Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])=[C:17]([F:28])[C:16]=2[F:29])=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[S:10][N:9]=1>>[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[C:17]([F:28])[C:16]=2[F:29])=[C:11]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[S:10][N:9]=1
Reactant: CCOC(=O)CCc1ccc(OCc2c(Cl)nsc2-c2ccc(OC)cc2)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(-c2snc(Cl)c2COc2ccc(CCCO)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 156 following Step 2 by LAH reduction of ethyl 3-(4-((3-chloro-5-(4-methoxyphenyl)isothiazol-4-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD): δ 7.53 (d, J=8.7 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 6.87-7.00 (m, 2H), 5.07 (s, 2H), 3.60 (d, J=6.6 Hz, 2H), 2.18 (d, J=7.2 Hz, 2H), 1.78-1.87 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C20H18ClF2NO3S, 426.1 (M+H). found 426.1.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([O:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1)[CH3:6])C.[OH-].[Na+].Cl>O.C(O)C>[F:15][C:14]([F:16])([F:17])[C:12]1[CH:13]=[C:8]([CH:9]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:11]=1)[O:7][CH:5]([CH3:6])[C:4]([OH:22])=[O:3]
Reactant: CCOC(=O)C(C)Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A stirred charge containing 0.05 mole of ethyl-2-[3,5-bis-(trifluoromethyl)phenoxy]propionate, 150 ml of ethyl alcohol, 8 g (0.1 mole) of 50% aqueous solution of sodium hydroxide and 25 ml of water was heated at reflux for 5 hours and at 25°-30° C. for 18 hours. After cooling to 5° C. 800 ml of water containing 15 g (0.15 mole) of concentrated hydrochloric acid was added slowly. After stirring at 0°-10° C. for one hour, the resulting solid was collected by filtration, washed with cold water and air-dried at 25°-30° C. A product with a melting point of 51°-53° C. was obtained with a yield of 97%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C:8]1[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=1
Reactant: COC(=O)C/C=C/c1ccc(Nc2ncccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C/C=C/c1ccc(Nc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
300 mg of methyl (E)-4-{4-((pyrimidin-2yl)amino)phenyl}-3-butenoate was dissolved in 5 ml of dioxane, followed by the addition of 3 ml of a 1N solution of sodium hydroxide. The obtained mixture was stirred at a room temperature for 2 hours, followed by the addition of 3 ml of 1N hydrochloric acid. The crystal thus formed was recovered by filtration and dried under a reduced pressure to obtain 200 mg of the title compound as a white crystal (yield: 70%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(OCC)(=O)C>[C:19]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:12])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 84.1 %

Procedure:
To a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained in Reference Example 40 and ethyl acetate (50 mL) were added pyridine (4.06 mL) and acetic anhydride (5.13 g), and the mixture was stirred at room temperature for 21 hrs. Ethyl acetate (200 mL) was added to the reaction mixture, and the mixture was washed with water (100 mL), an aqueous copper sulfate solution (40 mL), water (60 mL) and saturated brine (60 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (8.34 g) as a colorless oil.
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(CCC2C=CC(O)=CC=2)C=1.Cl.ClCCN(C(C)C)C(C)C.[CH:41]([N:44]([CH:76]([CH3:78])[CH3:77])[CH2:45][CH2:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][CH2:55][C:56]2[CH:61]=[C:60]([O:62]C)[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74]C)[CH:70]=3)[CH2:65]2)=[CH:50][CH:49]=1)([CH3:43])[CH3:42]>>[CH:76]([N:44]([CH:41]([CH3:43])[CH3:42])[CH2:45][CH2:46][O:47][C:48]1[CH:49]=[CH:50][C:51]([CH2:54][CH2:55][C:56]2[CH:61]=[C:60]([OH:62])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[CH:70]=[C:69]([OH:74])[CH:68]=[CH:67][C:66]=3[CH2:65]2)=[CH:52][CH:53]=1)([CH3:78])[CH3:77]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(OCCN(C(C)C)C(C)C)cc1)C2
Agent: CC(C)N(CCCl)C(C)C
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(O)cc1)C2
Agent: Cl
Product: CC(C)N(CCOc1ccc(CCc2cc(O)ccc2C2CCc3cc(O)ccc3C2)cc1)C(C)C
Yield: 35.8 %

Procedure:
Synthesized from 4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenol and (2-chloroethyl)diisopropylamine hydrochloride according to an analogous synthetic method to Preparation Example 40, diisopropyl{2-{4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenoxy}ethyl}amine (183 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (62 mg).
Reaction SMILES: C([C:9]1[C:14]([OH:15])=[CH:13][N:12]=[C:11]([CH2:16][CH:17]([NH:19][CH3:20])[CH3:18])[C:10]=1C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[ClH:29]>>[ClH:29].[ClH:29].[CH3:20][NH:19][CH:17]([CH3:18])[CH2:16][C:11]1[CH:10]=[CH:9][C:14]([OH:15])=[CH:13][N:12]=1
Reactant: CNC(C)Cc1ncc(O)c(C(=O)c2ccccc2)c1C(=O)c1ccccc1
Agent: Cl
Product: CNC(C)Cc1ccc(O)cn1

Procedure:
The solution of 0.15 g of dibenzoyl-2-(2-methylaminopropyl)-5-pyridinol in 5 ml of 5 N hydrochloric acid is refluxed for 23 hours, cooled, twice washed with 5 ml of diethyl ether and evaporated, to yield the 2-(2-methylaminopropyl)-5-pyridinol dihydrochloride, showing in the mass-spectrum peaks at 165, 151, 109 and 58 m/e.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14].I[CH3:16]>CN(C=O)C.C(Cl)(Cl)Cl.C(O)(C)C>[I:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]([CH3:16])[C:7]2=[O:14]
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Cn1cnc2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
Suspend sodium hydride (1.13 g, 47 mmol) in a solution of 6-iodo-3H-quinazolin-4-one (2.5 g, 9.2 mmol) in DMF. Stir at room temperature for 20 min, add iodomethane (6.6 g, 46 mmol) into the mixture and stir for 2 h. Dilute the mixture with 3:1 chloroform/isopropyl alcohol and wash with saturated sodium chloride solution. Dry the organic phase (sodium sulfate) and concentrate in vacuo. Purify the residue with flash chromatography (dichloromethane to dichloromethane/methanol) to give 2.5 g (95%) of the titled compound as a white solid. MS ES+ m/e 287 (M+1).
Reaction SMILES: [BrH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]#[CH:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]>>[Br:1][C:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=1)=[CH2:13]
Reactant: C#Cc1ccc(OC)c(OC)c1
Reactant: Br
Product: C=C(Br)c1ccc(OC)c(OC)c1
Yield: 86.7 %

Procedure:
According to the General Procedure D, HBr (33% in acetic acid, 1.11 ml, 0.50 g, 6.17 mmol) and 3,4-dimethoxyphenylacetylene (1.00 g, 6.17 mmol) are converted to give after workup and chromatography (SiO2, PE/EE 5:1, Rf=0.41) the title compound (1.30 g, 5.35 mmol, 87%) as a brown oil; C10H11BrO2 (243.10).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:21]([C:25]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](=[O:43])[CH2:35][CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:28][C:26]=1[NH2:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](=[O:43])[CH2:35][CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:28][C:26]=1[NH:27][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(CCC(=O)CC2CCCCCC2)cc1N
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Product: CCCCCCCCCCOc1ccc(C(=O)Nc2cc(CCC(=O)CC3CCCCCC3)ccc2C(C)(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 21, but using 4-decyloxybenzoic acid and 2-t-butyl-5-(4-cycloheptyl-3-oxobutyl)aniline as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as crystals, melting at 98°-99° C. (after recrystallization from a mixture of ethyl acetate and hexane). The 2-t-butyl-5-(4-cycloheptyl-3-oxobutyl)aniline used as a starting material was prepared following a similar procedure to that described in Preparation 7, but using 2-t-butyl-5-(4-cycloheptyl-3-oxobutyl)-1-nitrobenzene (prepared by a procedure similar to that described in Preparation 6).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[CH3:7])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:8]1([CH:6]([CH3:7])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)CC(C)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC(C)N1CCNCC1
Yield: 60.3 %

Procedure:
A solution of 513 (1.02 g, 3.40 mmol) and TFA (10 ml) in DCM (50 ml) was stirred at rt for 3 h. The reaction mixture was concentrated (azeotropes with DCM), diluted in water, and the pH was adjusted to around 8-9 with a saturated aqueous solution of sodium bicarbonate and 1N NaOH, and extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to afford the desired product 514 (411 mg, 2.05 mmol, 60% yield) as a yellow sticky oil that was used crude in the next step without any further purification. MS (m/z): 201.3 (M+H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]3[CH2:20][CH2:19][N:18]([C:21](OC)=O)[CH2:17][CH2:16][C:14]3=2)[CH:9]=[CH:8]1.O.[OH-].[Na+]>C1COCC1>[CH3:21][N:18]1[CH2:17][CH2:16][C:14]2[C:13](=[CH:12][CH:11]=[C:10]3[C:15]=2[NH:7][CH:8]=[CH:9]3)[CH2:20][CH2:19]1
Reactant: COC(=O)N1CCc2ccc3cc[nH]c3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2ccc3cc[nH]c3c2CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
Under N2, a flame-dried, 50-mL, two-necked flask was charged with LiAlH4 (0.10 g, equivalent by weight) and THF (3.0 mL) and cooled to 0° C. A solution of methyl 6,7,9,10-tetrahydroazepino[4,5-g]indole-8(1H)-carboxylate (0.105 g, 0.43 mmol) in THF (2.0 mL) was then added and the mixture was stirred at room temperature for 16 hours. Water (0.1 mL) was added slowly, followed by 15% NaOH (0.1 mL) and then water (0.3 mL). The mixture was stirred for 30 min, celite was added and the mixture was filtered through celite and the filtrate concentrated to give 84 mg (98%) of crude product. Crystallization from EtOAc/hexane affords 27 mg of the title product as a beige solid: mp 150–153° C.; 1H NMR (400 MHz, CDCl3) δ 8.09 (br, 1 H), 7.39 (d, J=8 Hz, 1 H), 7.17 (t, J=3 Hz, 1 H), 6.91 (d, J=8 Hz, 6.53 (dd, J=2, 3 Hz, 1 H), 3.10–3.05 (m, 4 H), 2.67–2.62 (m, 4 H), 2.40 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 135.5, 135.0, 126.5, 123.8, 123.8, 123.6, 121.9, 118.0, 103.1, 57.7, 56.8, 47.6, 36.2, 29.3; HRMS (FAB) calcd for C13H16N2+H 201.1392. found 201.1390.
Reaction SMILES: COC1C=CC(C[N:8]([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]([O:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:22])[CH2:19][CH2:18][O:17][C:16]=3[CH:33]=2)(=[O:11])=[O:10])=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[S:35]1[CH:36]=[CH:37][N:38]=[C:34]1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]2[N:20]([C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:22])[CH2:19][CH2:18][O:17][C:16]=2[CH:33]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
To a solution of 4-nitrophenyl 7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (0.050 g, 0.086 mmol) in DCM (0.172 ml) was added trifluoroacetic acid (0.165 ml, 2.146 mmol). The reaction was stirred at RT for 15 minutes until complete deprotection. The reaction was concentrated in vacuo and purified via 500-mg SCX column (product eluted cleanly with methanol wash) to yield, after concentration, 4-nitrophenyl 7-(N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazine-4(3 H)-carboxylate (0.036 g, 0.078 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.73 (br. s., 1 H) 8.28-8.38 (m, 2 H) 8.06 (d, J=8.71 Hz, 1 H) 7.55-7.64 (m, 2 H) 7.34 (dd, J=8.75, 2.20 Hz, 1 H) 7.22-7.30 (m, 2 H) 6.83 (d, J=4.60 Hz, 1 H) 4.36-4.48 (m, 2 H) 4.02-4.11 (m, 2 H). m/z (ESI) 462.9 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=Cc1ncccc1Br
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=Cc1ncccc1-c1cc(F)cc(F)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
To a solution of 3-bromo-pyridine-2-carbaldehyde (1.2 g, 6.45 mmol) dissolved in ethylene glycol dimethyl ether (25 mL), THF (10 mL) and saturated solution of Na2CO3 (9 mL) was added 3,5 difluorophenyl boronic acid (1.12 g, 7.10 mmol). Purge the mixture with Ar gas (10 min). To this mixture was added Pd(PPh3)4 (373 mg, 0.33 mmol) and stir under a positive pressure of Ar at 90° C. for 16 hours. The reaction mixture was quenched with a solution of saturated NaHCO3 (50 mL). Extract with CH2Cl2 (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a light yellow oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH: 80:20, v/v/v) afforded 3-(3,5-difluoro-phenyl)-pyridine-2-carbaldehyde as a white solid (0.86 g, 61%). 1H NMR (CDCl3) δ 6.59 (m, 1H), 6.92 (m, 2H), 7.60 (m, 1H), 7.76 (d, 1H, J=7.5 Hz), 8.88 (d, 1H, J=3.5 Hz), 10.11 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1>CN(C=O)C>[S:15]1[CH:16]=[CH:17][N:18]2[CH:2]=[C:3]([C:5]3[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=3)[N:13]=[C:14]12
Reactant: Nc1nccs1
Reactant: O=Cc1ccc(C(=O)CBr)cc1
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2cn3ccsc3n2)cc1

Procedure:
0.7 g (2.1 mM) 4-(2-Bromo-acetyl)-benzaldehyde and 2-aminothiazole (2 eq) are stirred in 15 ml DMF at 90° C. for 6 h. The DMF is evaporated and the residue suspended in ethyl acetate over night. The desired product is collected by filtration.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH3:14][Si:15]([CH:18](O)[CH3:19])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[O:12]
Reactant: O=C(O)CCCCc1ccccn1
Reactant: CC(O)[Si](C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOC(=O)CCCCc1ccccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
5-(2-Pyridyl)valeric acid (1.5 g, 8.4 mmol) was dissolved in N,N-dimethylformamide (25 ml), and trimethylsilylethanol (2.0 g, 16.7 mmol), WSC (3.2 g, 16.7 mmol) and HOBt (2.3 g, 16.7 mmol) were added thereto successively. The mixture was stirred at room temperature for 6 hrs. The solvent was evaporated, and the residue was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (60 g) column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give the titled compound (1.1 g, 49%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70](=[O:72])[CH3:71])=[CH:66][C:65]=1[O:73][CH3:74]>>[C:70]([C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:65]([O:73][CH3:74])[CH:66]=1)(=[O:72])[CH3:71]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(C(C)=O)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 37.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.43 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.21 g, 0.89 mmol), then reacted with 1-(4-amino-3-methoxyphenyl)ethanone (Bionet) (0.11 g, 0.67 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-acetyl-2-methoxy-phenyl)-amide as a light yellow solid (Yield 0.098 g, 37%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[I:16](O)(=O)=O.II.Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCCCCCC.C(Cl)(Cl)(Cl)Cl.O.C(O)(=O)C>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1
Reactant: COC[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: [O-][I+2]([O-])O
Agent: Cl
Agent: II
Agent: O=S([O-])([O-])=S
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCCC
Product: COC[C@H]1CC[C@H](c2ccc(I)cc2)CC1
Reaction time: 12 h

Procedure:
Into a 1 l three-neck flask were added compound (D) (100.0 g, 0.489 mol), acetic acid (344 ml), water (91 ml), iodic acid (20.6 g, 0.117 mol), iodine (54.5 g, 0.215 mol), CCl4 (40 ml) and conc. hydrochloric acid (14 ml), followed by stirring and further refluxing for 3 hours while heating on a mantle heater. After cooling, a 10% aqueous solution of sodium thiosulfate (15 ml) was added to cause the color of excess iodine to disappear, followed by adding n-heptane (200 ml ), transferring the mixture into a separating funnel, washing the resulting n-heptane layer with water till the aqueous layer becomes neutral, distilling off n-heptane under reduced pressure, dissolving the residue in n-hexane (50 ml), allowing the solution to stand at -10° to -20° C. for 12 hours, filtering off the resulting crystals and drying to obtain 4-(trans-4'-methyloxymethylcyclohexyl)iodobenzene (E) (81.3 g). M.P. 40.3°~ 42.3° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1.[CH:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>>[F:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:13][CH:12]=1)[O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:39]2[CH:40]=[CH:41][C:36]([CH:33]([CH3:35])[CH3:34])=[CH:37][CH:38]=2)=[C:24]([CH3:30])[CH:23]=1
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Oc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(OC(CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)C)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 128 starting from enantiomers of 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-4,4,4-trifluoro-butyl]-benzoylamino}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid. Isomer 1 MS: 540.2 [M−H]−, Isomer 2 MS: 540.2 [M−H]−.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:27])[C:15](=[O:26])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[CH:17][C:7]2=1)(=[O:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)C>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:16]1[C:15](=[O:26])[N:14]([CH3:27])[C:8]2[N:9]([CH3:13])[C:10]3[C:6]([C:7]=2[CH:17]=1)=[CH:5][C:4]([C:1](=[O:3])[CH2:2][C:31](=[O:30])[CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)=[CH:12][CH:11]=3
Reactant: CCOC(=O)COC1CCCCO1
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CC(=O)COC4CCCCO4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 80 above, with the compound from preparation 1.10E, 6-acetyl-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and (tetrahydropyran-2-yloxy)acetic acid ethyl ester.