Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: N#Cc1cccc(Cl)c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (2.86 g, 17.2 mmol) and 2-amino-3-chlorobenzonitrile (2.62 g, 17.2 mmol) in DCM (60 mL) was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (7.2 mL, 51.6 mmol) was added, followed by dropwise additiona of titanium (IV) chloride solution (1 N in DCM, 10.3 mL, 10.3 mmol). The reaction mixture was stirred at 0° C. for 2 hours, then at room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and the residue obtained was used in the following step without further purification.
Reaction SMILES: C[S-].[Na+].[ClH:4].C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([CH3:32])([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH3:20])=[N:15][N:14]=2)=[C:9]([C:33]([F:36])([F:35])[F:34])[CH:8]=1.O>CN(C=O)C>[ClH:4].[CH3:18][N:17]1[C:16]([C:19]([CH3:32])([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=2)[CH3:20])=[N:15][N:14]=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][C:9]=1[C:33]([F:34])([F:36])[F:35]
Reactant: COc1ccc(-c2nnc(C(C)(C)Oc3ccc(C(F)(F)F)cc3)n2C)c(C(F)(F)F)c1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(O)cc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 42.6 %

Procedure:
Sodium thiomethoxide (30 mg) was added to a solution of 3-[4-methoxy-2-(trifluoromethyl)phenyl]-4-methyl-5-{1-methyl-1-[4-(trifluoromethyl)phenoxy]ethyl}-4H-1,2,4-triazole monohydrochloride (87 mg) in DMF (3 ml) under a nitrogen atmosphere, followed by stirring at 100° C. for 17 hours. The reaction solution was stood to cool to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine in this order and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate). The resulting residue was powdered with diisopropylether, the resulting solid was dissolved in ethyl acetate (1 ml), and 4M hydrogen chloride-ethyl acetate was added thereto. The precipitated solid was collected by filtration and dried under reduced pressure to obtain, as a colorless solid, 4-(4-methyl-5-{1-methyl-1-[4-(trifluoromethyl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)phenol monohydrochloride (36 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[F:1][C:2]1[CH:9]=[C:8]([N:18]2[CH2:19][CH2:20][C@H:16]([C:13]([OH:12])([CH3:15])[CH3:14])[C@@H:17]2[CH3:21])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1cc(F)c(C#N)cc1F

Procedure:
Using 2,4,5-trifluorobenzonitrile (153 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (247 mg) and lithium carbonate (97 mg), the title compound was obtained as white crystals (yield: 183 mg) by an operation similar to that in Example 3.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1(S([N:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=4)=[CH:34][CH:35]=3)[C:30]3[CH:45]=[C:46]([Cl:49])[CH:47]=[N:48][C:29]2=3)(=O)=O)C=CC=CC=1.CO>C1COCC1>[Cl:49][C:46]1[CH:47]=[N:48][C:29]2[NH:28][C:36]3[C:31]([C:30]=2[CH:45]=1)=[CH:32][C:33]([C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)=[CH:34][CH:35]=3
Reactant: COc1ccc(-c2ccc3c(c2)c2cc(Cl)cnc2n3S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc3[nH]c4ncc(Cl)cc4c3c2)cc1
Yield: 85 %

Procedure:
At room temperature and under inert atmosphere, 1.0 M TBAF in THF (1.9 mL, 5 equiv.) was added a solution of 9-benzenesulfonyl-3-chloro-6-(4-methoxyphenyl)-9H-pyrido[2,3-b]indole (26) (169 mg, 0.376 mmol) in anhydrous THF (17 mL). The solution was refluxed for 2 h. The resulting mixture was then cautiously quenched at 0° C. with H2O. The mixture was extracted with EtOAc (3×10 mL). The resulting organic layers were dried over MgSO4, filtered, and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2/EtOAc 9:1) to afford R277 in 85% yield as a yellow solid; mp>220° C. (MeOH); IR: 3109, 3035, 2935, 2848, 1630, 1603, 1578, 1483, 1232, 1090, 1033, 800, 778, 700 cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 12.02 (bs, 1H), 8.74 (d, 1H, J=2.4 Hz), 8.49 (d, 1H, J=1.8 Hz), 8.42 (d, 1H, J=2.4 Hz), 7.76 (dd, 1H, J=1.8, 8.6 Hz), 7.55 (d, 1H, J=8.5 Hz), 7.06 (d, 1H, J=8.7 Hz), 3.81 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): δ 158.4 (C), 150.7 (C), 144.1 (CH), 138.8 (C), 133.2 (C), 132.1 (C), 128.3 (CH), 127.7 (2 CH), 126.2 (CH), 121.7 (C), 120.2 (C), 119.3 (CH), 126.6 (C), 114.4 (2 CH), 111.8 (CH), 55.2 (CH3); MS (ESI) m/z 309.1 [M+H]+; HRMS (EI): Calcd for C18H13ClN2O: 308.0716. Found: 308.0714.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[CH3:17][O:18][C:19]1[CH:23]=[CH:22][NH:21][C:20]=1[CH:24]=O>N1CCCCC1.CC(O)C>[CH3:17][O:18][C:19]1[CH:23]=[CH:22][NH:21][C:20]=1/[CH:24]=[C:3]1/[C:4]2[CH:9]=[C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:7][C:5]=2[NH:6][C:2]/1=[O:1]
Reactant: CC(C)(C)OC(=O)c1cc2c(s1)NC(=O)C2
Reactant: COc1cc[nH]c1C=O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2sc(C(=O)OC(C)(C)C)cc21
Temperature: 75 °C
Yield: 40.3 %

Procedure:
tert-Butyl 5,6-dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxylate (915 mg, 3.8 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (10 ml). 3-Methoxypyrrole-2-carboxaldehyde (3.8 mmol, 480 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (15 ml) and the precipitated solid was collected by filtration and washed with water to give 530 mg of tert-butyl (Z)-5,6-dihydro-4-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-oxo-4H-thieno [2,3-b]pyrrole-2-carboxylate as a red solid. MS(ES): m/e 347 [M+H].
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19](O)=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C)C=O>[C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([Cl:26])=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(NS(=O)(=O)c2cccc(C=CC(=O)O)c2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NS(=O)(=O)c2cccc(C=CC(=O)Cl)c2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a suspension of 3-(3-p-tolylsulfamoyl-phenyl)-acrylic acid (5d) (0.75 g, 2.36 mmol) in dichloromethane (10.0 ml): oxalyl chloride (0.62 ml, 7.08 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.79 g).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[H-].[Na+].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16](Cl)(=[O:18])=[O:17]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[O:11][CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:17]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccco1
Agent: [H-]
Agent: [Na+]
Product: Cc1noc(NS(=O)(=O)c2ccco2)c1Br
Yield: 20 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)furan-2-sulfonamide was prepared by the method of Example 1 with 5-amino-4-bromo-3-methyl-isoxazole (0.266 g, 1.5 mmol), NaH (60% oil dispersion) (0.15 g, 3.8 mmol) and furan-2-sulfonyl chloride (Example 36A) (0.30 mg, 1.8 mmol). Flash chromatography (50% EtOAc/hexane) and recrystallization from CHCl3 and hexane provided 90 mg (20% yield) of light yellow crystals (m.p. 117-119° C.).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[CH:7]=[CH:8][C:9](O)=[O:10])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>C1C=CC=CC=1>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[CH:7]=[CH:8][C:9]([N:23]=[N+:24]=[N-:25])=[O:10])[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCc1cc(C=CC(=O)O)ccc1OC(C)=O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: C=CCc1cc(C=CC(=O)N=[N+]=[N-])ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
22.2 g (0.09 mol) of 3-allyl-4-acetoxy-cinnamic acid are suspended in 100 ml of benzene and 13.2 ml (0.18 mol) of thionyl chloride are added. The reaction mixture is heated to the boil for half an hour under a reflux condenser and thereafter the solvent and excess thionyl chloride are removed by distillation under reduced pressure. The residual crude 3-allyl-4-acetoxy-cinnamic acid chloride is dissolved in 100 ml of absolute 1,2-dimethoxyethane, 17.5 g (0.27 mol) of sodium azide are added and the mixture is subsequently stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated under reduced pressure at 30°C. Hereupon, colourless crystals separate out. The crystallisation is completed by adding ether. 3-Allyl-4-acetoxy-cinnamic acid azide of melting point 87°-89°C (decomposition) is obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:15]([CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][C@H:11]([O:12][CH3:13])[C@@H:10]1[OH:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:31][C@@H:10]1[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@:15]([CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:14][CH:11]1[O:12][CH3:13])(=[O:34])[CH3:33]
Reactant: CO[C@H]1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.8 %

Procedure:
To a stirred solution of 201 (687 mg, 1.52 mmol) in anhydrous pyridine (4 mL) at 0° C. was added dropwise acetic anhydride (0.43 mL, 4.56 mmol). The reaction mixture was stirred for 2 days at room temperature, quenched with saturated aqueous sodium hydrogen carbonate (75 mL) and extracted with dichloromethane (150+75 mL). The combined extract was dried (MgSO4), the solvent was removed by distillation under reduced pressure and the residue was purified by chromatography over silica gel with dichloromethane as eluent to give the product 209 as a clear oil (β:α˜3:1, 750 mg, 100%); MS FAB: 463 (M−OCH3, 100%), 517 (M+Na, 28%); Found: C, 58.53; H, 6.16; C24H30O9S requires C, 58.29; H, 6.11%. Methyl 2-O-acetyl-3,5-di-O-benzyl-4-C-methanesulfonyloxymethyl-β-D-ribofuranoside (209□). 1H NMR (CDCl3): δ 7.36-7.18 (10 H, m, Bn), 5.27 (1 H, d, J 4.9 Hz, H-2), 4.88 (1 H, s, H-1), 4.55-4.44 (6 H, m, H-5′, Bn), 4.35 (1 H, d, J 5.0 Hz, H-3), 3.73 (1 H, d, J 9.2 Hz, H-5), 3.38 (1 H, d, J 9.3 Hz, H-5), 3.30 (3 H, s, OCH3), 2.95 (3 H, s, SO2CH3), 2.11 (3 H, s, OCCH3); 13C NMR (CDCl3): δ 169.91 (C═O), 137.83, 137.28, 128.49, 128.44, 127.99, 127.87, 127.77 (Bn), 105.40 (C-1), 82.65, 81.05, 74.55, 73.62, 73.56, 71.86, 70.22 (C-2, C-3, C-4, C-5, C-5′, Bn), 55.03 (OCH3), 37.14 (SO2CH3), 20.73 (OCCH3). Methyl 2-O-acetyl-3,5-di-O-benzyl-4-C-methanesulfonyloxymethyl-□-D-ribofuranoside (209β). 1H NMR (CDCl3): δ 7.36-7.18 (10 H, m, Bn), 5.09 (1 H, d, J 4.5 Hz, H-1), 4.95 (1 H, dd, J 4.5, 6.8 Hz, H-2), 4.65-4.44 (6 H, m, H-5′, Bn), 4.27 (1 H, d, J 6.6 Hz, H-3), 3.49 (1 H, d, J 9.9 Hz, H-5), 3.46 (3 H, s, OCH3), 3.36 (1 H, d, J 9.9 Hz, H-5), 2.92 (3 H, s, SO2CH3), 2.14 (3 H, s, OCCH3); 13C NMR (CDCl3): δ 170.41 (C═O), 137.59, 137.28, 128.56, 128.51, 128.49, 128.44, 127.98, 127.88 (Bn), 102.35 (C-1), 84.25, 77.53, 74.66, 73.67, 72.12, 70.39, 70.28 (C-2, C-3, C-4, C-5, C-5′, Bn), 56.07 (OCH3), 36.94 (SO2CH3), 20.63 (OCCH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[NH2:16].[Cl:21][CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].O>CC1C=C(C)N=C(C)C=1>[Cl:21][CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([O:6][CH2:5][C:4]3[CH:17]=[C:18]([F:20])[CH:19]=[C:2]([F:1])[CH:3]=3)[CH:8]=2)[NH:12][N:11]=1)=[O:27]
Reactant: Nc1n[nH]c2ccc(OCc3cc(F)cc(F)c3)cc12
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(Nc1n[nH]c2ccc(OCc3cc(F)cc(F)c3)cc12)c1cccc(CCl)c1
Temperature: 4 °C
Yield: 56 %

Procedure:
5-(3,5-Difluoro-benzyloxy)-1H-indazol-3-ylamine (550 mg, 2 mmol) was dissolved in sym-collidine, cooled to 4° C. and treated with neat 3-chloromethyl-benzoyl chloride (0.34 mL, 2.4 mmol). After 1 hour the reaction mixture was added drop wise into iced water, with stirring and separation of a yellow oil occurred. Then, EtOAc (50 mL) and 2N HCl (25 mL) were added. The organic phase was separated, washed with aqueous NaHCO3 (50 mL), brine, dried over sodium sulfate and evaporated to dryness. After purification over silica gel (eluent: DCM:MeOH 95:5) 378 mg of title compound were obtained as a whitish solid in 56% yield.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(O[CH:13]([CH3:16])[CH:14]=O)(=O)C>[Fe].CO>[CH3:8][O:7][C:1]([C:2]1[CH:14]=[C:13]([CH3:16])[O:4][C:3]=1[CH3:5])=[O:6]
Reactant: CC(=O)OC(C)C=O
Reactant: COC(=O)CC(C)=O
Agent: [Fe]
Solvent: CO
Product: COC(=O)c1cc(C)oc1C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
27 parts by weight of anhydrous iron-III chloride are added to a solution of 116 parts by weight of methyl acetoacetate in 120 parts by weight of methanol and thereafter 149 parts by weight of 85.5 percent strength α-acetoxypropionaldehyde are added dropwise, sufficiently slowly that the temperature does not rise above 37° C. The mixture is stirred overnight at room temperature (20° C.), is then boiled for 2 hours, and, when it has cooled, is worked up as described in Example 1. Distillation gives 116.6 parts by weight of 2,5-dimethylfuran-3-carboxylic acid methyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[S:8][C:7]([NH2:9])=[N:6][N:5]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[I-].[Na+].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:10]1([CH2:2][CH2:3][C:4]2[S:8][C:7]([NH2:9])=[N:6][N:5]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: Nc1nnc(CCCl)s1
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1nnc(CCN2CCOCC2)s1
Reaction time: 4 h

Procedure:
A mixture of 5-(2-chloro-ethyl)-[1,3,4]thiadiazol-2-ylamine (54a) (2.5 g, 15.3 mmol), morpholine (2.67 g, 30 mmol) and sodium iodide (0.15 g) is heated with stirring in toluene at 80° C. After adding triethylamine (2.13 ml, 15.3 mmol) heating is continued for an additional 4 hours. The solvent is removed and the residue is partitioned between water (pH 13) and n-butanol. The organic extract is dried (MgSO4) and the solid is removed to afford the titled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:35]=[CH:34][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>ClCCCl>[C:14]([C:18]1[CH:35]=[CH:34][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:11]([C:10]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:9]=2[NH:8][CH:7]=[CH:6]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1c(F)ccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)c(Cl)c2)C(=O)c2c(F)ccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
98 mg (0.55 mol) of 6-fluoro-1H-indol-7-carboxylic acid, 168 mg (0.50 mmol) of (4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine and 105 mg (0.55 mmol) of EDC.HCl were dissolved in 5 ml 1,2-dichloro-ethane. The reaction mixture was stirred at rt over night and heated to 80° C. for 3 h. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 108 mg (43%) product as a colorless viscous oil. MS (ISP) 497.2 (M+H)+.
Reaction SMILES: O.[S-2:2].[Na+].[Na+].[CH3:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][S:2][CH2:5][C:6]2[CH:13]=[CH:12][C:9]([CH3:10])=[CH:8][CH:7]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: [S-2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(CSCc2ccc(C)cc2)cc1
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
A solution of 269.0 g (1.12 mol) of sodium sulfide hydrate and 12.0 g of tetrabutylammonium hydrogen sulfate (phase transfer catalyst) in 300 ml of water is introduced into a reaction vessel provided with a stirrer and thermometer. 212.6 g (1.52 mol) of 4-methylbenzyl chloride are added dropwise at below 40° C. in the course of 30 minutes (min), while stirring intensively. The reaction mixture is stirred at room temperature (RT) for 4 1/2 hours (h) and then at 50°-60° C. for 1/2 h. The reaction mixture is cooled to 0°-5° C. and kept at this temperature for 1/2 h. The reaction mixture is filtered and the residue is dissolved in about 2 liters of ethyl acetate. The organic phase is extracted twice by shaking with deionized water (pH ~6) and dried over MgSO4. The ethyl acetate is removed on a rotary evaporator. The residue is dried overnight at RT under a high vacuum. 174.8 g (95% of theory) of di-(p-methylbenzyl) sulfide are obtained as slightly yellowish white crystals having a melting point of 74°-76° C.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=O)=[O:30])[CH:11]=1)=[O:9].[N:45]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(N(CC)CCN(C)C(=O)C1C=CC=C(C(NC2C=CC(N3CCCCC3)=CC=2C2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=CN=2)=O)C=1)C>>[N:22]1([C:20]2[CH:19]=[CH:18][C:17]([NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=3)[C:34]([N:48]3[CH2:49][CH2:50][CH2:51][N:45]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:46][CH2:47]3)=[O:36])=[O:30])=[C:16]([C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]4[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:43])([F:1])[F:44])[CH:4]=4)[CH:15]=[CH:14][N:13]=3)[CH:21]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CCN(CC)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid 4.1e and tert-butyl 1,4-diazepane-1-carboxylate using the procedure used to prepare N1-(2-(diethylamino)ethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-isophthalamide 4.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:21]([CH2:24][CH3:25])CC)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:14]([NH:8][C:6](=[O:5])[C@H:24]([CH2:25][C:10]2[CH:18]=[CH:17][CH:13]=[CH:12][CH:11]=2)[NH2:21])=[O:16])[CH2:17][CH2:18]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-(t-butoxycarbonylaminomethyl)benzoic acid (3.77 g), L-phenylalamine amide hydrochloride (3.01 g), triethylamine (2.25 g) and dry dichloromethane (100 ml) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.16 g) was added, under ice-cooling, and after cooling for 2 hours, the mixture was stirred under room temperature for 2 hours. The solvent was evaporated under a reduced pressure, water was added to the residue to effect powdering, and the powder was collected by filtration. The powder was washed with 10% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate, and then water, in this order, followed by drying, to give N-[4-(t-butoxycarbonylaminomethyl)benzoyl]-L-phenylalamine amide (I) (4.41 g). The structure was confirmed by NMR spectrum.
Reaction SMILES: CO[C:3]1[CH2:8][CH2:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=1[C:11]([O:13]CC)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][C:22]1=[O:27]>C(O)CO.CO>[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:20][N:21]1[CH2:26][CH2:25][N:24]2[C:3]3[CH2:8][CH2:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=3[C:11]([OH:13])=[C:23]2[C:22]1=[O:27]
Reactant: O=C1CNCCN1Cc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C1=C(OC)CCN(C)C1=O
Solvent: CO
Solvent: OCCO
Product: CN1CCc2c(c(O)c3n2CCN(Cc2ccc(F)c(Cl)c2)C3=O)C1=O
Temperature: 250 °C

Procedure:
A mixture of ethyl 4-methoxy-1-methyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carboxylate (0.27 g, 1.27 mmol) and 1-(3-chloro-4-fluorobenzyl)piperazin-2-one (0.92 g, 3.80 mmol) in ethylene glycol (2.5 mL) was heated in a sealed tube at 250° C. in a microwave reactor for 20 minutes with stirring. The resultant solution was diluted with methanol (2.5 mL) and cooled to 0° C. The white solid precipitate was filtered, washed successively with cold methanol and diethyl ether, and then dried under vacuum to provide the title compound.
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:16]=[CH:15][C:10]3[O:11][CH2:12][CH2:13][O:14][C:9]=3[CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:24][S:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][CH:33]=[CH:32]2>ClCCl>[CH:1]1([C:4]([C:32]2[C:31]3[C:35](=[C:27]([CH2:26][S:25][CH3:24])[CH:28]=[CH:29][CH:30]=3)[NH:34][CH:33]=2)([C:7]2[CH:16]=[CH:15][C:10]3[O:11][CH2:12][CH2:13][O:14][C:9]=3[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(O)(c1ccc2c(c1)OCCO2)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(C)(c3ccc4c(c3)OCCO4)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
400 mg (1.82 mmol) of the compound from Example 142A and 0.17 ml (2.18 mmol) of trifluoroacetic acid were added to 322 mg (1.82 mmol) of the compound from Example 8A in 3 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient) and by recrystallization from acetonitrile. 184 mg (27% of theory) of the title compound were obtained.