Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:5])[C:3]#[N:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][S:23](Cl)(=[O:25])=[O:24])=[CH:18][CH:17]=1.N1(C2CCCCCCC2)CCCCCCN1>O1CCCC1.C(OCC)(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:2]([S:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:24])=[O:25])([CH3:5])[C:3]#[N:4])=[CH:9][CH:10]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: CC(N)(C#N)COc1ccc(Cl)cc1
Agent: C1CCCC(N2CCCCCCN2)CCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C#N)(COc1ccc(Cl)cc1)S(=O)(=O)Cc1ccc(Cl)cc1

Procedure:
A solution of 2-amino-2-(4-chlorophenoxymethyl)-propionitrile (0.5 g, 0.24 mmol), 4-chlorophenyl-methylsulfonyl chloride (0.46 g, 2.4 mmol) and diazabicyclooctane (0.6 g, 2.4 mmol) in anhydrous tetrahydrofuran (20 ml) is stirred for about 16 hours. The reaction mixture is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate and the raw product received as the residue is purified by flash chromato-graphy (eluent: ethyl acetate/hexanes 1:3) to give the 2-(4-chlorophenoxy-methyl)-2-(4-chlorophenyl-methylsulfonyl)-propionitrile in form of colorless crystals, m.p. 119-120° C.
Reaction SMILES: C[NH:2][C:3]1([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]=NC(NC)=N1.Cl.[NH3:20].[CH3:21]O>>[NH3:2].[CH:16]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[N:20]=[CH:21][CH:7]=[CH:3][C:10]=3[C:18]=2[CH:17]=1
Reactant: CNC1=NC(NC)(c2c[nH]c3ccccc23)C=N1
Reactant: CO
Agent: Cl
Agent: N
Product: c1ccc2c(c1)[nH]c1ncccc12

Procedure:
This example describes the synthesis of compounds 7 and 8 of FIG. 5. A solution of 2-dimethylamino-4-(3-indolyl)imidazole 5.HCl (0.2 g, 0.76 mmol) in 40 mL of methanol saturated with ammonia (MeOH, sat. NH3) was allow to stir in the presence of air at 25° C. for 1 day during which time compound 7 precipitated from the solution as a dark solid and was collected by filtration. Resubjection of 7 to an ammonia saturated methanol solution in air for 7 days at 25° C. produced compound 8 as a orange solid after concentration of the reaction mixture in vacuo followed by Flash silica gel chromatography (CH2Cl2/MeOH(NH3), 19:1). The yield of compound 8 was 60%. Referring to FIGS. 21 and 22, Compound 7: 1H NMR (300 MHz, DMSO-d6) δ 11.98 (bs, 2H), 10.43 (s, 2H), 8.72 (m, 2H), 7.49 (m, 2H), 7.22 (m, 4H), 3.46 (bs, 6H); 13CNMR (100 MHz, DMSO-d6) δ 173.2 (sx2), 172.1 (sx2), 147.2 (sx2), 139.5 (dx2), 137.6 (sx2), 128.2 (sx2), 124.6 (dx2), 123.6 (dx2), 122.0 (dx2), 112.8 (dx2), 111.9 (sx2), 38.9 (qx4); HRFABMS calcd for C26H25N8 449.2202, found 449.2178. Referring to FIGS. 23-25, Compound 8: 1H NMR (300 MHz, DMSO-d6) δ 13.36 (s, 1H), 12.13 (s, 1H), 11.88 (bs, 1H), 11.00 (bs, 1H), 9.03 (d, J=7.7 Hz, 1H), 8.94 (bs, 1H), 7.96 (bs, 1H), 7.68 (dm, J=7.7 Hz, 1H), 7.55 (m, 2H), 7.42-7.28 (m, 3H), 3.37 (s, 6H); 13C NMR (100 MHz, DMSO-d6+D2O) δ 167.5 (s), 155.8 (s), 148.1 (s), 143.3 (d), 141.0 (s), 138.2 (s), 134.4 (s), 130.5 (s), 128.9 (d), 128.3 (d), 125.5 (d), 125.2 (s), 124.9 (d), 124.5 (d), 121.4 (d), 120.6 (d), 118.2 (s), 114.5 (d), 112.0 (d), 108.6 (s), 103.4 (s), 40.4 (qx2); HRFABMS calcd for C23H20N7 394.1780, found 394.1784.
Reaction SMILES: [CH2:1]([N:3]([CH2:6]C)[CH2:4]C)[CH3:2].C1C=CC2N([OH:17])N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:40]([CH2:41][CH2:42][CH3:43])=[C:39]([C:44]([NH:46][CH:47]3[CH2:49][CH2:48]3)=[O:45])[N:38]=[N:37]2)=[CH:32][CH:31]=1>ClCCl.Cl.CN(C)CC(O)=O>[CH:47]1([NH:46][C:44]([C:39]2[N:38]=[N:37][N:36]([C:33]3[CH:34]=[CH:35][C:30]([NH:29][C:2](=[O:17])[CH2:1][N:3]([CH3:6])[CH3:4])=[CH:31][CH:32]=3)[C:40]=2[CH2:41][CH2:42][CH3:43])=[O:45])[CH2:48][CH2:49]1
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CN(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
To a solution of N,N-dimethylglycine hydrochloride (0.17 mg), triethylamine (0.17 ml) and HOBt (0.18 g) in dichloromethane (10 ml) was added WSC (0.23 g), and the mixture was stirred at room temperature for 20 min. 1-(4-Aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.29 g) obtained in Example 1d) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with dichloromethane, and washed with aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by high performance liquid chromatography to give the title compound as a white powder (0.09 g, 24%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:38][NH2:39]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:39][CH2:38][C:34]5[S:33][CH:37]=[CH:36][CH:35]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCc1cccs1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NCc1cccs1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 39.6 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 2-thiophenemethylamine (available from Aldrich Chemical Company, Inc.; 70 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-[(thiophen-2-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid (47 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.24 (br s, 1H), 9.24 (t, J=5.9 Hz, 1H), 8.48 (s, 1H), 8.36 (dd, J=16.8, 2.0 Hz, 2H), 8.24 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (dd, J=8.4, 2.1 Hz, 1H), 7.94 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.40 (dd, J=5.1, 1.1 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 6.98 (dd, J=5.0, 3.5 Hz, 1H), 4.67 (d, J=5.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1.[CH2:45]([NH:47][CH3:48])[CH3:46]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][N:47]([CH2:45][CH3:46])[CH3:48])=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Reactant: CCNC
Solvent: C1CCOC1
Product: CCN(C)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.350 g, 0.541 mmol) and ethylmethylamine (1.0 mL, 12 mmol) in THF (8 mL) was stirred for 2 hours in a sealed tube at 70° C. Additional ethylmethylamine (1.0 mL, 12 mmol) was added, and the reaction mixture was stirred at 80° C. in sealed tube for 2 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. It was dried at 80° C. for 20 minutes in vacuo to yield {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-ethyl-methyl-amine as a yellow semi-solid (0.268 g, 92.7%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was then concentrated and dried in vacuo at 82° C. for 14 hours. The result was the hydrochloride as a light orange foam (0.266 g); Mass Spectrum (+EI, [M+H]+) m/z 534. 1HNMR (500 MHz, DMSO-d6): δ9.90-9.93 (s, br, 1H), 8.73-8.75 (m, 1H), 8.54-8.57 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.27 Hz), 7.70-7.74 (m, 1H), 7.56-7.63 (m, 2H), 7.30 (d. 1H, J=2.20 Hz), 7.15-7.26 (m, 4H), 7.04 (d, 1H, J=7.57 Hz), 5.73 (s, 2H), 4.36-4.38 (m, 2H), 3.40-3.55 (m, 3H), 3.09-3.14 (br, 1H), 2.78 (s, 3H), 1.19-1.23 ppm (m, 3H). Elemental Analysis for C29H28ClN3O3S.1.00 HCl.0.75 mol H2O: Calcd: C, 59.64; H, 5.26; N, 7.19; Found: C, 59.24; H, 5.17; N, 6.89.
Reaction SMILES: [CH2:1]([C@H:3]1[O:5][CH2:4]1)[Cl:2].[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.[K].C(Cl)Cl.O>CN(C=O)C>[C:6]1(=[O:16])[N:10]([CH2:4][C@H:3]([OH:5])[CH2:1][Cl:2])[C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12
Reactant: ClC[C@@H]1CO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CCl
Reaction time: 4.5 h

Procedure:
(S)-epichlorohydrin (III, 98.9% enantiomerically pure, 99.3 chemical % purity, 4.9605 g, 53.61 mmol) is added to a slurry of potassium phthalimide (VI, 5.031 g, 27.161 mmol, 0.507 eq) and phthalimide (VI, 11.836 g, 80.45 mmol, 1.5006 eq) in DMF (32 ml) and the mixture stirred at 50° for 4.5 hrs. The mixure is added to methylene chloride (50 ml) and water (50 ml) added. The solids are removed by filtration with reduced pressure and washed with methylene chloride (20 ml). The phases are separated in the filtrate and the aqueous washed with methylene chloride (50 ml). The combined organics were washed with water (50 ml) and the aqueous backextraceted with methylene chloride (50 ml) after adding water (25 ml). The combined organics are dried over sodium sulfate and saturated with hydrogen chloride gas at 6°. Water (100 ml) is added and the phases separated. The aqueous phase is washed with methylene chloride (2×50 ml) and the combined organic phases are dried over sodium sulfate. The organic phase is concentrated under reduced pressure and toluene added (77 ml). The mixture is concentrated under reduced pressure to 31 g net weight and toluene (50 ml) and heptane (75 ml) added. The solids are filtered off and washed with toluene/heptane (1/1, 20 ml). The filtrate is concentrated under reduced pressure to 17 g net weight, heptane (100 ml) added and the mixture concentrated under reduced pressure to 15 g net weight. Heptane (100 ml) and methylene chloride (100 ml) is added and the mixture concentrated under reduced pressure to 130 g net weight. The solids are filtered off and washed with heptane/methylene chloride (2/1, 3×15 ml). The filtrate is concentrated under reduced pressure to 11 g net weight and toluene (90 ml) then heptane (400 ml) added. The resultant slurry is then cooled to −20° and the product collected by filtration with reduced pressure, washed with heptane and dried to give a crude solid. Flash chromatography of the crude solid (silica gel; eluting with a gradient of 15-45% ethyl acetate/cyclohexane) gives the title compound as an analytical sample, NMR 3.11, 3.62, 3.68, 3.87, 3.95, 4.14-4.20, 7.70-7.76 and 7.82-7.88 δ; CMR 41.61, 47.27, 69.68, 123.53, 131.83, 134.26 and 168.65 δ; MS (CI, NH3), M/Z (relative intensity) 259 (1.4), 257 (17), 242 (0.11), 240 (0.31), 221 (100); [α]25D=−33 (C=0.712, CHCl3). NMR of the mosher ester derivative showed the product to have an enantiomeric purity of 96.2% upon comparison to the NMR of the mosher ester of the racemate.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[C:6]([O:9][C@@H:10]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[C@@H:31]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:30][C@H:11]1[O:12][C:13]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=2[CH3:26])=[C:16]([CH:27]([CH3:29])[CH3:28])[NH:15][N:14]=1)(=[O:8])[CH3:7].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([O:9][C@@H:10]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[C@@H:31]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:30][C@H:11]1[O:12][C:13]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:4]=[CH:3]/[CH2:2][CH2:1][OH:5])=[CH:21][C:20]=2[CH3:26])=[C:16]([CH:27]([CH3:29])[CH3:28])[NH:15][N:14]=1)(=[O:8])[CH3:7]
Reactant: C=CCCO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 90 °C
Yield: 50.6 %

Procedure:
Add 3-buten-1-ol (6.1 mL, 70 mmol) to a solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (15 g, 23.5 mmol) in acetonitrile (200 mL) and triethylamine (50 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (1.43 g, 4.7 mmol) and palladium acetate (526 mg, 2.35 mmol). After refluxing at 90° C. for 2 hours, cool and concentrate to remove the solvent under reduced pressure. Purify the resulting residue by flash chromatography (silica gel, gradient ethyl acetate/hexanes from 20-80% over 20 min, 330 g column) to provide the title compound (7.5 g, 11.9 mmol). MS (m/z): 631.2 (M+1), 629.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.S(Cl)(Cl)=O.[OH-].[NH4+:16]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:16])=[O:10])=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)cn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
A 500-mL RBF was charged with 5-chloro-2-pyridinecarboxylic acid (Ark Pharm, 10.00 g, 63.5 mmol) and thionyl chloride (Aldrich, 100 ml, 1371 mmol). A catalytic amount of DMF (0.2 ml) was added and the reaction mixture was heated to 80° C. under Argon atmosphere for 4 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was diluted with DCM (100 ml) and added slowly to a stirred solution of ammonium hydroxide (131 ml, 3364 mmol) at 0° C. After completed addition, the reaction mixture was allowed to stir an additional 10 min. The reaction mixture was concentrated under reduced pressure and the precipitate was filtered off. The solid was washed with water and dried to give the title compound (8.686 g, 55.5 mmol, 87% yield) as an off-white solid. MS m/z=157 [M+H]+. Calculated for C6H5ClN2O: 156
Reaction SMILES: [F:1][C:2]([F:29])([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH:3]([C:5]1[NH:6][C:7]([CH:10]([OH:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:9]=1)[OH:4].[H-].[Na+].[H][H].[CH3:34][Si:35](Cl)([CH3:37])[CH3:36]>C1COCC1>[F:29][C:2]([F:1])([C:22]([F:27])([F:28])[C:23]([F:26])([F:24])[F:25])[CH:3]([C:5]1[NH:6][C:7]([CH:10]([O:21][Si:35]([CH3:37])([CH3:36])[CH3:34])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:15])([F:14])[F:16])=[CH:8][CH:9]=1)[O:4][Si:35]([CH3:37])([CH3:36])[CH3:34]
Reactant: [H][H]
Reactant: OC(c1ccc(C(O)C(F)(F)C(F)(F)C(F)(F)F)[nH]1)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OC(c1ccc(C(O[Si](C)(C)C)C(F)(F)C(F)(F)C(F)(F)F)[nH]1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Recrystallized 2,5-bis(2',2',3',3',4',4',4'-heptafluoro-1'-hydroxybutyl)pyrrole (0.5 mmol, 0.2316 g) was dissolved in 25 ml of dry THF and transferred to a cooled (0° C.) suspension of sodium hydride (1.0 mmol, 0.024 g) in 60 mL of THF. When hydrogen evolution ceased (after 1 hour) trimethylsilyl chloride (1 mmol, 0.109 g) was added by syringe. The mixture became cloudy and was stirred at room temperature for 1 hour before the solvent was removed in vacuo. The remaining residue was partitioned between 10% sodium bicarbonate solution and pentane. The organic layer was washed twice with water and dried over magnesium sulfate, filtered and evaporated to leave a colorless oil (0.204 g, 0.34 mmol, 67%). 1H NMR (CDCl3, 360 MHz) 8.68 (broad s, 1 H) 6.15 (d, 2 H, J=2.7 Hz); 5.13 (dd, 2 H, J1=18.8 Hz, J2=5.0 Hz); 0.03 (s, 18 H).
Reaction SMILES: Cl.[F:2][C:3]1[N:27]=[CH:26][C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[C:14]([CH3:25])[CH:13]=3)[C:5]=2[CH:4]=1.[CH:28]1([CH2:33][C:34](Cl)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29]1.C1(C(N2CCC(OC3C=CC(NC4C5C=C(F)N=CC=5N=CN=4)=CC=3C)CC2)=O)CCCC1>>[CH:28]1([CH2:33][C:34]([N:22]2[CH2:23][CH2:24][CH:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:10]4[C:5]5[CH:4]=[C:3]([F:2])[N:27]=[CH:26][C:6]=5[N:7]=[CH:8][N:9]=4)=[CH:13][C:14]=3[CH3:25])[CH2:20][CH2:21]2)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCNCC1
Agent: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Agent: Cl
Product: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)CC2CCCC2)CC1

Procedure:
The title compound was prepared from (6-Fluoro-pyrido[3,4-d]pyrimidin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine (T) and cyclopentylacetyl chloride by a procedure analogous to that described for the synthesis of Cyclopentyl-{4-[4-(6-fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidin-1-yl}-methanone. MS: 464.3 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.90 (s, 1H), δ 8.86 (s, 1H), δ 8.57 (s, 1H), δ 8.19 (s, 1H), δ 7.035 (d, J=9.97, 2H), δ 4.58-4.59 (m, 1H), δ 3.71 (m, 2H), δ 3.30-3.93 (m, 2H), δ 2.31 (d, J=7.47, 2H), δ 2.17 (s, 3H), δ 2.08-2.12 (m, 1H), δ 1.80-1.95 (m, 1H), δ 1.43-1.73 (m, 10H), δ 1.05-1.10 (m, 2H).
Reaction SMILES: C([S:8][C:9]1([CH2:15][N:16]([CH2:18][CH2:19][P:20]([CH3:23])([CH3:22])=S)[CH3:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)C1C=CC=CC=1.[Na].[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl>[SH:8][C:9]1([CH2:15][N:16]([CH2:18][CH2:19][P:20]([CH3:23])[CH3:22])[CH3:17])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: CN(CCP(C)(C)=S)CC1(SCc2ccccc2)CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN(CCP(C)C)CC1(S)CCOCC1
Temperature: -50 °C

Procedure:
A solution of 4-benzylthio-4-[N-(2-dimethylphosphinothioylethyl)-N-(methyl)aminomethyl]-2,3,5,6-tetrahydro-4H-pyran (500 mg) in dry tetrahydrofuran (10 cm3) was placed in a flask fitted with a low temperature condenser (-50° C.), drying tube and gas inlet. The flask was flushed with nitrogen, the solution cooled to -50° C., and then dry ammonia (40 cm3) was condensed into the flask. Small pieces of sodium were then added to this mixture until the blue colouration persisted for at least 1 hour. The blue colouration was then discharged by the addition of ammonium chloride, and the mixture allowed to warm to room temperature. As the ammonia evaporated steps were taken to ensure that no air entered the apparatus. [The flask and its contents were then transfered to a glove box containing a nitrogen atmosphere for subsequent operations.] The reaction mixture was filtered and the solvent removed under reduced pressure to give a yellow oil containing some solid material. The oil was dissolved in chloroform, the solid removed by filtration, and the solvent removed under reduced pressure to give the phosphine as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:15]([OH:17])=O.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:15]([Cl:21])=[O:17]
Reactant: COc1cc2c(c(C(=O)O)c1OC)CCCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(c(C(=O)Cl)c1OC)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,3-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.20 g, 0.85 mmol) in DCM (5 mL) was added oxalyl chloride (0.09 mL, 1.06 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the 2,3-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH:23]1([C:26]([OH:28])=O)[CH2:25][CH2:24]1.[NH2:29][C@@H:30]([CH3:50])[C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][C:41]2[C:42]([NH2:49])=[N:43][C:44]([CH3:48])=[N:45][C:46]=2[Cl:47])[CH2:35][CH2:34]1)=[O:32]>C1COCC1.CCOC(C)=O>[NH2:49][C:42]1[C:41]([CH2:40][CH2:39][CH:36]2[CH2:35][CH2:34][N:33]([C:31](=[O:32])[C@@H:30]([NH:29][C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:28])[CH3:50])[CH2:38][CH2:37]2)=[C:46]([Cl:47])[N:45]=[C:44]([CH3:48])[N:43]=1
Reactant: O=C(O)C1CC1
Reactant: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)N)CC2)c(Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)NC(=O)C3CC3)CC2)c(Cl)n1
Yield: 78.9 %

Procedure:
Add 1-hydroxy-7-azabenzotriazole (281 mg, 2.03 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (430 mg, 2.21 mmol) to a slurry of cyclopropanecarboxylic acid (161 μL, 2.03 mmol), (2S)-2-amino-1-[4-[2-(4-amino-6-chloro-2-methyl-pyrimidin-5-yl)ethyl]-1-piperidyl]propan-1-one (600 mg, 1.84 mmol) in anhydrous THF (12 mL). Then add TEA (770 μL, 5.52 mmol) and stir the resulting mixture at RT for 12 h. Dilute the reaction mixture with EtOAc (10 mL), filter over diatomaceous earth, and concentrate the filtrate in vacuo. Purify the resulting residue by mass-guided HPLC reverse phase chromatography (Agilent® 1200 LCMS and MSD mass spectrometer, 75×30 mm Phenomenex Gemini-NX®, 5μ particle size column with a 10×20 mm guard, 12-46% ACN in 10 mM aqueous ammonium bicarbonate solution, pH 10, gradient over 9 min) to obtain the title compound as a colorless glass (572 mg, 78%). LC-ESMS m/z (35Cl/37Cl) 394.2/396.2 (M+H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][CH2:7][CH2:8][C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.CN([CH:22]=[O:23])C>>[Cl:3][C:10]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=[C:9]([CH2:8][CH2:7][Cl:6])[CH:22]=[O:23]
Reactant: Cc1ccc(CC(=O)CCCl)cc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Product: Cc1ccc(C(Cl)=C(C=O)CCCl)cc1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
390 ml of POCl3 are introduced dropwise, at a temperature of between 7° and 12° C., into a solution of 352.5 g of 4-chloro-1-(4-methylphenyl)butanone, prepared above according to Example 12 a), in 450 ml of DMF. The temperature is raised gradually, in the first instance to 50° C. over 2 h and then to 75° C. over 45 min. The mixture is poured on to ice and extracted three times with ether and the organic phases are combined, washed with water and then dried and evaporated to give 387.8 g of 3-chloro-2-(2-chloroethyl)-3-(4-methylphenyl)prop-2-en-1-al in the form of an oil, which is used as such in the next step.