Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:25]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: C=CCCCCCCCCCCCCCCCC
Reactant: Oc1ccccc1
Product: CCCCCCCCCCCCCCCCCCc1ccccc1O
Temperature: 70 °C

Procedure:
This example is directed to the preparation of a typical alkylated phenol component using the process disclosed in U.S. patent application Ser. No. 107,507 and alkyl phenol-formaldehyde condensates produced thereby. Octadecyl phenol was prepared by charging into a four-neck, 5-liter round bottom flask equipped with a mechanical stirrer, 933 grams of phenol (9.93 moles) and 286 grams of Amberlyst 15 catalyst. A reflux condenser, a thermometer, an addition funnel, and a nitrogen inlet tube were attached to the flask and the mixture was heated to 70° C. With stirring under a blanket of nitrogen, 834 grams (3.31 moles) of 1-octadecene was added dropwise over a period of about one hour. The temperature was raised to 90° C. and maintained at this temperature for four hours. The reaction mixture was then cooled to 50° C. and filtered to remove the catalyst. The excess phenol was removed by vacuum distillation. The yield was 1,008 grams, or 88%. The product had a refractive index of 1.4859 at 25° C., a viscosity of 38.0 cP at 40° C., and a hydroxyl number of 144 mg KOH/g. The infrared spectrum of the product showed absorption bands at 830 and 750 cm-1, which are characteristic of alkyl phenols. The aromatic substitution pattern was determined by 13C-NMR spectroscopy and showed that the ortho to para ratio was 2.0:1.0. The alkyl substitution pattern was determined by 1H-NMR spectroscopy and showed that the product consisted of 50 mole % 2-substituted alkylate and 50 mole %≥3-substituted alkylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:9]([OH:12])[CH2:10]Cl)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([C@@H:9]1[CH2:10][O:12]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reaction time: 0.33 h
Yield: 69.3 %

Procedure:
To a stirred solution of (R,R)-1-benzyl-3-chloro-2-hydroxypropylcarbamic acid tert-butyl ester (4.45 g, 15 mmol) in ethanol (125 mL) at 0° C. is added KOH (0.5M in ethanol, 36 ml, 18 mmol). After stirring for 20 min, the mixture is concentrated under reduced pressure and the residue is dissolved in ethyl acetate, washed with saturated ammonium chloride (aq), water and then brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting white solid is purified using General Purification Procedure E to afford the title compound as a white solid (2.7 g, 10.4 mmol).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.[CH2:16](O)[CH3:17]>Br.C(O)(=O)C>[CH2:16]([O:14][C:12](=[O:13])[CH2:11][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)=[O:15])[CH3:17]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Reactant: CCO
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)CCC(=O)c1ccc(O)cc1

Procedure:
In a 1 L round bottom flask, 4-(4-methoxyphenyl)-4-oxo-butyric acid (25 g, 106 mmol) in 48% HBr (125 mL) and acetic acid (250 mL) was heated to reflux 18 h. The reaction was cooled slightly and ethanol (250 mL) was added. The solvent was concentrated under vacuum. Additional ethanol (100 mL) was added and solvent concentrated under vacuum again. The resulting oil was crystallized from ethyl acetate/hexanes to produce 8.65 g (37%). MS m/z=223 (M+H).
Reaction SMILES: [C:1]([C:5]1O[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:13]>>[C:1]([C:5]1[NH:13][CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(=O)cco1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1cc(=O)cc[nH]1

Procedure:
A mixture of 2-tert-butyl-pyran-4-one (Step 1.6) (5.74 g, 37.7 mmol) and a 30% aqueous solution of ammonium hydroxide (100 mL) is stirred for 1 h at reflux, allowed to cool and concentrated. The residue is triturated with MeOH (200 mL) and filtered. The filtrate is concentrated and the residue purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1→92:7:1) to afford 4.46 g of the title compound as a yellow solid: ESI-MS: 152.0 [M+H]+; tR=1.45 min (System 1); TLC: Rf=0.11 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O>ClCCl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:22])=[O:15])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a suspension of 4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid of Step A (3.55 g, 0.0141 mmol) in dry dichloromethane (40 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (2 drops, cat.) followed by a 2.0 M solution of oxalyl chloride in dichloromethane (14.1 mL, 0.0283 mol) and the reaction mixture stirred at room temperature for 4.5 hours. The reaction mixture was then concentrated in vacuo to afford (4-chlorocarbonyl-benzyl)carbamic acid tert-butyl ester as a white solid. The crude acid chloride was dissolved in dry tetrahydrofuran (20 mL), added to a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (3 g, 9.42 mmol), and N,N-diisopropylethylamine (4.92 mL, 28.27 mmol) in dry tetrahydrofuran (20 mL), and the reaction mixture stirred at room temperature for 19 hours. The reaction was quenched by the addition of 2 M sodium hydroxide (20 mL) and then partitioned between ethyl acetate (200 mL) and 2 M sodium hydroxide (200 mL). The separated organic phase was washed with 2 M sodium hydroxide (200 mL), water (200 mL) and brine (200 mL), dried over magnesium sulfate, and concentrated in vacuo to afford an orange solid (3.95 g). Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in dichloromethane gave a colorless glass that was recrystallized from ethyl acetate/hexane to afford the title compound (1.29 g, 25%) as a cream crystalline solid, m.p. 171° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=O)[CH3:7])(=[O:4])=[O:3].[CH3:9][NH:10][NH2:11]>C1(C)C=CC=CC=1>[CH3:9][NH:10][N:11]=[C:6]([CH3:7])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CNN
Reactant: CC(=O)CS(C)(=O)=O
Solvent: Cc1ccccc1
Product: CNN=C(C)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
To a 100 ml volume four-necked flask, 1-methylsulfonyl-2-propanone (7-2-1) (4.99 g) and toluene (36.0 g) were added under a nitrogen atmosphere, and added dropwise 40 wt % of aqueous monomethylhydrazine solution (14-a) (3.96 g) at room temperature. The resulting mixture was stirred at room temperature for 16 hours, and then added additional 40 wt % of aqueous monomethylhydrazine solution (0.35 g). The resulting mixture was stirred for 24 hours, and refluxed with Dean-Stark apparatus under reduced pressure at the internal temperature of 50° C. After refluxing, the resulting mixture was cooled to 0° C., and filtered to give 3.56 g of 1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-1).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:11](O)[CH:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:20]#[N:21])[CH:8]=2)[CH2:3]1.[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1([CH3:22])[CH:11]=[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:20]#[N:21])[CH:8]=2)[CH2:3]1
Reactant: CC1(C)Cc2ccc(C#N)cc2C(Sc2ccccn2)C1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)C=C(Sc2ccccn2)c2cc(C#N)ccc2C1
Reaction time: 0.33 h

Procedure:
A mixture of 1 g of 2,2-dimethyl-4-(2-pyridylthio)-6-cyano-1,2,3,4-tetrahydro-3-naphthol, 0.3 g of NaOH and 35 ml of dioxane is boiled for 20 minutes. The mixture is cooled and filtered and the filtrate is evaporated and worked up in the customary manner to give 2,2-dimethyl-4-(2-pyridylthio)-6-cyano-1,2-dihydronaphthalene.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:42])(=[O:41])[NH:36]C(C)(C)C)=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:42])(=[O:41])[NH2:36])=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Yield: 65 %

Procedure:
The title compound was prepared from 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2-[5-(carbomethoxy)-2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step B) according to the procedure of Example 13, Step B, and was obtained in 65% yield as a white solid after flash chromatography, mp 182°-184° C., homogenous by TLC (19:1 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 555 (M+1)+.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@@H:12]([CH2:22][O:23][CH3:24])[O:11][C@H:10]1[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([CH2:49][N:50]([CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)[CH3:51])=[N:29][C:30]=2[NH:34][CH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH:52]1([N:50]([CH2:49][C:28]2[N:27]=[C:26]3[C:31]([N:32]=[CH:33][N:25]3[C@H:10]3[C@H:9]([OH:8])[C@H:13]([OH:14])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11]3)=[C:30]([NH:34][CH2:35][CH:36]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:29]=2)[CH3:51])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN(C)C4CCCCC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN(C)C4CCCCC4)nc32)[C@H](O)[C@@H]1O
Reaction time: 1 h
Yield: 88.4 %

Procedure:
N-(9-[(2R,3R,4R,5R)-3,4-Bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-2-{[cyclohexyl(methyl)amino]methyl}-9H-purin-6-yl)-N-(2,2-diphenylethyl)amine (133 mg, 0.16 mmol) (preparation 35) was dissolved in stirred tetrahydrofuran (1 ml) and a 1 molar solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 ml, 1 mmol) was added. The reaction mixture was stirred for 1 hr, then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (95:5:0.5) to give the title compound (83 mg) as a foam. MS: 587 (MH+).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[S:10]1>O1CCCC1>[OH:27][C:24]1[CH:25]=[CH:26][C:21]([C:9]2([S:10][C:11]3[CH:12]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14](=[O:15])[N:13]([CH3:16])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[S:7]2)=[CH:22][CH:23]=1
Reactant: Sc1ccccc1
Reactant: CN1C(=O)C(Cl)(c2ccc(O)cc2)Sc2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(Sc2ccccc2)(c2ccc(O)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a stirred solution of thiophenol (6.7 ml) in tetrahydrofuran (15 ml), 2-chloro-3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (4.0 g, compound No. 2) is added. The mixture is stirred for 3 hours at room temperature, and then concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4.5 g (90.0%) of the titled compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([Mg]Br)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][N:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:31]3[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[C:33]([O:34][CH3:35])[CH:32]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc([Mg]Br)cc1OC
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ncccc2c1=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ncccc3c2=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 100 mg (0.248 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide in THF 2 ml, was added 1.09 ml (0.545 mmol) 3,4-dimethoxyphenylmagnesium bromide. The reaction mixture was stirred at room temperature for 30 min, then quenched with saturated solution of NH4Cl, extracted with ethyl acetate and purified with flash chromatography to give the desired product 22 mg. LCMS observed for (M+H)+: 480.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC#N>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:22]
Reactant: CCOC(=O)CCCBr
Reactant: C1CNCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CCCN1CCCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
Sodium carbonate (2.12 g) was added to the solution of homopiperazine (10.0 g; 5 eq.) and ethyl 4-bromobutyrate (3.90 g; 1 eq.) in CH3CN (120 mL). The reaction was stirred at room temperature for 6 h. The reaction mixture was filtered thru a celite pad. The filtrate was concentrated. The remaining residual was dissolved in CHCl3 (120 mL), washed by H2O (50 mL×3) and brine (50 mL×1), dried by Na2SO4 and concentrated to give 4-[1,4]diazepan-1-yl-butyric acid ethyl ester (3.8 g), which was carried on for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:32])=[CH:13][CH:14]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:32])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19]1
Reactant: Cc1ccc2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CCC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
tert-Butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate (0.54 g, 1.24 mmol) was dissolved in CH2Cl2 (15 mL) followed by the addition of TFA (8 mL). The reaction was stirred for 1.5 h, and the solvents were evaporated to an oily liquid which was diluted with CH2Cl2 and neutralized with a 1 M aqueous NaOH solution. The organic layer was separated, and the aqueous layer was washed two times with CH2Cl2. After drying the combined organic phases over MgSO4, they were filtered, and concentrated to afford 2-(4-((R)-3-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol as a solid (0.354 g, 85%). LC/MS: m/z 335.7 (M+H)+ at 1.42 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[N:8](S(C3C=CC=CC=3)(=O)=O)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2cccc3ccccc23)cc2c(Cl)ncnc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Clc1ncnc2[nH]c(-c3cccc4ccccc34)cc12
Reaction time: 0.25 h
Yield: 69.1 %

Procedure:
To a stirred solution of 4-chloro-6-(1-naphthyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (350 mg, 0.73 mmol) in THF (2.50 mL) was added a solution of NaOH (205 mg, 5.13 mmol) in methanol (1.19 mL), and the mixture was stirred for 15 minutes. After quenching by addition of saturated NH4Cl solution (80.0 mL), the mixture was extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was dissolved in a small amount of methanol, and the suspension was filtered through a glass pad filter. The white solid was dried under high to afford the title compound (141 mg, 65%).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]2[CH2:18][NH:17][CH2:16][CH:15]2[N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[CH3:20])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>C1COCC1>[Br:1][CH2:2][C:3]([N:17]1[CH2:16][CH:15]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[C:24]([F:32])[CH:23]=2)[CH3:20])[CH:14]([C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)[CH2:18]1)=[O:4]
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)CBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 70 %

Procedure:
To a stirred solution of bromo-acetyl chloride (0.146 ml, 1.75 mmol) in THF (15 ml) at RT was added over 1 hour a solution of [(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (Intermediate VIII-1, 0.70 g, 1.66 mmol) and triethyl amine (0.25 ml, 1.83 mmol) in THF (10 mL). The reaction was stirred over night, quenched by addition of an aqueous solution of NaHCO3, and the product extracted with EtOAC. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 0.63 g (70%) of the title compound as a white solid. ES-MS m/e: 542.6 (M+H+).
Reaction SMILES: CN(CN(C)C)C.C(Cl)(=O)C.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)[CH:13]=1.C[N:29]([CH2:31][C:32]1C2C(=CC=C(OC3C=NC=CC=3)C=2)NC=1)C.[C-]#N.[K+].CI>C(Cl)Cl.CN(C=O)C.CCCCCC.CCOC(C)=O>[C:31]([CH2:32][C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([O:18][C:14]3[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=3)[CH:20]=2)[NH:24][CH:23]=1)#[N:29]
Reactant: c1cncc(Oc2ccc3[nH]ccc3c2)c1
Reactant: CN(C)Cc1c[nH]c2ccc(Oc3cccnc3)cc12
Agent: CN(C)CN(C)C
Agent: [C-]#N
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCc1c[nH]c2ccc(Oc3cccnc3)cc12

Procedure:
Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (0.829 g, 1.11 mL, 8.12 mmol) in CH2Cl2 (10 mL) with acetyl chloride (0.637 g, 0.573 mL, 8.12 mmol) followed by a solution of 5-(pyrid-3-yloxy)indole (1.23 g, 5.8 mmol) in CH2Cl2 (100 mL), gave after work-up: 3-(N,N-dimethylaminomethyl)-5-(pyrid-3-yloxy)indole as a gum. This was treated with finely ground potassium cyanide (1.246 g, 19 mmol) and methyl iodide (2.7 g, 1.18 mL, 19 mmol) in DMF (70 mL) for 16 hr, and after appropriate work-up and chromatography (silica gel; hexane/EtOAc; 0-60%), 3-cyanomethyl-5-(pyrid-3-yloxy)indole was obtained a gum, which solidified on standing, 0.655 g (45%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:31]([C:34]1[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][CH:35]=1)=[C:32]=[O:33]>ClCCl>[F:27][C:26]([F:29])([F:28])[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:33])[NH:31][C:34]4[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][CH:35]=4)=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)=[CH:20][CH:19]=1)([OH:30])[C:22]([F:23])([F:24])[F:25]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: Nc1ccc(N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)Nc2ccc(N3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2)cc1
Temperature: 100 °C
Yield: 73.7 %

Procedure:
2-(4-((4-(4-Aminophenyl)piperazin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.461 mmol, 200 mg) and ethyl 4-isocyanatobenzoate (0.554 mmol, 0.060 mL, 106 mg) were combined in dichloromethane and heated in a microwave at 100° C. for 10 minutes. The reaction mixture was concentrated under vacuum. The residue was purified by acidic preparative HPLC and SCX chromatography to afford the title compound (212.3 mg). MS (ESI) m/z 625.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=1)[C:5]([OH:7])=[O:6].O>CO.Cl.[Pd]>[ClH:1].[NH2:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1cc(Cl)cc(C(=O)O)c1
Reaction time: 0.5 h

Procedure:
A mixture of 3-chloro-5-nitrobenzoic acid (10.0 g) and 10% Pd/C (0.3 g) in MeOH (100 mL) and 6N HCl (30 mL) was shaken under 30 psi H2 in a Parr apparatus for 30 min, then filtered through Celite and evaporated. The residue was crystallized from 6N HCl to yield the product. More highly purified material was obtained by a second crystallization from water. 1H-NMR (d4-CD3OD): δ 7.24 (1H, dd, J=1.4, 2.0 Hz), 7.20 (1H, dd, J=1.6, 2.0 Hz), 6.87 (1H, t, J=2.0 Hz). 13C-NMR (d4-CD3OD): δ 167.6, 149.5, 134.3, 132.7, 117.8, 117.4, 113.9.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[CH2:17]1[CH:19]([C:20]([NH2:22])=[NH:21])[CH2:18]1.Cl>>[CH:19]1([C:20]2[NH:21][CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:22]=2)[CH2:17][CH2:18]1
Reactant: N=C(N)C1CC1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1-c1c[nH]c(C2CC2)n1
Yield: 85 %

Procedure:
As described for Example 57, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (1.5 g, 5 mmol) using cycloproylcarbamidine HCl instead of acetamidine HCl was converted to the title compound (1.2 g, 85%) which was obtained as an off-white solid. MS: m/e=266.3 [M+H]+.