Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([NH:12][C:13](=O)[CH2:14]COC)=[C:10]([NH:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:25].[CH3:26][OH:27]>O.C(=O)(O)[O-].[Na+]>[NH2:25][C:2]1[C:11]2[N:12]=[C:13]([CH2:14][O:27][CH3:26])[N:19]([CH2:20][C:21]([CH3:22])([CH3:23])[OH:24])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: COCCC(=O)Nc1c(Cl)nc2ccccc2c1NCC(C)(C)O
Reactant: CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 150 °C

Procedure:
N-[2-Chloro-4-(2-hydroxy-2-methylpropyl)amino-3-quinolinyl]-3-methoxypropanamide (6 g, Example 110) was added to 5% ammonia in methanol (60 mL). The mixture was heated in a Parr bomb for 5 hours at approximately 150° C. The solvent was evaporated under vacuum to give a brown residue. The residue was diluted with water and sodium bicarbonate then extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulfate then evaporated to provide a tan solid. The solid was purified by silica gel chromatography to provide 1.64 g of the desired product as a solid, m.p. 174-175° C. Analysis: Calculated: %C, 65.0; %H, 7.0; %N, 17.8; Found: %C, 64.8; %H, 7.0; %N, 17.7.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[NH2:4].[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([NH:4][NH:3][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)=[O:25])[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: NNc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
To a mixture of 2-hydrazinopyridine dihydrochloride (2.49 g, 13.7 mmol) and 1-Boc-piperidine-4-carboxylic acid (3.14 g, 13.7 mmol) in 30 mL of CH2Cl2 was added DIPEA (5.96 mL) followed by HOBT (2.22 g, 16.4 mmol) and EDC (3.93 g, 20.5 mmol) at rt. After stirring at rt for 18 h, the reaction mixture was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. Concentration under reduced pressure afforded the title compound (3.3 g) as a white solid. 1H NMR (500 MHz, CDCl3): δ 1.47 (s, 9H), 1.68-1.76 (m, 2H), 1.86-1.88 (m, 2H), 2.44 (m, 1H), 2.70-2.90 (br, 2H), 4.15-4.22 (br, 2H), 6.71 (d, J=8.5 Hz, 1H), 6.81 (t, J=6.4 Hz, 1H), 7.56 (m, 1H), 8.11 (d, J=5.0 Hz, 1H), 8.20˜8.55 (br s, 1H).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[O:7])(C)(C)C.Cl.[C:32]([O:36][C:37]([NH:39][C@H:40](C(O)=O)[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:32]([O:36][C:37]([NH:39][C@H:40]([C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH:20]([CH3:21])[CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[O:7])[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A mixture of 370 mg (0.87 mmole) of (2S, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-4-hydroxy-2-isopropyl-N-butylhexanamide (prepared as described in Preparation 4) and 5 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with diethyl ether. The solvent was once again removed by distillation under reduced pressure. This operation was repeated three times, and the final residue was then dried in vacuo for 8 hours. At the end of this time, the dried material was suspended in 10 ml of anhydrous tetrahydrofuran, and 260 mg (0.96 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to the suspension. After this, 0.15 ml (0.99 mmole) of 95% diethyl cyanophosphonate and 0.27 ml (1.94 mmole) of triethylamine were added, in that order, to the suspension, whilst ice-cooling and under an atmosphere of nitrogen, after which the mixture was stirred for 6 hours. The reaction mixture was then freed from the solvent by evaporation under reduced pressure, and the resulting residue was purified by medium pressure column chromatography through silica gel (using a 20:1 by volume mixture of methylene chloride and methanol as the eluent) to afford 470 mg (yield 93%) of the title compound as white crystals, melting at 201°-203° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 40 °C
Reaction time: 17 h
Yield: 25.8 %

Procedure:
To a suspension of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.17 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (15 μL, 0.19 mmol) and triethylamine (73 μL, 0.52 mmol). The reaction was stirred at 40° C. for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 22 mg (25%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.28-7.39 (m, 5 H), 7.15 (d, 1 H), 6.64 (s, 1 H), 5.65 (s, 2 H), 3.66 (d, 2 H), 3.19-3.30 (m, 1 H), 2.85-2.95 (m, 5 H), 2.11 (d, 2 H), 1.69-1.80 (m, 2 H); ES-MS m/z 502.31 [M+H]+, HPLC RT (min) 2.73.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:20]([CH3:22])=[O:21].[C:23](OC(=O)C)(=O)[CH3:24].C([O-])(=O)C.[Na+].C(OCC)(=O)C>O>[CH3:23][C:24]1[O:1][C:2]2[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][C:3]=2[C:20](=[O:21])[CH:22]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(=O)c2cc(Oc3ccccc3)c(NS(C)(=O)=O)cc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.9 %

Procedure:
There were mixed 3.21 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone, 5.45 g of acetic anhydride and 4.1 g of sodium acetate. The mixture was stirred for 1.5 hours at 130°-140° C. The reaction mixture was cooled to room temperature. 200 ml of ethyl acetate and 100 ml of water were added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to obtain 860 mg (yield: 25%) of 2-methyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 186.5°-187° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]3[O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[ClH:35]>CO>[ClH:35].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]3[O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccc3ccccc3c2)C1
Agent: Cl
Solvent: CO
Product: c1ccc2cc(COC3CNCCC3c3ccc4c(c3)OCO4)ccc2c1
Yield: 73 %

Procedure:
A solution of 190 mg (0.41 mmol) of tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in a mixture of 5 ml of methanol and 25% aqueous hydrochloric acid was heated under reflux for 1 hour. Subsequently, the solvent mixture was distilled off under reduced pressure. After recrystallization of the residue from a mixture of methanol and ether there were obtained 130 mg (73% of theory) of (3RS,4RS)-4-(1,3-benzodioxol-5-yl)-3-naphthalen-2-ylmethoxy-piperidine hydrochloride as a white powder; MS: 362 (M+H)+.
Reaction SMILES: COC1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:12]([NH2:13])=[C:11]([C:14]3[C:18](=[NH:19])[N:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28]C)=[CH:23][CH:22]=4)[C:16](=[O:30])[N:15]=3)[N:10]=[CH:9]2)=[CH:5]C=1.[CH:33]([O:40][CH2:41][CH3:42])(OCC)OCC.[CH3:43]C#N>S(=O)(=O)(O)O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:17]2[C:18]3=[N:19][CH:43]=[N:13][C:12]4[N:8]([CH2:7][C:6]5[CH:5]=[CH:42][C:41]([O:40][CH3:33])=[CH:32][CH:31]=5)[CH:9]=[N:10][C:11]=4[C:14]3=[N:15][C:16]2=[O:30])=[CH:22][CH:23]=1
Reactant: CC#N
Reactant: CCOC(OCC)OCC
Reactant: CCOc1ccc(CN2C(=N)C(c3ncn(Cc4ccc(OC)cc4)c3N)=NC2=O)cc1
Agent: O=S(=O)(O)O
Product: COc1ccc(Cn2c3ncnc4c(ncn4Cc4ccc(OC)cc4)c-3nc2=O)cc1
Yield: 76 %

Procedure:
To a suspension of 9 (1.0 g, 2.39 mmol, 1 equiv) in MeCN (10 mL), triethyl orthoformate (2.8 g, 19.13 mmol, 8 equiv) was added followed by 2 drops of sulfuric acid. The reaction mixture was heated at reflux for 1.5 h until starting material was disappeared (TLC). The precipitated product was filtered, washed with diethyl ether and dried under vacuum to afford 3 as pale yellow solid (0.77 g, 76%). mp: 175-177° C., IR: 1737 (C═O), 1610, 1589, 1251, 1176 cm−1. 1H NMR (400 MHz, d6-DMSO): δ=3.69 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 5.08 (s, 2H, CH2), 5.51 (s, 2H, CH2), 6.85 (d, J=8.2 Hz, 2H, Ar—H), 6.89 (d, J=8.2 Hz, 2H, Ar—H), 7.29 (d, J=8.2 Hz, 2H, Ar—H), 7.33 (d, J=8.2 Hz, 2H, Ar—H), 8.75 (s, 1H, Ar—C═N—H), 8.92 (s, 1H, Imid-H). 13C NMR (100 MHz, d6-DMSO): δ=43.4, 47.0, 55.6, 55.7, 114.4, 114.6, 128.5, 128.8, 129.2, 129.7, 129.8, 148.9, 150.3, 156.3, 159.2, 159.5, 160.2, 166.3. HRMS (FAB) Calcd for C23H20N6O3, 428.1597 (M+); observed m/z 429.1667 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18]([OH:20])=O)=[N:10]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:63][C:64]1[C:69]([OH:70])=[CH:68][CH:67]=[CH:66][N:65]=1>CN(C=O)C>[OH:70][C:69]1[C:64]([NH:63][C:18]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:17][C@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=2)=[O:20])=[N:65][CH:66]=[CH:67][CH:68]=1
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: Nc1ncccc1O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncccc1O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 30 %

Procedure:
Intermediate 1 (see Example 1.1, 50 mg, 0.181 mmol) was dissolved in DMF (1 mL). PyBOP (104 mg, 0.199 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.098 mL, 0.561 mmol) were added. The reaction mixture was stirred at room temperature for about 3 min. 2-aminopyridin-3-ol (19.93 mg, 0.181 mmol) was then added to the mixture to give an amber solution which was stirred overnight at room temperature. The mixture was purified by HPLC to provide the title compound (20 mg). LCMS m/z=369.2 [M+H]+; 1H NMR: (400 MHz, CD3CN) δ ppm 0.53 (td, J=4.8 and 3.5 Hz, 1H), 1.23 (td, J=7.9 and 4.8 Hz, 1H), 2.21-2.27 (m, 1H), 2.33-2.40 (m, 1H), 2.93 (d, J=16.5 Hz, 1H), 3.05 (dd, J=16.6 and 6.3 Hz, 1H), 7.16-7.23 (m, 1H), 7.23-7.32 (m, 2H), 7.73-7.83 (m, 3H), 9.80 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[Al].[OH2:11].CCCCCC.[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19]>ClCCl>[CH2:22]([O:21][C:18](=[O:20])[C:19]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:11])[CH3:23]
Reactant: CCOC(C)=O
Reactant: O
Reactant: c1ccc2c(c1)OCO2
Agent: [Al]
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc2c(c1)OCO2

Procedure:
A mixture of ethyl oxalyl chloride (50 ml, 0.45 mmol) and 1.3-benzodioxole (50 g, 0.41 mmol) in dichloromethane (40 ml) was added dropwise to a stirred slurry of aluminum thichloride (71 g, 0.53 mmol) in dichloromethane (500 ml) at 0° C. under a nitrogen atmosphere. After 2 hours the mixture was poured into iced water and the organic layer was washed with further volumes of water (3×500 ml), saturated sodium bicarbonate solution (500 ml) and brine (500 ml). The organic layer was dried (magnesium sulphate) and concentrated to give an orange oil. Flash column chromatography (90% hexane, 10% ethyl acetate) gave 30 g of the subtitle compound as a pale yellow oil.
Reaction SMILES: S([O-])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)=O.[Na+].[OH2:19]>>[C:5]([OH:19])(=[O:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
Example 1 is illustrated by FIG. 1. The thermally-insulated vessel B1 contains an emulsion whose continuous phase consists of 10 metric tons of water containing 1% by weight of a surface-active agent consisting of sodium lauryl sulfate; the dispersed phase of the emulsion is formed of 10 metric tons of stearic acid whose melting point is 69° C. The volume of the emulsion is 21.76 m3 at 80° C. and 20.62 m3 at 60° C. in view of the difference of the volumic mass of stearic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: CC(=O)NCC1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C[Sn](C)(C)c1ccncc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccncc3)c(F)c2)C(=O)O1
Reaction time: 4 h

Procedure:
A slurry of (±)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide (PREPARATION 18, 0.063 g, 0.165 mmol) and trimethyl(4-pyridyl)tin (0.060 g, 0.248 mmol) in 1,4-dioxane (5 ml) is degassed by repeated evacuation and filing with nitrogen. Bis(triphenylphosphine)palladium (II) chloride (0.012 g, 0.0165 mmol) is added, the reaction again degassed, and then the mixture is brought to reflux under nitrogen. After 4 hr TLC (silica gel, 10% methanol/chloroform) reveals some of the iodide still remains. The mixture is refluxed a further 20 hr, cooled to 20°-25°, and concentrated under reduced pressure. The residue is chromatographed over silica gel, eluting with a little chloroform and then methanol/chloroform (1%, 2%, and then 5%). The appropriate fractions are pooled and concentrated to give the enantiomerically enriched title compound, mp 190.5°-191.0°; [a]25D -16.4° (c 0.5, CHCl3). The following characteristics are noted for a racemic sample, mp 179°-180°; IR (internal reflectance) 3279, 3063, 1756, 1752, 1657, 1626, 1600, 1542, 1522, 1485, 1412, 1407, 1377, 1222, 1198 cm-1 ; NMR (CDCl3, 300 MHz) 8.67, 7.59, 7.50, 7.47, 7.33, 6.15, 4.84, 4.11, 3.85, 3.78-3.62, 2.04 δ; MS (m/z) 329 (39.8, M+), 285, 257, 201, 172, 73 and 42. ##STR3##
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1[CH2:20][CH2:19]C=CCCC=C[CH2:12][CH2:11][CH:10]=1.[C:21]1(C)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:8][C:5]1[CH2:4][CH2:3][CH2:12][CH2:11][CH2:10][CH2:9][CH2:20][CH2:19][C:2]([S:1][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:7][CH:6]=1
Reactant: C1=CCCC=CCCC=CCC1
Reactant: Oc1ccc(S)cc1
Reactant: Cc1ccccc1
Product: OC1=CC=C(Sc2ccccc2)CCCCCCCC1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To the reactor of Example 1 was added 100.8 grams of 4-mercaptophenol and 100 ml toluene. While maintaining the reaction mixture at 40° C. 32.6 grams of 1,5,9-cyclododecatriene was added over a 20 minute period. The mixture was agitated for 24 hours and then stripped to a pot temperature of 220° C. and 11 mm. Hg. to yield 46 grams of product.
Reaction SMILES: [CH2:1]([C:3]([C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([CH3:40])[CH:26]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:24])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:41][O:42][C:43](=[O:52])[CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49](Br)[CH:50]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:41][O:42][C:43](=[O:52])[CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49]([C:28]2[CH:29]=[CH:30][C:25]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]4([O:19][Si:20]([CH3:22])([CH3:23])[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:8]([CH3:24])[CH:7]=3)[CH2:1][CH3:2])=[CH:26][C:27]=2[CH3:40])[CH:50]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 140 °C
Yield: 67.8 %

Procedure:
A solution of 2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 32-(4); 54.1 mg, 0.0968 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 33.4 mg, 0.14 mmol), tetrakistriphenylphosphine palladium (15.6 mg, 0.0135 mmol) and potassium phosphate (30.8 mg, 0.14 mmol) in N,N-dimethylformamide (0.27 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the mixture was purified by silica gel chromatography (45% ethyl acetate/hexane) to give the title compound (38.2 mg, 67%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[S:13][C:14]4[CH2:15][NH:16][CH2:17][CH2:18][C:19]=4[N:20]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>ClCCl>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[S:13][C:14]4[CH2:15][N:16]([C:28](=[O:31])[CH2:29][CH3:30])[CH2:17][CH2:18][C:19]=4[N:20]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: C1CC(N2CCC(Oc3nc4c(s3)CNCC4)CC2)C1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CCc2nc(OC3CCN(C4CCC4)CC3)sc2C1
Yield: 71.5 %

Procedure:
A solution of 2-(1-Cyclobutyl-piperidin-4-yloxy)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (1.3 grams, 4 mmol, obtained in above step) and triethylamine (1.9 mL, 13 mmol) in dichloromethane (30 mL) was cooled to 0° C. Propionylchloride (0.4 mL, 5 mmol) in dichloromethane (5 mL) was added drop wise over a period of 15 minutes and stirred the reaction for 30 minutes. Reaction mass was poured onto ice cold water and the product was extracted with ethyl acetate (3×50 mL). Combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (methanol/chloroform, 2/98) to obtain the title compound (1.0 gram).
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-:3])=[O:2].N1C=CC=C[CH:13]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:13])[C:4]=1[N+:1]([O-:3])=[O:2])(=[O:20])[CH3:19]
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1c(O)cccc1O
Product: COc1cccc(OC(C)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.01 g (1.3 mmol) of 2-nitroresorcinol in 15 ml of dry pyridine 0.28 ml (1.36 mmol) of acetic anhydride was added dropwise at 0° C. The resulting mixture was allowed to warm to room temperature. After 1 h of stirring at room temperature the solvent was removed by evaporation in vacuo and the residue diluted to 10 ml with anhydrous acetonitrile. To this 2 g of anhydrous potassium carbonate was added followed by the addition of 1.5 ml of methyl iodide. The resulting suspension was stirred overnight at room temperature, filtered off and filtrate evaporated to dryness under reduced pressure to give 2.63 g of crude 3-methoxy-2-nitrophenyl acetate. This was dissolved in 15 ml of acetonitrile and 2 ml of concentrated ammonium hydroxide was added. The resulting mixture was allowed to stand for 30 minutes at room temperature and evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography to give 1.36 g (62% yield) of pure title compound as red crystals; 1H NMR (CDCl3) 3.92 (s, 3H, OMe); 6.51 (d, 1H, CH, J=8.5 Hz); 6.68 (d, 1H, CH, J=8.5 Hz); 7.35 (m, 1H, CH); 10.18 (s, 1H, OH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 13.9 g 4-(5-bromo-2-chloro-benzyl)-phenol in 140 ml dichloromethane is cooled in an ice bath. Then 7.54 g tert-butyldimethylsilylchlorid in 20 ml dichloromethane are added followed by 9.8 ml triethylamine and 0.5 g 4-dimethylaminopyridine. The solution is stirred for 16 h at ambient temperature and then diluted with 100 ml dichloromethane. The organic phase is washed twice with aqueous 1 M hydrochloric acid and once with aqueous sodium hydrogen carbonate solution and then dried over sodium sulfate. After the solvent has been removed the residue is filtered through silica gel (cyclohexane/ethyl acetate 100:1).