Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [FH:1].[NH:2]([C:6]1[C:23](=[O:24])[C@@H:22]2O[CH:21]2[C@@:20]2([CH3:26])[C:7]=1[CH:8]=[CH:9][C@@H:10]1[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]1[CH2:12][CH2:13][C:14]2=[O:27])[C:3]([CH3:5])=[O:4].F.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(Cl)(Cl)Cl>[C:3]([NH:2][C:6]1[C:23](=[O:24])[C:22]([F:1])=[CH:21][C@@:20]2([CH3:26])[C:7]=1[CH:8]=[CH:9][C@@H:10]1[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]1[CH2:12][CH2:13][C:14]2=[O:27])(=[O:4])[CH3:5]
Reactant: CC(=O)NC1=C2C=C[C@H]3[C@@H]4CCC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)C2O[C@H]2C1=O
Reactant: F
Agent: *CC*
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)NC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)C=C(F)C1=O
Temperature: -60 °C
Yield: 70 %

Procedure:
To a solution of anhydrous hydrogen fluoride (6 g) in tetrahydrofuran (11.8 g) and chloroform (6 ml) contained in a screw-capped polyethylene bottle chilled to about -60° C. was added a solution of 4-acetamino-1,2α-epoxy-androsta-4,6-diene-3,17-dione (3.554 g, 10 mmol) in chloroform (30 ml) likewise chilled to about -60° C. The hydrogen fluoride-tetrahydrofuran reagent was immersed in an acetone-dry ice bath while the steroid was being added. Additional chloroform (6 ml) was used to aid the transfer of the epoxide. Subsequently the reaction mixture was maintained at -30° C. for 4 h and then added gradually to a well agitated mixture of an aqueous solution of potassium carbonate, chloroform and ice. The organic layer was separated, the alkaline aqueous layer back-extracted twice with chloroform and the combined organic layers were evaporated to dryness. The residue was submitted to flash chromatography with ethyl acetate-ethanol to give pure 4-acetylamino-2-fluoroandrosta-1,4,6-triene-3,17-dione in 70% yield (2.502 g).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7](=[C:9]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=3)=[O:11])[NH:8][C:4]=2[CH:3]=1.O[CH2:31]C1C2N=NNC=2C=CC=1>C(O)C>[F:18][C:16]1[CH:17]=[C:12]([C:10](=[O:11])[C:9](=[C:7]2[NH:6][C:5]3[CH:28]=[CH:29][C:2]([NH:1][CH3:31])=[CH:3][C:4]=3[NH:8]2)[C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH:13]=[C:14]([F:19])[CH:15]=1
Reactant: OCc1cccc2[nH]nnc12
Reactant: Nc1ccc2c(c1)NC(=C(C(=O)c1ccccc1)C(=O)c1cc(F)cc(F)c1)N2
Solvent: CCO
Product: CNc1ccc2c(c1)NC(=C(C(=O)c1ccccc1)C(=O)c1cc(F)cc(F)c1)N2
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.3 %

Procedure:
To a solution of 2-(5-amino-1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3,5-difluorophenyl)-3-phenylpropane-1,3-dione (400 mg) and ethanol (10 ml) was added hydroxymethylbenzotriazole (168 mg) at room temperature, and the reaction solution was stirred at room temperature for 20 hours. The reaction solution was filtered and the resulting solid matter was dissolved in THF (10 ml). Thereto was added sodium borohydride (78 mg) at room temperature and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (10 ml) and the organic layer was washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100:1 (v/v)) to obtain 1-(3,5-difluorophenyl)-2-[5-methylamino-1,3-dihydro-2H-benzimidazol-2-ylidene]-3-phenylpropane-1,3-dione (163 mg, 48%).
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]([O:5][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH3:6])=[O:4]
Reactant: COCCOCCO
Reactant: O=C(O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COCCOCCOC(=O)CBr

Procedure:
A solution of 13.9 g (0.1 mmol) of bromoacetic acid in 40 ml of toluene was treated with 11.8 ml (0.1 mol) of diethylene glycol monomethyl ether and 0.8 g of p-toluenesulphonic acid monohydrate. The mixture was heated under reflux on a water separator until water no longer separated. The reaction mixture was washed in succession with water, saturated sodium bicarbonate solution and water. The organic phase was dried over sodium sulphate and concentrated. Flash chromatography of the residue on 500 g of silica gel (elution agent methylene chloride/ether 4:1) yielded 2-(2-methoxyethoxy)ethyl bromoacetate as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.[CH3:10][S-:11].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:11][CH3:10])[CH:5]=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(F)cc(Br)c1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
50.0 g of 1-bromo-3,5-difluorobenzene and 18.2 g sodium methanethiolate were stirred at 150° C. for 15 min in 300 ml of anhydrous DMF. Subsequently, the mixture was cooled to room temperature, poured onto 1 l of saturated aqueous ammonium chloride solution and extracted three times with 200 ml each of EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. 48.5 g of the title compound were obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([CH:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])[CH3:23].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:25]([O:24][CH2:22][CH3:23])=[O:26])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCC2
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of Intermediate 58 (99 mg) and triethylmethanetricarboxylate (0.14 mL) in anhydrous Toluene (3 mL) and anhydrous Tetrahydrofuran (THF) (3.00 mL) under a nitrogen atmosphere was added trimethylphosphine, 1M in Toluene (0.650 mL). The reaction was then cooled to −78° C. and diisopropyl azodicarboxylate (0.13 mL) added dropwise via syringe over 1 min. The reaction was stirred at −78° C. under an atmosphere of nitrogen for 90 mins before being allowed to warm to ambient temperature and stirred for a further 1 h. The reaction was concentrated in vacuo. The residue was taken up in dichloromethane (40 mL) and washed with water (40 mL), dried (hydrophobic frit) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-100% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product (139 mg). LC/MS MH+ 519, Rt 2.15 min (5 min run).
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([N:10]1[CH2:15][CH2:14][C:13]2([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([O:29]C)[C:23]=3[O:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11]1)[C:8]#[CH:9].[ClH:31].N1C=CC=CC=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.N1C=CC=CC=1>[Cl:31][CH:9]=[CH:8][CH2:7][N:10]1[CH2:15][CH2:14][C:13]2([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:29])[C:23]=3[O:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11]1
Reactant: Cl
Reactant: C#CCN1CCC2(CC1)c1ccccc1Oc1c(OC)cccc12
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Oc1cccc2c1Oc1ccccc1C21CCN(CC=CCl)CC1
Temperature: 200 °C

Procedure:
A mixture of 1'-(prop-2-ynyl)-4-methoxyxanthene-9-spiro-4'-piperidine hydrogen oxalate (1.3 g.) and pyridine hydrochloride prepared from pyridine (9 ml.) and concentrated hydrochloric acid (10 ml.) is heated at 200° C. for 10 minutes. The mixture is cooled and water (20 ml.) added. The solution is basified with dilute sodium carbonate solution and extracted with ether. The ether extract is washed with water, dried with MgSO4 and evaporated to dryness. The solid residue is recrystallised from ethyl acetate-petroleum ether (b.p. 80°-100° C.) to give 1'-(3-chloro-prop-2-enyl)-4-hydroxyxanthene-9-spiro-4'-piperidine, m.p. 153°-155° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH3:22])=[C:14]([N+:23]([O-])=O)[C:13]=2[C:26]2[C:27]([F:33])=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].CC(O)=O>[Fe].O>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[C:15]([CH3:22])=[C:14]([NH2:23])[C:13]=2[C:26]2[C:27]([F:33])=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)c(C)c([N+](=O)[O-])c2-c2cc(C)cnc2F)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)c(C)c(N)c2-c2cc(C)cnc2F)c1
Temperature: 80 °C
Yield: 83.1 %

Procedure:
A mixture of 3-(3′-(ethylsulfonyl)-4-methyl-3-nitro-5-(trifluoromethyl)biphenyl-2-yl)-2-fluoro-5-methylpyridine (6.4 g, 13.3 mmol), iron (3.7 g, 66.3 mmol), HOAc, (32 mL), and H2O (11 mL) was heated at 80° C. for 2 h. After completion the reaction was concentrated in vacuo. The residue was reconstituted in dichloromethane (100 mL), filtered, and rinsed with dichloromethane (3×30 mL). The organic phase was washed with sat. NaHCO3 (1×100 mL) and brine (1×50 mL), dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (1:1 hexanes/EtOAc) gave 5.0 g (83%) of the title compound as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 7.93 (s, 1H), 7.67-7.7.71 (m, 2H), 7.53 (t, 1H), 7.46-7.48 (m, 1H), 7.42 (s, 1H), 6.93 (s, 1H), 5.09 (s, 2H), 3.11 (q, 2H), 2.27 (s, 3H), 2.21 (s, 3H), 0.85 (t, 3H). MS (ES) [m+H] calc'd for C22H20F4N2O2S, 453; found 453.3.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].I[CH2:16][CH2:17][CH2:18][CH3:19].O>CC(N(C)C)=O>[Br:1][C:2]1[C:7]([NH:8][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Nc1cncnc1Br
Reactant: CCCCI
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCNc1cncnc1Br
Temperature: 60 °C
Yield: 22.7 %

Procedure:
A mixture of 4-bromopyrimidin-5-amine (1 g, 5.75 mmol), sodium tert-butoxide (1.11 g, 11.5 mmol) and 1-iodobutane (1.11 g, 6.03 mmol) in DMA (15 mL) was heated at 60° C. for 15 hours. The mixture was poured into water and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (hexanes-EtOAc 3:1) to afford 300 mg of the title compound. MS (ESI) m/z 230 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][NH:5][CH2:4][CH:3]1[OH:7].[OH-].[Na+].[C:11](Cl)(=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.O>[OH:7][CH:3]1[CH2:4][N:5]([C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:6][C:2]1([CH3:8])[CH3:1]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CNCC1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CN(C(=O)OCc2ccccc2)CC1O
Reaction time: 18 h
Yield: 72.9 %

Procedure:
A solution of 4,4-dimethylpyrrolidin-3-ol (2.58 g, 22.4 mmol) in dichloromethane (90 mL), was added 1N sodium hydroxide (90 mL, 90 mmol), then benzyl carbonochloridate (4.16 mL, 24.6 mmol) at rt. The mixture was vigorously stirred for 18 h. The reaction was diluted with dichloromethane and water. The organic phase was separated, dried and concentrated. The crude was purified by silica gel chromatography, eluting with 20-50% ethyl acetate in hexanes to afford benzyl 4-hydroxy-3,3-dimethylpyrrolidine-1-carboxylate (4.07 g, 73% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.52-7.28 (m, 5H), 5.14 (s, 2H), 3.97-3.80 (m, 1H), 3.74 (td, J=11.3, 5.2 Hz, 1H), 3.49 (d, J=5.5 Hz, 1H), 3.43-3.18 (m, 2H), 1.74 (br. s., 1H), 1.09 (d, J=3.3 Hz, 3H), 1.03 (d, J=4.6 Hz, 3H). MS (ES+) m/z: 250.1 (M+H); LC retention time: 2.84 min (analytical HPLC Method I).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)=O.ClCCl.[NH2:11][C:12]([C:14]1[CH:15]=[C:16]([F:36])[C:17]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:18][C:19]=1[Cl:20])=O>C(N(CC)CC)C>[Cl:20][C:19]1[N:18]=[C:17]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33])[C:16]([F:36])=[CH:15][C:14]=1[C:12]#[N:11]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(Cl)c(C(N)=O)cc1F
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Trichloroacetyl chloride (0.55 ml) was added dropwise to a dichloromethane (17 ml) suspension containing tert-butyl cis-2-(5-aminocarbonyl-6-chloro-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (1.74 g) and triethylamine (1.38 ml) under ice cooling, followed by stirring at room temperature for 1 hour. The solvent was distilled away under reduced pressure, and a saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 to 3:1), diisopropylether was added, solid matter was collected by filtration, and a white solid of tert-butyl cis-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (1.26 g) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:20]=[CH:19][C:14]3[O:15][CH2:16][CH2:17][O:18][C:13]=3[CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].ClC(Cl)(Cl)[C:23]([N:25]=C=O)=[O:24].N>O1CCCC1.CO>[NH2:25][C:23]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:20]=[CH:19][C:14]3[O:15][CH2:16][CH2:17][O:18][C:13]=3[CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:24]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: Cc1c(-c2ccc3c(c2)OCCO3)sc(N)c1C(N)=O
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(-c2ccc3c(c2)OCCO3)sc(NC(N)=O)c1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Amino-4-methyl-5-(1,4-benzodioxan-6-yl)-3-thiophencarboxamide (0.44 g) was dissolved in tetrahydrofuran (10 ml), cooled to 0° C. and trichloroacetylisocyanate (0.11 ml) added dropwise with stirring. Stirring was continued for a further 30 minutes at room temperature and then a solution of ammonia in methanol (8 ml of a 10% solution) was added and stirring was continued for a further 3 h. The solvent was evaporated and the residue treated with ethyl acetate and the product filtered off.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.Cl[CH2:10][C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O.P([O-])([O-])(O)=O.[Na+].[Na+].O>CN(C)C(=O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:1]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)NC(=O)CCl
Reactant: Nc1ccc(I)nn1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1cn2nc(I)ccc2n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
To a solution of 3-amino-6-iodopyridazine (10.0 g, 45.2 mmol) in N,N-dimethylacetamide (100 mL) were added tert-butyl (chloroacetyl)carbamate (14.0 g, 72.4 mmol) and disodium hydrogenphosphate (16.1 g, 113 mmol), and the mixture was stirred at 120° C. for 3 hr. After cooling the mixture to room temperature, water (400 mL) was added to the mixture, and the precipitated crystals were filtrated, and washed with acetonitrile and petroleum ether to give the title compound (10.2 g, 63%) as a green powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:23]#[N:24])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.O.P([O-])(OCC)(OCC)=[S:28].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:23](=[S:28])[NH2:24])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(C#N)c2ccc(OC(F)(F)F)cc2)cc1
Reactant: CCOP([O-])(=S)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(CC(C(N)=S)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 80 °C
Yield: 72.8 %

Procedure:
A mixture of 4-[2-cyano-2-(4-trifluoromethoxyphenyl)ethyl]benzoic acid methyl ester (8.76 g, 25.08 mmol), water (4.7 mL) and diethyl thiophosphate (4.67 mL, 27.8 mmol) was stirred and heated to 80° C. for two hours. The mixture was cooled and aqueous sodium hydrogen carbonate (100 mL, 10%) and ethyl acetate (200 mL) were added. The organic phase was washed with brine. Drying (MgSO4) and concentration in vacuo afforded 7 g of the crude material, which was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate:heptane 1:2, containing 2% ethanol. This afforded 2.6 g (27%.) of 4-[2-thiocarbamoyl-2-(4-trifluoromethoxy-phenyl)ethyl]benzoic acid methyl ester as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]([O:39][CH3:40])=[CH:31][N:30]=3)[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19][C@:18]2([C:43]([OH:45])=O)[CH2:42][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH:12]([CH3:46])[CH2:11][C@H:10]1[CH3:47])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:60]1([S:64]([NH2:67])(=[O:66])=[O:65])[CH2:63][CH2:62][CH2:61]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:60]1([S:64]([NH:67][C:43]([C@@:18]23[CH2:42][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH:12]([CH3:46])[CH2:11][C@@H:10]([CH3:47])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[C:32]([O:39][CH3:40])=[CH:31][N:30]=4)[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19]3)=[O:45])(=[O:66])=[O:65])[CH2:63][CH2:62][CH2:61]1
Reactant: NS(=O)(=O)C1CCC1
Reactant: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)O)C[C@H]4C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CCC5)C[C@H]4/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)O)C[C@H]4/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CCC5)C[C@H]4C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (2R,6S,7R,13aS,14aR,16aS,Z)-6-((tert-butoxycarbonyl)amino)-2-((4-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (70 mg, 0.108 mmol), CDI (34.9 mg, 0.215 mmol) in tetrahydrofuran (3 mL) was refluxed for 2 h. It was then cooled to rt and cyclobutanesulfonamide (32.0 mg, 0.237 mmol) was added and followed by DBU (0.036 mL, 0.237 mmol). The mixture was stirred at rt for 16 h. It was then concentrated and purified by silica gel chromatography, eluting with 40% acetone/hexane to isolate 70 mg of the diastereomers tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclobutylsulfonyl)carbamoyl)-2-((4-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate that was used as it was.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:7]=[CH2:8])[CH:2]([CH3:4])[CH3:3].C(NC(C)C)(C)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([N:5]([C@H:6]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH2:8])[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C[C@H](NCC(C)C)c1ccccc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: C=C[C@@H](c1ccccc1)N(CC(C)C)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of (1S)-N-isobutyl-1-phenylprop-2-en-1-amine (9a) (25 mg) and diisopropylamine (19 mg) in DCM (2.5 ml) at RT under N2 was added benzoyl chloride (21 mg). This mixture was stirred for 1 h. The reaction was evaporated and purified by flash chromatography (2% EtOAc/hexane) to afford the title compound (15 mg, 44%) as a pale oil. 1H NMR (300 MHz, CDCl3) δ 0.70 (d, 6H, J=6.6 Hz), 0.81 (bs, 3H), 1.75 (bs, 1H), 2.99-3.06 (m, 1H), 3.25-3.32 (m, 1H), 5.20-5.28 (m, 1H), 5.41 (d, 1H, J=9 Hz), 6.16 (bs, 1H), 7.25-7.46 (m, 5H). MS APCI, m/z=294 (M+1), LC/MS, 2.78 min. Chiral SFC was used to determine ee % by comparing this sample to a known sample of the racemic compound N-isobutyl-N-[(1-phenylprop-2-en-1-yl]benzamide 2.128 min (2.92%) and 2.639 min (97.07%) or 94% ee. Chiral SFC method: 5 μm Chiralpak AS-H column 4.6 mm×250 mm. Isocratic method 10% MeOH in carbon dioxide @ 2.20 ml/mn over 4 minutes.
Reaction SMILES: N[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].N([O-])=O.[Na+].[ClH:17]>C(O)(=O)C.P(=O)(O)(O)O.O>[Cl:17][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(C)c1N
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnn(C)c1Cl
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 44.3 %

Procedure:
23.7 g of ethyl 5-amino-1-methylpyrazole-4-carboxylate is dissolved in a mixture of 50 ml of concentrated hydrochloric acid, 34 ml of acetic acid and 28 ml of phosphoric acid. A solution of 10 g of sodium nitrite in 25 ml of water is added dropwise to the solution while cooling at -4° C. to -6° C. and stirring over a period of 35 minutes to prepare the diazonium salt solution. While cooling at 3° C. to 4° C., the diazonium salt solution is added dropwise to 140 ml of concentrated hydrochloric acid containing 13.9 g of cuprous chloride over a period of 45 minutes. The mixture is stirred at the same temperature for 1 hour, poured into 2l of ice water, and extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution, a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution in that order, and dried over anhydrous sodium sulfate. Ethyl acetate is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent, ethyl acetate:toluene=1:1) to give 11.7 g of the titled compound. Yield 44.3%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[C@@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[(S)-3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a white foam, MS (ESI+): m/z=425.0 [M+H]+.