Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:55])([CH3:54])[CH2:11][N:12]1[CH:21]=[C:20]([S:22]([N:25]2[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)(=[O:24])=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:39]3[CH:44]=[C:43]([C:45](=[O:50])[NH:46][CH:47]4[CH2:49][CH2:48]4)[CH:42]=[C:41]([F:51])[C:40]=3[CH3:52])[CH:18]=2)[C:13]1=[O:53])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:47]1([NH:46][C:45](=[O:50])[C:43]2[CH:42]=[C:41]([F:51])[C:40]([CH3:52])=[C:39]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:53])[N:12]([CH2:11][C:10]([CH3:55])([CH3:54])[CH2:9][OH:8])[CH:21]=[C:20]4[S:22]([N:25]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])[CH:44]=2)[CH2:49][CH2:48]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(S(=O)(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)(=O)N3CCCNCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
To a solution of tert-butyl 4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfonyl)-1,4-diazepane-1-carboxylate (Example 46d, 0.055 g) in DCM (4 mL) was added trifluoroacetic acid (1 mL), and the reaction was stirred at room temperature overnight. Toluene (6 mL) was added and the volatiles removed in vacuo (repeated 3 times). The residue was dissolved in methanol and purified by SCX, flushing with methanol (impurities), and eluting the product with 0.7 N methanolic ammonia. Purification by preparative HPLC (Phenomenex Gemini column using a 95-5% gradient of 0.2% aqueous trifluoroacetic acid in acetonitrile as eluent), evaporation of solvents and trituration with diethyl ether gave the title compound (0.011 g) as a white solid.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.ClC(OCC)=O.Cl.Cl.[CH2:36]([NH:43][NH2:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH2:36]([NH:43][NH:44][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: NNCc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NNCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 7.0 g linoleic acid in 250 ml methylenechloride cooled to -20° is added first 2.5 g triethylamine and then dropwise 2.7 g ethyl chloroformate. The reaction mixture is allowed gradually to come to room temperature and stirred for 2 hours. There is then added 5.0 g triethylamine followed by 4.9 g benzylhydrazine dihydrochloride and the reaction mixture then stirred for 16 hours. Thereafter the reaction mixture is extracted five times with portions of 2 N hydrochloric acid, then once with 2 N aqueous sodium hydroxide solution and washed extensively with saturated aqueous sodium chloride. The organic phase is then dried with anh. sodium sulphate, filtered and the filtrate evaporated i.v. to dryness. The residue is then chromatographed over silica gel, with chloroform as the eluent. The desired fractions* are collected, and evaporated i.v. to dryness to yield the title product as a viscous oil.
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O[C:28]1[CH:44]=[CH:43][C:31]([C:32]([O:34][CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:33])=[CH:30][CH:29]=1.C1CCC(N=C=NC2CCCCC2)CC1.CN(C1C=CC=CN=1)C>O1CCCC1>[C:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][C:28]3[CH:44]=[CH:43][C:31]([C:32]([O:34][CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:33])=[CH:30][CH:29]=3)=[O:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(C)OC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(C)CCCCCC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 330 ml of dehydrated tetrahydrofuran were dissolved 5.00 g of 4'-nonanoyloxybiphenyl-4-carboxylic acid and 6.76 g of 1-methylheptyl 4-hydroxybenzoate synthesized in (2) above. To the solution were added 6.18 g of DCC and 0.24 g of dimethylaminopyridine, followed by stirring for one day at room temperature.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]3[CH:20]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[ClH:26].[CH2:27]([OH:29])[CH3:28]>>[ClH:26].[C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18](=[NH:19])[O:29][CH2:27][CH3:28])=[CH:14][N:13]3[CH:20]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: CCO
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=N)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A suspension of 300 mg of N-phenyl-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 2) in 25 mL of ethanol containing 0.5 mL of DMF is cooled to 0° C. and then treated for 1 hour 40 minutes with hydrogen chloride gas. The reaction mixture is stirred at room temperature for 16 hours and then concentrated under reduced pressure to a small volume. The precipitate is filtered off by suction and washed with ethanol and ethyl ether to give 296 mg of ethyl 2-phenylcarbamoylimidazo[1,2-a]pyridine-6-carboximidate hydrochloride (1:1) in the form of a white solid, which is used without further purification for the rest of the synthesis.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][C:12]([OH:14])=[O:13]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: O=C(O)CBr
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
100 g 4-Aminobenzonitrile and 234.7 g bromoacetic acid in 1400 mL water were stirred for 15 min in round bottom flask. The reaction mixture was heated to 100° C. and maintained for 16 hours. The reaction mixture was cooled to 10° C. and stirred for 2 hours. The reaction mixture was filtered and washed with water to obtain 2-(4-cyanophenylamino) acetic acid of Formula (D).
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2C=C[CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49](O)=[O:50].CCN(C(C)C)C(C)C.C(N(C)CCN)(OC(C)(C)C)=O>CN(C=O)C>[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49]([NH:16][CH2:11][CH2:10][NH:15][CH3:14])=[O:50]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Agent: CN(CCN)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNCCNC(=O)c1sc2ncnc(Nc3cccnc3OC3CCOCC3)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
HATU (0.157 g, 0.41 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.145 g, 0.38 mmol) and Hünig's base (65 μL, 0.38 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. N-Boc-N-methylethylenediamine (335 μL, 1.88 mmol) was added, the coolant removed and the reaction mixture stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the crude product dissolved in DCM. The organic layer was washed with water, concentrated in vacuo (10 mL) and trifluoroacetic acid added (3.0 mL). The mixture was stirred at ambient temperature overnight, concentrated in vacuo and purified by ion-exchange chromatography (SCX-2 eluting with hydrochloric acid/MeOH→ammonia/MeOH). Further purification by flash-column chromatography (100% DCM→10% ammonia/MeOH/DCM) yielded the title compound as pale yellow solid (0.043 g, 25%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[C:19]([NH:22][C:23]1[S:24][C:25]([S:29](Cl)(=[O:31])=[O:30])=[C:26]([CH3:28])[N:27]=1)(=[O:21])[CH3:20]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:29]([C:25]2[S:24][C:23]([NH:22][C:19](=[O:21])[CH3:20])=[N:27][C:26]=2[CH3:28])(=[O:30])=[O:31])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 2-acetamido-4-methylthiazole-5-sulfonyl chloride (0.5 mmol) to obtain N-(5-(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)sulfamoyl)-4-methylthiazol-2-yl)acetamide. 1H NMR (CDCl3)) δ 2.1 (s, 3H), 2.2 (s, 3H), 5.9 (dt, 1H), 6.05 (s, 1H), 7.0-7.6 (m, 3H), 7.4 (dd, 1H), 8.0 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:32])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=1[F:31])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[F:31][C:16]1[CH:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:28])=[O:29])[CH:19]=[CH:20][C:15]=1[NH:14][C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2)c(F)c1

Procedure:
2-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 2 mmol) was dissolved in 20 mL DCM and 10 mL trifluoroacetic acid and stirred at ambient temperature for 1 hour. Concentrated solution, redissolved in 100 mL CHCl3, repeated CHCl3 co-concentration 3 times to yield title compound as an oil. (quant. yield) APCI (AP−): 361.1 (M−H)−.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CC(C)=O.C(OCC)(=O)C>[Cl:7][C:8]1[C:9]([N:23]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[S:24]([CH3:27])(=[O:26])=[O:25])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2
Reactant: COC(=O)CBr
Reactant: COc1nc2cc(Cl)c(Cl)c(NS(C)(=O)=O)c2nc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Yield: 79.7 %

Procedure:
Anhydrous potassium carbonate (1.60 g, 11.2 mmol) was added to a suspension of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-methanesulphonamide (see Preparation 3, 3.0 g, 9.4 mmol) in acetone (70 ml) with stirring. The mixture was heated at reflux for 15 minutes, cooled, and methyl bromoacetate (1.8 ml, 18.7 mmol) was added. The mixture was then heated at reflux for 2 h, cooled, diluted with ethyl acetate (300 ml) and washed with water (2×100 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate) to give the title compound as a white solid (3.177 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].N1C=CC=CC=1.[CH3:22][CH2:23][O:24]CC.C(Cl)(=O)C>O>[C:23]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])(=[O:24])[CH3:22]
Reactant: Nc1sccc1C(=O)c1ccccc1F
Reactant: CCOCC
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)Nc1sccc1C(=O)c1ccccc1F

Procedure:
To a mixture of 3.90 g of 2-amino-3-(o-fluorobenzoyl)thiophene, 3.90 g of pyridine and 170 ml of anhydrous ether is added dropwise 3.90 g of acetyl chloride. Then the reaction mixture is stirred under reflux for 7 hours. After cooling, the reaction mixture is poured into water. The ether layer is separated and washed with water, and dried over sodium sulfate. The solvent is removed under reduced pressure to give an oily residure, which is crystallized from ether to give 2-acetylamino-3-(o-fluorobenzoyl)thiophene having a melting point of 143.5° - 144.5°C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:26]=[CH:25][C:16]2[O:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[O:20][C:15]=2[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:27]1([C:38](O)=[O:39])[CH:28]=[CH:29][CH:30]=[C:31]2[CH2:37][CH2:36][CH2:35][CH:34]=[CH:33][C:32]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:38]([C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[CH2:37][CH2:36][CH2:35][CH:34]=[CH:33][C:32]=23)=[O:39])[CH2:12][C:13]2[CH:26]=[CH:25][C:16]3[O:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[O:20][C:15]=3[CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)propan-1-ol (250 mg, 0.67 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (125 mg, 0.67 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1.00 mmol) and 1-hydroxybenzotriazole hydrate (102 mg, 0.67 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (257 mg, 69%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][C@H:7]([NH:13][S:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:8]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)N1CCCCC1)CN2
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)N1CCCCC1)CN2Cc1ccccc1

Procedure:
The title compound was prepared from 155A and benzaldehyde by procedures analogous to those described in Example 22A. HPLC: 99% at 7.2 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 411 [M+1]+. Chiral HPLC 100% e.e.; retention time=29.7 min; Conditions: AD (4.6×250 mm); Eluted with 25% isopropanol in hexane for 60 min at 1 mL/min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH3:6].[I-].[Na+].[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:29]([F:30])=[CH:28][C:27]([F:31])=[C:26]([NH2:32])[C:22]=3[C:23](=[O:25])[CH:24]=2)=[CH:15][C:14]=1[F:33])(=[O:11])[CH3:10].[H-].[Na+]>CN(C)C=O.O>[C:9]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:29]([F:30])=[CH:28][C:27]([F:31])=[C:26]([NH2:32])[C:22]=3[C:23](=[O:25])[CH:24]=2)=[CH:15][C:14]=1[F:33])[CH2:2][CH2:3][CH2:4][O:5][CH3:6])(=[O:11])[CH3:10]
Reactant: COCCCCl
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
949 mg of 1-chloro-3-methoxypropane and 1.30 g of sodium iodide were dissolved in 20 ml of dimethylformamide under argon atmosphere and the mixture was stirred at 90° C. for 2 hours. The reaction solution was cooled on ice and 1.51 g (4.35mmol) of Compound 27 obtained in Example 27 and 89 mg of sodium hydride (60% oil dispersion) were added thereto. The mixture was stirred at room temperature for 1 hour, 943 mg of 1-chloro-3-methoxypropane and 191 mg of sodium hydride (60% oil dispersion) were added, the temperature was raised to 60° C. and the mixture was stirred for 2 days. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 1.18 g (65%) of 2-[4-[N-acetyl-N-(3-methoxypropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH:21]=[CH2:22].CCCCCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:22][CH2:21][C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 98.8 %

Procedure:
In N,N-dimethylformamide (4 ml) was dissolved the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (101 mg, 0.333 mmol) obtained in Example 5. After addition thereto of t-butyl acrylate (146 μl, 1.00 mmol) and 1,8-diazabicyclo[5,4,0]undece-7-en (151 μl, 1.00 mmol), stirring was conducted at room temperature for 1 week. The reaction mixture was then concentated. The residue thus obtained was subjected to flash chromatoraphy on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated, whereby the title compound (142 mg, 0.329 mmol, 99%) was obtained as a colorless oil.
Reaction SMILES: C(Cl)(Cl)[Cl:2].CO.N[C@H](C([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:34]([NH:36][C@H:37]([C:45]([O:47][CH3:48])=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)CC1C=CC=CC=1>CC(O)=O>[NH2:18][C@H:19]([C:27]([NH:29][C@H:30]([C:34]([NH:36][C@H:37]([C:45]([O:47][CH3:48])=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.[ClH:2]
Reactant: ClC(Cl)Cl
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1)C(C)C
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)C(C)C
Product: Cl

Procedure:
Compound (iii) (6.87 g) was BOC-deprotected in 2 N HCl in EtAc (100 ml) for 2 hours at room temperature when a white solid precipitated (5.84 g) representing 97% yield of product. M.P. 243°-245° (decomposition). T.L.C. in 9:1 CHCl3 :MeOH (I2 stain) shows one spot at Rf 0.59. [α]D25 =8.8° (C=1, AcOH). (v) BOC.PhePheValPheOMe
Reaction SMILES: [N+:1](=C)=[N-].[CH2:4]([N:11]1[C:23]2[C:22]([S:24][CH3:25])=[C:21]([CH2:26][C:27]([OH:29])=O)[CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C>C(OCC)C>[CH2:4]([N:11]1[C:23]2[C:22]([S:24][CH3:25])=[C:21]([CH2:26][C:27]([NH2:1])=[O:29])[CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CSc1c(CC(=O)O)ccc2c3ccccc3n(Cc3ccccc3)c12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CSc1c(CC(N)=O)ccc2c3ccccc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An excess of a solution of diazomethane in diethyl ether was added to a solution of 150 mg of 9-benzyl-1-methylthiocarbazol-2-acetic acid, as obtained in Example 5, in 3 ml of diethyl ether. The resulting reaction mixture was stirred for 10 minutes at room temperature and then glacial acetic acid was added. The reaction mixture was next concentrated by evaporation under reduced pressure. 10 ml of saturated methanolic ammonia was added to a solution of the resulting residue in 5 ml of methanol, and the reaction mixture was stirred for 7 days at room temperature. After this time, the reaction mixture was concentrated by evaporation under reduced pressure and the resulting residue was subjected to column chromatography using 400 mg of silica gel using, as eluent, a 4:1 by volume mixture of hexane and ethyl acetate to yield 131 mg of the title compound as an amorphous solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([C:17]3[CH:30]=[CH:29][C:20]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[O:22])=[CH:19][N:18]=3)[C:14]=2[O:15]C)=[CH:6][C:5]=1[F:31])#[N:2].[Cl-].[Li+]>CC(N(C)C)=O.CS(C)=O>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([C:17]3[CH:30]=[CH:29][C:20]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[O:22])=[CH:19][N:18]=3)[C:14]=2[OH:15])=[CH:6][C:5]=1[F:31])#[N:2]
Reactant: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(CC#N)c(F)c3)c2OC)nc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(CC#N)c(F)c3)c2O)nc1
Yield: 57.2 %

Procedure:
Combined 6-(4-(4-(cyanomethyl)-3-fluorophenyl)-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide (27 mg, 0.064 mmol) and lithium chloride (27.0 mg, 0.638 mmol) in DMA (1.0 mL) and heated at 60° C. for 24 h. The reaction mixture was diluted with 0.2 mL DMSO and purified by prep HPLC (formic acid conditions) to give the title compound (15 mg, 57.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (quin, J=6.7 Hz, 2H) 3.25 (s, 3H) 3.30-3.37 (m, 2H) 3.40 (t, J=6.3 Hz, 2H) 4.03 (s, 2H) 7.42 (br. s., 1H) 7.52-8.06 (m, 2H) 8.41 (br. s., 1H) 8.50-8.82 (m, 3H) 8.91 (d, J=1.5 Hz, 1H) 13.28 (br. s., 1H). MS m/z 410 [M+H]+.