Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=[CH:7]2>ClCCl>[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=[CH:7]2
Reactant: COc1ccc2cc(C(C)=O)ccc2c1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1ccc2cc(O)ccc2c1
Yield: 88.6 %

Procedure:
In a 3 L two-neck round bottom flask, equipped with a reflux condenser and a dropping funnel, 2 L of hydrochloric acid (d=1.16) were stirred and heated to boiling. A solution of 6.06 g (30.3 mmol) of 1-(6-methoxy-2-naphthyl)-1-ethanone (prepared as described in Arsenijevic et al., Org. Synth. Coll. 6:34 (1988), the disclosure of which is incorporated herein by reference) in a minimum amount of dichloromethane was added, and the mixture was stirred and heated at reflux for 2 hours. The hot solution was filtered through a mineral wool plug to remove oily residue. The solid that separated after cooling was filtered on a glass frit and dissolved in 130 mL of ethyl acetate. The solution was washed with brine, dried with anhydrous magnesium sulfate and evaporated to give 5 g (89%) of 1-(6-hydroxy-2-naphthyl)1-ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13])[CH:5]=[CH:6][CH:7]=1.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13])[C:16](=[O:15])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCC(=O)Nc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1cccc(Cl)c1
Yield: 88.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 34(B), from N-(3-chlorophenyl)pent-4-ynamide (630 mg, 3.03 mmol) and (BOC)2O (795 mg, 3.64 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column 100% DCM as eluent) to afford 824 mg of tert-butyl 3-chlorophenyl(pent-4-ynoyl)carbamate as a colorless oil (Yield: 88%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 54.5 °C
Reaction time: 5 h
Yield: 59.8 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), and 10 mL of N,N-dimethylformamide. The resulting mixture was refluxed under stirring at 52-57° C. in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 0.85 g (reaction yield: 59.8%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][S-:13].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([S:13][CH3:12])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(Cl)nc(Cl)c1
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a solution of 2,6-dichloro-4-nitropyridine (3.8 g; 0.02 mol) in dimethylformamide (50 ml) cooled with an ice-bath was sodium thiomethoxide (1.4 g; 0.02 mol) slowly added. After stirring for 3 hours, the reaction mixture was quenched with water (300 ml) and extracted 3 times each with a hexane/ethyl acetate mixture (100 ml; 1/1). The combined extracts were dried with anhydrous magnesium sulphate and the solvent was removed in vacuo. Purification by silica gel flash column chromatography afforded 2,6-dichloro-4-methylthiopyridine (2.9 g; 74%) as a colorless oil.
Reaction SMILES: S[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[CH:6]=2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Sc1cc2ccccc2s1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCN(c3cc4ccccc4s3)CC2)cc1
Yield: 46.5 %

Procedure:
To a solution of 2-mercaptobenzothiophene (1.8 g, 10.8 mmol) in toluene under nitrogen was added N-benzylpiperazine (1.88 ml, 10.8 mmol) and the mixture heated at reflux for 1.5 h. Left to cool, concentrated in vacuo and product recrystallised from diethyl etherhexane to yield the title compound (1.55 g), m.p. 160°-161° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[CH:19]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]3[CH:15]=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[CH:19]=1
Reactant: Brc1ccc2c(c1)oc1ccccc12
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc2oc3cc(Br)ccc3c2c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Chlorosulfonic acid (3.75 mL, 56 mmoles) was added dropwise to a solution of 3-bromo-dibenzofuran (9.21 g, 37.3 mmoles) in 150 mL of chloroform at room temperature. The reaction was stirred for 5 hours, cooled to 0° C., filtered, and washed the solid with cold dichloromethane. This solid (6.12 g, 18.7 mmoles) was mixed with phosphorous pentachloride (12.9 g, 61.7 mmoles) and the mixture was heated to 110° C. for 4 hours. The mixture was cooled to room temperature and quenched with ice water. Filtered the resulting suspension to give the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].S(Cl)(Cl)=O.[Cl:7][S:8]([OH:11])(=O)=[O:9].[CH2:12]([O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])[CH2:13][CH3:14]>ClCCl>[Cl:7][S:8]([C:22]1[CH:23]=[CH:24][C:16]([O:15][CH2:12][CH2:13][CH3:14])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19])(=[O:11])=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: CCCOc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A three-neck flask, equipped with a 5M aqueous sodium hydroxide scrub (550 ml), was charged with thionyl chloride (40 ml, 0.55 mol) and chlorosulphonic acid (150 ml, 2.26 mol) and the stirred mixture cooled to about −10° C. A solution of 2-n-propoxybenzoic acid (100 g, 0.55 mol) in dichloromethane (200 ml) was added over 20 minutes, ensuring that the reaction temperature was maintained below 5° C., then the reaction mixture was allowed to warm to room temperature. The resulting solution was added over 1 hour to stirred, ice-cold water, whilst maintaining the temperature at about 0° C., and stirring continued for a further 30 minutes. The mixture was filtered and the solid thus obtained was washed with cold water (100 ml) and dried under vacuum to give the title compound (122.2 g, 80%) as a white solid. δ (DMSOd6): 1.13 (3H, t), 2.00 (2H, m), 4.32 (2H, t), 7.23 (1H, d), 8.21, (1H, m), 8.82 (1H, d).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.CCCCCC.[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C:20](=[O:26])[CH2:19]2.C(=O)([O-])[O-].[K+].[K+]>CCOCC>[O:4]1[CH:5]=[CH:6][C:2]([C:20]2([OH:26])[CH:21]3[CH2:24][CH2:25][N:18]([CH2:23][CH2:22]3)[CH2:19]2)=[CH:3]1
Reactant: O=C1CN2CCC1CC2
Reactant: Brc1ccoc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1(c2ccoc2)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.8 %

Procedure:
A stirred solution of 3-bromofuran (5.0 g of technical grade, 0.034 mole) in dry ether (130 ml) at -60° C. under nitrogen was treated with 1.6M n-butyllithium in hexane (18.7 ml, 0.030 mole) and then stirred for 5 minutes. A solution of 1-azabicyclo[2.2.2]octan-3-one (3.37 g, 0.027 mole) in dry ether (10 ml) was added and the resulting mixture stirred for 40 minutes at -60° C., then allowed to warm to room temperature. The mixture was treated with potassium carbonate solution (100 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was chromatographed on basic alumina eluting with ethyl acetate. The pale yellow oil obtained crystallised on standing. This material was recrystallised from acetone to give the title compound (D20) as a white solid (1.40 g, 21%) m.p. 130°-133° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][Si](C(C)C)(C(C)C)C(C)C)[O:7][C@H:6]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][CH:29]=[N:30][C:31]=2[NH:35][C@@H:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37]1)(=[O:3])[CH3:2].F>N1C=CC=CC=1.O1CCCC1>[C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][CH:29]=[N:30][C:31]=2[NH:35][C@@H:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Temperature: 25 °C
Yield: 82.1 %

Procedure:
(2R,3S,4R,5R)-2-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-5-{[(triisopropylsilyl)oxy]methyl}tetrahydrofuran-3,4-diyl diacetate (0.305 g, 0.49 mmol) was stirred in pyridine (2 mL) and tetrahydrofuran (2 mL). Hydrofluoric acid in pyridine (2.0 M) was added (15 drops) and the reaction was stirred at room temperature for thirty minutes. The reaction was quenched using saturated sodium bicarbonate then extracted using ethyl acetate (3×10 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The brown residue was purified by column chromatography (30-50% ethyl acetate/hexanes followed by ethyl acetate) to give the title compound as a white solid (0.188 g, 82%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].[NH:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C([BH3-])#N.[Na+].C=O>C(O)C.C(O)(=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]4)[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: O=C(O)C1CNC1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.7 %

Procedure:
A solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D92) (120 mg), 3-azetidinecarboxylic acid (64.8 mg) and acetic acid (0.1 mL) in ethanol (10 mL) was stirred at room temperature for 15 min, then sodium cyanoborohydride (60.4 mg) was added. The mixture was stirred at room temperature for 6 h, then formaldehyde (0.11 mL) was added. The mixture was stirred at room temperature overnight. After concentration, the residue was acidified with 2M HCl to pH 5-6, ethyl acetate was added, the organic phase was washed with saturated brine, then dried and evaporated. The residue was purified by Mass Directed AutoPrep to afford 1-[(3-{2-[3-cyano-4-(2-methylpropyl)phenyl]-1,3-thiazol-5-yl}-2-ethylphenyl)methyl]-3-azetidinecarboxylic acid (E43) (32 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 0.92 (6H, d), 1.05 (3H, t), 1.98 (1H, m), 2.76 (4H, m), 3.65 (1H, m), 4.27 (4H, m), 4.54 (2H, br. s.), 7.40 (1H, m), 7.48 (2H, m), 7.62 (1H, d), 7.94 (1H, s), 8.22 (1H, dd), 8.35 (1H, d), 10.21 (1H, br s), 13.19 (1H, br s). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C27H29N3O2S requires 459. found 460.2 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([NH2:12])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:30]3[CH:38]=[CH:39][C:40]([C:42](O)=[O:43])=[CH:41][C:29]=3[N:28]=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.ClCCl>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:31]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[C:30]3[CH:38]=[CH:39][C:40]([C:42]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[S:9]([NH2:12])(=[O:11])=[O:10])=[O:43])=[CH:41][C:29]=3[N:28]=2)=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Reactant: NS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccccc1C(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A suspension of compound 49 (0.060 g, 0.14 mmol) and thionyl chloride (0.051 mL) in benzene (2 mL) was refluxed for 2 h under an argon atmosphere. The reaction mixture was cooled to rt and concentrated on a rotary evaporator. The residue was coevaporated with benzene (2×) to afford the acid chloride as a white solid (0.062 g, 100%). Sodium hydride (0.0101 g, 0.252 mmol, 60% dispersion in oil was added to a solution of phenylsulfonamide (0.0425 g, 0.270 mmol) in dimethylformamide (1 mL) at rt under an argon atmosphere. After 1 h, dichloromethane was added (1 mL), followed by the acid chloride of 49 at 0° C. The reaction was warmed to rt. After 1 h, the reaction was diluted with dichloromethane and quenched with 1 N hydrochloric acid. The aqueous layer was washed with dichloromethane (3×). The combined organic layers were dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified by column chromatography (silica gel, 25% acetone/toluene (v/v)). This material was further purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford 55 as a white solid (0.0219 g, 54%). 1H NMR (CDCl3) δ 8.71 (d, 1H, J=1.1 Hz), 8.05 (m, 3H), 7.82 (d, 1H, J=8.8 Hz), 7.69 (d, 2H, J=9.1 Hz), 7.58 (m, 1H), 7.51-7.36 (m, 7H), 7.21 (d, 2H, 8.8 Hz), 5.16 (s, 2H), 4.52 (m, 1H), 2.32 (br m, 2H), 2.01 (br m, 4H), 1.80 (br m, 1H), 1.35 (br m, 3H); ESI-MS m/e 566.4 (M+1); HPLC purity (ELSD)>95%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([S:21](Cl)(=[O:23])=[O:22])[CH:20]=1>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[S:21]([C:19]2[CH:20]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=2[O:25][CH3:26])(=[O:22])=[O:23])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)NCC2
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of 2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (1.34 g, 7.6 mmol) in dichloromethane (66 ml) and pyridine (1.6 ml) was treated with 5-chloro-2-methoxy-benzenesulfonyl chloride (1.83 g, 7.6 mmol, 1 equiv.). The mixture was stirred at room temperature overnight, then diluted with dichloromethane and washed with water. The organic phase was dried with Na2SO4 and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient), yielding 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester, 2.2 g (77% yield). MS (ISP): m/e=382.1 (M+H+.), δH (300 MHz; CDCl3) 7.99 (1H, d), 7.93 (1H, s), 7.61 (1H, d), 7.37 (1H, dd), 7.11 (1H, d), 6.77 (1H, d), 4.04 (2H, t), 3.83 (3H, s), 3.56 (3H, s), 3.02 (2H, t).
Reaction SMILES: [CH2:1]([N:8]([C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][C:13]([C:26]#[N:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:30].[Na+]>S(=O)(=O)(O)O>[CH2:1]([N:8]([C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:26]([NH2:27])=[O:30])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CN(Cc1ccccc1)C(C)(C)CCC(C#N)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN(Cc1ccccc1)C(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1

Procedure:
A solution of 4-(N-benzyl-N-methylamino)-1-cyano-1,1-diphenyl-4-methylpentane (1.0 g-see Preparation 12) in 90% sulphuric acid (10 ml) was heated at 90° for 1 hour. The mixture was poured onto ice (100 g), basified to a pH of about 12 by the addition of 40% aqueous sodium hydroxide and extracted with dichloromethane (2×100 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.6 g.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([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][CH2:25][CH2:26][CH3:27])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Br:28]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl>[Br:28][C:9]1[C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[C:6]2=[N:7][C:8]=1[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][CH2:25][CH2:26][CH3:27]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCCCCCCCCCCCCCCCc1cc(C)c2c(n1)N(C)CC2
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCc1nc2c(c(C)c1Br)CCN2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 278 mg (0.75 mmol) of 1,4-dimethyl-6-hexadecyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 4 mL of chloroform was added 108 mg (0.38 mmol) of 1,3-dibromo-5,5-dimethylhydantoin in portions at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction was quenched by the addition of 5 mL of sat aq NaHCO3. The mixture was extracted with chloroform and the combined organic layer was washed with brine and dried over MgSO4. The concentrated residue was purified by flash chromatography on a silica gel column (20 1.7 cm). Elution with 100:1 hexanes/ethyl acetate gave the product as a white solid: yield 331 mg (98%); nip 49-50° C.; silica gel TLC Rf 0.78 (8:1:1 hexanes/ethyl acetate/methanol); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=7.2 Hz), 1.25-1.31 (m, 28H), 1.66 (quint, 2H, J=7.6 Hz), 2.08 (s, 3H), 2.55 (t, 2H, j=8.0 Hz), 2.80 (t, 2H, J=8.4 Hz), 2.90 (s, 3H), 3.38 (t, 2H, J=8.0 Hz) and 6.13 (s, 1H); 13C NMR (CDCl3), δ 14.1, 19.5, 22.7, 25.2, 28.7, 29.4, 29.57, 29.61, 29.65, 29.68, 29.71, 29.71, 29.71, 29.71, 29.71, 29.71, 31.9, 33.0, 38.1, 52.4, 110.9, 120.3, 141.1, 156.8 and 161.8; mass spectrum, m/z 451.3 and 453.2 (M+H)+ (theoretical 451.3 and 453.3); mass spectrum (APCI), m/z 451.2680 and 453.2697 (M+H)+ (C25H44N2Br requires 451.2688 and 453.2667).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[CH2:17][C:18](=O)[CH2:19][CH3:20])=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:19]([C:18]1[NH:8][C:9]2[C:10]([CH:17]=1)=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH3:20]
Reactant: CCC(=O)Cc1cc(OC)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc2cc(OC)ccc2[nH]1
Yield: 58 %

Procedure:
1-[2-(tert-Butoxycarbonylamino)-5-methoxyphenyl]-2-butanone (7.33 g, 0.025 mol) in 120 mL of CH2Cl2 and 20 mL of trifluoroacetic acid was stirred for 20 hours, washed with water, NaHCO3 solution and the product chromatographed on silica (eluted with 20% EtOAc/hexane) to give 2.54 g (58% yield) of 2-ethyl-5-methoxy-1H-indole as a white solid, mp 49-50° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:37]>C1COCC1.O1CCOCC1>[ClH:37].[ClH:37].[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][CH2:29][N:26]1[C:22]2[N:23]=[CH:24][N:25]=[C:20]([C:17]3[CH:18]=[CH:19][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:16]=3)[C:21]=2[CH:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2ccc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CNC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidine-1-carboxylate (4 g, 7.87 mmol) in 20 mL of THF was added 20 mL of 4 N HCl in dioxane. After being stirred at room temperature for 1 hour, the solvents were removed in vacuo to give 3.9 g (99%) of the desired product {3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride, which was used for the next reaction. LC-MS: [M+H]+=409.3.
Reaction SMILES: [OH:1]O.[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[N:9][CH:10]=1)[CH3:4].O>CC(O)=O>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[N+:9]([O-:1])[CH:10]=1)[CH3:4]
Reactant: CCc1ccc(NC(=O)C(C)(C)C)nc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc(NC(=O)C(C)(C)C)[n+]([O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
H2O2 (30%, 34 mL, 0.33 mol) was added to a solution of N-(5-ethylpyridin-2-yl)pivalamide (22 g, 0.11 mol) in HOAc (200 mL). The mixture was stirred overnight at 80° C. The reaction mixture was poured into water and was extracted with EtOAc. The organics were washed with sat. Na2SO3 and NaHCO3 before being dried over MgSO4. The solvent was evaporated in vacuo to afford 5-ethyl-2-pivalamidopyridine 1-oxide (16 g, 67%), which was used for the next step without further purification.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:4])[CH3:2].ClS([N:29]=[C:30]=O)(=O)=O>O1CCCC1>[C:30]([C:15]1[N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:13]([C:10]2[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:12][CH:11]=2)=[CH:17][CH:16]=1)#[N:29]
Reactant: CCS(=O)(=O)Nc1ccc(-c2cccn2C(=O)OC(C)(C)C)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
tert-Butyl 2-{4-[(ethylsulfonyl)amino]phenyl}-1H-pyrrole-1-carboxylate (3.0 g, 8.58 mmol) was dissolved in tetrahydrofuran (85 mL) and cooled to −78° C., followed by the slow addition of chlorosulfonyl isocyanate. After tert-Butyl 2-{4-[(ethylsulfonyl)amino]phenyl}-1H-pyrrole-1-carboxylate was consumed, dimethyl formamide (6.86 mL) was added and the solution allowed to warm to room temperature. After 2 hours, the mixture was cooled and partitioned between water and diethyl ether. The combined organic layers were dried over magnesium sulfate, and concentrated. The residue was purified by silica gel flash chromatography (hexane/ethyl acetate; 7:3) to afford the title compound (1.84 g, 57%). The title compound was used immediately in the next step.