Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].CCCCCC.[CH3:19][O:20][CH2:21]Cl>O1CCCC1>[CH2:1]([N:3]([CH2:10][CH2:11][O:12][CH2:19][O:20][CH3:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: COCCl
Reactant: CCN(CCO)c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CCOCOC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
55.7 g (0.34 mol) of N-ethyl-N-(2-hydroxylethyl)aniline was dissolved in 250 ml of anhydrous tetrahydrofuran, and 162 ml (1.2-fold equivalent weight) of a 2.5M hexane solution n-butyllithium was dropwise added thereto over a period of 30 minutes at 0° C. in an atmosphere of argon, followed by stirring at 0° C. for 30 minutes. Next, to the reaction solution obtained, 30.0 g (1.09-fold equivalent weight) of methoxymethyl chloride was dropwise added, and the solution was heated and refluxed for 12 hours, followed by cooling. The precipitate formed was removed by filtration, and thereafter the filtrate obtained was concentrated under reduced pressure. The oily residue thus obtained was distilled under reduced pressure to obtain 63 g of N-ethyl-N-[2-(methoxymethyl)oxyethyl]aniline (yield: 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3OC)[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[C:17]([F:43])[CH:16]=2)[CH:5]=[CH:4][N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[C:17]([F:43])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccnc(N)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc([C@H]2CCCC[C@@H]2Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2F)ccn1
Yield: 57.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-2-(2-aminopyridin-4-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (42.7 mg, 0.0698 mmol) prepared in Example 35c, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (18.6 mg, 58%) as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=O)[NH:6][N:7]=1)[CH3:2].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:8]2[NH:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][C:14]=3[N:19]=2)[NH:6][N:7]=1)[CH3:2]
Reactant: CCc1cc(C=O)[nH]n1
Reactant: COc1ccc(N)c(N)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(-c2nc3cc(OC)ccc3[nH]2)[nH]n1

Procedure:
Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 138 mg of 4-methoxy-1,2-phenylenediamine, and 153 mg of sodium metabisulphite, in 1 ml of ethanol and 3 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a reverse-phase HPLC (5 mm C18 phase, dimensions 100×25 mm, flow rate 20 ml/min, elution gradient: acetonitrile/0.07% TFA-water/0.07% TFA from 5-95 to 95-5 (v/v)), and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 61 mg of 2-(5-ethyl-2H-pyrazol-3-yl)-5-methoxy-1H-benzimidazole are obtained in the form of a brown lacquer, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH:13]=[CH:12][C:11](OC)=[C:10]([C:16]#[N:17])[C:9]1=[O:18].O.[NH2:20][NH2:21].C(O)C>CN(C)C=O>[NH2:17][C:16]1[C:10]2[C:9](=[O:18])[N:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])[CH:13]=[CH:12][C:11]=2[NH:21][N:20]=1
Reactant: COc1ccn(-c2ccncc2Cl)c(=O)c1C#N
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1n[nH]c2ccn(-c3ccncc3Cl)c(=O)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
A mixture of 3′-chloro-4-methoxy-2-oxo-2H-[1,4′-bipyridine]-3-carbonitrile obtained in Step C (0.35 g), hydrazine monohydrate (0.17 g), ethanol (10 mL) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 2 hr. The solvent was evaporated under reduced pressure, to the residue was added isopropyl ether, and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (0.30 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][C:5]([O:7]C)=[O:6].Cl>[OH-].[Na+].O>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: COC(=O)CC(OC)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(CC(=O)O)OC
Yield: 79.1 %

Procedure:
50 g (0.33 mol.) of Methyl 3,3-dimethoxy-propanoate in 200 ml of 2N NaOH solution in water were refluxed 2 hours. After cooling the solution was acidified with hydrochloric acid then extracted two times with 200 ml of CH2Cl2. The extracts were dried on sodium sulfate and evaporated to leave 35 g (Yield=78%) of 3,3-dimethoxy-propanoic acid as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][C:33](Cl)=[O:34]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:33](=[O:34])[CH2:32][C:28]4[S:27][CH:31]=[CH:30][CH:29]=4)[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(Cl)Cc1cccs1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)Cc5cccs5)c4)CC3)cccc2n1
Yield: 42 %

Procedure:
The title compound was prepared in 42% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2-thienylacetyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:25])([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[CH:14]([F:16])[F:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:22][C:21]1[CH:20]=[CH:19][C:18]([O:17][C:13]([F:12])([F:25])[CH:14]([F:15])[F:16])=[CH:24][CH:23]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(OC(F)(F)C(F)F)cc1
Product: O=C(Nc1ccc(OC(F)(F)C(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 169.2 using 5-bromo-6-chloro-nicotinic acid and 4-(1,1,2,2-tetrafluoroethoxy)aniline to afford a solid. UPLC-MS (Condition 3), tR=1.2 min, m/z=424.9 [M+H]+.
Reaction SMILES: [NH:1]1[C:6](=O)[CH2:5][O:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C1COc2ncccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1cnc2c(c1)NCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
1H-pyrido[2,3-b][1,4]oxazin-2-one (113 mg, 0.75 mmol) was dissolved in tetrahydrofuran (3.5 ml) and then cooled to 0□. 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (1.5 ml, 1.5 mmol) was added thereto dropwise. After stirring for 2 hours at room temperature, 0.1 ml of water, 0.2 ml of 10% aqueous solution of sodium hydroxide, and 0.3 ml of water were added in this order under stirring. After filtering precipitates, the filtrate was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain colorless liquid (90 mg, 88%).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O)C.C([O-])(=O)C.[Na+].Cl.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH3:31])N)=[CH:25][CH:24]=1.ClC1C=CC(N(C)N=O)=CC=1>C(O)(=O)C.O.[Zn]>[Cl:22][C:23]1[CH:24]=[C:25]2[C:26](=[CH:27][CH:28]=1)[N:29]([CH3:31])[C:6]([CH2:5][C:4]([OH:3])=[O:15])=[C:8]2[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(N)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: CN(N=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(CC(=O)O)c(-c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of γ-phenyl acetoacetic acid ethyl ester (2.88 g) in a mixture of acetic acid (30 ml) and water (10 ml) were added sodium acetate (1.83 g) and 1-(4-chlorophenyl)-1-methyl hydrazine hydrochloride (2.73 g) {prepared from 4-chloro-N-methyl-N-nitroso aniline by subjecting to reduction with zinc powder in a mixture of acetic acid and water [m.p.171°-174° C.; NMR (200 MHz, DMSO-d6) ppm: 3.14(3H,s), 7.20(2H,d,J=9 Hz), 7.29(2H,d,J=9 Hz)]}. The mixture was stirred for 15 minutes at room temperature, then for 20 minutes at 110° C. The reaction mixture was concentrated, which was dissolved in ethyl acetate. The solution was washed with water, dilute hydrochloric acid, water, an aqueous solution of sodium hydrogencarbonate and water, successively, which was then dried, followed by distilling off the solvent. The residue was purified by means of a silica gel (30 g) column chromatography (hexane-ethyl acetate=4:1) to give ethyl ester of 5-chloro-1-methyl-3-phenylindole-2-acetic acid as an oily substance (4.34 g). [NMR (200 MHz, CDCl3) ppm: 10 1.29(3H,t,J=7 Hz), 3.76(3H,s), 3.86(2H,s), 4.24(2H,q,J=7 Hz), 7.17-7.62(8H,m)]
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:17]=[C:16]2[C:11]([C@:12]([NH:21][C:22]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[S:23])([CH3:20])[C@@H:13]([CH2:18]O)[CH2:14][O:15]2)=[CH:10][CH:9]=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(Cl)Cl>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C@@:12]3([CH3:20])[N:21]=[C:22]([NH:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[S:23][CH2:18][C@H:13]3[CH2:14][O:15][C:16]=2[CH:17]=1
Reactant: C[C@@]1(NC(=S)NC(=O)c2ccccc2)c2ccc(F)cc2OC[C@@H]1CO
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@]12N=C(NC(=O)c3ccccc3)SC[C@H]1COc1cc(F)ccc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DCM (40 mL) and pyridine (0.539 mL, 6.67 mmol) were added to rel-N-(((3S,4S)-7-fluoro-3-(hydroxymethyl)-4-methylchroman-4-yl)carbamothioyl)benzamide from step F4 (832 mg, 2.22 mmol), under an atmosphere of dry nitrogen. The mixture was cooled to −78° C. Triflic anhydride (0.751 mL, 4.44 mmol) was slowly added to the reaction solution over 10 min. The resulting mixture was stirred for 15 min and then further stirred for 1 h while warming to 0° C. After adding ethyl acetate, a saturated solution of sodium bicarbonate was added. The mixture was extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was dissolved in dichloromethane and one drop of water and one drop of TFA was added. The reaction was stirred for 15 min, then concentrated in vacuo to afford rel-N-((4aR,10bS)-8-fluoro-10b-methyl-4,4a,5,10b-tetrahydrochromeno[4,3-d][1,3]thiazin-2-yl)benzamide. The crude product was used for subsequent chemistry without further purification. LCMS (M+H)+=357.2.
Reaction SMILES: [OH:1][C:2]1([CH3:15])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:16].C(OCC)C>>[ClH:16].[CH3:15][C:2]1([OH:1])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Product: CC1(O)CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (1.0 g, 4.6 mmol) was added hydrogen chloride, 1.0 M solution in diethyl ether (4.6 ml, 4.6 mmol). The reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated down to give a yellow oil which was used directly in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][OH:9].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:27])[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]([NH:5][CH2:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[Cl:1])=[O:12])=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: CC(C)(CO)C(=O)NCc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(NC(=O)OCC(C)(C)C(=O)NCc2ccccc2Cl)cc1
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To a solution of N-(2-chlorobenzyl)-3-hydroxy-2,2-dimethylpropanamide (30 mg, 0.12 mmol), in CH2Cl2 were added DMAP and 4-ethylphenylisocyanate (21 μL, 0.15 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated. The resulting residue was to purify on RP-HPLC to give 3-(2-chlorobenzylamino)-2,2-dimethyl-3-oxopropyl 4-ethylphenylcarbamate (10 mg, 17%). LRMS (M+H+) m/z 389.1.
Reaction SMILES: [CH2:1]([N:8]1[CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]([C:16](OC)=[O:17])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]([CH2:16][OH:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCCC(C)N(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CCCC(CO)CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 1-benzyl-7-methyl-2-oxoazepane-3-carboxylate (2-4, 3.8 g, 14 mmol, 1.0 equiv) in THF (70 mL) at 0° C. under nitrogen was added solid lithium aluminum hydride (2.6 g, 69 mmol, 5.0 equiv) and the resulting mixture was stirred at 0° C. for 1.5 hours. Excess LAH was quenched with water (2 mL) and 15% aqueous sodium hydroxide solution (2 mL). The mixture was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes gradient) to yield (1-benzyl-7-methylazepan-3-yl)methanol (2-5) as a clear oil. 1H NMR (400 MHz, CDCl3) 7.36 (m, 5H), 3.68-1.49 (m, 18H). LRMS m/z (M+H) 234.3 found, 234.2 required.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([F:22])[CH:15]=1.FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]([OH:19])[C:17]1[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][C:16]=1[F:22]
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Reactant: O=Cc1ccc(Br)cc1F
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: OC(c1ccc(Br)cc1F)c1ccccc1C(F)(F)F

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (60 mmol) and 4-bromo-2-fluorobenzaldehyde (54 mmol) using the procedure described for compound (96) (12.3 g, 74%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]4[O:31][C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[O:24][CH2:23]4)=[CH:18][CH:17]=3)[CH2:14][C:9]2=[N:8][N:7]=1)=O)C.[CH3:32][NH2:33]>C(O)C>[CH3:32][NH:33][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]4[O:31][C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[O:24][CH2:23]4)=[CH:18][CH:17]=3)[CH2:14][C:9]2=[N:8][N:7]=1)=[O:3]
Reactant: CCOC(=O)c1nnc2n1CCN(Cc1ccc([C@H]3COc4cccnc4O3)cc1)C2
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1nnc2n1CCN(Cc1ccc([C@H]3COc4cccnc4O3)cc1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of compound 240 (75 mg, 0.18 mmol) in a solution of 33% methylamine in ethanol (1.0 mL) is stirred at 90° C. in a pressure tube. After 18 hours, the mixture is gradually cooled to rt. The mixture is filtered, and the solids are washed with chilled ethanol and chilled methanol then air dried to give the title product. (LC/MS method 16: ES+ m/z 407.3 [M+H]+, Rt=2.73 min)
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[S:19])[NH:15][C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH3:23])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[OH-].[Na+].[CH3:26]I.Cl>O.CCO>[OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16]([S:19][CH3:26])=[N:15][C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH3:23])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: CI
Reactant: CCCn1c(=O)[nH]c(=S)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)nc(SC)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-3-propyl-6-thioxo-1,3,6,7-tetrahydro-purin-2-one (120 mg, 0.36 mmol) was suspended in 3 mL of H2O and 1.5 mL of EtOH. NaOH was added as a solution in 0.4 mL of H2O, followed by MeI. The reaction mixture was stirred at rt for 1 h. It was then neutralized with 0.1 N HCl and extracted with CHCl3. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford essentially quantitative amount of the titled compound.
Reaction SMILES: O[C:2]1[C:3]2[NH:20][C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.P(Cl)(Cl)([Cl:23])=O>O1CCOCC1>[Cl:23][C:2]1[C:3]2[NH:20][C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccccc2)nc2c1[nH]c1ccccc12
Solvent: C1COCCO1
Product: Clc1nc(-c2ccccc2)nc2c1[nH]c1ccccc12

Procedure:
A mixture of 4-Hydroxy-2-phenyl-5H-indolo[3,2-d]pyrimidine (800 mg), phosphorous oxychloride (10 mL), and dioxane (10 mL) was refluxed for 40 min. The reaction mixture was concentrated in vacuo and the residue was treated with saturated ammonium chloride and methylene chloride. After drying over magnesium sulfate the solvent was removed in vacuo and the residue was triturated with ether/hexane to afford 4-Chloro-2-phenyl-5H-indolo[3,2-d]pyrimidine (Compound 3) as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([S:13](Cl)(=[O:15])=[O:14])[CH2:11][CH3:12].[C:17]1([S:23]([N:26]2[C:30]3=[N:31][CH:32]=[C:33]([NH:42][C:43](=[O:47])[CH2:44][C:45]#[N:46])[C:34]([NH:35][CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[C:29]3[CH:28]=[CH:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:17]1([S:23]([N:26]2[C:30]3=[N:31][CH:32]=[C:33]([NH:42][C:43](=[O:47])[CH2:44][C:45]#[N:46])[C:34]([NH:35][CH:36]4[CH2:41][CH2:40][N:39]([S:13]([CH2:10][CH2:11][CH3:12])(=[O:15])=[O:14])[CH2:38][CH2:37]4)=[C:29]3[CH:28]=[CH:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: N#CCC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCC(Nc2c(NC(=O)CC#N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.107 ml, 0.615 mmol) and 1-propanesulfonyl chloride (0.035 ml, 0.308 mmol) were added sequentially to a solution of N-[1-benzenesulfonyl-4-(piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-cyano-acetamide (hydrochloride salt) (0.205 mmol) in CH2Cl2 (2 ml) at 25° C. The reaction mixture was stirred for 3 h at 25° C., then was partitioned between saturated NaHCO3 (6 ml) and CH2Cl2 (2 ml). The phases were separated using a phase separation column (Biotage) and the organic layer was concentrated under reduced pressure to give crude N-{1-benzenesulfonyl-4-[1-(propane-1-sulfonyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-cyano-acetamide as a brown oil/solid. LCMS (Method G, ESI): RT=0.88 min, m+H=545.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](ON=C(C1C=CC=CC=1)C#N)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[NH2:27][C@@:28]1([C:48]([OH:50])=[O:49])[C@H:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[C@@H:32]([OH:44])[C@@H:31]2[C@H:29]1[C@H:30]2[C:45]([OH:47])=[O:46]>O1CCOCC1.O>[C:8]([O:12][C:13]([NH:27][C@@:28]1([C:48]([OH:50])=[O:49])[C@H:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[C@@H:32]([OH:44])[C@@H:31]2[C@H:29]1[C@H:30]2[C:45]([OH:47])=[O:46])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 91.8 %

Procedure:
Triethylamine (212.80 mL, 154.49 g, 1.53 mol) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (125.33 g, 508.90 mmol) are added sequentially to a suspension of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (140 g, 339 mmol) in 1,4-dioxane (203.56 mL), and water (0.6 mL/mmol-pure-LR, 203.56 mL), at ambient temperature. After 4.5 hours, add additional 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (25.07 g, 101.78 mmol) and triethylamine (23.64 mL, 17.17 g, 169.63 mmol) to the reaction and stir at 50° C. overnight. Cool to 23° C., dilute with water (500 mL), and wash with methyl tert-butyl ether (6×500 mL). Dilute the aqueous phase with 10% aq. HCl (300 mL; final pH=2) and extract with ethyl acetate (2×500 mL). The ethyl acetate extracts are dried over MgSO4 and concentrated in vacuo to yield the title compound (148.3 g, 92% yield).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc(Br)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(4-bromophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 80% overall yield. FDMS m/e=444, 446 (M+ of free base). α[D]589 =-7.52 (c=0.45, methanol).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:8]=2[C:9](OC)=[O:10])[C:5](=[O:18])[N:4]([CH3:19])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[N:6]([C:7]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:8]=2[CH2:9][OH:10])[C:5](=[O:18])[N:4]([CH3:19])[N:3]=1
Reactant: COC(=O)c1cccc(C)c1-n1c(Cl)nn(C)c1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1cccc(CO)c1-n1c(Cl)nn(C)c1=O
Temperature: 25 °C
Yield: 69.9 %

Procedure:
To a solution of the title compound of Step C (7.0 g, 24.8 mmol) in dichloromethane (60 mL) cooled to -78° C. under a nitrogen atmosphere was added a 1 Molar solution of DIBAL (diisobutylaluminum hydride) in dichloromethane (62 mL, 62 mmol). After the addition was complete, the reaction mixture was allowed to warm to room temperature for 1 h. An additional portion of 1 Molar solution of DIBAL in dichloromethane (31 mL) was added at -78° C. and the mixture warmed to room temperature for 1 h. The reaction was quenched with 1 N HCl and extracted three times with dichloromethane. The combined organic phases were washed with saturated ammonium chloride solution, dried (MgSO4) and concentrated under reduced pressure. The residue was triturated to afford 4.4 g of the title compound of Step D as a solid. 1H NMR (CDCl3): δ 7.44 (apparent d,2H), 7.33 (t,1H), 4.46 (m,2H), 3.57 (s,3H), 2.66 m,1H), 2.18 (s,3H).