Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[K].[C:13]1([SH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>C(O)C>[C:13]1([S:19][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: SC1=CCCCC1
Agent: [K]
Solvent: CCO
Product: Nc1cc(SC2=CCCCC2)ccc1[N+](=O)[O-]

Procedure:
To a solution of 6.9 g (0.04 mole) of 5-chloro-2-nitroaniline in 50 ml of absolute ethanol there is added 6.0 g of the potassium salt of 1-cyclohexene-1-thiol [J. Praktische Chemie 34, 116 (1966)]. The mixture is heated on the steam bath for 0.5 hour, filtered and the filtrate is reduced in volume in vacuo. The resulting solid is filtered off and crystallized from absolute ethanol to yield 5.3 g, m.p. 100°-102°.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:31][N:32]1[CH2:37][CH2:36][CH2:35][CH:34]([NH2:38])[CH2:33]1>>[CH3:18][N:15]1[C:14]([C:19](=[O:21])[NH:38][CH:34]2[CH2:35][CH2:36][CH2:37][N:32]([CH3:31])[CH2:33]2)=[C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])[CH:17]=[N:16]1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Reactant: CN1CCCC(N)C1
Agent: Cl
Product: CN1CCCC(NC(=O)c2c(NC(=O)c3nc(C4CC4)cnc3Nc3cncnc3)cnn2C)C1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (25 mg, 66 μmol; example 236, step 3) and 1-methyl-piperidin-3-ylamine dihydrochloride (12 mg, 66 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (11 mg, 33%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.C1([O:28][C:29](=O)[NH:30][C:31]2[CH:32]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:35][CH:36]=2)C=CC=CC=1>C(#N)C>[C:33]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:35][CH:36]=[C:31]([NH:30][C:29]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:8]3[CH2:7][CH2:6][C:3]4([CH2:4][CH2:5]4)[C@H:2]([OH:1])[CH2:9]3)[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:28])[CH:32]=1
Reactant: O=C(Nc1cccc(-c2ccccc2)c1)Oc1ccccc1
Reactant: C[C@@H]1NCCN(CCCCN2CCC3(CC3)[C@H](O)C2)C1=O
Solvent: CC#N
Product: C[C@H]1C(=O)N(CCCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1cccc(-c2ccccc2)c1
Yield: 82.7 %

Procedure:
A solution of (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-3-methyl-piperazin-2-one (intermediate 27; 50 mg, 0.17 mmol) and biphenyl-3-ylcarbamic acid phenyl ester (PCT Int. Appl. WO20050443810; 49 mg, 0.17 mmol) in acetonitrile (1 mL) was stirred at room temperature for 72 h, then concentrated under vacuum. Chromatography (SiO2; dichloro-methane/methanol/25% aq. ammonia solution 90:10:0.25) furnished the title compound (69 mg, 83%). White foam, MS (ISP)=491.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][CH:25]([CH2:34][OH:35])[CH2:26][NH:27][C:28]1[CH2:32][S:31][C:30](=[O:33])[N:29]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:32]2/[C:28]([NH:27][CH2:26][CH:25]([OH:24])[CH2:34][OH:35])=[N:29][C:30](=[O:33])[S:31]/2)[CH2:8][CH2:7]1
Reactant: O=C1N=C(NCC(O)CO)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCC(O)CO)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.86 g) in 2-propanol (20 mL) were added 4-[(2,3-dihydroxypropyl)amino]-1,3-thiazol-2(5H)-one (1.56 g) and piperidinium acetate (0.794 g). The reaction mixture was stirred at 80° C. for 1 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and recrystallized from ethyl acetate/heptane to give the title compound (1.22 g).
Reaction SMILES: C([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=O)=C.C([N-]C(C)C)(C)C.[Li+].[Br:17][C:18]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:19]=1C(OC)=O.Cl>C1COCC1.O>[Br:17][C:18]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:19]=1[C:4]1[CH2:5][CH2:6][CH2:7][N:3]=1
Reactant: C=CN1CCCC1=O
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(C2=NCCC2)c(Br)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
Treat a solution of 1-vinylpyrrolidin-2-one (2 g, 8.58 mmol) in dry THF (30 mL) with lithium diisopropylamide (LDA) (13 mL, 31.45 mmol) at −20° C. under N2 atmosphere and stir at the same temperature for 30 min. Then add methyl 2-bromo-4-fluorobenzoate (2 g, 8.58 mmol) and stir it over the weekend. Add an HCl (12 N, 9 mL) solution and water (12 mL). Remove the THF and add HCl (12 N, 12 mL) and water (15 mL). Heat it to 100° C. for 15 h. Cool the mixture to RT and add a 5% NaOH solution. Extract the solution with ether, dry over magnesium sulfate, and remove the solvent. Purify the residue by column chromatography (hexane to ethyl acetate) to give the title compound (0.42 g, 27%). MS (ES) m/z 244 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].N1CC[CH2:23][CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:19][CH2:23][CH2:22][CH2:20]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Product: COc1cc(N2CCC(N3CCCC3)CC2)ccc1[N+](=O)[O-]

Procedure:
1-(3-Methoxy-4-nitro-phenyl)-4-pyrrolidin-1-yl-piperidine was prepared in an analogous fashion to [1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-yl]dimethyl-amine of Example 475a replacing Dimethylamine with Pyrrolidine. The crude material was used after workup without further manipulation (350 mg, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:16][NH2:17])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1)=[O:4].C(N(CC)CC)C.[CH2:25]([O:27][C:28](=[O:33])[CH2:29][C:30](Cl)=[O:31])[CH3:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:16][NH:17][C:30](=[O:31])[CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:33])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CN)CN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)NCC1(C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
3-Aminomethyl-azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.11 g; 12.7 mmol) and triethylamine (1.95 ml; 14.01 mmol) in CH2Cl2 (55 ml) are cooled to 0° C. under stirring. Chlorocarbonyl-acetic acid ethyl ester (1.9 g; 12.74 mmol) in CH2Cl2 (15 ml) is added dropwise within 15 minutes. The reaction mixture is warmed to room temperature and stirred for 30 minutes, poured on 10% aqueous NaHCO3 and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered, evaporated and purified via chromatography (SiO2; TBME/MeOH 97:3) to yield the title compound as colorless resin (3.8 g; 77%), which crystallizes slowly.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[CH3:40][C:41]([O:44][C:45]([N:47]1[CH2:54][CH2:53][CH2:52][C@H:48]1[C:49](O)=[O:50])=[O:46])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:49]([C@@H:48]2[CH2:52][CH2:53][CH2:54][N:47]2[C:45]([O:44][C:41]([CH3:43])([CH3:42])[CH3:40])=[O:46])=[O:50])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Yield: 51 %

Procedure:
5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol) was treated with 1-{[(1,1-dimethylethyl)oxy]carbonyl}-L-proline (0.022 g, 0.103 mmol), DIPEA (0.090 mL, 0.514 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.079 g, 0.309 mmol) as in the general procedure described herein. The crude product was purified by silica gel chromatography (hexanes/ethyl acetate) to afford the title compound (0.035 g, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.51 (s, 1H), 9.77 (s, 1H), 8.95 (s, 1H), 7.88-7.98 (m, 1H), 7.77 (s, 1H), 7.44 (s, 3H), 7.33-7.40 (m, 1H), 7.27-7.33 (m, 1H), 7.19-7.26 (m, 1H), 7.07 (s, 1H), 4.52 (s, 2H), 4.15 (m, 1H), 3.24-3.45 (m, 2H), 2.14 (m, 1H), 1.62-1.92 (m, 3H), 1.36 (s, 3H), 1.23 (s, 6 H). MS: m/z 666 (M+1).
Reaction SMILES: [CH:1]([CH:19]1[CH2:24][C:23](=[O:25])[O:22][C:20]1=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O.C(O)(=O)CCC(O)=[O:31]>>[CH:1]([CH:19]([CH2:24][C:23]([OH:22])=[O:25])[C:20]([OH:31])=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)CCC(=O)O
Reactant: CCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Solvent: O
Product: CCCCCCCCCCCCCCCCC=CC(CC(=O)O)C(=O)O
Temperature: 80 °C

Procedure:
This is lactonized-2-octadecenyl succinic acid which is prepared as follows: A half mole (175 g) of 2-octadecenyl succinic anhydride and 0.55 mole (10 g) of water were mixed and heated in a reaction flask for a half hour at 80° C. Infrared analysis showed that complete conversion of the anhydride to succinic acid had occurred. While stirring at 80° C., 0.5 g of concentration sulfuric acid was added, and the reaction temperature was increased to 130°-140° C. Heating at 140° C. for 1.5 hours completely converted the di-carboxylic acid to the desired lactone acid products. When the cooled mixture was diluted with ether, a white solid separated from solution. Infrared analysis of the isolated solids revealed the presence of a 5-ring lactone acid (strong bands at 5.67 and 5.82 microns). Cooling the supernatant gave more solids. Further fractional crystallization of later crops afforded 6-ring lactone acid products. The combined weight of all crops revealed that the yield of lactone acid product was quantitative. A recrystallized sample of 5-ring lactone product melted at 112° C. and analyzed for 71.50% carbon, 10.77% H and 16.67% oxygen. Theory requires 71.49% C, 11.18% H, and 17.32% O.
Reaction SMILES: C(O[C:6](=O)[NH:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:10][CH2:9]1)(C)(C)C.[F:28][C:29]([F:40])([F:39])[O:30][C:31]1[CH:38]=[CH:37][C:34](C=O)=[CH:33][CH:32]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:26][C:15]1([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([N:7]=[CH:6][C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]([F:28])([F:39])[F:40])=[CH:38][CH:37]=3)[CH2:9][CH2:10]2)[O:19][C:18]2=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]2[CH2:16]1
Reactant: CC(C)(C)OC(=O)NN1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CN2CCN(N=Cc3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A mixture of tert-butyl[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]carbamate prepared in Example 493 (40 mg, 0.11 mmol), 4-trifluoromethoxybenzaldehyde (24 mg, 0.13 mmol), trifluoroacetic acid (0.08 ml) and methylene chloride (1 ml) was stirred at room temperature for 3 hours. The mixture was added a saturated sodium hydrogencarbonate solution for neutralization followed by extraction with methylene chloride. The solution was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=3/1) to afford N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-N-(4-trifluoromethoxybenzylidene)amine (19 mg, yield 40%) as a white powder.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:9]2=[N:10][C:11]([Br:23])=[C:12]([O:14]C(=O)C3C=CC=CC=3)[CH:13]=[C:8]2[CH:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:24]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:9]2=[N:10][C:11]([Br:23])=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)c(Br)nc2n1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(O)c(Br)nc2n1C(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to Example 3, intermediate d) from 5-benzoyloxy-6-bromo-pyrrolo [2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester and potassium carbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7](=[CH:10][N:11]([CH3:13])C)[CH:8]=[O:9])=[CH:4][CH:3]=1.NC[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7](=[CH:10][NH:11][CH2:13][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=[O:9])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CN
Reactant: CN(C)C=C(C=O)Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CNC=C(C=O)Oc1ccc(Cl)cc1

Procedure:
2-(4-Chlorophenoxy)-3-dimethylaminoacrylaldehyde (11.3 g., 50 mmoles) was dissolved in 200 ml. of ethanol, mixed with a solution of ethyl glycinate (14 g., 100 mmoles) in 90 ml. of 1 N sodium hydroxide and refluxed for 15 hours. Ethanol was evaporated in vacuo, the aqueous residue diluted with 150 ml. of water and product extracted into 200 ml. of ethyl acetate. The ethyl acetate was back-washed with water and concentrated to an oil. Trituration of the oil with 100 ml. of ether gave crystalline 2-(4-chlorophenoxy)-3-carbethoxymethylaminoacrylaldehyde in two crops (7.3 g., Rf 0.55 on silica gel thin layer chromatography with ethyl acetate-1/hexane-1/5% acetic acid as eluant).
Reaction SMILES: [N:1]1[NH:2][C:3]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:5]=1.Cl.[CH:28]1([C:31]2([F:35])[CH2:34][NH:33][CH2:32]2)[CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:1]1[N:2]=[C:3]([NH:6][C:7]2[CH:12]=[C:11]([N:33]3[CH2:34][C:31]([CH:28]4[CH2:30][CH2:29]4)([F:35])[CH2:32]3)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])=[CH:17][CH:16]=3)[N:8]=2)[NH:4][CH:5]=1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Nc3ncn[nH]3)n2)cc1)C1CC1
Reactant: FC1(C2CC2)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Sc2nc(Nc3nnc[nH]3)cc(N3CC(F)(C4CC4)C3)n2)cc1)C1CC1
Yield: 10.7 %

Procedure:
Compound I-6 was prepared according to the procedure of compound I-1 using N-(4-(4-(2H-1,2,4-Triazol-3-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide (140 mg, 0.36 mmol), 3-cyclopropyl-3-fluoroazetidine hydrochloride (62 mg), DiPEA (0.14 mL) in 1,4-dioxane (5 mL). After purification by column chromatography, the obtained material was further purified by preparative HPLC to yield 18 mg of desired product after evaporation and lyophilization, purity: 99+% (HPLC method A, Rf=8.466 minutes).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:4]=2[CH:3]=1.Cl.[CH3:15]O>>[CH3:15][O:12][C:11]([C:9]1[CH:8]=[CH:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][C:4]=2[CH:10]=1)=[O:13]
Reactant: CO
Reactant: Cc1cc2cc(C(=O)O)ccc2s1
Agent: Cl
Product: COC(=O)c1ccc2sc(C)cc2c1

Procedure:
A solution of 2-methylbenzo[b]thiophene-5-carboxylic acid (17.4 g) in methanol (250 ml) was saturated with hydrogen chloride and then heated under reflux for 30 minutes. The solid which crystallised out on cooling was filtered off and dried to give 2-methylbenzo[b]thiophene-5-carboxylic acid methyl ester (16.7 g), m.p. 97°-98°.
Reaction SMILES: [CH3:1][C:2](=[CH:7][CH2:8][C:9]#[CH:10])[CH:3]([OH:6])[C:4]#[CH:5].[CH:11]([CH:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:15](Cl)=[O:16])([CH3:13])[CH3:12].N1C=CC=CC=1>>[CH:11]([CH:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:15]([O:6][CH:3]([C:2]([CH3:1])=[CH:7][CH2:8][C:9]#[CH:10])[C:4]#[CH:5])=[O:16])([CH3:13])[CH3:12]
Reactant: C#CCC=C(C)C(O)C#C
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: C#CCC=C(C)C(C#C)OC(=O)C(c1ccc(Cl)c(Cl)c1)C(C)C
Yield: 87.5 %

Procedure:
By the same procedure as in Example 1, 1.22 g (10.0 millimoles) of 4-methylocta-4-ene-1,7-diyne-3-ol, 2.66 g (10.0 millimoles) of α-isopropyl-3,4-dichlorophenylacetyl chloride and 1.58 g (20.0 millimoles) of pyridine are reacted, followed by purification on silica gel column. Thus, 3.18 g of the objective ester is obtained as a pale yellow oily substance (87.5% of theoretical yield). nD24.0 1.5314.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[O-:24])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.CS(O[CH2:31][CH:32]1[CH2:34][C:33]1([F:36])[F:35])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:35][C:33]1([F:36])[CH2:34][CH:32]1[CH2:31][O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:7]3[N:6]=[CH:5][C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:24])[O:25][C:32]([CH3:34])([CH3:33])[CH3:31])[CH3:21])=[CH:3][C:2]=3[F:1])[O:9][C:10]=2[CH:16]=1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(O)cc3o2)c(F)c1)NC(=O)[O-]
Reactant: CS(=O)(=O)OCC1CC1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC4(F)F)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Triethylamine (14.1 mL) was added to a solution of hexachloroethane (7.46 g) and triphenylphosphine (9.91 g) in acetonitrile (50 mL) at room temperature, and the mixture was stirred at room temperature for 10 min. Then a mixture of tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate (5.31 g) and acetonitrile (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (10.7 g) as a mixture with impurities. A mixture of [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (4.28 g, a mixture with impurities), (2,2-difluorocyclopropyl)methyl methanesulfonate (0.494 g), potassium carbonate (0.367 g), and DMF (30 mL) was stirred at 60° C. for 1 hr. Then additional (2,2-difluorocyclopropyl)methyl methanesulfonate (0.494 g) and potassium carbonate (0.367 g) were added, and the mixture was stirred at 60° C. for 1 hr. Then additional (2,2-difluorocyclopropyl)methyl methanesulfonate (0.494 g) and potassium carbonate (0.367 g) were added, and the mixture was stirred at 60° C. for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.39 g) as a pale yellow solid.
Reaction SMILES: [CH:1]([Si:3]([CH2:10][CH2:11][CH3:12])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])=[CH2:2].[C:13]1([PH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:10]([Si:3]([CH2:1][CH2:2][P:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])[CH2:11][CH3:12]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=C[Si](CCC)(CCC)CCC
Product: CCC[Si](CCC)(CCC)CCP(c1ccccc1)c1ccccc1
Reaction time: 86 h

Procedure:
The vinyl tripropyl silane was then reacted with diphenyl phosphine with u.v. initiation for 86 hours in a manner described in Example 1. The conversion was about 95%. The mixture was fractionally distilled to yield approximately 63% of the theoretical yield of the product as a clear, colorless, mobile liquid. The product distilled at 155°-156° C. at 0.10 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:23]([C@@H:21]([NH:20][C:16]([CH:9]2[CH2:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18])[CH3:22])=[CH:24][CH:25]=1)=[O:28]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CC1(C)CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2CC(C)(C)CCN2C(=O)OC(C)(C)C)cc1
Yield: 44.2 %

Procedure:
The title compound (D59) (230 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 1-(tert-butoxycarbonyl)-4,4-dimethylpiperidine-2-carboxylic acid (320 mg; described in J. Med. Chem. 1997, 40, 2491-2501) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (295 mg). Reaction time: 18 hrs
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CO.S(=O)(=O)(O)O.[C:21](=O)([O-])O.[Na+]>ClCCCl>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:21])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 68 %

Procedure:
To a solution of 4-hydroxy-3-nitrobenzoic acid (15.8 g, 86.3 mmol) in 1,2-dichloroethane (150 mL) were added methanol (14 mL) and conc. sulfuric acid (0.5 mL) and the mixture was heated to 80° C. and stirred. Methanol (9 mL) was added on the way and the mixture was stirred for 21 hours. The reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution (400 mL) and extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give methyl 4-hydroxy-3-nitrobenzoate as a yellow solid (11.5 g, 68%).