Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:3][C:5]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:22]([O-:24])=[O:23])[C:15](=[O:17])[O:16]1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C1OC(Cl)(c2ccccc2)c2c1cccc2[N+](=O)[O-]
Reaction time: 4 h

Procedure:
To 37 ml of thionyl chloride was added 40 g of 2-benzoyl-3-nitrobenzoic acid. The mixture was heated and stirred for 4 hours on an oil bath kept at a temperature of 50° to 60° C. Excess thionyl chloride was distilled away under reduced pressure, and 40.2 g of 3-chloro-3-phenyl-4-nitrophthalide was obtained as a brown oily substance. Separately, 9.0 g (0.08 mol.) of potassium tert-butoxide and 9.3 g (0.07 mol.) of 5-methylbenzotriazole were added to 300 ml of dried dimethylformamide, and stirred for 20 minutes at room temperature. The resulting mixture was cooled to 5° C. and thereto, was added dropwise gradually the previously prepared solution containing 20 g (0.07 mol.) of 3-chloro-3-phenyl-4-nitrophthalide in 100 ml of dried dimethylformamide as the mixture was kept at 5° C. After the dropwise addition, the cooling bath was removed, and the stirring was further continued for 5 hours at room temperature. Thereto, 300 ml of a saturated aqueous solution of ammonium chloride was added subsequently. The reaction mixture was extracted with ethyl acetate repeatedly, and the extract was washed with water. The rsulting organic layer was dried over anhydrous sodium sulfate, and the sodium sulfate was filtered off with suction. The filtrate was concentrated to obtain 27.5 g of oily substance. This oily substance was separated and purified by flash column chromatography (silica gel: 1 Kg, eluate: hexane-ethyl acetate (2:1 by volume) mixture) to obtain the intended compound, 3-phenyl-3-(5-methyl-1-benzotriazolyl)-4-nitrophthalide, in the form of white crystals. Yield 6.9 g, Melting Point 240° to 248° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:29]=[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:31]=[CH:32][C:33]=1[Cl:34]>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([N:35]2[CH2:40][CH2:39][N:38]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]5[S:17][CH:18]=[CH:19][N:20]=5)(=[O:14])=[O:13])=[CH:9][CH:10]=4)[CH:5]=[CH:4][N:3]=3)[CH2:37][CH2:36]2)[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(Cl)nccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(N3CCN(c4ccc(Cl)c(Cl)c4)CC3)nccc2c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
1-Chloro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (from Example 73, step 2; 0.050 g, 0.153 mmol) and potassium carbonate (0.106 g, 0.767 mmol) were dissolved in DMF (1.023 ml). 1-(3,4-dichlorophenyl)piperazine (0.071 g, 0.307 mmol) was added and the reaction was stirred overnight at 120° C. The reaction was filtered through a syringe filter and purified via HPLC (Phenominex C18 column, 150×30 mm, 5 micron; gradient elution 25 to 70% MeCN:H2O with 0.1% TFA modifier). The product fractions were concentrated and passed through a SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford 1-(4-(3,4-dichlorophenyl)piperazin-1-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.40 (d, J=1.8 Hz, 1H), 8.28 (d, J=8.9 Hz, 1H), 8.23 (d, J=5.7 Hz, 1H), 7.88 (dd, J=1.9, 8.8 Hz, 1H), 7.63 (d, J=5.8 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 7.28 (d, J=4.6 Hz, 1H), 7.22 (d, J=2.9 Hz, 1H), 7.02 (dd, J=2.8, 9.1 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 3.46 (s, 8H). m/z (ESI) 521.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C@@H]2[C@H](C(N)=O)C[C@@:9]1(C1C=CC=CC=1)[C@H](OCC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)CC2)C1C=CC=CC=1.CNC.[CH2:44]([N:51]1[C@@H:56]2[C@H:57]([C:59]3[N:60]=[N:61][N:62]([CH2:64][C:65]([OH:67])=O)[N:63]=3)[CH2:58][C@@:52]1([C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)[C@H:53]([O:68][CH2:69][C:70]1[CH:75]=[C:74]([C:76]([F:79])([F:78])[F:77])[CH:73]=[C:72]([C:80]([F:83])([F:82])[F:81])[CH:71]=1)[CH2:54][CH2:55]2)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH2:44]([N:51]1[C@@H:56]2[C@H:57]([C:59]3[N:60]=[N:61][N:62]([CH2:64][C:65](=[O:67])[N:8]([CH3:9])[CH3:1])[N:63]=3)[CH2:58][C@@:52]1([C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)[C@H:53]([O:68][CH2:69][C:70]1[CH:75]=[C:74]([C:76]([F:79])([F:77])[F:78])[CH:73]=[C:72]([C:80]([F:83])([F:82])[F:81])[CH:71]=1)[CH2:54][CH2:55]2)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: O=C(O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Agent: CNC
Product: CN(C)C(=O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1

Procedure:
Prepared in analogous manner to (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxamide (Example 75) using dimethylamine (2.0M solution in THF) and (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(2-carboxymethyl-2H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 145).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:60]=[CH:61][CH:62]=1)[C:22]([NH:24][C:25]1[C:26]([CH3:59])=[C:27]([C:34]([C:36]2[CH:37]=[CH:38][C:39]([NH:52][C:53](=[O:58])[C:54]([F:57])([F:56])[F:55])=[C:40]([CH:51]=2)[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=[O:35])[N:28]2[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]2)=[O:23])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:60]=[CH:61][CH:62]=1)[C:22]([NH:24][C:25]1[C:26]([CH3:59])=[C:27]([C:34]([C:36]2[CH:37]=[CH:38][C:39]([NH:52][C:53](=[O:58])[C:54]([F:55])([F:56])[F:57])=[C:40]([CH:51]=2)[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=[O:35])[N:28]2[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]2)=[O:23]
Reactant: Cc1c(NC(=O)c2cccc(OCCNC(=O)OC(C)(C)C)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(NC(=O)c2cccc(OCCN)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
16 ml (0.20 mol) of trifluoroacetic acid are added to the suspension of 6.28 g (8.28 mmol) of benzyl 5-({1-[(3-{2-[(tert-butoxycarbonyl)amino]ethoxy}benzoyl)-amino]-2-methylindolizin-3-yl}carbonyl)-2-[(trifluoroacetyl)amino]benzoate in 40 ml of dichloromethane. After stirring at ambient temperature for 30 minutes, the reaction medium is poured into 1 l of a saturated aqueous solution of sodium bicarbonate. The precipitate is filtered, washed thoroughly with water and then with diisopropyl ether and dried, so as to obtain 4.5 g (82%) of a yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][C@@H:30]1[CH3:35])([CH3:28])[CH3:27]>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:32]4[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[C@@H:30]([CH3:35])[CH2:31]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CC(C)N1CCNC[C@@H]1C
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C(C)C)[C@@H](C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-isopropyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.50 (m, 9H) 2.33 (d, J=2.53 Hz, 3H) 2.88-3.64 (m, 5H) 3.89 (br. s., 2H) 4.22-4.92 (m, 1H) 7.53-7.69 (m, 1H) 7.70-7.79 (m, 1H) 7.84-8.79 (m, 4H) 9.49-10.25 (m, 1H). ESI-MS m/z [M+H]+ 463.3.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].C[O:27][C:28]([C:30]1[NH:31]N=C(OCC2C(C3C=CC=CC=3)=NOC=2C)C=1)=O>>[OH:27][CH2:28][CH2:30][NH:31][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)nn1C
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NCCO)n(C)n1
Yield: 86 %

Procedure:
As described for example 6, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (73 mg, 0.21 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted to the title compound (68 mg, 86%) which was obtained as a white solid. MS: m/e=376.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[C:9]=1I.[C:18]([Cu])#[N:19]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[C:9]=1[C:18]#[N:19]
Reactant: N#C[Cu]
Reactant: Fc1ccccc1-c1[nH]c2cncnc2c1I
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccccc2F)[nH]c2cncnc12
Yield: 17 %

Procedure:
6-(2-fluorophenyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine and CuCN in DMF were heated for 30 min at 175° C. in a microwave vial. The reaction mixture was filtered through a metal scavenging resin column, rinsed with DMF (˜10 mL), and purified by HPLC (10-75% MeCN/H2O with 1% formic acid) to give 29 mg of desired (17% yield). LC-MS calculated for C13H7FN4: 238.2, found 239.09 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25].C(O)(C(F)(F)F)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)c1nc2cc(N)ccc2n1CC1CCC(F)(F)CC1
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-amine (440 mg, 1.37 mmol) and DMAP (165 mg, 1.37 mmol) were dissolved in 50 mL of DCM. Ethanesulfonyl chloride (0.170 mL, 1.78 mmol) was added dropwise and the solution was stirred at rt for 2.5 h. The solution was washed with saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was purified by silica gel flash chromatography using EtOAc as eluent. The fractions were concentrated and the residue was dissolved in 25 mL of MeOH. TFA (0.155 mL, 2.06 mmol) was added dropwise and the solution was stirred at rt for 30 min. The solvent was evaporated and the product was precipitated in ether affording the title compound as its corresponding TFA salt. Yield: 565 mg (78%). 1H NMR (400 MHz, METHANOL-D4) δ 1.29 (t, J=7.42 Hz, 3 H), 1.48-1.60 (m, 2 H), 1.64 (s, 9 H), 1.66-1.72 (m, 2 H), 1.73-1.82 (m, 2 H), 1.99-2.09 (m, 2 H), 2.18 (m, 1 H), 3.11 (m, 2 H), 4.50 (d, J=7.62 Hz, 2 H), 7.38 (dd, J=9.08, 2.05 Hz, 1 H), 7.72 (d, J=2.15 Hz, 1 H), 7.85 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 414.0.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([F:25])([F:24])[F:13]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(C)c1
Yield: 96 %

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (ABCR AV19078; 3 g; 13.10 mmol; 1 eq.), 2-(trifluoromethyl)phenylboronic acid (Aldrich 393606; 2.74 g; 14.41 mmol; 1.10 eq.), potassium carbonate (9.05 g; 65.48 mmol; 5 eq.) and tetrakis(triphenylphosphine)palladium(0) (1.51 g; 1.31 mmol; 0.10 eq.) in toluene (15 mL) and water (15 mL) was refluxed for 3 hours. The resulting mixture was filtered through a short pad of Celite, which was further washed with toluene. After evaporation of the solvent, the residue was taken up in ethyl acetate and washed successively with sat. aq. NaHCO3, water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (3.7 g, 96%) as a brown oil.
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].O.N>CN(C=O)C.O>[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH2:3])=[O:27]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cccc(Cl)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
EDCI hydrochloride (22.0 g) and 1-hydroxybenzotriazole (11.4 g) were added to a solution of 2-amino-3-chlorobenzoic acid (12.8 g) in DMF (100 mL), and subsequently ammonia water (22.0 ml) was added thereto. The reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 2-amino-3-chlorobenzamide (9.7 g). Iron(III) chloride hexahydrate (6.3 g) and cyclopropanecarbaldehyde (1.3 ml) were added to a suspension of the obtained 2-amino-3-chlorobenzamide (2.0 g) in water (30 ml), and the mixture was stirred overnight at 100° C. After cooling, water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 8-chloro-2-cyclopropylquinazolin-4(1H)-one (2.0 g). Compound (115) was obtained as a yellow solid (yield based on 6 steps: 18%) according to Example 114(2) using the obtained 8-chloro-2-cyclopropylquinazolin-4(1H)-one instead of compound (114a).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:13][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].S(=O)(=O)(O)O>C1C=CC=CC=1.C(OCC)C>[OH:19][C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)[N:14]([CH3:13])[C:15](=[O:20])[CH2:16][CH2:17]1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CN1C(=O)CCC1=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CN1C(=O)CCC1(O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a Grignard prepared from 37 g. (0.16 mole) of 3-bromobenzotrifluoride and 3.7 g. (0.16 mole) of magnesium turnings in 100 ml. of dry diethylether, there is added dropwise over a period of about 10 minutes 12.2 g. (0.11 mole) of N-methylsuccinimide in 100 ml. of dry benzene. The resulting mixture is stirred and refluxed for about 4 hours and then allowed to stand overnight at room temperature. Stirring is resumed and 40 ml. of 50% sulfuric acid is added dropwise at such a rate to maintain a gentle reflux. After an additional 0.5 hours, the water layer is separated and washed twice with 50 ml. of benzene. The organic layers are combined and washed with 50 ml. of sodium carbonate and then twice more with 50 ml. of water. The resulting layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting residue is crystallized from methylene chloride/hexane to give 5-hydroxy-1-methyl-5-(m-trifluoromethylphenyl)pyrrolidone; m.p. 137°- 139°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]([O:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:21][CH:17]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]([O:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])=[C:2]([F:1])[CH:3]=1)[CH:18]([CH3:20])[CH3:19])(=[O:24])[CH3:23]
Reactant: CCCCC(OCOC)c1ccc(C(O)C(C)C)cc1F
Reactant: CC(=O)OC(C)=O
Product: CCCCC(OCOC)c1ccc(C(OC(C)=O)C(C)C)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A mixture of 1-[3-fluoro-4-[1-(methoxymethoxy)pentyl]phenyl]-2-methylpropanol (104 mg), acetic anhydride (66 mg) and N,N-dimethylaminopyridine (2 mg) was stirred at room temperature for 1 hour. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (85:15) to give 1-[3-fluoro-4-[1-(methoxymethoxy)pentyl]phenyl]-2-methylpropyl acetate (113 mg) as an oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([CH2:8][F:9])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:17]>CCOCC>[NH2:1][C@H:2]([C:6]([CH2:8][F:9])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:17]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)CF
Agent: Cl
Solvent: CCOCC
Product: CC(C)[C@H](N)C(=O)CF
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Boc-ValCH2F (0.48 g, 2.06 mmol) in ether (10 mL) was added a saturated solution of HCl in ether (25 mL). The mixture was stirred for 30 minutes at room temperature. The solvent was evaporated under reduced pressure at room temperature. The residue was quickly triturated with ether (2×30 mL) and then was pumped dry, giving 0.24 g of ValCH2F hydrochloride. Boc-Ala-Ala-ProOH (Enzyme Systems Products, 0.503 g, 1.41 mmol) was dissolved in THF (5 mL) and was cooled to -20° C. NMM (0.155 mL, 1.41 mmol) was added, followed by IBCF (0.183 mL, 1.41 mmol). After 5 minutes, this mixture was charged with a solution of ValCH2F hydrochloride (0.24 g, 1.41 mmol) in DMF (2 mL). A second equivalent of NMM (0.155 mL, 1.41 mmol) was added. The mixture was stirred at -15° C. for 15 minutes. 1 molar HCl (15 mL) was added. The product was extracted with ethyl acetate (2×15 mL). The combined extracts were washed with saturated aqueous NaHCO3 (15 mL), brine (15 mL), dried over MgSO4, filtered, and evaporated to dryness The residue was slowly crystallized at -20° C. from CH2Cl2 /hexane, giving 0.47 g (47% from Boc-ValCH2F of Boc-Ala-Ala-Pro-ValCH2F.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[NH:7]1)=[O:5])C.[OH-].[Li+]>>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([CH:8]2[NH:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:10][CH:9]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:25][CH:24]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2)C(c2ccc(C(C)(C)C)cc2)N1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(C2NC(C(=O)O)CC2S(=O)(=O)c2ccccc2)cc1

Procedure:
In analogy to the procedure described in example 253e, 5-(4-tert-butylphenyl)-4-(phenylsulfonyl)pyrrolidine-2-carboxylic acid ethyl ester was saponified in the presence of lithium hydroxide to give the title compound as colorless solid which was used in the next step without further purification. MS (ESI): m/z=388.2 [M+H]
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH2:21]1[CH:23]([CH:24](O)C#N)[CH2:22]1>CC(O)=O.C1COCC1.[OH-].[Na+]>[CH:23]1([CH2:24][N:4]2[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]2)[CH2:21][CH2:22]1
Reactant: N#CC(O)C1CC1
Reactant: OC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC1CCN(CC2CC2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
3-Hydroxy-pyrrolidine (5.65 g, 65 mmol, 1.0 equiv) was dissolved in 100 mL of 1% AcOH in THF and cooled to 0° C. Na(OAc)3BH (24 g, 114 mmol, 1.75 equiv) and cyclopropylcarboxaldehyde (5.0 g, 71 mmol, 1.1 equiv) were added and the resulting mixture was stirred at 0° C. for 1 h and room temperature overnight (16 h). The reaction was diluted with 200 mL of 2 N NaOH, and the product was extracted 3×200 mL of CH2Cl2. The organic extracts were combined, dried over Na2SO4, decanted and concentrated to yield the desired product as a free-flowing oil (7.26 g, 79%) which was used without further purification; MS, m/z 142=M+1.
Reaction SMILES: [C:1]([NH:5][CH:6]([CH2:23][OH:24])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]1[CH:17]=[CH:18][C:19](=S)[NH:20][N:21]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:26][NH2:27]>>[C:1]([NH:5][CH:6]([CH2:23][OH:24])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]1[N:21]=[N:20][C:19]([NH:26][NH2:27])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(OCC(CO)NC(C)(C)C)c(-c2ccc(=S)[nH]n2)c1
Reactant: NN
Solvent: O
Product: Cc1ccc(OCC(CO)NC(C)(C)C)c(-c2ccc(NN)nn2)c1

Procedure:
6-[2-(2-t-Butylamino-3-hydroxypropoxy)-5-methylphenyl]-3(2H)-pyridazinethione was treated with hydrazine hydrate in a similar manner to the procedure described in Example 2 (vi) to give 3-[2-(2-t-butylamino-3-hydroxypropoxy)-5-methylphenyl]-6-hydrazinopyridazine as an oil which was isolated as the hemisulphate, m.p. 172°-178° C. (Found: C, 54.6; H, 7.1; N, 17.5; S, 3.9% C18H27N5O2. 0.5H2SO4 requires: C, 54.8; H, 7.2; N, 17.8; S, 4.1%
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]([C:17]([NH2:19])=[O:18])=[CH:12][CH:11]=1)[CH3:2].[CH3:20]N(C)C=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]([C:17]([NH2:19])=[O:18])=[CH:12][CH:11]=1)[CH:2]=[CH2:20]
Reactant: CN(C)C=O
Reactant: CCOc1ccccc1-c1ccc(C(N)=O)c(=O)[nH]1
Product: C=CCOc1ccccc1-c1ccc(C(N)=O)c(=O)[nH]1

Procedure:
In a similar manner to that of Example 47, the product of Example 47 (1.89 g) gave the title compound, 1.74 g, m.p. 210°-212° C. (from dimethylformamide).
Reaction SMILES: [CH3:1][S:2][CH3:3].ClCl.[NH2:6][C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Br:13].N1C=CC=CC=1>ClCCl>[Br:13][C:8]1[CH:9]=[N:10][N:11]([CH3:12])[C:7]=1[N:6]=[S:2]([CH3:3])[CH3:1]
Reactant: Cn1ncc(Br)c1N
Reactant: CSC
Agent: ClCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1ncc(Br)c1N=S(C)C

Procedure:
A solution of 0.60 mL (8.2 mmol) of dimethyl sulfide in 30 mL of dichloromethane was cooled to -20° C. and 0.50 g (7.0 mmol) of chlorine was added through a sparge tube with cooling and stirring. Subsequently, 1.0 g (5.7 mmol) of 5-amino-4-bromo-1-methylpyrazole and then 1.0 g (12.7 mmol) of pyridine were added with cooling and stirring. A 2 mL aliquot of this mixture was removed and the light yellow solids present were collected by filtration and washed with deuteroacetonitrile.