Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].[C:13](=[O:20])([O:16][CH:17](Cl)[CH3:18])[O:14][CH3:15]>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[C:13](=[O:20])([O:16][CH:17]([O:11][C:7](=[O:12])[C:8]([CH3:10])=[CH2:9])[CH3:18])[O:14][CH3:15]
Reactant: C=C(C)C(=O)O
Reactant: COC(=O)OC(C)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OC(C)OC(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.8 %

Procedure:
Potassium tert. butoxide (3.70 g, 0.033 mol ) was added to a solution of methacrylic acid (2.84 g, 0.033 mol) in DMF (100 ml). Methyl 1-chloroethyl carbonate (4.55 g, 0.033 mol) from Example 1u(i) above was added to the resulting suspension. 18-crown-6 (0.61 g, 2.3 mmol) was then added and the reaction mixture was left with stirring at room temperature for 3 days. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in chloroform (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography gave 4.46 g (72%) of the title product.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:8]=2[N:7]=[C:6]1[C:17]1[C:22](F)=[CH:21][CH:20]=[CH:19][C:18]=1[F:24].FC1C=CC=C(F)C=1CBr.[H-].[Na+].[CH2:42]([O:44]C(=O)C)C.CCCCCC>C1COCC1>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:8]=2[N:7]=[C:6]1[C:17]1[C:22]([O:44][CH3:42])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24]
Reactant: O=[N+]([O-])c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reactant: CCOC(C)=O
Agent: Fc1cccc(F)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(F)c1-c1nc2c([N+](=O)[O-])cccc2n1Cc1c(F)cccc1F
Reaction time: 8 h

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole (2.00 g, 8 mmol)was added 2,6-difluorobenzylbromide (2.0.2 g, 9.76 mmol, 130 M%) dissolved in THF (20 mL) was added NaH (0.84 g, 21 mmol, 290 M%). After 8 h, the reaction was quenched with m ethanol and concentrated. The residue was dissolved in CH2Cl2, and washed with water and NaCl (sat. aq.). The combined washings were dried (Na2SO4), filtered, concentrated. The crude product was purified by flash chromatography eluting with ethylacetate:hexane (1:1) (2.33 g, 5.64 mmol, 78%). M.p. 189-192° C. 1H-NMR (200 MHz, CD2Cl2) δ8.11 (dd, J=8.1, 1.0 Hz, 1H, H5), 7.84 (dd, J=8.1, 1.0 Hz, 1H, H7), 7.52 (m, 1H, H4′), 7.40 (dd, J=8.1 Hz, 1H, H6), 7.26 (m, 1H, H4″), 6.89-6.74 (m, 4H, H3′,5′,35″,5″), 5.36 (d, J=3.4 Hz, 2H, CH2PhF2 (rotamers)), 3.73 (s, 3H, OCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:3]=1[C:4]([NH:6][C:7](=[O:25])[NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)=[O:5].[OH-].[Na+:33].O>C(O)(C)C>[Na+:33].[Cl:1][C:2]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:3]=1[C:4]([NH:6][C:7](=[O:25])[NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][CH2:18][CH:19]([C:22]([O-:24])=[O:23])[CH2:20][CH2:21]1)=[O:5]
Reactant: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cc(F)ccc1N1CCC(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cc(F)ccc1N1CCC(C(=O)[O-])CC1

Procedure:
The solution of 100 mg of 1-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-fluoro-phenyl}piperidine-4-carboxylic acid in 8 ml of isopropanol at 60° C. is admixed with the equimolar amount of 2N sodium hydroxide solution and, after the addition of 20 ml of water, cooled slowly with stirring. The precipitated product is filtered off with suction, washed with isopropanol and water and dried under reduced pressure.
Reaction SMILES: [CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]2)=[CH:13][CH2:12]4)[CH2:3][CH2:2]1.C(OC(=O)C)(=O)C.N1C=CC=CC=1.[C:38]([O:41][C@H:42]1[CH2:59][CH2:58][C@@:57]2([CH3:60])[C:44](=[CH:45][CH2:46][C@@H:47]3[C@@H:56]2[CH2:55][CH2:54][C@@:52]2([CH3:53])[C@H:48]3[CH2:49][CH2:50][C@@H:51]2[O:61][CH:62]2[CH2:64][CH2:63]2)[CH2:43]1)(=[O:40])[CH3:39]>O>[CH:6]1([CH2:7][CH2:39][C:38]([O:41][C@H:42]2[CH2:59][CH2:58][C@@:57]3([CH3:60])[C:44](=[CH:45][CH2:46][C@@H:47]4[C@@H:56]3[CH2:55][CH2:54][C@@:52]3([CH3:53])[C@H:48]4[CH2:49][CH2:50][C@@H:51]3[O:61][CH:62]3[CH2:64][CH2:63]3)[CH2:43]2)=[O:40])[CH2:8][CH2:9][CH2:10][CH2:5]1.[C:57]1([CH2:58][CH2:59][C:42]([O:24][C@H:16]2[CH2:17][CH2:18][C@@:19]3([CH3:20])[C:14](=[CH:13][CH2:12][C@@H:11]4[C@@H:21]3[CH2:22][CH2:23][C@@:6]3([CH3:7])[C@H:8]4[CH2:9][CH2:10][C@@H:5]3[O:4][CH:1]3[CH2:2][CH2:3]3)[CH2:15]2)=[O:41])[CH:44]=[CH:45][CH:46]=[CH:47][CH:56]=1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC5CC5)[C@@]4(C)CC[C@@H]32)C1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](OC(=O)CCC5CCCC5)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](OC(=O)CCc5ccccc5)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1

Procedure:
17β-(Cyclopropyloxy)androst-5-en-3β-ol is treated with acetic anhydride and pyridine. The mixture is poured into water and extracted with ethyl acetate. The ethyl acetate layer is separated and dried and the solvent is evaporated to leave as a residue, 3β-acetyloxy-17β-(cyclopropyloxy)androst-5-ene. 3β-(Cyclopentanepropionyloxy)-17β-(cyclopropyloxy)androst-5-ene and 3β-(benzenepropionyloxy)-17β-(cyclopropyloxy)androst-5-ene are obtained in a similar way using the appropriate acid chlorides.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[CH2:13]([O:15][C:16](=[O:19])[CH2:17]I)[CH3:14]>CC#N>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)[CH3:14]
Reactant: CCOC(=O)CI
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Solvent: CC#N
Product: CCOC(=O)Cc1c[nH]c2cc(N)ccc12

Procedure:
(6-Amino-1H-indol-3-yl)-acetic acid ethyl ester (B-17) was synthesized following the general scheme above starting from 6-nitroindole and iodo-acetic acid ethyl ester. Overall yield (24%). HPLC ret. time 0.95 min, 10-99% CH3CN, 5 min run; ESI-MS 219.2 m/z (MH+).
Reaction SMILES: COC(=O)C1C=CC(C#C[C:12]2[CH:13]=[C:14]([CH:26]3[CH2:28]C3)[C:15]3O[C:19]4(CC4)[CH2:18][C:17]([CH3:24])([CH3:23])[C:16]=3[CH:25]=2)=CC=1F.C(O[C:34](=O)[C:35]1[CH:40]=CC(I)=CC=1)C.C([N:45](CC)CC)C.O1CCCC1>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:35]1([N:45]2[C:25]3[C:16](=[CH:15][C:14]([C:26]#[CH:28])=[CH:13][CH:12]=3)[C:17]([CH3:23])([CH3:24])[CH2:18][CH2:19]2)[CH2:34][CH2:40]1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: COC(=O)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1ccc2c(c1)C(C)(C)CCN2C1CC1

Procedure:
Following general procedure F and using 1-cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 53, 0.11 g, 0.43 mmol), ethyl-4-iodo-benzoate (Reagent A, 0.11 g, 0.9 mmol), triethyl amine (3 mL), tetrahydrofuran(3 mL), copper(I)iodide (0.02 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent, the title compound was obtained (0.05 g, 31%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[S:15][C:16]4[CH2:26][C:21]5([O:25][CH2:24][CH2:23][O:22]5)[CH2:20][CH:19]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:17]=4[N:18]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1.O>CC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[S:15][C:16]4[CH2:26][C:21](=[O:22])[CH2:20][CH:19]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:17]=4[N:18]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1.[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[S:15][C:16]4[CH2:26][C:21]([O:22][CH3:23])([O:25][CH3:24])[CH2:20][CH:19]([C:27]5[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=5)[C:17]=4[N:18]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(s2)CC2(CC3c3ccc(F)cc3)OCCO2)ccc1-n1cnc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3c(s2)CC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Product: COc1cc(Nc2nc3c(s2)CC(OC)(OC)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Yield: 19 %
Yield: 47 %

Procedure:
A solution of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(4-fluorophenyl)-5,7-dihydro-4H-spiro[benzo[d]thiazole-6,2′-[1,3]dioxolan]-2-amine (569 mg, 1.109 mmol) in acetone (7.9 mL)/water (1.6 mL)/70% HClO4 (1.6 mL) was stirred at 50° C. overnight. The crude product was purified using preparatory HPLC (Column: Phenomenex Luna C18 30×100 mm, Solvent A=10 mM ammonium acetate in 95:5 water/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 water/ACN. Flow rate: 40 ml/min, 30-100% B, 15 min) to afford 273 mg (47% yield) of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(4-fluorophenyl)-4,5-dihydrobenzo[d]thiazol-6(7H)-one and 120 mg (19% yield) of the titled compound as a yellow solid. Data for example 83: LC-MS (M+H)+ 515.2. 1H NMR (400 MHz, methanol-d4) δ ppm 7.82 (d, J=2.27 Hz, 1 H) 7.64 (d, J=1.51 Hz, 1 H) 7.19-7.27 (m, 2 H) 7.18 (d, J=1.51 Hz, 1 H) 7.13 (d, J=8.56 Hz, 1H) 6.96-7.06 (m, 2 H) 6.66 (dd, J=8.56, 2.27 Hz, 1 H) 3.95-4.05 (m, 1 H) 3.33 (s, 3H) 3.31 (s, 3 H) 3.25 (s, 3 H) 3.12 (dt, J=16.12, 2.01 Hz, 1 H) 2.92 (dd, J=16.12, 3.02 Hz, 1 H) 2.48 (ddd, J=13.79, 5.73, 2.39 Hz, 1H).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[C:1]1([S:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(Sc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Sc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
A mixture of methyl 4-(phenylthio)benzoate (5 g, 20.4 mmol), lithium hydroxide monohydrate (1.1 g, 26 mmol), tetrahydrofuran (5 mL), methanol (1 mL) and water (1 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 4-(phenylthio)benzoic acid as a white solid (4.5 g, 96%). LRMS (M+H+) m/z: calcd 230.04. found 230.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH3:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH3:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.7 %

Procedure:
A solution of triphenylphosphine (279 mg, 1.06 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (189 mg, 1.06 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid (300 mg, 0.97 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (213 mg, 2.13 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2(-4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (330 mg, 87%) as a pale yellow solid: mp 178-179° C.; EI-HRMS m/e calcd for C19H24N2O3S2 (M+) 392.1228, found 392.1230.
Reaction SMILES: Br[C:2]1[C:3](C)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[O:12]1[CH2:16][CH2:15][O:14][CH:13]1[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>C1(C)C=CC=CC=1.CCO>[O:12]1[CH2:16][CH2:15][O:14][CH:13]1[C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=2)=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: OB(O)c1ccc(C2OCCO2)c(C(F)(F)F)c1
Reactant: Cc1c(Br)cccc1C(N)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: NC(=O)c1cccc(-c2ccc(C3OCCO3)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 3-bromo-2-methylbenzamide (Ex IV-2) and 4-(1,3-dioxolan-2-yl)-3-(trifluoromethyl)phenylboronic acid (I-IX-8) according to the procedure described in Example IX-10, using PhMe/EtOH (4:1) as organic colsovent. LC/MS (method A) 2.36 min; m/z 351 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[CH:13]([Mg]Br)=[CH2:14]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]2[C:3]=1[CH:13]=[CH:14][NH:10]2
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(Br)c2cc[nH]c12
Temperature: -40 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
To a solution of 4-bromo-1-ethyl-2-nitro-benzene (8.7 g, 0.037 mol) in THF at −40° C. was added vinylmagnesium bromide (132 ml, 0.132 mol) dropwise, and the mixture was stirred at −40° C. for a further 2 h. The reaction mixture was diluted with water, extracted with EtOAc, dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography to afford the title compound (1.35 g, 16%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>C/C(/O)=C/C(C)=O.C=C.C=C.[Rh].O1CCOCC1.O>[F:8][C:9]([F:20])([F:19])[C:10]1[CH:15]=[CH:14][C:13]([C@@H:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1C=CCCC1
Agent: [Rh]
Agent: C=C
Agent: CC(=O)/C=C(/C)O
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCC[C@@H](c2ccc(C(F)(F)F)cc2)C1
Temperature: 100 °C

Procedure:
To a 40 ml microwave flask containing dioxane/H2O (10/1) (22 mL) was added cyclohexen-1-one (1.35 g, 14.0 mmol), acetylacetonatobis(ethylene)rhodium(I) (0.36 g, 1.40 mmol), R-2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl (0.88 g, 1.40 mmol) and 4-(trifluoromethyl)-phenylboronic acid (5.0 g, 28.0 mmol). The mixture was heated in the microwave (Personal Chemistry) at 100° C. for 20 minutes. The material was transferred to a separatory funnel and extracted with ethyl acetate (150 mL). The resulting organic layer was washed with NaHCO3 (75 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The mixture was purified on SiO2 (hexane/ethyl acetate 4/1) to provide the title compound. [α]D=+13.62 c=10 (CH3OH). 1H NMR (CD3OD, 300 MHz); δ 1.72-2.20 (m, 5H), 2.35-2.73 (m, 3H), 3.06-3.15 (m, 1H), 7.40-7.42 (m, 2H), 7.46-7.63 (m, 2H). MS (+ESI) m/z 242 (M+NH4—H2O)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][CH:42]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22]([N:39]3[CH2:44][CH2:43][CH:42]([C:45](=[O:46])[NH2:47])[CH2:41][CH2:40]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:4])[CH3:2]
Reactant: NC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC(C(N)=O)CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 100.9 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), piperidine-4-carboxylic acid amide (70 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) and 4 mL of N,N-dimethylformamide were then added to the solution successively. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(4-carbamoyl-piperidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 7a (180 mg, yield 98%) as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]([CH3:22])([CH3:21])[CH2:5]1.[CH2:23](Br)[CH:24]=[CH2:25].CCCCCCC>O1CCCC1.C(OCC)(=O)C>[CH2:25]([O:3][CH:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]([CH3:21])([CH3:22])[CH2:5]1)[CH:24]=[CH2:23]
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C=CCOC1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1
Temperature: 35 °C
Yield: 69.9 %

Procedure:
Sodium hydride (2.65 grams, 110 mmol) is added to a solution of 30.0 grams (105 mmol) of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine in 150 ml of tetrahydrofuran under nitrogen. The reaction mixture is heated at reflux for three hours, cooled to 35° C., and treated with 12.7 grams (110 mmol) of allyl bromide. The reaction mixture is heated at reflux for one hour, then partitioned between ethyl acetate (150 ml) and water (50 ml). The organic layer is washed with saturated sodium chloride solution (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in heptane (50 ml) and passed through a pad of silica gel (eluent 5:1 heptane:ethyl acetate). The crude product is purified by flash chromatography (silica gel; 9:1 heptane:ethyl acetate to afford 23.9 grams (70% yield) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:2].[CH2:12]=[O:13].C(N(CC)CC)C>CC(C)=O>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][OH:13])[CH:4]=1)=[O:2]
Reactant: C=O
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=Cc1cn(CO)c2ccccc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
The mixture of 5.81 g of 3-formyl-1H-indole, 1.80 g of paraformaldehyde and 0.40 g of triethylamine was stirred at 120 ° C. for 3 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered, and then the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.08 g of 3-formyl-1H-indole-1-ylmethanol.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[C:15]([N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@@H:2]1[CH3:1])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-tert-butyl 3-methylpiperazine-1-carboxylate (6.00 g, 30.0 mmol) was dissolved in dry DMF (40 mL) and N,N-diisopropylethylamine (DIEA) (6.00 mL). Benzoyl chloride (3.65 mL, 31.5 mmol) was added drop-wise and the reaction was stirred at rt for 16 hours. The reaction was taken up in ethyl acetate (200 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organic phase was dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-50% ethyl acetate gave an off-white solid.
Reaction SMILES: C(OC([NH:8][N:9]1[CH2:14][C:13]([C:15]2[CH2:19][C:18]([CH3:21])([CH3:20])[O:17][N:16]=2)=[N:12][N:11](C(OC(C)(C)C)=O)[C:10]1=[O:29])=O)(C)(C)C.C(Cl)(=O)C.C[O-].[Na+]>CCO.CO>[NH2:8][N:9]1[CH2:14][C:13]([C:15]2[CH2:19][C:18]([CH3:20])([CH3:21])[O:17][N:16]=2)=[N:12][NH:11][C:10]1=[O:29]
Reactant: CC(C)(C)OC(=O)NN1CC(C2=NOC(C)(C)C2)=NN(C(=O)OC(C)(C)C)C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CCO
Solvent: CO
Product: CC1(C)CC(C2=NNC(=O)N(N)C2)=NO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-(tert-butoxycarbonylamino)-6-(5,5-dimethyl-4H-isoxazol-3-yl)-3-oxo-5H-1,2,4-triazine-2-carboxylate (2.50 g, 5.51 mmol) in EtOH (30 mL) at 0° C. was slowly added acetyl chloride (2.16 mL, 27.6 mmol). After completion of the addition, the reaction mixture was allowed to warm to room temperature and stirring was continued for an additional 20 h. The reaction mixture was cooled to 0° C. and carefully treated with NaOMe in MeOH until pH 7 was reached. The volatiles were removed in vacuo and the residual was repeatedly diluted with acetonitrile and evaporated. The remaining solids were stirred for 10 min with hot acetonitrile and filtered. Concentration of the filtrate furnished the desired product as an off-white solid. LCMS (Method K) RT 0.47 min. [M+H]+ 212.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[Br:27]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@:14]2([Br:27])[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@]2(Br)C(C)=O)C1

Procedure:
3α-Acetoxy-5α-pregnan-20-one (3 g, 360.5 g/m, 8.3 mmol), N-bromosuccinimide (2.7 g, 178 g/m, 15 mmol), and benzoyl peroxide (200 mg, 242 g/m, 0.83 mmol) dissolved in 50 ml of carbon tetrachloride were refluxed overnight (ca. 16h). The reaction mixture was cooled, filtered, and washed with sodium bisulfite, water, and brine, and then concentrated to give a crude reddish oil.