Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C@@H:26]([OH:36])[C@H:27]([NH:30][C:31](=[O:35])[CH:32]([Cl:34])[Cl:33])[CH2:28][F:29])=[CH:22][CH:21]=2)=[CH:16][N:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:34][CH:32]([Cl:33])[C:31]([NH:30][C@H:27]([CH2:28][F:29])[C@H:26]([OH:36])[C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:16]=[N:15][C:14]([CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:19][CH:18]=2)=[CH:25][CH:24]=1)=[O:35]
Reactant: CC(C)CCN(Cc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCNCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 125.2 %

Procedure:
To a solution of (5-{4-[(1R,2S)-2-(2,2-Dichloro -acetylamino)-3-fluoro-1-hydroxy-propyl]-phenyl}-pyridin-2-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (8 mg, 0.014 mmol) in dry CH2Cl2 (0.04 mL) is added trifluoroacetic acid (0.04 mL) and resulting reaction mixture is stirred at room temperature for 2 hours. Solvent is evaporated in vacuo to get brown crude, which is washed with diethyl ether: pentane (1:9), to give the title compound (8 mg): 1H-NMR (400 MHz, DMSO-d6) δ 0.89 (d, 6H, J=6.40 Hz), 1.52-1.58 (m, 2H), 1.60-1.65 (m, 1H), 3.01 (bs, 1H), 4.20-4.23 (m, 2H), 4.29-4.31 (m, 0.5H), 4.36-4.38 (m, 2H), 4.40-4.44 (m, 0.5H), 4.57-4.59 (m, 0.5H), 4.70-4.71 (m, 0.5H), 4.91-4.93 (m, 1H), 6.02 (d, 1H, J=4.28 Hz), 6.52 (s, 1H), 7.49 (d, 2H, J=8.24), 7.57 (d, 1H, J=8.16 Hz), 7.73 (d, 2H, J=8.28 Hz), 8.19 (dd, 1H, J1=8.16 Hz, J2=2.32 Hz), 8.65 (d, 1H, J=8.96 Hz), 8.96 (d, 1H, J=1.96 Hz), 9.00 (bs, 2H). LC-MS (m/z): [M+H]=456.1.
Reaction SMILES: C(OC([NH:8][CH:9]([C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])[CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])=O)(C)(C)C.C(OC([N:37]1[C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([S:46]([OH:48])=[O:47])[C:40]=2[CH:39]=[CH:38]1)=O)(C)(C)C.[Li]>>[NH:37]1[C:45]2[C:40](=[C:41]([S:46]([NH:8][CH:9]([C:21]([N:23]3[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]3)=[O:22])[CH2:10][CH2:11][C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=[O:16])(=[O:48])=[O:47])[CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38]1
Reactant: CC1CCN(C(=O)C(CCc2cccc(C(=O)O)c2)NC(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)n1ccc2c(S(=O)O)cccc21
Agent: [Li]
Product: CC1CCN(C(=O)C(CCc2cccc(C(=O)O)c2)NS(=O)(=O)c2cccc3[nH]ccc23)CC1

Procedure:
Example 84 is prepared from 3-[3-tert-butoxycarbonylamino-4-(4-methyl-piperidin-1-yl)-4-oxo-butyl]-benzoic acid and lithum 1-(tert-butoxycarbonyl)-1H-indole-4-sulfinic acid in the same manner as Example 71. ESI MS Calc. 483.2; Found. 484.8 (M+H)+.
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: COc1ccc(OCCCCCCCI)c(Cl)c1
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 18.4 %

Procedure:
[II; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)7, R is C2H5, R' is CH3CO] was prepared from 0.57 g of lithium hydride, 13.9 g of diethyl acetonylphosphonate and 27.8 g of 7-(2-chloro-4-methoxyphenoxy)-heptyl iodide according to the procedure of Example 2(b). The product was chromatographed on Florisil and further purified by preparative thin layer chromatography (TLC) on silica gel to give 5.9 g of diethyl [1-acetyl-8-(2-chloro-4-methoxyphenoxy)-octyl]phosphonate as a yellow oil; MIC vs. herpes simplex type 2=6 mcg/ml. The NMR spectrum was consistent with the assigned structure.
Reaction SMILES: COCCOC.Br[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1
Reactant: CCOC(=O)c1cc(CBr)on1
Reactant: OB(O)c1cc(F)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cc(Cc2cc(F)ccc2F)on1
Yield: 58.7 %

Procedure:
1,2-Dimethoxyethane (8 mL) and water (2 mL) were added to the mixture of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (1.00 g; 4.27 mmol), 2,5-difluorophenylboronic acid (0.773 g; 4.70 mmol), tetrakis(triphenylphosphine)palladium(0) (0.248 g; 0.640 mmol) and sodium carbonate (0.911 g; 8.55 mmol). The mixture was irradiated in a microwave oven at 130° C. for 20 minutes. After cooling, the reaction mixture was extracted with ethyl acetate and water. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent: 5 to 40% of ethyl acetate in heptane) to give 0.67 g (59%) of ethyl 5-(2,5-difluorobenzyl)isoxazole-3-carboxylate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([F:11])[CH2:8][NH:7]1.Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2.C(N(C(C)C)C(C)C)C>C(O)CCC>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([F:11])[CH2:8][N:7]1[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][NH:21]2
Reactant: F[C@@H]1CN[C@@H](COc2ccccc2Cl)C1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: F[C@H]1C[C@H](COc2ccccc2Cl)N(c2ncnc3[nH]cnc23)C1

Procedure:
7.8 780 mg of (2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidine and 525 mg of 6-chloropurine are irradiated at 120° C. in the microwave for 6 h together with 1.2 ml of N-ethyldiisoproylamine and 40 ml of 1-butanol, during which a pressure of 10 bar arises. After conventional aqueous work-up, the residue obtained is crystallised from ether, giving 350 mg of 6-[(2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidin-1-yl]-9H-purine (“A7”) as beige crystals; Rt.: 1.790 min; [M+H]+348.2; m.p. 143-144°;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[CH2:8]([O:10][C:11](=[O:41])[CH2:12][C:13]1[CH:22]=[C:21]([C:23](=[O:39])[C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3CCNCC3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:40])[CH:19]=2)[CH:14]=1)[CH3:9].C=O.C([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH2:8]([O:10][C:11](=[O:41])[CH2:12][C:13]1[CH:22]=[C:21]([C:23](=[O:39])[C:24]2[CH:25]=[CH:26][C:27]([S:30]([N:33]3[CH2:7][CH2:6][N:3]([CH3:1])[CH2:4][CH2:5]3)(=[O:32])=[O:31])=[CH:28][CH:29]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:40])[CH:19]=2)[CH:14]=1)[CH3:9]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCNCC3)cc2)c2cc(F)ccc2c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)c2cc(F)ccc2c1
Reaction time: 0.25 h
Yield: 59 %

Procedure:
Triethylamine (0.04 mL, 0.27 mmol) was added to a stirred mixture of {6-fluoro-4-[4-(piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid ethyl ester (0.10 g, 0.17 mmol) in acetonitrile (4 mL) at 0° C. and the reaction mixture was stirred for 15 minutes. Formaldehyde (0.02 mL, 0.83 mmol) and sodium cyanoborohydride (0.017 g, 0.27 mmol) were added to the reaction mixture at 0° C., then the mixture was stirred for another 15 minutes. The reaction mixture was neutralized to pH ˜7 by gradual addition of acetic acid. The reaction mixture was concentrated, and the residue was made alkaline by the addition of a 2.0 N aqueous solution of KOH. The resulting mixture was extracted with diethyl ether (2×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Silica gel (100-200 mesh) column chromatography (4:1 ethyl acetate-hexanes) afforded 0.05 g (60%) of {6-fluoro-4-[4-(4-methyl-piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid ethyl ester as an off-white sticky solid. MS cald. for C26H27FN2O5S ([M+H]+) 499, obsd. 499.3.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH:8]=[CH:7]2)(=O)[CH3:2].[C:27](#[N:31])[CH2:28][C:29]#[N:30]>N1C=CC=CC=1>[C:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][N:14]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1]([CH3:2])=[C:28]([C:27]#[N:31])[C:29]#[N:30])[CH:5]=3)[CH:10]=2)[CH2:19][CH2:18]1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: N#CCC#N
Reactant: CC(=O)c1ccc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Solvent: c1ccncc1
Product: CC(=C(C#N)C#N)c1ccc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Reaction time: 5.5 h
Yield: 77 %

Procedure:
tert-Butyl 4-(6-acetyl-2-naphthyl)-1-piperazinecarboxylate (177 mg, 0.5 mmol), prepared as described in Example 1(d), was heated with 40 mg (0.6 mmol) of malononitrile in 4 mL pyridine at 105-110° C. After 5.5 hours, an additional 24 mg of malononitrile was added, and heating was continued for a total of 12 hours and 40 minutes. The mixture was cooled and evaporated in vacuo. Polar components of the mixture were removed by column chromatography (70-230 mesh silica, Φ20×120 mm, chloroform), and the product, tert-butyl-4-[6-(2,2-dicyano-1-methylvinyl)-2-naphthyl]-1-piperazinecarboxylate, was finally purified by radial chromatography (silica, 2 mm, chloroform). 155 mg (77%) of tert-butyl-4-[6-(2,2-dicyano-1-methylvinyl)-2-naphthyl]-1-piperazinecarboxylate were obtained, which, after recrystallzation from dichloromethane—petroleum ether mixture, melted at 169-171° C. Anal. Calculated for C24H26N4O2: C, 71.62; H, 6.51; N, 13.92. Found: C, 71.62; H, 6.66; N, 13.87. 1H NMR: δ 1.50 (s, 9H, —C(CH3)3), 2.72 (s, 3H, CH3), 3.34 and 3.64 (t, J=5.1 Hz, 8H, piperazine), 7.09 (d, 1H, 5-H), 7.33 (dd, 1H, 7-H), 7.58 (dd, 1H, 3-H), 7.74 (d, 1H, 4-H), 7.81 (d, 1H, 8-H), 8.02 (d, 1H, 1-H); J5,7=2 Hz, J7,8=9.1 Hz, J1,3=2 Hz, J3,4=9.1 Hz.
Reaction SMILES: [OH-:1].[Na+].BrBr.[Cl:5][C:6]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:7]=1[C:14](=[O:16])C.Cl>O.O1CCOCC1>[Cl:5][C:6]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:7]=1[C:14]([OH:16])=[O:1]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1Cl
Reactant: [OH-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Cl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.9 %

Procedure:
Sodium hydroxide (45.42 g, 1.090 mol) was dissolved in water (220 ml), and while cooling with ice, bromine (16.85 ml, 0.327 mol) was dripped therein over a period of 5 minutes. After stirring the reaction solution at 0° C. for 15 minutes, a dioxane (220 ml) solution of 2′,3′,4′-trichloroacetophenone (24.40 g, 0.109 mol) was dripped therein at 0° C. over a period of 30 minutes. After stirring at room temperature for 14 hours, water (350 ml) was added and then washed with dichloromethane (350 ml). The aqueous layer obtained was gradually made acidic with concentrated hydrochloric acid while cooling with ice and the resulting crystals were filtered out. After washing the filtered-out crystals with water, the water was removed by azeotropic distillation with toluene. 22.33 g (91%) of the title compound was thereby obtained as a pale yellow powder.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].N1C=CN=C1>CO.CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[O:22])[CH2:15][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1)[CH3:21]
Reactant: CCOC(=O)C(=O)CBr
Reactant: O=[N+]([O-])c1ccc2nc(S)[nH]c2c1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CSc1nc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 2-mercapto-5-nitrobenzimidazole (195 mg, 1.0 mmol) and ethyl 3-bromopyruvate (0.150 mL, 1.19 mmol) in methanol (2.5 mL) and acetone (2 mL) was added imidazole (68 mg, 1.0 mmol). The resulted solution was shaken at 20° C. for 4 hour. After the removal of solvents under vacuum, the residue was triturated with ethyl ether. The ether phase was discarded. The residue was treated with sodium bicarbonate aqueous solution and ethyl ether. The ether phase was washed successively with sodium bicarbonate aqueous solution, water, and dried over magnesium sulfate. Evaporation to dryness under vacuum gave 200 mg (65% of yield) of the expected product, 3-(5-nitro-1H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester. Proton NMR showed the product was sufficiently pure to be used without further purification. 1H-NMR (D3COD, 300 MHz) δ (ppm): 8.35 and 8.08 (2 br. s, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.50 and 7.28 (2 br. s, 1H), 4.42 (q, J=7.1 Hz, 2H), 4.41 (br. s, 1H), 4.06 (br. s, 1H), 1.30 (t, J=7.1 Hz, 3H). MS (ESI) m/z: 310 (M+1, 100).
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21]>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:19]([C:20]([OH:22])=[O:21])[CH:18]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Reactant: Nc1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(Nc2ncc(Br)c(Nc3ccccc3)n2)c1

Procedure:
Using an analogous method to that described in Method 1, but starting from 4-anilino-5-bromo-2-chloropyrimidine and 3-aminobenzoic acid, the product was obtained. NMR: 7.2-7.4 (m, 4H), 7.55-7.6 (m, 3H), 7.8 (dd, 1H), 7.95 (s, 1H), 8.4 (s, 1H), 9.3 (br s, 1H), 10.2 (br s 1H); MS (MH+): 385, 387.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1.[CH3:18]I>C1COCC1.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([N:11]([CH3:18])[C:12]2[CH:17]=[N:16][CH:15]=[N:14][CH:13]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: Clc1cc(Br)cc(Nc2cncnc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cncnc1)c1cc(Cl)cc(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
NaH (24 mg, 1.0 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (2.2 mL) was added. The slurry was cooled to 0° C. and compound 34 (255 mg, 0.896 mmol, 1.00 eq) was added as a solution in THF (2.2 mL). After stirring at 0° C. for 30 minutes methyl iodide (61.5 μL, 1.00 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 248 mg (93%) of the title compound as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.64 (s, 1H), 7.25 (t, J=1.7 Hz, 1H), 7.16 (t, J=1.9 Hz, 1H), 7.07 (t, J=1.9 Hz, 1H), 3.32 (s, 3H); ES-MS [M+1]+: 298.1.
Reaction SMILES: [C:1]1([C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[C:2]=1[C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[N+:21]([O-])([O-:23])=[O:22].[K+]>O>[N+:21]([C:5]1[CH:6]=[C:1]([C:13]([OH:15])=[O:14])[C:2]([C:10]([OH:12])=[O:11])=[C:3]([C:7]([OH:9])=[O:8])[CH:4]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cccc(C(=O)O)c1C(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])cc(C(=O)O)c1C(=O)O
Yield: 50.4 %

Procedure:
To a stirred mixture of 125 g of 1,2,3-benzenetricarboxylic acid and 900 ml of concentrated sulfuric acid at 60°-70° C is added, gradually over a 2 hour period, 312 g of potassium nitrate. The mixture is heated at 135°-140° C for 16 hours, cooled and treated with ice and water. Some solid is separated out and is dissolved in water. The entire aqueous mixture is extracted with ether, the extract is washed with water and dried over magnesium sulfate. The ether is concentrated to a small volume, and petroleum ether is added to precipitate a white solid. The solid is collected and dried to give 76.5 g of 5-nitro-1,2,3-benzenetricarboxylic acid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]([SH:15])=[N:13][N:12]=[C:11]3[C:16]3[C:21]([OH:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH3:25])[CH3:24])[C:17]=3O)=[CH:7][CH:8]=2)[CH2:3][C:2]21[O:30]CCO2.O.CC1C=CC(S(O)(=O)=[O:40])=CC=1>CC(C)=O>[OH:22][C:21]1[CH:20]=[C:19]([OH:40])[C:18]([CH:23]([CH3:24])[CH3:25])=[CH:17][C:16]=1[C:11]1[N:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][C:2](=[O:30])[CH2:3]3)[C:14]([SH:15])=[N:13][N:12]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)c1ccc(O)c(-c2nnc(S)n2-c2ccc3c(c2)CC2(C3)OCCO2)c1O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1cc(-c2nnc(S)n2-c2ccc3c(c2)CC(=O)C3)c(O)cc1O
Temperature: 25 °C
Yield: 902.9 %

Procedure:
Compound 10 (160 mg, 0.38 mmol) was stirred in acetone (7 mL) and water (2 mL) at 63° C. in the presence of p-TsOH (5 mg, cat. amount) for 2 h. After cooled to room temperature, water was added and the reaction mixture was extracted with EtOAc. Combined organic layers were washed with water and brine and dried over Na2SO4. Purification of the concentrated crude product by column chromatography (EtOAc:Hexane=1:1) afforded the title product as a white solid (100 mg, 69%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](O)=[O:36].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:35](=[O:36])[C:34]1[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=1[Cl:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 67.7 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 88 mg (0.560 mmol) of 2-chlorobenzoic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (179 mg, 68%) is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.42, FD-MS: M+ =565, 567.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]1[C:15]([C:16]2(O)[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([C:25]#[N:26])[CH:23]=3)[NH:18][C:17]2=[O:28])=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:8].S(Cl)([Cl:32])=O>ClCCl>[Cl:32][C:16]1([C:15]2[C:10]([O:9][CH2:7][CH3:8])=[N:11][CH:12]=[CH:13][CH:14]=2)[C:24]2[C:19](=[CH:20][C:21]([F:27])=[C:22]([C:25]#[N:26])[CH:23]=2)[NH:18][C:17]1=[O:28]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2cc(F)c(C#N)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(Cl)C(=O)Nc2cc(F)c(C#N)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
0.47 ml (5.81 mmol) of pyridine was added to 1.3 g (4.15 mmol) of 3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile in 30 ml of dichloromethane. After the reaction mixture had been cooled to 0° C., 0.42 ml (5.81 mmol) of thionyl chloride was added dropwise. The mixture was stirred at room temperature for one hour and then poured into ice-water. After stirring for 15 minutes, the organic phase was separated off. The aqueous phase was extracted several times with dichloromethane. The combined organic phase was dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. 1.13 g of 3-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile were obtained as a solid which was employed without further purification in the next stage.
Reaction SMILES: FC1C(F)=CC([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](CCS(C)(=O)=O)[C:16](=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=C(OC)C=1.[F:40][C:41]([F:53])([F:52])[O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B(O)O>>[CH3:16][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[O:42][C:41]([F:53])([F:52])[F:40]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: CNc1cnccc1-c1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b) and 2-(trifluoromethoxy)phenylboronic acid after a reaction time of 7 hours at 90° C. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (91%). MS (ESI): m/z=269.090 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.Cl.[F:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][NH2:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(N(CC)CC)C.Cl>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][NH:26][C:11]([C:8]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:10][CH2:9]2)=[O:12])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: O=C(Cl)C1(c2ccccc2Cl)CC1
Reactant: COc1ccc(CCN)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C2(c3ccccc3Cl)CC2)cc1F
Reaction time: 1 h

Procedure:
A solution of 1-(2-chlorophenyl)cyclopropane carbonyl chloride (25 g) in dichloromethane (100 ml) was added dropwise to a vigorously stirred mixture of 2-(3-fluoro-4-methoxyphenyl)ethylamine hydrochloride (23.9 g), triethylamine (70 ml) and dichloromethane (400 ml) and the mixture was then stirred for 1 hour. Excess 6N hydrochloric acid was then added. The resulting solution was washed with water, dried over potassium carbonate, and the solvent removed in vacuo to give N-[2-(3-fluoro-4-methoxyphenyl)ethyl]-1-(2-chlorophenyl)cyclopropane carboxamide which was added molten to polyphosphate ester (365 g) under nitrogen. The mixture was heated at 100° C. for 17 hours, then added to water (600 ml) and washed with ether (600 ml). 20% Aqueous ammonia solution was added to the aqueous phase to give pH 8-9.The resulting precipitate was collected by filtration, washed with water, dried in air and recrystallised from boiling acetonitrile to give 1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7 -methoxy-3,4-dihydroisoquinoline, m.p. 172°-176° C.