Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CON(C)[C:11]([C:13]1[O:17][CH:16]=[N:15][C:14]=1[CH3:18])=[O:12].C(O)C.[Cl-].[Na+]>O1CCCC1>[C:1]1([C:11]([C:13]2[O:17][CH:16]=[N:15][C:14]=2[CH3:18])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CON(C)C(=O)c1ocnc1C
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ncoc1C(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Phenyllithium (1.8M solution in cyclohexane-diethylether, 11.7ml) in dry tetrahydrofuran was stirred and cooled to -70° C. under an atmosphere of dry nitrogen and N-methoxy-N-methyl-4-methyl-5-oxazolecarboxamide (3.0g) in dry tetrahydrofuran was added dropwise. After 30 minutes the mixture was allowed to warm to room temperature. Ethanol (5ml) was added followed by saturated aqueous sodium chloride. The mixture was extracted with dichloromethane and the material thus obtained was purified by flash chromatography to give the title compound. M.p. 84-86° C. 1H Nmr (CDCl3) 2.59 (3H, s), 7.5-7.68 (3H, m) and 7.96-8.06) (3H, m) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[OH-].[K+].O1CCO[CH2:18][CH2:17]1>>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]3[C:2]=2[N:1]=[CH:18][CH:17]=[CH:12]3)[CH:7]=[CH:8][CH:9]=1
Reactant: C1COCCO1
Reactant: Nc1c(C=O)ccc2cccnc12
Agent: [K+]
Agent: [OH-]
Product: c1cnc2c(c1)ccc1cccnc12

Procedure:
2.5 g of 6,6′-bis(trifluoromethanesulphonyloxy)-3,3,3′,3′-tetramethyl-1,1′-spirobiindane, 2.2 g of 4-acetylphenylboronic acid, 12 ml of 2M sodium carbonate and 0.40 g of tetrakis(triphenylphosphine)palladium(0) were added to a solvent mixture of 50 ml of toluene and 30 ml of ethanol, and then refluxing carried out for 12 hours under nitrogen so that a Suzuki coupling reaction was conducted and, by treatment in the normal way, 1.5 g of 6,6′-bis(4-acetylphenyl)-3,3,3′,3′-tetramethyl-1,1′-spirobiindane was obtained. 1.50 g of this diacetyl derivative was reacted with 1.26 g of 8-amino-7-quinolinecarbaldehyde and 0.9 g of potassium hydroxide in dioxane at 60° C. and, by treatment in the normal way, Phen-4 (1.40 g) shown below was obtained. 1H-NMR (CDCl3, ppm): 9.21 (d, 2H), 8.35 (d, 4H), 8.25 (t, 4H), 8.09 (d, 2H), 7.80−7.59 (m, 12H), 7.34 (d, 2H), 7.24 (d, 2H), 2.46 (d, 4H), 1.52 (s, 6H), 1.46 (s, 6H)
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13](I)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[CH3:22][C:23]([OH:40])([CH3:39])[CH2:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:28]4[CH:27]=[N:26][N:25]([CH2:24][C:23]([OH:40])([CH3:39])[CH3:22])[CH:29]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: NC(=O)c1nc2n(c1I)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2c(C(N)=O)nc3n2C2CC(C2)c2cc(F)c(Br)cc2-3)cn1

Procedure:
10-bromo-9-fluoro-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propan-2-ol similarly to as described in Example 4 to produce crude 10-bromo-9-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. This intermediate was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 11 mg (10%) of 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-3-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[N:14]1[N:13]([CH2:9][CH2:10][C:11]#[C:12][C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=12
Reactant: C#CCCn1nc2ccccc2n1
Reactant: Nc1cccc(Br)n1
Product: Nc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 30.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 6-bromo-pyridin-2-ylamine (960 mg, 5.55 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (950 mg, 5.55 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/AcOEt 1:1) to yield 0.45 g (1.71 mmol, 31%) of 6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine as a brown solid
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[O:12][C@@H:7]1[C:8]([O:10]C)=[O:9])(=O)C.[OH-].[Na+:14]>CO.ClCCl>[Na+:14].[O:12]1[C@@H:6]([CH2:5][OH:4])[C@H:7]1[C:8]([O-:10])=[O:9]
Reactant: COC(=O)[C@H]1O[C@H]1COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C([O-])[C@H]1O[C@H]1CO
Temperature: 5 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A modification of the general procedure of Manchand, et. al. (Manchand, et al., 1988) is employed. A solution of methyl (2S,3S)-4-acetoxy-2,3-epoxybutanoate (81.8 g, 465 mmol) in methanol (450 mL) is cooled in an ice bath to 5° C. The solution is treated with solid sodium hydroxide at such a rate that the temperature remained less than 15° C. This mixture is stirred at 5° C. for 3 hours and diluted with dichloromethane (200 mL). The mixture is stirred at room temperature for 30 minutes. The solid is collected by filtration and washed with dichloromethane (200 mL). The resulting filter cake is dried in vacuo at room temperature to yield the title compound as a solid (58.8 g, 90% theoretical yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[F:12].I[CH3:14]>C1COCC1>[Cl:3][C:4]1[C:5]([F:12])=[CH:6][CH:7]=[C:8]([CH2:10][O:11][CH3:14])[N:9]=1
Reactant: OCc1ccc(F)c(Cl)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(F)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To a suspension of sodium hydride (0.48 g, 12 mmol, 60% dispersion in mineral oil) in THF (15 mL) at 5° C. under nitrogen was added (6-chloro-5-fluoropyridin-2-yl)methanol (1.57 g, 9.28 mmol) suspended in THF (20 mL). The resulting suspension was stirred at this temperature for 30 minutes and then iodomethane (0.75 mL, 12 mmol) was added slowly. The reaction was warmed to room temperature over 48 hours. Further iodomethane was added (173 μL, 2.8 mmol) and stirring at room temperature was continued for 4 hours followed by the addition of further sodium hydride (110 mg, 2.75 mmol) at 5° C. The reaction was continued stirring for 24 hours before quenching with water (10 mL) and saturated aqueous ammonium chloride solution (20 mL) until pH=7. The solution was extracted with diethyl ether (3×50 mL). The organic layers were dried over sodium sulphate, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 20-50% DCM in pentane to afford the title compound (600 mg, 37% yield).
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:11]1)=[O:5].[CH3:35][NH:36][CH3:37]>>[CH3:35][N:36]([CH3:37])[C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:11][N:12]([CH:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[CH2:13]1)=[O:5]
Reactant: CNC
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1F)NC1CN(C2CCC(c3ccccc3)CC2)C1
Product: CN(C)c1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
2-Fluoro-N-{[1-(4-phenyl-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-5-trifluoromethyl-benzamide (as prepared in Example 66, 50 mg, 0.11 mmol) was treated with dimethyl amine (Aldrich, 40 wt. % in water, ˜2 mL) in a sealed tube under microwave irradiation at 120° C. for 20 min. The solvent was removed and the residue was purified on a silica gel column using a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:16]=[C:17]([CH:21]([NH2:23])[CH3:22])[CH:18]=[N:19][CH:20]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:26][N:27]=[C:28]=[O:29]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:16]=[C:17]([CH:21]([NH:23][C:28]([NH:27][CH3:26])=[O:29])[CH3:22])[CH:18]=[N:19][CH:20]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3cncc(C(C)N)c3)s2)cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)NC(C)c1cncc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of Example 4D (0.32 g, 0.0009 mol) in methylene chloride (15 mL) was added excess methyl isocyanate (0.25 mL) and the mixture was stirred at room temperature for 0.5 hours. After quenching with methanol (10 mL), the solvent was concentrated and the residue was purified on silica gel (75˜100% ethyl acetate in hexane) to give 0.28 g of the title compound (76% yield). 1H NMR (300 MHz, DMSO-d6) 5 ppm 1.29 (d, J=6.25 Hz, 6 H) 1.34 (d, J=6.99 Hz, 3 H) 2.51 (d, J=4.78 Hz, 3 H) 4.55-4.70 (m, 1 H) 4.71-4.85 (m, 1 H) 5.72 (q, J=4.41 Hz, 1 H) 6.48 (d, J=8.09 Hz, 1 H) 6.96-7.07 (m, 2 H) 7.28-7.39 (m, 2 H) 7.77-7.81 (m, 1 H) 7.83 (s, 1 H) 8.42 (d, J=1.84 Hz, 1 H) 8.67 (d, J=2.21 Hz, 1 H). MS (ESI), m/z 413.1 (M+1)+.
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.[Cl:9][C:10]1[C:15](/[C:16](/O)=[CH:17]\[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[N:19]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[N:38]1([C:44](=[S:46])[NH2:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[Cl:9][C:10]1[C:15]([C:16]2[N:45]=[C:44]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[S:46][C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[N:19]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28]
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Reactant: NC(=S)N1CCOCC1
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Yield: 95 %

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step A using NBS (0.41 g, 2.29 mmol), N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide (1.0 g, 2.18 mmol) and 4-morpholinecarbothioamide (0.35 g, 2.40 mmol) the title compound was obtained as a yellow solid (1.27 g; 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.74 (s, 1H), 8.31 (d, J=5.5 Hz, 1H), 7.28-7.75 (m, 8H), 6.20 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.7 Hz, 4H), 3.54 (t, J=4.6 Hz, 4H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:12])[C:10]=2[N:11]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1.C(N(CC)CC)C>CC(N(C)C)=O>[NH2:12][C:9]1[C:10]2[N:11]=[C:2]([N:13]3[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]3)[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: Nc1ncnc2ccc(Cl)nc12
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc3ncnc(N)c3n2)C1
Temperature: 100 °C
Reaction time: 42 h
Yield: 66.2 %

Procedure:
To 40 mL screw-cap vials was added 6-chloropyrido[3,2-d]pyrimidin-4-amine (2.00 g, 11.1 mmol) followed by tert-butyl N-[(3S)-3-piperidyl]carbamate (1.1 equiv., 12.2 mmol, 2.44 g) then dimethylacetamide (10 mL) and triethylamine (3 equiv., 33.2 mmol, 4.65 mL). The reaction was capped and shaken at 100° C. for 42 h, then an additional 24 h at 115° C. The reaction was cooled to room temperature, then partitioned with ethyl acetate:water. Residual chloride starting material was removed by filtration. The filtrate phases were separated, and the organics dried over sodium sulfate, filtered and concentrated, yielding 2.53 g of product. 1H NMR (400 MHz, DMSO) δ 8.19-8.13 (s, 1H), 7.81-7.74 (d, J=9.3 Hz, 1H), 7.43-7.39 (d, J=9.1 Hz, 1H), 6.95-6.85 (d, J=6.6 Hz, 1H), 4.32-4.19 (m, 2H), 3.50-3.38 (m, 1H), 3.19-3.04 (m, 1H), 2.96-2.85 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.67 (m, 1H), 1.60-1.34 (m, 11H). LCMS M/Z (M+H)=345.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][NH:7][C:8](=[O:27])[CH2:9][N:10]1[C:16](=[O:17])[C:15]2[CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=[CH:21][C:14]=2[N:13]([CH3:25])[C:12](=[O:26])[CH2:11]1)[CH3:2].[CH2:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][NH:7][C:8](=[O:27])[CH2:9][N:10]1[C:16](=[O:17])[C:15]2[CH:18]=[C:19]([NH:22][C:37]([NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:38])[CH:20]=[CH:21][C:14]=2[N:13]([CH3:25])[C:12](=[O:26])[CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)CN1CC(=O)N(C)c2ccc([N+](=O)[O-])cc2C1=O
Reactant: O=C=NCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCNC(=O)CN1CC(=O)N(C)c2ccc(NC(=O)NCc3ccccc3)cc2C1=O

Procedure:
Catalytic hydrogenation of 3-[2-(1-methyl-7-nitro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-propionic acid ethyl ester in EtOH in the presence of 10% Pd/C at RT and atmospheric pressure followed by acylation with benzylisocyanate as described in Example 1d) gave 3-[2-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino]-propionic acid ethyl ester: mp. 100-102° C.; MS (ISP): 496 (M+1)+.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([N:11]2[C:10](=[O:19])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]2[S:1][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1
Reactant: ClCc1ccncc1
Reactant: Cc1ccc(-n2c(S)nc3ccccc3c2=O)cc1
Agent: Cl
Product: Cc1ccc(-n2c(SCc3ccncc3)nc3ccccc3c2=O)cc1
Yield: 60.8 %

Procedure:
The title compound was prepared in a yield of 60.8%, using 2-mercapto-3-(4-methylphenyl)-4(3H)-quinazolinone in place of 2-mercapto-3-phenyl-4(3H)-quinazolinone and 4-chloromethylpyridine hydrochloride in place of 2-chloromethyl4-methylpyridine hydrochloride.
Reaction SMILES: C(O[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([Cl:18])=[N:16][CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)C.C(OC([N:27]1[C:31]2[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=2[N:29]=[CH:28]1)=O)(C)(C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:18][C:17]1[C:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([C:28]3[NH:27][C:31]4[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=4[N:29]=3)=[O:19])=[CH:10][CH:9]=2)=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: CC(C)(C)OC(=O)n1cnc2ccc(F)cc21
Reactant: CCOC(=O)c1ccc(Oc2nccnc2Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccc(F)cc2[nH]1
Reaction time: 3.5 h

Procedure:
A solution of 4-(3-Chloro-pyrazin-2-yloxy)-benzoic acid ethyl ester (20 g, 84.7 mmol) and 6-fluoro benzoimidazole-1-carboxylic acid tert-butyl ester (21.2 g, 76.3 mmol) in freshly dried THF (150 mL) was cooled to −78° C. LiHMDS (106 mL, 106 mmol) was added slowly to it over 1.2 h. The reaction mixture was stirred at the same temperature for 3.5 h. The reaction was brought to −20° C. and slowly quenched with addition of 2N HCl until pH 3-4. The resulting mixture was stirred at RT for 1 h, extracted with ethyl acetate (3×200 mL), and washed with water (2×100 mL). The organic layer was dried (Na2SO4) and concentrated. To the crude product was added methanol (70 mL). After stirring for 1 h, the solid was collected by filtration to give the title compound. MS (ESI, pos. ion) m/z: 369.2 (M+1). IC50 (uM) +.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.OCC1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)=[CH:17][CH:16]=1.N1CCCC1>ClCCl>[N:3]1([CH2:6][C:7]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:17][CH:16]=2)[CH2:4][CH2:5][CH2:2][CH2:1]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(CO)cc2)C1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(CN3CCCC3)cc2)C1
Temperature: 0 °C
Reaction time: 7.5 h
Yield: 56.3 %

Procedure:
Triethylamine (0.47 g, 3.4 mmol) and methanesulfonyl chloride (0.12 ml, 1.6 mmol) were added to an ice-cooled solution of 3-(4-hydroxymethylphenyl)-1-(tert-butoxycarbonyl)piperidine (0.39 g, 1.34 mmol) in dichloromethane and stirred for 7.5 hr. Pyrrolidine (1.0 ml, 12 mmol) was added to the solution and stirred overnight. Organic solvents were removed under reduced pressure after addition of water and extracted with ethyl acetate, washed with water and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure and the residue was purified by silica gel chromatography (eluent; ethyl acetate to ethyl acetate/methanol=1/1, then methanol only) to give 3-(4-(1-pyrrolidinyl)methylphenyl)-1-(tert-butoxycarbonyl)piperidine (0.26 g, 56%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH:10]([OH:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.Br[CH2:37][C:38]1[CH:47]=[C:46]2[C:41]([CH:42]=[CH:43][CH:44]=[N:45]2)=[CH:40][CH:39]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH:10]([O:34][CH2:37][C:38]2[CH:47]=[C:46]3[C:41]([CH:42]=[CH:43][CH:44]=[N:45]3)=[CH:40][CH:39]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: BrCc1ccc2cccnc2c1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Agent: Br
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3cccnc3c2)cc1

Procedure:
In analogy to the procedure described in example 1(b) the (3RS,4RS)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was alkylated with 7-bromomethyl-quinoline hydrobromide (1:1) [J. Am. Chem. Soc. 77, 1054(1955)] to yield the (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as an amorphous light yellow solid; MS: 613 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O>CO.[Ni]>[NH2:11][C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: CC(=O)c1ccc(F)c(N)c1

Procedure:
39 g of 4'-fluoro-3'-nitroacetophenone, melting point: 44° C., were hydrogenated in 390 ml of methanol at 20 atm. and 40° C. in the presence of Raney-Nickel to give the 3'-amino-4'-fluoro-acetophenone, melting point: 70° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2C(=O)C3=CC=CC=C3[C:10]2=[O:19])[N:5]=[C:4]([C:20]2[N:21]=[C:22]([N:25]=[C:26]([NH2:28])[NH2:27])[S:23][CH:24]=2)[CH:3]=1.O.[NH2:30]N>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:30])=[O:19])[N:5]=[C:4]([C:20]2[N:21]=[C:22]([N:25]=[C:26]([NH2:28])[NH2:27])[S:23][CH:24]=2)[CH:3]=1
Reactant: NN
Reactant: NC(N)=Nc1nc(-c2cc(Cl)cc(CN3C(=O)c4ccccc4C3=O)n2)cs1
Solvent: CCO
Solvent: O
Product: NC(=O)NCc1cc(Cl)cc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 32.3 %

Procedure:
A mixture of 4-(4-chloro-6-phthalimidomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (1.10 g) and hydrazine mono-hydrate (400 mg) in ethanol (200 ml) was refluxed for 5 hours. After the solvent and excess hydrazine monohydrate were removed by concentration, water (10 ml) was added to the residue and the suspension was adjusted to pH 2 with 6N-hydrochloric acid. The resulting precipitate was filtered off, washed with water (5 ml) and the filtrate and the washing solution were combined. After the solution was readjusted to pH 4 with aqueous sodium bicarbonate, potassium cyanate (320 mg) was added to the solution and the mixture was stirred for 14 hours at ambient temperature. The reaction mixture was readjusted to pH 4 with 6N-hydrochloric acid, additional potassium cyanate (215 mg) was added and the solution was further stirred for 8 hours. The mixture was made basic to pH 10 with aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of N,N-dimethylformamide and water to give 4-(4-chloro-6-ureidomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.28 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH:15]=[C:14](Br)[CH:13]=[N:12]2)[CH:5]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH:15]=[C:14]([C:23]3[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[CH:13]=[N:12]2)[CH:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cccc(Cn2cc(Br)cn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cccc(Cn2cc(-c3ccc(C#N)cc3)cn2)c1
Yield: 31.5 %

Procedure:
Charge a microwave vial with 3-(4-bromo-pyrazol-1-ylmethyl)-benzoic acid methyl ester (0.60 g, 2.00 mmol), 4-cyanophenylboronic acid (0.35 g, 2.40 mmol), potassium carbonate (0.50 g, 4.80 mmol) and tetrakistriphenylphosphine palladium (0) (0.23 g, 0.2 mmol). Flush the vessel with inert gas and seal. Dissolve the contents of the vial in 10 mL of a 4:1 dioxane-water mixture and microwave at 150° C. for 5 minutes. Dilute the reaction mixture with EtOAc, dry over sodium sulfate, filter and concentrate to give an oil. Purify the residue by flash chromatography using a gradient of 0-50% EtOAc/hexanes to afford 0.20 g, 32% yield of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzoic acid methyl ester as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[Br:10]Br>CCOCC.[Fe]>[Br:10][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH3:9])=[CH:4][C:5]=1[F:8]
Reactant: Cc1cc(F)ccc1F
Reactant: BrBr
Agent: [Fe]
Solvent: CCOCC
Product: Cc1cc(F)c(Br)cc1F
Temperature: -5 °C
Reaction time: 3 h

Procedure:
A mixture of 2,5-difluorotoluene (25 g, 0.20 mol) and iron powder (11 g, 0.2 mol) was cooled to −5° C. Bromine was added dropwise such that the internal temperature of the reaction did not rise above 0° C. After stirring for 3 hours, the mixture was diluted with ether, filtered and washed with aqueous sodium thiosulfate solution. The aqueous layer was extracted with ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Distillation at atmospheric pressure gave 34 g of 1-bromo-2,5-difluoro-4-methyl-benzene as a colorless oil (b.p. 180 oC). 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, 1H, J=6.0, 8.5 Hz), 6.93 (m,1H), 2.23 (s, 3H) ppm.