Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][C:13]1[N:28]=[CH:27][C:16]2[N:17]([CH:24]([CH3:26])[CH3:25])[C:18]3[C:23]([C:15]=2[C:14]=1[CH2:29][CH3:30])=[CH:22][CH:21]=[CH:20][CH:19]=3.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39](O)=[O:40])=[CH:33][CH:32]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([NH:12][C:13]2[N:28]=[CH:27][C:16]3[N:17]([CH:24]([CH3:26])[CH3:25])[C:18]4[C:23]([C:15]=3[C:14]=2[CH2:29][CH3:30])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:40])=[CH:33][CH:32]=1
Reactant: O=C(O)CCc1ccncc1
Reactant: CCc1c(N)ncc2c1c1ccccc1n2C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCc1c(NC(=O)CCc2ccncc2)ncc2c1c1ccccc1n2C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
EDAC (0.035 g, 0.18 mmol) was added to a solution of 3-amino-4-ethyl-9-isopropyl-9H-pyrido[3,4-b]indole (Method 5; 0.03 g, 0.12 mmol), DMAP (0.007 g, 0.06 mmol) and 3-(pyridin-4-yl)propanoic acid (Method 6; 0.027 g, 0.18 mmol) in DMF (10 ml). The mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane and a saturated solution of sodium bicarbonate. The organic layer was separated, washed with brine, dried over magnesium sulphate and then evaporated to dryness in vacuo. The crude product was purified by flash chromatography eluting over a gradient of 0-10% MeOH in DCM. NMR (CDCl3) 8.72 (s, 1H), 8.51 (m, 2H), 8.19 (d, 1H), 7.59 (d, 2H), 7.47 (s, 1H), 7.29 (m, 1H), 7.20 (m, 2H), 5.05 (m, 1H), 3.12 (m, 4H), 2.78 (m, 2H), 1.73 (d, 6H), 1.31 (t, 3H); m/z 388.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[O:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCCCCOc1ccccc1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCCCCCCOc2ccccc2)c(Nc2ccncc2)c1=O

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 6-phenoxyhexylamine.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([O:16]CC)=[O:15])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn(Cc2ccccc2)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)ncn1Cc1ccccc1
Temperature: 80 °C
Yield: 90.7 %

Procedure:
Part A: To a magnetically stirred solution of ethyl N-benzyl-5-methyl-1H-imidazole-4-carboxylate (8.4 gram, 0.0345 mol) in methanol (200 ml) was slowly added a solution of KOH (7.3 gram, 85% grade, 0.110 mol) and the resulting mixture was heated at 80° C. for 2 hours. The solution was cooled to room temperature and concentrated HCl (9.2 ml) was subsequently added. The formed precipitate was collected by filtration to give N-benzyl-5-methyl-1H-imidazole-4-carboxylic acid (6.77 gram, 91% yield). Melting point: 292° C. (decomposition).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Br:7])=[O:3].Cl.[Cl:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][Cl:15].C(N(CC)CC)C>ClCCl>[Br:7][CH2:6][CH2:5][O:4][C:2]([N:12]([CH2:13][CH2:14][Cl:15])[CH2:11][CH2:10][Cl:9])=[O:3]
Reactant: O=C(Cl)OCCBr
Reactant: ClCCNCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCBr)N(CCCl)CCCl
Temperature: 7.5 °C
Reaction time: 18 h

Procedure:
2-Bromoethyl chloroformate (5.6 mL, 50 mmol) was added to a stirred suspension of bis(2-chloroethyl)amine hydrochloride (9.8 g, 55 mmol) in 250 mL of dry dichloromethane at 0-5° C. under argon over 2 min followed by 28 mL (200 mmol) of triethylamine over 20 min. The mixture was stirred at 5-10° C. for 3 h and at room temperature for 18 h, then suction filtered. The filtrate was concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[O:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:18]=1)([O-:7])=[O:6].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl.C(=O)(O)[O-].[Na+].[Ti](Cl)(Cl)(Cl)Cl>[CH:2]([N:13]1[C:12]2[CH:18]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=[CH:10][C:11]=2[O:17][CH2:16][CH2:15][CH2:14]1)([CH3:4])[CH3:1]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCCO2
Reactant: CC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)N1CCCOc2ccc([N+](=O)[O-])cc21
Reaction time: 2 h
Yield: 42 %

Procedure:
Acetone (0.284 mL, 3.86 mmol) was added to a solution of 2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (0.250 g, 1.29 mmol) in 1,2-Dichloroethane (5 mL), followed by 1.00 M of Titanium tetrachloride in Methylene chloride (1.29 mL). The reaction mixture was stirred for 2 hours. Then, Sodium triacetoxyborohydride (1.36 g, 6.44 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with 30 mL DCM, 30 mL saturated sodium bicarbonate and extracted. The organic layer was then concentrated and purified by column chromatography (ISCO 0-60% EtOAc) to give 9-Isopropyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as orange solids (128 mg, 42%). LCMS: 237; 1H-NMR (DMSO): 7.47 (m, 2H), 6.91 (d, 1H, J=8.5 Hz), 4.31 (m, 2H), 3.86 (sept, 1H, J=6.5 Hz), 3.30 (m, 2H), 1.92 (m, 2H), 1.19 (d, 6H, J=6.5 Hz).
Reaction SMILES: [I-:1].C([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[C@@H:15]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16][CH2:17][N+:18]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH3:19])(=O)CCC>CO>[I-:1].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[C@@H:15]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:16][CH2:17][N+:18]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:21])[CH3:22])[CH3:19]
Reactant: CCCC(=O)Oc1ccc(C)cc1[C@H](CC[N+](C)(C(C)C)C(C)C)c1ccccc1
Agent: [I-]
Solvent: CO
Product: Cc1ccc(O)c([C@H](CC[N+](C)(C(C)C)C(C)C)c2ccccc2)c1

Procedure:
(3R)-3-[2-(butyryloxy)-5-methylphenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminium iodide (from Example 22) was hydrolysed with methanol, resulting in the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4]N(C)C)[CH3:3].[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][OH:14]>C(O)(=O)C>[CH3:1][N:2]([CH2:4][C:12]1[O:8][C:9]([CH2:13][OH:14])=[CH:10][CH:11]=1)[CH3:3]
Reactant: OCc1ccco1
Reactant: CN(C)CN(C)C
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(CO)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
A solution of bis(dimethylamino)methane (112 g, 1.1 mol) in acetic acid (200 ml) was added dropwise with cooling (10° C.) to a stirred solution of 2-furanmethanol (98 g, 1.0 mol) in acetic acid (1000 ml). The mixture was stirred at room temperature for 18 hours and acetic acid was removed at 60° C. under reduced pressure. Ice (200 g) was added to the residue which was made basic with 40% aqueous sodium hydroxide (with external cooling). The mixture was extracted with ethyl acetate and the extracts were evaporated and distilled to give 5-dimethylaminomethyl-2-furanmethanol (145 g, 94%) b.p. 92°-96° C./0.2 0.5 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:33][CH:23]2[CH2:22][CH2:21][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[CH:18]=3)[CH2:25][CH2:24]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Reactant: NC1CCCCC1
Product: COc1cc(-c2cc(CN3CCC(NC4CCCCC4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-pieridone (400 mg) and cyclohexylamine (134 mg) were react ed in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:27])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21]4)=[CH:14][CH:13]=3)=[C:9]([C:28]3[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=3)[S:8][C:7]=2[CH:36]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:27])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21]4)=[CH:16][CH:17]=3)=[C:9]([C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)[S:8][C:7]=2[CH:36]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCC3CCCN(C)C3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CN1CCCC(COc2ccc(C(=O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)C1
Yield: 53.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-[(1-methylpiperidin-3-yl)methoxy]benzoyl)benzo[b]thiophene (878 mg, 1.75 mmol), ethane thiol (8.75 mmol), and aluminum chloride (1.40 g, 10.S mmol) were converted to 447 mg (54%) of the title compound by the procedure of Example 16. MS(FD) 473(M+). IR (CHCl3) ν max 3205, 2954, 1599, 1467, 1266, 1171.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][NH:16]C(=O)C(F)(F)F)=[CH:13][CH:12]=2)[N:3]=1.CN>CO>[NH2:16][CH2:15][C:14]1[CH:23]=[CH:24][C:11]([CH2:10][O:9][C:4]2[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([Cl:8])[CH:5]=2)=[CH:12][CH:13]=1
Reactant: Nc1nc(Cl)cc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Agent: CN
Solvent: CO
Product: NCc1ccc(COc2cc(Cl)nc(N)n2)cc1
Temperature: 25 °C

Procedure:
65 mg (0.18 mmol) N-[4-(2-amino-4-chloropyrimidin-6-yloxymethyl)-benzyl]-2,2,2-trifluoro-acetamide (15) is dissolved in 1 mL methanol and treated with 2 mL methylamine (33% in ethanol). The reaction mixture is stirred at room temperature over night and all volatiles are removed in vacuo. The product is used without further purification in the next step. ESI-MS m/z 265.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl[CH2:21][CH2:22][CH2:23][N:24]1[C:29](=[O:30])[C:28]([CH2:31][OH:32])=[CH:27][N:26]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:25]1=[O:41]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[C:29](=[O:30])[C:28]([CH2:31][OH:32])=[CH:27][N:26]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])[C:25]3=[O:41])[CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[CH:3]=1
Reactant: Fc1ccc(N2CCNCC2)c(OCC(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1cc(CO)c(=O)n(CCCCl)c1=O
Product: C[Si](C)(C)CCOCn1cc(CO)c(=O)n(CCCN2CCN(c3ccc(F)cc3OCC(F)(F)F)CC2)c1=O

Procedure:
substituting 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-5-hydroxymethyl-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione gave 3-(3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-hydroxymethyl-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[BH4-].[Na+].S(=O)(=O)(O)O.C1C=CC=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8]([CH:7]=[CH:6][CH2:5]2)=[CH:9][CH:10]=1
Reactant: O=C1CCc2cc(Br)ccc21
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)CC=C2

Procedure:
Reduction of 5-bromo-1-indanone E1 with sodium borohydride in MeOH followed by dehydration of the resulting alcohol with sulfuric acid in refluxing benzene at about 80° C. affords 6-bromo-1H-indene E2 (CAS# 33065-61-1; see, Young J R, Huang S X, Walsh T F, Wyvratt M J, Yang Y T, Yudkovitz J B, Cui J, Mount G R, Ren R N, Wu T-J, Shen X, Lyons K A, Mao A-H, Carlin J R, Karanam B V, Vincent S H, Cheng K and Goulet M T, Bioorg. Med. Chem. Lett. 2002, 12 (5), 827-832).
Reaction SMILES: [N:1]([CH:4]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[NH:6][C:5]1=[O:23])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][CH:4]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[NH:6][C:5]1=[O:23]
Reactant: COc1ccc(C2Cc3ccccc3NC(=O)C2N=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2Cc3ccccc3NC(=O)C2N)cc1
Temperature: 25 °C

Procedure:
A solution of 2,3,4,5-tetrahydro-3-azido-4-(4-methoxyphenyl)-1H-1-benzazepin-2-one (170 mg, 0.552 mmol) in 5 mL of wet tetrahydrofuran was treated with triphenylphosphine (256 mg, 1 mmol, 1.8eq) and the resulting mixture heated at reflux for 6 hours, then cooled to room temperature. The solvent was removed under vacuum and the residue was purified on a silica gel column (eluant 10% MeOH/CH2Cl2) to give the product in quantitative yield. 1H NMR (400 MHz, CDCl3): 1.35 (br s, 2H), 2.90 (dd; 6,13 Hz; 1H), 3.05 (dd; 12, 13 Hz; 1H), 3.67 (m, 2H), 3.77 (s, 3H), 6.84 (d, 8Hz, 2H), 7.01 (d, 8 Hz, 1H), 7.13-7.30 (m, 5H), 8.22 (br s, 1H). FAB-MS: calculated for C17H18N2O2 282; found 283 (40%).
Reaction SMILES: CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.[CH3:51][O:52][C:53](=[O:62])[CH2:54][CH2:55][C:56]1[CH2:60][CH2:59][C:58](=[O:61])[CH:57]=1.CCCCCC>C(OCC)(=O)C>[CH3:51][O:52][C:53](=[O:62])[CH2:54][CH2:55][CH:56]1[CH2:60][CH2:59][C:58](=[O:61])[CH2:57]1
Reactant: COC(=O)CCC1=CC(=O)CC1
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)CCC1CCC(=O)C1
Yield: 88.1 %

Procedure:
General procedure B using (S)-p-tol-BINAP and 3-(3-oxo-cyclopent-1-enyl)-propionic acid methyl ester (0.084 g, 0.5 mmol) gave, after 24 h at 0° C. and flash chromatography (4:1, then 2:1 hexane:ethyl acetate), the title compound as a clear oil (0.075 g, 88% yield). Spectroscopic data were consistent with previously reported data for this compound.15 [α]D25° C.−112° (c 1.3, CHCl3). Conversion of the title compound to the corresponding benzyl ester followed by chiral HPLC analysis (Chiracel OD column) indicated that the title compound was obtained in 91% ee.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:19]([C@@:22]1([CH2:65][O:66][CH2:67][CH2:68][Si:69]([CH3:72])([CH3:71])[CH3:70])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:24]([C@@H:42]([CH2:62][CH3:63])[CH2:43][O:44][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:23]1=[O:64])[CH:20]=[CH2:21]>C1COCC1.CCOC(C)=O>[CH2:19]([C@@:22]1([CH2:65][O:66][CH2:67][CH2:68][Si:69]([CH3:72])([CH3:71])[CH3:70])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[N:24]([C@@H:42]([CH2:62][CH3:63])[CH2:43][OH:44])[C:23]1=[O:64])[CH:20]=[CH2:21]
Reactant: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O

Procedure:
A 1M solution of TBAF in THF (2.15 mL, 2.15 mmol) was added to a solution of (3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one (Example 414, Step A; 860 mg, 1.074 mmol) in THF. The reaction was heated to reflux for 3 hours. After cooling, it was diluted with EtOAc and washed with HCl (1N in water). The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated to give the crude material as a glass which was purified by chromatography on silica eluting with 20% EtOAc in hexane, to provide the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([O:18][CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17].C(=O)([O-])[O-].[K+].[K+].P(OCC)(OCC)(O[CH2:31][CH3:32])=O>O>[CH2:31]([N:10]1[C:11]2[C:6](=[CH:5][C:4]([O:18][CH3:19])=[C:3]([O:20][CH3:21])[C:2]=2[F:1])[C:7](=[O:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]1)[CH3:32]
Reactant: CCOP(=O)(OCC)OCC
Reactant: CCOC(=O)c1c[nH]c2c(F)c(OC)c(OC)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(CC)c2c(F)c(OC)c(OC)cc2c1=O
Temperature: 120 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
A mixture of ethyl 8-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (41 g, 139 mmol) and potassium carbonate (28.8 g, 208 mmol) in triethyl phosphate (118 ml, 694 mmol) was stirred at 120° C. for 5 h. LCMS indicated completion of the reaction. Then the reaction mixture was cooled down and diluted with water, extracted with DCM, dried over sodium sulfate and evaporated in vacuo. The crude material was purified by reverse phase automatic C-18 column chromatography (Combiflash RF, 130 g column), eluting with Acetonitrile/Water (10-80%) to afford ethyl 1-ethyl-8-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (26 g, 80 mmol, 57.9% yield) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C@H:16]([NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:27]([O:29][CH3:30])=[O:28])[CH2:4][C@@H:3]1[OH:31].OS(O)(=O)=O>C1(O)CCCCC1>[OH:1][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C@H:16]([NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:27]([O:29][CH:30]2[CH2:18][CH2:19][CH2:2][CH2:3][CH2:4]2)=[O:28])[CH2:4][C@@H:3]1[OH:31]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Agent: O=S(=O)(O)O
Solvent: OC1CCCCC1
Product: CC(C)CCN[C@@H]1C[C@]2(C)[C@@H](C(=O)OC3CCCCC3)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)[C@@H](O)C[C@]3(C)[C@H]21
Yield: 81.8 %

Procedure:
Methyl 2β,3α-dihydroxy-11α-(3-methylbutylamino)-5α-androstane-17β-carboxylate (410 mg) in cyclohexanol (2.5 ml) was heated at 100° C. with concentrated H2SO4 (0.2 ml) for 24 h. The cooled mixture was concentrated by evaporation and the residue purified by column chromatography using ethyl acetate/ammonia 50:1 to give an oil (194 mg). This was purified further by preparative t.l.c. in ethyl acetate/ammonia 50:1 to give the title compound (40 mg), [α]D +17°, νmax 1725 cm-1.
Reaction SMILES: CN([CH:4]=[C:5]1[C:9](=O)[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)C.[O-]CC.[Na+].[F:22][C:23]([F:28])([F:27])[C:24]([NH2:26])=[NH:25]>C(O)C.C(OCC)(=O)C.Cl>[F:22][C:23]([F:28])([F:27])[C:24]1[N:26]=[CH:4][C:5]2[CH2:6][NH:7][CH2:8][C:9]=2[N:25]=1
Reactant: N=C(N)C(F)(F)F
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ncc2c(n1)CNC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the product from Step A (500 mg) in anhydrous ethanol (25 mL) was added sodium ethoxide (2.33 mL, 21% in ethanol). After stirring for 5 min, trifluoroacetamidine (700 mg) was added and the resulting mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed sequentially with 5% aqueous citric acid solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was deprotected by dissolving in 1N methanolic hydrogen chloride for 1 h. The resulting solution was concentrated and chromatographed on a Biotage® system (silica gel cartridge, gradient from 10% to 18% of 10% concentrated aqueous ammonium hydroxide in methanol/dichloromethane) to yield the title compound. LC-MS=190.0 (M+1).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.CN1CCOCC1.Cl[C:16]([O:18][CH3:19])=[O:17]>C(OCC)(=O)C>[CH3:19][O:18][C:16]([N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7])=[O:17]
Reactant: O=C1C=CC(=O)N1
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)N1C(=O)C=CC1=O
Reaction time: 0.5 h

Procedure:
To a 1000 ml 3-neck round bottom flask was added 400 ml of ethyl acetate. The flask was placed in an ice bath and the temperature was allowed to drop to about 0° C. To the cooled flask was sequentially added with stirring 7.76 g of maleimide and 8.8 ml of N-methylmorpholine. Then, through an addition funnel was added to the stirring mixture 6.26 ml of methyl chloroformate at a rate so as not to raise the temperature above 3° C. Through the addition funnel was then added 5 ml of ethyl acetate as washing and the washing was added to the reaction mixture. The reaction mixture was stirred for 30 minutes at between 0°-3° C. Thereafter, the reaction mixture was filtered through a Buchner funnel. The flask was washed 2× with 10 ml of ethyl acetate and the washings were also filtered. The resulting precipitate was washed 2×with 10 ml of ethyl acetate. The combined filtrate and washings were extracted with 100 ml of ice cold water, dried (10 g Na2SO4), and evaporated to dryness under reduced pressure. The residue was redissolved in 50-100 ml of ethyl acetate:isopropylether (40:60/v:v) using a water bath at 60° C. The resulting solution was filtered, cooled until crystals appeared. After 30 minutes in an ice bath, the cooled solution and crystals were filtered through a sintered glass funnel and the crystals washed 2× with 20 ml of isopropyl ether. The crystals were vacuum dried overnight. M.P. 61°-63° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[CH3:29])[CH2:17][C:16]1([CH3:31])[CH3:30])=O)(C)(C)C>C(Cl)Cl>[CH3:30][C:16]1([CH3:31])[CH2:17][N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[CH3:29])[C:19](=[O:21])[CH2:20][NH:15]1
Reactant: Cc1c(F)cccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)cccc1N1CC(C)(C)NCC1=O
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
2.8 ml of trifluoroacetic acid (37 mmol) was added to a solution of 1.25 g of 2,2-dimethyl-4-(3-fluoro-2-methylphenyl)-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (67c) (3.7 mmol) in methylene chloride (5.6 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 0.9 g of the title compound (yield: quant.).