Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8]C(CNS(CCCCl)(=O)=O)COC(=O)NCCCCCCCCCCCCCCCCCC)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:42]([S:58][CH2:59][CH:60](OC)[CH2:61][NH:62][S:63]([CH2:66][CH2:67][CH2:68][I:69])(=[O:65])=[O:64])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>>[CH2:1]([O:5][C:6]([NH:8][CH:60]([CH2:61][NH:62][S:63]([CH2:66][CH2:67][CH2:68][I:69])(=[O:64])=[O:65])[CH2:59][S:58][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)OCCCC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)NC(=O)OCCCC

Procedure:
2-Butoxycarbonylamino-3-(3-chloropropylsulfonylamino)-1-hexadecylthiopropane III e4 is allowed to react and worked up by the same procedure as described in (5). m.p. 82°-83° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(I)cc1
Reactant: Clc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Ic1ccc(Nc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 54.7 %

Procedure:
Under an argon atmosphere, 2-chloropyrimidine (16.5 g) and acetic acid (11.7 ml) were added to a solution of 4-iodoaniline (30 g) in dioxane (500 ml), and the resulting mixture was stirred for 13 hours while heating the mixture to reflux. The reaction solution was cooled to room temperature and saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extracting the resulting mixture 4 times with ethyl acetate. Organic layers were washed 3 times with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=4/1). The product was recrystallized from dichloromethane/hexane mixed solvent to obtain N-(4-iodophenyl)pyrimidin-2-amine (22.27 g). NMR (H1, CDCl3): δ 6.73(1H, t, J=4.6 Hz), 7.18 (1H, brs), 7.40-7.42 (2H, m), 7.59-7.61 (2H, m), 8.41 (2H, d, J=4.6 Hz)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH:21]=O)=[CH:10][CH:9]=2)(=[O:4])=[O:3].[S:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[S:25].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([CH:21]=[C:29]1[S:23][C:24](=[S:25])[NH:26][C:27]1=[O:28])=[CH:10][CH:9]=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cnc2ccc(C=O)cc2c1-c1ccccc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cnc2ccc(C=C3SC(=S)NC3=O)cc2c1-c1ccccc1
Yield: 76.9 %

Procedure:
A mixture of 3-methanesulfonyl-4-phenyl-quinoline-6-carbaldehyde (example 611,78 mg, 0.25 mmol), rhodanine (67 mg, 0.50 mmol), sodium acetate (82 mg, 1.0 mmol), and acetic acid (2.5 mL) was heated under the microwave irradiation at 160 degrees for 40 min. After cooling to about room temperature, the reaction mixture was filtered, and the solid was collected, washed with water, dried to give 5-(3-methanesulfonyl-4-phenyl-quinolin-6-ylmethylene)-2-thioxo-thiazolidin-4-one (82 mg, 76%) with a yellow color. LC-MS m/e 427 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:15][CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[CH3:11])=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: Cc1ccccc1CN
Product: Cc1ccccc1CNC(=O)c1cncc(Br)c1

Procedure:
Prepared from 5-bromonicotinic acid and 2-methylbenzylamine using procedures as described in Example 1H. MS (APCI) m/z 305, 307 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnn4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnn4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridazinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.15 g) was dissolved in methylene chloride (6.0 ml), and a solution of m-chloroperbenzoic acid (61 mg) in methylene chloride (4.5 ml) was added to the mixture at −78° C., and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridazinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 259) (62 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C>C(O)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccc(Cl)cc2)C1
Solvent: O=CO
Product: Clc1ccc(COC2CCNC2)cc1
Yield: 68.2 %

Procedure:
A solution of 3-(4-Chloro-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.28 g, 0.9 mmol) in aqueous 90% formic acid (7.5 mL) was stirred at (0° C.) for 30 min. then at room temperature overnight. The solvents were removed under reduced pressure and the residue was treated with saturated aqueous potassium carbonate and extracted twice with n-butanol. The combined organic extracts was concentrated and the residue was purified by flash chromatography (SiO2, dichloromethane-methanol-ammonium hydroxide, 8:8:1 then 50:10:1) to afford the subtitle compound 3-(4-Chloro-benzyloxy)-pyrrolidine (0.13 g, 70%).
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.Cl[S:29]([C:32]1[C:33]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:34]([N+:41]([O-:43])=[O:42])[CH:35]=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])(=[O:31])=[O:30]>>[N+:41]([C:34]1[CH:35]=[C:36]([CH:40]=[C:32]([S:29](=[O:31])(=[O:30])[NH2:8])[C:33]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:37]([OH:39])=[O:38])([O-:43])=[O:42]
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-3-nitro-4-phenylbenzoic acid, and following the procedure described, 3-nitro-4-phenyl-5-sulfamylbenzoic acid is obtained as a hydrate with a melting point of 119°-121° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.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>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
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: CCO
Solvent: COCCOC
Product: COc1cccc(-c2ccc([N+](=O)[O-])cc2C)c1
Reaction time: 18 h
Yield: 90.1 %

Procedure:
A solution of 2-bromo-5-nitrotoluene (40.0 gm, 185 mmol) in 1,2-dimethoxyethane (600 mL) was added to tetrakis(triphenylphosphine)palladium(0) (9.77 gm, 9.25 mmol) under nitrogen at room temperature. A solution of 3-methoxyphenylboronic acid (31.5 gm, 207 mmol) in ethanol (150 mL) was added. Finally, 2M aqueous sodium carbonate (800 mL) was added and the mixture was heated under reflux with rapid mechanical stirring for 18 h. After being cooled, the mixture was partitioned between ethyl acetate and water and the organic phase was dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography on silica gel eluting with hexane:ethyl acetate=98:2 then 95:5 gave 1-(3-methoxyphenyl)-2-methyl-4-nitrobenzene (40.55 gm, 90%).
Reaction SMILES: [O:1]=[C:2]([CH2:7][Cl:8])[CH2:3][C:4]([OH:6])=[O:5].[C-:9]#[N:10].[Na+].Cl>O>[C:9]([C:2]([OH:1])([CH2:7][Cl:8])[CH2:3][C:4]([OH:6])=[O:5])#[N:10]
Reactant: [C-]#N
Reactant: O=C(O)CC(=O)CCl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CC(O)(CCl)CC(=O)O
Yield: 82 %

Procedure:
68.8 g of 3-oxo-4-chlorobutyric acid (94.2 percent purity by NMR) (0.476 mols) was mixed with 200 ml of distilled water in a three neck flask fitted with a thermometer, dropping funnel, stirrer and connected via an ice condenser to a nitrogen bubbler which was connected to a NaOh trap in series. Sodium cyanide (24.5 g) (0.50 mol) was dissolved in 75 ml of water and placed in the dropping funnel. The contents of the flask were cooled in an ice bath and the NaCN solution added at 10°-15°C to give a pH of 8. The mixture was brought to a pH of 0.8 with 46 ml (0.568 mol) concentrated HCl and then extracted with five 100 ml. portions of ether. The combined ether extract was dried with anhydrous MgSO4. After filtering off the drying agent and washing the solids with ether, the ether was evaporated on a rotary evaporator at 35°-40°C. Assay of the 78.3 g of product by NMR showed 80.6 percent 3-cyano-3-hydroxy-4-chlorobutyric acid, 8.22 percent water, 3.53 percent acetoacetic acid and 7.6 percent ether. The last traces of ether and water were quite difficult to remove. The yield was 82 percent.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:6]=1[O:20][CH3:21])[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[CH3:21][O:20][C:6]1[CH:7]=[C:8]([C:11](=[O:19])[CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:10][C:5]=1[O:4][CH2:1][CH2:2][CH3:3]
Reactant: C=CCOc1ccc(C(=O)CC(=O)C(C)(C)C)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCOc1ccc(C(=O)CC(=O)C(C)(C)C)cc1OC
Reaction time: 2 h

Procedure:
A 50 ml eggplant type flask equipped with a magnetic stirrer, a dropping funnel, a reflux condenser and a gas-introducing tube was charged with 250 mg of a 5% palladium/carbon dispersed in 25 ml of ethanol and 5.0 g (24 mmol) of 1-(4-allyloxy-3-methoxyphenyl)-4,4-dimethylpentane-1,3-dione. After completely replacing the atmosphere of the reaction system with hydrogen, stirring was continued for 2 hours at room temperature. A light yellow oily material was obtained by removing the palladium/carbon by filtration and subsequently distilling off the solvent. Thereafter, the thus obtained oily material was subjected to silica gel column chromatography using hexane/ethyl acetate (10/1-5/1 (v/v)) as a developer to obtain 4.0 g (80% in yield) of the compound of interest, 1-(3-methoxy-4-propoxyphenyl)-4,4-dimethylpentane-1,3-dione, as an achromatic solid substance. This compound is hereinafter referred to as Compound (1d).
Reaction SMILES: C(Cl)Cl.[CH2:4]([CH:6]([C:9]1[C:10]2[N:11]([C:16]([C:20]3[CH:24]=[CH:23][O:22][C:21]=3[CH3:25])=[C:17]([CH3:19])[N:18]=2)[N:12]=[C:13]([CH3:15])[CH:14]=1)[CH2:7][CH3:8])[CH3:5].[Br:26]N1C(=O)CCC1=O>O>[Br:26][C:23]1[O:22][C:21]([CH3:25])=[C:20]([C:16]2[N:11]3[N:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH:6]([CH2:7][CH3:8])[CH2:4][CH3:5])[C:10]3=[N:18][C:17]=2[CH3:19])[CH:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3ccoc3C)c(C)nc12
Solvent: O
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3cc(Br)oc3C)c(C)nc12
Yield: 70 %

Procedure:
A CH2Cl2 solution (2 mL) of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(2-methyl-furan-3-yl)-imidazo[1,2-b]pyridazine (42.3 mg, 0.14 mmol) under a CaSO4 drying tube is treated with N-bromosuccinimide (27.6 mg, 0.16 mg). After 30 minutes the reaction mixture is poured into H2O (25 mL) and extracted into CH2Cl2 (2×25 mL). The combined organic extracts are washed with sat. NaCl, dried over Na2SO4, filtered, and concentrated. The crude product is purified by chromatography using hexane-ethyl acetate gradient (100% hexane to 12% ethyl acetate in hexane) to elute the title product (36.9 mg, 70% yield) as a white solid. ES-MS (m/z): calc'd for C18H22BrN3O: 375.1. found 376.3 (M+H). 1H NMR (400 mHz, CDCl3): δ 6.67 (s, 1H), 6.50 (s, 1H), 3.33 (m, 1H), 2.53 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 1.90-1.73 (m, 4H), 0.86 (t, J=7.3 Hz, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[O:16])[NH:4][C:3]1([CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[C:39]1([N:45]2[C:49](Cl)=[N:48][N:47]=[N:46]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:49]3[N:45]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:46]=[N:47][N:48]=3)[CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)=[O:16])[NH:4][C:3]1([CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNCC2)cc1
Reactant: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCN(c3nnnn3-c3ccccc3)CC2)cc1
Yield: 4 %

Procedure:
To a solution of the title compound of 40B (100 mg, 0.20 mmol) and (1-phenyl-1H-tetrazol-5-yl chloride (50 mg, 0.30 mmol) in CH3CN (1 ml) was added K2CO3 (0.08 9, 0.06 mmol). The mixture was stirred overnight. After removal of CH3CN, the reaction mixture was partitioned between CH2Cl2 and H2O. After separation, the organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was chromatographed on silica gel with MeOH—CHCl3—NH4OH (1:99:0.1) as eluents to afford the title compound as a white solid, 5 mg (0.077 mmol, 4% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:13][CH2:12]3)[N:7]([CH2:15][C:16]3[CH:35]=[CH:34][C:19]4/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2[nH]c(C3CC3)nc12
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CC4)nc4c(Cl)cccc43)cc2COc2cc(F)ccc21
Yield: 65.7 %

Procedure:
Using 4-chloro-2-cyclopropyl-1H-benzo[d]imidazole (EP1988091; 64 mg, 0.34 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.34 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (105 mg, 67%) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][C:5]#[CH:6].Br[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[CH2:3]([O:7][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C:5]#[CH:6]
Reactant: C#CCCO
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#CCCOCCC(=O)OCC
Yield: 90.9 %

Procedure:
Sodium hydride (4.6 g of 60% dispersion in mineral oil) was added to a stirred solution of but-3-yn-1-ol (16.2 g, 0.23 mol, Lancaster) in dry toluene (200 ml). After stirring for 2 hours at 25° C. a solution of ethyl 3-bromopropionate (20.8 g, 0.115 mol, Lancaster) was added. The reaction mixture was stirred and refluxed for 7 hours. Ethyl 3-(but-3-ynyloxy)propionate (17.8 g) was obtained by quenching the cooled reaction mixture in water, extracting with ether, washing with brine, drying over anhydrous magnesium sulphate followed by evaporation.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li]CCCC.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:49])[CH:47]=O)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].O>C1COCC1>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH:46]([CH3:49])[CH:47]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=2)=[CH:43][CH:44]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C=CC(C)Cc2ccc(C(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
A solution of (4-methoxyphenyl)methyltriphenylphosphonium bromide (2.40 g, 5.18 mmol, 1.0 equiv.) in THF (10 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 3.2 mL, 5.18 mmol, 1.0 equiv.) at 0° C., the red suspension was stirred at 0° C. for 15 min. 3-(4-tert-Butylphenyl)-2-methylpropanal (1.59 g, 7.77 mmol, 1.5 equiv.) in THF (4 mL) was added, and the mixture was stirred at 0° C.→25° C. for 12 h. After addition of H2O at 25° C., the aqueous layer was extracted with hexanes, the combined organic phases were dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 995:5→99:1) to yield 1.33 g (83%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[OH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:47][CH:48]1[CH2:53][CH2:52][N:51]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]2)=[O:11])=[CH:20][CH:19]=3)=[O:23])[CH2:50][CH2:49]1
Reactant: OC1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(O)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-hydroxy piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](\[Br:14])/[C:7](=[O:13])[O:8][CH:9]([CH3:12])[CH2:10][CH3:11])[C@H:3]1[C:15]([OH:17])=[O:16].[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20]>>[CH3:18][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](\[Br:14])/[C:7](=[O:13])[O:8][CH:9]([CH3:12])[CH2:10][CH3:11])[C@H:3]1[C:15]([O:17][C@H:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=1)=[O:16]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCC(C)OC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Product: CCC(C)OC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Step B of Example 43, (1R,cis,Z) 2,2-dimethyl-3-[2-bromo-3-oxo-3-(1-methylpropoxy)-1-propenyl]-cyclopropane carboxylic acid and (S)α-cyano-3-phenoxybenzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[2-bromo-3-oxo-3-(1-methylpropoxy)-1-propenyl]-cyclopropanecarboxylate with a melting point of 76° C. and a specific rotation of [α]D20 =+21.5°±2° (c=0.7% in chloroform).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[F:42])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([F:38])=[C:13]([NH:15][C:16]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[C:29]([F:37])[CH:28]=4)=[CH:26][C:21]3=[N:20][CH:19]=2)=[O:17])[CH:14]=1)=[O:8].[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[F:42])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([F:38])=[C:13]([NH:15][C:16]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:37])[CH:28]=4)=[CH:26][C:21]3=[N:20][CH:19]=2)=[O:17])[CH:14]=1)=[O:8]
Reactant: COC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCc5ccc(F)c(F)c5)ccc4F)cnc3c2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)O)c(F)c4)ccn23)c1

Procedure:
A solution of methyl 4-(3-(5-(3,4-difluorobenzylcarbamoyl)-2-fluorophenylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-2-fluorobenzoate (Example 7.1, step 1) (497 mg, 0.862 mmol) and 2M NaOH (4311 μL, 8.62 mmol) in MeOH (2874 μL) was stirred at RT overnight. The solvent was removed in vacuo and the residue was acidified with 2M HCl to pH 2 and extracted with DCM. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([OH:34])[C:30]([F:32])([F:33])[F:31])=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Product: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-(4-bromo-phenyl)-2,2,2-trifluoro-ethanol White solid. MS (ESI): 503.1 MH+).