)(C)C)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CC(=O)OC)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product from step (i) (100 mg) was dissolved in methanol (3 ml) and 4N—HCl in dioxane added. The mixture was stirred at rt for 5 h and purified by RPHPLC, which afforded the title compound. Yield 80 mg
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)([O:3][CH2:4][CH3:5])=[O:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].N1C=CC=CC=1>C(O)C>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:15]2[C:14]3[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1Nc1cccc(Br)c1

Procedure:
A mixture of 14.8 g of 3-carbethoxy-4-chloro-6,7-dimethoxylquinoline, 9.46 g of 3-bromoaniline, 4.05 ml of pyridine, and 150 ml of ethanol was refluxed for 30 min, evaporated to remove ethanol, and partitioned with dichloromethane-aq sodium bicarbonate. The organic layer was washed with water, dried, and concentrated. The residue was recrystallized from ethanol to give a white solid, mp 155-158° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([N+:12]([O-])=O)[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C.[C].[Pd]>[NH2:12][C:9]1[CH:8]=[C:7]([C:15](=[O:17])[CH3:16])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:10]=1[OH:11]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1cc(N)c(O)c(C(C)(C)C)c1
Reaction time: 3 h
Yield: 71.7 %

Procedure:
After adding 10% palladium-carbon (50% wet) (100 mg) to a solution of 1-[3-(tert-butyl)-4-hydroxy-5-nitrophenyl]-1-ethanone (1.00 g, 4.22 mmol) in ethyl acetate (10 ml) at room temperature, the mixture was hydrogenated for 3 hours under normal pressure. The 10% palladium-carbon was then filtered through celite and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (Wakogel-C200,10 g) to yield the title compound (627 mg, 71.8% yield) as a light red powder from the ethyl acetate-hexane (1:4˜1:3) fraction.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: C1CCNC1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCCl)CC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCN3CCCC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(4-chloro-butane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 255) and pyrrolidine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C25H36N6O4SF [(M+H)+]535.2500, observed 535.2498.