Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([S:11][CH3:12])[N:8]=[C:7]([NH:13][NH:14][C:15](=[O:34])[C@H:16]([CH2:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:17][N:18]([O:21]C3CCCCO3)[CH:19]=[O:20])[C:6]=2[F:35])[CH2:4][CH2:3][CH2:2]1>CC(O)=O.O>[N:1]1([C:5]2[N:10]=[C:9]([S:11][CH3:12])[N:8]=[C:7]([NH:13][NH:14][C:15](=[O:34])[C@H:16]([CH2:28][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:17][N:18]([OH:21])[CH:19]=[O:20])[C:6]=2[F:35])[CH2:2][CH2:3][CH2:4]1
Reactant: CSc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CCC2)n1
Solvent: CC(=O)O
Solvent: O
Product: CSc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCC2)n1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
[(2R)-3-{2-[6-(1-Azetidinyl)-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (68 mg, 0.13 mmol) was dissolved in a mixture of AcOH/H2O (20 mL, 4:1) and stirred at RT until LCMS indicated completion of the deprotection (overnight). The reaction mixture was concentrated to dryness under vacuum and purified by RP-HPLC to provide [(2R)-3-{2-[6-(1-azetidinyl)-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (25 mg, 44%). LCMS: (M+H)+: 427.2.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[C:15]([O:20][CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=1)(=[O:4])=[O:3].[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:32]=1)[C:27](O)=[O:28]>>[CH3:1][S:2]([CH2:5][CH2:6][N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[C:15]([O:20][CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=1)[C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:32]=[C:24]([C:23]([F:38])([F:22])[F:37])[CH:25]=1)(=[O:3])=[O:4]
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1ncccc1-c1ccncc1NCCS(C)(=O)=O
Product: COc1ncccc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (2-methanesulfonyl-ethyl)-(2-methoxy-[3,4]bipyridinyl-3′-yl)-amine and 2,6-bis(trifluoromethyl) isonicotinic acid (Key Organics Ltd.) after a reaction time of 15 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (14%). MS (ESI): m/z=549.10 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:10][C:11]2[CH2:12][O:13][C:14]([CH3:30])([CH3:29])[C:15]([F:28])([F:27])[C@:16]([C:19]3[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]=3[F:26])([CH3:18])[N:17]=2)=[CH:5][CH:4]=1.[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH2:51])=[N:47]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:10][C:11]2[CH2:12][O:13][C:14]([CH3:30])([CH3:29])[C:15]([F:28])([F:27])[C@:16]([C:19]3[CH:24]=[C:23]([NH:51][C:48]4[CH:49]=[CH:50][N:46]([CH3:45])[N:47]=4)[CH:22]=[CH:21][C:20]=3[F:26])([CH3:18])[N:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cn1ccc(N)n1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccn(C)n4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 80.9 %

Procedure:
Prepared in an analogous manner as described for intermediate A9A or A13A from (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A8B) (210 mg, 315 μmol) and commercially available 1-methyl-1H-pyrazol-3-amine [CAS no 1904-31-0] (62.4 mg, 629 μmol). The (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-6,6-difluoro-5-(2-fluoro-5-(1-methyl-1H-pyrazol-3-ylamino)phenyl)-5,7,7-trimethyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (174 mg, 80.9%) was obtained as a light yellow foam. MS (ISP): m/z=684 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([C@@H:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)=[O:13])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[O:30]=[S:31]1(=[O:40])[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1>CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([C@@H:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:37]([N:34]2[CH2:35][CH2:36][S:31](=[O:40])(=[O:30])[CH2:32][CH2:33]2)=[O:38])=[O:13])[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2C(=O)N2CCS(=O)(=O)CC2)no1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (S)-perhydro-azepine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide hydrochloride (0.30 g, 1.13 mmol), DIPEA (0.32 g, 2.48 mmol) and DMAP (16.0 mg, 0.13 mmol) is stirred at room temperature for 15 minutes. 1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl chloride (0.27 g, 1.35 mmol) (prepared according to method M step 1) is added drop wise at 0° C. to the reaction mixture that is slowly warmed up to room temperature and stirred for 14 hours. The reaction mixture is diluted with EtOAc, washed with water and brine. After drying the organic phase over anhydrous Na2SO4, removal of the solvent under reduced pressured affords the crude product that is purified by prep TLC to afford the title product; m/z 427 [M+H+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([F:25])[CH:19]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[O:12][C:3]=23)=[C:20]([F:25])[CH:19]=1
Reactant: N#Cc1cnc2c(oc3ccccc32)c1Cl
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: N#Cc1cnc2c(oc3ccccc32)c1Nc1ccc(Cl)cc1F
Temperature: 25 °C
Yield: 40.4 %

Procedure:
A mixture of 200 mg (0.88 mmol) of 4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 0.11 mL (0.97 mmol) of 4-chloro-2-fluoroaniline in 6 mL of 2-ethoxyethanol is heated at reflux temperature for 4 days. A catalytic amount of pyridine hydrochloride is added and the reaction mixture is heated at reflux temperature overnight then cooled to room temperature. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is dried over sodium sulfate, filtered through a pad of diatomaceous earth and concentrated in vacuo to provide 120 mg (40%) of a beige solid, mp 259–261° C.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[F:23][C:24]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:30]=[CH:31][C:24]=2[F:23])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCCc1ccc(F)c(C#N)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCc1ccc(F)c(-c2nc(-c3c(F)cccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.34 g), 2-fluoro-5-undecylbenzonitrile (1.09 g), anhydrous aluminum chloride (0.55 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 1.04 g of desired compound (refractive index: 1.5419).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C:4]([N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:38])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:13]2[C:14]([C:19](=[O:38])[C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)(=[O:29])=[O:30])=[CH:24][CH:23]=1)=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:39]
Reactant: COC(=O)C(=O)N(c1ccccc1)c1ccccc1C(=O)CCc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(Cc2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)c(=O)c2ccccc2n1-c1ccccc1

Procedure:
A mixture of N-(2-{3-[4-(4-methylpiperazine-1-sulfonyl)-phenyl]-propionyl}-phenyl)-N-phenyl-oxalamic acid methyl ester (ca. 0.5 mmol) and K2CO3 (128 mg) in MeOH (30 mL) was heated at reflux for 1 h. The reaction mixture was then cooled and evaporated under reduced pressure. The residue was partitioned between water (25 mL) and EtOAc (25 mL), the organic layer separated, and the aqueous layer extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified twice by flash chromatography (DCM/MeOH) and once by preparative TLC (DCM/MeOH, 95:5) to afford 3-[4-(4-methylpiperazine-1-sulfonyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylic acid methyl ester as light brown solid. MS=532.0 [M+H]+. MP=210.0-212.0° C.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:42])[CH:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)O>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH:33]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([OH:42])=[O:31])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)Cc1ccccc1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1
Product: O=C(O)C(Cc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]-thiophen-3-yl)-biphenyl-4-ol, and 3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 165-167° C.; MS m/e 540 (M+);
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[N:12]1[C:16](=[O:17])[CH2:15][C:14]([NH:18][C:19]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=2[Cl:28])=[N:13]1.[N+](C1C(=O)N=NC=1)([O-])=O>FC(F)(F)C(O)=O.[Fe]>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[N:12]1[C:16](=[O:17])[CH2:15][C:14]([NH:18][C:19]2[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=2[Cl:28])=[N:13]1
Reactant: O=C1CC(Nc2cc([N+](=O)[O-])ccc2Cl)=NN1c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Fe]
Agent: O=C1N=NC=C1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Cl)c(NC2=NN(c3c(Cl)c(Cl)c(Cl)c(Cl)c3Cl)C(=O)C2)c1

Procedure:
Iron powder (3.5 g) was added in portions over five minutes to a slurry of 1-(2,3,4,5,6-pentachlorophenyl)-3-(2'-chloro-5'-nitroanilino)-2-pyrazoline-5-one (5 g) in trifluoroacetic acid (50 ml) at 70° C. The yellow color of the nitropyrazolone rapidly disappeared, and after stirring at 70°-75° C. for ten minutes the hot solution was separated from any unreacted iron and added to stirred ice-water (400 ml). The resultant off-white precipitate of the aminopyrazolone was filtered off, washed with water and dried. The yield was 4.6 g (98%); single spot by thin layer chromatography.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[CH2:18][C:17]2[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[N:34][CH:35]=1>>[CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:9]1[CH2:10][CH2:11][C:12]2[C:17](=[C:16]([C:30]3[CH:35]=[N:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cn1
Reactant: OB(O)c1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Product: Cc1ccc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CC3)cn1
Yield: 63 %

Procedure:
The title compound was synthesized as described for Intermediate example I-48 in 63% yield starting from [(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen-1-yl]boronic acid and 5-bromo-2-methylpyridine (1.6 equiv): 1H NMR (400 MHz, CDCl3) δ ppm 8.45 (d, 1 H), 7.48 (dd, 1 H), 7.30-7.36 (m, 4 H), 7.23-7.29 (m, 5 H), 7.07-7.23 (m, 4 H), 7.00 (d, 1 H), 3.63 (s, 4 H), 2.90-3.04 (m, 2 H), 2.74-2.86 (m, 1 H), 2.68-2.73 (m, 2 H), 2.67 (s, 3 H), 2.11-2.19 (m, 1 H), 1.67-1.82 (m, 1 H); MS (ESI) m/z 420[M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].[CH:25]1([N:28]2[CH:32]=[C:31](I)[CH:30]=[N:29]2)[CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:31]3[CH:30]=[N:29][N:28]([CH:25]4[CH2:27][CH2:26]4)[CH:32]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Reactant: Ic1cnn(C2CC2)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C4CC4)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 1-cyclopropyl-4-iodo-1H-pyrazole.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])=[CH:29][CH:28]=2)[S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:35][CH2:34][C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:16]([CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:38])=[O:5])[S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])=[CH:28][CH:29]=1)([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(C(C)(C)CO)cc2)S(=O)(=O)c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)c1ccc(CN(Cc2cccc(OCC(=O)O)c2)S(=O)(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
A solution of (3-{[[4-(2-hydroxy-1,1-dimethyl-ethyl)-benzyl]-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester (108 mg, 0.199 mmol) in CH2Cl2 (2 mL) was cooled to 0° C. and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 1 h. The solution was concentrated in vacuo, by azeotroping with CH2Cl2 (3×). The residue was dissolved in THF and 1N HCl (0.4 mL) was added. The solution was concentrated in vacuo, azeotroping with CH2Cl2 (3×). Purification by radial chromatography using a solvent gradient (CH2Cl2 to 20% MeOH in CH2Cl2) provided the title compound (34 mg). 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.69 (s, 1H), 8.11 (d, 1H), 7.52 (m, 1H), 7.21 (d, 2H), 7.09 (m, 1H), 7.02 (d, 2H), 6.76 (d, 1H), 6.70 (m, 2H), 4.86 (s, 2H), 4.32 (m, 4H), 3.48 (s, 2H), 1.22 (s, 6H); MS 485.2 (M+1), 483.4 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCCCCCCn1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CCCCCCCn1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
217 mg of compound 8 was obtained in a similar manner to those described in the Examples 1 and 2 using 701 mg of ethyl 4-(2-aminophenoxy)butyrate and 470 mg of 3-(1-heptylindol-5 -yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH3:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH:13]=[CH:14]2)[CH:9]=[CH:8]3)[CH2:5][CH2:4]1.I>C(O)(=O)C>[CH3:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: I
Solvent: CC(=O)O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
In a manner similar to that described in Example 9A, treat each of the 1,4,6-pregnatriene-3,20-dione derivatives prepared in Example 13A(1) with dry hydrogen iodide in glacial acetic acid. Isolate and purify each of the resultant products in a manner similar to that described to obtain the 7α-iodo derivative of each of the 1,4-pregnadiene-3,20-dione starting compounds of Example 13A(1), respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH:23]=[O:24])[CH:17]=2)=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:25])[C:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH2:23][OH:24])[CH:17]=2)=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1-c1ccc(F)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: Cc1cc(OCc2ccccc2)cc(C)c1-c1ccc(F)c(CO)c1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
4′-(Benzyloxy)-4-fluoro-2′,6′-dimethylbiphenyl-3-carbaldehyde 18a (390 mg, 1.17 mmol) were dissolved in 5 mL of methanol, followed by addition of sodium borohydride (66 mg, 1.75 mmol). The reaction solution was stirred for 30 minutes. The resulting solution was mixed with 10 mL of acetone and concentrated under reduced pressure. The residue was mixed with 10 mL of water and extracted with ethyl acetate (10 mL×3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (4′-(benzyloxy)-4-fluoro-2′,6′-dimethylbiphenyl-3-yl)methanol 18b (370 mg) as a colorless slime, which was directly used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:27][CH2:26][CH2:25][CH:8]3[S:9](=[O:24])(=[O:23])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][C:7]3([CH3:28])[C:6]=2[CH:29]=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH3:40])[C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.N1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+].O>[Cl:30][C:31]1[CH:32]=[C:33]([CH3:40])[C:34]([C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:27][CH2:26][CH2:25][CH:8]4[S:9](=[O:23])(=[O:24])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[N:12][C:7]4([CH3:28])[C:6]=3[CH:29]=2)=[O:38])=[N:35][CH:36]=1
Reactant: Cc1cc(Cl)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=NC2(C)c3cc(N)ccc3OCCC2S(=O)(=O)C1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)C1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)C1CCO2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
Crude tert-butyl ((4aRS,11bRS)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (70 mg, 0.165 mmol) was suspended in DMF (2 ml) and sonicated for 1 min. 5-Chloro-3-methylpyridine-2-carboxylic acid (34.0 mg, 0.198 mmol), pyridine (0.04 ml, 0.496 mmol) and HATU (94 mg, 0.248 mmol) were added and resulting suspension was stirred for 45 min at RT. The mixture was diluted with EtOAc (8 ml) and saturated NaHCO3 solution (3 ml). Water was added to dissolve precipitated solids. The organic layer was separated, washed with water and concentrated, and the resulting concentrate/residue was purified by FC on 12 g RediSep Gold column using 10-80% EtOAc in heptane to afford tert-butyl ((4aRS,11bRS)-10-(5-chloro-3-methylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (76 mg, 0.132 mmol, 80% yield) as white solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.[CH2:13](Br)[C:14]#[CH:15].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[CH3:1][N:2]([CH2:15][C:14]#[CH:13])[CH:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCc2cccnc21
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCN(C)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-methyl-5,6,7,8-tetrahydroquinolin-8-amine, 5, (0.50 g, 3.08 mmol) in THF (15 mL) was added propargyl bromide (0.28 mL, 3.08 mmol), sodium iodide (0.05 g, 0.31 mmol) and sodium carbonate (0.98 g, 9.24 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water, extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude solid was used without further purification: 1H NMR (d6-DMSO) δ 8.30 (d, J=4.4 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.13 (dd, J=8.0, 5.2 Hz, 1H), 3.74 (dd, J=4.8, 4.8 Hz, 1H), 3.47 (ddd, J=16.8, 2.4, 2.4 Hz, 2H), 3.06 (s, 1H), 2.80-2.60 (m, 2H), 2.12 (s, 3H), 2.12-1.87 (m, 2H), 1.74-1.68 (m, 1H), 1.62-1.55 (m, 1H); ESI+ MS: m/z (rel intensity) 201.1 (100, [M+H]+).
Reaction SMILES: [Br:1][CH:2]1[CH2:10][CH2:9][C:8]2[N:7]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:5][C:4]=2[C:3]1=[O:21].[CH2:22]([CH:24]1[O:26][CH2:25]1)[Br:23].[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:2]1[C:3]2([O:26][CH:24]([CH2:22][Br:23])[CH2:25][O:21]2)[C:4]2[CH:5]=[CH:6][N:7]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:8]=2[CH2:9][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C3=O)cc1
Reactant: BrCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CBr)O2)cc1
Reaction time: 19 h
Yield: 72.3 %

Procedure:
A mixture of 5-bromo-1-p-toluenesulfonyl-4-oxo-4,5,6,7-tetrahydroindole (100 parts), epibromohydrin (1.2 molar equivalents) and stannic chloride (0.1 molar equivalent) in carbon tetrachloride (1500 parts) is kept at 0° C. to 2° C. for 19 hours. The reaction mixture is carefully mixed with 5N-sodium hydroxide to adjust at pH 10, shaken and organic layer separated. By washing with water, drying and concentration, the organic layer gives 72.3% yield of 5-bromo-4'-bromomethyl-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane diastereomer mixture. Amounts show ratios to the starting 5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-one.