Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:9]2)([O-:3])=[O:2].C(Cl)CCl.[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)[O:15][C:14](=[O:16])[CH2:13][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH:9]=[CH:10]1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)Cn1ccc2cccc([N+](=O)[O-])c21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cn1ccc2cccc([N+](=O)[O-])c21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.2 %

Procedure:
A mixture of 2-(7-nitro-1H-indol-1-yl)acetic acid (0.15 g, 0.681 mmol), EDC (0.131 g, 0.681 mmol), DMAP (0.128 g, 1.048 mmol) and (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.220 g, 0.524 mmol) in dry DCM (15 ml) was stirred at room temperature for 16 hours. Aqueous 2N HCl was added, and the organic phase was separated and dried over sodium sulfate; the solvent was removed and the crude was triturated with MeOH. The precipitate was filtered, washed with MeOH and dried affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(7-nitro-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.066 g, 0.106 mmol, 20% yield). MS/ESI+ 622.1 [MH]+; [αD]=−112.6, c=0.22, MeOH; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 8.00 (dd, 1H), 7.82 (dd, 1H), 7.52 (d, 1H), 7.22 (t, 1H), 7.16 (d, 1H), 7.05 (d, 1H), 6.92 (dd, 1H), 7.06 (t, 1H), 6.76 (d, 1H), 5.95 (dd, 1H), 5.30 (d, 1H), 5.17 (d, 1H), 3.90 (d, 2H), 3.33-3.54 (m, 1H), 3.18 (dd, 1H), 0.99-1.39 (m, 1H), 0.48-0.72 (m, 2H), 0.36 (q, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@:13]([CH2:15][CH2:16]3)([CH3:14])[CH2:12][C@H:11]([OH:21])[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.C(O)C.Cl>C1(C)C=CC=CC=1>[CH3:14][C@@:13]12[CH2:15][CH2:16][C@H:17]3[C@@H:8]([CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([OH:2])[CH:20]=[CH:19][C:18]=43)[C@@H:9]1[CH2:10][C@@H:11]([OH:21])[CH2:12]2
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)C[C@H](O)C[C@@H]12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Yield: 69.2 %

Procedure:
0.55 g of 3-methoxy-13α-estra-1,3,5(10)-trien-16α-ol is dissolved hot under a cover gas in 10 ml of toluene. A mixture of 2.3 ml of diisobutylaluminum hydride and 5.4 ml of toluene is added in drops to this solution and refluxed until the reaction is completed (about 4 hours). 2.1 ml of ethanol is added to the cooled batch, and 6 ml of semi-concentrated hydrochloric acid is carefully added while being cooled. After extraction with ethyl acetate, the organic phase is washed neutral and dried on magnesium sulfate. 362 mg of 13α-estra-1,3,5(10)-triene-3,16α-diol is obtained. The recrystallization from methanol yields colorless crystals; flash point 224 . . . 231° C.; [α]D=+61° (pyridine, c=1.13).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)[C:6]=2[CH:33]=1.[N:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=O)[O:42]C2C=CC=CC=2)=[CH:36][CH:35]=1>O1CCOCC1>[F:29][C:28]([F:31])([F:30])[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:13]2[CH2:12][CH2:11][CH:10]([N:7]3[C:6]4[CH:33]=[C:2]([NH:1][C:41]([NH:40][C:37]5[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=5)=[O:42])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH2:15][CH2:14]2)=[CH:18][CH:19]=1)([OH:32])[C:24]([F:25])([F:26])[F:27]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: Nc1ccc2ncn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)c2c1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc2ncn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)c2c1
Yield: 12.7 %

Procedure:
2-(4-((4-(6-Amino-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.212 mmol, 0.1 g) and phenyl pyridin-4-ylcarbamate (0.318 mmol, 0.068 g) were combined and heated in a Reactivial in dioxane (2 mL) for 2 days. The solvent was removed and the resulting residue purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 8% methanol/dichloromethane) to afford the title compound (16 mg).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:29])[N:18]([C@@H:22]4[CH2:27][CH2:26][NH:25][CH2:24][C@H:23]4[OH:28])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:40]=O>>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:29])[N:18]([C@@H:22]4[CH2:27][CH2:26][N:25]([CH3:40])[CH2:24][C@H:23]4[OH:28])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1O
Product: CN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)C2=O)[C@H](O)C1

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-hydroxy-1-methyl piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-hydroxypiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 271) and formaldehyde following General Procedure R.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[N:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=3)[NH:22][N:21]=2)=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:29][C:25]3[CH:24]=[C:23]4[C:28]([C:20](/[CH:19]=[CH:18]/[C:15]5[CH:14]=[CH:13][N:12]=[CH:17][CH:16]=5)=[N:21][NH:22]4)=[CH:27][CH:26]=3)[C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Reactant: O=C1Cc2cc(Br)cnc2N1
Product: O=C1Nc2ncc(Br)cc2C1=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Yield: 72 %

Procedure:
The title compound (64 mg, 64%) was synthesized as a greenish yellow solid according to the method described for Example A67 (oil temp 75° C., reflux 2 h) using 5-bromo-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (42.6 mg, 0.2 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR indicated 7:6 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=5.2 Hz, 2H), 8.34 (d, J=8.4 Hz, 1H), 8.26 (d, 1H), 8.22 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 7.93 (d, 1H), 7.89 (d, J=16.8 Hz, 1H), 7.72 (t, J=4.8 Hz, 2H), 7.55 (d, J=16.0 Hz, 1H); MS ESI 444.3 [M+H]+, calcd for [C22H14BrN5O+H]+ 444.0.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:16]=[CH:17][O:18]C)=[C:11]([CH:15]=1)[C:12]([OH:14])=O>>[Cl:6][C:7]1[CH:15]=[C:11]2[C:10]([CH:16]=[CH:17][O:18][C:12]2=[O:14])=[CH:9][CH:8]=1
Reactant: COC=Cc1ccc(Cl)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: O=c1occc2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
Concentrated sulphuric acid (15 ml) was added to 5-chloro-2(2-methoxyvinyl)-benzoic acid (4.43 g) at 0° C. The mixture was stirred for 2 hours, then diluted with ice/water. The product was extracted with ethyl acetate (3×15 ml) and the combined extracts washed with saturated sodium bicarbonate solution. The solution was dried (magnesium sulfate), filtered and concentrated. The residue was purified by flash chromatography (0-5% ethyl acetate/hexane) to afford the sub-title compound as a white solid (3.04 g, 81%). mp 109.8-110.9° C. 1H NMR (400 MHz, CDCl3) δ 6.51(1H, d), 7.28-7.32(1H, m), 7.41(1H, d), 7.64-7.70(1H, m), 8.28(1H, m) ppm.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1ccccc1Cl
Product: CC1(C)OC(=O)Nc2ccc(-c3ccccc3Cl)cc21

Procedure:
6-(2-Chloro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was prepared, according to the procedure of Example 4 from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 2-chlorophenyl boronic acid, as a white solid: mp 181-182° C.; MS (ESI) m/z 288 ([M+H]+, 70%); Anal. Calcd. For C16H14ClNO2: C, 66.79; H, 4.90; N, 4.87. Found: C, 66.78; H, 4.82; N, 4.55.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][S:6][CH:7]=1.[NH2:8][CH2:9][CH2:10][SH:11]>>[NH2:8][CH2:9][CH2:10][S:11][CH2:2][C:3]1[N:4]=[N:5][S:6][CH:7]=1
Reactant: OCc1csnn1
Reactant: NCCS
Product: NCCSCc1csnn1

Procedure:
Reacting 4-hydroxymethyl-1,2,3-thiadiazole with cysteamine by the procedure of Example 1 gives 4-[(2-aminoethyl)thiomethyl]-1,2,3-thiadiazole. From this compound by the procedures of Example 1, 2 and 3, the following products are prepared:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:6][CH2:7]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]([NH2:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(O)C>[CH:10]([NH:13][CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:12])[CH3:11]
Reactant: CCOC(=O)/C=C/CBr
Reactant: CC(C)N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/CNC(C)C
Yield: 65.8 %

Procedure:
Ethyl 4-bromocrotonate (25.0 g) was added dropwise to a solution of isopropylamine (7.7 g) and triethylamine (13.2 g) in ethanol (200 ml) at room temperature under stirring and taking an hour. The mixture was stirred for 5.5 hours at room temperature. After removing the solvent, to the residue was added ethyl acetate, and the mixture was extracted with 1N hydrochloric acid. Ethyl acetate was added to the hydrochloric acid layer, and alkalified by addition of potassium carbonate powder. After removing the separated oily substance, the ethyl acetate layer was taken out, and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and distilled to remove the solvent to give the title compound (14.6 g) as pale yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:19]1([CH2:25][C:26](=[NH:30])OCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[ClH:17].[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1c(F)cccc1Cl
Yield: 37.7 %

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (5.05 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) and recrystallisation from ethanol/ether to obtain the product (1.53 g), m.p. 115°-123° C.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br)#[N:8].C(=O)([O-])[O-].[K+].[K+].[ClH:23]>C(O)C>[ClH:23].[C:7]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][N:1]1[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1)#[N:8]
Reactant: C1=CCNCC1
Reactant: N#Cc1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccccc1CN1CC=CCC1

Procedure:
1,2,3,6-Tetrahydropyridine (5.0 g.) was added to a mixture of 2-cyanobenzyl bromide (11.8 g.) and potassium carbonate (9.16 g.) in ethanol (80 ml.). The mixture obtained was heated under reflux for 2.5 hours, cooled and evaporated. Water (120 ml.) was added to the residue and the oily mixture obtained was extracted with ether (3×50 ml.). The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue oil was dissolved in toluene (20 ml.) to give a solution, which was treated with a slight excess of methanolic hydrogen chloride. The mixture was evaporated and the solid residue which was left was triturated with acetone, collected by filtration, and recrystallised from a mixture of ethanol and ethyl acetate to give 1-(2-cyanobenzyl)-1,2,3,6-tetrahydropyridine hydrochloride, as colourless needles (7.1 g), m.p. 219°-221° C.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[S:15][CH:16]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.CC1C=CC(S(O[CH:31]([CH2:35][CH3:36])[CH2:32][O:33][CH3:34])(=O)=O)=CC=1>O.C(#N)C>[CH3:34][O:33][CH2:32][C@@H:31]([N:11]1[C:7]2[CH:6]=[CH:5][NH:4][C:3](=[O:2])[C:8]=2[C:9]([C:12]2[CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[S:15][CH:16]=2)=[N:10]1)[CH2:35][CH3:36]
Reactant: CCC(COC)OS(=O)(=O)c1ccc(C)cc1
Reactant: COc1nccc2[nH]nc(-c3csc(C(N)=O)c3)c12
Solvent: O
Solvent: CC#N
Product: CC[C@@H](COC)n1nc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21

Procedure:
The racemic form of the title compound was obtained using 4-(4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide obtained in Step A of Example 148 and 1-methoxybutan-2-yl 4-methylbenzenesulfonate, in the same manner as in Step B of Example 148 and Step C of Example 148. The obtained racemic form was resolved by HPLC (column: L-column2 ODS (trade name) 20 mmID×150 mmL, 5 μm, manufactured by Daicel Chemical Industries, mobile phase: water/acetonitrile (containing 10 mM ammonium carbonate)) to give the title compound having a shorter retention time.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[O:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]2([OH:15])[CH2:18][CH2:17][CH2:16]2)=[CH:3][C:4]=1[F:9]
Reactant: Fc1cc(Br)ccc1Cl
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: OC1(c2ccc(Cl)c(F)c2)CCC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of 4-bromo-1-chloro-2-fluorobenzene (2.99 g, 14.27 mmol) in tetrahydrofuran (50 mL) was added n-butyllithium (5.71 mL, 14.27 mmol, 2.5 m in hexane) over 5 minutes. The reaction was stirred at −78° C. for 15 min, and cybutanone (1.0 g, 14.27 mmol) was added dropwise. After 15 minutes, the reaction mixture was quenched by the addition of saturated aqueous of NH4Cl (50 mL) and diethyl ether (50 mL). The layers were separated, and the aqueous was extracted with additional diethyl ether (2×50 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered concentrated under reduced pressure. The residue was purified by RP-HPLC (preparative reversed-phase high pressure liquid Chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min) to provide the title compound as a solid. MS (ESI) m/z 201[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[O:23]=[C:24]([CH3:28])[C:25](O)=[O:26]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[C:25]([OH:26])[C:24](=[O:23])[CH3:28]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Reactant: CC(=O)C(=O)O
Product: CC(=O)C(O)=NOCCC1=C(C)/C(=C/c2ccncc2)c2ccc(F)cc21

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 2-oxopropionic acid by the method of Example 1.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[C:27]([F:38])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[F:38][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([F:31])[C:28]=1[O:32][CH2:33][C:34]([F:35])([F:36])[F:37]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCC(F)(F)F)c(F)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCC(F)(F)F)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (29 mg, 0.166 mmol) with 2-bromo-N-{4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}acetamide (60 mg, 0.139 mmol) in the presence of NaH (5.0 mg, 0.208 mmol) in dry DMF (5.0 mL) to give 20 mg of the product as a white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 3.17 (s, 3H), 3.39 (s, 3H), 4.86 (q, J=8.7 Hz, 2H), 5.32 (s, 2H), 6.23 (s, 1H), 7.35 (s, 1H), 7.69 (s, 1H), 7.72 (s, 1H), 7.83 (s, 1H), 12.70 (br s, 1H); ESI-MS (m/z) 530.11 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:28]=[C:27]([NH:29][CH:30]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:31][N:32]3[CH:36]=[CH:35][N:34]=[CH:33]3)[CH:26]=[CH:25][C:8]=2[C:9]([NH:11][C@@H:12]([CH2:20][CH2:21][C:22](=[O:24])[NH2:23])[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O>[C:1]1([C:7]2[CH:28]=[C:27]([NH:29][CH:30]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:31][N:32]3[CH:36]=[CH:35][N:34]=[CH:33]3)[CH:26]=[CH:25][C:8]=2[C:9]([NH:11][C@@H:12]([CH2:20][CH2:21][C:22](=[O:24])[NH2:23])[C:13]([OH:15])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(N)=O)NC(=O)c1ccc(NC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CC[C@H](NC(=O)c1ccc(NC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccccc1)C(=O)O
Yield: 91 %

Procedure:
A solution of compound tert-butyl (2S)-2-{2-(4-fluorophenyl)-4-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethylamino]benzoylamino})-4-carbamoylbutyrate (example 15) (0.09 g; 0.15 mmole) in TFA (3 ml) was stirred at room temperature for 30 minutes. After evaporation to dryness, the residue was purified on reverse phase silica, eluting with methanol/ammonium carbonate buffer (2 g /1, pH 7). The appropriate fractions were concentrated and freeze-dried to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:18]O)[CH:5]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[Br-:20].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CC(=O)OCC>[Br:20][CH2:18][C:4]1[CH:5]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COc1ccc(CNc2cc(F)cc(CO)c2)cc1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cc(F)cc(CBr)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A mixture of [3-fluoro-5-(4-methoxy-benzylamino)-phenyl]-methanol (522 mg, 2 mmol) and triphenylphosphine dibromide (1.27 g, 3 mmol) in dichloromethane (6 ml) was stirred in an ice bath for 30 min. The mixture was then warmed up to room temperature, diluted with EA (20 ml), washed with saturated aqueous sodium bicarbonate solution followed by brine, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexane (1:10)) to afford 570 mg (88%) of a pale yellow syrup. 1H NMR (200 MHz, CDCl3) δ 3.86 (3H, s), 4.30 (2H, s), 4.40 (2H, s), 6.41 (1H, m), 6.56-6.60 (2H, m), 6.90-6.96 (2H, m), 7.31-7.35 (2H, m).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8](O)=[C:7]([O:13][CH3:14])[C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].[CH2:17](Cl)[C:18](=[CH2:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:19][C:18]([CH3:20])=[CH2:17])=[C:7]([O:13][CH3:14])[C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: C=C(C)CCl
Reactant: COc1c(O)cc(C)c(OC(C)=O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)Cc1cc(C)c(OC(C)=O)c(OC)c1OC
Yield: 84 %

Procedure:
A suspension (200 ml) of 4-acetoxy-2,3-dimethoxy-5-methylphenol (26 g), methallyl chloride (13 ml) and potassium carbonate (18 g) in N,N-dimethylformamide was stirred under an atmosphere of argon at 65° C. for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the title compound (27 g, 84%) as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][CH2:10][CH2:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15]=3[O:14][C:13]=2[CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N(Br)C(=[O:31])C1.O>CO>[C:1]1([CH2:7][CH2:8][S:9]([CH2:10][CH2:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15]=3[O:14][C:13]=2[CH3:27])=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1cccc2c(CCSCCc3ccccc3)c(C)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: O
Product: COC(=O)COc1cccc2c(CCS(=O)CCc3ccccc3)c(C)oc12
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
Methyl (3-(2-(2-phenylethylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetate (340 mg) was dissolved in methanol (15 ml) and the obtained solution was cooled to −10° C. To this solution, NBS (190 mg) was added for 5 minutes and the resulting mixture was stirred at −10° C. for 30 minutes. This reaction solution was poured into water layer (100 ml) and the resultant was extracted twice with ethyl acetate (30 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: dichloromethane/ethyl acetate=2/1) using silica gel to obtain the desired compound (225 mg, yield: 64%).