Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:19]3[CH:18]=[CH:17][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Brc1cccc2ccccc12
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3ccccc3c2)CCN(C)C1

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 4 mmol), 1-bromonaphthalene (0.828 g, 4 mmol), K3PO4 (0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-naphthalen-2-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (20 mg). 1H NMR (HCl salt, CD3OD) δ (ppm): 8.15 (d, 1H), 8.05 (d, 1H), 7.7 (bs, 1H), 7.6-7.50 (m, 2H), 7.41-7.4 (m, 2H), 7.1 (t, 1H), 6.95 (d, 1H), 6.7-6.65 (dd, 1H), 4.9-4.8 (m, 1H), 4.5-4.4 (m, 1H), 3.8-3.79 (m, 1H), 3.6-3.59 (m, 1H), 3.2 (s, 3H), 2.85-2.8 (m, 1H), 2.6-2.59 (m, 1H), 2.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[CH:25]12[O:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]2.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[OH:31])[CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: C1CCC2OC2C1
Reactant: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCNC3)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCN([C@@H]2CCCC[C@H]2O)C3)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(2-chlorophenyl)-2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2, 500 mg, 1.33 mmol), cyclohexene oxide (1.34 mL, 13.3 mmol), and trietylamine (0.55 mL, 3.99 mmol) in ethanol (14 mL) was heated at reflux for 20 h. The solution was cooled to rt, and evaporated. The residue was purified by silica gel column, eluting with 3:1 to 2:1 hexanes:ethyl acetate. The product, racemic trans-2-[1-(2-chlorophenyl)-2-(4-methoxyphenyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]cyclohexanol, was isolated as a pale yellow solid (398 mg, 63%). LC-MS m/z (MH+) 437.1, retention time 2.45 min (method 1).
Reaction SMILES: Br[C:2]#[C:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][C:36]([OH:40])([C:38]#[CH:39])[CH3:37]>[Pd].[Cu](I)I.COCCOC>[CH3:35][C:36]([OH:40])([C:38]#[C:39][C:2]#[C:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:37]
Reactant: C#CC(C)(C)O
Reactant: BrC#Cc1ccccc1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(O)C#CC#Cc1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of bromophenylacetylene (5.0 g, 27.6 mmol), potassium carbonate (9.54 g, 69.0 mmol), copper iodide (0.54 g, 2.8 mmol), palladium on carbon (5%, 500 mg), triphenylphosphine (0.72 g, 2.8 mmol), 2-methyl-3-butyn-2-ol (11.6 g, 138 mmol) and 1,2-dimethoxyethane (100 ml) was stirred overnight at 100° C. The product mixture was evaporated. Chromatography on silica gel with petroleum and ethyl acetate (2:1), gave the title compound. Yield 1.06 g (21%).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:5]2[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[S:14][C:4]=2[C:3]=1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[F:25].[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)=[O:27].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[C:3]1[C:4]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:5]=2[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH:26]=[O:27]
Reactant: COC(=O)Cn1c(Br)c(C2CCCCC2F)c2sc(C(=O)OC)cc21
Reactant: O=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Cn1c(-c2ccccc2C=O)c(C2CCCCC2F)c2sc(C(=O)OC)cc21
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution (0.1 M) of methyl 5-bromo-6-(2-fluorocyclohexyl)-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in dioxane was treated with (2-formylphenyl)boronic acid (1.5 eq.); aq. Na2CO3-solution (2 N, 8.5 eq.) was added and the solution was degassed, and then treated with Pd(PPh3)4 (0.1 eq.). A balloon with argon was installed, the mixture was placed in an oil bath preheated at 115° C. and stirred for 30 min, then cooled and diluted with EtOAc and brine. The organic phase was separated, washed with 1N HCl and brine, dried and concentrated. The residue was purified by chromatography (PE/EtOAc) to give the title compound (56%); some starting material (21%) was recovered. 1H-NMR (400 MHz, CDCl3, 300K, δ) 9.78&9.85* (bs, 1H.), 8.06 (dd, 1H, J 7.7, 1.3), 7.67 (s, 1H), 7.73-7.60 (m, 2H), 7.44 (bd, 1H, J 7.5), 4.50&4.55* (d, 1H, J 17.8&17.6), 4.44&4.48* (d, 1H, J 17.8&17.6), 4.73-4.49 (m, 1H), 3.91 (s, 3H), 3.62&3.63* (s, 3H), 2.42-2.34 (m, 1H), 2.18-2.12 (m, 1H), 1.83-1.07 (m, 7H); MS (ES+) m/z 458 (M+H)+. * Refers to two different conformers.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=4)[N:19]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:18]=3)[C:14]([C:40]#[N:41])=[CH:13][N:12]=2)[CH3:9])[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[NH2:46][CH:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=4)[N:19]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:18]=3)[C:14]([C:40]#[N:41])=[CH:13][N:12]=2)[CH3:9])[CH2:4][CH2:3]1
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(=O)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(N)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
2-((R)-1-(4-oxocyclohexyl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (105 mg, 0.1802 mmol) was disolved in methanol (5 mL) and dichloromethane (5 mL). Ammonium acetate (138.9 mg, 118.7 μL, 1.802 mmol), followed by sodium triacetoxyborohydride (38.19 mg, 0.1802 mmol) were added and the reaction mixture was stirred for 4 hours at room temperature. The mixture was partitioned between dichloromethane and a saturated solution of sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness to afford the desired product as a yellow solid (95 mg, 90% yield).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][O:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.N[C:22]1C=CC=C(C(OC)=O)C=1OC[C@H](NC(OC(C)(C)C)=O)C(O)=O>>[CH3:22][C@H:7]1[O:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3][C:2](=[O:1])[C@H:8]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1cccc(N)c1OC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Product: C[C@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Yield: 46 %

Procedure:
In a similar manner to that described for the preparation of (S)-tert-butyl 4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate except the crude product was purified by silica gel chromatography, (S)-3-(2-amino-6-(methoxycarbonyl)phenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (1.5 g, 4.83 mmol) was converted to the title compound (0.65 g, 46%) as a white solid.
Reaction SMILES: [C:1]([N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])N=CC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC=CC=1NN=CC.[CH2:31]1[CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:35][C:33](=O)[CH2:32]1.C(=O)C.Cl>O.C(O)(=O)C>[C:1]([N:9]1[C:33]2[CH2:32][CH2:31][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][C:35]=2[C:18]2[C:13]1=[C:14]([Br:19])[CH:15]=[CH:16][CH:17]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=NN(C(=O)c1ccccc1)c1ccccc1Br
Reactant: O=C1CCC(C(=O)O)CC1
Agent: CC=NNc1ccccc1Br
Agent: CC=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C1CCc2c(c3cccc(Br)c3n2C(=O)c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
A solution of acetaldehyde 1-benzoyl-1-(2-bromophenyl)hydrazone, prepared from 11 g. of acetaldehyde 2-bromophenyl hydrazone (see below), and 9.16 g. of cyclohexanone-4-carboxylic acid in 25 ml. glacial acetic acid was heated on a hot plate until evolution of acetaldehyde was no longer detected (about two hours), 25 ml. glacial acetic acid saturated with hydrogen chloride was added and heating was continued for 30 minutes. The mixture was cooled and cautiously diluted with water, and the resulting solid was collected by filtration and washed with water to give 2.24 g. of the title compound; m.p. 196°-198°C. (chloroform-heptane).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[C:13]([F:30])[CH:12]=2)[CH2:6]1)=[N+]=[N-].N1C=CC=CC=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(OCC)(=O)C.[Pd]>[C:37]([NH:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[C:13]([F:30])[CH:12]=2)[CH2:6]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A solution of 14.92 g (35.5 mmol) of the azide 4 in 2000 mL of ethyl acetate was treated with 2 g of 10% palladium on carbon followed by hydrogenation at one atmosphere for 24 h. The flask was flushed with nitrogen, followed by sequential addition of 14.0 g (14.4 ml, 177.5 mmol) of pyridine and 9.1 g (8.4 mL, 88.8 mmol) of acetic anhydride. The mixture was stirred at ambient temperature for 72 h, followed by filtration through celite. The filtrate was extracted with water, 1N copper sulfate solution, dried and concentrated in vacuo to afford a tan solid. This material was purified by silica gel chromatography to afford 12.7 g (82%) of the product 5 as a powdery white solid, mp 153°-159° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[I-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:28]1[CH:27]=[CH:26][C:5]([C:6](=[O:7])[NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[CH:4][C:3]1=[O:2])[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1=O

Procedure:
From 2-methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium iodide and ethyl bromoacetate in DMF. ES-MS m/e (%): 495 (M+Na+, 25), 473 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:15].[C:16](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[CH3:16][O:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:8][CH2:9][CH2:10]1)[CH2:6][C:5]2=[O:15]
Reactant: O=C1CC2(CCC2)Oc2ccc(O)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To the stirred solution of 6-hydroxyspiro[chromene-2,1′-cyclobutan]-4-(3H)-one (8 g, 39.215 mmol) in dry dimethylformamide (150 ml), potassium carbonate (16.28 g, 117.64 mmol) and methyl iodide (4.88 ml, 78.431 mmol) were added and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 h. After the completion of the reaction, the reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (3×300 ml), the combined organic layers washed with water (3×100 ml), brine (60 ml), dried (Na2SO4), filtered and concentrated to yield 8.13 g of the product; 1H NMR (300 MHz, CDCl3) δ 1.67-1.77 (m, 1H), 1.85-1.97 (m, 1H), 2.11-2.18 (m, 2H), 2.23-2.34 (m, 2H), 2.87 (s, 2H), 3.77 (s, 3H), 6.88 (d, J=9.6 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 7.25 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
A mixed solution of 10 g of 2-bromonitrobenzene, 8.2 g of 4-methylphenylboronic acid, 25.4 g of tripotassium phosphate, 3.9 g of tetrabutylammonium bromide, 270 mg of palladium acetate and 150 ml of dimethylformamide was heated and stirred under a nitrogen gas stream at 130° C. for 3 hours. The solution was cooled to room temperature and 100 ml of water was poured into the solution, followed by extraction with 150 ml of ethyl acetate. The organic layer was washed twice with 100 ml of water, dried over magnesium sulfate and then evaporated. The concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 8.6 g of 2-(4-methylphenyl)nitrobenzene.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH2:10][CH2:9][N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.Cl>>[CH2:17]([N:8]1[CH2:9][CH2:10][CH:11]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1c1ccsc1
Agent: Cl
Product: O=C(O)C1CN(Cc2ccccc2)CCC1c1ccsc1

Procedure:
The product from step c) (4.5 g, 13.7 mmol) was treated with 4 M HCl at 100° C. for 16 hours. Next, the reaction was evaporated to dryness, azeotrope with toluene (2×50 ml) and placed on the high vacuum to give the subtitle compound that was used without further purification. MS calculated for C17H19NO2S−H 300, observed 300.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]C=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3=NC=CC=C3CC2)=[N:27]C(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3=[N:27][CH:17]=[CH:16][CH:15]=[C:14]3[CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCc3cccnc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCc3cccnc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 8.47, 7.61, 7.18, 5.30, 3.05, 2.81, 2.78, 1.98, 1.33–1.19; (MS/CI) calcd for C16H19N4Br+H 348.3, found 347.1.
Reaction SMILES: CC1N=C(C)N(C2N=C(SC)N=C([C@@H]3C[C@H]3[C:19]3[N:23]([CH3:24])[C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[N:20]=3)C=2)N=1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:24][N:23]1[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]=[CH:19]1
Reactant: CSc1nc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cnc2ccccc21
Reaction time: 3 h

Procedure:
To a solution of trans-2-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (1-5) (250 mg, 0.64 mmol, 1.0 eq.) in CH2Cl2 (5.0 mL) was added meta-chloroperbenzoic acid (274 mg, 1.59 mmol, 2.5 eq.) at room temperature and the reaction was stirred for 3 hours. The reaction was quenched by addition of saturated sodium bicarbonate solution (10 mL) and extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (100% ethyl acetate) to afford trans-2-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylsulfonyl)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (1-6) as a pale yellow foam. 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.72-7.67 (m, 1H), 7.34-7.23 (m, 3H), 3.84 (s, 3H), 3.38 (s, 3H), 3.11-3.03 (m, 1H), 2.96 (s, 3H), 2.96-2.87 (m, 1H), 2.42 (s, 3H), 2.18-2.06 (m, 2H). LRMS m/z (M+H) 424 found, 424 required.
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH3:21])[CH2:20][CH2:19][CH2:18][C:7]2([O:11][C:10](=[O:12])[N:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8]2)[CH2:6]1)=[N+]=[N-].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:1][CH2:4][C:5]1([CH3:21])[CH2:20][CH2:19][CH2:18][C:7]2([O:11][C:10](=[O:12])[N:9]([CH2:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:8]2)[CH2:6]1
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CN=[N+]=[N-])C2)OC1=O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)CN1CC2(CCCC(C)(CN)C2)OC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a light green 0° C. solution of 7-(azidomethyl)-7-methyl-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (10.0 g, 34.0 mmol) and nickel (II) chloride hexahydrate (8.07 g, 34.0 mmol) in MeOH (226 mL) was added sodium borohydride (1.93 g, 51.0 mmol) in six portions. The reaction quickly became black and was allowed to stir at 0° C. for 3 h. The reaction mixture was concentrated and partitioned between 1 N NaOH (350 mL) and EtOAc (350 mL). The biphasic mixture was filtered through celite, and the layers were separated. The aqueous layer was extracted with EtOAc (2×150 mL). The combined organics were dried over MgSO4, filtered, and concentrated to afford the title compound (8.65 g, 90% crude yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.33 (dd, J=8.53, 13.80 Hz, 2H), 3.06 (d, J=14.05 Hz, 1H), 2.93 (d, J=14.05 Hz, 1H), 2.43 (s, 2H), 1.99 (dt, J=1.76, 13.55 Hz, 1H), 1.89 (dt, J=3.48, 13.87 Hz, 1H), 1.69 (d, J=14.05 Hz, 1H), 1.57 (dt, J=4.11, 13.87 Hz, 1H), 1.29-1.47 (m, 3H), 1.15-1.28 (m, 1H), 1.08 (s, 3H), 0.96 (s, 9H).
Reaction SMILES: [Cl-].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5].O.[C:13]1(C)[C:14]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl.O.O1CCOCC1>O1CCOCC1>[S:19]([C:14]1[CH:13]=[CH:18][C:17]([CH3:2])=[CH:16][CH:15]=1)([O-:22])(=[O:20])=[O:21].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: CCCC[n+]1ccn(C)c1
Agent: Cl
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
86.3 g (0.494 mol) of 1-butyl-3-methylimidazolium chloride and 94.9 g (0.499 mol) of toluenesulfonic acid monohydrate are dissolved in 50 ml of 1,4-dioxane at RT. 58 ml of HCl-containing water/dioxane azeotrope are subsequently distilled off at atmospheric pressure (85-101° C). After 22 additional azeotropic distillations with 200 ml of dioxane each time and drying of the distillation residue under reduced pressure at 1.3 Pa and 80° C., 1-butyl-3-methylimidazolium tosylate is obtained. The yield is approximately quantitative.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:20][CH:22]3[CH2:23][O:24]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClCC1CO1
Reactant: Clc1ccc(-c2cc[nH]n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccn(CC3CO3)n2)cc1Cl
Yield: 81.7 %

Procedure:
A stirred solution of 3-(3,4-dichlorophenyl)pyrazole (300 mg, 1.4 mmol) in DMF (5 mL) was treated with cesium carbonate (550 mg, 1.69 mmol) and epichlorohydrin (1.1 mL, 14.0 mmol) at room temperature for 18 h. The crude reaction mixture was then partitioned between EtOAc (50 mL) and water (35 mL). The aqueous phase was further extracted (2×50 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield crude product. Purification by column chromatography (silica, 25% EtOAc/hexanes) afforded 308 mg (82%) of the title compound. 1NMR (400 MHz, CDCl3): 7.83 (d, J=2 Hz, 1H), 7.54 (dd, J=2, 8 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 6.48 (d, J=2 Hz, 1H), 4.45 (dd, J=3, 9.7 Hz, 1H), 4.12 (dd, J=6, 15 Hz, 1H), 3.31 (m, 1H), 2.81 (dd, J=4.0, 4.6 Hz, 1H), 2.47 (dd, J=2.6, 4.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:13]1[C:12]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=2[N:10]=[C:9]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[O:8][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: BrCC1CCCC1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CCCC3)n(Cc3cccc(Cl)c3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-[1-(3-chloro-benzyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-phenol (Example 53, intermediate a) and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Colorless powder (29%). MS (Turbo Spray): m/z=487.1 (M+H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:22]=[CH:21][C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.O>CN(C)C=O>[N:1]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:21][CH:22]=1)=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CBr)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Sodium azide (210 mg, 1.15 eq) was added to a solution of 4-(4-bromomethylbenzyl)-nitrobenzene (901 mg) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 2 hours, poured into water, and extracted with diethyl ether (3×). The organic phase was washed with water (3×), dried (MgSO4), and evaporated to dryness. Chromatography on silica gel, eluting with hexane/ethyl acetate, gave 4-(4-azidomethylbenzyl)-nitrobenzene (492 mg, 62%) as a yellow oil.