Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:26]([C:27]2[S:31][C:30]([S:32](Cl)(=[O:34])=[O:33])=[CH:29][CH:28]=2)=[CH:25][C:24]([C:36]([F:39])([F:38])[F:37])=[N:23]1>CN(C1C=CN=CC=1)C.ClCCCl>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:26]([C:27]2[S:31][C:30]([S:32]([N:12]3[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]3)(=[O:34])=[O:33])=[CH:29][CH:28]=2)=[CH:25][C:24]([C:36]([F:39])([F:37])[F:38])=[N:23]1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)s1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN1CCN(S(=O)(=O)c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)s2)CC1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
Triethylamine (0.15 mL, 1.1 mmol) and a small amount of DMAP were dissolved in 1,2-dichloroethane (2 mL) in a reaction vial. This solution was treated with 1-methyl piperazine (50 μL, 0.45 mmol) followed by 5-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonyl chloride (145 mg, 0.34 mmol) as a solution in 1,2-dichloroethane (1 mL). After stirring 4½ hours at ambient temperature the reaction was quenched by dilution with CH2Cl2 and water. Saturated NaHCO3 was added and the basic aqueous was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product as a pale yellow oil. This crude product was purified by flash column chromatography eluting with a gradient from CH2Cl2 to 16% acetonitrile/CH2Cl2 to afford 1-(5-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophen-2-ylsulfonyl)-4-methylpiperazine (90.5 mg, 54% yield) as a brittle white foam. MS(ES): 491 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14]Br)=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])=[O:4].[C:26]([O-:29])(=[O:28])[CH3:27].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14][O:29][C:26](=[O:28])[CH3:27])=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])=[O:4]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cc2cc(CBr)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(COC(C)=O)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
1-BOC-5-bromomethyl-7-nitro-indole-2-carboxylic acid methyl ester (10.0 g, 24.2 mmol) prepared in Step B of Preparation 37 was dissolved in N,N-dimethylformamide (50 mL). Sodium acetate (2.4 g, 29.0 mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was purified by column chromatography to give the title compound (4.7 g, Yield 50%).
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:24]([CH:28]=1)[C:25](O)=[O:26])[CH2:2][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].[NH:37]([CH2:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40].C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[C:54]1([CH2:53][O:52][C:50](=[O:51])[CH2:49][N:37]([C:25](=[O:26])[C:24]2[CH:28]=[C:20]([O:19][CH2:1][CH2:2][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])[CH:21]=[CH:22][C:23]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:38][C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(CNCC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.2 %

Procedure:
A mixture of 1.0 g (2.0 mmol) of 5-(octadecyloxy)-2-(phenylmethoxy)benzoic acid in 5 ml of thionyl chloride was heated to reflux for 1 hour and then concentrated at reduced pressure. The resultant acid chloride was dissolved in 30 ml of anhydrous THF and added dropwise to a stirred mixture of 0.785 g (2.5 mmol) of dibenzyl iminodiacetate and 0.85 ml (6.1 mmol) of triethylamine in 10 ml of THF. The reaction mixture was stirred at room temperature for 20 hours and the solvent was removed at reduced pressure. The product was purified by HPLC using 5% ethyl acetate-hexane to give 0.70 g (44% yield) of N-[5-(octadecyloxy)-2-(phenylmethoxy) benzoyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[CH2:14]([NH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cccc(N)c1C
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)c1cccc(NCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a stirred solution of ethyl 3-amino-2-methylbenzoate (1.00 g, 5.58 mmol) in DCE (20 ml) was added benzaldehyde (569 μl, 5.58 mmol) followed by acetic acid (0.64 ml, 11.2 mmol). The reaction was stirred at room temperature for 1 h and then sodium triacetoxyborohydride (1.77 g, 8.37 mmol) was added and the reaction stirred for 2 h. Distilled water (20 ml) was added and solid NaHCO3 was added until the aqueous phase was pH7 and the phases were separated. The aqueous phase was washed with DCM (2×5 0 ml), the combined organics were then washed with brine (50 ml), dried using Na2SO4, filtered and evaporated to afford the title compound as a yellow oil (1.52 g, 96%) which was used in the next stage without any further purification. LC-MS 95%, m/z=270.0, 1H NMR (500 MHz, Chloroform-d) δ 7.42-7.32 (m, 4H), 7.32-7.28 (m, 1H), 7.17-7.06 (m, 2H), 6.73 (dd, J=7.8, 1.1 Hz, 1H), 4.40 (s, 2H), 4.36 (q, J=14.3, 5.3 Hz, 2H), 4.08 (br. s, 1H), 2.35, (s, 3H), 1.39 (t, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][Si](C(C)(C)C)(C)C)=[CH:53][CH:52]=3)[CH:46]([OH:65])[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[CH:53][C:54]([OH:57])=[CH:55][CH:56]=3)[CH:46]([OH:65])[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc(O[Si](C)(C)C(C)(C)C)cc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc(O)cc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Yield: 64.5 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (41.9 mg) in CH2Cl2 (1.5 mL.) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL. of a 10% w/v solution). The mixture was stirred 3H at 0° C. and then 3H at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 2:1 hexanes/acetone) affording 23.9 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis are consistent with the desired structure).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:18]([C:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27])([CH3:22])[CH3:21])#[N:19].Cl.C(N=C=NCCCN(C)C)C.CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:18]([C:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:10]=1)=[O:27])([CH3:22])[CH3:21])#[N:19]
Reactant: Nc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cc3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a solution of 3-(4-nitrophenoxy)aniline (4.69 g, 20.4 mmol) and 3-(1-cyano-1-methylethyl)benzoic acid (3.98 g, 21.0 mmol) produced in Example A7(ii) in pyridine (100 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.69 g, 24.5 mmol) and N,N-dimethylpyridine-4-amine (151 mg, 1.24 mmol), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added methanol (50 mL) and the mixture was further stirred at the same temperature for 30 min. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with dilute hydrochloric acid (150 mL×2) and saturated aqueous sodium hydrogencarbonate solution (150 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (8.10 g, 99%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[C:16]([CH3:17])=[CH:15][C:14]([I:18])=[CH:13][C:10]=1[CH:11]=O>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:16]([CH3:17])=[CH:15][C:14]([I:18])=[CH:13][C:10]=1[CH2:11][NH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cc1cc(I)cc(C=O)c1N
Reactant: CCOC(=O)CN
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNCc1cc(I)cc(C)c1N

Procedure:
A mixture of freshly prepared ethyl glycinate (2.58 g), 2-amino-5-iodo-3-methylbenzaldehyde (4.03 g) and 3Å molecular sieves (2 g "Fluka A.G." [Trade Mark] article No. 69828) was heated with stirring under reflux in chloroform (50 cm3) for 4 hours. The cooled solution was filtered, evaporated in vacuo, and the residue taken into ethanol (30 cm3) and treated with sodium cyanoborohydride (1.43 g). After stirring for 72 hours ethanol was removed in vacuo and the residue was partitioned between chloroform (50 cm3) and aqueous ammonia (50 cm3, S.G. 0.88). The aqueous phase was further extracted with chloroform (2×100 cm3) and the combined organic extracts were dried (MgSO4) and evaporated to give the title compound as a crude oil, (2.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[CH2:7][NH2:8].CCN(C(C)C)C(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[C:45]([C:49]1[O:53][N:52]=[C:51]([NH2:54])[CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>ClCCl>[C:45]([C:49]1[O:53][N:52]=[C:51]([NH:54][C:37]([NH:8][CH2:7][C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:15]=[CH:14]3)=[O:43])[CH:50]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3CNC(=O)Nc3cc(C(C)(C)C)on3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a cooled (0° C.) solution of 5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)-benzylamine (0.364 g, 1.04 mmol) and DIEA (0.5 mL, 2.08 mmol) in dichloromethane (10 mL) was added triphosgene (0.131 g, 0.374 mmol). The mixture was stirred at 0° C. for 1 hour and then stirred at room temperature for 18 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and suspended in dichloromethane (10 mL) making a 0.123 M solution. 0.4 mL of this solution (0.015 g, 0.048 mmol) was treated with 5-tert-butyl-isoxazol-3-ylamine (0.008 g, 0.053 mmol). The product was obtained in 44% yield. MS (APCI+) m/z 480 (M+1) detected.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:12]([SH:15])[CH:13]=[CH2:14]>C(O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:15][CH2:12][CH:13]=[CH2:14])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C=CCS
Solvent: CCO
Product: C=CCSc1ccc([N+](=O)[O-])c(N)c1

Procedure:
To a solution of 7 g of 2-nitro-5-chloroaniline in 200 ml of absolute ethanol there is added 4.2 of allyl mercaptan and 2.5 g of Na-methoxide. Then the mixture is refluxed for three hours, the solvent is evaporated and the residue is chromatographed on neutral alumina (Activity IV). Elution with ether-petroleum ether yields 4.6 g of 2-nitro-5-(2-propenylthio)aniline.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:16])[NH:11]2.[I-].[Na+].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.CN(C)C=O.CC(C)=O>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C:10](=[O:16])[NH:11]3)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1CCc2c(cccc2OCCCCl)N1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCc2c(cccc2OCCCN2CCN(Cc3ccccc3)CC2)N1
Reaction time: 7 h
Yield: 84 %

Procedure:
24 Grams of 5-(3-chloropropoxy)-3,4-dihydrocarbostyril and 17 g of sodium iodide are mixed with 300 ml of acetone and heated for 3 hours under refluxing conditions. Then, 300 ml of dimethylformamide, 12 g of triethylamine and 18 g of 4-benzylpiperazine are added thereto and the reaction is carried out at 60°-70° C. for 7 hours with stirring conditions. The reaction mixture is concentrated under a reduced pressure to obtain a viscous liquid, then 300 ml of 3% sodium hydrogencarbonate aqueous solution is added. The organic layer is extracted with chloroform and washed with water. After drying the chloroform layer, the chloroform is removed by distillation. The residue thus obtained is washed with ether and recrystallized from methanol to obtain 32 g (yield: 84%) of 5-[3-(4-benzylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 157°-159° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C1COCC1>[N:8]1([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCNC1
Reactant: C=CC(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)CCN1CCCC1
Reaction time: 3.5 h

Procedure:
Ethyl acrylate (110.0 g; 1.1 mol) was dissolved in THF (250 ml). To this a solution of pyrrolidine (71.5 g; 1.0 mol) in THF (100 ml) was added dropwise in 75 minutes, after which stirring was continued for 3.5 hours at room temperature. The reaction mixture was evaporated by means of a rotary evaporator. The yield was 161.8 g (94%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:57])([CH3:56])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:55])([C@@:17]4([CH3:54])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([NH:36][CH2:37][CH2:38][N:39]2[CH2:45][C@H:44]5[N:46]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:41]([CH2:42][CH2:43]5)[CH2:40]2)[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59].[OH-].[Li+]>C1COCC1.CO>[C:50]([O:49][C:47]([N:46]1[C@H:41]2[CH2:42][CH2:43][C@@H:44]1[CH2:45][N:39]([CH2:38][CH2:37][NH:36][C@:20]13[CH2:32][CH2:31][C@@H:30]([C:33]([CH3:35])=[CH2:34])[C@@H:21]1[C@@H:22]1[C@@:17]([CH3:54])([CH2:18][CH2:19]3)[C@@:16]3([CH3:55])[C@@H:25]([C@:26]4([CH3:29])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:57])([CH3:56])[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=3)=[CH:28][CH2:27]4)[CH2:24][CH2:23]1)[CH2:40]2)=[O:48])([CH3:51])([CH3:52])[CH3:53].[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@H]4CC[C@@H](C3)N4C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@H]4CC[C@@H](C3)N4C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of (1R,5S)-tert-butyl 3-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, 2 TFA (30 mg, 0.030 mmol) in THF (0.75 mL) and MeOH (0.25 mL) was added a solution of lithium hydroxide (1N) (0.148 mL, 0.148 mmol). The reaction mixture was stirred at 75° C. After 1 h, the reaction mixture was cooled to rt and purified by reverse phase prep-HPLC using HPLC method 7 and dried to give 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, 2 TFA (22.2 mg, 0.021 mmol, 69.0% yield) as pale yellow solid. LC/MS: m/e 768.8 (M+H)+, 2.34 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.96 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 5.13 (d, J=5.4 Hz, 1H), 4.84 (br. s., 1H), 4.68 (s, 1H), 4.36 (br. s., 2H), 3.68-3.32 (m, 6H), 2.98 (d, J=10.3 Hz, 2H), 2.70 (br. s., 1H), 2.08 (br. s., 7H), 1.97-1.82 (m, 2H), 1.70 (d, J=5.9 Hz, 1H), 1.66 (s, 3H), 1.63-1.51 (m, 5H), 1.49 (s, 9H), 1.47-1.39 (m, 5H), 1.39-1.27 (m, 4H), 1.27-1.15 (m, 3H), 1.11 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.97-0.94 (m, 3H), 0.89 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:33])=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[C:21]=3[Cl:31])[CH:17]=1)[N:5]=2.[CH3:34][CH:35]([CH3:39])[C:36](Cl)=[O:37].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:31][C:21]1[C:22]([C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36](=[O:37])[CH:35]([CH3:39])[CH3:34])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=[CH:14][C:15]=1[F:33])=[O:32]
Reactant: CC(C)C(=O)Cl
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)ccc3F)c2Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (0.16 g, 0.33 mmol) produced in Example C71(iv) and N,N-dimethylpyridine-4-amine (0.12 g, 1.00 mmol) in pyridine (2 mL) was added dropwise 2-methylpropanoyl chloride (0.12 g, 1.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (114 mg, 63%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[CH2:21]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH2:22][CH2:23][C:24]#[CH:25].P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: C#CCCCOCCCCCCBr
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (Example 1vi) (500 mg) in DMF (15 ml) under nitrogen at 0° was treated with sodium hydride (60% dispersion in mineral oil, 96 mg) and the mixture stirred at 20° for 10 min. A solution of 6-bromohexyl 4-pentyn-1-yl ether (WO 02/066422) (545 mg) in DMF (1 ml) was added and the mixture stirred at 20° for 18 h. Phosphate buffer solution (pH 6.5) and water were added and the mixture was extracted with EtOAc. The extract was washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue, which was purified by flash chromatography on silica gel. Elution with EtOAc-PE (2:3) gave the title compound (700 mg). LCMS RT=3.48 min.