Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:24])[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C(OCC)(=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:24])[C:16](=[O:17])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)c1ccccc1)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccccc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
To a solution of the compound (0.455 g) obtained in Example 13 in ethyl acetate (3 mL) was added 4N hydrogen chloride/ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 24 hr with heating. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was made basic with 2N aqueous sodium hydroxide solution. The organic layer was separated, washed with water, and the solvent was evaporated under reduced pressure to give the title compound (0.27 g, 75%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C@H:7]([C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=O)[O:8][C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.B#B.Cl>C1COCC1.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C@H:7]([CH2:16][NH:18][CH:19]([CH3:20])[CH3:21])[O:8][C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)NC(=O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)NC[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Yield: 208.9 %

Procedure:
A solution of cis-6-chloro-4-phenyl-N-(2-propyl)-1,3-benzodioxan-2-carboxamide (6.6 g, 20.0 mmoles) in 400 ml of anhydrous THF was treated with 80 ml (80 mmoles) of diborane in THF solution (1M as BH3) and the reaction mixture was worked up essentially as described in Example 5b. The oily amine was converted to the hydrochloride in anhydrous ether; 7.4 g of colorless powder was obtained. Recrystallization from absolute EtOH gave 5.96 g (84%) of colorless crystals; mp 224.5°-225.5°.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:33][C:34]([CH3:37])=[N:35][N:36]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[S:33][C:34]([CH3:37])=[N:35][N:36]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1nnc(Br)s1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1nnc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3c(c2)ncn3C2CC2)s1
Temperature: 100 °C
Yield: 51.9 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (120 mg, 0.292 mmol), 2-bromo-5-methyl-1,3,4-thiadiazole (104.5 mg, 0.584 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.96 mL, 0.96 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (33.7 mg, 0.029 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH: DCM=5:95) to give light yellow solids, 58.1 mg (yield 51.9%). 1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.69 (d, J=1.2 Hz, 1H), 7.60 (broad s, 1H), 7.44 (d, J=1.3 Hz, 1H), 4.84 (p, J=6.0 Hz, 1H), 3.73 (m, 1H), 3.46-3.36 (m, 1H), 3.26-3.15 (m, 1H), 2.90-2.79 (m, 1H), 2.76 (s, 3H), 2.47-2.20 (m, 2H), 1.34 (d, J=6.0 Hz, 3H), 1.19-1.09 (m, 2H), 1.06 (m, 2H) ppm; MS (ESI+) m/z 384 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[OH-].[Li+].O.C(OCC)(=O)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([C:19]([NH:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:20])=[CH:17][N:18]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cccc(C(=O)OC)c3)cn2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cccc(C(=O)O)c3)cn2)C1
Temperature: 22.5 °C
Reaction time: 72 h
Yield: 92.6 %

Procedure:
A solution of (R)-methyl 3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoate (21.3 g, 43.5 mmol) in THF (100 mL) was cooled to 5° C. Aqueous 1.9M lithium hydroxide solution (50 mL, 96 mmol) was added via addition funnel, maintaining the temperature below 14° C., followed by a 30-mL water rinse of the addition funnel. The reaction mixture was warmed to 20-25° C. and was stirred at that temperature for 72 hours. The mixture was concentrated to remove THF, and then was cooled to 8° C. Hydrochloric acid (1N, 80 mL) was added dropwise, and a precipitate began to form. Ethyl acetate (200 mL) was added to dissolve the solids, and the layers were separated, and the aqueous phase was further extracted with ethyl acetate (2 times with 100 mL). The combined organics were washed with brine (4 times with 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid (20.4 g) was slurried in ethanol (250 mL) and heated to 75° C., resulting in a yellow solution. Water (250 mL) was added slowly, forming a precipitate, and the mixture was heated to 90° C. to dissolve the solids. The solution was then cooled to 30° C. and was held at that temperature for 16 hours. The mixture was further cooled to −1.5° C. for 3 hours. The resulting crystals were collected by filtration, rinsed with water (50 mL), and then dried to afford (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid (19.2 g). 1H NMR (500 MHz, CD3OD) δ 8.73 (s, 2H), 8.03 (s, 1H), 7.94 (d, 1H), 7.59 (d, 1H), 7.45 (t, 1H), 7.01 (dd, 1H), 6.92 (m, 2H), 6.86 (m, 1H), 4.60 (s, 2H), 4.37 (m, 1H), 4.14 (dd, 1H), 4.06 (dd, 1H), 3.92 (m, 4H), 2.07 (m, 1H), 1.97 (m, 2H), 1.58 (m, 1H), 1.29 (t, 3H). Chiral SFC: Chiralcel OJ-H, 4.6 mm×25 cm, 70:30 CO2:methanol, 0.2% isopropylamine, 2.5 mL/min, 210/254 nM; retention time (R)-enantiomer (Example 1) 4.13 min, (S)-enantiomer 2.35 min. MS (ES+) 477.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH:15]([CH3:20])[C:16](=O)[O:17]C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][NH2:23]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:23][NH:22][C:16](=[O:17])[C:15]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)C(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Product: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)[nH][nH]c1=O
Temperature: 25 °C

Procedure:
A solution of 419 mg (1.4 mmol) of 1-(tert-butoxycarbonyl)-4-(1,3-dioxo-3-methoxy-2-methyl-prop-1-yl)piperidine (from Step B) and 0.26 mL (8.4 mmol) of hydrazine in 5 mL of toluene was refluxed for 50 minutes. The reaction was cooled to rt and placed in the freezer overnight. After decanting the solvent, the white solid was triturated with Et2O to provide the title compound, which was used without further purification. 1H-NMR (500 MHz) δ 1.49 (s, 9H), 1.55–1.63 (m, 2H), 1.77–1.79 (m, 2H), 1.90 (s, 3H), 2.69–2.77 (m, 3H), 4.22 (m, 2H), 5.15–5.79 (br m, 2H).
Reaction SMILES: C(O)(=O)C(O)=[O:3].[CH3:7][N:8]1[C@@H:24]2[CH2:25][C:13]3[CH:14]=[CH:15][C:16]([O:28][CH3:29])=[C:17]4[O:18][C@H:19]5[C:20]([O:26]C)=[CH:21][CH:22]=[C:23]2[C@:11]5([C:12]=34)[CH2:10][CH2:9]1.[OH-].[Na+]>O.C(O)(=O)C.OO>[CH3:7][N:8]1[C@@H:24]2[CH2:25][C:13]3[CH:14]=[CH:15][C:16]([O:28][CH3:29])=[C:17]4[O:18][CH:19]5[C:20]([CH:21]=[CH:22][C@:23]2([OH:3])[C@:11]5([C:12]=34)[CH2:10][CH2:9]1)=[O:26]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: O=C(O)C(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 2 °C
Yield: 82 %

Procedure:
6-Benzyloxy-4,5α-epoxy-3-methoxy-17-methylmorfina-6,8(14)-diene (52.5 g) is dissolved in a solution prepared by dissolving 9.8 g of oxalic acid in 35 ml of water, 10 ml of acetic acid and 21.2 ml of 30% hydrogen peroxide are added. The reaction mixture is stirred at 20° C. until total conversion of the benzyl analogue of thebaine, the reaction mixture is cooled down to 2° C., 8% aqueous solution of NaOH is added with stirring until pH of 9.2. Precipitated crystals of 14-hydroxycodeinone are filtered off, washed with water and dried. The procedure yields ca. 37 g of 14-hydroxycodeinone (82%). Further procedure of preparation of Oxycodone hydrochloride is the same as in Example Ib) and Ic).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:31])[CH2:15][N:16]2[C:21](=[O:22])[C:20]3[C:23]([CH3:30])=[C:24]([C:26]([O:28]C)=[O:27])[S:25][C:19]=3[N:18]=[CH:17]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.O.[OH-].[Li+]>C1COCC1.CO>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:31])[CH2:15][N:16]2[C:21](=[O:22])[C:20]3[C:23]([CH3:30])=[C:24]([C:26]([OH:28])=[O:27])[S:25][C:19]=3[N:18]=[CH:17]2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)c1sc2ncn(CC(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(=O)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2ncn(CC(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of methyl 3-(2-(3,5-bis(trifluoromethyl)phenylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, (3.3 g, 6.75 mmol) in THF (30 mL), MeOH (10 mL), and H2O (10 mL) was added lithium hydroxide monohydrate (1.42 g, 33.8 mmol). The reaction mixture was then stirred at RT overnight. The reaction mixture was concentrated, diluted with H2O (30 mL) and washed with DCM (2×30 mL). The aqueous layer was acidified (pH˜2) with 1M HCl and the resultant precipitate was filtered and dried to give 1.9 g of 3-(2-(3,5-bis(trifluoromethyl)phenylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (yield: 59%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[CH:27]1[CH:26]=[CH:25][N:17]2[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:14]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:3]4[CH:4]=[CH:5][N:1]([C:28](=[O:30])[CH3:29])[N:2]=4)=[CH:7][CH:8]=3)=[O:13])[CH2:15][C:16]=12
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)n1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
To a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.50 g) in dry pyridine (10 ml) was added acetic anhydride (0.20 g). After stirring at room temperature for 18 hours the reaction mixture was poured into water and the precipitate was collected by filtration. The crude product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. This solution was filtered through a short column of hydrous sodium magnesium silicate, eluting with several additional volumes of dichloromethane. The eluant was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.46 g), m.p. 192-194° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:3][CH2:2]1.Cl[CH:18]([CH:24]=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]3[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][N:16]=[C:12]3[CH:11]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nc1cc(OCCN2CCOCC2)ccn1
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(OCCN3CCOCC3)ccn12

Procedure:
4-(2-Morpholinoethoxy)pyridin-2-amine (1.37 g, 6.14 mmol) was dissolved in ethanol (20 ml) and treated with ethyl 2-chloro-3-oxopropanoate (5% solution in benzene, 30 mL). The mixture was refluxed overnight. The reaction mixture was cooled and concentrated to afford a beige solid (1.31 g), which was purified by chromatography on silica, eluting with a gradient from 50% EtOAc/Hexanes to 100% EtOAc, followed by 10% MeOH/DCM to provide 1.0 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[C:22]([CH3:29])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=1>[Pd].CCO.C(Cl)Cl>[NH2:26][C:24]1[CH:23]=[C:22]([CH3:29])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH:6]=2)=[C:2]([CH3:1])[CH:25]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 6 h

Procedure:
A mixture of the title C compound, 4-(2,6-dimethyl-4-nitrophenoxy)-2-(4-fluoro-benzenesulfonyl)phenol (0.69 g, 1.65 mmol) and palladium on activated carbon (10 wt. %; 69 mg) in 10 mL of EtOH and 10 mL of CH2Cl2 is stirred under hydrogen atmosphere (H2, 1 atm) for 6 h. The catalyst is removed by vacuum filtration through celite, washed with a 1/1-mixture of EtOH and CH2Cl2, and the combined filtrate and washings are concentrated and dried under vacuum to give 4-(4-amino-2,6-dimethylphenoxy)-2-(4-fluorobenzenesulfonyl)phenol: NMR (DMSO-d6) 1.93 (s, 6H), 4.92 (s, 2H), 6.34 (s, 2H), 6.85 (d, 1H, J=9), 7.00 (dd,1H, J=9,3), 7.12 (d, 1H, J=3), 7.43 (app t, 2H, J=9), 7.94 (dd, 2H, J=9, 5), 9.41 (s, 1H), 10.4 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:13](=[O:23])[NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH:16]1[OH:22])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>ClCCCl>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:13](=[O:23])[NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH2:17][CH:16]1[OH:22])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCNCC1O
Solvent: ClCCCl
Product: COc1ccc(S(=O)(=O)N2CCCC(NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(O)C2)cc1
Reaction time: 0.08 h

Procedure:
[(S)-1-(3-Hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid-tert-butyl ester (compound 2g, 0.8 g, 2.33 mmol) was dissolved in 1,2-dichloroethane (DCE, 20 ml). Then, morpholinemethyl polystyrene resin beads (1.26 g, 3.7 mmol/g, Nova) were added and the solution was shaken for 5 minutes. Then, p-methoxybenzenesulfonyl chloride (0.48 g, 2.33 mmol) was dissolved in DCE (10 ml), and this solution was added to the reaction mixture. The reaction was shaken overnight, filtered, washed with DCE (2×10 ml), then CH2Cl2 (10 ml). The combined organics were concentrated in vacuo, and used in the next reaction without further purification: M+H+=514.2.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH2:13][CH2:12][CH2:11][N:10]3[N:14]=[CH:15][C:16]([CH2:17][NH2:18])=[C:9]23)C=CC=CC=1.[CH:31](OCC)=[O:32]>>[N:14]1[N:10]2[CH2:11][CH2:12][CH2:13][NH:8][C:9]2=[C:16]([CH2:17][NH:18][CH:31]=[O:32])[CH:15]=1
Reactant: CCOC=O
Reactant: NCc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CCC2
Product: O=CNCc1cnn2c1NCCC2
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A suspension of 1-(4-triphenylmethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methylamine (8.4 g) in ethyl formate (30 ml) was stirred at 50° C. for 16 hours. After evaporation of the solvent in vacuo, the residue was triturated with ethyl acetate and dried in vacuo to give N-[(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methyl]formamide (3.0 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([O:24][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[C:6]([F:8])[CH:7]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1nccn1-c1ccc(N)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(NC(=O)OCc2ccccc2)cc1F
Reaction time: 16 h
Yield: 93.5 %

Procedure:
5-Amino-2-(2-methylimidazol-1-yl)fluorobenzene (34.25 g, 0.179 M) was dissolved in dry dichloromethane (600 ml) under nitrogen, and cooled to −5°. Pyridine (17.7 g, 0.224 M) was added, followed by benzyl chloroformate (33.7 g, 0.197 M) over 20 minutes. The mixture was stirred and the temperature allowed to rise to ambient over 16 hours. Aqueous sodium bicarbonate (5%, 250 ml) was added, the organic layer separated, the aqueous layer re-extracted with dichloromethane (2×300 ml), and combined extracts dried (magnesium sulfate). After filtration and evaporation, the residue was recrystallised from toluene (400 ml) to give title product (54.5 g). NMR (DMSO-d6) δ: 2.13 (s, 3H); 5.18 (s, 2H); 6.89 (s, 1H); 7.17 (s, 1H); 7.41 (overlapping m, 7H); 7.73 (dd, 1H); 10.21 (br, 1H). MS (ESP): 326 (MH+) for C18H16FN3O2
Reaction SMILES: [Si:1]([O:18][C:19]1[C:24]2[CH2:25][CH2:26][CH2:27][CH:28]([CH2:30][OH:31])[CH2:29][C:23]=2[CH:22]=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([N:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>N1C=CC=CC=1>[C:32]1([N:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39](=[O:40])[O:31][CH2:30][CH:28]2[CH2:27][CH2:26][CH2:25][C:24]3[C:19]([O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:29]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC(CO)C2)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](Oc1cccc2c1CCCC(COC(=O)N(c1ccccc1)c1ccccc1)C2)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 90.4 %

Procedure:
A mixture of [1-(tert-butyldiphenylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]methanol (200 mg) and diphenylcarbamoyl chloride (324 mg) in pyridine (5 ml) was stirred at 100° C. for 48 hours. After cooling, the reaction mixture was poured into 6N-hydrochloric acid (13 ml) under ice-cooling and extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogencarbonate solution, water, and then brine. It was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 15:1 to 10:1) to give [1-(tert-butyldiphenylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]methyl N,N-diphenylcarbamate (262.7 mg) as an amorphous solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[S:12]([NH2:22])(=[O:21])([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[O:13]>>[S:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])=[CH:16][CH:15]=1)(=[O:13])(=[O:21])[NH2:22]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(CCl)Nc1ccccc1
Product: NS(=O)(=O)c1ccc(NCC(=O)Nc2ccccc2)cc1

Procedure:
α-Chloracetanilide (17.0 g) and sulfanilamide (34.5 g) were heated together in an autoclave for 8 hours at 120°C. The mixture was triturated with 2N HCl and filtered to yield 27.5 g, m.p. 257°-258°C (acetone).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][S:8]([CH2:11][CH2:12][OH:13])(=[O:10])=[O:9])([O-])=O.C(=O)(O)[O-].[Na+]>Cl.C1COCC1.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][S:8]([CH2:11][CH2:12][OH:13])(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)CCO)c1
Agent: [Ti+3]
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Nc1cccc(CS(=O)(=O)CCO)c1
Reaction time: 18 h

Procedure:
Titanium(III)chloride solution (about 15%) in about 10% hydrochloric acid (MERCK (MDA) INCL SCHUCHARDT, 114 ml) was added to a stirred solution of 2-[(3-nitrobenzyl)sulfonyl]ethanol (9.0 g; 36.7 mmol) in THF (384 ml) at room temperature and the batch was stirred for 18 hours. By adding aqueous sodium bicarbonate solution the pH value of the reaction mixture was raised to 7-8 before the batch was extracted with ethyl acetate (2×). The combined organic phases were washed with brine, dried (Sodium sulfate), filtered and concentrated. The residue was purified by column chromatography (DCM/ethanol 95:5) to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[OH-].[NH4+:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH2:18])=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reaction time: 18 h
Yield: 57.4 %

Procedure:
A solution of 5.6 g (0.02 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated while stirring with 3 ml (0.04 mole) of 57% ammonium hydroxide. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 6.6 g. Recrystallization from ethanol-water yielded 3.0 g of white granular crystals, m.p. 179°-184° C. A second recrystallization from isopropanol yielded 2.7 g (51.7%) of fine white crystals, m.p. 185°-187° C.
Reaction SMILES: C(O[C:4]1[C:5]([NH:11][C@@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:26])([F:25])[F:24])[CH:20]=3)[O:15][C:14]([CH3:28])([CH3:27])[C@H:13]2[OH:29])=[N:6][S:7](=[O:10])(=[O:9])[N:8]=1)C.[CH3:30][NH:31][CH3:32]>>[CH3:28][C:14]1([CH3:27])[C@@H:13]([OH:29])[C@H:12]([NH:11][C:5]2[C:4]([N:31]([CH3:32])[CH3:30])=[N:8][S:7](=[O:10])(=[O:9])[N:6]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:24])([F:25])[F:26])[CH:20]=2)[O:15]1
Reactant: CCOC1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O
Reactant: CNC
Product: CN(C)C1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O

Procedure:
In a method similar to Example 3, the product of Example 1, Step 2 (0.250 g, 0.572) was converted to the title compound with dimethylamine gas to give, after recrystallization from diethyl ether/hexane, 0.19 g (76%) of product as a white solid: mp 135°-140° C.; 1H NMR (DMSO-D6): δ 8.09 (br s, 1H), 7.23 (br s, 1H), 7.10 (d, 1H), 6.82 (d, 1H), 5.84 (br s, 1H), 4.77 (m, 1H), 3.75 (m, 1H), 3.35 (s, 3H), 2.53 (s, 3H), 1.38 (s, 3H), 1.19 (s, 3H); IR (KBr): 3400, 1600 cm-1 ; MS (m/z) 437 (MH+, 100%), 419 (65), 245 (35) 177 (70); [α]D25 = -85.4 (THF).