Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:24]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCCCCCCCc1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCCc1ccc(O)cc1

Procedure:
A mixture of 31.8 gms 9(4-hydroxyphenyl)-nonanoic acid, 15 gm molecular sieves (3A), 320 ml methanol, and 5 ml H2SO4 was refluxed for 48 hrs. The reaction mixture was cooled, filtered through diatomaceous earth, and the methanol removed in vacuo. The residue was dissolved in CHCl3, washed twice with 5% NaHCO3, twice with water, and once with NaCl solution. The aqueous phase was back-washed with ether. The organic layers were filtered, combined, dried over MgSO4, treated with decolorizing carbon, and filtered through diatomaceous earth. The solvents were removed in vacuo and the resulting solid was crystallized from hexanes:CH2Cl2 to give 23.5 gms of product, mp. 52°-4°. A further 4 gms ester was recovered from the mother liquors, after a second crystallization.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>ClCCl>[C:1]1([CH:7]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[CH:8]2[CH2:12][CH2:11][N:10]([CH2:30][C:29]([O:28][CH3:27])=[O:32])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(C(c2ccccc2)C2CCNC2)c1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN1CCC(C(c2ccccc2)c2cccc(C)c2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
A solution of 3-(phenyl(m-tolyl)methyl)pyrrolidine (3.0 g, 12 mmol) and triethylamine (1.8 mL, 12.9 mmol) in dichloromethane (30 mL) was stirred at 0° C. for 10 min, and then methylbromoacetate (1.5 mL, 15.8 mmol) was added dropwise. After stirring the reaction mixture at 0° C. for 3 h, reaction mixture was warmed to room temperature and concentrated under reduced pressure. To the residue was added water and the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was dissolved in dichloromethane and precipitated with diethyl ether to afford 1.6 g of methyl 2-(3-(phenyl(m-tolyl)methyl)pyrrolidin-1-yl)acetate.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]2[C@@H:11](I)[C@H:7]([C@@H:8]([C:21]([O:23][CH3:24])=[O:22])[N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:7]([C@@H:8]([C:21]([O:23][CH3:24])=[O:22])[N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](OC(C)=O)[C@@H]([C@H]2I)N1[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](OC(C)=O)C2)N1[C@H](C)c1ccccc1

Procedure:
A solution of methyl (1S,3S,4S,6R,7S)-6-acetyloxy-7-iodo-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 42-3 (1.73 g) in methanol (20 mL) containing 20% Pd(OH)2 (173 mg) and triethylamine (0.6 mL) was stirred at room temperature for 1.5 hrs under 1 atm pressure with hydrogen.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([S:27]([C:30]2[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 50 °C
Yield: 115.1 %

Procedure:
Trimethylsilylacetylene (0.70 mL, 4.94 mmol) and triethylamine (2.80 mL, 19.74 mmol) were added to a stirred solution of 4-(4-bromo-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 2.468 mmol) in dry dichloromethane (12 mL), then the reaction mixture was degassed with argon for 30 minutes at room temperature. To the reaction mixture were added Pd(PPh3)2Cl2 (0.173 g, 0.25 mmol) and CuI (0.047 g, 0.25 mmol), then the reaction mixture was heated at 50° C. for 14 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and then concentrated in vacuo to yield a crude residue, which was dissolved in dichloromethane (20 mL) and washed with water (2×5 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a black colored crude product, which was finally purified using silica gel (100-200 mesh) column chromatography (2:23 ethyl acetate-hexanes to 2:18 ethyl acetate in hexanes) to furnish 1.20 g (80%) of 4-(4-trimethylsilanylethynyl-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester as a brown solid. MS cald. for C20H30N2O4SSi [(M+NH4)+] 440, obsd. 440.0.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[C:17](Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>N1C=CC=CC=1>[C:17]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Yield: 86 %

Procedure:
3-Lauroyl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline was prepared by acylation of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline with lauroyl chloride in pyridine.
Reaction SMILES: [CH2:1]([S:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[K+].Cl>CO.O>[CH2:1]([S:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 55 °C
Yield: 66.7 %

Procedure:
Methyl 4-dodecylsulfonylbenzoate (5), (approximately 63.43 mMole) was suspended in methanol (100 mL), and 85%-potassium hydroxide (10.5 g, 64.67 mMole) in water (20 mL) added. The mixture was heated to 50-60° C. for 15 minutes during which time the solid went into solution. The solution was then cooled and added to ice cold 2N-HCl (1 L). The white solid was filtered off, washed with water, then methanol and finally air-dried to give 15.0 g of 4-dodecylsulfonylbenzoic acid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[I:8][C:9]1[NH:13][C:12]([C@@H:14]2[CH2:19][C@@H:18]3[C@@H:16]([CH2:17]3)[N:15]2C(OC(C)(C)C)=O)=[N:11][CH:10]=1>C(Cl)Cl>[I:8][C:9]1[NH:13][C:12]([C@@H:14]2[CH2:19][C@@H:18]3[C@@H:16]([CH2:17]3)[NH:15]2)=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(I)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Ic1cnc([C@@H]2C[C@H]3C[C@H]3N2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
TFA (1 mL, 12.98 mmol) was added dropwise to a solution of (1R,3S,5R)-tert-butyl 3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (450 mg, 1.20 mmol) in DCM (5 mL) at room temperature. The mixture was stirred for 2 h at room temperature, then, the volatiles were removed and the residue was taken in MeOH (5 mL) and filtered through a Strata XC MCX cartridge. The cartridge was washed with methanol (30 mL) and the compound was release from the cartridge by eluting with a solution of 2M of ammonia/methanol (40 mL) and concentrated to give (1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (283 mg, 1.03 mmol, 86% yield) as white solid. LC-MS retention time 0.448 min; m/z 275.94 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.17 (s, 1H), 4.20 (dd, J=10.4, 7.3 Hz, 1H), 3.08 (td, J=6.2, 2.6 Hz, 1H), 2.38 (dd, J=12.5, 7.3 Hz, 1H), 2.19 (ddd, J=12.7, 10.5, 4.9 Hz, 1H), 1.68-1.74 (m, 1H), 0.85 (ddd, J=6.6, 4.4, 2.8 Hz, 1H), 0.61-0.67 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:30][C:17]3[C:18]4[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:19]=4[O:20][CH2:21][CH2:22][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[Cl-].[NH4+].C[N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:30][C:17]3[C:18]4[CH:26]=[CH:25][C:24]([C:27]([NH2:34])=[O:28])=[CH:23][C:19]=4[O:20][CH2:21][CH2:22][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3ncnn3-c3ccc(F)cc3F)sc1-2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc2c(c1)OCCc1cc(-c3ncnn3-c3ccc(F)cc3F)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with ammonium chloride, HATU and DIPEA in THF to give 328 as a colorless solid after reverse phase HPLC. MS: (ESI+) 425.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:29]4[CH:28]=[N:27][C:26]([NH2:25])=[CH:31][CH:30]=4)[CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.5) (0.185 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.18 g, 85%). MS (ISP) 428.0 [(M+H)+]; mp 227° C.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH:15]([CH3:31])[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH:15]([CH3:31])[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH:18]=2)=[CH:6][CH:5]=1
Reactant: CC(Cc1ccnc(NC(=O)OC(C)(C)C)c1)Oc1ccc([N+](=O)[O-])c2ccccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: CC(Cc1ccnc(NC(=O)OC(C)(C)C)c1)Oc1ccc(N)c2ccccc12
Yield: 99.8 %

Procedure:
A solution of tert-butyl 4-(2-(4-nitronaphthalen-1-yloxy)propyl)pyridin-2-ylcarbamate (48) (271 mg, 0.614 mmol) in MeOH (30 mL) was passed through a Thales H-cube (1.0 mL·min−1, 30° C., 55 mm, 10% Pt/C Cat-Cart, full hydrogen mode) and the volatiles were removed in vacuo to afford the title compound (49) (241 mg, 100%) as a purple foam: m/z 394.0 (M+H)+ (ES+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([O:20][CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:21][O:20][C:18]1[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]=[CH:16][N:17]=1
Reactant: COc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncnc(N2CCNCC2)n1

Procedure:
Prepared in analogy to example 4.10(c) from 4-(4-Methoxy-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester and trifluoroacetic acid. MS (m/e): 196.4 (MH+, 100%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1([CH3:26])[C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:25])[O:13]1>O>[CH3:11][C:12]1([CH3:26])[O:13][C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:2]3[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=3)=[CH:18][C:17]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#CCc1cccc(Br)c1
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(CC#N)c3)cc21

Procedure:
Prepared according to the procedure B from 3-bromophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid. White solid: mp 188-190° C. 1H-NMR (DMSO-d6) δ10.33(s, 1H), 7.62(m, 2H), 7.55 (m, 2H), 7.48 (d, 1H J=8.00 Hz), 7.33 (d, 1H, J=7.57 Hz), 6.99 (d,1H, J=8.81 Hz) 4.09 (s, 2H), 1.67 (s, 6H); MS m/z 291(M−H). Anal. Calc. for (C18H16N2O2)2. 0.3 H2O: C,72.61, H, 5.62, N, 9.41. Found: C, 73.00, H,5.43, N, 8.81
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:25])[C:22]=3[F:24])[C:17]([S:26][C:27]3[C:28]([F:38])=[C:29]([CH:35]=[CH:36][CH:37]=3)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:16]2[CH:39]2[CH2:41][CH2:40]2)[CH:12]=[N:11]1)(C)(C)C>Cl.O1CCOCC1>[Cl:25][C:21]1[C:22]([F:24])=[C:23]2[C:18]([C:17]([S:26][C:27]3[CH:37]=[CH:36][CH:35]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:28]=3[F:38])=[C:16]([CH:39]3[CH2:40][CH2:41]3)[N:15]2[C:13]2[CH:12]=[N:11][N:10]([CH2:9][CH2:8][CH2:7][C:6]([OH:42])=[O:5])[CH:14]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCCC(=O)OC(C)(C)C)c3)c3c(F)c(Cl)ccc23)c1F
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCCC(=O)O)c3)c3c(F)c(Cl)ccc23)c1F
Yield: 30.8 %

Procedure:
A solution of compound 2 (100 mg, 0.29 mmol) in 4.0 M HCl in 1,4-dioxane (2 mL) under inert atmosphere was stirred at 0° C.-RT for 16 h. The volatiles were removed in vacuo and the residue was diluted with water (5 mL), basified with aq. NaHCO3 (5 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. This was purified by acid-base treatment to afford 3 (50 mg, 56%) as a white solid. 1H NMR (500 MHz, DMSO-d6): 12.75 (br s, 1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.59 (t, J=7.0 Hz, 1H), 7.22-7.10 (m, 3H), 6.84 (t, J=7.5 Hz, 1H), 4.33 (q, 2H), 4.22 (t, J=7.0 Hz, 2H), 2.21 (t, J=7.5 Hz, 2H), 2.06-2.03 (m, 2H), 1.81-1.78 (m, 1H), 1.32 (t, J=7.0 Hz, 3H), 0.89-0.88 (m, 2H), 0.82-0.81 (m, 2H); MS: m/z 560.7 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[N:13]1([C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: O=C1CCCc2cc(Br)ccc21
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)CCC(N1CCCC1)=C2
Yield: 97.4 %

Procedure:
To a 250 ml round bottomed flask was added 5.00 g (22.21 mmol) of the 6-bromotetralone afforded above in Step B; 70 ml of dry toluene and 3.1 g (3.7 ml) of pyrrolidine. The flask was equipped with a Dean-Stark trap, a condenser, a nitrogen inlet tube and a magnetic stirrer and the reaction refluxed for four hours. The solvent was evaporated under vacuum to afford 6.02 g (97.4%) of the subtitle compound as a brown crystalline material which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:5].Cl>S1(CCCC1)(=O)=O.C(OCC)(=O)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:2]2[NH:1][C:8]3[N:9]=[CH:10][CH:11]=[CH:12][C:7]=3[NH:6][C:4](=[O:5])[C:3]=2[CH:14]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2cccnc2Cl)c1
Agent: Cl
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)C(=O)Nc1cccnc1N2
Temperature: 220 °C
Yield: 70.2 %

Procedure:
A solution of 2-amino-N-(2-chloropyridin-3-yl)-5-methylbenzamide (2.515 g, 9.61 mmol) in sulfolane (15 mL) was treated with hydrogen chloride (0.25 mL, 1.0 mmol; 4N in dioxane). The reaction mixture was heated to 220° C. under microwave conditions for 8 minutes. The reaction mixture was then diluted with ethyl acetate (75 mL) and washed with water (5×50 mL). The organic layer (aqueous emulsion) was concentrated to give an aqueous slurry which was filtered and washed with water (50 mL). The product was dried under high vacuum at 60° C. to afford 8-methyl-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.52 g) that was used without further purification. LCMS [M+H]: 226.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:18]1(O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:18]1([O:1][C:2]2[CH:3]=[C:4]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Reactant: OC1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(OC2CCCCC2)c1
Reaction time: 16 h
Yield: 55.1 %

Procedure:
To a solution of (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate (100 mg, 0.421 mmol), cyclohexanol (0.180 ml, 1.686 mmol) and PPh3 (221 mg, 0.843 mmol) in THF (2 ml), was added DEAD (0.133 ml, 0.843 mmol) dropwise, under N2, at room temperature. The resulting yellow solution was stirred for 3 hours, at which point another batch of cyclohexanol (0.180 ml, 1.686 mmol), PPh3 (221 mg, 0.843 mmol), and 10 min later DEAD (0.133 ml, 0.843 mmol), was added at room temperature. The reaction mixture was stirred for 16 hours and then concentrated. The crude clear oil was re-dissolved in DMSO and purified by reverse phase HPLC. The combined product fractions were desalted by addition of equal amount of EtOAc and about 250 mg Na2CO3 in a separatory funnel. The phases were separated and the organic washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (S)-tert-butyl 1-(3-(cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232 mmol, 55.0% yield) as a clear colourless film. LCMS m/z 305.0/264.0 (the parent not observed, just the Boc fragments) (M+H)+, Rt 1.12 min.
Reaction SMILES: [C:1]([N:9]=[C:10]=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1>ClCCl>[C:2]1([C:1]([NH:9][C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[O:11])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To an ice-bath cooled solution of benzoyl isocyanate (7.725 ml, 0.0525 Mol) in dichloromethane (400 ml) was added 4-amino-1-benzyl piperidine (10 g, 10.72 ml, 0.0525 Mol) dropwise. When the addition was complete the solution was allowed to stir at room temperature for 1 h then the solvent was removed by rotary evaporation. The residue was triturated with diethyl ether and collected by filtration to give the required product as a white solid 15.4 g (87%). Mp. 179°-180° C. 1H NMR (DMSO) δ 1.51 (2H, m), 1.86 (2H, m), 2.14 (2H, m), 2.69 (2H, m), 3.47 (2H, s), 3.65 (1H, m), 7.24-7.33 (5H, m), 7.50 (2H, t, J=7.9 Hz), 7.61 (1H, t, J=7.9 Hz), 7.96 (2H, d, J=7.9 Hz), 8.69 (1H, d, J=7.8 Hz), 10.67 (1H, br s); MS (CI) m/e 338 [MH]+. Anal. Found C, 70.99; H, 6.86; N, 12.41. C20H23N3O2 requires C, 71.19; H, 6.87; N, 12.45%.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-])=[CH:3][CH:2]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>C(O)(C)C>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[N:10]=[C:11]([C:24]#[N:25])[CH:12]=[CH:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: Cc1ccc(C=Cc2cccc[n+]2[O-])cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: COS(=O)(=O)OC
Product: Cc1ccc(C=Cc2cccc(C#N)n2)cc1

Procedure:
In a variation to the procedure referred to in example1, 2-(2-p-tolyl-vinyl)-pyridine 1-oxide (9.8 g, 46 mmol) was reacted first with dimethylsulfate (5.8 g, 46 mmol) and then with NaCN (2.74 g, 56 mmol). After extraction and crystallization 6-(2-p-tolyl-vinyl)-pyridine-2-carbonitrile (5.8 g, 57%) was obtained as a yellow crystalline material. Mp. 137–138° C. (isopropanol), MS: m/e=220 (M+)
Reaction SMILES: C[N:2]([CH2:4][C:5]1[N:9](C(CCCCCC)C(O)=O)[C:8]2[CH:20]=[CH:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:31]=NNN=3)=[CH:23][C:7]=2[N:6]=1)[CH3:3].N1C[CH2:38][CH2:37][CH2:36]1>C1COCC1>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[CH:21]=[CH:20][C:8]2[NH:9][C:5]([CH2:4][N:2]3[CH2:3][CH2:38][CH2:37][CH2:36]3)=[N:6][C:7]=2[CH:23]=1)#[N:31]
Reactant: C1CCNC1
Reactant: CCCCCCC(C(=O)O)n1c(CN(C)C)nc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc2[nH]c(CN3CCCC3)nc2c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
2-Chloromethyl-5-2-cyanophenyl)-1H-benzimidazole (2.28 mmoles, 0.54 g--see Example 35) and pyrrolidine (5.26 mole, 0.375 g.) were dissolved in THF and stirred at room temperature. The solvents were removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and concentrated to yield 0.583 g of 5-(2-Cyanophenyl)-2-(1-pyrrolidinomethyl)-1H-benzimidazole.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.C([O:16][C:17](=O)[CH2:18][CH:19]1[CH2:24][CH2:23][C:22]([N:31]([CH3:33])[CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)C.[Cl-].[NH4+]>C1COCC1>[CH3:33][N:31]([CH3:32])[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:23][CH2:24][CH:19]([CH2:18][C:17]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([F:6])=[CH:8][CH:9]=2)=[O:16])[CH2:20][CH2:21]1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)CC1CCC(c2ccccc2)(N(C)C)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)Nc2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6 M solution in hexane; 11.9 ml; 19 mmol) was added dropwise at 0° C. to a solution of 4-fluoroaniline (1.06 g; 9.5 mmol) in 10 ml THF. The mixture was allowed to come to RT and was subsequently stirred for 1 h. A solution of (4-dimethylamino-4-phenyl-cyclohexyl)-acetic acid ethyl ester (2.5 g; 8.6 mmol) in 15 ml THF was added dropwise at −78° C. The mixture was subsequently stirred for 1 h and then allowed to come to RT. It was hydrolysed with ammonium chloride solution and extracted with MC. After concentration, the crude product was taken up in ether. A solid then remained (less polar diastereoisomer; 1.37 g; 45%); the supernatant was chromatographed on silica gel (eluent:ether). 315 mg (10%) of the more polar diastereoisomer were obtained.