Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[C@@H:8]3[O:10][C@@H:9]3[C@H:3]1[CH2:4][CH:5]([O:11]C([C@@H](C1C=CC=CC=1)CO)=O)[CH2:6]2.Br.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][N:2]1[C@@H:7]2[C@@H:8]3[O:10][C@@H:9]3[C@H:3]1[CH2:4][CH:5]([OH:11])[CH2:6]2
Reactant: CN1[C@@H]2CC(OC(=O)[C@H](CO)c3ccccc3)C[C@H]1[C@@H]1O[C@@H]12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN1[C@@H]2CC(O)C[C@H]1[C@@H]1O[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
5.45 g (0.023 mol) of scopine hydrobromide was suspended in 30 mL of DCM, and then 5 g (0.036 mol) of potassium carbonate was added. The reaction mixture was stirred at room temperature for one hour and then filtered on Goch P3 and washed with acetonitrile several times, (using about 10 ml of acetonitrile). After evaporation of the filtered solution, 2.78 g of scopine base was obtained (77.5% yield). 3.0 g (0.02 mol) of scopine base was suspended at room temperature in 27 mL of dimethylformamide, then 2.7 g (0.02 mol) of anhydrous potassium carbonate was added, and the mixture was stirred at room temperature for about 60 minutes. 4.9 g (0.02 mol) of methyl di-(2-thienyl)glycolate were dissolved in 9 mL of dimethylformamide, and, with 1.33 g (0.0096 mol) of anhydrous potassium carbonate, they were added to the reaction mixture at about 60-65° C. The suspension was heated to 65° C., under vacuum (70-100 mbar), and under nitrogen stripping (2.2-2.4 L/min) for 18 hours. At the end of the reaction the distilled DMF was re-added to the reaction mixture and other 2 volumes of DMF, for a total of 15 volumes (45 mL), were added. The reaction mixture was cooled to 0° C., and acidified to a pH of 3 with 33 mL of 2M HBr (temperature during addition below 20° C.). The obtained solution was extracted twice with 15 mL toluene, and the combined aqueous phases were then cooled to 0-5° C., and basified with 7.1 g of solid potassium carbonate to a pH of 9. After one hour at 0° C., the solid was filtered on Goch P3, and washed five times with 30 mL of water to obtain a pH of 7. The solid was dried under vacuum at 45° C. for 16 hours yielding 5.1 g (69.5% yield, 98.5% HPLC purity)
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[N:14]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:30]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[N:14]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CCCCC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 230A (0.034 g, 0.08 mmol) in tetrahydrofuran (2 mL) and methanol (0.0064 mL, 0.16 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.06 mL, 0.12 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (5 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 98:2 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (t, J=6.99 Hz, 3 H) 1.37 (m, 4 H) 1.55 (m, 2 H) 2.73 (m, 2 H) 5.90 (t, J=6.80 Hz, 1 H) 7.07 (t, J=7.72 Hz, 1 H) 7.26 (m, 2 H) 7.52 (m, 2 H) 7.60 (d, J=8.09 Hz, 1 H) 7.66 (d, J=8.09 Hz, 1 H) 8.09 (d, J=8.09 Hz, 1 H) 16.27 (s, 1 H). MS (ESI−) (M−H)− m/z 425.
Reaction SMILES: [CH3:1][C:2](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]>[Ir].C(Cl)Cl>[CH3:1][CH:2]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)=Cc1ccccc1
Agent: [Ir]
Solvent: ClCCl
Product: CCOC(=O)C(C)Cc1ccccc1
Yield: 86.7 %

Procedure:
According to the general procedure, a solution of ethyl 2-methyl-3-phenylacrylate (34 mg, 0.18 mmol) and iridium catalyst (S)-32 (5.7 mg, 0.0036 mmol, 2.0 mol %) in CH2Cl2 (1.8 mL) was hydrogenated. Removal of the solvent in vacuo and standard purification gave 36 (30 mg, 88%) as a colorless oil. [α]20D +28.4 (c 1.0, CHCl3); CSP HPLC analysis (Chiralcel OB-H; eluent: 99.5:0.5 hexanes/i-PrOH, 0.5 mL/min) determined a 91:9 er (82% ee) [tR(minor) 8.52 min, tR(major) 10.10 min]; 1H NMR (300 MHz, CDCl3) 7.31-7.16 (m, 5H), 4.09 (q, 2H, J=6.9 Hz), 3.08-2.98 (m, 1H), 2.79-2.64 (m, 2H), 1.21 (d, 3H, J=7.2 Hz), 1.16 (d, 3H, J=6.3 Hz) ppm; 13C NMR (75 MHz, CDCl3) 176.1, 139.4, 128.9, 128.3, 126.2, 60.2, 41.4, 39.7, 16.7, 14.1 ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][CH:12]=O)=[CH:2]1.[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:23]=2[N:24]=1.C([BH3-])#N.[Na+]>>[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][N:20]([CH2:12][CH:11]=[CH:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:21][CH2:22][C:23]=2[N:24]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: O=CC=Cc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Product: Nc1nc2c(s1)CCN(CC=Cc1c[nH]c3ccccc13)CC2
Yield: 11 %

Procedure:
Prepared from 3-(3-indolyl)acrolein and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine by reductive amination with 0.9 equivalents of sodium cyanoborohydride. Purification of the crude product by column chromatography is carried out using neutral aluminium oxide of activity stage I (toluene/ethyl acetate/ethanol=4:1:0.5). Yield: 11% of theory, Melting point: 155°-160° C.
Reaction SMILES: [CH2:1]([C:3]1[S:25][C:6]2=[N:7][C:8]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[N:5]2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO>[CH2:1]([C:3]1[S:25][C:6]2=[N:7][C:8]([N:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)=[CH:9][C:10](=[O:11])[N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2c(=O)cc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2s1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nn2c(=O)cc(N3CCNCC3)nc2s1
Reaction time: 18 h
Yield: 83.4 %

Procedure:
To a solution of tert-butyl 4-(2-ethyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (3.39 g, 9.28 mmol, 1.0 equiv) in 40 mL of dichloromethane is added trifluoroacetic acid (10 ml, 130 mmol, 14 equiv). The mixture stirred for 18 h, after which it is concentrated in vacuo and azeotroped with dichloroethane to give a yellow solid. The crude residue is dissolved in MeOH and purified by HPLC to give 2-ethyl-7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (2.053 g, 83% yield) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 5.30 (s, 1H), 3.37-3.44 (m, 4H), 2.94 (q, J=7.56 Hz, 2H), 2.64-2.73 (m, 4H), 1.25 (t, 3H); LCMS: (electrospray+ve), m/z 266.0 (MH)+; HPLC: tR=2.71 min, UV254=100%. HRMS (ESI): m/z calcd for C11H16N5OS [M+H]+266.1069. found 266.1073.
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2.O.C([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:14]1([CH2:1][CH:2]2[C:7](=[O:8])[CH:6]3[CH2:9][CH2:10][N:3]2[CH2:4][CH2:5]3)[C:15]2[C:16](=[CH:1][CH:2]=[CH:7][CH:6]=2)[CH2:18][CH2:17]1
Reactant: CCN(CC)CC
Reactant: C=C1C(=O)C2CCN1CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Product: O=C1C2CCN(CC2)C1CN1CCc2ccccc21
Temperature: 80 °C
Reaction time: 19 h

Procedure:
To a stirred solution of 2-methylene-3-quinuclidinone (0.5 g, 0.0028 mol) in water (6 ml) indoline (0.66 g, 0.0057 mol), triethylamine (0.84 g, 0.0084 mol) and tetra-n-butyl ammonium bromide (90 mg, 0.00028 mol) were added and the reaction mixture were allowed to stir at 80° C. for 18-20 h. The reaction mixture was quenched with ice-cold water (20 ml), extracted with dichloromethane (3×50 ml), the organic layers were washed with brine and dried over sodium sulphate, filtered and concentrated to get the crude product which was purified as greenish yellow solids (125 mg, 17%) by column chromatography on neutral silica gel using chloroform as eluent.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(O)[CH3:10])[CH2:3][CH2:2]1.I>C(O)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:10])[CH2:3][CH2:2]1
Reactant: CC(O)(CCN1CCOCC1)c1ccccc1-c1ccccc1
Agent: I
Solvent: CC(=O)O
Product: CC(CCN1CCOCC1)c1ccccc1-c1ccccc1

Procedure:
A mixture of 3.1 g of 1-morpholino-3-p-biphenylylbutan-3-ol, 10 ml of 67% hydriodic acid and 18 ml of acetic acid is heated at 150° for 1.5 hours. 1-Morpholino-3-p-biphenylyl-butane is obtained after cooling and working up in the customary manner.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1
Reactant: COCCOCCOCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COCCOCCOCCc1ccc(N)cc1
Reaction time: 3 h
Yield: 103.4 %

Procedure:
A portion of 14 (5.77 g, 20.2 mmol) was dissolved in 40 mL of acidic ethanol, and a catalytic amount of 10% palladium on carbon was added. The mixture was hydrogenated on a Parr apparatus (60 psi, 70° C.) for 3 hours. The mixture was then filtered over Celite, washing with ethanol. Solid sodium bicarbonate was added, and the mixture was stirred for 2 hours and, then filtered. The solvent was removed by distillation at reduced pressure, leaving a brown oil (5.0 g, 98% yield). IR (neat) 3441.82, 3349.64, 2893.88, 2238.41, 1634.41, 1516.36, 1449.79, 1234.71, 1101.56, 906.97, 722.62 cm−1. 1H NMR (400 MHz, CDCl3) δ 6.65 (ABq, J=8.7 Hz, Δv=51.5 Hz, 4H), 4.01 (t, J=5.4 Hz, 2H), 3.77 (t, J=4.6 Hz, 2H), 3.69 (app t, J=5.6 Hz, 2H), 3.65 to 3.59 (m, 4H), 3.51 (app t, J=4.9 Hz, 2H), 3.34 (s, 3H), 3.0 (brs, 2H). 13C NMR (100 MHz, CDCl3) δ 152.30, 140.58, 116.75, 116.24, 72.31, 71.14, 71.02, 70.93, 70.30, 68.49, 59.44.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].C(Cl)(Cl)Cl.CO>C(Cl)Cl.N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17]([NH:13][S:10]([C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=1)(=[O:11])=[O:12])=[O:18]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: NS(=O)(=O)c1ccc2ccoc2c1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(NS(=O)(=O)c1ccc2ccoc2c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzofuran-6-sulfonamide (120 mg, 0.608 mmol) in CH2Cl2 (3.6 mL) and pyridine (2.3 mL) is added DMAP (75 mg, 0.611 mmol) and 2,4-dichlorobenzoyl chloride (153 mg, 0.730 mmol) and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with CH2Cl2 then washed with 2 M HCl (2×) and dried (MgSO4). The organic solution is filtered and evaporated under vacuum to give the crude product. Flash chromatography on silica gel eluting with a gradient {CH2Cl2to CH2Cl2:(CHCl3:MeOH) [4:1(9:1)]} gives the title compound as a tan solid. ES(−)MS m/z 368, (M−H)− consistent with 2 Cl.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8](C[C@@H]3CCCN3C(OC(C)(C)C)=O)[N:9]=[C:10](C3C=CC(OC4C=CC=C(F)C=4F)=CC=3F)[C:3]=12.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[CH:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2S)-tert-butyl 2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carboxylate (1.97 g, 3.65 mmol, 1.00 equiv) in DCM (30 mL) was added trifluoroacetic acid (7.5 mL). The resulting solution was stirred for 4 h at room temperature. This solution was concentrated under reduced pressure. This resulted in 2.4 g (Crude) of 3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-(S)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetic acid salt as a reddish oil. MS (ESI, pos. ion) m/z: 441 (M+1)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][C:24]=2[C:25]#[N:26])[CH:19]=[CH:18][N:17]=1>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:2]3[CH:3]=[C:4]4[N:11]([CH3:12])[CH2:10][CH2:9][N:5]4[C:6](=[O:8])[N:7]=3)=[CH:27][C:24]=2[C:25]#[N:26])[CH:19]=[CH:18][N:17]=1
Reactant: N#Cc1cc(CO)ccc1Oc1ccnc(Cl)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccnc(Cl)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (65 mg, 0.350 mmol), sodium hydride (22 mg, 0.550 mmol) and 2-((2-chloropyridin-4-yl)oxy)-5-(hydroxymethyl)benzonitrile (91 mg, 0.350 mmol) in DMF (2 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>C1C=CC=CC=1>[C:29]([O:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:18][CH:17]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1
Reactant: OCc1ccc(OCCCCc2ccc(Cl)cc2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc(OCCCCc2ccc(Cl)cc2)cc1)c1cccnc1

Procedure:
A mixture of 6.0 g (0.02 mol) of 4-[4-(4-chlorophenyl)butoxy]phenylmethanol and 20.2 g triethylamine is added to 5.3 g(0.03 mol) of hydrochloride of nicotinoyl chloride in 100 ml anhydrous benzene with stirring and the mixture is refluxed for 20 hrs. Thereupon, the solvent is distilled off in vacuo, and water is added.
Reaction SMILES: [BH3-]C#N.[Na+].Cl.[NH2:6][C:7]1[NH:11][CH:10]=[N:9][C:8]=1[C:12]([NH2:14])=[O:13].C(O)(=O)C.[CH2:19]([O:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)[CH3:20]>CO>[CH2:19]([O:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:6][C:7]1[N:11]=[CH:10][NH:9][C:8]=1[C:12]([NH2:14])=[O:13])[CH3:20]
Reactant: CCOC(C)(C)C=O
Reactant: NC(=O)c1nc[nH]c1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(C)(C)CNc1nc[nH]c1C(N)=O
Temperature: 25 °C
Yield: 90 %

Procedure:
NaCNBH3 (0.077 g, 1.23 mmol) was added to 5-amino-4-imidazolecarboxamide hydrochloride (0.200 g, 1.23 mmol) and acetic acid (141 μL, 2.46 mmol) in methanol (1.5 mL). 2-Ethoxy-2-methylpropanal (0.286 g, 2.46 mmol) obtained from Example 1(b) was added drop by drop. After 1.5 h more 2-Ethoxy-2-methylpropanal (0.300 g, 2.58 mmol) was added followed by more 2-Ethoxy-2-methylpropanal after 0.5 h (0.424 mg, 3.65 mmol). The reaction mixture was stirred at r.t. 17 h after which it was concentrated and purified by flash silica gel chromatography (CHCl3/MeOH; 20:1-9.1), to give the title compound as an oil in 90% yield (0.251 g). MS (ESI) m/z 227 (M+1).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][NH2:37])[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(CNc2nccc(-n3cnc4ccccc43)n2)CC1
Temperature: 100 °C
Yield: 56.6 %

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 1) (115 mg, 0.42 mnmol) and 1-Benzyloxycarbonyl-4-(aminomethyl)piperidine (122 mg, 0.49 mmol) were dissolved in DMF-toluene (1:1, 5 mL), and the mixture was heated at 100° C. for 5 h. After cooling, the mixture was diluted with EtOAc and washed with H2O to remove DMF followed by brine. The organic extract was dried over Na2SO4, and the solvent was removed under reduced pressure to give 105 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.38 (br s, 1H); 8.18 (m, 1H); 7.85 (m, 1H); 7.4-7.28 (m, 7H); 6.79 (d, J=5.5 Hz); 5.12 (s, 2H); 4.22 (br s, 2H); 3.43 (m, 1H); 2.78 (br s, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=O)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:7]=[C:8]([CH:9]=[CH:22][CH:23]=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=Cc1cccc(-n2cccn2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1cccc(-n2cccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(1H-pyrazol-1-yl)-benzaldehyde (prepared as described in Reference Example 3) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 199 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].OS(O)(=O)=O.[BrH:16].CC(N=NC(C#N)(C)C)(C#N)C.OO>ClC1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:5]([Br:8])=[CH:6][CH:7]=1)[CH2:9][Br:16]
Reactant: Cc1c(Br)ccc(Br)c1C
Reactant: Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: OO
Solvent: Clc1ccccc1
Product: Cc1c(Br)ccc(Br)c1CBr
Temperature: 70 °C
Reaction time: 14 h

Procedure:
183.2 g (0.65 mol) of 3,6-dibromo-1,2-xylene are initially charged in 750 ml of chlorobenzene, and 2 g of conc. H2SO4 and 270.7 g (1.57 mol) of 47% strength hydrobromic acid are then added. The reaction mixture is heated to 70° C. and 0.3 g of AIBN are added. Over 14 h, 237.7 g (0.7 mol) of a 10% strength solution of hydrogen peroxide are added at 75-77° C., the mixture is stirred for another 120 min., washed 2× with 250 ml of water and once with 250 ml of saturated sodium bicarbonate solution, and the chlorobenzene is then distilled off.
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[CH:12][N:13]=[CH:14][C:15]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:10]2[CH:9]=[CH:8]1.[H-].[Na+].[CH3:29]C1C=CC(S(OC)(=O)=O)=CC=1>C1COCC1>[CH3:29][N:17]([CH2:16][C:15]1[CH:14]=[N:13][CH:12]=[C:11]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:25])[CH3:26])[CH:8]=[CH:9][C:10]=12)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)NCc1cncc2c1ccn2COCC[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cncc2c1ccn2COCC[Si](C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of tert-butyl (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methylcarbamate (300 mg, 0.796 mmol) in anhydrous THF (30 mL) at 0° C. was slowly added NaH (60% in mineral oil, 48 mg, 1.194 mmol) and stirred at 0° C. for 30 min. To the mixture was added methyl 4-methylbenzenesulfonate (178 mg, 0.955 mmol) followed by stirring at RT for 18 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with petroleum ether:EtOAc (2:1) to afford 232 mg (74.6%) of tert-butyl methyl((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methyl)carbamate as a yellow solid. MS (ESI): m/z=392.2 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.CS(C)=O.C([O-])([O-])=O.[K+].[K+]>O>[OH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:2]1
Reactant: N#Cc1ccc(F)cc1
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CC[C@@H](O)C2)cc1
Yield: 99.9 %

Procedure:
Dissolve (R)-pyrrolidin-3-ol (0.08 mL, 1.00 mmol) and 4-fluorobenzonitrile (121 mg, 1.00 mmol) into 1 mL of DMSO. Add K2CO3 (276 mg, 2.00 mmol) and heat the mixture at 120° C. for 16 h. LC-MS analysis indicates the desired intermediate. Add 10 mL of H2O. Filter the precipitate and dry in a Buchner funnel for 1 h to give 188 mg of 4-((R)-3-hydroxy-pyrrolidin-1-yl)-benzonitrile.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1[C:25]2[C:20](=[C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]3=[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]3=2)[CH:19]=[C:18](O)[N:17]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:18]1[N:17]=[CH:16][C:25]2[C:20]([CH:19]=1)=[C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]1=[C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=21)(=[O:5])=[O:4]
Reactant: Oc1cc2c3ccccc3c3ccccc3c2cn1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1cc2c3ccccc3c3ccccc3c2cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic anhydride (5.2 g, 19 mmol) was added to a mixture of dibenzo[f,h]isoquinolin-3-ol (0.91 g, 3.7 mmol), pyridine (1.2 g, 15 mmol) and dichloromethane 100 mL under nitrogen at 0° C. and stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3. The organic layer was washed with water and dried on Na2SO4. The residue was purified by flash chromatography on silica (hexane:ethyl acetate) to give (1.1 g, 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][C:23]=1[O:30][CH3:31]>C(OCC)C>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=2)[OH:27])=[CH:24][C:23]=1[O:30][CH3:31]
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Reactant: COc1cc(C=O)ccc1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C(O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: -72 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene, prepared as described in Procedure N, (1.00 g, 3.44 mmol) in diethyl ether in (10 mL) at −72° C. was added 2.5 M n-BuLi (1.37 mL, 3.44 mmol) dropwise. Upon completion of addition, the reaction mixture was stirred for 15 minutes at −72° C., then 4-fluoro-3-methoxybenzaldehyde (0.53 g, 3.44 mmol) was added while the reaction mixture temperature was maintained below −52° C. The reaction mixture was stirred for 3 h at −72° C. The reaction mixture was quenched by the addition of 1N HCl and the aqueous portion was extracted with EtOAc (2×). The combined organic layers were washed with sat. NaCl, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by ISCO using a gradient of 0-50% EtOAc/hexane as eluent to yield (4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol (0.83 g, 66% yield). HPLC: RT=3.85 min (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient, flow rate 4 mL/min, monitoring at 220 nm); 1H NMR (CDCl3): 7.05-6.8 (m, 6H), 5.87 (tt, J=2.8, 52.9 Hz), 5.75 (s, 1H), 3.85 (s, 3H).