Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH:13]1([CH2:16][N:17]([CH2:39][CH2:40][CH3:41])[C:18]([C:20]2[N:24]3[CH2:25][CH2:26][N:27]([C:28]4[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=4[CH3:36])[C:23]3=[N:22][C:21]=2[CH2:37]C)=O)[CH2:15][CH2:14]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:13]1([CH2:16][N:17]([CH2:18][C:20]2[N:24]3[CH2:25][CH2:26][N:27]([C:28]4[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=4[CH3:36])[C:23]3=[N:22][C:21]=2[CH3:37])[CH2:39][CH2:40][CH3:41])[CH2:15][CH2:14]1
Reactant: CCCN(CC1CC1)C(=O)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCN(Cc1c(C)nc2n1CCN2c1c(C)cc(C)cc1C)CC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A solution of Red-Al (3.3 M in toluene, 0.70 mL, 2.33 mmol) was added dropwise to a solution of 2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylic acid cyclopropylmethyl-propyl-amide (0.177 g, 0.46 mmol) in toluene (3 mL) at 0° C. After stirring at room temperature for 24 h, the reaction mixture was cooled to 0° C. and I N sodium hydroxide (10 mL) was added dropwise. The above mixture was extracted with dichloromethane (40 mL), and the organic extracts were washed with water and dried over anhydrous sodium sulfate. Solvents were removed in vacuo to afford the title compound as a light yellow oil which solidified upon cooling (109 mg, 65% yield). The purity of the product was determined to be 91% by LC/MS. 1H NMR (CDCl3, 300 MHz) δ 6.85 (s, 2H), 4.09-3.96 (m, 4H), 3.45 (s, 2H), 2.44 (t, J=7.1 Hz, 2H), 2.29 (d, J=6.5 Hz, 2H), 2.23 (s, 3H), 2.19 (s, 6H), 2.04 (s, 3H), 1.46 (quintet, J=7.3 Hz, 2H), 1.28-1.25 (m, 1H), 0.87 (t, J=7.2 Hz, 3H), 0.49-0.46 (m, 2H), 0.09-0.06 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 155.4, 137.1, 136.9, 136.0, 135.0, 129.7, 117.7, 58.5, 55.5, 53.8, 48.0, 42.4, 20.9, 20.3, 18.2, 13.3, 12.0, 8.9, 4.0. Mass spec.: 367.24 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[C:4]([NH:7][C:8](=[O:21])[CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:20])[S:5][CH:6]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)=[C:4]([NH:7][C:8](=[O:21])[CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:20])[S:5][CH:6]=1
Reactant: O=C(Cn1c(=O)ccc2ncccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cnc(-c2c(Cl)csc2NC(=O)Cn2c(=O)ccc3ncccc32)n1

Procedure:
To a solution of N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetamide (0.047, 0.12 mmol) in DMF (0.4 mL) was added potassium carbonate (0.041 g, 0.30 mmol) and iodomethane (17 uL, 0.27 mmol). After 2 h the reaction mixture was partitioned between H2O and ethyl acetate. The organic phase was collected, dried (sodium sulfate), filtered and concentrated under reduced pressure. The desired product was submitted to prep HPLC for further purification. Retention time (min)=4.407, method [8], MS (ESI) 403.1 (M+H). 1H NMR (CDCl3) δ 12.40 (s, 1H), 8.32 (d, J=5.1 Hz, 1H), 8.07 (s, 1H), 7.56 (d, J=8.1 Hz, 1H) 7.41 (d, J=5.1 Hz, 1H), 7.39 (d, J=5.1 Hz, 1H) 6.81 (s, 1H), 4.89 (s, 2H), 4.02 (s, 3H), 3.47-3.42 (m, 2H), 3.03-2.98 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.C(N(CC)CC)C.Cl[C:45]([O:47][CH3:48])=[O:46]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:18][CH2:19][N:20]([C:45]([O:47][CH3:48])=[O:46])[CH2:21][CH2:22]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCNCC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCC(c2nc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c(-c3nc4ccccc4s3)c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
Into a solution of tert-butyl (3R)-3-[[5-(1,3-benzothiazol-2-yl)-6-oxo-2-(piperidin-4-yl)-1,6-dihydropyrimidin-4-yl]amino]piperidine-1-carboxylate (100 mg, 0.20 mmol, 1.00 equiv) and triethylamine (29.7 mg, 0.29 mmol, 1.50 equiv) in dichloromethane (5 ml) was added methyl chloroformate (14.8 mg, 0.16 mmol, 0.80 equiv). The resulting mixture was stirred for 2 h at room temperature. Concentration under reducing pressure gave 100 mg of the title compound as a crude product, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 569.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH:76]5[CH2:81][CH2:80][O:79][CH2:78][CH2:77]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3F)ncc21
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
To a mixture of 0.070 g (0.161 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182) and 4 mL of dimethylformamide was added 0.0346 g (0.256 mmole) of 1-hydroxybenzotriazole, 0.0950 g (0.250 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1253 g (0.936 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0248 g (0.246 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0504 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N-(tetrahydro-pyran-4-yl)-benzamide (I-225).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[NH:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[S:14](Cl)(=[O:16])=[O:15].[OH:18][CH2:19][C@:20]([OH:37])([CH3:36])[C:21](=[O:35])[C@@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH:24]([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[NH:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[S:14]([O:18][CH2:19][C@:20]([OH:37])([CH3:36])[C:21](=[O:35])[C@@H:22]([NH:27][C:28]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:34])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:15])=[O:16]
Reactant: C#CCNC(=O)c1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)[C@](C)(O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNC(=O)c1ccc(F)c(S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
2-Fluoro-5-(prop-2-yn-1-ylcarbamoyl)benzene-1-sulfonyl chloride (3, 2.52 g, 9.14 mmol) was added dropwise to tert-butyl ((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)carbamate (2.65 g, 9.14 mmol), DIEA (1.91 mL, 10 mmol) and DMAP (0.1 g, 0.914 mmol) in DCM (30 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was washed with 2N HCl and brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (30% EtOAc/Hep) to give product as an oil (3.62 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([Br:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O.[Na]>C(O)(C)C>[Br:1][C:2]1[CH:13]=[C:12]([Br:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(Br)cc1Br
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(Br)cc1Br

Procedure:
using isopropyl 2,4-dibromo-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2,4-dibromo-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H-NMR (CDCl3, 400 MHz) 8.03 ppm (s, 1H), 4.72 ppm (s, 1H), 5.23 ppm (m, 1H), 2.96 ppm (m, 2H), 2.83 ppm (m, 2H), 2.17 ppm (m, 2H), 1.35 ppm (d, 6H),
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C1COCC1>[Pd].C(O)C>[F:11][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([F:1])[C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(F)c(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A mixture of 4-(2,6-difluoro-4-nitrophenyl)morpholine (4.71 g, 19.3 mmol), THF (30 mL), ethanol (30 mL) and Pd/C (2.0 g, 10%) was stirred at rt under H2 overnight. The mixture was filtered and concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as a yellow solid (3.62 g, 88%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.S(Cl)([Cl:16])=O>CCCCCC>[CH3:1][N:2]1[C:6]([C:7]([Cl:16])=[O:8])=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1
Reactant: O=S(Cl)Cl
Reactant: Cn1nc(C(F)(F)F)cc1C(=O)O
Solvent: CCCCCC
Product: Cn1nc(C(F)(F)F)cc1C(=O)Cl
Yield: 67.3 %

Procedure:
A mixture of 0.19 g of 1-methyl-3-trifluoromethyl-1H-pyrazole-5-carboxylic acid, 0.15 g of thionyl chloride and 5 ml of hexane was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.14 g of 1-methyl-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride. To a mixture of 0.22 g of N-(2-aminobenzoyl)-N′-ethoxycarbonylhydrazine and 10 ml of pyridine was added 0.14 g of the resulting 1-methyl-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride and the mixture was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and a deposited precipitates were collected by filtration to obtain 0.23 g of the present compound (3) of the formula:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([C:10]([O:12]CC)=O)=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>CN(C)C=O.[Cl-].[Na+].O.O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[C:10](=[O:12])[C:9]2[C:4](=[N:5][C:6]([S:15][CH3:16])=[N:7][CH:8]=2)[NH:3][C:25]1=[O:26]
Reactant: CCOC(=O)c1cnc(SC)nc1N
Reactant: O=C=Nc1ccccc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2c(=O)n(-c3ccccc3Cl)c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (5.26 g, 131 mmol) was added to a solution of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate (20.0 g, 94 mmol, US 2005/0020590) in N,N-dimethylformamide (700 mL) at 0° C. After 10 minutes, 1-chloro-2-isocyanatobenzene (15.9 mL, 131 mmol) was added dropwise to the mixture. The reaction was warmed to room temperature and stirred for 6 hours. The reaction mixture was diluted with brine (200 mL) and water (1000 mL) and extracted with ether (700 mL 2×). The aqueous layer was acidified with 5% citric acid (until pH=4-5), treated with brine, and extracted with ethyl acetate (2×). The combined organic layers were washed with water (2×), dried over MgSO4, filtered, and concentrated to remove most of the solvent. The mixture was filtered, and the solid was washed with cold ethyl acetate, and oven dried to provide the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: C1CCNCC1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(N5CCCCC5)n4)cc3)cc12

Procedure:
Using piperidine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 1.6 (m, 6H); 2.98 (m, 2H); 3.55 (m, 2H); 3.84 (m, 4H); 7.19 (m, 2H); 7.49 (m, 2H); 7.93 (d, 2H, J=8 Hz); 8.20 (m, 31H); 8.44 (d, 1H, J=5 Hz); 8.69 (bt, 1H); 12.14 (bs, 1H). MS (ion spray) m/z 451 (M+H)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(Cl)Cl.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17].[CH3:18][CH:19]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:20]>CCOCC>[CH3:18][C:19]1([CH3:20])[C:13]2[C:14](=[CH:15][C:16]3[CH2:8][C:9](=[O:17])[CH2:10][C:11]=3[CH:12]=2)[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21]1
Reactant: O=C1Cc2ccccc2C1
Reactant: CC(C)CCC(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)CC(=O)C3
Temperature: -20 °C

Procedure:
A 1 L 3-neck flask was charged with AlCl3 (80.8 g, 0.606 mol), fitted with a mechanical stirrer, and a 250 mL addition funnel, charged with anhydrous methylene chloride (370 mL). The slurry was cooled to −20° C. and stirred. The addition funnel was then charged (in two portions over the course of the reaction) with a solution of 2-indanone (40.0 g, 0.303 mol) {Note: Aldrich brand 2-indanone was rinsed with ether to remove brown impurities}, 2,5-dichloro, 2,5-dimethylhexane (55.4 g, 0.303 mol) and anhydrous methylene chloride (180 mL). The solution was dripped onto the cold, stirring AlCl3 slurry over the course of 50 min. After stirring for 2.5 h after the addition was complete, a solution of 2,5-dichloro, 2,5-dimethylhexane (13 g, 0.071 mol) and anhydrous methylene chloride (42 mL). After stirring an additional hour, the reaction mixture was poured onto ice (1 L) and treated with ether (500 mL). The organic layer was separated and the aqueous layer extracted with ether (2×200 mL). The combined organic layers were washed with 2.5 M NaCl (aq) (3×75 mL) then water (25 mL) then dried over MgSO4. The dried organic solution was filtered into a 3 L flask and the solvent was slowly removed with a nitrogen blowing over the surface of the solution. The solid that remained was washed with cold pentane and the solids isolated by filtration. The product, a fine crystalline material, was separated manually from a small amount of chunky oily solids that contained product and an impurity. Yield 21 g.
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:5][CH2:4]1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>O.C(O)C>[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH:17]3[CH2:18][O:19]3)=[CH:12][CH:13]=2)[CH2:4][CH2:5]1
Reactant: Oc1ccc(OCC2CC2)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1cc(OCC2CO2)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.46 g of sodium hydroxide in 1.8 ml water and 14 ml ethanol, 1.64 g of p-(cyclopropylmethoxy)-phenol and 5.54 g of epichlorohydrin is stirred at room temperature in a nitrogen atmosphere for 24 hours and left at room temperature for 21/2 days. The solvent is evaporated in vacuo and the residue is taken up in ether, washed with water and sodium chloride solution. After drying over anhydrous magnesium sulfate, the solution is filtered and concentrated under reduced pressure to yield p-(cyclopropylmethoxy)-phenoxymethyloxirane which is used directly in the condensation.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=O)=[CH:12][CH:11]=1>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[CH3:1][C:2]([S@:5]([N:7]=[C:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([C:9]([F:8])([F:20])[F:21])[CH:18]=2)[CH2:14][CH2:15]1)=[O:6])([CH3:4])[CH3:3]
Reactant: O=C1CCc2ccc(C(F)(F)F)cc21
Reactant: CC(C)(C)[S@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N=C1CCc2ccc(C(F)(F)F)cc21
Temperature: 75 °C

Procedure:
To a stirred solution of (R)-2-methylpropane-2-sulfinamide (578 mg, 4.77 mmol) and 6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (1.00 g, 5.00 mmol) in THF (4 mL) at rt was added tetraethoxytitanium (1.88 mL, 9.08 mmol). The reaction mixture was heated at 75° C. for 16 h. The reaction mixture was allowed to cool and used directly in the next step. LC-MS (ESI) 304.0 (M+H), RT=2.20 min (Method B).
Reaction SMILES: [F:1][CH:2]([F:13])[CH:3]([CH3:12])[CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[S:14]1[C:18]2=[CH:19][CH:20]=[CH:21][C:22]([S:23]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=3)(=[O:25])=[O:24])=[C:17]2[N:16]=[CH:15]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:13][CH:2]([F:1])[CH:3]([CH3:12])[CH2:4][C:5]1([OH:11])[CH2:6][CH2:7][N:8]([C:31]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][S:23]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]4[S:14][CH:15]=[N:16][C:17]=34)(=[O:25])=[O:24])=[CH:35][CH:34]=2)=[O:32])[CH2:9][CH2:10]1
Reactant: CC(CC1(O)CCNCC1)C(F)F
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(CC1(O)CCN(C(=O)c2ccc(NS(=O)(=O)c3cccc4scnc34)cc2)CC1)C(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask was added 4-(3,3-difluoro-2-methylpropyl)piperidin-4-ol (110 mg 0.57 mmol), 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (190 mg, 0.57 mmol), DIPEA (367 mg, 2.8 mmol), HATU (261 mg, 0.69 mmol), and DCM (5 mL). The mixture was stirred at r.t. for 16 hours. After washing with brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Purification by a standard method gave the desired compound. 1H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.20 (d, J=8.1 Hz, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.94 (s, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.6 Hz, 2H), 5.90-5.61 (m, 1H), 4.36 (s, 1H), 3.57-3.42 (m, 1H), 3.21 (s, 2H), 2.24 (d, J=7.6 Hz, 1H), 2.05 (s, 1H), 1.86-1.77 (m, 2H), 1.36 (dd, J=14.8, 6.3 Hz, 4H), 1.10 (d, J=7.0 Hz, 3H). LC-MS: m/z 510.5 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][C:7]1[N:8]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])[NH2:30])=[CH:25][C:24]=2[CH3:32])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][NH:21][N:22]=3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.[OH-].[Li+]>CO.C1COCC1>[N:22]1[NH:21][N:20]=[N:19][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]([C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:31])[NH2:30])=[CH:25][C:24]=3[CH3:32])[C:7]([CH2:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:11][CH:10]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-c3nn[nH]n3)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(-c2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.9 %

Procedure:
To 3-{1-(4-carbamoyl-2-methyl-phenyl)-5-[4-(2H-tetrazol-5-yl)-phenyl]-1H-pyrrol-2-yl}-propionic acid ethyl ester (26B) (16 mg, 0.035 mmol.) in 1:1 MeOH/THF (1.0 mL) was added aq. 1.0 N lithium hydroxide (2 eq). The reaction mixture was allowed to stir at rt for 16 h. The reaction mixture was poured into 10 mL ice-water solution which was extracted with diethyl ether. The aqueous layer was acidified with aq HCl (2 N) to pH=2, and then was extracted with diethyl ether. The combined organic layers were dried over Na2SO4. The solvent was removed under vacuum to yield the desired target 3-(5-(4-(2H-tetrazol-5-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid (26C) (15 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:12](=O)[CH:13]([CH:21]([C:25]2[CH:42]=[CH:41][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])=[O:30])=[CH:27][CH:26]=2)[CH2:22][CH2:23][CH3:24])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:45]1([NH:51][NH2:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>N1C=CC=CC=1.CCOC(C)=O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]([C:12]2[N:51]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:52]=[C:3]3[C:4]=2[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]3[Cl:1])[CH:21]([C:25]2[CH:42]=[CH:41][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:26]=2)[CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(C(=O)c1cc(C(F)(F)F)cc(Cl)c1F)c1ccc(Cl)cc1
Reactant: NNc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCC(c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1c2cc(C(F)(F)F)cc(Cl)c2nn1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of the major diastereomer of tert-butyl N-(4-{1-[2-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-1-(4-chlorophenyl)-2-oxoethyl]butyl}benzoyl)-β-alaninate (EXAMPLE 2, Step A, 100 mg, 0.153 mmol) in pyridine (1.5 mL) was added phenylhydrazine (0.083 mL, 0.076 mmol). The mixture was stirred at 80° C. for 18 hours in a sealed tube. The mixture was diluted with EtOAc then washed with 2 N HCl (aq) then saturated NaCl (aq). The organic layer was dried over sodium sulfate, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to afford the title compound. This diastereomer was resolved to provide enantiopure material by HPLC on a ChiralPak IA column (2 cm×25 cm) eluting with 9 mL/min of 5% EtOH/n-heptane. LC1 2.98 min. (M-tBu+H)+ 668.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]([CH:8]1[C:12](=O)[CH2:11][O:10][CH2:9]1)=[O:7].OS(O)(=O)=O>O.CCOCC>[CH3:4][O:5][C:6]([CH:8]1[CH:12]([C:1]#[N:2])[CH2:11][O:10][CH2:9]1)=[O:7]
Reactant: COC(=O)C1COCC1=O
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1COCC1C#N
Reaction time: 16 h

Procedure:
To a stirred solution of 3.9 g (60 mmol) KCN in 5.5 ml of water at 4° C., a solution of 2.9 g (20 mmol) of 4-oxo-tetrahydro furane 3-carboxylic acid methyl ester in ether (26 ml) was added. To the precipitate of salts, 3.5 ml H2SO4 (18 N) was added and stirred for 16 hours. Then the organic solution was separated, the salts were washed twice with benzene, dried over sodium sulfate and concentrated in vacuo to give 4-cyano-tetrahydro furane 3-carboxylic acid methyl ester.