Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>O1CCOCC1>[N:32]1([C:29]2[CH:28]=[CH:27][C:26]([NH:25][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:24])=[CH:31][CH:30]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCOCC3)cc2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
A dry 50 mL flask was charged with N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (prepared below, 70 mg, 0.217 mmol) and Dioxane (10 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (200 mg, 1.122 mmol), and the mixture was stirred for 24 h at 100° C. Subsequently, the reaction mixture was cooled to room temperature. The resulting suspension was concentrated in vacuo and the resulting solid residue was recrystallized from iPrOH (˜5 mL). The solid recovered through filtration then was subjected to flash silica gel chromatography using a 5% MeOH/CHCl3 eluant mixture to afford the title compound in 33% yield (35 mg, 0.072 mmol).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][N:6]=1)=[O:4].[NH:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18]>C(O)C>[OH:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:20][OH:21])[C:11]([C:8]1[CH:7]=[N:6][C:5]([C:3]([N:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: OCCNCCO
Reactant: COC(=O)c1cnc(C(=O)OC)cn1
Solvent: CCO
Product: O=C(c1cnc(C(=O)N(CCO)CCO)cn1)N(CCO)CCO
Temperature: 20 °C

Procedure:
A solution of 500 mg of 2,5-dimethoxycarbonylpyrazine and 0.48 cm3 of diethanolamine in 3 cm3 of ethanol is heated to a temperature in the region of the reflux temperature for 3 hours. The reaction mixture is cooled to 20° C. and the white solid formed is then filtered off and washed with 2 cm3 of ethanol. 600 mg of N,N,N′,N′-tetrakis(2-hydroxyethyl)pyrazine-2,5-dicarboxamide are thus obtained in the form of a white solid melting at 143° C. [1H NMR spectrum (250 MHz, (CD3)2SO-d6, at a temperature of 403 K, δ in ppm): from 3.50 to 3.80 (mt, 16H: 4×NCH2CH2O); 4.32 (mt, 4H: 4×OH); 8.76 (s, 2H: ═CH at 3 and ═CH at 6)].
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][NH2:9]>ClC1C=CC=CC=1>[CH3:8][NH:9][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5]
Reactant: O=C1C=CC(=O)O1
Reactant: CN
Solvent: Clc1ccccc1
Product: CNC(=O)/C=C\C(=O)O

Procedure:
The same reactor as used in Example 7 was adopted. This reactor was charged with a solution 53 g of maleic anhydride in 200 g of chlorobenzene. Then, methylamine gas was blown in gradually and piecemeal at 30° C. at a rate of 4.3×10-3 mol/min. over a period of two hours to produce a white slurry of N-methyl maleinamic acid. Subsequently, the slurry and 22.5 g of ortho-phosphoric acid (purity 89% by weight), 0.1 g of phenothiazine, and 0.02 g of zinc acetate added thereto were heated at 134° C. for two hours to effect reaction. Thereafter, the resultant reaction mixture was cooled to 40° C., filtered, and distilled under a vacuum to expel chlorobenzene. Consequently, there was obtained 45 g of light yellow N-methyl maleimide having purity of 92.1% by weight. The yield of the product is calculated to be 72.5 mol% based on methylamine as the raw material.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]([CH2:21][CH3:22])[C:14]1=[O:23])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([N:17]1[C:18](=[O:19])[N:13]([C:9]([CH3:11])([CH3:12])[CH3:10])[C:14](=[O:23])[N:15]([CH2:21][CH3:22])[C:16]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCn1c(=O)[nH]c(=O)n(C(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCn1c(=O)n(Cc2ccccc2)c(=O)n(C(C)(C)C)c1=O
Yield: 62.3 %

Procedure:
7.7 g (45 mmol) of benzyl bromide are added dropwise at room temperature to a solution of 10 g (46.9 mmol) of 1-tert.-butyl-3-ethyl-1,3,5-triazine-2,4,6-trione and 9.9 g (93 mmol) of sodium carbonate. The reaction mixture is refluxed for 6 hours. After it has cooled, the solid constituents are separated off, and the reaction solution is concentrated. The residue is taken up in methylene chloride and washed twice with water. After the organic phase has been dried over sodium sulphate, it is concentrated and distilled in vacuo. 8.5 g (60% of theory) of 5-benzyl-1-tert.-butyl-3-ethyl-1,3,5-triazine-2,4,6-trione are obtained as a highly viscous oil having a boiling point of 170° C./0.03 mbar.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[S:18]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=[O:20])=[O:19]
Reactant: Cn1cccc1CCN
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: Cn1cccc1CCNS(=O)(=O)c1cc(Cl)ccc1Cl

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and 2,5-dichlorobenzenesulphonylchloride analogously to Example A.
Reaction SMILES: [CH3:1][NH:2][NH2:3].O=[C:5]([CH2:12][CH3:13])[CH2:6][C:7](OCC)=[O:8]>CO>[CH2:12]([C:5]1[CH:6]=[C:7]([OH:8])[N:2]([CH3:1])[N:3]=1)[CH3:13]
Reactant: CNN
Reactant: CCOC(=O)CC(=O)CC
Solvent: CO
Product: CCc1cc(O)n(C)n1
Temperature: 45 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Methylhydrazine (31.6 g, 0.687 mol) in methanol (100 mL) was added dropwise to a solution of ethyl 3-oxopentanoate (100 g, 0.694 mol) in methanol (280 mL) over a period of 45 min, during which time the temperature increased to 45° C. The reaction mixture was then allowed to stir at room temperature overnight and then evaporated, affording 84.5 g (97%) of the crude title product.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([C@H:12](O)[CH3:13])[C@@H:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C@H:8]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C@H:6]2[N:7]=1.CCN(S(F)(F)[F:42])CC>ClCCl>[F:42][C@H:12]([C@H:10]1[O:11][C@H:5]2[C@H:6]([N:7]=[C:3]([N:2]([CH3:35])[CH3:1])[S:4]2)[C@@H:8]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C@@H:9]1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH3:13]
Reactant: COc1ccc(CO[C@H]2[C@H](OCc3ccc(OC)cc3)[C@H]3N=C(N(C)C)S[C@H]3O[C@@H]2[C@@H](C)O)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CO[C@H]2[C@H](OCc3ccc(OC)cc3)[C@H]3N=C(N(C)C)S[C@H]3O[C@@H]2[C@H](C)F)cc1
Yield: 84.9 %

Procedure:
A solution of (R)-1-((3aR,5R,6S,7R,7aR)-2-(dimethylamino)-6,7-bis(4-methoxybenzyloxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (280 mg, 0.56 mmol) in dichloromethane (10 mL) was treated with DAST (900 mg, 5.59 mmol) at −78° C. for 10 min and at 0° C. for 1 hr. The reaction was quenched by sat. aqueous Na2CO3 solution (30 mL), and extracted with dichloromethane (2×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue, which was purified by silica gel column, eluted with 1-2% methanol in dichloromethane to give compound 50 as a yellow syrup (240 mg, 85%). (ES, m/z): [M+H]+ 505.0; 1H NMR (300 MHz, CDCl3) δ 7.22-7.43 (m, 4H), 6.83-6.94 (m, 4H), 6.38-6.50 (m, 1H), 4.58-4.78 (m, 6H), 3.75-3.90 (m, 8H), 3.46-3.50 (m, 1H), 3.05-3.18 (m, 6H), 1.27-1.36 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.C([O-])(=O)C.[Na+].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C(O)(=O)C>[OH:13][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:12])[NH:10]2
Reactant: Nc1ccc(O)c2c1NC(=O)CC2
Reactant: CS(=O)(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Nc1ccc(O)c2c1NC(=O)CC2
Yield: 54.1 %

Procedure:
5.0 g of 8-amino-5-hydroxy-3,4-dihydrocarbostyril was suspended in 30 ml of acetic acid, and 4.0 g of sodium acetate was added to the suspension while stirring. 3.5 g of methanesulfonyl chloride was then added to the mixture followed by heating for 7 hours while refluxing. After completion of the reaction, 100 ml of water was added to the reaction mixture which was then concentrated to dryness under reduced pressure. The resulting residue was added to 200 ml of water, and the mixture was stirred. The crystals formed were recovered by filtration, washed with water and recrystallized from methanol to obtain 3.89 g of 5-hydroxy-8-methanesulfonylamino-3,4-dihydrocarbostyril as colorless amorphous crystals having a melting point of 269.4°-269.8° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].Cl[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26].N1C=CC=CC=1>C(OCC)C>[C:25](=[O:26])([O:21][C:19]1[CH:20]=[C:15]([N:5]2[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=[C:4]2[O:3][CH2:1][CH3:2])[C:16]([F:23])=[CH:17][C:18]=1[Cl:22])[O:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCOC(=O)Cl
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCOC(=O)Oc1cc(-n2c(OCC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5 -hydroxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone and n-butyl chloroformate with pyridine in diethyl ether there is obtained n-butyl {5-[2-ethoxy-6-oxo-4 -trifluoromethyl-1(6H) -pyrimidinyl]-2-chloro-4-fluorophenyl} carbonate, m.p. 100°-102° C.;
Reaction SMILES: Cl.Cl.[CH2:3]([C@:5]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:9][CH2:8][C@H:7]([NH2:10])[CH2:6]1)[CH3:4].[CH3:29][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:3]([C@:5]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:9][CH2:8][C@H:7]([NH:10][CH:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH3:29])[CH2:6]1)[CH3:4]
Reactant: CC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](NC2CCOCC2C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of (1S,3S)-3-ethyl-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (100 mg, 0.20 mmol), 3-methyltetrahydro-4H-pyran-4-one (96 mg, 0.71 mmol), and triethylamine (0.11 mL, 0.79 mmol) in methylene chloride (3 mL) was added sodium triacetoxyborohydride (96 mg, 0.45 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3 and extracted with methylene chloride three times. The combined organics were dried (MgSO4), filtered, concentrated, purified by flash column chromatography (NH4OH/MeOH/EtOAc) to yield the desired product (38 mg, 40%). MS calculated for C24H35F3N4O2: (M+H) 469.3; found 469.3.
Reaction SMILES: O[C:2](=[O:23])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1.O[N:25]1[C:29]2C=[CH:31][CH:32]=[CH:33][C:28]=2N=N1.Cl.CN(C)CCCN=C=NCC.N1CCCCC1>C(Cl)Cl>[N:25]1([C:2](=[O:23])[CH2:3][CH2:4][C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=3)[N:8]=[C:7]([C:21]#[N:22])[N:6]=2)[CH2:31][CH2:32][CH2:33][CH2:28][CH2:29]1
Reactant: N#Cc1nc(CCC(=O)O)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNCC1
Solvent: ClCCl
Product: N#Cc1nc(CCC(=O)N2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(3-hydroxy-3-oxopropyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (64 mg) in DCM (6 mL) was added 1-hydroxybenzotriazole (30 mg) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (38 mg). The solution was stirred at room temperature for 15 min and piperidine (22 mg) added. After standing for 18 h, the reaction mixture was washed with HCl (1M, 2×5 ml), H2O then brine and dried with sodium sulfate. After removal of solvent, crystallisation from a trace of acetone/ether gave 4-(3-piperidin-1-yl-3-oxopropyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile as a white solid, 35 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)[CH3:21]
Reactant: CCI
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.7 %

Procedure:
To 6-hydroxy-3,4-dihydro-2(1 H)-quinolinone (90.2 g, 0.55 mol, 1 equiv) in DMF (1.8 L) was added potassium carbonate (228 g, 1.65 mol, 3 equiv). The slurry was stirred for 45 min. at 25° C., then iodoethane (114 g, 0.73 mol, 1.33 equiv) was added and stirring was continued for 12 hours. The mixture was filtered, the filtrate was poured into water, and the white precipitate was collected via filtration, washed with water (500 mL), and dried under high vacuum to provide 6-(ethyloxy)-3,4-dihydro-2(1H)-quinolinone (72.3 g, 69%). 1H NMR (400 MHz, DMSO) δ, 1.25 (t, J=7.2 Hz, 3H), 2.35 (m, 2 H), 2.78 (m, 2H), 3.90(m, 2H), 6.70-6.73 (m, 3H), 9.83 (br, 1H).
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:33]C(=O)OC(C)(C)C)[C:17]([NH:19][C:20]2[N:24]([CH3:25])[N:23]=[C:22]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)[CH:21]=2)=[O:18])=[CH:11][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][C@@H:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=1)[C:17]([NH:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)[CH:21]=1)=[O:18]
Reactant: Cc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NC(=O)OC(C)(C)C)n(C)n2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)n(C)n2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 100 flask was added tert-butyl (S)-3-(4-fluorophenyl)-1-(1-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxopropan-2-ylcarbamate TFA 16.1.E (529 mg, 0.93 mmole), 20 ml of DCM, and 10 ml of TFA. The reaction was stirred at room temperature for 12 hours at which time the solvent was removed to give (2S)-2-amino-3-(4-fluorophenyl)-N-(1-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazol-5-yl)propanamide diTFA 16.1F as a yellow solid (560 mg 100% yield). LCMS ESI (pos.) m/e: 354.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O>[N:17]([CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(N=[N+]=[N-])C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 1-t-butoxycarbonyl-3-(methanesulfonyloxy)azetidine (4.71 g, 18.7 mmol) (obtained as described in Reference Example 57(1)) in dimethylformamide (140 ml) was added sodium azide (3.65 g, 56.1 mmol), and the mixture was stirred in an oil bath (90° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (4:1) as the eluant to afford 3-azido-1-(t-butoxycarbonyl)-azetidine (3.44 g, yield 93%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.[CH2:17]([N:19]1[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[S:32](Cl)(=[O:34])=[O:33])[CH2:20]1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH2:17]([N:19]1[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[S:32]([NH:1][C:2]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]3[C:5]([C@@H:6]4[CH2:16][C@@H:7]4[CH2:8][O:9]3)=[CH:4][CH:3]=2)(=[O:33])=[O:34])[CH2:20]1)[CH3:18]
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: CCN1CC[C@H](Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CC[C@H](Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OC[C@H]2C[C@@H]32)C1
Temperature: 40 °C
Yield: 25.8 %

Procedure:
A solution of methyl 5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.19 g) in DCM (10 mL) and pyridine (3.5 mL) was treated with a solution of 2-((S)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 114, 0.26 g) in DCM (5 mL) and the mixture was stirred and heated at 40° C. for 1 hour. The resultant mixture was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM and methanol with a gradient of 0-25%, then flushed with 100% methanol to give methyl (1aS,7bR)-5-[2-((S)-1-ethylpyrrolidin-3-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.107 g) as a gum.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][C:34](O)=[O:35]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:34](=[O:35])[CH2:33][O:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)=[CH:11][C:12]=1[F:17]
Reactant: O=C(O)COc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Agent: Cl
Product: O=C(COc1ccccn1)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and (pyridin-2-yloxy)acetic acid monohydrochloride, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:10](=[O:19])[C@@H:9]2[CH2:20][CH2:21][C@@H:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[OH:23])[CH:5]=[CH:6][CH:7]=1.[OH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]2[C@H:8]([C:4]3[CH:3]=[C:2]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([OH:31])[CH:37]=4)[CH:7]=[CH:6][CH:5]=3)[C@@H:9]([CH2:20][CH2:21][C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[OH:23])[C:10]2=[O:19])=[CH:13][CH:14]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2cccc(Br)c2)N1c1ccc(F)cc1
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2cccc(-c3cccc(O)c3)c2)N1c1ccc(F)cc1
Yield: 44.6 %

Procedure:
(3R,4S)-4-(3-Bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (43 mg, 0.091 mmol) was coupled with 3-hydroxyphenyl boronic acid (18 mg, 0.13 mmol) under standard Suzuki conditions illustrated by Example 42. Purified by chromatography (silica gel, 10% to 90% ethyl acetate-hexane) to afford (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-3-yl)azetidin-2-one (19.7 mg, 45% yield); Rf 0.30 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.57-7.40 (m, 3H), 7.34-7.22 (m, 6H), 7.10 (ddd, 7.7, 1.6, 0.9 Hz 1H), 7.04-6.90 (m, 5H), 6.84 (ddd, J=8.2, 2.6, 0.9 Hz, 1H), 5.10 (br s, 1H), 4.72 (t, J=5.9 Hz, 1H), 4.67 (d, J=2.4 Hz, 1H), 3.16 (ddd, J=5.0, 2.6, 2.4 Hz, 1H), 2.26 (br s, 1H), 2.08-1.88 (m, 4H) ppm.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Product: CNCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1

Procedure:
The title compound was prepared (0.351 g, 77%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.595 g, 1.324 mmol) and methylamine (1.86 g, 60.0 mmol). 190-192 mp ° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2].O.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([O:23][C:27](=[O:29])[CH3:28])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@@H]1CC2

Procedure:
A solution of 1-acetoxy-3-methoxyestra-1,3,5(10)-triene-17β-ol (0.95 g, 2.8 mM) in 20 ml of acetic anhydride and 5 ml of pyridine is heated on a steam bath for 1 hr. The resulting yellow solution is cooled and poured into 300 ml of cold H2O. The suspension is filtered, and the resulting white solid is recrystallized from methanol-H2O to give 1,17β-diacetoxy-3-methoxyestra-1,3,5(10)-triene as a white solid, yield 0.75 g (70%); m.p. 120°-121°.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1>>[C:11]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: NC1CCc2ccccc21
Product: COc1cccc(C(=O)NC2CCc3ccccc32)c1

Procedure:
The title compound was prepared from (rac)-1-aminoindan (1.6 g, 12.3 mmole) and m-anisoyl chloride (1.9 g, 13.54 mmole) as in Ex. 46; crystallization from EtOAc:hexane gave 2:0 g (7.2 mmole, 59w) white solid, mp: 140° C.