Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([CH:22]=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.[CH:24]1([Mg]Br)[CH2:26][CH2:25]1>O1CCCC1>[CH:24]1([CH:22]([C:18]2[C:17]3[N:13]4[CH2:12][CH2:11][CH2:10][N:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])[C:14]4=[N:15][C:16]=3[CH:21]=[CH:20][CH:19]=2)[OH:23])[CH2:26][CH2:25]1
Reactant: O=Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: OC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (3.00 g, 8.67 mmol) in tetrahydrofuran (25 mL) was added dropwise cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 11.6 mL, 11.6 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 h. The reaction was quenched by methanol, and the mixture was neutralized with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-60% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol to give the title compound as a colorless crystal (1.71 g, 4.40 mmol, 76%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][N:21](C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[CH:26]([N:28]([CH3:30])N)=[O:27].C1CCN2C(=NCCC2)CC1>C(O)C>[Cl:25][C:6]1[C:7]([F:24])=[CH:8][C:9]2[C:4]([CH:5]=1)=[N:3][C:2]1[N:21]([N:28]([CH:26]=[O:27])[CH3:30])[CH:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12](=[O:13])[C:11]=1[CH:10]=2
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reactant: CN(N)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1cn(N(C)C=O)c2nc3cc(Cl)c(F)cc3cc2c1=O
Yield: 86.9 %

Procedure:
The 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine is prepared under the conditions described in Example 1 but starting from 19.25 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate, 4.05 g of N-formyl-N-methylhydrazine and 1.6 g of DBU in 200 cm3 of ethanol. 16.4 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-1,4-dihy drobenzo [b][1,8]naphthyridine are obtained in the form of a colourless solid melting at 296°-298° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18]([CH3:32])=[CH:19][C:20]([OH:31])=[C:21]([CH:30]=1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[C:18]([CH3:32])=[CH:19][C:20]([O:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:30]=1
Reactant: Cc1cc(O)c(C(=O)c2ccccc2)cc1Cl
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)c(Cl)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 140 °C
Reaction time: 7 h
Yield: 90.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 5-chloro-2-hydroxy-4-methylbenzophenone (443 mg), and 4-dimethylaminopyridine (220 mg) were suspended in o-dichlorobenzene (1 ml), and the mixture was stirred at 140° C. for 7 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (175 mg, yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](C2C=CC=CC=2)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(C(=O)CCC(O)=O)C=CC=1Cl.ClC1C=C(C(O)CCC(O)=O)C=CC=1Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:13][C:12](=[O:14])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCC(c1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)CCC(=O)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)CCC(O)c1ccc(Cl)c(Cl)c1
Product: O=C1CCC(c2ccc(Cl)c(Cl)c2)O1

Procedure:
A novel three-step process for preparing 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid is disclosed, which involves (1) reducing 4-(3,4-dichlorophenyl)-4-ketobutanoic acid to 4-(3,4-dichlorophenyl)-4-hydroxybutanoic acid; (2) then converting the intermediate hydroxy acid formed in the first step to 5-(3,4-dichlorophenyl)-dihydro-2(3H)-furanone, and (3) thereafter reacting the resulting gamma-butyrolactone compound with benzene in a Friedel-Crafts type reaction to form the desired final product. The latter compound is known to be useful as an intermediate leading to cis-(1S)(4S)- -N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine (sertraline), which is known to be a preferred anti-depressant agent in the field of medicinal chemistry. The aforementioned 5-(3,4-dichlorophenyl)-dihydro-2(3H)-furanone and 4-(3,4-dichlorophenyl)-4-hydroxybutanoic acid are both novel compounds.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH2:8][CH2:9][C:2]1=2.S(=O)(=O)(O)O.[NH2:15][C:16]([NH2:18])=[O:17]>>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:15][C:16]([NH2:18])=[O:17])[CH2:7][CH2:8][CH2:9][C:2]1=2
Reactant: NC(N)=O
Reactant: C1=Cc2ccsc2CC1
Agent: O=S(=O)(O)O
Product: NC(=O)NC1CCCc2sccc21

Procedure:
A sample of 6,7-dihydrobenzo[b]thiophene is stirred in the cold in 96% sulfuric acid containing 4- 6 mole equivalents of urea. After 1 hour the mixture is poured on ice and the organic phase is removed. Evaporation of the organic phase to dryness in vacuo affords 4,5,6,7-tetrahydrobenzo[b]-thien-4-ylurea.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([N:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]([O:39][C:40]4[CH:45]=[CH:44][C:43]([F:46])=[C:42](Cl)[CH:41]=4)=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34]([O:36][CH3:37])=[O:35])[C@@H:29]([CH3:38])[CH2:28][CH2:27]4)[CH:21]=[N:20]2)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>ClCCl>[C:8]([O:12][C:13]([N:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]([O:39][C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=4)=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34]([O:36][CH3:37])=[O:35])[C@@H:29]([CH3:38])[CH2:28][CH2:27]4)[CH:21]=[N:20]2)[CH2:16]1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)c(Oc3ccc(F)c(Cl)c3)c2CC[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 593 %

Procedure:
Trifluoroacetic acid (1.0 mL, 6.49 mmol) was added to a solution of (S)-methyl 6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3-chloro-4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.098 g, 0.033 mmol) in dichloromethane (1.0 mL) and the reaction mixture stirred at rt for 2 h. The mixture was then concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl (S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.105 g, 100%) as an off-white solid. MS (ESI, pos. ion) m/z 437 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18](O)=[O:19])[C:15]2[N:21]=[CH:22][CH:23]=[CH:24][C:14]=2[C:13](=[O:25])[N:12]=1.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:19])[C:15]2[N:21]=[CH:22][CH:23]=[CH:24][C:14]=2[C:13](=[O:25])[N:12]=1
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 68.6 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (116 mg, 1 equiv), ethyl 2-methyl-2-[4-({[4′-trifluoromethyl)-4-biphenyl]-methyl}amino)-1-piperidinyl]propanoate (Int. B2) (150 mg, 1 equiv), HATU (151 mg, 1.2 equiv), DMF (2.72 ml) and DIPEA (0.17 ml, 3 equiv) was shaken at room temperature for 3.25 h. The reaction mixture was partitioned between ethyl acetate/methanol and aqueous sodium bicarbonate, the organic layer was brine-washed, dried and treated with activated charcoal (250 mg). Flash chromatography (silica, 3-4% methanol in DCM) gave ethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate as a white solid (178 mg).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25]C1C=CC(CN)=NC=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1ccc(CN)nc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1ccc(CNc2nc(C)c(C)c(NC3CCCCC3)n2)nc1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(5-methylpyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.97-1.33 (m, 5H), 1.51-1.69 (m, 5H), 1.87 (s, 3H), 2.24 (d, J=6.0 Hz, 6H), 3.73 (s, 1H), 4.57 (d, J=5.6 Hz, 2H), 7.20 (d, J=7.79 Hz, 1H), 7.56 (d, J=8.06 Hz, 2H), 8.06 (t, J=5.6 Hz, 1H), 8.33 (s, 1H), 12.90 (bs, 1H); MS (ESI) m/z 326.1 (M+1)+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].I[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)([CH3:4])[CH3:3]
Reactant: Ic1ccc(-c2ccccn2)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 71.5 %

Procedure:
Trimethylsilylacetylene (4.1 mL, 28.8 mmol) and tetrakis(triphenylphosphine)palladium (0) (832 mg, 0.72 mmol) were added to a suspension of (1) (4.06 g, 14.4 mmol) and copper (I) iodide (274 mg, 1.44 mmol) in triethylamine (120 mL) that had been deoxygenated with argon. The mixture was deoxygenated with argon and then stirred under argon at room temperature for 40 hours. Aqueous hydrochloric acid (3 M, 320 mL) and dichloromethane (250 mL) were added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with aqueous hydrochloric acid (3 M, 30 mL), water (250 mL), brine (250 mL), dried over anhydrous magnesium sulfate, filtered and then the solvent was completely removed. The residue was purified by column chromatography over silica using a dichloromethane/light petroleum mixture (1:4) as the eluent. The main band was isolated and the solvent completely removed to give (2) (2.59 g, 72%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[N:12]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2].Cl.[NH2:27][OH:28].C(N(CC)CC)C>CCO>[CH3:25][N:23]([CH3:24])[C:21](=[O:22])[CH2:20][N:12]([C@@H:7]1[C:8]2[C:4](=[C:3]([C:1](=[NH:2])[NH:27][OH:28])[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: NO
Reactant: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C#N)cccc21
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C(=N)NO)cccc21
Temperature: 85 °C
Yield: 98.4 %

Procedure:
Prepared using General Procedure 3. To a solution of (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-yl(2-(dimethylamino)-2-oxoethyl)carbamate (3.8 g, 11.07 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (1.92 g, 27.67 mmol) and triethylamine (2.8 g, 27.67 mmol). The reaction solution was heated to 85° C. for 2 h. The solvent was removed under vacuum and the residue partitioned between DCM (3×10 mL) and water (10 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to produce 4.10 g (87.7%) of (S)-tert-butyl 2-(dimethylamino)-2-oxoethyl(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)carbamate, which was 65% pure and used directly in the next experiment. LCMS-ESI (m/z) calculated for C19H28N4O4; 376.45. found 377.2 [M+H]+, tR=1.85 min.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:28])=O>>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([Cl:28])=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2)nc1
Yield: 99.6 %

Procedure:
4-(5-n-Decyl-2-pyrimidyl)benzoic acid (2.0 g) prepared in the above (3) was added to thionyl chloride (10 g) and a slight amount of N,N-dimethylformaide was added thereto and the mixture was refluxed for 4 hours. Excess thionyl chloride was distilled off to obtain the titled compound (2.1 g).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[OH:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N+:10]([CH3:18])[N:9]([CH3:19])[C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+].[CH3:28]I.O>CS(C)=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:28][O:6][C:7]1[C:8]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N+:9]([CH3:19])[N:10]([CH3:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CI
Reactant: Cn1c(-c2ccccc2)c(O)c(-c2ccccc2)[n+]1C
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(-c2ccccc2)n(C)[n+](C)c1-c1ccccc1
Temperature: 60 °C
Yield: 53 %

Procedure:
4-Hydroxy-1,2-dimethyl-3,5-diphenylpyrazolium perchlorate (7 g, 0.02 mole) in DMSO (2.5 ml) is added to 5% sodium hydroxide (0.84 g, 0.02 mole) in DMSO (100 ml), dropwise with stirring. The mixture is warmed to 60° C for 5 minutes, then stirred at room temperature for 4 hours. The reaction mixture (75 ml) is treated with methyl iodide (0.43 g, 0.013 mole) and the mixture is stirred at room temperature for 16 hours, then heated at 40° C for 2 hours. On pouring into water, a solid precipitates with melting point 88° C. One crystallization from methanol gives the product with melting point 132°-132.5° C in 53% yield.
Reaction SMILES: [H-].[Na+].I[CH3:4].O.[N+:6]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)([O-:8])=[O:7]>O1CCCC1>[CH3:4][O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:16][CH:15]=1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
16 g (60%) of sodium hydride was dispersed in 20 ml of tetrahydrofuran. To this, 100 ml of a solution in which 50 g of p-nitrobenzyl alcohol was dissolved in tetrahydrofuran, was added in drops while cooling with ice. The mixture was stirred for one hour at room temperature, and thereafter 56 g of iodomethane was added in drops while cooling with ice, and the mixture was further stirred for 3 hours at room temperature. To the reaction solution was added water, and a mixture was extracted with ethyl acetate. The extracted solvent was distilled off under reduced pressure, and the resulting product was purified by silica gel chromatography to obtain 40 g of p-methoxymethylnitrobenzene.
Reaction SMILES: C[Mg]Br.[CH3:4]COCC.[CH:9]12[O:14][CH:13]1[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:10]2>C1COCC1>[OH:14][CH:13]1[CH:9]([CH3:4])[CH2:10][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1
Reactant: CCOCC
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1CN(C(=O)OCc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
3M methylmagnesium bromide in ether (99 ml, 296 mmol) was added dropwise over 1 hour to a suspension of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (26 g, 119 mmol) and copper bromide-dimethyl sulfide complex (24.38 g, 119 mmol) in anhydrous THF (250 ml) at −40° C. under a nitrogen atmosphere. The reaction was allowed to stir at this temperature for an additional 1 hour before cautiously quenching of the reaction using 125 mL sat. ammonium chloride. The reaction was then allowed to warm to rt and diluted with water (125 mL), then extracted with ethyl acetate (3×150 mL). Ethyl acetate phases were combined, washed with brine, then dried with Na2SO4. After concentration, the crude material was purified by flash chromatography. (+/−)-Benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate (24.5 g, 104 mmol, 88% yield) was obtained as light yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.28-7.46 (5H, m), 5.14 (2H, s), 3.93-4.05 (1H, m), 3.63-3.78 (2H, m), 3.25-3.43 (1H, m), 3.12 (1H, ddd, J=13.26, 10. This material was resolved using the following chiral SFC conditions: column: CHIRALPAK® AD-H 5×25 cm, 5 μm, Column Temp. 40° C., Flow rate: 290 mL/min, Mobile Phase: CO2/MeOH=82/18, injection volume: 2.5 mL (Conc. 118 mg/mL), detector wavelength: 212 nm. The isolated isomers were named “Pk1” and “Pk2” in the elution order. Fractions containing Pk2 were concentrated to afford 10 g of (3R,4S)-benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate as a yellow oil. 84, 5.17 Hz), 2.06-2.26 (1H, m), 1.90 (1H, d, J=8.36 Hz), 1.03 (3H, dd, J=6.71, 5.39 Hz); LCMS (CHROMOLITH® RP-18e 2.0×50 mm, 0.8 mL/min, Solvent A: 10% MeOH/water with 0.1% TFA, Solvent B: 90% MeOH/water with 0.1% TFA, gradient with 0-100% B over 4 minutes) retention time: 2.56 min; MS(ES+) m/z: 236.0 (M+H+); HPLC retention time: 3.028 min (analytical HPLC Method H). Chiral purity: 99.9% ee (chiral HPLC conditions: column: CHIRALPAK® AD-H (25×0.46 cm, 5 μm), 30% MeOH in CO2, 3 mL/min, 40° C., 200-400 nm, 100 bars).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[C:30]([Si:34]([CH3:44])([CH3:43])[O:35][CH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([Si:34]([CH3:44])([CH3:43])[O:35][CH:36]1[CH2:41][CH2:40][CH:39]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:38][CH2:37]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OC1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O)=[CH:3][CH:2]=1.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].N1C=CC=CC=1>O>[CH3:30][C:29]1[CH:31]=[CH:32][C:26]([S:23]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:4]2[CH:5]=[CH:6][C:1]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:2][CH:3]=2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCCOc1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CCCCCCCCOc2ccc(-c3ccccc3)cc2)cc1

Procedure:
A mixture of 33.26 g of 8-([1,1'-biphenyl]-4-yloxy)-1-octanol, 23.37 g of tosyl chloride and 200 ml of pyridine was allowed to stand in a refrigerator overnight. Then water was added, the solid collected, washed with water and dissolved in chloroform. This solution was washed with dilute hydrochloric acid then saturated aqueous sodium bicarbonate, dried and the solvent removed, giving the desired compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[C:4]([NH2:16])[CH:3]=1.O>C(O)(=O)C.OO>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]2=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:7][N:16]=[C:4]2[CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(-c3ccccc3)onc2c1
Yield: 33.5 %

Procedure:
A solution of 31.6 g (0.15 mole) of 4-methyl-2-aminobenzophenone in 350 ml of glacial acetic acid and 175 ml of 30% hydrogen peroxide was let stand at ambient temperature for 72 hr. The solution was poured into 3 liters of water and a solid gradually crystallized. The solid was collected by filtration, washed with water and recrystallized from 2-propanol. The precipitate was slurried in 200 ml of carbon tetrachloride and filtered. The filtrate was concentrated to yield 10.5 g (35%) of title compound, m.p. 77.78° C. after recrystallization from 2-propanol.