Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[CH:34][N:35]=2)[N:32]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([N:33]=[CH:34][N:35]=4)[N:32]=3)[CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1ccc2ncnn2n1
Reactant: NCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc(C(OC2CCN(CCCCNc3ccc4ncnn4n3)CC2)c2ccccc2)cc1
Yield: 9.1 %

Procedure:
4-(Diphenylmethoxy)-1-piperidinebutanamine (1.83 g) and 6-chloro[1,2,4]triazolo[1,5-b]pyridazine (557 mg) were dissolved in n-butanol (30 ml), followed by addition of N-ethyldiisopropylamine (931 mg). The mixture was refluxed under heating for 14 hours. After being cooled, the mixture was concentrated under reduced pressure, followed by addition of ice-water and extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to a silica-gel column chromatography and eluted with a mixture of ethyl acetate, methanol and triethylamine (45:5:1). Fractions containing the objective compound were collected and concentrated. The resulting crystals were collected, washed with ethylether and dried to yield the title compound (149 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]([O-])([O-])[O:16]C.[Cl-].[Ce+3].[Cl-].[Cl-].[CH2:24](O)C>>[CH3:24][O:11][CH:10]([O:16][CH3:15])[C@@H:9]1[CH2:12][CH2:13][CH2:14][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: COC([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: CCO
Agent: [Ce+3]
Agent: [Cl-]
Product: COC(OC)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
tert-Butoxycarbonyl-L-prolinal is acetalized with methyl orthoformate in a 0.4 M solution of cerium chloride in ethanol to give tert-butoxycarbonyl-L-prolinal dimethyl acetal as a colorless syrup.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[C:21](=O)[C:22]([N:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])=O)(C)(C)C.[F-].[Cs+].C[Si]([N:40]=[C:41]=[N:42][Si](C)(C)C)(C)C.Cl>C(#N)C.ClCCl>[NH2:40][C:41]1[N:42]=[C:21]([C:22]([N:24]2[CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:32]2)=[O:23])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=2)[N:8]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Cc1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4.9 g of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxo-acetyl)phenyl]acetate are dissolved in 100 ml of acetonitrile under argon. 1.7 g of caesium fluoride are added, and 3 ml of bis(trimethylsilyl)carbodiimide are added dropwise to the solution over the course of 5 min. The mixture is stirred at room temperature for 15 min, and 20 ml of dichloromethane are then added. After addition of 20 ml of hydrochloric acid (1N), the product precipitates out as white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:6]([C:12]([OH:14])=[O:13])=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=O)[CH3:2].Cl.[NH2:25][OH:26].N1[CH:32]=[CH:31]C=CC=1>C(O)C>[CH2:31]([O:14][C:12]([C:6]1[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[CH:4]2[C:1]([CH3:2])=[N:25][O:26][C:9]2([CH3:10])[NH:8][C:7]=1[CH3:11])=[O:13])[CH3:32]
Reactant: NO
Reactant: c1ccncc1
Reactant: CC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC2(C)ON=C(C)C2C1c1ccccc1[N+](=O)[O-]

Procedure:
A mixture of 5-acetyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-pyridinecarboxylic acid (J. A. Berson and E. Brown, J. Amer. Chem. Soc., 77, 444 (1955), 2.34 g), hydroxylamine hydrochloride (0.71 g), pyridine (0.81 g), and ethanol (50 mL)) was heated under reflux on a steam bath for 4 hours, then evaporated on a rotary evaporator. The residue was dissolved in hot methanol, and the solution was filtered. The filtrate was concentrated on a rotary evaporator, and chilled in an ice-bath to cause a separation of a precipitate. The precipitate was collected on a filter, and recrystallized once more from methanol to give the titled product (0.1 g), mp 211.5°-212.5° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[N:22][C:23]#[N:24])SC)[N:8]=1.[CH3:28][NH2:29]>C(O)C>[F:1][C:2]([F:27])([F:26])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:29][CH3:28])=[N:22][C:23]#[N:24])[N:8]=1
Reactant: CSC(=NC#N)NCCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CN
Solvent: CCO
Product: CNC(=NC#N)NCCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h

Procedure:
A solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-cyano-2-methylisothioureido)butylthio]pyrimidine (0.17 g.) in 33% w/v methylamine in ethanol was left at room temperature for 18 hours and then evaporated to dryness. The residue was triturated with ether and the insoluble solid collected and recrystallised from ethyl acetate to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(2-cyano-3-methylguanidino)butylthio]pyrimidine, m.p. 179°-180°.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:20]=[CH:19][C:15]2=[N:16][O:17][N:18]=[C:14]2[CH:13]=1)C.[OH-].[Li+]>O1CCCC1>[N:16]1[O:17][N:18]=[C:14]2[CH:13]=[C:12]([O:11][C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([OH:21])=[O:3])[CH:20]=[CH:19][C:15]=12
Reactant: CCOC(=O)c1cccnc1Oc1ccc2nonc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1Oc1ccc2nonc2c1
Yield: 95.8 %

Procedure:
A solution of 2-(benzo[2,1,3]oxadiazol-5-yloxy)-nicotinic acid ethyl ester (2.2 g) in tetrahydrofuran (75 mL) was treated with 1M aqueous lithium hydroxide (23.1 mL) at ambient temperature for 16 h. The solution was concentrated in vacuo to remove the tetrahydrofuran, and then acidified with 1N hydrochloric acid. The resulting precipitate was filtered and dried to give the title compound (1.90 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>S(Cl)(Cl)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:26]2[CH2:31][CH2:30][S:29][CH2:28][CH2:27]2)=[O:9])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)([O-:3])=[O:2]
Reactant: C1CSCCN1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Nitro-5-(trifluoromethyl)benzoic acid (2.96 g, 12.6 mmol) was allowed to reflux in thionyl chloride (6 mL) for 6 h. The resulting solution was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting solid was taken up in CH2Cl2 (20 mL) and iPr2NEt (2.6 mL, 15.1 mmol) and thiomorpholine (1.4 mL, 13.8 mmol) was added. The reaction was stirred at RT for 1 h and then diluted with CH2Cl2 (50 mL). The organic layer was washed with aq. HCl (1 M, 25 mL), 9% aq. Na2CO3 (25 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (3-nitro-5-(trifluoromethyl)phenyl)(thiomorpholino)-methanone.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=O)[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[O:25][C:24]([CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[O:25][C:24]([CH2:26][CH2:27][NH:28][C:10]([C:7]3[NH:8][N:9]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=3)=[O:12])=[CH:23][CH:22]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CC(C)(C)c1cc(C(=O)O)[nH]n1
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Product: CC(C)(C)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Yield: 33 %

Procedure:
The title compound was synthesized as in Example 17 starting from 5-tert-butyl-2H-pyrazole-3-carboxylic acid and 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine. Crude product was purified by chromatography (silica column, eluent: 3% MeOH/DCM) to give 53 mg (33%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.27 (s, 9H), 2.97 (t, 2H), 3.54 (q, 2H), 6.33 (m, 1H), 6.39 (br s, 1H), 7.02 (d, 1H), 7.62 (m, 2H), 7.86 (d, 1H), 8.20 (s, 1H), 12.88 (s, 1H).
Reaction SMILES: [C:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])(CC)C.CN(C)[CH:27]=[O:28]>O1CCCC1.C(OCC)(=O)C>[F:19][C:14]1[C:13]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:27]=[O:28]
Reactant: CCCCCCCCCCC#Cc1ccccc1F
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 7.00 g (27.0 mmol) of 2-(1-dodecynyl)fluorobenzene in tetrahydrofuran (60 ml) at -78° C. was added slowly sec-butyllithium (1.3M, cyclohexane) (21 ml). The mixture was stirred at -78° C. for 30 min, and dimethylformamide (2.8 ml) was added dropwise. The mixture was stirred for 5 min at -78° C. and allowed to warm to room temperature. The mixture was diluted with ethyl acetate and washed with water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated in vacuo. The residue was flash chromatographed on silica gel (eluted with ethyl acetate/heptane/1:10). The appropriate fractions were collected and evaporated. The residue was chromatographed a second time over silica gel (eluted with dichloromethane) to afford 7.10 g (91%) of product.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[N+](CC)([O-])=[O:28].[CH2:32]1[CH2:42]CN2C(=NCCC2)CC1>CCOC(C)=O>[C:1]([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:42](=[O:28])[CH3:32])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC[N+](=O)[O-]
Reactant: CCOC(=O)C(Cc1ccc(F)c([N+](=O)[O-])c1)(NC(C)=O)C(=O)OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(C(C)=O)c([N+](=O)[O-])c1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To diethyl 2-acetamido-2-(4-fluoro-3-nitrobenzyl)malonate (7.41 g) and nitroethane (6.0 mL) in EtOAc was added DBU (9.0 mL) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the residue was dissolved in methanol (35 mL). Aqueous H2O2 (30%, 10.2 mL) and 10% aqueous NaHCO3 (10.2 mL) were added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with 1 N HCl, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (10-20% EtOAc in DCM), affording diethyl 2-acetamido-2-(4-acetyl-3-nitrobenzyl)malonate. 1H NMR (400 MHz, MeOD): δ 7.73 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 4.25 (q, J=7.2 Hz, 4H), 3.72 (s, 2H), 2.53 (s, 3H), 2.03 (s, 3H), 1.28 (t, J=7.2 Hz, 6H); 13C NMR: δ 172.99, 168.22, 153.68, 147.48, 140.96, 137.31, 136.82, 128.99, 126.79, 68.62, 63.95, 54.01, 38.58, 22.32, 14.36; ESI-MS (m/z) 395.38(MH+).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[C:34]=1[N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>O.ClCCl>[F:32][C:33]1[C:34]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[C:35]([CH2:39][N:40]2[CH2:45][CH2:44][N:43]([C:12]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])=[O:14])[CH2:42][CH2:41]2)[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Fc1cccc(CN2CCNCC2)c1N1CCOCC1
Reactant: OC(C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2cccc(F)c2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.4 %

Procedure:
A 50 mL round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan-2-ol (120 mg, 0.710 mmol, 1.00 equiv), triphosgene (70.0 mg, 0.240 mmol, 0.33 equiv), dichloromethane (10 mL). N,N-Diisopropylethylamine (338 mg, 2.62 mmol, 3.65 equiv) was added dropwise. The mixture was stirred at room temperature for 2 hours. 4-[2-Fluoro-6-(piperazin-1-ylmethyl)phenyl]morpholine (200 mg, 0.720 mmol, 1.00 equiv) was added. The resulting solution was stirred for 2 hours at room temperature and diluted with H2O (10 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4). The crude product (217 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 125.4 mg (36% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[3-fluoro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. 1H NMR-300 MHz (CDCl3) δ 7.07-7.18 (m, 2H), 6.94-7.01 (m, 1H), 5.71-5.83 (m, 1H), 3.88 (br, 4H), 3.80 (br, 2H), 3.52-3.54 (m, 4H), 3.10 (br, 4H), 2.49-2.52 (m, 4H). LCMS (ESI, m/z): 474 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][C:16]([N:23]([CH2:28][CH2:29]C=C)[S:24]([CH3:27])(=[O:26])=[O:25])=[C:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=2)[O:13][C:12]=1[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)=[O:10]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][CH2:29][CH2:28][N:23]([C:16]1[N:15]=[C:14]2[O:13][C:12]([C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=3)=[C:11]([C:9](=[O:10])[NH:8][CH3:7])[C:19]2=[CH:18][C:17]=1[CH:20]1[CH2:22][CH2:21]1)[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: C=CCCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Reactant: C=CC(=O)OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC=CC(=O)OC)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of Grubbs II catalyst (4.7 mg, 0.005 mmol, 0.05 equiv) in DCM (1.0 mL) was added methyl acrylate (95 mg, 1.1 mmol, 10 equiv) followed by a solution of 6-(But-3-enyl-methanesulfonyl-amino)-5-cyclopropyl-2-p-tolyl-furo[2,3-b]pyridine-3-carboxylic acid methylamide (50 mg, 0.11 mmol, 1.0 equiv) in DCM (1.0 mL). The solution was stirred at room temperature for 2 hours, after which the solvent was removed under vacuum. The residue was purified by silica gel column chromatography, EtOAc/heptane 70% to give product 35 mg. MS (ESI) m/z 512.6 (M+1). Retention time=1.50 min, Method LC-C8 broad range-NpH.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([OH:21])[C:18]([CH3:22])=[CH:17][C:16]=2C2(C3C=CC=CC=3)C3C(=CC=CC=3)NC2=O)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(S(Cl)(=O)=O)=CC=1)(C)(C)C.NC1C=CC(C)=C(O)C=1>ClCCl.N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:22])=[C:19]([OH:21])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C2(c3ccccc3)C(=O)Nc3ccccc32)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1O
Agent: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(N)cc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1O
Reaction time: 8 h
Yield: 78 %

Procedure:
As another non-limiting example, 4-tert-butyl-N-[5-hydroxy-4-methyl-2-(2-oxo-3-phenyl-2,3-dihydro-1H-indol-3-yl)-phenyl]-benzenesulfonamide (compound 1430) was synthesized by adding dropwise 4-tert-butyl-benzenesulfonyl chloride (8 g, 34 mmol) in 5 mL dichloromethane to a stirring solution of 5-Amino-2-methyl-phenol (4 g, 32 mmol) in 20 mL pyridine and letting the mixture spin overnight at room temperature. The resulting mixture was concentrated in vacuo and the product was purified by column chromatography to yield 8 g (78%) of 4-tert-butyl-N-(3-hydroxy-4-methyl-phenyl)-benzenesulfonamide. A mixture of 3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one (3.9 g, 17 mmol), 4-tert-butyl-N-(3-hydroxy-4-methyl-phenyl)-benzenesulfonamide (7 g, 22 mmol) and p-toluenesulfonic acid (6.5 g, 32 mmol) in dichloroethane was refluxed for 12 hours. The resulting mixture was cooled to room temperature to yield a colorless solid. The solid was filtered and purified using column chromatography to yield 8 g (88%) of the desired product (compound 1430).
Reaction SMILES: [NH2:1][C:2]1[C:17](Br)=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[Cl:19].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:17](/[CH:22]=[CH:21]/[C:20]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[Cl:19]
Reactant: CCOC(=O)N1CCc2cc(Br)c(N)c(Cl)c2CC1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cc2c(c(Cl)c1N)CCN(C(=O)OCC)CC2
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 4.37 g of ethyl 7-amino-8-bromo-6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 40 ml of DMF were added 2.1 ml of ethyl acrylate, 230 mg of tris-o-tolylphosphine, 85 mg of palladium(II) acetate, and 3.6 ml of triethylamine, followed by stirring at 120° C. for 3 hours. The reaction mixture was diluted with EtOAc, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow solid was stirred and washed in diisopropylether to obtain 3.125 g of ethyl 7-amino-6-chloro-8-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[C:22]([Cl:23])=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=3[Cl:24])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:27][C:28]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:29]=1[C:30]([N:32]=[C:33]=[O:34])=[O:31]>C1(C)C=CC=CC=1>[F:27][C:28]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:29]=1[C:30]([NH:32][C:33]([NH:20][C:19]1[CH:21]=[C:22]([Cl:23])[C:16]([O:15][C:14]2[CH:25]=[CH:26][C:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])=[CH:12][CH:13]=2)=[C:17]([Cl:24])[CH:18]=1)=[O:34])=[O:31]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(Oc2ccc(S(=O)(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(Oc2ccc(S(=O)(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a 250 mL flask equipped with stirrer, condenser, under nitrogen atmosphere was added 10 g (0.023 mol) of 4-(4-[4-chlorophenylsulfonyl]phenoxy)-3,5-dichloroaniline and 130 mL of toluene. The mixture was heated up to 80° to obtain a clear solution. A solution of 6.82 g of 2,6-difluorobenzoylisocyanate and 4 mL of toluene was added. The resulting mixture was stirred at 80° for 1.5 hours. The reaction mixture was cooled and filtered to give 14.2 g (0.023 mol) of a white solid; mp 207.2°-209.2° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].CN1CCOCC1.[O:13]=[P:14](Cl)(Cl)Cl.Cl.[Cl:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][Cl:25]>>[CH2:3]1[CH2:4][O:5][P:14]([N:22]([CH2:23][CH2:24][Cl:25])[CH2:21][CH2:20][Cl:19])(=[O:13])[NH:1][CH2:2]1
Reactant: NCCCO
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CN1CCOCC1
Product: O=P1(N(CCCl)CCCl)NCCCO1
Temperature: 25 °C

Procedure:
3-aminopropanol (2.1 g, 0.028 mol) and N-methylmorpholine (12.9 eq) are placed into a three-necked flask and stirred at room temperature. After cooling the mixture in the flask, POCl3 (4.3 g, 0.028 mol) is slowly dropped into the mixture. After adding POCl3, the mixture in the flask is stirred at room temperature for 15 hours. After that, bis(2-chloroethyl)amine hydrochloride] (5 g, 0.028 mol) is added into the mixture in the flask. The mixture in the flask is heated to about 40° C. and stirred for 6 hours. (The conversion yield determined with HPLC is about 10.0%.)
Reaction SMILES: [H-].[Na+].P([CH2:11][C:12]#[N:13])(OCC)(OCC)=O.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]2[O:20][CH2:21][C:22](=O)[C:18]=2[CH:17]=1>C1COCC1>[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]2[O:20][CH:21]=[C:22]([CH2:11][C:12]#[N:13])[C:18]=2[CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc2c(c1)C(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2occ(CC#N)c2c1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
Under inert atmosphere, 83 mmol of sodium hydride are suspended in 100 ml of anhydrous THF. The temperature is cooled at -15° C. and 83 mmol (14.7 g) of (EtO)2POCH2CN in 50 ml of THF are dropply added. Then 55 mmol (9 g) of compound obtained in stage A in 100 ml of THF are dropwised at -15° C. The solution is stirred during 2 hours at that temperature before being hydrolysed. The mixture is extracted with ethyl acetate and the organic layers are washed with brine, dried over magnesium sulfate and concentrated. The title product is obtained after purification by chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:18]=[N+:19]=[N-:20].[Na+].Cl>C1(C)C=CC=CC=1>[NH:18]1[C:6]([C:5]2[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=2)=[N:7][N:20]=[N:19]1
Reactant: N#Cc1ccc(N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2nnn[nH]2)cc1
Yield: 44.1 %

Procedure:
A mixture of p-amino benzonitrile (2 g, 16.9 mmol), triethylamine hydrochloride (3.49 g, 25.38 mmol) and sodium azide (1.65 g, 25.38 mmol) were taken in anhydrous toluene (20 ml) and heated to reflux for 24 hr. The reaction mixture was cooled to room temperature and neutralized with dilute hydrochloric acid. The resultant precipitate was filtered, washed with water then dried to give 4-(1H-tetrazol-5-yl)-phenylamine (1.2 g, 44%).