Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][N:4]1[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]1.Cl[C:13]1[N:18]=[C:17]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)[C:16]([Cl:33])=[CH:15][N:14]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1>[Cl:33][C:16]1[C:17]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)=[N:18][C:13]([NH:9][C:7]2[CH:6]=[N:5][N:4]([CH2:3][C:2]([F:1])([F:10])[F:11])[CH:8]=2)=[N:14][CH:15]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: Nc1cnn(CC(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(CC(F)(F)F)c3)ncc2Cl)CC1
Temperature: 120 °C
Yield: 26 %

Procedure:
A mixture of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine (0.160 g, 0.967 mmol), 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.101 g, 0.300 mmol) and TsOH.H2O (0.010 g, 0.051 mmol) in 1,4-dioxane (2.0 mL) was heated to 120° C. for 3 hours in the microwave. The mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound 29 (0.036 g, 26%). LCMS-D: rt 3.402 min; m/z 465.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][C:9]([O:11]CC1C=CC=CC=1)=[O:10])[CH2:4][CH3:5])[CH3:2]>[C].[Pd].C(O)C>[CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCCC(=O)O
Yield: 75.1 %

Procedure:
A mixture of benzyl 4-(N,N-diethylamino)butanoate (33.8 g), palladium-carbon (5%, 7 g) and ethanol (500 ml) was subjected to catalytic hydrogenation at room temperature and 1 atm. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 4-(N,N-diethylamino)butanoic acid (16.2 g, 75%). mp. 45°-47° C.
Reaction SMILES: CC(C)([O:4][C:5]1[N:10]=[C:9]([O:11]C(C)(C)C)[C:8]([C:16]2(O)[C:22]3[N:23]=[C:24]([CH3:26])[O:25][C:21]=3[CH2:20][CH2:19][C:18]3[CH:27]=[C:28]([CH2:31][CH3:32])[CH:29]=[CH:30][C:17]2=3)=[CH:7][N:6]=1)C.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:31]([C:28]1[CH:29]=[CH:30][C:17]2[CH:16]([C:8]3[C:9](=[O:11])[NH:10][C:5](=[O:4])[NH:6][CH:7]=3)[C:22]3[N:23]=[C:24]([CH3:26])[O:25][C:21]=3[CH2:20][CH2:19][C:18]=2[CH:27]=1)[CH3:32]
Reactant: CCc1ccc2c(c1)CCc1oc(C)nc1C2(O)c1cnc(OC(C)(C)C)nc1OC(C)(C)C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1ccc2c(c1)CCc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A stirred solution of the product from step (i) (0.60 g) in dichloromethane (15 ml) was treated with triethylsilane (0.225 ml) and cooled to 0° C. Boron trifluoride etherate (0.65 ml) was added in four equal portions at 5 minute intervals and the reaction stirred at room temperature for 16 hours. The reaction was poured into saturated sodium bicarbonate solution (200 ml) and extracted with ethyl acetate. The extracts were dried (MgSO4) and evaporated to give a yellow solid which was purified by reverse phase chromatography eluting with 50% to 80% methanol in 0.1% aqueous ammonium acetate.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:20]([O:22][C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[O:35][N:34]=[C:33]([CH2:36][OH:37])[N:32]=2)=[CH:26][CH:25]=1)[CH3:21].[Cl:39][C:40]1[C:41]([OH:50])=[C:42]([C:47](=[O:49])[CH3:48])[CH:43]=[CH:44][C:45]=1O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH2:20]([O:22][C:23](=[O:38])[C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]2[O:35][N:34]=[C:33]([CH2:36][O:37][C:45]3[CH:44]=[CH:43][C:42]([C:47](=[O:49])[CH3:48])=[C:41]([OH:50])[C:40]=3[Cl:39])[N:32]=2)=[CH:28][CH:29]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(Cc2nc(CO)no2)cc1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Cc2nc(COc3ccc(C(C)=O)c(O)c3Cl)no2)cc1
Reaction time: 1.5 h
Yield: 34 %

Procedure:
Add polymer support PPh3 (287 mg, 0.86 mmol to a solution of 4-(3-hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester (80 mg, 0.41 mmol) in anhydrous CH2Cl2 (8 mL) under argon gas at room temperature. Add 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (115 mg, 0.62 mmol) to the mixture, followed by diisopropyl azodicarboxylate (194 μL, 0.86 mmol). After 1.5 hours at room temperature, remove the polymer by filtration and concentrate the filtrate. Purify the residue by flash column chromatography using 30% ethyl acetate/hexane to give the title compound (60 mg, 34%). LC-MS (m/e): 429 (M−1).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:21](I)=[CH:20][C:15]4[O:16][CH2:17][CH2:18][O:19][C:14]=4[CH:13]=3)[NH:8]2)=[C:4]([NH2:23])[N:3]=1.C1C(=O)N(I)C(=O)C1.C(O)(C(F)(F)F)=O>CC#N>[O:16]1[CH2:17][CH2:18][O:19][C:14]2[CH:13]=[C:12]([CH2:11][C:7]3[NH:8][C:9]4[C:5]([N:6]=3)=[C:4]([NH2:23])[N:3]=[C:2]([F:1])[N:10]=4)[CH:21]=[CH:20][C:15]1=2
Reactant: Nc1nc(F)nc2[nH]c(Cc3cc4c(cc3I)OCCO4)nc12
Agent: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1nc(F)nc2[nH]c(Cc3ccc4c(c3)OCCO4)nc12
Yield: 77 %

Procedure:
2-fluoro-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-6-amine (S10-5). S10-4 (0.310 g, 1.03 mmol), NIS (0.301 g, 1.34 mmol), CH3CN (20 mL), TFA (2.34 g, 1.56 mL, 20.5 mmol) was stirred at rt overnight. The mixture was dried under reduced pressure and the residue chromatographed (CH2Cl2:MeOH:AcOH, 120:1:0.5 to 90:1:0.5) to give 0.340 g (77%) of a mixture of S10-5 (m/z 428.2 [M+H]+) along with diiodinated compound (m/z 554.1 [M+H]+). LC-MS shows ratio of S10-5 to diiodinated compound to be 83:17. This mixture was not separated but used further in the following step. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 7.37 (s, 1H), 6.82 (s, 1H), 4.25 (s, 4H), 4.18 (s, 2H); MS (ESI) m/z 428.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)[CH3:2].[CH3:8][O:9][CH2:10][CH2:11]Cl.C(N(CC)CC)C>>[CH3:8][O:9][CH2:10][CH2:11][N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[CH2:1][CH3:2]
Reactant: COCCCl
Reactant: CCc1ncc[nH]1
Solvent: CCN(CC)CC
Product: CCc1nccn1CCOC
Reaction time: 72 h

Procedure:
In an autoclave of 100 mL, 2-ethylimidazole (19.2 g, 200 mmol) was made reacted with chloroethyl methyl ether (22.7 g, 240 mmol) at 140 deg C. for 72 hours. Brown liquid that was obtained was washed with 120 mL of a compound liquid of ethanol and ether (volume ratio thereof is 1:5), and then made reacted with triethylamine (20.2 g, 200 mmol) in the autoclave of 100 mL at 130 deg C. for 24 hours. Solid salts that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 20 cm. The product was a transparent liquid which has a boiling point of 160-163 deg C. when a pressure is 10 Pa. 1H-NMR measurement of obtained amine was performed, and it was confirmed that chemical shifts, δ (ppm), are 6.95 (d, 1H), 6.75(d, 1H), 4.08-4.05(t, 2H), 3.62-3.60 (t, 2H), 3.27(s, 3H), 2.68-2.62 (m, 2H), and 1.25-1.22 (t, 3H), and 1-(2-methoxyethyl)-2-ethyl imidazole was synthesized.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:13]=[C:14]([NH:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]3[NH:28]C(=O)OC(C)(C)C)[N:15]=[N:16][C:17]=2[C:18](=[O:20])[NH2:19])[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(O)C>ClCCl>[NH2:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:21][C:14]1[N:15]=[N:16][C:17]([C:18]([NH2:19])=[O:20])=[C:12]([NH:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:10]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C(C)(C)C)n2)c(C(N)=O)nn1
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)n1
Reaction time: 14 h
Yield: 37.5 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(5-(6-tert-butylpyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)cyclohexylcarbamate (192 mg, 397 μmol) in dichloromethane (2 mL) was added TFA (747 mg, 505 μL, 6.55 mmol). After 14 h, the mixture was concentrated in vacuo then purified by chromatography (spherical silica, 50 g, 0-20% of a 9:1 MeOH:NH4OH solution in dichloromethane, 30 min) to give a pale brown gum. This was triturated with ethanol and concentrated to give a yellow solid. Trituration again with hot ethanol, followed by decanting of the supernatant, gave 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-tert-butylpyridin-2-ylamino)pyridazine-3-carboxamide (57 mg, 149 μmol, 37%) as a cream powder after drying under high vacuum. 1H NMR (DMSO-d6) δ: 11.80 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 7.98 (s, 1H), 7.55-7.76 (m, 2H), 6.96-7.09 (m, 1H), 6.77 (dd, J=8.1, 0.5 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 3.67 (br. s., 1H), 3.03-3.12 (m, 1H), 1.45-1.72 (m, 8H), 1.22-1.41 (m, 11H); MS (EI/CI) m/z: 384.2 [M+H].
Reaction SMILES: [C:1]([O:5][CH:6]([CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3].[CH2:23]([SH:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>C(O)C>[CH2:23]([S:35][CH2:3][CH2:2][C:1]([O:5][CH:6]([CH2:7][S:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: C=CC(=O)OC(CSc1ccccc1)CSc1ccccc1
Reactant: CCCCCCCCCCCCS
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCSCCC(=O)OC(CSc1ccccc1)CSc1ccccc1

Procedure:
A solution of 15 grams of 1,3-bis-(phenylthio)-2-propyl acrylate, 9.2 grams of dodecanethiol, and 1 milliliter of "Triton B" in 75 milliliters of ethanol was heated under reflux for 53/4 hours. The reaction mixture was allowed to cool and was then poured into water. The oil which precipitated was separated by extraction with toluene and the toluene solution was stripped on a rotary evaporator. There remained 24.0 grams of a light colored oil which was identified as 1,3-bis-(phenylthio)-2-propyl 3-(dodecylthio)propionate by means of its NMR spectrum.
Reaction SMILES: [F:1][C:2]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21]O)=[CH:18][C:17]=3[CH2:23][CH3:24])[N:12]=2)=[CH:7][CH:6]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:55]1[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]1.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21][N:55]4[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]4)=[CH:18][C:17]=3[CH2:23][CH3:24])[N:12]=2)=[CH:7][CH:6]=1
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3F)cc2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3F)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (5-{5-[4-(2,3-difluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-4-ethyl-2-thienyl)methanol (0.18 g, 0.43 mmol) that was obtained in Example 18 (18b), carbon tetrabromide (0.17 g, 0.52 mmol), triphenylphosphine (0.14 g, 0.52 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.10 g, 0.86 mmol), and N,N-diisopropylethylamine (0.15 mL, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography using a mixed solvent of ethyl acetate and hexane (5:5) to afford the title compound (0.20 g) in a yield of 91% as a pale yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH3:37][C:38]([CH3:40])=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH:38]([CH3:40])[CH3:37])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: CC(C)=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Product: CC(C)N1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,4R)-3-fluoro-1-(1-methylethyl)piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,4R)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 381) and acetone (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: B.[Na].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[C:24]([CH2:26][CH:27]=[O:28])[C:23]([OH:29])=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=3)[N:19]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:4]>CO>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[C:24]([CH2:26][CH2:27][OH:28])[C:23]([OH:29])=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=3)[N:19]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:4]
Reactant: CCOc1ccc(-c2nc(-c3cc(CC=O)c(O)c(C(=O)OC)c3)cs2)cc1OCC
Agent: B
Agent: [Na]
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cc(CCO)c(O)c(C(=O)OC)c3)cs2)cc1OCC
Yield: 43.6 %

Procedure:
111 mg of sodium boron hydride was added to a solution of 1.3 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-formylmethylphenyl)thiazole in 30 ml of methanol, with stirring under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. After the completion of a reaction, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (eluent: dichloromethane/n-hexane=4/1) and recrystallized from diethyl ether to obtain 570 mg of 2-(3,4-diethoxyphenyl)-4-[3-methoxycarbonyl-4-hydroxy-5-(2-hydroxyethyl)phenyl]-thiazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](O)=[O:14])=[O:7])(C)([CH3:3])[CH3:2].[F:16][C:17]([F:37])([F:36])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.FC(F)(F)C1C=C(S(N2C[C@H]3[C@H](N)CC[C@H]3C2)(=O)=O)C=CC=1>>[O:14]=[C:13]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([S:24]([C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:36])[F:37])=[CH:23][CH:22]=3)(=[O:25])=[O:26])[CH2:31]2)[CH2:34][CH2:33]1)[C@@H:9]([NH:8][C:6](=[O:7])[O:5][CH:1]([CH3:3])[CH3:2])[CH2:10][CH2:11][CH3:12]
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Product: CCC[C@H](NC(=O)OC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-2-(isopropoxycarbonylamino)pentanoic acid from Step A of Example 263 for (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid and (3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 256 for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 266: 1H NMR (501 MHz, pyridine-d5) δ ppm 8.08 (d, J=8.2, 2H), 7.96 (d, J=4.8, 1H), 7.82 (d, J=8.3, 2H), 7.18 (d, J=4.5, 2H), 5.01 (hept, J=6.2, 1H), 4.45 (dd, J=14.0, 7.7, 1H), 4.11 (dt, J=13.0, 6.7, 1H), 3.67 (dd, J=10.2, 3.0, 1H), 3.30 (dd, J=10.2, 7.6, 1H), 3.16-3.07 (m, 2H), 2.57 (h, J=9.3, 2H), 1.99-1.85 (m, 2H), 1.86-1.72 (m, 2H), 1.58-1.50 (m, 1H), 1.45 (ddd, J=20.8, 11.7, 7.2, 2H), 1.26 (ddd, J=13.1, 10.9, 6.6, 1H), 1.19 (d, J=6.2, 3H), 1.16 (d, J=6.2, 3H), 0.84 (t, J=7.4, 3H); MS (ESI+) m/z 520 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:14][C:15]4[C:16](=[CH:17][CH:18]=[C:19]5[N:20]=[C:21]([CH3:24])[O:22][C:23]5=4)[O:25][CH2:26]3)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3
Temperature: 77.5 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmole) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.97 g, 4.92 mmole) were combined in 30 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica, gel using 85% hexane/methylene chloride to remove impurities and methylene chloride to elute the product, the (S)-enantiomer of the title compound, which was a yellow solid (m.p. 196° C.) after evaporation of the solvent (0.21 g, 40%). MS (ESI) m/z 402(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=[CH:4][CH:3]=1.[C:21]([CH:24]=[C:25]=[O:26])(=[O:23])[CH3:22]>CCOC(C)=O>[C:16]([C:15]1[CH:14]=[C:13]([CH:20]=[CH:19][CH:18]=1)[O:12][CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:25](=[O:26])[CH2:24][C:21](=[O:23])[CH3:22])[CH:10]=2)[CH:6]=[CH:7]1)#[N:17]
Reactant: N#Cc1cccc(OCn2ccc3ccc(N)cc32)c1
Reactant: CC(=O)C=C=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc2ccn(COc3cccc(C#N)c3)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 3-((6-amino-1H-indol-1-yl)methoxy)benzonitrile (2.62 g, 9.95 mmol) in EtOAc (20 mL) was added acetyl ketene (1.0 g, 11.9 mmol) and the mixture was stirred at 80° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (2.70 g, 78%).
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=1)[CH:7]=[CH:6][CH:5]=2.[CH:25]1([Mg]Br)[CH2:27][CH2:26]1.O1CCCC1.Cl>C1(C)C=CC=CC=1>[CH:25]1([C:2]2[CH2:3][C:4]3[C:9]([CH:10]=2)=[C:8]([C:11]2[CH:12]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:16]=2)[CH:7]=[CH:6][CH:5]=3)[CH2:27][CH2:26]1
Reactant: CC(C)(C)c1cc(-c2cccc3c2C=C(Br)C3)cc(C(C)(C)C)c1
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2cccc3c2C=C(C2CC2)C3)cc(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
A solution of compound 6 (16.1 g, 42.0 mmol, 1 equiv) and anhydrous toluene (200 mL) was treated with [1,1′-bis(diphenylphos-phino)ferrocene]dichlopalladium(II) DCM adduct (3.43 g, 4.2 mmol, 0.1 equiv). After stirring for 10 minutes, 0.5 M cyclopropylmagnesium bromide in tetrahydrofuran (420 mL, 210 mmol, 5 equiv) was added dropwise. The reaction was heated at 60° C. overnight. The reaction was cooled with an ice bath, acidified with 1N HCl to pH 3 and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with saturated brine (800 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on an AnaLogix (65-200 g) column with dry-loading, eluting with heptanes to give compound 7 (7.0 g, 48% yield) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1.[S:15]([NH:25][NH2:26])(C1C=CC(C)=CC=1)(=O)=O.S(Cl)(Cl)=O>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:26]=[N:25][S:15][CH:13]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: CC(=O)c1ccc(CCCCCl)cc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: ClCCCCc1ccc(-c2csnn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 125 ml round-bottomed flask equipped with condenser and N2 inlet were added 6.25 g (29.65 mmol) p-(4-chlorobutyl)acetophenone, 5.57 g (29.65 mmol) tosylhydrazine, and 50 ml ethanol. The reaction was refluxed 3.5 hours, cooled, and evaporated. The residue was taken up in 23.4 ml (326 mmol) thionyl chloride and stirred at room temperature for 3 hours. The reaction mixture was evaporated and the residue chromatographed on silica gel using hexane/methylene chloride as eluent to afford an oil, 6.1 g (81.5%). NMR (CDCl3): 1.84 (m, 4H), 2.73 (m, 2H), 3.58 (m, 2H), 7.3 and 7.95 (m, 4H), 8.59 (s, 1H).
Reaction SMILES: [C@H:1]1([NH2:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21]>CN(C=O)C>[NH2:10][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][C@H:1]2[NH:11][C:20](=[O:21])[NH:19][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][CH:6]=1
Reactant: Nc1ccc2c(c1)[C@H](N)CC2
Reactant: CCOC(=O)CN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)N[C@@H]1CCc2ccc(N)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
(R)-2,3-dihydro-1H-indene-1,6-diamine (1 eq, 100 mg, 0.46 mmol) and triethylamine (2.5 eq, 158 μL, 1.15 mmol) were dissolved in 2 mL of DMF. The reaction mixture was cooled at 0° C. and ethyl isocyanatoacetate (1 eq, 59 mg, 51 μL, 0.46 mmol) was added dropwise and stirred for 2 hours at 0° C. The reaction mixture was concentrated and purified on reverse phase (H2O/MeCN) to afford the compound 46 (26 mg, 21%) as a white solid Rf=0.26. 1H NMR (300 MHz, DMSO): δ 6.91 (d, J=7.8, 1H), 6.47-6.39 (m, 2H), 6.36 (d, J=8.3 Hz, 1H), 6.11 (t, J=5.9 Hz, 1H), 5.02-4.88 (m, 3H), 4.13 (q, J=7.1 Hz, 2H), 3.83 (d, J=6.0, Hz 2H), 2.87-2.57 (m, 2H), 2.40-2.25 (m, 1H), 1.72. 1.56 (m, 1H), 1.31-1.17 (t, J=7.2 Hz, 3H). HPLC method A tr=5.60 nm (93.4%). ESI-MS m/z: 278.2 [M+H]+.