Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH:6]=[N:7][CH:8]=1)=O.[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:5]2[CH:4]=[C:3]([CH2:1][NH:23][S:20]([CH3:19])(=[O:22])=[O:21])[CH:8]=[N:7][CH:6]=2)=[CH:10][C:11]=1[O:17][CH3:18])#[N:14]
Reactant: CS(N)(=O)=O
Reactant: COc1cc(-c2cncc(C=O)c2)ccc1C#N
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: COc1cc(-c2cncc(CNS(C)(=O)=O)c2)ccc1C#N
Temperature: 140 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
(General reductive amination procedure): Titanium(IV) isopropoxide (0.098 ml, 0.336 mmol) was added dropwise to a mixture of 4-(5-formyl-pyridin-3-yl)-2-methoxy-benzonitrile (40 mg, 0.168 mmol) and methanesulfonamide (23.96 mg, 0.252 mmol) in toluene (10 mL). The resulting mixture was heated to 140° C. (bath temperature) for 3 hr. After concentration, the residue was dissolved in CH2Cl2 (10 mL). NaBH(OAc)3 (107 mg, 0.504 mmol) was added at room temperature. The resulting mixture was stirred at room temperature overnight (18 h). The reaction was quenched by the addition of saturated NaHCO3 solution (10 mL). The mixture was filtered, and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (15 mL×3). The combined extracts were dried over Na2SO4. After filtration and concentration, the residue was purified by isco column (MeOH—CH2Cl2, v/v, 15 to 3%) and yielded a colorless solid (31 mg). HRMS 317.08431 M+, C15H15N3O3S requires 317.08341, ESI-MS m/z: 318.0 [M+H]+, 1H NMR (400 MHz, CDCl3) δ ppm 2.94 (s, 3H), 3.96 (s, 3H), 4.38 (d, J=6.3 Hz, 2H), 4.70 (m, 1H), 7.06 (d, J=1.24 Hz, 1H), 7.16 (m, 1H), 7.60 (d, J=8 Hz, 1H), 7.87 (s, 1H), 8.57 (d, J=2 Hz, 1H), 8.73 (d, J=2 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].[NH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][OH:30]>>[OH:30][CH2:29][CH:28]([NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:21])[F:23])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26])[CH2:31][CH3:32]
Reactant: CCC(N)CO
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Product: CCC(CO)NC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 2-amino-1-butanol in a manner similar to that described in Example 11.
Reaction SMILES: [CH2:1]([N:11]1[C:16](=[O:17])[CH:15]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)([CH2:14]2)[C:12]1=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(O)C.[Pd]>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]23[CH2:14][CH:15]2[C:16](=[O:17])[N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:12]3=[O:27])=[CH:23][CH:22]=1
Reactant: CCCCCCCCCCN1C(=O)C2CC2(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCN1C(=O)C2CC2(c2ccc(N)cc2)C1=O

Procedure:
Following the procedure of Example 3, a solution of 6.0 g of 3-n-decyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione in 120 ml of ethanol is hydrogenated in the presence of 0.3 g of 5% palladium on carbon and worked up, affording the title compound which melts at 92°-94° C. after recrystallisation from ethyl acetate. The starting material is synthesised in accordance with Example 3, starting from 4.6 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione, 0.72 g of sodium hydride (pract. Fluka) and 5.3 ml of 1-decyl bromide. The product is a yellow oil with Rf=0.50 on thin-layer silica gel plates in the system hexane/ethyl acetate (1:1).
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([CH2:23][C:24]3[N:28](C=C)[N:27]=[CH:26][N:25]=3)=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:12]=1.[BH4-].[Na+]>O.[OH-].[Na+].[Hg]>[NH:28]1[C:24]([CH2:23][C:13]2[N:11]3[CH:12]=[C:7]([F:6])[CH:8]=[CH:9][C:10]3=[N:15][C:14]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:25][CH:26]=[N:27]1
Reactant: C=Cn1ncnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Agent: [BH4-]
Agent: [Hg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(-c2nc3ccc(F)cn3c2Cc2ncn[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
To a solution of mercuric trifluroacetate (128 mg, 0.30 mmol) in 0.3 mL of water was added 0.3 mL of THF. The yellow suspension thus formed was mled to 0° C., and 6-fluoro-2-(4-fluorophenyl)-3-((1-vinyl-1H-1,2,4-triazol-5-yl)methyl)imidazo[1,2-a]pyridine (101 mg, 0.30 mmol) was added portion wise. After the addition was over, the reaction mixture was allowed to warm to room temperature and stirred for 12 h. After cooling to 0° C., 0.3 mL of 3 N NaOH followed by 0.3 mL of 0.5 M NaBH4 in 3 N NaOH was added to the mixture. The mercury was allowed to settle, and the supernatant liquid decanted and extracted with CH2CH2. The extract was dried over anhydrous Na2SO4 and concentrated to give the crude product which was purified silica gel chromatography. 28 mg, 30% yield. m/e+=312 (M+H+). 1H-NMR (400 MHz, CD3OD, δ): 8.41 (m, 1H), 8.33 (s, 1H), 7.79 (m, 2H), 7.60 (m, 1H), 7.33 (m, 1H), 7.21 (m, 2H), 4.53 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][C:9]=2[Cl:24])=[O:4].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[F:35].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[NH4+].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:25]([CH3:26])[CH3:27])=[N:7][C:8]2[C:13]([C:14]=1[C:31]1[CH:32]=[CH:33][C:34]([F:35])=[C:29]([Cl:28])[CH:30]=1)=[CH:12][C:11]([Cl:23])=[CH:10][C:9]=2[Cl:24])=[O:4]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)c1c(C(C)C)nc2c(Cl)cc(Cl)cc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)c1c(C(C)C)nc2c(Cl)cc(Cl)cc2c1-c1ccc(F)c(Cl)c1
Temperature: 100 °C
Yield: 59.6 %

Procedure:
A suspension of 6,8-dichloro-2-isopropyl-4-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid methyl ester (85.0 mg, 0.181 mmol, Eq: 1.00), 3-chloro-4-fluorophenylboronic acid (34.7 mg, 0.199 mmol, Eq: 1.1), potassium phosphate tribasic (57.7 mg, 0.272 mmol, Eq: 1.5) and tetrakis(triphenylphosphine)palladium (0) (6.27 mg, 0.00543 mmol, Eq: 0.0300) in dioxane (2.5 ml) was heated to 100° C. for 4 h. The suspension was cooled to RT overnight, then diluted with sat. NH4Cl solution and extracted with ethyl acetate (3×). The combined organic layers were washed with sat. NH4Cl solution and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 99:1) to afford the title compound as white solid (46 mg). MS (ESI): 426.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1.[H-].[Na+].[CH3:15][O:16][CH2:17][CH2:18][CH2:19]Br>CN(C=O)C>[CH3:15][O:16][CH2:17][CH2:18][CH2:19][N:3]1[CH:2]([CH3:1])[CH2:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[S:4]1(=[O:12])=[O:11]
Reactant: COCCCBr
Reactant: CC1Cc2ccsc2S(=O)(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCN1C(C)Cc2ccsc2S1(=O)=O
Temperature: -20 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
The product from Step B (800 mg, 3.94 mmol) was dissolved in DMF (10 mL) and the solution was cooled to -20° C. Sodium hydride (236 mg of an oil dispersion, 5.91 mmol) was added followed by 3-methoxypropyl bromide (1.8 mL, 11.82 mmol) and this mixture was warmed to 0° C. and stirred for 4 hr. The reaction mixture was poured into ice/water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts were washed with water (2×50 mL) and brine (2×50 mL), dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 10% methanol/methylene chloride) to give the desired product (890 mg, 82%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]([CH3:19])[CH2:16][CH2:17][OH:18])[CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].[OH-].[Na+]>C(Cl)Cl.O>[C:27]([O:18][CH2:17][CH2:16][N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]=1)[CH3:19])(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: CN(CCO)CCOCCc1ccc2sccc2c1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCOCCc1ccc2sccc2c1)CCOC(=O)C(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
In 5 mL of methylene chloride is dissolved 0.50 g of 2-{[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-(methyl)amino}-1-ethanol. The solution thus obtained is cooled to −60° C., to which are added 0.37 mL of triethylamine and 0.31 mL of pivaloyl chloride. The mixture is stirred at the same temperature as above for 30 minutes and then at ambient temperature for one hour. Water is added to the reaction mixture, pH is adjusted to 9.0 with 1 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=100:1 to 50:1) to obtain 0.54 g of 2-{[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl](methyl)amino}ethyl pivalate as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](O)=[O:13])[CH:6]=[CH:5]2.B.C1COCC1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][OH:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(F)ccc2c1
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc2cc(F)ccc2c1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of 6-fluoro-naphthalene-2-carboxylic acid (3.0 g, 15.8 mmol) was added BH3.THF (31.6 mL, 31.6 mmol). The reaction mixture was stirred overnight before being concentrated. To the residue was added diethyl ether (100 mL) and NaOH solution (10 mL). The organic layer was separated, dried and concentrated. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane 1:7) to afford (6-fluoro-naphthalen-2-yl)-methanol (2.28 g, 82%).
Reaction SMILES: Cl.C(OC([O:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[C:9]=1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)C)C>CC(O)C>[OH:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[C:9]=1[CH2:17][N:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1
Reactant: CCOC(C)Oc1ccc2c(c1CN1CCN(C)CC1)OCO2
Agent: Cl
Solvent: CC(C)O
Product: CN1CCN(Cc2c(O)ccc3c2OCO3)CC1
Reaction time: 0.25 h
Yield: 61 %

Procedure:
Aqueous HCl (300 ml, 0.5N) was added to a stirred solution of 5-(1-ethoxyethoxy)-4-(4-methylpiperazinylmethyl)-1,3-benzodioxole (16.0 g, 49.7 mmol) in 2-propanol (300 ml) at room temperature, and stirring was continued for 15 minutes. The solution was extracted with diethyl ether, the aqueous layer was neutralised (pH=7) by adding aqueous NaOH(2N), and the water layer was evaporated in vacuo. The residue was extracted with diethyl ether (3 times). The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo to yield a crude oil (9.6 g). This oil was purified by flash chromatography (eluent: acetone/ethyl acetate=1/1 (v/v)) to yield 5-hydroxy-4-(4-methylpiperazinylmethyl)-1,3-benzodioxole (7.6 g, 61% yield, compound No. 8) as a solid, m.p. 85°-87° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[C@@H:5]([O:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[C:9]([CH3:30])[CH:8]=1)C.[OH-].[Na+]>>[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:31][CH3:32])[C:4]([OH:33])=[O:3])=[CH:8][C:9]=2[CH3:30])=[CH:23][CH:22]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(C)c1)OC
Agent: [Na+]
Agent: [OH-]
Product: COC(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(C)c1)C(=O)O

Procedure:
The title compound was prepared from compound from Step F under Standard hydrolysis procedure C using NaOH.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11])([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br>CCOCC>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH2:11][Br:17])([O-:3])=[O:2]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
o-Nitroacetophenone (8.3 g, 50 mmol) in ether (100 ml) was treated with aluminium chloride (catalytic amount) followed by bromine (2.55 ml, 50 mmol) over 10 mins and the reaction stirred for 30 mins. The reaction was quenched with aqueous sodium bicarbonate, the ether layer separated, dried (MgSO4) and evaporated under reduced pressure. The residue was taken up in ethyl acetate, the solution was dried (MgSO4), and evaporated under reduced pressure to yield o-nitro phenacyl bromide as a yellow oil (9.45 g, 77%); δH(CDCl3) 7.2-8.35(4H, m, aryl), 4.30(2H, S, CH2).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])=[C:5]([C:17]([F:20])([F:19])[F:18])[NH:4][N:3]=1>[Pd].CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:17]([F:19])([F:18])[F:20])[NH:4][N:3]=1
Reactant: Cc1n[nH]c(C(F)(F)F)c1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1n[nH]c(C(F)(F)F)c1C(=O)O
Yield: 74 %

Procedure:
A mixture of benzyl 3-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (74 g, 285 mmol), Pd/C (45 g, 10% on C) and EtOAc (1 L) was treated in a Parr apparatus at room temperature with H2 (15 psi) for 5 hours. The catalyst was filtered off over Celite and the solvent was removed in vacuo. Et2O (1 L) and water (200 mL) were added and the aqueous layer was made slightly basic (pH 8-9) with Na2CO3. The layers were separated and the aqueous layer was extracted with Et2O (5×200 mL). To the aqueous layer was added dropwise conc. HCl until pH 4-5 and followed by extraction with Et2O (3×500 mL). The combined organic layers were dried (MgSO4), filtered, evaporated in vacuo to give the title compound in 74% yield 7.4 g; m.p. 308-310° C. (dec.) m/z 195 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)(=O)=O)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[C:39]([OH:41])=[O:40].C([O-])([O-])=O.[Na+].[Na+].CCN(C(C)C)C(C)C.[Li+].[OH-].Cl>C1COCC1.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:32][C@H:33]4[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]4[C:39]([OH:41])=[O:40])[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: N[C@H]1CCCC[C@@H]1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)(=O)=O)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)[C@H]1CCCC[C@@H]1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-chloro-3-(5-fluoro-4-methylsulfonyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (0.49 g, 1.05 mmol), (1S,2S)-2-amino-cyclohexanecarboxylic acid (0.30 g, 2.10 mmol), freshly ground Na2CO3 (0.22 g, 2.10 mmol), and iPr2NEt (0.37 mL, 2.10 mmol) in THF (10 mL) and CH3CN (2 mL) were heated in a sealed vessel to 130° C. for 30 minutes under microwave irradiation. The mixture was cooled to room temperature. A solution of 1N LiOH (3.1 mL, 3.1 mmol) was added and the mixture was stirred at 120° C. for 10 minutes under microwave irradiation. The mixture was acidified with 1N HCl until pH 2 under vigorous stirring. The newly formed solid was collected by vacuum filtration. The solid was washed with small amounts of water and EtOAc. The solid was dried in vacuo to provide the desired product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[F:1]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(F)c1
Product: COC(=O)c1ccc(C)cc1F
Reaction time: 48 h

Procedure:
2-Fluoro-4-methylbenzoic acid (30.0 g, 195 mmol) was dissolved in MeOH (600 mL, 10 mol), and 12 M HCl (3.2 mL, 39 mmol) was added. The mixture was heated to reflux and stirred for 48 hours, then cooled and concentrated. The recovered material was dried in vacuo for 24 hours to obtain Intermediate (6a) as a white solid that was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([NH:2][C:3]1([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1)(=[O:28])[CH3:27]
Reactant: COC(=O)C1(N)CCc2cc(OC)ccc2C1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(C)=O)CCc2cc(OC)ccc2C1

Procedure:
Methyl 2-amino-6-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate hydrochloride (13.6 g., 50 mM) was suspended in dry dichloromethane (200 ml.). The suspension was stirred and cooled in ice, and dry triethylamine (16.8 ml., 120 mM) was added, followed by acetyl chloride (4.3 ml., 60 mM). The mixture was stirred at room temperature for 16 hr. The solvent was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate (1 l.) and water (500 ml.). The mixture was separated and the organic phase was washed successively with water (500 ml.), 2N hydrochloric acid (2×500 ml.), water (500 ml.) and saturated brine (500 ml.). The organic phase was dried (Na2SO4) and the solvent evaporated in vacuo. The solid was crystallised from ethyl acetate/petroleum ether (b.p. 60°-80°) to give methyl 2-acetylamino-6-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate, m.p. 160°-1°.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[C:8]([Cl:23])=[C:7]([CH3:24])[C:6]=1[C:25](=[O:27])[CH3:26].[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:23][C:8]1[C:7]([CH3:24])=[C:6]([C:25](=[O:27])[CH3:26])[C:5]([O:4][CH2:3][CH2:2][NH:33][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[O:21][CH3:22]
Reactant: NC1CCCC1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccccc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCNC2CCCC2)c1OCCCc1ccccc1
Temperature: 65 °C
Yield: 68 %

Procedure:
Example 34b (217 mg, 0.48 mmol) was reacted with cyclopentylamine as described under General Procedure B (except heated to 65° C.) and the crude was purified by flash chromatography (silica-gel, MeOH/DCM 5:95) yielding the title compound (151 mg, 68%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.32-7.19 (m, 5H), 4.14 (t, J=5.1 Hz, 2H), 4.07 (t, J=6.3 Hz, 2H), 3.88 (s, 3H), 3.24-3.04 (m, 1H), 2.87-2.79 (m, 4H), 2.49 (s, 3H), 2.19 (s, 3H), 2.10-2.04 (m, 2H), 1.85-1.78 (m, 3H), 1.69-1.66 (m, 2H), 1.56-1.51 (m, 2H), 1.35-1.31 (m, 2H). MS (ES+) m/z 460 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:24][CH3:25])[C:13]3[C:18]([C:19]=2[C:20]#[N:21])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=3)=[CH:7][CH:6]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(#N)C>[CH2:24]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=2)[C:19]([C:20]#[N:21])=[C:11]1[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:6][CH:7]=1)[CH3:25]
Reactant: C1COCCN1
Reactant: CCn1c(-c2ccc(OCCBr)cc2)c(C#N)c2ccc(OC)cc21
Solvent: CC#N
Product: CCn1c(-c2ccc(OCCN3CCOCC3)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 85 °C
Yield: 96.2 %

Procedure:
2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (40 mg, 0.1 mmol), prepared as in step A above, is combined with morpholine (50 μL, 0.58 mmol) and acetonitrile (1.0 mL). This is heated at 85° C. for 2 h. The reaction mixture is then partitioned between CH2Cl2 and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (6/4, acetone/hexanes) yields 1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile (39 mg, 96%) as a white solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[CH3:23])[C:13]=1[O:24]S(C)(=O)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[CH3:23])[C:13]=1[OH:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(C)cccc2c1OS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(C)cccc2c1O
Reaction time: 1 h

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(3,5-dimethyl-1-(methylsulfonyloxy)naphthalen-2-yl)acetate (0.19 g, 0.48 mmol) in THF (3 mL) cooled to 0° C. was treated with tetrabutylammonium fluoride (1M in THF, 1.4 mL, 1.4 mmol). After 1 hour, saturated NaHCO3 was added and the aqueous layer extracted with EtOAc. The combined organics are washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification via Yamazen column chromatography afforded (S)-ethyl 2-tert-butoxy-2-(1-hydroxy-3,5-dimethylnaphthalen-2-yl)acetate that is contaminated with a small percentage of an inseparable, uncharacterized side product. 1H-NMR: 400 MHz, (CDCl3) δ: 8.96 (s, 1H); 8.13 (obs m, 1H); 7.30 (obs m, 2H); 5.51 (s, 1H); 4.23-4.05 (m, 2H); 2.62 (br s, 6H); 1.31 (s, 9H); 1.19 (t, J=7.2 Hz, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[CH:29]1([CH2:35][CH2:36][CH2:37][C@@H:38]([C:47]([NH:49][CH:50]([C:54]([O:56][CH3:57])=[O:55])[C:51](=[O:53])[CH3:52])=O)[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.O>[C:43]([O:42][C:40](=[O:41])[CH2:39][C@H:38]([C:47]1[O:53][C:51]([CH3:52])=[C:50]([C:54]([O:56][CH3:57])=[O:55])[N:49]=1)[CH2:37][CH2:36][CH2:35][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([CH3:44])([CH3:46])[CH3:45]
Reactant: COC(=O)C(NC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C)C(C)=O
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)oc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
A suspension of triphenylphosphine (9.49 g, 36.18 mmol), iodine (7.98 g, 31.44 mmol) and triethylamine (8.49 ml, 60.75 mmol) in tetrahydrofuran was cooled to −78° C. then treated with tert-butyl (3R)-6-cyclohexyl-3-({[1-(methoxycarbonyl)-2-oxopropyl]amino}carbonyl)hexanoate (Preparation 68) (4.86 g, 11.80 mmol) over 15 minutes. The mixture was stirred at −78° C. for 30 minutes then at 0-5° C. for 2 hours. The mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:pentane (0:100 to 10:90) to afford the title compound as a colourless oil (2.92 g).