Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C@H:19]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>N1C=CC=CC=1.ClCCl>[NH2:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:33](=[O:34])[O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:8][CH:7]=3)=[CH:10][N:11]([C@H:19]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CN)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CNC(=O)OCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of trans-5-[4-(aminomethyl)phenyl]-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.119 mol) in pyridine (2 mL) and dichloromethane (2 mL) was cooled to 0° C. then treated with benzyl chloroformate (22 mg, 0.131 mmol). The mixture was warmed to ambient temperature and stirred an additional 2 hours, evaporated and the residue purified by preparative reverse-phase chromatography to give trans-benzyl N-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzyl)carbamate: 1H NMR (DMSO-d6, 400 MHz) 8.13(s, 1H), 7.85(t, 1H), 7.3-7.42(m, 10H), 6.02(bs, 2H), 5.06(s, 2H), 4.54(m, 1H), 4.26(d, 2H), 1.44-2.37(m, 20H); RP-HPLC (Hypersil HS C18, 5 m, 100 A, 250×4.6 mm; 5%-50% acetonitrile over 25 min, 1 mL/min) tr 22.15 min.; MS:MH+ 554.3.
Reaction SMILES: [O:1]1CCC(C(O)=O)C1.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[CH:18]1([NH:17][C:16](=[O:1])[NH:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of 3.16 g of tetrahydro-3-furoic acid (27 mmol; 1 equiv.) in 25 mL anhydrous dichloromethane was added 7.85 g of dicyclohexylcarbodiimide (38 mmol; 1.4 equiv.) and 4.54 mL triethylamine (32.6 mmol; 1.2 equiv.). N-methyl-20 methanolamine hydrochloride was then added, followed by 60 mg of DMAP (4-dimethylamino)pyridine. An exothermic reaction ensued and a further 25 mL of dichloromethane were added. The mixture was stirred at ambient temperature overnight, then filtered through diatomaceous earth and concentrated. The residue was treated with ether and the white solid filtered off and removed. The solvent was removed from the mother liquor and the residue purified by column chromatography on SiO2 using 15-25% EtOAc in hexanes as eluent mixtures to provide the desired amide as a colorless oil (55% of theoretical yield) that still contained 10% of dicyclohexyl urea. This was used without further purification in the next reaction.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:25][C@@H:24]2[C@:11]([CH3:29])([CH2:12][C@H:13]([OH:28])[C@H:14]3[C@H:23]2[CH2:22][CH2:21][C:20]2[C@:15]3([CH3:27])[CH2:16][CH2:17][C:18](=[O:26])[CH:19]=2)[C@@:6]1([OH:30])[C:7](=[O:10])[CH2:8]O)[CH:2]=[CH2:3].[Cl-:31].[Li+]>CN(C)C=O.O>[CH2:1]([O:4][C@@H:5]1[CH2:25][C@@H:24]2[C@:11]([CH3:29])([CH2:12][C@H:13]([OH:28])[C@H:14]3[C@H:23]2[CH2:22][CH2:21][C:20]2[C@:15]3([CH3:27])[CH2:16][CH2:17][C:18](=[O:26])[CH:19]=2)[C@@:6]1([OH:30])[C:7](=[O:10])[CH2:8][Cl:31])[CH:2]=[CH2:3]
Reactant: [Cl-]
Reactant: C=CCO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl

Procedure:
A solution of 16α-allyloxy-11β,17,21-trihydroxypregn-4-ene-3,20-dione, 21-methanesulfonate (4.6 mmoles) in 60 ml of dimethylformamide is refluxed for 1 hour under nitrogen with 5 g of lithium chloride. The solution is cooled, diluted with water and filtered. The solid is dissolved in chloroform, washed with 5% hydrochloric acid, water, dried, and evaporated in vacuo to yield the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:36])[C@H:14]([CH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][CH2:32][CH2:33][NH2:34])=[C:25]([Cl:35])[CH:24]=1)[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:36])[C@H:14]([CH2:22][C:23]1[CH:24]=[C:25]([Cl:35])[C:26]([O:30][CH2:31][CH2:32][CH2:33][NH:34][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:27]([Cl:29])[CH:28]=1)[NH:15][C:16](=[O:21])[C:17]([F:20])([F:18])[F:19]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(OCCCN)c(Cl)c1)NC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1cc(Cl)c(OCCCNC(=O)c2ccccc2)c(Cl)c1)NC(=O)C(F)(F)F
Yield: 105.3 %

Procedure:
A solution of benzoyl chloride (94 mg, 0.669 mmol) in ethyl acetate (2 ml) was added dropwise to a two-layer solution of O-(3-aminopropyl)-3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester hydrochloride (209 mg, 0.461 mmol) and sodium bicarbonate (150 mg, 1.79 mmol) in ethyl acetate (3 ml)-water (2 ml) with stirring under ice cooling and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (20 ml) and the organic layer was separated, washed with brine and dried. The solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=2−1) to give O-(3-benzoylaminopropyl)-3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester (253 mg, 100%) as a colorless oil.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:16])([CH3:15])[CH3:14].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCO>[F:16][C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:7]
Reactant: CC(C)(F)CCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)(F)CCCCCO
Reaction time: 41 h
Yield: 87.1 %

Procedure:
A stirred solution of the product from Step III (3.34 g, 0.0144 mol) in absolute EtOH was treated with pyridinium p-toluenesulfonate (0.47 g, 0.00187 mol) and kept under nitrogen at ambient temperature for 41 hours. The mixture was concentrated and the residue, dissolved in EtOAc, was washed with aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 5 to 20% EtOAc-hexane to give 1.86 g of 6-fluoro-6-methyl-1-heptanol.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([O:16]P(OCCCC)(OCCCC)=O)CCC>OS(O)(=O)=O>[C:2]1([CH:1]=[O:16])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOP(=O)(OCCCC)OCCCC
Reactant: Cc1cccc2ccccc12
Agent: O=S(=O)(O)O
Product: O=Cc1cccc2ccccc12
Yield: 25.7 %

Procedure:
The same reaction was tried in a modified cell, without the crank 23. 2 g (14 mmol) of 1-methylnaphthalene in 3 g of tributylphosphate was allowed to react for 40 hours with electrochemically produced Co(III) sulphate at 40°-45° C. The electrolyte solution was composed of 0.12M Co(II) sulphate in 2M H2SO4. The current was 200 mA. The organic material isolated from this run was placed on a silica gel column, which was eluted with a solution of 5% ether in petroleum ether (bp=60°-80° C.). The initial band consisted of 860 mg (6 mmol, 43%) of starting material. The second band yielded 447 mg (2.9 mmol) of 1-naphthaldehyde. The aldehyde yield was 36% based on consumed starting material. The aldehyde yield was 36% based on consumed starting material. The infrared spectrum of the product was identical to that of an authentic sample.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5](=[CH2:16])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][C:5](=[CH2:16])[C:4]([OH:17])=[O:3])=[CH:14][CH:13]=1
Reactant: C=C(CCCc1ccc(Cl)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C(CCCc1ccc(Cl)cc1)C(=O)O

Procedure:
25 g of 5-(4-chlorophenyl)-2-methylenevaleric acid ethyl ester, 100 ml of a 2 N sodium hydroxide solution and 50 ml of ethanol are stirred at 50° for 3 hours. After cooling, 100 ml of 2 N hydrochloric acid are added slowly, while cooling with ice, to the reaction mixture which is then extracted 4 times, with 50 ml of diethyl ether each time. The united organic phases are washed with water, dried over sodium sulfate and concentrated. 20.5 g of 5-(4-chlorophenyl)-2-methylenevaleric acid remain as a brown oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.[I:21]CCI>CCCCCC.C(OCC)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([I:21])=[CH:12][N:13]=2)=[CH:7][CH:8]=1
Reactant: ICCI
Reactant: FC(F)(F)c1ccc(-c2nccs2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: FC(F)(F)c1ccc(-c2ncc(I)s2)cc1
Yield: 46.5 %

Procedure:
In a manner similar to Step C of Example 1, the reaction of 5.45 grams (0.0238 mole) of 2-(4-trifluoromethylphenyl)thiazole, 9.5 ml of a 2.5 M solution of n-butyllithium in hexane, and 6.71 grams (0.0238 mole) of 1,2-diiodoethane in 40 ml of diethyl ether produced 3.93 grams of 2-(4-trifluoromethylphenyl)-5-iodothiazole as a solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=2)[CH2:31][CH2:32]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3C)CC2)n(-c2ccccc2)n1

Procedure:
146 mg (78%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.413 mmol), 1-(2,3-dimethylphenyl)piperazine (79 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: Nc1ncnn2c(-c3ccc(CN4CCOCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 28 %

Procedure:
Using a procedure similar to that of Example 282, step 2, with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and morpholine as starting material, 55 mg (28%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.60 (t, 4 H), 3.50 (s 2 H), 2.405 (t, 4 H); ES-MS m/z 516.25 [M+H]+, HPLC RT (min) 2.61.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N+:18]([O-])=[C:17]([CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[NH:14][C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:30]C(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH2:20][O:30][C:27](=[O:29])[CH3:28])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[NH:14][C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1=[N+]([O-])C(NC(=O)OCc2ccccc2)C(=O)Nc2c(C)cccc21
Solvent: ClCCl
Product: CC(=O)OCC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2c(C)cccc21
Reaction time: 96 h
Yield: 71.1 %

Procedure:
A mixture of (3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide (2.83 g,) and acetic anhydride (7.6 ml, 10 eq.mol) in methylene chloride (60 ml) was stirred for 4 days. From the reaction mixture methylene chloride was removed in vacuo. To the residue was added a mixture (60 ml) of diisopropyl ether and n-hexane (1:1). The resultant crystalline powder was collected by filtration and washed with diisopropyl ether to give (3RS)-3-benzyloxycarbonylamino-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepine-2-one (2.26 g, 71.1%) as a crystalline powder.
Reaction SMILES: [NH-][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([OH:13])=[O:12].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[C:5]1(=[O:7])[O:13][C:11](=[O:12])[C:3]2=[CH:2][CH:10]=[CH:9][CH:8]=[C:4]12
Reactant: [NH-]c1cccc(C(=O)O)c1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2ccccc21
Temperature: 80 °C

Procedure:
13.8 g (0.04 mol) of this amidylphthalic acid are mixed with 1.4 g of anhydrous sodium acetate and 25 ml of acetic anhydride and the mixture is heated to 80° C. for 30 minutes, whilst stirring. The resulting reaction solution is evaporated to dryness, the residue is extracted with 60 ml of hot benzene and the benzene solution is filtered using animal charcoal. After evaporating the benzene, the residue is dried for 24 hours at 60° C./0.05 mm Hg. 9.95 g (80% theory) of crystalline 3-(bicyclo[1.2.2]hept-5-ene-2,3-dicarboxylic acid imidyl)-phthalic anhydride are obtained; melting point 178°-180° C.
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][NH:11][CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[O:27][CH3:28]>>[CH2:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:27][CH3:28])[CH2:10][C@H:9]1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNC[C@H](C)N1Cc1ccccc1
Reactant: COc1cc2cccnc2cc1Br
Product: COc1cc2cccnc2cc1N1C[C@@H](C)N(Cc2ccccc2)[C@@H](C)C1

Procedure:
The title compound was prepared from cis-1-benzyl-2,6-dimethylpiperazine (Org. Prep. Proc. 1976, 8, 19) and 7-bromo-6-methoxyquinoline (J. Org. Chem. 1990, 55, 2019) using a similar procedure to Description 2 (75%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:31])=[O:30])[CH:4]=1)#[N:2].[C:32](C1C=CC([C@@H]2C(C#N)=C(C)N(C3C=CC=C(C(F)(F)F)C=3)C(=O)N2)=C([S@](C)=O)C=1)#N.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:32])=[C:5]([S@:29]([CH3:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[S@](C)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[S@](C)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
The reaction was carried out under argon. The diastereomer mixture of (RS,4S)-4-[4-cyano-2-(methylsulfinyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile and (SS,4S)-4-[4-cyano-2-(methylsulfinyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (535 mg, 1.2 mmol) was initially charged in absolute THF (12 ml), and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (1.45 ml; 1.2 eq.) was added at −78° C. After 20 min of stirring at −78° C., iodomethane (854 mg; 5 eq.) was added and the mixture was stirred for 16 h with gradual warming from −78° C. to RT. The reaction mixture was then concentrated under reduced pressure, saturated ammonium chloride solution (50 ml) was added and the mixture was then extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over solid sodium sulfate, filtered and concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a solid (488 mg, 88% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]#[N:17])=[CH:4][CH:3]=1.[CH2:18](N)[CH2:19][NH2:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[NH:20][CH2:19][CH2:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1Sc1ccc(Cl)cc1
Reactant: NCCN
Product: Clc1ccc(Sc2ccccc2CC2=NCCN2)cc1

Procedure:
2-[2-(4-Chloro-phenylsulfanyl)-benzyl]-4,5-dihydro-1H-imidazole was prepared from 2-(4-chloro-phenylsulfanyl)-phenyl-acetonitrile and ethylene diamine in analogy to Example 19 b): white solid; MS (EI): 302.9 ((M+H)+.).
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[H-].[Na+].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]1([CH:7]([N:9]2[CH2:12][CH:11]([O:13][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:10]2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccccn1
Reactant: CC(c1ccccc1)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(c1ccccc1)N1CC(Oc2ccccn2)C1
Temperature: 65 °C
Yield: 14.3 %

Procedure:
The maleate salt of 1-(1-phenylethyl)-3-azetidinol (65 g, 0.22 mole) was partitioned between toluene and dilute sodium hydroxide and was extracted once with toluene. The organic layer was dried (sodium sulfate) and concentrated. The residue was dissolved in 125 ml of dimethylformamide and added dropwise to a stirred suspension of 9.6 g (0.24 mole) of sodium hydride (washed three times with isooctane) in 400 ml of dimethylformamide at 25°-35° C. The solution was heated to 65° C. and 35 g (0.22 mole) of 2-bromopyridine was added dropwise while heating to 75° C. The solution was stirred and heated at 90° C. for 1 hr followed by heating at 120° C. for 2.75 hr. The mixture was stirred at room temperature overnight and concentrated. The residue was partitioned between water and isopropyl ether. The organic layer was washed twice with water, dried (sodium sulfate), filtered and concentrated. Crude yield was 30 g. The residue was distilled to give 8 g of product, bp 128°-134° C./0.01 mm.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)([CH3:7])=[O:6].[C:9]([O:12][CH2:13][C:14]([NH:34][C:35](=[O:37])[CH3:36])([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:15][O:16][C:17](=[O:19])[CH3:18])(=[O:11])[CH3:10]>ClCCCl>[C:17]([O:16][CH2:15][C:14]([NH:34][C:35](=[O:37])[CH3:36])([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:5](=[O:6])[CH3:7])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)[CH2:13][O:12][C:9](=[O:11])[CH3:10])(=[O:19])[CH3:18]
Reactant: CC(=O)NC(CCc1ccc(-c2ccccc2)cc1)(COC(C)=O)COC(C)=O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)NC(CCc1ccc(-c2ccc(C(C)=O)cc2)cc1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of AlCl3 (16 mmol) in DCE (20 mL) is added AcCl (8 mmol) in one portion. After stirring at room temperature for 30 min, to the solution is added acetic acid 2-acetoxymethyl-2-acetylamino-4-biphenyl-4-yl-butyl ester (2 mmol) in DCE (5 mL). After an additional 30 min, the mixture is poured into ice-cold 1 N NaOH and is extracted with DCM. The organic phase is washed with 1 N HCl, brine and dried over Na2SO4. After concentrating, the crude material is purified by column chromatography using EtOAc/hexane (2/1) to give the desired product as a white solid. MS: (ES+): 439.2 (M+1)+.
Reaction SMILES: [NH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[NH2:2].[CH2:11]([CH2:13][CH2:14][CH2:15][C:16](CC([O-])=O)=[O:17])[CH3:12]>>[O:17]=[C:16]1[N:1]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[N:2]=[C:14]([CH2:13][CH2:11][CH3:12])[CH2:15]1
Reactant: CCCCCC(=O)CC(=O)[O-]
Reactant: N#Cc1ccc(NN)cc1
Product: CCCC1=NN(c2ccc(C#N)cc2)C(=O)C1

Procedure:
From the reaction of 4-hydrazinobenzonitril and ethylbutyrylacetate, 4-(4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzonitrile is obtained. Subsequent reaction with 2-ethylaniline yields 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzonitrile, Mp 196.7° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](N)[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3].S(=O)(=O)(O)[OH:16].N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O.C(O)C>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: CS(=O)(=O)n1ccc2ccc(N)cc21
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)n1ccc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-methansulfonyl-6-amino indole (2.10 g, 10.0 mmol), prepared as described in Forbes, et al., J. Med. Chem. (1996) 39:4968, was suspended in 40 ml of water, then cooled in an ice bath. Concentrated sulfuric acid (3 ml) was added slowly dropwise. The mixture was warmed to room temperature for 5 min then cooled back down to 0° C. A solution of NaNO2 (Mallinckrodt, 0.76 g, 11.0 mmol) in 10 ml of water was added slowly and the resultant foam was treated with 10 ml of ethanol. The mixture was added in portions to a boiling solution of CUSO4 (J. T. Baker, 16.0 g, 0.1 mol) in 75 ml of water. After 15 min, the mixture was cooled. The brown solid which had formed was broken up with a glass stirring rod. NaHCO3 was added to neutralize the reaction and the product was extracted with ethyl acetate (2×100 ml). The extracts were dried (anhydrous MgSO4) and concentrated to give 1-methansulfonyl-1H-indol-6-ol (1.62 g), a brown oil which was used with out purification.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[C:5]=1[C:6](Cl)=[O:7])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[CH2:6][OH:7])([CH3:15])[CH3:14]
Reactant: CC(C)c1cccc(C(C)C)c1C(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1CO
Temperature: 25 °C

Procedure:
A solution of 2,6-diisopropylbenzoyl chloride (11.65 g, 0.052 mol), in ethyl ether (100 mL) was added over 20 minutes to a suspension of lithium aluminum hydride (1.9 g, 0.050 mol) in ethyl ether (200 mL) keeping the temperature below -15° C. The reaction mixture was allowed to slowly warm to room temperature and was then cooled to zero. The reaction was quenched by careful addition of sodium bisulfate solution until no further reaction was evident. The mixture was diluted with ether (200 mL), the ether washed with brine. The grey goo (lithium/aluminum salts) was washed several times with ether, the ether washes were combined, dried (magnesium sulfate), filtered, and concentrated to an oil which solidified, 10.67 g,