Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:23]1[CH2:24][CH2:25][N:20]([C:14]2[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[CH:16][N:15]=2)[CH2:21][CH2:22]1)=[O:6]
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cc1Br
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Br)CC2)c(C)c1
Yield: 85.4 %

Procedure:
Using 2,4-dibromobenzoic acid (500 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (343 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (691 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1F)[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>CS(C)=O>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1[NH:31][CH:28]1[CH2:30][CH2:29]1)[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1F
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1NC1CC1
Yield: 83 %

Procedure:
A solution of 4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,5-trifluorobenzoic acid ethyl ester (Example 2a, 1.95 g, 5.01 mmol) and cyclopropylamine (14.0 mL, 201 mmol) in dimethyl sulfoxide (5 mL) is heated in a sealed glass tube for 44.5 hours at 100° C. Compressed air is blown into the black solution to remove excess cyclopropylamine. The solution is concentrated under high vacuum and purified by flash column chromatography (1:9 ethyl acetate/hexanes) to afford the title compound (1.77 g). 1H NMR (CDCl3): δ 7.32 (dd, 1H), 4.81-4.67 (bs, 1H), 4.35-4.16 (m, 3H), 3.95-3.40 (m, 4H), 2.92-2.80 (m, 1H), 2.25-2.08 (m, 1H), 1.97-1.77 (m, 1H), 1.46 (s, 9H), 1.34 (t, 3H), 0.72-0.63 (m, 2H), 0.57-0.49 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:29]C1C=CC(C2CCC3C(=CC=C(OC4N=CC(N)=CC=4)C=3)O2)=CC=1>C(OCC)(=O)C.CCCCCCC>[F:29][C:4]1[CH:5]=[CH:6][C:1]([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)=[CH:2][CH:3]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1

Procedure:
N-{6-[2-(4-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methane sulfonamide was prepared as described for N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl] methane sulfonamide in Example 46 starting from 442 mg of 6-[2-(4-fluorophenyl)-chroman-6-yloxy]-pyridin-3-ylamine (Example 76). The product was passed through silica gel using ethyl acetate-heptane (10:3) as an eluant and then crystallised from diethyl ether. 1H NMR (400 MHz, CDCl3) δ: 8.09 (d, 1H, J 2.8 Hz), 7.72 (dd, 1H, J 8.9, 2.8 Hz), 7.40 (m, 2H), 7.08 (m, 2H), 6.92-6.87 (m, 4H), 6.74 (s, 1H), 5.03 (dd, 1H, J 10.4, 2.3 Hz), 3.01 (m, 1H), 3.00 (s, 3H), 2.80 (m, 1H), 2.19 (m, 1H), 2.07 (m, 1H).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Li].[CH2:6](Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1.N>[CH2:1]([OH:4])[C:2]#[C:3][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: C#CCO
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCC#CCO
Reaction time: 1 h

Procedure:
A mixture of 56.1 g of propargyl alcohol in 100 ml of tetrahydrofuran and 15.6 g of lithium in 1 liter of ammonia containing a trace of ferric chloride is stirred for 1 hour. A 76.4 ml portion of hexadecyl bromide is added and the mixture refluxed for 8 hours then evaporated. The residue is dissolved in ether and washed with 10% hydrochloric acid, dried and purified by flash chromatography, to give 47.4 g of the desired compound as white platelets, mp. 60° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[CH:8]([OH:10])[CH3:9].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:6]([C:7]1[O:11][C:1](=[O:2])[O:10][C:8]=1[CH3:9])([CH3:13])([CH3:12])[CH3:5]
Reactant: O=C(Cl)Cl
Reactant: CC(O)C(=O)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1oc(=O)oc1C(C)(C)C
Reaction time: 20 h

Procedure:
Forty-four g of a 12.5% solution of phosgene in toluene is added over 30 min to a well stirred solution of 4,4-dimethyl-2-hydroxy-3-pentanone (4.85 g, 37.3 mmol) in toluene, 90 ml, at 0°-5° C. Following this addition, a solution of pyridine, 11.4 ml, in toluene, 25 ml, is then added to the cooled reaction mixture over 30 min. After stirring at 20°-25° C. for 20 hours, the reaction mixture is washed with 3N HCl and water saturated with NaCl. The toluene extract is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. After addition of p-toluenesulfonic acid hydrate, 100 mg, to the residue, it is stirred neat at 160° C for 24 hours. The resulting black liquid is dissolved in ethyl acetate, washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the residue is distilled to give 3.5 g of product, bp 82°-4° C. at 3mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])C)[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C=NC(N3CCN(S(CC4(C(O)=O)CC[O:58][CH2:57][CH2:56]4)(=O)=O)CC3)=NC=2)=CC=1>>[OH:28][NH:27][C:25]([C:24]1([CH2:23][S:20]([N:17]2[CH2:16][CH2:15][N:14]([C:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:9][N:10]=3)[CH2:19][CH2:18]2)(=[O:21])=[O:22])[CH2:29][CH2:31][O:58][CH2:57][CH2:56]1)=[O:26]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: O=C(O)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCOCC1
Product: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCOCC1
Yield: 92 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methyl-butyramide, from 4-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-tetrahydropyran-4-carboxylic acid (0.29 g), to provide the title compound as a white solid (0.27 g, 92%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:7][NH:8][C:9](=[O:21])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=1>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:7][NH:8][C:9](=[O:21])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: CCOC(=O)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(C(=O)O)cs1
Reaction time: 8 h

Procedure:
Sodium hydroxide (24 mL, 24 mmol, 1N in water) was added to an ethanol (50 mL) solution of ethyl 2-(3-(3,4-dichlorobenzyl)ureido)thiazole-4-carboxylate (Example 38) (1.8 g, 4.8 mmol). The mixture was stirred overnight. The ethanol was removed by evaporation and the aqueous solution was filtered then the filter was washed with water (20 ml). The pH of the filtrate was adjusted to less than three with concentrated HCl. The precipitate was filtered, washed with water and dried to afford 2-(3-(3,4-dichlorobenzyl)ureido)thiazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[C:5]#[N:6].C([O-])([O-])=[O:12].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[C:5]([NH2:6])=[O:12]
Reactant: N#Cc1ccc(I)c(F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 251549.91 %

Procedure:
To a solution of 3-fluoro-4-iodobenzonitrile (2.7 g, 0.010 mmol) in DMSO (6.0 mL), K2CO3 (0.450 g, 0.003 mmol) and 30% H2O2 (2.4 mL) were added at 0-10° C. and the reaction mass was stirred at RT for 2 h. After completion of the reaction, the reaction mass was quenched in ice cold water. The obtained solid product was filtered off to afford 2.0 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 7.48-7.51 (m, 2H), 7.66 (br s, 1H), 7.69-7.70 (m, 1H), 8.09 (brs, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(C)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-methylphenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 11, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>ClCCl.O>[CH2:12]([NH:20][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCNS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.07 h
Yield: 95 %

Procedure:
A solution of toluene-4-sulfonyl chloride (5.0 g, 0.026 mol) in dry dichloromethane (150 ml) was cooled to 0° C. during the dropwise addition of n-octylamine (9.6 ml, 0.058 mol) with stirring over 4 minutes. The reaction mixture was then allowed to stir for 30 minutes before being diluted with dichloromethane (200 ml) and water (200 ml). The organic layer was separated and washed consecutively with 1 M HCl, 0.5 M Na2CO3 and brine before being dried over anhydrous Na2SO4. The solution was filtered and concentrated in vacuo to a crude solid which was purified by flash chromatography (silica gel, 11% ethyl acetate in hexane) to give the title compound as a white solid (7.0 g, 94%). This material was then used immediately in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[Br:13]Br>CO>[Br:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Solvent: CO
Product: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.3 %

Procedure:
To a stirred suspension of 5-Nitro-1H-indazole (15.0 g, 92.0 mmol) in 400 ml methanol was added bromine (4.7 ml, 92.0 mmol) dropwise at room temperature. The mixture was stirred at room temperature overnight. The solvent was evaporated to dryness to afford the title compound, (25.0 g, 100%); MS (ES+) m/e 243 [M+H]+.
Reaction SMILES: [CH3:1][P:2]([CH3:10])([CH:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6])=[O:3].[CH3:11][O:12][CH2:13][N:14]=[C:15]=[O:16]>O1CCOCC1.C(N(CC)CC)C>[CH3:1][P:2]([CH3:10])([CH:4]([O:9][C:15](=[O:16])[NH:14][CH2:13][O:12][CH3:11])[C:5]([O:7][CH3:8])=[O:6])=[O:3]
Reactant: COC(=O)C(O)P(C)(C)=O
Reactant: COCN=C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COCNC(=O)OC(C(=O)OC)P(C)(C)=O
Reaction time: 24 h
Yield: 103.2 %

Procedure:
0.2 g of triethylamine is first added to a solution of 12.5 g (0.075 mol) of methyl 2-(dimethylphosphinoyl)-2-hydroxy-acetate in 50 ml of absolute dioxane, and 6.6 g (0.075 mol) of methoxymethyl isocyanate in 20 ml of absolute dioxane are then added dropwise. The mixture is stirred at 25° for 24 hours, the solvent is stripped off and the residue is recrystallized from diisopropyl ether/ethyl acetate. 19.6 g (98%) of the desired product of melting point 101° are obtained.
Reaction SMILES: [Na].[CH:2]1[C:7]([CH:8]=O)=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1.[C:13]([O:22]CC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18]CC)=[O:17]>C(O)C>[CH2:11]1[O:12][C:4]2[CH:3]=[CH:2][C:7]([CH:8]=[C:15]([CH2:14][C:13]([OH:22])=[O:21])[C:16]([OH:18])=[O:17])=[CH:6][C:5]=2[O:10]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CCC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: O=C(O)CC(=Cc1ccc2c(c1)OCO2)C(=O)O

Procedure:
Dissolving 19.14 g of metal sodium in 400 ml of ethanol, 110.8 ml of diethyl succinate and 100 g of piperonal were added, and the solution was heated and refluxed for 3 hours. The reaction solution was concentrated in vacuo, and the residue was dissolved in 700 ml of water, and washed with 300 ml of diethyl ether. The water layer was stirred in ice, adjusted to pH 1 by concentrated hydrochloric acid, and extracted with 300 ml of diethyl ether. The diethyl ether layer was washed once with saturated brine, and dried over magnesium sulfate anhydride, and concentrated in vacuo. The obtained oily residue was dissolved by 181.4 g in 350 ml of ethanol, and 400 ml of 5N sodium hydroxide was added to stir overnight at room temperature. The reaction solution was concentrated in vacuo, and the residue was washed with 200 ml of diethyl ether. The water layer was stirred in ice, adjusted to pH 1 by concentrated hydrochloric acid, and extracted with 400 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate anhydride, and concentrated in vacuo. To the obtained residue, 300 ml of diethyl ether was added to solidify, and the captioned compound was obtained. Yield: 67.34 g.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:3]=1[C:4]#[N:5].[O-:20][C:21]#[N:22].[Na+].FC(F)(F)C(O)=O>ClCCl>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=2)[N:1]=[C:21]([OH:20])[N:22]=1
Reactant: N#C[O-]
Reactant: COc1cc(N)c(C#N)cc1OCc1ccccc1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2nc(O)nc(N)c2cc1OCc1ccccc1
Reaction time: 0.75 h
Yield: 60.5 %

Procedure:
A solution of 2-amino-5-benzyloxy-4-methoxybenzonitrile (26.7 g, 0.10 mol) in dichloromethane was treated with sodium cyanate (17.1 g, 0.26 mol) and then trifluoroacetic acid (20.9 ml, 0.26 mol) was added dropwise to the resulting mixture at room temperature. After 45 minutes, the mixture was diluted with dichloromethane (11) and stirred for a further 18 hours. The mixture was then concentrated under reduced pressure and partitioned between methanol and 2N aqueous sodium hydroxide and stirred for 2 hours. The methanol was then removed under reduced pressure and the yellow solid isolated by filtration, washing sequentially with water, acetone and diethyl ether to afford the subtitle compound as a yellow solid (18.0 g, 54%). A further quantity of product was obtained by concentration of the filtrate, acidification with concentrated hydrochloric acid (95 ml), warming on a steam bath for 5 minutes, cooling and neutralisation with solid potassium carbonate. The solid obtained was isolated by filtration, washing sequentially with water, ethanol and diethyl ether to afford the subtitle compound as a yellow solid (12.11 g, 93% combined yield). Rf 0.23 (0.880 aqueous ammonia:methanol:dichloromethane 2:14:84, v/v). MS m/z 298 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(F)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1cccc(F)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-(3-fluorophenyl)acetic acid (I52) (1.10 g, 4.09 mmol) in THF (50 ml), were added N,N′-methanediylidenedicyclohexanamine (1.01 g, 4.90 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.66 g, 4.90 mmol), and (R)-quinuclidin-3-ol (0.62 g, 4.90 mmol). The reaction was stirred at RT for hours, and the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(3-fluorophenyl)acetate (1.55 g; quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=O)[C:7]2=[O:18].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:54][C:55]1[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:56]=1[CH2:57][NH2:58]>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:13][CH2:14]1)[CH:9]=[C:8]([C:15]([NH:58][CH2:57][C:56]1[CH:59]=[CH:60][C:61]([Cl:63])=[CH:62][C:55]=1[Cl:54])=[O:17])[C:7]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: NCc1ccc(Cl)cc1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O

Procedure:
15.0 g of 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (for preparation see DE 3420743 or Y. Kimura et al. J. Med. Chem. 1994, 37 (20), 3344) are dissolved in 500 ml of DMF, and 31.3 g of PyBOP and 10.6 g of 2,4-dichlorobenzylamine are added. After one day the solvent is removed on a rotary evaporator and the residue is purified by flash chromatography on silica gel (toluene/ethyl acetate 95:5). 21.2 g (93% of theory) of the title compound are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1.[C:10]([O-:13])([O-])=[O:11].[K+].[K+].Cl>CCO.O>[C:3]([O:13][C:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:11])([CH3:7])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CCCNC1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 249.7 %

Procedure:
A 250-mL 3-necked round-bottomed flask was charged with a solution of piperidine-3-carboxylic acid (4.0 g, 30.39 mmol, 1.00 equiv, 98%) in EtOH (70 mL), tert-butoxycarbonyl (8.2 g, 36.86 mmol, 1.21 equiv, 98%) and K2CO3 (4.3 g, 30.54 mmol, 1.00 equiv, 98%). The resulting mixture was stirred overnight at room temperature overnight. Then, the mixture was diluted with water. The pH was adjusted to 3 with aqueous 10% HCl resulting in a precipitate. The mixture was then filtered to collect solids that were washed with water and dried in a vacuum oven under reduced pressure to afford 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid as white solid (8.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH:25][C:26]1[C:27]([N+:36]([O-:38])=[O:37])=[C:28]([CH3:35])[CH:29]=[CH:30][C:31]=1C(O)=O.ClCCl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:31]1[CH:30]=[CH:29][C:28]([CH3:35])=[C:27]([N+:36]([O-:38])=[O:37])[C:26]=1[OH:25]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: Cc1ccc(C(=O)O)c(O)c1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1c1ccc(C)c([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
16.5 g of L-proline methyl ester and 27.2 g of N,N'-dicyclohexylcarbodiimide were successively added to an ice-cooled and constantly stirred solution of 25.2 g of 3-hydroxy-2-nitro-p-toluic acid dissolved in a mixture consisting of 480 ml of dichloromethane and 43 ml of N,N'-dimethylformamide. The whole mixture was stirred at ice-cooled temperature for 1 hour and then at room temperature for 1 hour. After the reaction, the separated crystalline precipitate was filtered off, and the filtrate was washed with 10% aqueous hydrochloric acid, 5% aqueous solution of sodium hydrogen carbonate and 5% aqueous solution of sodium carbonate. The layer of 5% aqueous solution of sodium carbonate was acidified with hydrochloric acid and extracted with chloroform. The chloroform layer was dehydrated and concentrated. The residue was recrystallized from 50% ethanol, and there was obtained 32.7 g of 1-(3-hydroxy-2-nitro-p-toluyl)-L-proline methyl ester as yellow-colored prismatic crystal having a melting point of 111° to 113.5° C.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[NH:4][C:5]([CH:23]([F:25])[F:24])=[C:6]([C:21]#[N:22])[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:8]=1[C:9]#[N:10].[C:27](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[F:26][CH:2]([F:1])[C:3]1[N:4]([CH3:27])[C:5]([CH:23]([F:24])[F:25])=[C:6]([C:21]#[N:22])[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:8]=1[C:9]#[N:10]
Reactant: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)N(C)C(C(F)F)=C3C#N)cc12
Reaction time: 0.5 h

Procedure:
A solution of 100 mg (0.277 mmol) 2,6-bis(difluoromethyl)-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 13) in DMF (1.5 ml) was cooled to 0° C., and 108 mg (0.33 mmol) caesium carbonate were added at this temperature. After stirring for 30 min, 21 μl (0.33 mmol) methyl iodide were added dropwise at room temperature, and the mixture was stirred at rt overnight. After this, additional methyl iodide (20 μl) was added, and stirring at rt was continued for further 48 h. The reaction mixture was then filtered, and the filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA isocratic 40:60 v/v) to give 12 mg (11% of th.) of the title compound.