Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:28][CH2:29][CH2:30][CH3:31])[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][N:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CO>CN(C=O)C.C(Cl)(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[C:10](=[N:9][N:8]=3)[CH:11]=[C:12]3[O:13][CH2:1][O:2][C:3]3=[CH:4]4)[N:14]([CH2:28][CH2:29][CH2:30][CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: CCCCN(C(=O)c1cc(OC)c(OC)cc1I)c1cnnc2cc3c(cc12)OCO3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2cc(OC)c(OC)cc2c2nnc3cc4c(cc3c21)OCO4
Temperature: 25 °C
Yield: 20 %

Procedure:
A mixture of N-(6,7-Methylenedioxycinnolin-4-yl)-N-(n-butyl)-2-iodo-4,5-dimethoxybenzamide (1.0 mmol equiv.), Pd(OAc)2 (0.2 mmol equiv.), P(o-tolyl)3 (0.4 mmol equiv.), and Ag2CO3 (2.0 mmol equiv) was heated to reflux in DMF (30 mL per mmol equiv.) with stirring. The reaction mixture was allowed to cool to room temperature, diluted with CHCl3, and filtered through Celite. The sicciate was extensively washed with 10% CH3OH in CHCl3. The filtrate was concentrated in vacuo and the residue chromatographed on silica gel using chlorofomm:methanol to provide the title compound (123 mg, 0.2 mmol) in 27% yield with a reaction time 90 min; mp 299° C.; IR (KBr) 1654; 1H NMR (CDCl3) δ 1.06 (t, 3H, J=7.4), 1.56 (m, 2H), 2.13 (m, 2H), 4.09 (s, 3H), 4.17 (s, 3H), 4.49 (m, 2H), 6.26 (s, 2H), 7.62 (s, 1H), 7.85 (s, 1H), 7.87 (s, 1H), 8.65 (s, 1H); 13C NMR (CDCl3) δ 13.8, 20.2, 31.1, 48.6, 56.3, 56.6, 98.8, 102.7, 104.2, 106.5, 107.9, 119.7, 149.1, 150.1, 150.9, 151.4, 153.6, 154.2, 162.9; HRMS calcd for C22H21N3O5H, 408.1559; found 408.1543
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]([O:47][CH3:48])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]=1[O:49][CH3:50]>>[CH3:50][O:49][C:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]([O:47][CH3:48])=[CH:46][C:37]=1[CH2:36][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(OC)c3ccccc3c2OC)cc1

Procedure:
(ff) In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylate with 2-chloromethyl-1,4-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-{4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a pale yellow syrup; MS: 689 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][CH2:31][CH2:32][OH:33]>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH2:30][CH2:31][CH2:32][OH:33])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:20])[F:21])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC(F)(F)F
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCO)c(=O)n2CCCC(F)(F)F
Temperature: 60 °C
Yield: 69.2 %

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione (1.0 g, 3.0 mmol) in DMF (15 ml) was treated with caesium carbonate (1.16 g, 3.6 mmol) and 3-bromo-1-propanol (0.3 ml, 3.3 mmol). The mixture was heated at 60° C. for 4 h and then cooled and evaporated. The residue was partitioned between EtOAc (50 ml) and water (50 ml). The organic phase was dried (MgSO4), filtered and evaporated. The product was purified by flash chromatography using a gradient elution from cyclohexane to EtOAc. Product-containing fractions were combined and evaporated to give the title compound as a colourless oil (0.82 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31](O)[C:32]([F:35])([F:34])[F:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.[Cl:48]CCl.C(N(CC)CC)C.CS(Cl)(=O)=O>>[Cl:48][CH:31]([C:18]1[CH:17]=[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:47][CH:46]=3)[N:10]=2)[C:21]([NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[N:20][CH:19]=1)[C:32]([F:35])([F:34])[F:33]
Reactant: ClCCl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)C(F)(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(Cl)C(F)(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 1.5 h
Yield: 10 %

Procedure:
To a solution of 1-(5-(4-(bis(4-methoxyb enzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethanol (0.172 g, 0.266 mmol) in dichloromethane (3.00 mL, 0.266 mmol) was added triethylamine (0.093 mL, 0.664 mmol) and methanesulfonyl chloride (0.042 mL, 0.531 mmol) at 0° C. and the mixture was stirred at the same temperature for 1.5 h. The reaction was quenched with saturated NH4Cl and water at 0° C., and the separated aqueous layer was extracted with DCM (2×10 mL) and the combined organic layers were dried over Na2SO4, and concentrated and dried under vacuum to give the crude 4-(5-(1-chloro-2,2,2-trifluoroethyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.177 g, 0.0266 mmol), which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:34][CH3:35])[C:28]=1[O:29]S(C)(=O)=O)[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH2:37]([O:39][CH2:40][CH2:41][N:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N:44]=[C:43]1[N:51]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:38].C(N(CC)C(C)C)(C)C.ClCCl.CO>C(#N)C>[CH3:35][O:34][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[OH:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:54]2[CH2:55][CH2:56][CH2:57][N:51]([C:43]3[N:42]([CH2:41][CH2:40][O:39][CH2:37][CH3:38])[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH2:52][CH2:53]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OS(C)(=O)=O
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(O)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 16 h

Procedure:
Combine 1-(3,5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.77 g, 1.46 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (1.0 g, 1.8 mmol), and N,N-diisopropylethylamine (0.76 g, 4.4 mmol) in acetonitrile (36 mL). Heat to reflux. After 16 hours, cool and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol/concentrated aqueous ammonia 6/1/0.1 to give the title compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]2[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:15][OH:16]>>[C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[N:13]=[C:15]=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCCCC1c1ccccc1
Reactant: CO
Agent: Cl
Product: O=C=N[C@@H]1CCCC[C@H]1c1ccccc1
Temperature: 110 °C

Procedure:
To a solution of 2-phenylcyclohexylamine (2.28 mmol) in methanol was added HCl (4.0 M in dioxane, 0.57 mL). The solution was concentrated and treated with phosgene solution (20% in toluene, 16.0 mL). The reaction was heated at 110° C. overnight and concentrated in vacuo.
Reaction SMILES: Br[CH:2]([C:4]1[C:5]([F:27])=[CH:6][C:7]2[O:16][CH2:15][CH2:14][N:13]3[C:9](=[N:10][C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)=[CH:12]3)[C:8]=2[CH:26]=1)[CH3:3].[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([CH:2]([C:4]2[C:5]([F:27])=[CH:6][C:7]3[O:16][CH2:15][CH2:14][N:13]4[CH:12]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[N:10]=[C:9]4[C:8]=3[CH:26]=2)[CH3:3])[CH2:32][CH2:31]1)[CH3:29]
Reactant: CCN1CCNCC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C(C)Br)c(F)cc2OCC3)n(C(C)C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCN1CCN(C(C)c2cc3c(cc2F)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Yield: 65 %

Procedure:
A solution of 9-(1-bromoethyl)-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (85 mg, 0.20 mmol), N-ethylpiperazine (27 μL, 0.22 mmol) and DIPEA (54 μL, 0.30 mmol) in dioxane (2 mL) was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (Si-PPC, gradient 0-10% 2 M NH3/MeOH in DCM) to give 374 (61 mg, 0.13 mmol, 65% over 2 steps) as a white solid. LCMS (Method K): RT 2.74 min [M+H]+ 468.2. 1H NMR (CD3OD, 400 MHz): δ 8.55 (1H, d, J=8.2 Hz), 7.68 (1H, s), 6.76 (1H, d, J=11.1 Hz), 5.83 (1H, sept., J=6.7 Hz), 4.48 (4H, br s), 3.84 (1H, q, J=6.8 Hz), 2.50 (8H, br s), 2.38 (2H, q, J=7.4 Hz), 2.33 (3H, s), 1.53 (3H, d, J=6.7 Hz), 1.52 (3H, d, J=6.7 Hz), 1.40 (3H, d, J=6.8 Hz), 1.03 (3H, t, J=7.4 Hz)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][CH2:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=[CH:17]1.O>CN(C=O)C.C(Cl)(Cl)Cl>[C:1]1(=[O:11])[N:5]([CH2:14][CH2:15][N:16]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:18]=[CH:17]2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCn1cnc(-c2ccccc2)c1-c1ccccc1
Agent: [K]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCn1cnc(-c2ccccc2)c1-c1ccccc1
Yield: 73 %

Procedure:
Step 2): A mixture of potassium phthalimide (0.21 g, 1.1 mmol) and 1-(2-chloroethyl)-4,5-diphenylimidazole (0.32 g, 1.1 mmol) in dry DMF (10 ml) was heated at 60°-70° C. for 6 hours. The reaction mixture was cooled, diluted with chloroform, poured into water and extracted with chloroform. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (40% ethyl acetate in chloroform) to give 1-(2-phthalimidoethyl)-4,5-diphenylimidazole (73.0%).
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[CH:29]([NH:31][C@H:32]([C:37](O)=[O:38])[CH2:33][CH2:34]SC)=[O:30]>>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][S:18][C:37](=[O:38])[CH:32]([NH:31][CH:29]=[O:30])[CH2:33][CH3:34])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Reactant: CSCC[C@H](NC=O)C(=O)O
Product: CCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 43.9 %

Procedure:
The title compound (0.28 gm) was prepared from 9-fluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol (0.5 gm) and N-formyl-L-methionine (0.76 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH2:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=4)[N:19]=[CH:18][C:17]=3[O:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[O:31]=[C:32]1[CH2:37][S:36][C:35]2[CH:38]=[CH:39][C:40](C(O)=O)=[N:41][C:34]=2[NH:33]1>>[CH3:29][O:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([C@H:11]3[CH2:12][CH2:13][C@H:8]([NH:7][C:6]([C:40]4[CH:39]=[CH:38][C:35]5[S:36][CH2:37][C:32](=[O:31])[NH:33][C:34]=5[N:41]=4)=[O:30])[CH2:9][CH2:10]3)[CH2:27][C:26]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Product: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)c2ccc4c(n2)NC(=O)CS4)CC1)CO3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 6 and in analogy to Example 1 using [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1CCN2C(=NCCC2)CC1.C([O:23][C:24](=O)[CH2:25][C:26]([C:28]1[C:29]([NH:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[N:30][C:31]([S:34][CH3:35])=[N:32][CH:33]=1)=[O:27])C.Cl>CCOC(C)=O>[CH:37]1([N:36]2[C:29]3[N:30]=[C:31]([S:34][CH3:35])[N:32]=[CH:33][C:28]=3[C:26]([OH:27])=[CH:25][C:24]2=[O:23])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CCOC(=O)CC(=O)c1cnc(SC)nc1NC1CCCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CSc1ncc2c(O)cc(=O)n(C3CCCC3)c2n1
Temperature: 120 °C
Yield: 97 %

Procedure:
Diisopropylethylamine (12 mL) and DBU (1.62 mL) were added to 3-(4-cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl)-3-oxo-propionic acid ethyl ester (3.0 g, 9.29 mmol) and the resulting mixture was heated to 120° C. for 1 h. The reaction mixture was then cooled to RT and acidified with HCl (1 M aq) to pH 1. The resulting mixture was diluted with EtOAc and washed 3× with HCl (1 M aq). The combined aqueous layers were extracted with EtOAc and then 3× with a 1:1 mixture of isopropanol and chloroform. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to afford 2.5 g (97% yield) of 8-cyclopentyl-5-hydroxy-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine (example C.4) (161 mg, 0.5 mmol) and 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (146 mg, 57%). MS (ISP) 513.3 [(M+H)+]; mp 292-293° C.
Reaction SMILES: [Br:1][C:2]1[C:15](=[O:16])[N:14]([CH:17]([CH3:19])[CH3:18])[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[CH3:20][NH2:21]>O1CCOCC1>[Br:1][C:2]1[C:15](=[O:16])[N:14]([CH:17]([CH3:19])[CH3:18])[C:5]2[N:6]=[C:7]([NH:21][CH3:20])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: CN
Reactant: Cc1nc(S(C)=O)nc2c1cc(Br)c(=O)n2C(C)C
Solvent: C1COCCO1
Product: CNc1nc(C)c2cc(Br)c(=O)n(C(C)C)c2n1
Temperature: 110 °C
Yield: 100 %

Procedure:
To a stirred solution of 6-bromo-8-isopropyl-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (175 mg, 0.508 mmol) in 1,4-dioxane (2.5 mL) was added methyl amine (0.80 mL, 2.0 M in THF, 1.6 mmol). The mixture was sealed and heated at 110° C. microwave for 15 min. The solvent was evaporated and the crude product was washed with EtOAc/Hexane to give the title compound (158 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH3:36])=[CH:31][CH:30]=1.C(N(C(C)C)C(C)C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([N:35]([C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)[CH3:36])=[CH:31][CH:30]=1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(N(C)C(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.2 %

Procedure:
To a solution of 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, step 3, 80 mg, 0.2 mmol) and 4-methylamino-benzoic acid methylester (35 mg, 0.21 mmol) in dichloromethane (4 ml) were added N-ethyldiisopropylamine (29 mg, 0.22 mmol) and PyBroP (95 mg, 0.2 mmol). The mixture was stirred for 17 h at room temperature. The reaction solution was extracted with brine/water, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (5 g silica gel, heptane/AcOEt 8:2=>7:3) to give the title compound (37 mg) as a white solid. MS (m/e)=541.3 [M+H+].
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([S-:6])=[S:5].[K+].[NH2:8][C:9]1[N:14]=[C:13]([CH2:15]Cl)[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1>C(O)C.O>[NH2:8][C:9]1[N:10]=[C:11]([O:17][CH3:18])[CH:12]=[C:13]([CH2:15][S:5][C:4]([O:3][CH2:2][CH3:1])=[S:6])[N:14]=1
Reactant: COc1cc(CCl)nc(N)n1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=S)SCc1cc(OC)nc(N)n1

Procedure:
16.0 g of potassium ethylxanthogenate and 17.4 g of 2-amino-4-chloromethyl-6-methoxy-pyrimidine are refluxed in 100 ml of ethanol for 30 minutes. After the reaction solution has cooled, it is diluted with about 1 litre of water, and the product which precipitates is separated and dried. The yield is 22.5 g (87% of theory) of 2-amino-4-methoxy-6-ethoxythiocarbonylthiomethyl-pyrimidine, m.p. 91°-93° C.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][C@H:6](O)[CH2:5][C@@H:4]1[C:9]([OH:11])=[O:10])[CH3:2].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCOCC>C(Cl)Cl.C([C@@H]1C[C@H]2C[C@@H]1C(=O)O2)C>[CH2:1]([CH:3]1[CH2:7][CH:6]2[CH2:5][CH:4]1[C:9](=[O:10])[O:11]2)[CH3:2]
Reactant: CC[C@@H]1C[C@H](O)C[C@@H]1C(=O)O
Agent: CC[C@@H]1C[C@H]2C[C@@H]1C(=O)O2
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCOCC
Product: CCC1CC2CC1C(=O)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a scalemic mixture enriched in (1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g, 5.96 mmol) in DCM (60 mL) was added TEA (2.5 mL, 18 mmol) and BOP-Cl (1.821 g, 7.15 mmol). The reaction mixture was stirred at ambient temperature for about 2 h then poured into Et2O (350 mL). The solid was removed by filtration while washing with Et2O (50 mL). The filtrate was concd under reduced pressure to give a yellow oil which was dissolved in DCM (5 mL) and Et2O was added to give a solid. The supernatant was decanted and the solid was washed with additional Et2O. The combined organic extracts were concd under reduced pressure to give a scalemic mixture enriched in crude (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one containing about 15 mol % TEA (0.912 g, 99%): 1H NMR (CDCl3) δ 4.85 (s, 1H), 2.88 (s, 1H), 2.19 (m, 2H), 2.08 (m, 1H), 1.69 (m, 1H), 1.41 (m, 3H), 0.97 (t, J=5.4, 3H).
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:46][CH:47]([C:49]1[C:50](=[O:66])[NH:51][C:52]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[C:58]([O:64][CH3:65])[CH:57]=2)=[N:53][N:54]=1)[CH3:48]>>[OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([NH:46][CH:47]([C:49]1[C:50](=[O:66])[NH:51][C:52]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[C:58]([O:64][CH3:65])[CH:57]=2)=[N:53][N:54]=1)[CH3:48])=[O:7])[CH3:3]
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1OC
Reactant: CC(O)C(CCCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1OC

Procedure:
1.01 g (4.55 mmol) of 2-(1-hydroxyethyl)-5-phenylpentanoic acid are reacted analogously to Example 39A with 0.67 g (4.96 mmol) of 1-hydroxy-1H-benzotriazole, 1.05 g (10.3 mmol) of 4-methylmorpholine, 0.95 g (4.96 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 1.20 g (4.13 mmol) of 6-(1-aminoethyl)-3-(3,4-dimethoxybenzyl)-1,2,4-triazin-5(4H)-one to give 2-(1-hydroxyethyl)-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-tri azin-6-yl]-ethyl)}5-phenylpentanamide.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:2]1=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH2:27][CH2:28][C:29](=[O:31])[CH3:30]>>[O:31]=[C:29]([CH3:30])[CH2:28][CH2:27][O:13][C:12]([C:4]1[C:2](=[O:3])[O:1][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:14]
Reactant: O=C(O)c1cc2ccccc2oc1=O
Reactant: CC(=O)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)CCOC(=O)c1cc2ccccc2oc1=O

Procedure:
Coumarin-3-carboxylic acid (25.0 g, 131 mmol) is dissolved into 100 mL of 4-hydroxy-2-butanone with ˜0.050 g of para-toluene sulfonic acid in a round bottom flask equipped with a stir bar and condenser packed with molecular sieves. The pressure is reduced to ˜15 mmHg and the system is refluxed for 10 hours. The solvents are removed by rotary evaporation. The solid organic residue is purified by column chromatography using 3:1 ethyl acetate:hexanes to yield 2-oxo-2H-chromene-3-carboxylic acid 3-oxo-butyl ester.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.C[O-:13].[Na+]>CC#N.CO>[O:13]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[O:3]1
Reactant: C[O-]
Reactant: CCOC(=O)c1cnc(Cl)o1
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: O=C(O)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-chlorooxazole-5-carboxylate (1.816 g, 10.34 mmol) was solubilised in MeCN (20 ml) and MeOH (20 ml). Sodium methoxide (9 ml, 25% solution in MeOH, 41.4 mmol) was added and the reaction mixture was heated at reflux overnight. The solvent was removed under reduced pressure and the crude product was dissolved in MeOH (20 ml) and 2M NaOH(aq) (20 ml) and stirred at RT overnight. The resulting mixture was acidified with 1M HCl and evaporated under reduced pressure. The residue was triturated with a minimal volume of 5M HCl and filtered. The solid was slurried with ice chips (approx. 10 ml), filtered, washed with water and dried under high vacuum to afford the title compound;