Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH:10]=2)[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].C(O)(=O)C.[CH:50]1([CH:53]=O)[CH2:52][CH2:51]1.[BH3-]C#N.[Na+]>CO.Cl>[CH:50]1([CH2:53][N:2]2[CH2:3][CH2:4][CH:5]([O:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]4[CH2:23][CH2:22][CH:21]([N:24]5[C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=6[CH2:27][O:26][C:25]5=[O:34])[CH2:20][CH2:19]4)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:38])[F:39])[CH:10]=3)[CH2:6][CH2:7]2)[CH2:52][CH2:51]1
Reactant: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Reactant: O=CC1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Cc1ccc(OC2CCN(CC3CC3)CC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.30 g, 0.5 mmol) from Example 2 in MeOH (7.5 mL) was added sodium acetate (82 mg, 1.0 mmol), acetic acid (0.10 mL, 1.7 mmol), and cyclopropane carboxaldehyde (75 mg, 1.1 mmol). The mixture was stirred at ambient temperature for 30 min and NaBH3CN (61 mg, 1.0 mmol) was added. The solution was stirred for 18 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (3×25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3:0.3 CH2Cl2 :MeOH:NH4OH as eluant. The free base was dissolved in MeOH containing 1.5 equivalents of 3 N aqueous HCl. The resulting solution was evaporated under reduced pressure and the residue was lyophilized from CH3CN:H2O to give the hydrochloride salt of the title compound as an amorphous solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@@H:23]3[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]3[OH:25])[N:21]=[CH:22][C:15]=12.C(=O)(O)[O-].[K+].O>CN(C)C=O.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]3[N:20]([C@@H:23]4[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]4[OH:25])[N:21]=[CH:22][C:15]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@H]1O[C@@H](n2ncc3c(S)ncnc32)[C@H](O)[C@@H]1O
Reactant: ClCCCCCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](n2ncc3c(SCCCCCc4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Yield: 9.2 %

Procedure:
Crude 5-phenylpentyl chloride (1.3 g) was added to a stirred solution of 4-mercapto-1-β-D-ribofuranosylpyrazolo [3,4-d]pyrimidine (2.0 g) and potassium bicarbonate (0.7 g) in N,N-dimethylformamide. The reaction mixture was heated on a steam bath for 25 hours. An additional 0.7 g of potassium bicarbonate was added and after heating for 1 hour more, the mixture was poured into water. The cooled aqueous mixture was extracted with chloroform. The chloroform soluble material was chromatographed on a silica gel column. The fractions containing the compound were combined and evaporated. Trituration with ether gave 0.4 g of crude product. This was dissolved in ethyl acetate and washed with water. The dried ethyl acetate solution was evaporated and purified by reversed phase chromatography in methanol water (80:20 vol/vol) to give 0.28 g of product m.p. 72°-75° C. (indefinite).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12]C)=[O:10])[NH:5][NH:4]1.C(N(CC)CC)C.II>CO>[F:18][C:2]([F:1])([F:17])[C:3]1([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([O:11][CH3:12])=[O:10])[N:4]=[N:5]1
Reactant: CCOC(=O)c1cccc(C2(C(F)(F)F)NN2)c1
Agent: II
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cccc(C2(C(F)(F)F)N=N2)c1
Yield: 27 %

Procedure:
Ethyl 3-(3-(trifluoromethyl)diaziridin-3-yl)benzoate (Preparation 199, 226 mg, 0.87 mmol) was stirred in methanol (10 mL) with triethylamine (0.36 mL, 2.61 mmol). Iodine (662 mg, 2.61 mmol) was dissolved in 2 mL methanol and added portion-wise until an orange-brown colour persisted. The reaction mixture was evaporated in vacuo and the residue was diluted with 1M aq. NaOH (30 mL) and then extracted with EtOAc (3×30 mL). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to afford the title compound as a gum in 27% yield, 60 mg. This material was used in the next step without further purification.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[C:9]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=[O:14].[F:21][C:22]([F:37])([S:33](F)(=[O:35])=[O:34])[C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26]>C1COCC1>[F:37][C:22]([F:21])([S:33]([O:16][C:11]1[CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[C:8]([Cl:7])=[CH:15][C:12]=1[CH:13]=[O:14])(=[O:35])=[O:34])[C:23]([F:31])([F:32])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26]
Reactant: O=Cc1cc(Cl)c(C(F)(F)F)cc1O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)c(C(F)(F)F)cc1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 0.07 h

Procedure:
A 1.04 M THF solution of t-BuOK (4.9 mL, 5.1 mmol) was added to a 0° C., THF solution (4 mL) of 5-chloro-2-hydroxy-4-(trifluoromethyl)benzaldehyde (1.0 g, 4.6 mmol). After 4 min, neat 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (1.7 mL, 9.3 mmol) was added and the ice bath was removed. After 1 h at room temperature, AcOH (1 mL) was added and the resulting mixture was concentrated. The resulting material was diluted with DCM and 1M aqueous HCl, the layers were separated, and the organic layer was washed with 1 M NaHCO3, dried (Na2SO4), and concentrated to yield the title compound that was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[CH:8][CH:7]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].CO>C1(C)C=CC=CC=1>[CH3:16][N:14]([CH:13]=[C:7]([C:6](=[O:10])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: c1csc(-c2ccno2)c1
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(C)C=C(C#N)C(=O)c1cccs1
Yield: 87.3 %

Procedure:
A mixture of 5-(2-thienyl)isoxazole (4.3 kg) and dimethylformamide dimethylacetal (6.1 kg; Lancaster) in toluene (12 L; Barton) is heated at reflux. As methanol forms it is removed by distillation. Solid forms from the reaction mixture. The reaction mixture is cooled and diluted with methyl-t-butyl ether (8 L; Van Waters). The precipitate is collected by filtration and washed with methyl-t-butyl ether (4 L). The solid is slurried with acetone (10 L; Batron) and hexanes (10 L; Mallinckrodt), then filtered and washed with hexanes (4 L). After drying in vacuo there is obtained 5.124 kg of α-[(dimethylamino)methylene]-β-oxo-2-thiophenepropane-nitrile (87% yield).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.O>O1CCCC1>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: O=C1CCCN1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCN1CCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride(555 mg/13.9 mmol) in tetrahydrofuran (50 ml) was added 2-pyrrolidinone (0.7 ml/9.26 mmol) at ice-cooling temperature. The mixture was stirred for 1 h at ambient temperature, and then 1,4-dibromobutane (10 g/46.3 mmol) was added at the same temperature. The resulting mixture was stirred overnight. Water (10 ml) was added to the mixture and the mixture was extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and brine succesively, then dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (80g/dichloromethane:methanol=100:0-100:5-100:10) to give a colorless oil(2.0 g/90%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8]([CH3:22])=[N:9][N:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=12.[Br:23]N1C(=O)CCC1=O>ClCCl>[Br:23][C:5]1[S:4][C:3]([C:7]2[C:8]([CH3:22])=[N:9][N:10]3[C:15]([CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=23)=[C:2]([Cl:1])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nc2c(-c3sccc3Cl)c(C)nn12
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nc2c(-c3sc(Br)cc3Cl)c(C)nn12
Reaction time: 2 h

Procedure:
Dissolve 3-(3-chloro-thiophene-2-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (1.16 g, 3.5 mmol) in dichloromethane (15 mL) and add N-bromosuccinimide (0.69 g, 3.85 mmol) in one aliquot. Stir 2 h under an inert atmosphere and confirm the reaction is complete using TLC. Dilute the reaction with dichloromethane (50 mL), wash with water (75 mL), brine (50 mL), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to give a yellow solid (1.56 g, quantative yield). 1H NMR (400 MHz, DMSO): 7.39 (s, 1H), 6.88 (s, 1H), 3.48-3.44 (m, 1H), 2.45 (s, 3H), 2.39 (s, 3H), 1.80-1.73 (m, 4H), 0.76 (t, J=7.0 Hz, 6H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12](Cl)=[O:13])(=[O:8])=[O:7].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[F:18][C:17]1[CH:16]=[CH:15][C:11]([C:12](=[O:13])[C:22]2[CH:23]=[CH:24][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[S:6]([Cl:5])(=[O:8])=[O:7]
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc(F)c(S(=O)(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(F)c(S(=O)(=O)Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
To a suspension of aluminium chloride (2.1 g, 15.7 mmol) in methylene chloride (50 mL) is added 3-chlorosulfonyl-4-fluoro benzoyl chloride (10.5 mmol). The reaction mixture is stirred at room temperature for 10 minutes then anisole (1.36 g, 12.5 mmol) is added. After the mixture is stirred at room temperature for 16 h, the reaction is quenched with 6 N HCl, and extracted with methylene chloride three times. The combined organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate/hexane: 1:9) followed by recrystallization (methylene chloride-hexane) provides 1.8 g (54% yield) of the title compound as a white solid. 1H NMR (CDCl3): δ 8.41 (m, 1H), 8.20 (m, 1H), 7.82 (d, J=15 Hz, 2H), 7.50 (t, 1H), 7.08 (d, J=15 Hz, 2H), 3.95 (s, 3H).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C@@H:10]2[CH2:12][C@H:11]2[C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH:4]=1)[NH2:2].[Si:23]([O:30][C@@H:31]([CH3:40])[C:32]([N:34]=[C:35](N(C)C)[CH3:36])=O)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(=O)(O)[O-].[Na+]>C(O)(=O)C.COCCOC>[Si:23]([O:30][C@H:31]([C:32]1[N:1]([C:3]2[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C@@H:10]3[CH2:12][C@H:11]3[C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH:4]=2)[N:2]=[C:35]([CH3:36])[N:34]=1)[CH3:40])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(=NC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C)N(C)C
Reactant: Cc1nc(NN)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: Cc1nc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2[C@H](C)O[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of Intermediate 6 (1.8 g, 6.1 mmol) in acetic acid (40 ml) was added Intermediate 13 (4.0 g, 14.7 mmol) as a crude reaction mixture in 1,2-dimethoxyethane (40 mL). The reaction mixture was allowed to stir for 5 minutes at room temperature and then heated at 80° C. for 1 h. The reaction was cooled to room temperature, poured carefully over saturated aqueous sodium bicarbonate solution (200 mL), and the aqueous layer was made basic to pH˜8 by the addition of solid sodium bicarbonate. The solution was extracted with ethyl acetate (200 mL) and the organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-60% EtOAc/hexanes) to afford 13-1 as an oil. MS: m/z=504.4 (M+H).
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:32]1(/[CH:38]=[CH:39]/[C:40](Cl)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:26])([CH3:27])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)[C:40](=[O:41])/[CH:39]=[CH:38]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc3c(c2)C(=O)OC(C)(C)O3)cc1
Reactant: O=C(Cl)/C=C/c1ccccc1
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)/C=C/c2ccccc2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The title compound was prepared following the procedure E using 6-[(4-dec-1-ynylbenzyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and (2E)-3-phenylacryloyl chloride. HPLC, Rt: 6.3 min (purity: 95.5%).
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[NH2:15][C:16]1[C:17]([NH:31][CH2:32][CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)=[CH:18][C:19]([NH:22][C:23]2[CH:28]=[N:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=2)=[N:20][CH:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[C:29]([C:26]1[N:27]=[CH:28][C:23]([NH:22][C:19]2[N:20]=[CH:21][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[C:17]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[CH:18]=2)=[N:24][CH:25]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCNCC1
Reaction time: 2 h
Yield: 29.7 %

Procedure:
Triethylamine (11 μL, 0.082 mmol) and acetic anhydride (8 μL, 0.082 mmol) were added to a solution of tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)-pyridin-4-ylamino)-methyl)-piperidine-1-carboxylate (29 mg, 0.068 mmol) in DMF (1 mL) at 0° C. After 2 hours, the mixture was loaded onto a MP-TsOH SPE cartridge, and eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated. Purified by preparative HPLC gave N-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)acetamide (7.4 mg, 32%).
Reaction SMILES: O[CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>C(Cl)Cl.O>[N:24]([CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: OC1CCCc2cccnc21
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: [N-]=[N+]=NC1CCCc2cccnc21
Temperature: 40 °C
Yield: 49 %

Procedure:
To a stirred solution of 8-hydroxy-5,6,7,8-tetrahydroquinoline (71.6 g, 0.480 mol) in CH2Cl2 (500 mL, 1.0 M) at room temperature was added triethylamine (126 mL, 0.904 mol) followed by methanesulfonyl chloride (55 mL, 0.711 mol). The resulting mixture was heated to 40° C. overnight then cooled to room temperature. The mixture was poured into water (350 mL), diluted with CH2Cl2 (350 mL), and the phases were separated. The organic phase was washed with brine (2×250 mL), dried (Na2SO4), and concentrated. The resultant oil was dissolved in DMF (570 mL), treated with sodium azide (63.1 g, 0.971 mol), and heated at 70° C. overnight. The mixture was cooled to room temperature, then evaporated and the residual slurry was poured into brine (500 mL) and extracted with ether (4×500 mL). The combined organic extracts were washed with brine (2×100 mL), dried (Na2SO4), and concentrated. The crude material was filtered through a short plug of silica gel (CH2Cl2) to provide 41.0 g (46% from 5,6,7,8-tetrahydroquinoline) of 8-azido-5,6,7,8-tetrahydroquinoline as a red oil.
Reaction SMILES: [C:1]1([CH2:11]O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc2c1CCCC2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: ClCc1cccc2c1CCCC2
Yield: 56 %

Procedure:
61 g (0.376 mol) of (5,6,7,8-tetrahydro-1-naphthyl)methanol with a purity of 78 % are dissolved in 450 ml of chloroform, in the presence of 35 g (0.38 mol) of pyridine. 90 ml of thionyl chloride in solution in 30 ml of chloroform are introduced dropwise and between 30 and 40°C into the solution which is obtained and this is heated under reflux for 6 hours. After partial evaporation of the chloroform and the thionyl chloride excess, washing is carried out with water and with a sodium bicarbonate solution, followed by drying over anhydrous sodium sulphate. Distillation of the oily residue permits the isolation of a liquid of boiling point b.p.0.5 = 81°-83°C, with a purity of 86 % (vapour phase chromatography), and this is taken up in 150 ml of hot hexane. The crystallisation is seeded by scratching with a glass rod. There are isolated 29.5 g of a product melting at 51°-52°C, with a yield of 56 % (theoretical yield = 53 g, depending on the degree of purity of the starting product). Vapour phase chromatography confirms a purity of 100 %.
Reaction SMILES: CC(OC)=O.[Li+].[CH3:7][CH:8]([N-:10]C(C)C)C.[F:14][C:15]([F:43])([F:42])[O:16][C:17]1[CH:18]=[C:19]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=2)=[N:24][S@@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH:20]=[CH:21][CH:22]=1.[NH4+].[Cl-]>CCOCC.CCOC(C)=O>[F:41][C:38]([F:39])([F:40])[O:37][C:33]1[CH:32]=[C:31]([C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][C:15]([F:43])([F:42])[F:14])[CH:18]=2)=[N:24][S@@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH:36]=[CH:35][CH:34]=1.[C:8]([CH2:7][C:23]([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][C:15]([F:14])([F:42])[F:43])[CH:18]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=1)#[N:10]
Reactant: CC(C)[N-]C(C)C
Agent: CC(C)(C)[S@@](=O)N=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: COC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)NC(CC#N)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
(R)—N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide was prepared as described for Procedure 11. Under an argon atmosphere, CH3COOMe (0.70 mL, 8.83 mmol, 2.0 eq) was stirred in anhydrous Et2O (50 mL) in an oven-dried round bottomed flask at −78° C. LDA (2.0 M, 4.4 mL, 8.8 mmol, 2.0 eq) was added dropwise. The resulting mixture was stirred at −78° C. for 30 min. (R)—N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide (2.0 g, 4.42 mmol) in Et2O (10 mL) was added dropwise to the above stirred solution. The reaction mixture was stirred at −78° C. for 1.5 h. Saturated NH4Cl was added, followed by the addition of EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes=0 to 100%) to give N-(2-cyano-1,1-bis(3-(trifluoromethoxy)phenyl)-ethyl)-2-methylpropane-2-sulfinamide as light tan oil (1.96 g, yield: 84.1%). LC-MS (ESI) 528.34 (M+H), retention time=4.00 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run); 1H NMR (400 MHz, CDCl3) δ ppm 7.36 (d, J=8.0 Hz, 2H), 7.31 (t, J=8.0 Hz, 1H), 7.25-7.18 (m, 2H), 7.14-7.05 (m, 3H), 6.14 (s, 1H), 3.93 (d, J=16.1 Hz, 1H), 3.54 (d, J=15.9 Hz, 1H), 3.86 (m, 2 H), 3.49 (s, 3H), 1.26 (s, 9H). 13C NMR (400 MHz, CDCl3) ppm 22.71, 43.84, 51.68, 56.41, 63.69, 118.63, 119.52, 120.49, 121.35, 124.27, 125.73, 129.81, 129.92, 143.83, 147.52, 149.33, 171.93.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10](OC)=[O:11])[C:5]=12.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC>C1COCC1.C(OCC)(=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[C:5]=12
Reactant: COC(=O)c1cccn2ccnc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cccn2ccnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 40 %

Procedure:
To a cold solution of methyl imidazo[1,2-a]pyridine-8-carboxylate (5.55 g, 31.53 mmol, 1 eq) in THF (100 mL) was added LAH in ether (1 M solution in ether, 4 equiv.) and then stirred at rt for 6 h. The reaction mixture was cooled to 0° C. and quenched with water/15% NaOH/water. Reaction mixture was diluted with ethyl acetate and stirred at room temperature for 15 min and then filtered. The solid was washed with ethanol and the organic layers were combined, dried and evaporated to give the alcohol, which was purified by column chromatography to yield the desired product in 40% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](S(C)=O)[N:9]=2)=[CH:4][CH:3]=1.[NH2:17][CH:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:17][CH:18]3[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH2:23]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CS(=O)c1nccc(-c2ccc(Br)cc2)n1
Product: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1

Procedure:
4-(4-Bromo-phenyl)-2-methanesulfinyl-pyrimidine (0.25 g, 0.84 mmol) and 4-amino-2,2,6,6,-tetramethylpiperidine (1 ml) were heated for 45 minutes at 130° C. Evaporation and chromatography on silicagel (EtOAc/MeOH/ammonia:95/4.5/0.5 to 90/9/1) gave the title compound as white crystals. Yield: 260 mg (78%).