Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]([CH2:6][CH2:7][NH2:8])[N+:3]([O-:5])=[O:4].C[O-].[Na+].[C:12]([N:14]=[C:15]([C:20]1[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=1)OCCC)#[N:13]>CN(C=O)C>[NH2:26][C:23]1[N:22]=[CH:21][C:20]([C:15](=[N:8][CH2:7][CH2:6][O:2][N+:3]([O-:5])=[O:4])[NH:14][C:12]#[N:13])=[CH:25][CH:24]=1
Reactant: NCCO[N+](=O)[O-]
Reactant: CCCOC(=NC#N)c1ccc(N)nc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CNC(=NCCO[N+](=O)[O-])c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a solution of 2-nitroxyethylamine hydrochloride (1.36 g, 9.54 mmol) in DMF (3.5 ml) was added sodium methoxide (470 mg, 8.7 mmol) followed by a solution of propyl N-cyano-6-amino-3-pyridinecarboximidate (355 mg, 1.74 mmol) in DMF (2 ml) described in Example 5 of Experimental Example 1, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was evaporated under reduced pressure. The residue was suspended in water and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform as an eluent to give the title compound (284 mg, yield 74%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([NH:31][S@@:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].I[CH:45]([CH3:47])[CH3:46]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C:9]([NH:31][S@@:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)I
Reactant: CC(C)(C)[S@@](=O)NC(Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(Cc2ccccc2)(N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1F
Yield: 125.2 %

Procedure:
At rt to a solution of 4:1 diastereomeric mixture (R)—N-(1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (578 mg, 1.06 mmol) in DMF (10 mL) was added K2CO3 (800 mg, 5.80 mmol) and the slurry was stirred vigorously. 2-Iodopropane (220 mg, 1.27 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with ether (50 mL), washed successively with 10% LiCl (2×20 mL) and water (20 mL). The organic portion was dried over Na2SO4, filtered and concentrated to yield (R)—N-(1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide as a pale orange foam (780 mg, 100% yield).
Reaction SMILES: Br[C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][O:4][CH:3]1OCC.[O-]CC.[Na+]>C1(C)C=CC=CC=1>[O:4]1[CH:5]=[CH:6][C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3]1
Reactant: CCOC(=O)C1(Br)CCOC1OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccoc1
Temperature: 50 °C

Procedure:
To a nitrogen-purged, 300-mL, three-neck, round-bottom flask equipped with a thermocouple/thermowell, addition funnel, distillation head, and magnetic stirrer was charged 75 mL of toluene and 26.71 g (0.100 mole) of distilled ethyl 3-bromo-2-ethoxytetrahydro-3-furoate and 42 mL (0.11 mole) of 21 % alcoholic sodium ethoxide. The mixture was heated to 50° C. while following the course of reaction by GC. An additional 17 mL (0.046 mole) of sodium ethoxide solution was needed to complete the reaction. The pressure of the system was lowered to about 210 mm to distill the ethanol/toluene azeotrope. When most of the ethanol was removed the mixture was cooled to room temperature and 50 mL of 5% hydrochloric acid was added. The layers were separated and the aqueous layer was extracted once with 25 mL of toluene. The two organic layers were combined and washed with 50 mL of 5% aqueous sodium bicarbonate and 50 mL of saturated sodium bicarbonate. The solution was dried over anhydrous magnesium sulfate and decolorizing carbon then filtered. Solvent was removed from the filtrate by distillation through a 1 0-inch Vigreux column at atmospheric pressure. The resulting ethyl 3-furoate weighed 11.25 g. Analysis by GC showed 90.4 area% ethyl 3-furoate and 9.6 area% toluene. The assay-yield of ethyl 3-furoate was 10.2 g (72.6% of theory). The identity of the product was confirmed by NMR and mass spectrometry.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=[O:10].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])[CH:4]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1cc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)ccn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 4-methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 10.38 (s, 1H) 8.64 (s 1H) 7.95 (s, 4H) 7.72 (s, 1H) 7.51 (s, 1H) 7.31 (s, 1H) 7.11 (s, 1H) 6.99 (s, 1H) 3.04 (s, 3H) 2.64 (s, 3H). MS: (ES) m/z=464.9 (M++1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.CC(O)(C)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>[C:17]1([CH3:16])[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[C:2]1[N:7]=[C:6]([CH2:8][N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(CCC)Cc1cccc(Br)n1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: CCCN(CCC)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Temperature: 50 °C
Yield: 47.4 %

Procedure:
N-[(6-Bromopyridin-2-yl)methyl]-N-propylpropan-1-amine (7.0 g, 26 mmol) was dissolved in 1,2-dimethoxyethane (100 mL). Tetrakis(triphenylphosphine)palladium(0) (1.49 g, 1.29 mmol) was added and the solution was heated to 50° C. for 15 minutes. The solution was cooled and 2,4,6-trimethylbenzeneboronic acid (4.44 g, 27.1 mmol) in 30 mL 1,2 dimethoxyethane was added followed by potassium tert-butoxide (5.79 g, 51.6 mmol) in 30 mL of tBuOH. The reaction was heated at 90° C. for 0.5 h. The solution was filtered through filter paper and concentrated. Flash chromatography gave 3.83 g of the title compound (48% yield).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:42]1[CH2:62][CH2:61][CH2:60][C@H:43]1[C:44]([NH:46][C@H:47]([C:56]([O:58][CH3:59])=[O:57])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=1)=[O:45]>CN(C)C=O.C(OCC)(=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:42]1[CH2:62][CH2:61][CH2:60][C@H:43]1[C:44]([NH:46][C@H:47]([C:56]([O:58][CH3:59])=[O:57])[CH2:48][C:49]1[CH:50]=[CH:51][C:52]([OH:55])=[CH:53][CH:54]=1)=[O:45])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3.5 g of Boc-Ile (16 mmol) is reacted with 3.8 g of 1-hydroxybenzotriazole (2.4 mmol) and 3.7 g of N,N'-dicyclohexylcarbodiimide (18 mmol) for 1 hour at 0° C., and then the solution of Pro-Tyr-OMe in 15 cm3 of dimethylformamide, prepared earlier, is added. After stirring for 1 hour at 0° C. and then for 10 hours at 20° C., the precipitate of dicyclohexylurea is separated off by filtration and the filtrate is concentrated. The residue obtained is dissolved in ethyl acetate and the solution obtained is washed successively with a 1M solution of citric acid, a solution of sodium bicarbonate and a solution of sodium chloride. The organic layer is dried over sodium sulphate. After removal of the solvent, the crude product is purified by chromatography on a column of silica gel (height 45 cm, diameter 2.5 cm), by eluting with ethyl acetate and mixtures of ethyl acetate with hexane. 3.8 g of Boc-Ile-Pro-Tyr-OMe are obtained, the properties of which are as follows:
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=O>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:29][C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:19]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2ccccc2n1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc2ccccc2n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available quinoline-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.57 min.; [M+H]+: 363.36 g/mol.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Li+].CC([N-]C(C)C)C.CN([CH:19]=[O:20])C.O>C1COCC1>[Br:1][C:2]1[S:3][C:4]([CH:19]=[O:20])=[CH:5][C:6]=1[CH3:7]
Reactant: CN(C)C=O
Reactant: Cc1ccsc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C=O)sc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-3-methylthiophene (2.66 g, 15.0 mmol) in dry THF (10 mL) at −65° C. was added LDA solution (15.0 mmol) dropwise. After stirring for 30 min, DMF (3.0 g, 10.0 mmol) in dry THF (3 mL) was added dropwise and the reaction was stirred at −65° C. for 2 h. The reaction was warmed to room temperature and water was added. The quenched mixture was extracted with EtOAc (3×100 mL). The combined extract was washed with brine and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43]([O:45]C)=O)=[N:8]1.O.[OH-].[Li+].[CH3:53][C@@H:54]([NH2:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.O.ON1C2C=CC=CC=2N=N1>O1CCCC1.O1CCCC1.O>[C:55]1([C@H:54]([NH:61][C:43]([C:42]2[CH:47]=[CH:48][CH:49]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:22]6[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=6)([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:45])[CH3:53])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: C[C@@H](N)c1ccccc1
Agent: On1nnc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), (R)-(+)-α-methylbenzyl amine (0.240 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 30–60% ethyl acetate/hexanes gave the title compound (0.393 g, 86% yield). ES-MS (m/z) 493 [M+1(−Tr)]+
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (40.2 g, 165 mmol) in CH2Cl2 (500 mL) and AcOH (60 mL) was added dihydro-2H-pyran-4-one (17.3 g, 173 mmol) and sodium triacetoxyborohydride (73.6 g, 330 mmol). The reaction mixture was stirred at RT for 20 hours. Then saturated NaHCO3 aq. was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was concentrated in vacuo. The residue was triturated with ethyl ether, and resultant precipitate was collected to afford the titled compound as a white solid (39.1 g, 72%). 1H-NMR (400 MHz, DMSO-d6) δ ppm; 7.01 (s, 1H), 6.98 (s, 1H), 5.00 (d, J=7.6 Hz, 1H), 3.84-3.87 (m, 2H), 3.79 (s, 3H), 3.54-3.56 (m, 1H), 3.43 (m, 2H), 2.14 (s, 3H), 1.81-1.84 (m, 2H), 1.47-1.55 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=1)=[O:5]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)NCc1ccc(Cl)cc1

Procedure:
In a similar manner to Example 52b, 3-chloro-2,2-dimethylpropionyl chloride (27.4 g) in dichloromethane (100 ml) was added to 4-chlorobenzylamine (25.0 g) and triethylamine (24.6 ml) in dichloromethane (400 ml) to give 3-chloro-N-(4-chlorobenzyl)-2,2-dimethylpropionamide, m.p. 97°-98° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:25])[NH:23][CH3:24])[CH:17]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1([CH3:26])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:25])[NH:23][CH3:24])[CH:17]=1
Reactant: CNC(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNC(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 43.1 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(methylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (85 mg, 0.24 mmol) in methanol (4.6 mL) and 1N sodium hydroxide aqueous solution (3.6 mL, 3.6 mmol) was heated to reflux for 1 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo to give white solid, which was dissolved in water and acidified with 1N hydrochloric acid solution to pH=2. The precipitated white solid was collected by filtration and back-dissolved in aqueous sodium hydroxide solution, then was acidified with 1 M hydrochloric acid solution again to pH=7. The white precipitated solid was collected by filtration and dried in vacuo to afford 35 mg of 3,3-dimethyl-2-(3-(methyl carbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 42.9%. LC-MS (M+1)=339.2.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].CI.[CH3:18]N1C2C=C(C(OC)=O)C=CC=2N=C1>C1COCC1>[CH3:18][N:3]1[C:4]2[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=2[N:1]=[CH:2]1
Reactant: COC(=O)c1ccc2ncn(C)c2c1
Reactant: COC(=O)c1ccc2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc2c(c1)ncn2C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of methyl 1H-benzo[d]imidazole-6-carboxylate (9.5 g, 53.9 mmol) in THF (100 mL) had NaH (2.59 g, 64.7 mmol) added at 0° C. After stirring for 30 min, CH3I (13.23 g, 93.2 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction was then quenched by addition of water and extracted with DCM (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated to give a mixture of two isomeric products methyl 1-methyl-1H-benzo[d]imidazole-6-carboxylate and methyl 1-methyl-1H-benzo[d]imidazole-5-carboxylate (8.0 g, Yield 78%). LCMS (m/z): 191.06 (M+1). This crude mixture was used directly in the next step.
Reaction SMILES: F[C:2](F)(F)[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22]>C(O)(=O)C>[C:16]1([N:21]2[C:5](=[O:7])[CH2:4][C:3]([C:2]3[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=3)=[N:22]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A mixture of 5 g (27.2 mmol) of ethyl trifluoroacetoacetate and 4.86 g (27.2 mmol) of 2-chlorophenylhydrazine hydrochloride in 50 ml of acetic acid was heated at 100° C. with stirring overnight. The mixture was concentrated in vacuo (70° C.), the residue was disolved in methanol and concentrated in vacuo. The residue was triturated in methylene chloride, cooled (0° C.), and the white solid was filtered to afford 3.01 g (42%) of 2,4-dihydro-2-(2-chlorophenyl)-5-trifluoromethyl-3H-pyrazol-3-one (Formula III: R1 =2-Cl--Ph; R2 =CF3 ; R3=H) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Li]CCCC.[CH:19]([N:22]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[C:26]([CH3:32])[CH:25]=1)([CH3:21])[CH3:20].OS([O-])(=O)=O.[K+]>C(OCC)C.C1COCC1>[CH:34]1([N:22]([CH:19]([CH3:21])[CH3:20])[C:23](=[O:33])[C:24]2[CH:29]=[CH:28][C:27]([CH:30]([OH:31])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[C:26]([CH3:32])[CH:25]=2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: Cc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1C=O
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(O)c2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2C)cc(OC)c1OC
Temperature: -8 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cold (-15° C.) solution Of 3,4,5-trimethoxybromobenzene (965 mg, 3.9 mmol) in ethyl ether (15 ml) is added n-BuLi (3 ml of 1.6 M solution in hexane). The reaction mixture is stirred at -8° C. for 10 min., diluted with THF (5 ml) and warmed to 0° C. After stirring for 5 min., the reaction is cooled to -30° C. and a solution of 4-formyl-3-methylbenzoic acid N-isopropyl-N-cyclohexyl amide (1.12 g, 3.9 mmol) in THF (5 ml) is added. After stirring at -30° C. for 10 min. and warming to room temperature, the reaction is poured onto 0.5 N KHSO4 and extracted with ethyl acetate. The organic layer is washed with saturated NaCl solution and dried (MgSO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[O:9]=[C:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH2:3][CH:2]=[O:1]
Reactant: O=C1CCCN1CCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCN1CCCC1=O
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of N-(2-Hydroxyethyl)-2-pyrrolidone (5.00 g, 38.8 mmol) and triacetoxyperiodinane (24.6 g, 58.0 mmol) in CH2Cl2 was stirred at ambient temperature for approximately 64 hours. The reaction mixture was evaporated in vacuo and the residue was triturated with Et2O. After filtration of the solids, the mother liquor was evaporated in vacuo to provide the product as a crude oil: 1H NMR (CDCl3) δ 9.60 (1H, s), 4.16 (2H, s), 3.46 (2H, t, J=7 Hz), 2.45 (2H, t, J=8 Hz), 2.11 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22](I)[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:19].[CH2:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:23]=[C:22]([CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:19]
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(I)cc3Cl)c2c1
Reactant: C=CCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCCC=Cc1ccc(Cn2c(C)nc3ccc(C(=O)OCC)cc32)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A mixture of 1-(2-chloro-4-iodobenzyl)-6-(ethoxycarbonyl)-2-methylbenzimidazole (1.21 g), 1-hexene (1.12 g), palladium acetate (II) (0.09 g), triphenylphosphine (0.21 g), tri-n-butylamine (1.49 g), and N,N-dimethylformamide (15 ml) was stirred overnight at 60° C. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluate: hexane/ethyl acetate=1/2) to obtain 1-(2-chloro-4-(1-hexen-1-yl)benzyl)-6-(ethoxycarbonyl)-2-methyl-benzimidazole (0.99 g). In accordance with the method of Production Example 5, this product was immediately converted to the desired compound (0.64 g) containing about 10% of 6-carboxy-1-(2-chloro-4-(1-hexen-2-yl)benzyl)-2-methyl-benzimidazole. This compound was immediately subjected to the next step.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]3[CH2:14][CH2:15][CH2:16][C@@H:9]23)=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)#[CH:18]>>[F:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12](=[O:13])[CH2:11][C@H:10]4[CH2:14][CH2:15][CH2:16][C@@H:9]34)=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1cccc(F)c1
Reactant: O=C1C[C@H]2CCC[C@H]2N1c1ccc(I)cn1
Product: O=C1C[C@H]2CCC[C@H]2N1c1ccc(C#Cc2cccc(F)c2)cn1
Yield: 96 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, step 7 using (3aR,6aR)-1-(5-iodopyridin-2-yl)hexahydro-cyclopenta[b]pyrrol-2(1H)-one (107 mg, 0.326 mmol) (Example 1, step 6) and 1-ethynyl-3-fluorobenzene to yield 100 mg (96%) of the title compound as a viscous yellow oil; MS: m/e=321.2 (M+H+).