Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][S:12](=[S:21])([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19]Br)=[O:13].[Cl-].[Cs+]>>[CH3:11][S:12](=[S:21])([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:8])=[O:13]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CS(=O)(=S)OCCOCCBr
Agent: [Cl-]
Agent: [Cs+]
Product: CS(=O)(=S)OCCOCCOC(=O)c1ccc(N)cc1
Yield: 14.7 %

Procedure:
In a manner analogous to that above, the reaction of p-aminobenzoic acid (671 mg; 4.90 mmol), 1-(5-bromo-3-oxapentyl) methanethiosulfonate (1.29 g, 4.9 mmol) and CsCl (1.63 g, 5 mmol) yielded 7-(4-aminophenyl)-7-oxo-3,6-dioxaheptyl methanethiosulfonate (230 mg). 1H NMR (500 MHz, (CD3)2SO) δ 7.62 (d, J=8.7 Hz, 2H), 6.55 (d, J=8.7 Hz, 2H), 5.95 (s, br., 2H), 4.27 (t, J=4.7 Hz, 2H), 3.77 (t, J=6.0 Hz, 2H), 3.73 (t, J=4.7 Hz, 2H), 3.50 (s, 3H), 3.39 (t, J=6.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].C([O:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17](O)=[O:18])(=O)C>CC(C)=O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10])[NH:8][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[OH:14]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1ccccc1O
Yield: 100.1 %

Procedure:
2,6-Dichloro-4-aminophenol (0.37 g.) was dissolved in acetone (30 ml.) to which pyridine (0.32 ml.) was added. While mixing, an acetone solution (10 ml.) of the acid chloride prepared from acetylsalicylic acid (0.38 g.) was added by drops. After the reaction was completed, the solution was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and then was washed with water then with 1N-hydrochloric acid. After evaporating off the ethyl acetate under reduced pressure the resulting residue was dissolved in a mixture of methanol and 2N-sodium hydroxide (10 ml. each). The solution was agitated for several hours then acidified with 2N-hydrochloric acid to precipitate the product. By recrystallization in acetone-water, white needle-like crystals of 3',5'-dichloro-2,4'-dihydroxybenzanilide (0.62 g.) were obtained. The yield was 78% and the melting point was 217°-219° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>C(Cl)Cl>[C:29]([O:21][CH2:20]/[CH:19]=[C:17](/[CH2:16][CH2:15][CH2:14][C@@H:12]([CH2:11][CH2:10][CH2:9][C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13])\[CH3:18])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: O=C(Cl)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C(=C\COC(=O)c1cccnc1)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a mixture consisting of 10 0 g of phytol, 9.0 g of triethylamine and 50 ml of methylene chloride was added 7.2 g of nicotinic chloride at 30°-40° C. The resulting mixture was stirred for 2 hours at the same temperature. After the completion of the reaction, the reaction mixture was washed with dilute hydrochloric acid, 3% aqueous sodium hydrogencarbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant; n-hexane:ethyl acetate=9:1) to obtain 12.1 g (yield: 90%) of oily phytyl nicotinate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8].C(=O)([O-])[O-].[Li+].[Li+].Br[CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)=[C:11]([OH:16])[CH:10]=1)=[O:8]
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCCC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)CCCC(=O)c1ccc(OCCCC/C=C/c2ccc(OC)cc2)c(O)c1
Yield: 14.6 %

Procedure:
Under the conditions of example 2C, 1.8g of 5-(3,4-dihydroxyphenyl)-5-oxo-pentanoic acid methyl ester in 19 ml of dimethylformamide is reacted in the presence of 1.4g of lithium carbonate with 2.05g of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up and chromatographed. 470 mg of 5-(3-hydroxy-4[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-phenyl)-5-oxo-pentanoic acid methyl ester of melting point 78°-80° C. is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][O:14][Na]>CO>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:14][CH3:13])=[N:3][C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: CO[Na]
Reactant: Clc1ccc2c(Cl)ncnc2c1
Solvent: CO
Product: COc1nc(-c2ccccc2)nc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask containing 4,7-dichloroquinazoline (250 mg, 0.91 mmol) equipped with a reflux condenser was evacuated and refilled with Ar several times. MeONa (2 mL, 25% wt in MeOH, 8.7 mmol) and anh. MeOH (20 mL) were added and the reaction mixture was heated to reflux under Ar for 5 h. The reaction was cooled to rt and stored at rt overnight then partitioned between DCM (80 mL) and H2O (10 mL). The aqueous layer was extracted with DCM (1×). The combined organics were washed (brine), dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 8.55-8.62 (m, 2H), 8.08 (d, J=9.2 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.52-7.48 (m, 3H), 7.45 (dd, J=2.0 Hz, 8.8 Hz, 1H), 4.28 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH:10]=[C:9]([O:11]C)[CH2:8][C:7]([O:13]C)=[CH:6]1.Cl>O1CCCC1.O>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH2:6][C:7](=[O:13])[CH2:8][C:9](=[O:11])[CH2:10]1
Reactant: CNCCC1C=C(OC)CC(OC)=C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNCCC1CC(=O)CC(=O)C1
Temperature: 50 °C
Yield: 82.6 %

Procedure:
To a stirred solution of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine (5.5 g, 27.9 mmol) in 20 ml of tetrahydrofuran was added 10 ml of 6 N hydrochloric acid in one portion. The warm solution was heated for 15 min. at 50° C. and concentrated to give a light yellow oil. The crude oil was dissolved in 25 ml of water, and the solution was mixed with 50 g of Dowex 50×8 resin (previously washed with 2 N HCl and deionized water) in a sintered glass funnel. After a few minutes, the aqueous solution was drawn out by suction, and the resin rinsed with four 50 ml-portions of water, and then with eight 35 ml-portions of 2 M aqueous pyridine. Pyridine fractions 3-8 were pooled and concentrated to give 3.9 g of 5-[(2-methylamino)ethyl]-cyclohexane-1,3-dione. An analytical sample crystallized from water and had mp 171°-4° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[C:8]=1[F:16])(=O)=O.[C:19]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[C:22]([O:21][C:19](=[O:20])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[C:8]=2[F:16])=[CH:29][C:28]=1[F:36])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1F
Reactant: N#Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1F
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1F
Yield: 16.5 %

Procedure:
A solution of 3.75 g of 4-cyano-2,3-difluorophenyl trifluoromethanesulfonate in 220 mL of dioxane is admixed at ambient temperature with 5 g of N-Boc-4-amino-3-fluorophenylboronic acid, 3.87 g of sodium carbonate in solution with 56 mL of distilled water and then 1.81 g of tetrakistriphenylphosphinepalladium. The reaction mixture is heated for 3 h at reflux and then poured, after cooling, into the distilled water. This mixture is extracted with ethyl acetate, the organic phase is decanted, washed a number of times with distilled water, then with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The solid obtained is chromatographed on a silica column (eluent: cyclohexane/ethyl acetate, 90/10 by volume). Evaporation to dryness under reduced pressure of the fractions containing the expected product gives 0.75 g of tert-butyl(4′-cyano-3,2′,3′-trifluorobiphenyl-4-yl)carbamate in the form of a pale pink solid, whose characteristics are as follows:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:11])=[CH:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9].[CH2:12]([O:14][C:15](=[O:21])[C:16](OCC)=[O:17])[CH3:13].CC[O-].[Na+]>CCO>[CH2:12]([O:14][C:15](=[O:21])[C:16](=[O:17])[CH2:9][C:8](=[O:10])[CH2:7][CH2:6][CH:5]=[C:4]([CH3:11])[CH3:3])[CH3:13]
Reactant: CC(=O)CCC=C(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CCC=C(C)C
Temperature: 25 °C
Yield: 43.9 %

Procedure:
Sodium hydride (0.465 g, 19.4 mmol) was added slowly to a NaCl ice bath containing EtOH (5.88 mL, 3.3 M) stirring under N2. 6-Methylhept-5-en-2-one (2.4412 g, 19.3 mmol) and diethyloxalate (2.63 mL, 19.4 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred for 6 hours, at which point the reaction was judged complete by TLC. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated, and purified by silica gel chromatography (Combiflash column, 70:30:3 Hexanes:CH2Cl2:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 1.9190 g (43.8%) of 49. 1H (CDCl3, 400 MHz): δ 14.44 (1H, broad s), 6.34 (1H, s), 5.06 (1H, t, J=7.3 Hz, 4.33 (2H, q, J=7.1 Hz), 2.49 (2H, t, J=7.3 Hz), 2.31 (2H, q, J=7.3 Hz), 1.66 (3H, s), 1.60 (3H, s), 1.35 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 202.83, 166.39, 162.08, 133.42, 121.90, 101.64, 62.40, 40.92, 25.59, 23.34, 17.61, 13.96 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 25.59, 17.62, 13.97; CH2 carbons: 62.40, 40.92, 23.34; CH carbons: 121.90, 101.64 ppm. HPLC: 11.007 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2F)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:23]1[C:27]2=[N:28][C:29]([CH2:32][NH2:33])=[CH:30][CH:31]=[C:26]2[CH2:25][CH2:24]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:33][CH2:32][C:29]2[N:28]=[C:27]3[NH:23][CH2:24][CH2:25][C:26]3=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2F)cc1
Reactant: NCc1ccc2c(n1)NCC2
Agent: Cl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccc3c(n2)NCC3)cc1

Procedure:
The titled compound was prepared from N-(4-tert-butyl-phenyl)-2-fluoro-nicotinamide and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 402 (M+H). Calc'd. for C24H27N5O—401.51.
Reaction SMILES: [C:1]1([CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1>C(Cl)Cl>[Cl:41][C:39]1[CH:38]=[C:37]([S:42]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:43])=[O:44])[CH:36]=[C:35]([Cl:34])[CH:40]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Fc1ccc(CNCc2ccccc2CNCc2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1)N(Cc1ccc(F)cc1)Cc1ccccc1CNCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a mixture of N,N′-(1,2-phenylenebis(methylene))bis(1-(4-fluorophenyl)methanamine) (1 g, 2.8 mmol, 1 eq) in DCM (HPLC grade 50 mL) at 0° C. was added triethylamine (0.87 g, 8.6 mmol, 3 eq) followed by 3,5-dichlorobenzenesulfonyl chloride (0.52 g, 2.1 mmol, 0.75 eq). The mixture was stirred at 0° C. for 1 h, before being concentrated to dryness. Water was added to the residue and the aqueous mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 before being evaporated under reduced pressure. The resulting residue was purified by silica gel (230-400) column chromatography eluting with 6% ethyl acetate in hexane to afford the desired product (0.8 g, 53%). 1H NMR (400 MHz, CD3OD) δ 7.76-7.72 (m, 1H), 7.33-7.23 (m, 2H), 7.20-7.17 (m, 2H), 7.13-7.10 (m, 4H), 7.03-6.95 (m, 4H), 6.80-6.77 (m, 2H), 4.80 (s, 2H), 4.30 (s, 2H), 3.70 (s, 2H), 3.60 (s, 2H). MS (ESI): 562.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[CH:13][CH:12]=3)[O:8][C:7](=[O:23])[C:6]=2[CH:24]=1.O.[NH2:27][NH2:28].O1CCCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[O:8])=[C:6]([C:7]([NH:27][NH2:28])=[O:23])[CH:24]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3ccnn3-c3ncccc3Cl)nc12
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1ccnn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 0.50 g of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.13 ml of hydrazine monohydrate and 20 ml of tetrahydrofuran was stirred at room temperature for 4 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of ethyl acetate and hexane to obtain 0.44 g of N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[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]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[CH:16][N:15]=3)[CH2:21][CH2:22]2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: Cc1cc(C(=O)O)ccc1Br
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(C)c3)CC2)c(C)c1
Yield: 90.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 67 and using 4-bromo-3-methylbenzoic acid (4.3 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (3.8 g) described in Preparation Example 47, the title compound (7 g) was obtained.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][CH:30]=1>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:29]4[CH:34]=[CH:33][C:32]([I:35])=[CH:31][CH:30]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(NO)c1ccc(I)cc1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccc(I)cc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-4-iodo-benzamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.88 min; Mass spectrum (ESI+): m/z=582 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:16]=[C:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26](=[O:43])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([C:36]5[N:37]([CH3:42])[N:38]=[C:39]([CH3:41])[CH:40]=5)=[O:35])[CH:28]=4)=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:44])=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH:16]=[C:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([C:27]4[CH:28]=[C:29]([NH:33][C:34]([C:36]5[N:37]([CH3:42])[N:38]=[C:39]([CH3:41])[CH:40]=5)=[O:35])[CH:30]=[CH:31][CH:32]=4)=[O:43])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:44])=[CH:13][CH:14]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CNC(=O)OC(C)(C)C)cc3)c2)n(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CN)cc3)c2)n(C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A dry 100 mL round bottom flask equipped with an Ar(g) inlet was charged with {4-[(6-{3-[(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-amino]-benzoyl}-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzyl}-carbamic acid tert-butyl ester (as prepared in Example 203, 0.113 g, 0.186 mmol) and CH2Cl2 (0.622 mL). The resulting solution was cooled to 0° C. in an ice bath. TFA (0.015 mL) was then added and the reaction mixture was allowed to stir at 0° C. for 30 minutes after which the bath was removed and the reaction was allowed to stir at room temperature for an additional 1 h. Subsequently the reaction mixture was neutralized with saturated NaHCO3(aq) and then washed with EtOAc (3×20 mL). The combined organic layer was then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was chromatographed over silica (5% MeOH/95% CHCl3) to afford pure 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (3-{3-[(4-aminomethyl-phenylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-6-carbonyl}-phenyl)-amide in 61% yield (0.057 g, 0.113 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][C:12]#[CH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([C:22]1[S:23][C:24](Br)=[CH:25][CH:26]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([C:22]1[S:23][C:24]([C:13]#[C:12][CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:14])=[CH:25][CH:26]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: C#CCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)s1
Product: CC(C)(C)OC(=O)c1ccc(C#CCNC(=O)OCc2ccccc2)s1

Procedure:
The title compound of Step B was prepared from prop-2-ynyl-carbamic acid benzyl ester and 5-bromo-thiophene-2-carboxylic acid tert-butyl ester in an analagous manner to Step A of Preparation 2.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH2+:5][CH2:6][CH:7]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]=[S:31]>>[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]1[N:5]([CH2:6][CH:7]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:4][CH2:3][S:31]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: ClCC[NH2+]CC1CCCCCCCCCCC1
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CCCCCCCCCCC1

Procedure:
Methyl cyclododecanecarboxylate was reduced according to Method B2b, Step 1 to give cyclododecylmethanol. The alcohol was converted to cyclododecylmethylbromide according to Method B2b, Step 2. The halide was reacted with 2-hydroxyethylamine according to Method B2b, Step 3 to give N-(2-hydroxyethyl)-N-(cyclododecylmethyl)amine. The alcohol was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(cyclododecylmethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclododecylmethyl)-1,3 -thiazolidine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]([O:12]CC1C=CC=CC=1)=O.[CH3:20][CH2:21][Mg+].[Br-]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1([OH:12])[CH2:21][CH2:20]1
Reactant: O=C(CCOC1CCCCO1)OCc1ccccc1
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: OC1(CCOC2CCCCO2)CC1
Temperature: 18 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a mixture of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate (150 mg, 0.568 mmol) in 2 mL of THF was added Ti(Oi-Pr)4 (0.18 mL, 0.568 mmol, d=0.955 g/L, Ardrich) via a syringe under nitrogen at rt. After stirring at 18° C. for 30 min, EtMgBr (0.48 mL, 1.42 mmol, 3M ether solution, Aldrich) was added via a syringe pump over 2 hrs. The reaction was quenched with 5 mL of water, after benzyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate was consumed completely (monitored by TLC). The mixture was filtered through a celite pad and the filtrate was extracted with ethyl acetate (30 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (10:1 (v/v) petroleum ether/EtOAc) to afford 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)cyclopropanol as colorless oil (60 mg, 57%).
Reaction SMILES: [Br:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4].[OH:16]S(O)(=O)=O.[N+]([O-])(O)=O>>[Br:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)C(Br)C12CC3CC(CC(C3)C1)C2
Solvent: O=[N+]([O-])O
Product: O=C(O)C(Br)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
α-Bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) is then reacted with H2SO4 and HNO3 to produce α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q). More specifically, α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q) is prepared from α-bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) by first charging an Erlen-Meyer flask with H2SO4. The flask is then cooled in an ice bath and 50% HNO3 is added to the flask. The solid α-bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) is then added to the mixture in portions which maintain the temperature under 28° C. The reaction is then heated to 60° C. with stirring until a clear solution is obtained. When the reaction is complete, it is cooled to and maintained at room temperature. Water is then added to quench the reaction. The resulting slurry is cooled in an ice bath and then filtered to obtain α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q). See also Example 18 herein.