Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](O)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:29]1[C@H:38]2[C@@H:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:29]3[C@H:38]4[C@@H:33]([CH2:34][CH2:35][CH2:36][CH2:37]4)[CH2:32][CH2:31][CH2:30]3)=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CC[C@H]2NCCC[C@@H]2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cs2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@H]43)cs2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid t-butyl ester (0.1 g, 0.32 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.96 mmol), trans-decahydroquinoline (1:1 mixture of the trans-isomers; 0.35 mmol) and HATU (0.35 mmol) were added and the reaction stirred at room temperature for 5 hours. The solvent was evaporated and the residue was purified by HPLC, eluting with 10%-90% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.09 g). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.9 (s, 1H), 4.2 (m, 2H), 3.7 (m, 1H), 3.5-3.3 (m, 2H), 3.0-2.7 (m, 3H), 2.25 (m, 1H), 2.0 (m, 2H), 1.8-1.5 (m, 8H) 1.5 (s, 9H), 1.4-1.0 (m, 6H).
Reaction SMILES: ClCCC1OC=[N:6]C=1C.[N+:10]([CH:13]=[C:14]([NH:27][CH3:28])[NH:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][C:21]1[O:25][CH:24]=[N:23][C:22]=1C)([O-:12])=[O:11].NC1OC(CCCl)=CN=1>>[N+:10]([CH:13]=[C:14]([NH:27][CH3:28])[NH:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][C:21]1[O:25][C:24]([NH2:6])=[N:23][CH:22]=1)([O-:12])=[O:11]
Reactant: Cc1ncoc1CCCl
Reactant: CNC(=C[N+](=O)[O-])NCCSCCc1ocnc1C
Agent: Nc1ncc(CCCl)o1
Product: CNC(=C[N+](=O)[O-])NCCSCCc1cnc(N)o1

Procedure:
Using 5-(2-chloroethyl)-4-methyloxazole as starting material in the procedure of Example 21 the product is 1-nitro-2-methylamino-2-[2-(2-(4-methyl-5-oxazolyl)ethyl)thioethylamino]ethylene. Also, using 2-amino-5-(2-chloroethyl)oxazole (prepared by reacting 2-amino-5-(2-hydroxyethyl)oxazole with thionyl chloride) in the procedure of Example 21 gives 1-nitro-2-methylamino-2-[2-(2-(2-amino-5-oxazolyl)ethyl)thioethylamino]ethylene
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=1)OC1C=CC=CC=1)#[N:2].[NH:27]([C:29]1[C:30]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][C:31]=2[N:32]=[CH:33][N:34]=1)[NH2:28]>C(O)(C)C>[N:32]1[C:31]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:30]=2[C:29]([N:27]2[C:1]([NH2:2])=[N:3][C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:17][CH:18]=3)=[N:28]2)=[N:34][CH:33]=1
Reactant: NNc1ncnc2c1CCCCCC2
Reactant: N#CNC(=Nc1ccc(OCCN2CCCC2)cc1)Oc1ccccc1
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc(OCCN3CCCC3)cc2)nn1-c1ncnc2c1CCCCCC2
Temperature: 150 °C
Yield: 78 %

Procedure:
A mixture of N-Cyano-N′-{[4-(pyrrolidin-1-yl-ethoxy)]phenyl}-O-phenylisourea (50 mg; 0.14 mmol; 1.0 equiv) and 4-hydrazino-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine (28 mg; 0.14 mmol; 1 equiv) in 1 mL of isopropanol was heated in the microwave apparatus at 150° C. for 15 min. Purification by silica gel column chromatography eluted with CH2Cl2/MeOH/Et3N (95/5/1) gave 1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-N3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #20, as a pale-yellow solid (50 mg; 78% yield); 1H-NMR (DMSO-d6, 300 MHz) 8.85 (br. s, 1H), 8.71 (s, 1H), 7.53 (br. s, 2H), 7.43 (d, J=9.0 Hz, 2H), 6.83 (d, J=8.7 Hs, 2H), 4.05-3.98 (m, 2H), 3.40-3.22 (m, 4H), 3.00-2.95 (m, 2H), 2.72-2.58 (m, 4H), 1.92-1.83 (m, 2H), 1.78-1.68 (m, 6H), 1.48-1.32 (m, 4H) ppm; MS (ES) 449.54 (M+H), 447.25 (M−H).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH:6]([N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:7]>>[CH:6]([N:8]1[C:9]2[CH:10]=[C:11]([S:2]([OH:5])(=[O:4])=[O:3])[CH:12]=[CH:13][C:14]=2[S:15][C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:7]
Reactant: O=CN1c2ccccc2Sc2ccccc21
Reactant: O=S(=O)(O)Cl
Product: O=CN1c2ccccc2Sc2ccc(S(=O)(=O)O)cc21
Temperature: 20 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
Into a reactor, equipped with mechanical stirrer and thermometer, chlorosulfonic acid (17.49 g) and, slowly under stirring, N-formyl-phenothiazine (7.5 g) were charged, under nitrogen at 20° C. The reaction mixture was left under stirring at 20° C. for 3 hours. The HPLC analysis showed the formation of N-formyl-phenothiazine-2-sulfonic acid (75% yield).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[CH2:7]1[CH2:11]O[CH2:9][CH2:8]1>[Pd]>[O:1]1[C:5]2[CH:11]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:6]
Reactant: C1CCOC1
Reactant: O=C1NCCO1
Agent: [Pd]
Product: O=c1[nH]c2ccccc2o1
Reaction time: 3 h
Yield: 65 %

Procedure:
A mixture of oxazolidinone of formula 32 (1.00 g, 2.25 mmol) and 10% Pd/C (150 mg) in THF (50 mL) was shaken under an atmosphere of H2 at 50 psi for 3 hours. The reaction vessel was flushed with N2, then Et3N (1.25 mL) and COCl2 (1.20 mL of a 20% solution in toluene, 2.25 mmol) were added and the reaction stirred for 2 hours. The reaction was quenched with saturated NaHCO3, filtered, and the THF removed under reduced pressure. The aqueous solution was extracted with EtOAc. The organic layer was dried (Na2SO4) and the solvent removed under reduced pressure. Purification by chromatography (silica gel 1:2 to 4:5 EtOAc: hexanes) gave a benzoxazolidinone intermediate (510 mg, 65%): 1H NMR (500 MHz, CD3OD+CDCl3) δ 7.59 (br s, 1H), 7.22 (d, J=8 Hz, 1H), 7.06 (d, J=8 Hz, 1H), 4.76-4.70 (m, 2H), 4.16-4.07 (m, 1H), 3.88-3.84 (m, 1H), 3.44 (br s, 2H), 1.41 (s, 9H); CI-MS (m/z): 350 [M+H]+.
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]#[N:15])=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31]>C(O)C>[CH3:29][O:28][C:25]1[CH:24]=[C:23]([O:30][CH3:31])[C:22]([O:21][CH3:20])=[CH:27][C:26]=1/[N:15]=[N:14]/[C:11]1[CH:12]=[CH:13][C:8]([S:7]([F:16])([F:17])([F:18])([F:19])[F:6])=[CH:9][CH:10]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: COc1ccc(OC)c(OC)c1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: COc1cc(OC)c(OC)cc1/N=N/c1ccc(S(F)(F)(F)(F)F)cc1
Reaction time: 0.1 h
Yield: 72.5 %

Procedure:
Diazonium salt 1 (14.1 mg, 0.0443 mmol) and 1,2,4-trimethoxybenzene (15.6 mg, 0.0928 mmol) were dissolved in 0.148 g of 95% aqueous ethanol. After 0.1 h, a red solid precipitated. After filtration the red solid was purified by SiO2 column chromatography (7:3 hexane/ethyl acetate) to give 27c as a red oil (12.8 mg, 72%): IR (ATR): {tilde over (v)}=2941, 1607, 1598, 1505, 1472, 1436, 1269, 1209, 1126, 1093, 1030, 839, 824 cm−1. MS (GC, EI): m/z=398 [M+], 140, 110. 1H NMR (500 MHz, CDCl3): δ=7.91 (d, J=9.0 Hz, 2H), 7.86 (d, J=9.0 Hz, 2H), 7.44 (s, 1H), 6.64 (s, 1H), 4.07 (s, 3H), 4.01 (s, 3H), 3.93 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ=154.74 (C), 154.70 (C), 154.3 (C), 154.0 (C), 144.1 (C), 135.1 (C), 126.9 (2CH), 122.4 (2CH), 98.8 (CH), 97.5 (CH), 57.6 (CH3), 56.22 (CH3), 56.17 (CH3) ppm. 19F NMR (470 MHz, CDCl3): δ=84.4 (quint, J=150 Hz, 1 F), 63.3 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>O1CCCC1>[CH:13]1([CH2:12][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[O:35])=[CH:7][CH:6]=2)[C:9]([OH:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)O)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.4 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid (130 mg, 0.56 mmol) in tetrahydrofuran (10 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.23 mL, 1.34 mmol) and nicotinoyl chloride hydrochloride (99 mg, 0.54 mmol). The reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 90/10 ethyl acetate/heptane) afforded 3-cyclopentyl-2-{4-[(pyridine-3-carbonyl)-amino]-phenyl}-propionic acid (40.9 mg, 21.7%) as a yellow solid: mp 160-163° C.; EI-HRMS m/e calcd for C21H23NO3 (M+) 337.1677, found 337.1670.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](Cl)=[O:18])[CH3:13]>CN(C)C(=O)C.C(OCC)C>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[O:9])(=[O:10])[NH2:11])=[O:18])[CH3:13]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCOC(=O)CC(=O)Nc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-benzenesulfonamide (5 g, 29 mmol) was dissolved in N,N-dimethylacetamide (25 mL) and diethyl ether (25 mL). Ethyl-3-chloro-3-oxo-propionate (4.6 g, 30.45 mmol) was added into the above reaction solution. The reaction mixture was stirred at 25° C. for 3 h. The product started to precipitate and was collected by vacuum filtration. The solid was dissolved in ethyl acetate (200 mL) and extracted with water (200 mL). The aqueous layer was back-extracted with ethyl acetate (200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, N-(2-sulfamoyl-phenyl)-malonamic acid ethyl ester, as a white solid, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ: 1.23 (3H, t, J=7.0 Hz), 3.61 (2H, s), 4.14 (2H, quartet, J=7.0 Hz), 7.29-7.33 (1H, m), 7.53 (2H, bs), 7.56-7.60 (1H, m), 7.84-7.86 (1H, m), 7.97-7.99 (1H, m), 9.54 (1H, bs). LC-MS (ESI) calcd for C11H14N2O5S 286.06, found 287.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([CH2:28][CH2:29][C:30](O)=[O:31])[CH:3]=1.[NH2:33][C:34]1[C:39]([NH2:40])=[CH:38][C:37]([I:41])=[CH:36][N:35]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[NH2:33][C:34]1[C:39]([NH:40][C:30](=[O:31])[CH2:29][CH2:28][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:5]=2)=[CH:38][C:37]([I:41])=[CH:36][N:35]=1
Reactant: Nc1cc(I)cnc1N
Reactant: Cc1cc(CCC(=O)O)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: Cc1cc(CCC(=O)Nc2cc(I)cnc2N)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 50 °C
Yield: 54.9 %

Procedure:
1.30 g of 3-[4-methyl-6-(trityl-amino)-pyridin-2-yl]-propionic acid acid and 724 mg of 2,3-diamino-5-iodo-pyridine are dissolved in 37 ml of pyridine and sequentially treated with 1.06 g of O-[(ethoxycarbonyl)canomethylene-amino]—N,N,N′,N′-tetramethyl-uronium tetrafluoro-borate and 579 μl of diisopropylethyl amine. The reaction mixture is warmed to 50° C. for 24 h. Thereafter the solvents are evaporated in vacuo. The remaining residue is coevaporated twice with toluene yielding 3.55 g of crude product. Purification by chromatography on LiChroprep® NH2 (25-40 μm, Merck, Darmstadt) (75 g, eluent: toluene/ethyl acetate 1:1) affords 1.08 g of the title compound as an amorphous solid. ESI-MS: 640.0 (MH+). TLC: Rf=0.16 (toluene/ethyl acetate 1:1, LiChroprep® NH2 HPTLC).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](O)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:24][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(Cl)nc1C(C)C
Temperature: 80 °C
Yield: 75.5 %

Procedure:
In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.00 g (3.43 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 0.5 mL (3.9 mmol.) of thionyl chloride, 3.44 mL of toluene, and 0.11 ml, of N,N-dimethylformamide. The mixture was heated to 80° C. for 3 hours, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, and poured into an ice/water mixture. The resulting aqueous mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution. The neutralized aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure, to obtain 0.80 g of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product. The yield was 76% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:6](=[O:20])[N:5]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]([CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[C:9]2[C:8](=[O:11])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:6](=[O:20])[N:5]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[N:3]=1
Reactant: CC(C)=CCBr
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2[nH]c(Cl)nc2n(COC(=O)C(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCn1c(Cl)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,2-Dimethylpropionic acid [8-chloro-3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester (600 mg) and potassium carbonate (630 mg) were suspended in N,N-dimethylformamide (10 ml), and 4-bromo-2-methyl-2-butene (183 μl) was added to the suspension at room temperature. After the reaction mixture was stirred at room temperature for 24 hours, the mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After the solvent was removed by distillation from the organic layer, the residue was purified by silica gel column chromatography to give 470 mg of the title compound from the elution fraction of hexane-ethyl acetate (3:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][C:2]=1[CH3:10].[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:4]4[CH:5]=[CH:6][N:1]=[C:2]([CH3:10])[CH:3]=4)=[CH:29][C:28]=3[C:34]([F:37])([F:35])[F:36])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]2[CH2:40][CH2:41][O:42][CH2:43][CH2:44]2)=[O:18])[CH2:14][CH2:15]1)#[N:12]
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCOCC2)CC1
Reactant: Cc1cc(B(O)O)ccn1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: Cc1cc(-c2ccc(S(=O)(=O)[C@@H]3C[C@H](OC4CCOCC4)[C@@H](C(=O)NC4(C#N)CC4)C3)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared in analogy to example 62 using 2-picoline-4-boronic acid instead of 2,4-difluorophenylboronic acid and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-(tetrahydro-pyran-4-yloxy)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 169) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 576.2 (M−H)−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5 g of N,N′-carbonyldiimidazole are introduced into a solution of 5 g of indole-2-carboxylic acid in 50 ml of dry tetrahydrofuran; after stirring for 12 hours at ambient temperature, 3.7 g of benzyl alcohol are added and the reaction mixture is brought to its reflux temperature; this is maintained for 8 hours, before removing the solvent by distillation under reduced pressure. The residue is dissolved in ethyl acetate and the organic phase is washed with a N aqueous NaOH solution and then dried before evaporation of the solvent.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>ClCCl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:17][CH:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)N
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1cc(F)c(Br)cc1F

Procedure:
According to general procedure C, 4-Bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0.68 mmol) and isopropylamine were stirred together in dichloromethane (1 mL) for 16 hours. The reaction afforded 4-bromo-2,5-difluoro-N-isopropylbenzenesulfonamide (0.16 g) after purification. HPLC purity 96.6% at 210-370 nm, 10.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C9H10BrF2NO2S−H+, 311.95109; found (ESI-FTMS, [M−H]1−), 311.95114
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:14][S:15]([O:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
(S)-Tetrahydrofuran-3-ol 2a (300 mg, 3.40 mmol) and triethylamine (687 mg, 6.80 mmol) were dissolved in 20 mL of dichloromethane in an ice bath, followed by addition of methanesulfonyl chloride (908 mg, 7.93 mmol). The reaction solution was warmed up to room temperature and stirred for 2 hours. The resulting solution was mixed with 10 mL of dichloromethane, washed with water (30 mL×2), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-tetrahydrofuran-3-yl methanesulfonate 2b as a yellow oil (522 mg, yield 92.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[Cl:40]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:36]=[CH:35][C:34]([Cl:33])=[C:39]([Cl:40])[CH:38]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(Cl)c(Cl)c3)ccc2n1-c1ccc(OC(F)(F)F)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.34 mmol, see step (b) Example 9) and 3,4-dichlorophenylboronic acid (130 mg, 0.68 mmol). Yield 100 mg (50%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH:9]1([CH2:14][N:15]2[CH2:19][C:18]34[CH2:29][CH:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[CH:17]3[CH2:16]2)[C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]4=2)[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>C(Cl)Cl>[C:5]([C:32]1[CH:31]=[CH:30][C:21]2[CH:22]3[CH2:29][C:18]4([CH2:19][N:15]([CH2:14][CH:9]5[CH2:13][CH2:12][CH2:11][CH2:10]5)[CH2:16][CH:17]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=43)[C:20]=2[CH:33]=1)(=[O:7])[CH3:6]
Reactant: c1ccc2c(c1)C1CC3(CN(CC4CCCC4)CC23)c2ccccc21
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Yield: 110 %

Procedure:
To a suspension of 5.0 g (37.39 mmoles) of aluminum chloride in 75 ml of methylene chloride, cooled to 0°, was added dropwise 3.0 g (38.2 mmoles) of acetyl chloride. Then 5.0 g (13.7 mmoles) of 2-cyclopentylmethyl-2,3,8,12b-tetrahydro1H-3a,8methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole was added portionwise. The reaction mixture was heated at reflux for several hours and then poured into 1N aqueous hydrochloric acid. The product was extracted with methylene chloride, and the extracts were washed with water, with 1N aqueous sodium hydroxide, with water and dried over potassium carbonate. The solvent was evaporated to leave 5.6 g of 5-acetyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole as an oil; nmr spectrum: δ 1.0-4.0 (m, 19); 2.5 (s, 3); 7.1-7.25 (m, 5); 7.7-7.9 (m, 2). The 220MHz nmr spectrum showed that the product contained approximately 83% of the 5-acetyl isomer. A sample was purified by crystallization of the trifluoroacetate salt from ether/ethyl acetate and then of the hydrochloride salt from acetone, mp, 160-172° (dec.); ir. 1700 cm-1 (COCH3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Cl[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:33][C:32](=[O:34])[O:31][C:30]([CH3:36])([CH3:35])[C:29]=2[CH:37]=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]3[NH:33][C:32](=[O:34])[O:31][C:30]([CH3:36])([CH3:35])[C:29]=3[CH:37]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Br)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Quantities of 6.23 gm (0.033 mol) of 4-bromothiophenol and 8.28 gm (0.06 mol) of potassium carbonate are stirred into 100 ml of dimethylsulfoxide, dried over a molecular sieve in a nitrogen atmosphere at ambient temperature for 15 minutes, and then mixed with 8.51 gm (0.03 mol) of 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one. After stirring for one hour at ambient temperature, water is added in batches until a thick crystal slurry is produced. This is subjected to suction filtration, dried, and recrystallized from ethyl acetate/diisopropyl ether.