Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:56])[CH2:55][NH:54][CH2:53]1>>[C:28]([C:32]1[N:33]=[C:34]([N:54]2[CH2:55][C:52]([F:56])([F:51])[CH2:53]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: FC1(F)CNC1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC(F)(F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-difluoroazetidine hydrochloride and isolated as light-yellow gum (11.9 mg, 64%). MS (m/e): 393.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[BH3-]C#N.[Na+]>C(O)(=O)C>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: COc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc([N+](=O)[O-])cc2OC)cc1
Yield: 72.9 %

Procedure:
This compound was prepared according to General Method 3 (EXAMPLE 1) from 2-amino-5-nitroanisole (1.00 g, 5.95 mmol), p-anisaldehyde (1.62 g, 11.9 mmol), NaBH3CN (0.373 g, 5.95 mmol) in 100 mL acetic acid to afford 1.25 g (75%) of (2-methoxy-4-nitrophenyl)-(4-methoxybenzyl)amine, an orange solid, after washing the crude product with 4:1 hexanes:EtOAc. Data for (2-methoxy-4-nitrophenyl)-(4-methoxybenzyl)amine: Rf 0.80 (3:2 EtOAc:hexanes); 1NMR (500 MHz, CDCl3) δ 7.88 (dd, 1H, J=8.8, 2.4), 7.64 (d, 1H, J=2.4), 7.22-7.28 (m, 2H), 6.85-6.90 (m, 2H), 6.51 (d, 1H, J=9.0), 5.31 (broad s, 1H), 4.38 (d, 2H, J=5.4), 3.93 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25]([OH:32])(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].ON1[C:38](=O)[CH2:37][CH2:36][C:35]1=O.CC(N=C=NC(C)C)C>C1COCC1>[CH2:27]([CH:26]([CH2:35][CH2:36][CH2:37][CH3:38])[C:25]([OH:32])=[O:31])[CH2:28][CH2:29][CH2:30][CH2:1][CH3:2].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5]
Reactant: CCCCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CC(C)N=C=NC(C)C
Solvent: OCC(O)CO
Solvent: C1CCOC1
Product: CCCCCCC(CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous THF (50 mL). Hexanoic acid (11.96 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) and N-hydroxysuccinimide (0.183 g, 1.59 mmol) were both dissolved in the solution. When the catalysts were fully dissolved, N,N-diisopropylcarbodiimide (15.0 mL, 97.03 mmol) was pipetted into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was stripped of THF via rotoevaporation and redissolved into chloroform. The organic layer was washed 2× with sodium bicarbonate buffer and 2× with deionized water to remove unreacted starting materials. The chloroform was removed to yield a clear viscous liquid. NMR analysis supported full conversion of hydroxyl groups to the hexanoic esters.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[C:18](Cl)=[N:19][N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+].CO.O>CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][N:13]3[C:17]4[C:18]([O:30][CH3:29])=[N:19][N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[N:15]=[CH:14]3)=[CH:25][CH:26]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cn1nc(Cl)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nn(C)c(=O)c2ncn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c12
Yield: 39 %

Procedure:
The procedure of Example 34 was repeated except that 1-[4-(4-chlorobenzoyl)benzyl]-5-methyl-7-chloroimidazo[4,5-d]pyridazin-4(5H)-one was used as the starting compound. Thus, this starting compound (52 mg) was dissolved in methanol (5 ml) followed by addition of 28% sodium methoxide/methanol (0.5 ml), and the mixture was refluxed for 3 hours. To this reaction mixture was added a large quantity of water and the resulting crystals were rinsed with water and dried under reduced pressure to provide 20 mg (yield 39%) of the title compound. 1H-NMR (CD3OD) δ: 3.73(3H,s), 3.97(3H,s), 5.70(2H,s), 7.41(2H,d,J=8.4Hz), 7.51(2H,d,J=8.8Hz), 7.73(2H,d,J=8.6Hz), 7.76(2H,d,J=8.2Hz), 8.36(1H,s).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]3[N:25]=[CH:26][C:27]([C:28](O)=O)=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[OH:33][NH:34][C:35]([C:37]1[S:38][C:39]([S:42](=[O:45])(=[O:44])[NH2:43])=[CH:40][CH:41]=1)=[NH:36]>>[F:32][C:2]([F:1])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[N:18]3[N:25]=[CH:26][C:27]([C:28]4[O:33][N:34]=[C:35]([C:37]5[S:38][C:39]([S:42]([NH2:43])(=[O:45])=[O:44])=[CH:40][CH:41]=5)[N:36]=4)=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14]
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(OCC(F)(F)F)c5)nc34)n2)s1

Procedure:
The title compound was prepared from 5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) (237 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/hexane) and crystallization (dichloromethane) as a yellow solid (220 mg, 67%). MS. (ISP) 659.3 [(M+H)+]; mp 255° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14](OCC)=[O:15])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][OH:15])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1conc1-c1ccc(Cl)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1conc1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a solution of ethyl 3-(3,4-dichlorophenyl)isoxazole-4-carboxylate (7.80 g) in tetrahydrofuran (60 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 60 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-(3,4-dichlorophenyl)-4-isoxazolylmethanol (6.43 g, yield 96%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 103–104° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([CH2:41][NH2:42])=[C:35]2[CH2:34][CH2:33]1>>[NH:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([CH2:41][NH:42][C:24]3[C:23]([C:21]([NH:20][C:12]4[CH:11]=[C:10]5[C:15]([C:16]([CH3:19])([CH3:18])[CH2:17][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]5)=[CH:14][CH:13]=4)=[O:22])=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:35]2[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3F)ccc2C(C)(C)C1
Reactant: NCc1ccnc2c1CCN2
Agent: Cl
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccnc4c3CCN4)ccc2C(C)(C)C1

Procedure:
The titled compound was prepared from 7-[(2-fluoro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 529 (M+H). Calc'd. for C30H36N6O3—528.65.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C=CN=C1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:31]([C:33]1[N:34]=[C:35]([C@@H:38]([NH2:49])[CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)[S:36][CH:37]=1)[CH3:32]>C(Cl)Cl>[CH2:31]([C:33]1[N:34]=[C:35]([C@@H:38]([NH:49][C:11](=[O:13])[CH2:10][CH2:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)[S:36][CH:37]=1)[CH3:32]
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)CCC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Benzoylpropionic acid (0.250 g) is dissolved in CH2Cl2 (5 mL), N-methyl imidazole (0.333 mL) is added and the resulting solution is cooled to 0° C. after which a solution of p-toluenesulfonyl chloride (0.320 g) in CH2Cl2 (2 mL) is added dropwise. After 0.5 hours (S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethanamine, 3, (0.388 g) is added. The reaction is stirred for 18 hours at room temperature and then concentrated in vacuo. The resulting residue is dissolved in EtOAc and washed with 1N HCl and brine. The solution is dried over Na2SO4, filtered, and concentrated and the crude material purified over silica to afford 0.415 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15](=[O:17])[CH3:16])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Br)cn1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 2-amino-5-bromopyridine (0.50 g, 2.9 mmol) in THF (10 mL) was added pyridine (343 mg, 4.3 mmol) and acetic anhydride (295 mg, 2.9 mmol) at room temperature and stirred overnight. To the mixture water (30 mL) was added, extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, concentrated to give the title compound (0.58 g, 92%) as a white solid LCMS: 215 [M+2]+; 1HNMR (400 MHz, DMSO-d6) δ 2.09 (s, 3H), 7.97 (dd, J=8.8, 2.4 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 8.41 (d, J=1.2 Hz, 1H), 10.64 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.[CH3:14][C:15](OC(C)=O)=[O:16]>C1COCC1>[C:15]([NH:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1)(=[O:16])[CH3:14]
Reactant: CCOC(=O)c1nc(Br)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(Br)ccc1NC(C)=O
Temperature: 60 °C

Procedure:
To a solution of ethy 3-amino-6-bromo-pyridine-2-carboxylate (10 g, 40.8 mmol) in THF (50 ml) was added Ac2O (12 ml, 127.8 mmol) at ambient temperature then the solution was heated to 60° C. for 3 h. The solution was allowed to cool to ambient temperature then concentrated under reduced pressure and dissolved in ethyl acetate. This afforded the product in crystalline form. The mother liquor was purified using flash chromatography eluting with ethyl acetate/heptane, gradient, giving ethyl 3-acetamido-6-bromo-pyridine-2-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[N:4]=1)#N.[OH2:23].C(OCC)(=O)C.[OH2:30]>Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[N:4]=[C:3]([C:1]([OH:30])=[O:23])[CH:8]=1
Reactant: COc1cc(C#N)nc(Oc2cccc(OC(F)(F)F)c2)c1
Reactant: O
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(OC(F)(F)F)c2)nc(C(=O)O)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2-cyano-4-methoxy-6-[3-(trifluoromethoxy)phenoxy] pyridine (1.72 g, 0.0055 mol) was suspended in about 15 ml of concentrated hydrochloric acid. The obtained suspension was stirred at about 100° C. for about 4 hours. After being allowed to stand for cooling, the obtained reaction solution was mixed with water, and then distributed in ethyl acetate-water. The organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated, thereby obtaining an aimed product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13](Cl)(=[O:15])[CH3:14]>>[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: Brc1ccc(C2CCCN2)cc1
Product: CC(=O)N1CCCC1c1ccc(Br)cc1

Procedure:
The title compound was prepared from 2-(4-bromophenyl)pyrrolidine and acetyl chloride using a similar procedure to that described in description 25.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=[O:12].[Cl:24][C:25](Cl)([Cl:28])[C:26]#[N:27].Cl>[Zn].CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:12])[C:25]([C:26]#[N:27])([Cl:28])[Cl:24]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: O=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: N#CC(Cl)(Cl)C(O)COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 246.7 %

Procedure:
To a mixture of 0.60 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde, 0.29 g of zinc dust and 10 ml of N,N-dimethylformamide was added 0.040 g of trichloroacetonitrile with stirring at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was poured into 10 ml of diluted hydrochloric acid and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water; dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-cyano-3,3-dichloro-2-hydroxypropyloxy)butyloxy)benzene (yield, 46%), nD24.0 1.5460.
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].CC1C=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.CI>C(OCC)C>[CH2:3]([C:1]1[CH:2]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)[CH3:4]
Reactant: Cc1ccc2ccccc2n1
Reactant: [Li]C(C)CC
Solvent: CI
Solvent: CCOCC
Product: CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
sec-Butyllithium (1.3 M in cyclohexane, 19.3 mL, 25.1 mmol, 1.2 eq.) was added dropwise to a 0° C. solution of 2-methylquinoline (2.84 mL, 3.0 g, 21.0 mmol, 1.0 eq.) in dry diethyl ether (75 mL). After the addition was complete the cooling bath was removed and the mixture was stirred at r.t. for 1.5 h. The reaction mixture was cooled to 0° C. and methyl iodide (1.96 mL, 4.46 g, 31.4 mmol, 1.5 eq.) was added dropwise. After the addition was complete the cooling bath was removed and the reaction was stirred at r.t. for 3 h. Water (50 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (50 mL) and were dried over sodium sulfate and concentrated under reduced pressure which gave the crude product (4.82 g) as an orange oil. The crude product was purified by column chromatography (SiO2, 1:5 ethyl acetate-cyclohexane) which yielded the product (3.03 g, 92% yield) as a clear yellow oil; 1H NMR (500 MHz, CDCl3) δ 1.41 (t, J=7.5 Hz, 3H, CH3), 3.01 (q, J=7.5 Hz, 2H, CH2), 7.31 (d, J=8.5 Hz, 1H, Ar), 7.48 (t, J=7.5 Hz, 1H, Ar), 7.68 (t, J=7.5 Hz, 1H, Ar), 7.77 (d, J=8.0 Hz, 1H, Ar), 8.04 (d, J=8.5 Hz, 1H, Ar), 8.07 (d, J=8.5 Hz, 1H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[N:25]=[C:24]([CH2:26][C:4]([C:3]2[CH:8]=[C:9]([NH:12][C:13](=[O:14])[O:15][CH2:16][CH:17]=[CH2:18])[CH:10]=[CH:11][C:2]=2[F:1])=[O:6])[CH:23]=[CH:22][N:21]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)OC)c1
Reactant: Cc1ccnc(Cl)n1
Product: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1
Yield: 69.9 %

Procedure:
Using multiple interations of a procedure analogous to the procedure described in Intermediate 11 using methyl 2-fluoro-5-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (104 g, 411 mmol) and 2-chloro-4-methylpyrimidine (59 g, 493 mmol), the title compound of Step B was obtained (100 g, 69.9% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.67-13.75 (br, 1H), 8.50-8.53 (m, 0.3H), 8.31-8.38 (m, 1H), 7.50-7.82 (m, 2.6H), 6.56-7.20 (m, 3.5H), 6.20-6.25 (m, 1H), 5.82-6.01 (1.3H), 5.20-5.40 (m, 2.6H), 4.50-4.61 (m, 2.6H), 4.31-4.41 (m, 0.9H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=1)[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=1)[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:11]
Reactant: COC(=O)COc1cccc(CCCCO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1cccc(CCCC=O)c1
Temperature: -70 °C
Yield: 73.3 %

Procedure:
To a solution of oxalyl chloride (1.26 ml) in methylene chloride (30 ml) at -70° C., a solution of dimethylsulfoxide (2.11 ml) in methylene chloride (3.0 ml) was added dropwise. To the obtained solution, a solution of methyl 3-(4-hydroxybutyl)phenoxyacetate (1.94 g) in methylene chloride (8.0 ml) was added dropwise. Triethylamine (6.9 ml) was added dropwise thereto while the reaction temperature was maintained at -70° C. The reaction mixture was warmed slowly to -40° C. over a 30 min period and then quenched by addition of a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted with ether. The extract was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:2) to give the title compound (1.41 g) having the following physical data.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]2[NH:25][N:26]=[CH:27][C:20]=12.C(N(C(C)C)CC)(C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH:9]=[CH:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([NH:17][C:19]3[N:24]=[CH:23][N:22]=[C:21]4[NH:25][N:26]=[CH:27][C:20]=34)[CH2:15][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ncnc2[nH]ncc12
Reactant: N[C@H]1CC[C@H](C=CCCc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C(=C[C@H]1CC[C@H](Nc2ncnc3[nH]ncc23)CC1)CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.330 g of trans-4-(4-phenyl-but-1-enyl)-cyclohexyl-amine, 0.222 g of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (R. K. Robins, J. Amer. Chem. Soc., 78, 784-790 (1956)), 0.376 mL of di-isopropyl-ethylamine and 1.0 mL of dimethyl-formamide were combined and allowed to stir at room temperature for 18 h. The reaction was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate. The ethyl acetate extract was dried over sodium sulfate, filtered, concentrated to an oil and chromatographed on silica using ethyl acetate to 5% methanol/ethyl acetate to give a crude product as a foam, (350 mg, 70%). Purification of the crude material (60 mg) using C-18 reversed phase chromatography (1% trifluroacetic acid in acetonitrile/water) gave 0.025 g of pure product as a foam: HRMS=348.2173.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:35](N)=[O:36])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=3)[C:6]=2[CH:34]=1.[OH-:38].[K+].O.Cl>CO>[Cl:1][C:2]1[C:3]([C:35]([OH:36])=[O:38])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:25])=[O:26])=[O:22])=[CH:16][CH:17]=3)[C:6]=2[CH:34]=1
Reactant: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1nc2cc(C(=O)O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 25.6 %

Procedure:
A mixture of 6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide (Example 111, 140 mg, 0.26 mmol) and KOH (63 mg, 0.8 mmol) in methanol (10 mL) was stirred at 100° C. for 1 day. The mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL), dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (10:1) to afford 36 mg (25%) of the title compound as white solids: mp 145-150° C.; MS (ESI) m/z 541 (M+H)+; 1H-NMR (DMSO-d6) δ 8.10 (1H, s), 7.76 (2H, d, J=7.9 Hz), 7.36-7.47 (6H, m), 7.10 (1H, s) 3.28 (2H, m), 2.69-2.81 (4H, m), 2.34 (3H, s), 1.24 (3H, t, J=7.5 Hz); IR (KBr) αmax : 3450, 1701, 1517, 1340, 1163, 1091, 900 cm−1.
Reaction SMILES: [CH2:1]([C:5]1[N:6](OCOC([Si](C)(C)C)C)[C:7](/[C:10](/[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH2:34][C:35]([OH:37])=[O:36])=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)/[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[OH-].[Na+]>O.Cl.[Cl-].[Na+].O>[CH2:1]([C:5]1[NH:6][C:7](/[C:10](/[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH2:34][C:35]([OH:37])=[O:36])=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)/[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C(=C(\Cc2ccc3c(c2)OCO3)C(=O)O)c2ccc(OC)cc2OCC(=O)O)n1OCOC(C)[Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCCCc1ncc(/C(=C(\Cc2ccc3c(c2)OCO3)C(=O)O)c2ccc(OC)cc2OCC(=O)O)[nH]1

Procedure:
To a flask containing (2E)-3(2-n-butyl-1-trimethylsilylethyloxymethoxy-1H-imidazol-5-yl)-3-(2-carboxymethoxy-4-methoxyphenyl)-2-(3,4-methylenedioxybenzyl)prop-2-enoic acid (32 mg, 0.05 mmol) was added at 0° HF.pyridine (3 ml) and the reaction stirred for 15 min. The solution was diluted with water (1-2 ml), 3N HCl (1 ml), and brine (2 ml). The pH was raised to 3.5 with addition of 2.5N NaOH and the solution extracted with EtOAc (5x). The EtOAc was removed under reduced pressure and the residue taken up in water which was acidified to pH 3.5 with 1 drop of 1N HCl. The copious white ppt was collected and air dried to afford the hydrochloride salt of the title compound as a tan solid. (15 mg, 59% )