Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[P:6](Cl)(Cl)=[N:5][P:4](Cl)(Cl)=[N:3][P:2]=1(Cl)Cl.[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>N1C=CC=CC=1>[CH2:13]([O:17][P:2]1([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=[P:4]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[N:5]=[P:6]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[N:1]=1)[CH2:14][CH2:15][CH3:16]
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Reactant: CCCCO
Solvent: c1ccncc1
Product: CCCCOP1(OCCCC)=NP(OCCCC)(OCCCC)=NP(OCCCC)(OCCCC)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a chilled solution (0°-5° C.) of triphosphonitrilic chloride (0.018 mole) in 26 ml of pyridine, butanol (0.34 mole) was added. The mixture was stirred at room temperature overnight, diluted with petroleum ether and washed with dilute HCl, NaHCO3, and water successively. After removal of solvent, the product IIa was obtained in a yield of 90%. Found (and calcd. for C24H54N3O6P3 /M.W. 574): C 48.96 (50.25); H 9.29 (9.49); N 7.71 (7.33) and P 16.11 (16.23).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18])[CH2:6][O:7][CH3:8].[I-].[CH3:23][N:24]1[C:32]2[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:34][N+](C)(C)C)=[CH:25]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:19])([CH3:20])[CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:34][CH:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[N:24]([CH3:23])[CH2:25]2)[C:10]1=[O:18])[CH2:6][O:7][CH3:8]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: COCC(n1c(=O)[nH]c2ccccc21)C(C)(C)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC(n1c(=O)n(CC2CN(C)c3cccc(C)c32)c2ccccc21)C(C)(C)C(=O)OC
Temperature: 100 °C
Reaction time: 4 h
Yield: 23.6 %

Procedure:
To a mixture of 4-methoxy-2,2-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butyric acid methyl ester (137 mg, 0.47 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (225 mg, 0.65 mmol) in DMF (2.5 mL) was added K2CO3 (200 mg, 1.45 mmol). The mixture was stirred at 100° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 50% EtOAc in Hexane as the eluent to afford the desired 3-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-2,2-dimethyl-butyric acid methyl ester (50 mg, 24%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][OH:13].[H-].[Na+].[CH3:16][S:17](Cl)(=[O:19])=[O:18].P([O-])([O-])([O-])=O>C1COCC1>[CH3:16][S:17]([O:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:19])=[O:18]
Reactant: OCCCC=COC1CCCCO1
Reactant: CS(=O)(=O)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCC=COC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
The alcohol 106 (147 mg, 0.791 mmol) was added to a suspension of NaH (60% in oil, 38 mg, 0.95 mmol, 1.2 equiv) in THF (5 mL). The resulting mixture was stirred at 25° C. for 30 min and cooled to 0° C. before CH3SO2Cl was added dropwise. The reaction mixture was stirred 15 min at 0° C. and 15 min at 25° C. Phosphate buffer (100 mL, pH 7) was added and the mixture extracted with CH2Cl2 (2×50 mL). The combined organic phase was dried (Na2SO4) and the solvent was removed under vacuum. Chromatography (SiO2, 2×25 cm, 30% EtOAc-hexane containing 2% Et3N) afforded 107 (205 mg, 208 mg theoretical, 98%) as a colorless oil as a mixture of E- and Z-olefin isomers (50:50): 1H NMR (CDCl3, 400 MHz) δ 6.24 (dt, J=12.3, 1.3 Hz, 0.5 H), 6.14 (dt, J=6.3, 1.4 Hz, 0.5H), 5.05 (dt, J=12.3, 7.5 Hz, 0.5H), 4.88 and 4.85 (two t, J=3.1, 3.4 Hz, 1H), 4.43 (m, 0.5H), 4.15 (m, 1H), 3.83 and 3.54 (two m, 2H), 3.05 (s, 3H), 2.17 and 1.98 (two m, 2H), 1.85-1.49 (m, 8H).
Reaction SMILES: C([O:8][C:9](=[O:33])[CH:10]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:15]=1[S:24]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH2:11][CH:12]=[CH2:13])C1C=CC=CC=1.[OH-].[Na+]>CO.O>[CH3:23][O:22][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:14]([CH:10]([CH2:11][CH:12]=[CH2:13])[C:9]([OH:33])=[O:8])=[C:15]([S:24]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)(=[O:26])=[O:25])[CH:16]=1
Reactant: C=CCC(C(=O)OCc1ccccc1)c1cc(OC)c(OC)cc1S(=O)(=O)N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCC(C(=O)O)c1cc(OC)c(OC)cc1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred mixture 2-[4,5-dimethoxy-2-(morpholine-4-sulfonyl)-phenyl]-pent-4-enoic acid benzyl ester (3.25 g, 6.83 mmol) in methanol (28 cm3) under an atmosphere of dry nitrogen was added sodium hydroxide (820 mg, 20.5 mmol) dissolved in water (7 cm3). The mixture completely dissolved while stirring at ambient temperature for 20 hours. The volatile fractions were removed in vacuo and water (30 cm3) was added to the mixture. The aqueous mixture acidified with 6N HCl to pH 1.0 and was extracted with dichloromethane (3×30 cm3). The combined extracts were washed with brine (30 cm3), dried over sodium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to a crude golden oil. The oil was triturated in Et2O (30 cm3), vacuum filtered, washed with Et2O (2×10 cm3) and vacuum dried to constant weight to afford the title compound as (2.30 g, 87.54%) with a positive ion ESI (M+H)+386.2.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:13]=[N:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]=1.[C:16]([O:20][C:21](=[O:32])[NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][OH:31])[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:16]([O:20][C:21](=[O:32])[NH:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][C:4]2[CH:13]=[N:12][C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=3)[N:5]=2)[CH2:27][CH2:28]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: COc1ccc2ncc(Cl)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.7 %

Procedure:
Sodium hydride (55% purity, 62 mg, 1.48 mmol, 1.5 eq) is added at room temperature to a stirred solution of 2-chloro-7-methoxy-quinoxaline (200 mg, 0.99 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL), followed by [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (268 mg, 0.99 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated, and the residue is extracted with dichloromethane (3×20 mL) and water (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:1:0 to 0:9:1, v/v/v) to afford {1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as an orange solid (210 mg, 52% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[CH:17]([O:19][C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23])[CH3:18].[OH-:28].[Na+].O>C(O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[CH:17]([O:19][C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]([NH2:23])=[O:28])[CH3:18]
Reactant: CC(Oc1ncccc1C#N)c1nnc(-c2ccccc2C(F)(F)F)n1C
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(Oc1ncccc1C(N)=O)c1nnc(-c2ccccc2C(F)(F)F)n1C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2-(1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)nicotinonitrile (270 mg) was dissolved in ethanol (10 ml), a 1M aqueous sodium hydroxide solution (3.7 ml) was added thereto, followed by stirring at 70° C. for 5 hours. The reaction solution was cooled to room temperature, and water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid was washed with ethyl acetate, to obtain, as a colorless solid, 2-(1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)nicotinamide (120 mg).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:21][CH3:22].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:21][CH3:22])(=[O:3])[CH3:2]
Reactant: CCc1cc(-c2ccccc2)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(-c2ccccc2)ccc1OC(C)=O
Yield: 90 %

Procedure:
4.6 g (45 mmol) of acetic anhydride are added dropwise to a solution of 7.3 g (37 mmol) of 4-hydroxy-3-ethyl-biphenyl and 3.2 g (40 mmol) of pyridine in 60 ml of chloroform, and the mixture is boiled under reflux for 3 hours. The solution is allowed to cool and then washed with water and dilute hydrochloric acid and the organic phase is dried and concentrated. 8.0 g (yield: 90% of theory) of 4-acetoxy-3-ethyl-biphenyl are obtained as a very clear oil of log p=3.92 (pH=2.3).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:5]([O:18][CH3:19])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:34]=[CH:33][C:24]2[S:25][C:26]([S:29](Cl)(=[O:31])=[O:30])=[C:27]([CH3:28])[C:23]=2[CH:22]=1>>[OH:10][CH2:9][CH2:8][C:7]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[C:5]([O:18][CH3:19])[CH:4]=[CH:3][C:2]=1[NH:1][S:29]([C:26]1[S:25][C:24]2[CH:33]=[CH:34][C:21]([Cl:20])=[CH:22][C:23]=2[C:27]=1[CH3:28])(=[O:31])=[O:30]
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COc1ccc(N)c(CCO)c1N1CCN(C)CC1
Product: COc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(CCO)c1N1CCN(C)CC1

Procedure:
The title compound (E126) was prepared from 2-[6-amino-3-methoxy-2-(4-methylpiperazin-1-yl)phenyl]ethanol (D32) (74 mg, 0.28 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (78 mg, 0.28 mmol) using the method of Example 1 (18 mg, 13%). MH+=510.
Reaction SMILES: C(O)(=O)C(O)=O.C(O[C:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14][N:13](CC2C=CC=CC=2)[CH2:12]1)(=O)C.[OH-].[Na+].C(Cl)[Cl:39]>>[ClH:39].[C:30]1([CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: ClCCl
Reactant: CC(=O)OC1(c2ccccc2Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cl
Product: c1ccc(Cc2ccccc2C2CCNC2)cc1
Reaction time: 8 h

Procedure:
25.9 g of 3-acetoxy-1-benzyl-3-(α-phenyl-2-tolyl)pyrrolidine oxalate of Example 57 is suspended at 0° C. in 500 ml CH2Cl2 and stirred with a slight excess of 5% NaOH for 1/2 hour. The organic layer is washed with water, dried (Na2SO4), and concentrated to an oil. This oil is dissolved in 200 ml of i-propanol and the solution is made acidic with a very slight excess of HCl/i-propanol and hydrogenated with 5 g of Pd on carbon (10%) at 70° C. and 60 psig for 8 hours. After filtration the solution is diluted with 700 ml of ether and after cooling the product is collected by filtration. Recrystallization from methanol-ether (40 ml-160 ml) provides 3-(α-phenyl-2-tolyl)pyrrolidine hydrochloride, mp 148°-149° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][C:44]=1[O:45][CH3:46])[N:41]=[CH:40][N:39]=[C:38]2[O:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[C:48]([O:47][C:38]3[C:37]4[C:42](=[CH:43][C:44]([O:45][CH3:46])=[C:35]([O:34][CH3:33])[CH:36]=4)[N:41]=[CH:40][N:39]=3)[CH:49]=2)=[O:19])[N:7]([CH2:20][CH:21]([CH3:22])[CH3:23])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4CC(C)C)c3)c2cc1OC
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.47 mmol), N,N-Diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (92 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (60 mg, 38%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 7.61 (m, 1H), 7.57 (m, 1H), 7.37-7.41 (m, 2H), 7.24 (m, 1H), 6.94 (m, 1H), 6.01 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.71 (d, J=7.6 Hz, 2H), 2.07 (m, 1H), 1.20 (s, 9H), 0.83 (d, J=6.4 Hz, 6H); LC-MS (ESI) m/z 519 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl-:15].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:2]3[CH:7]=[CH:6][C:5]([Cl:15])=[CH:4][CH:3]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Clc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 203.1 %

Procedure:
A suspension of 4-(4-Bromo-phenyl)-piperidin-4-ol (4.02 g, 15.7 mmol) in chlorobenzene (30 ml) was added dropwise to a suspension of aluminium chloride (7.32 g, 54.9 mmol) in chlorobenzene (10 ml) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours, quenched by addition of ice then methyl t-butyl ether added. After stirring for 1 hour the precipitate was collected by filtration washed with water, methyl t-butyl ether and water to afford the title compound (5.59 g, 92% yield). LC/MS: (PS-33) Rt 3.57 [M+H]+350, 352.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[CH3:31]>>[CH3:31][C:22]1[CH:23]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:29]=[CH:30][C:21]=1[O:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(C)c1

Procedure:
The title compound was prepared from 7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) and methyl 4-bromo-3-methylbenzoate using the method outlined in Example 128 (211 mg, 29%); NMR (CDCl3) δ 1.49 (9H, s), 2.32 (3H, m), 2.86 (4H, m), 3.55 (4H, m), 3.89 (3H, s), 6.71-6.81 (3H, m), 7.08 (H, m), 7.80 (H, m), 7.94 (H, s)
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:6][CH2:5][N:4]([C:7]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:8]=2[CH:9]=[N:10][CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:3]1.[SH:23][C@@H:24]([CH2:28][C:29]([OH:31])=[O:30])[C:25](O)=[O:26]>C1(C)C=CC=CC=1>[F:21][C:20]1[C:7]([N:4]2[CH2:5][CH2:6][C:2]([F:1])([F:22])[CH2:3]2)=[C:8]([CH:9]2[N:10]([CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:25](=[O:26])[C@H:24]([CH2:28][C:29]([OH:31])=[O:30])[S:23]2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C[C@H](S)C(=O)O
Reactant: CC(C)(C)CCN=Cc1cccc(F)c1N1CCC(F)(F)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)O)SC1c1cccc(F)c1N1CCC(F)(F)C1

Procedure:
N-(2-(3,3-Difluoropyrrolidin-1-yl)-3-fluorobenzylidene)-3,3-dimethylbutan-1-amine (400.2 mg, 1.281 mmol) was taken in toluene and (S)-2-mercaptosuccinic acid (192.3 mg, 1.281 mmol) was added. The reaction mixture was refluxed overnight with a Dean Stark trap to remove the water. Then the reaction mixture was concentrated, triturated with ether and dried overnight to give 2-((5S)-2-(3-fluoro-2-(3,3-difluoropyrrolidin-1-yl)phenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid which was used directly in the next step. The product was identified by LC/MS. LC/MS: m/z=445.5M+1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([NH:19][CH3:20])=[O:18])[C:11]([C:25]([CH3:27])=[CH2:26])=[CH:10][N:9]=2)=[CH:5][C:4]([CH3:28])=[N:3]1.N#N>C(O)C.O=[Pt]=O>[CH3:1][N:2]1[C:6]([NH:7][C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([NH:19][CH3:20])=[O:18])[C:11]([CH:25]([CH3:26])[CH3:27])=[CH:10][N:9]=2)=[CH:5][C:4]([CH3:28])=[N:3]1
Reactant: C=C(C)c1cnc(Nc2cc(C)nn2C)cc1Nc1ccccc1C(=O)NC
Agent: O=[Pt]=O
Agent: N#N
Solvent: CCO
Product: CNC(=O)c1ccccc1Nc1cc(Nc2cc(C)nn2C)ncc1C(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.3 %

Procedure:
A solution of 2-[2-(2,5-dimethyl-2H-pyrazol-3-ylamino)-5-isopropenyl-pyridin-4-ylamino]-N-methyl-benzamide (0.13 g, 0.345 mmole, 1 eq) in ethanol (10 mL) was degassed with N2 and to this PtO2(0.012 g, 0.052 mmole, 0.15 eq) was added. The resulting mixture was stirred at room temperature under H2 atmosphere with balloon pressure for 10 h. After completion of the reaction, it was filtered through a celite bed which was then washed with ethanol (10 mL). The filtrate was evaporated under reduced pressure to give a solid residue which was purified by washing with diethyl ether to give the title compound as a gray solid (80 mg, 61%). 1H-NMR (400 MHz, DMSO-d6): δ 1.24-1.26 (d, 6H, J=6.76 Hz), 2.05 (s, 3H), 2.75-2.76 (d, 3H, J=4.48 Hz), 2.89-3.10 (m, 1H), 3.53 (s, 3H), 5.96 (s, 1H), 6.67 (s, 1H), 6.85-7.10 (m, 1H), 7.40-7.50 (m, 2H), 7.65-7.67 (d, 1H, J=7.76 Hz), 7.86 (s, 1H), 8.36 (s, 1H), 8.60-8.70 (brs, 1H), 9.89 (s, 1H). LC-MS [M+H]+=379.2.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][N:13]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccncn1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccncn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
p-Anisaldehyde (320 g, 2.35 mol, 1.0 equiv; Aldrich, St. Louis, Mo.) and 4-aminopyrimidine (246 g, 2.58 mol, 1.1 equiv; AK Scientific, Inc., Union City, Calif.) were dissolved in anhydrous DCM (8.0 L). To this solution under N2 atmosphere at room temperature was added a solution of Ti (Oi-Pr)3Cl (1348 g, 5.17 mol, 2.2 equiv; Aldrich) in anhydrous DCM (1 L) in one portion and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then cooled to 10° C. and NaBH(OAc)3 (1495 g, 7.05 mol, 3.0 equiv; Aldrich) was added in portions over 30 min followed by the addition of acetic acid (10 mL). (Note: A mild exotherm of 10-19° C. was observed). Upon completion of the addition, the reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction was monitored using LC/MS. Product formation was observed along with many other peaks. Upon completion the reaction mixture was quenched slowly and carefully pouring over a well-stirred saturated aqueous NaHCO3 (30 L). The crude product was then extracted with dichloromethane (3×12 L) and the organic extracts were combined, washed with brine (5 L), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was initially triturated with hexanes to obtain a solid. The crude solid was further triturated with MTBE to remove most of the impurities. The crude product was purified using column chromatography eluting with MeOH/ethyl acetate (2:98 to 5:95) to afford N-(4-methoxybenzyl)pyrimidin-4-amine (INTERMEDIATE OO) as a white solid with >99% purity (129 g, 26% yield). 1H NMR (400 MHz, DMSO) δ ppm 8.40 (s, 1H), 8.02 (d, J=6.1 Hz, 1H), 7.82 (t, J=6.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 2H), 6.98-6.77 (m, 2H), 6.48 (s, 1H), 4.43 (s, 2H), 3.72 (s, 3H). m/z (ESI) 216.0 (M+H)+
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:8][C:7]=12.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[C:25]2[CH2:33][CH2:32][NH:31][CH2:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([N:31]3[CH2:32][CH2:33][C:25]4[C:24]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=5)=[N:29][CH:28]=[N:27][C:26]=4[CH2:30]3)=[O:14])=[CH:9][NH:8][C:7]=12
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-c2ncnc3c2CCNC3)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
To a flask containing 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.264 g, 0.884 mmol) was added a solution of 4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, TFA (0.5 g, 1.149 mmol) in DMF (8 mL) followed by Hunig's Base (0.772 mL, 4.42 mmol) and finally TBTU (0.369 g, 1.149 mmol). After stirring the mixture at rt for 4 h, it was quenched with 10 mL of water and concentrated under reduced pressure. The residue was diluted with water (25 mL) and sat. aq. ammonium chloride (25 mL) added to the mixture. The mixture was extracted with dichloromethane (3×40 mL). The combined organic layers were washed with sat. aq. NaHCO3, dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by BIOTAGE® flash chromatography using a 0-6% MeOH in dichloromethane gradient. The expected product, 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethane-1,2-dione (0.333 g, 0.675 mmol, 76% yield), was isolated as a brown solid. LC/MS: m/z 493 (M+H)+, 495.13 (M+3H)+, 2.177 min (method 3). 1H NMR (500 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1H) 9.05-9.19 (m, 1H) 8.66-8.78 (m, 1H) 8.33-8.44 (m, 1H) 7.99-8.12 (m, 2H) 7.82 (s, 1H) 7.50-7.60 (m, 1H) 4.66-4.91 (m, 2H) 3.63-3.92 (m, 5H) 3.11-3.32 (m, 2H).