Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1)#[N:6].[C:15]([N:34]1[CH:38]=[C:37](I)[N:36]=[CH:35]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1.[Zn].C(Cl)(Cl)Cl>[C:15]([N:34]1[CH:38]=[C:37]([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[N:36]=[CH:35]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: BrCCBr
Product: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 3 h

Procedure:
To an oven dried 500 ml flask was added Zn (92 mmol, 5.96 g) and then 45 mL of distilled THF via syringe. To this well stirred mixture was added 1,2-dibromoethane (9.2 mmol, 1.72 g) via pipet. This mixture was stirred at ambient temperature for 3 hr and then a solution of p-cyanobenzylbromide (59.5 mmol, 11.68 g) in THF (50 mL) was added via addition funnel over 20 minutes. The resulting mixture was stirred at ambient temperature for 6 hr. Then a mixture of 1-trityl-4-iodoimidazole (45.8 mmol, 20 g) and bis-triphenylphosphinedichloronickel (4.6 mmol, 3.0 g) was added. This was stirred at ambient temperature for 36 hr. A saturated ammonium chloride solution (125 mL) was added. Stirring was continued for 3 hr and then 1 L of chloroform was added to this mixture. The chloroform layer was drawn off, washed with dilute sodium bicarbonate then saturated sodium chloride. Dried with sodium sulfate and evaporated to a thick oil. Purified on a silica gel column eluted with chloroform to provide the title compound. 1H-NMR (CDCl3): 4.0 ppm (s, 2H); 7.1-7.6 ppm (20H); 6.6 ppm(s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:23])[CH:5]=2)[CH2:3][CH2:2]1.COCCOC.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH:42]=[CH:41][CH:40]=[N:39]2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)(=O)C.O>[N:38]1([C:35]2[CH:36]=[CH:37][C:32]([CH2:31][C:13]3[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:5][C:6]([OH:23])=[C:7]([CH:12]=3)[C:8]([O:10][CH3:11])=[O:9])=[CH:33][CH:34]=2)[CH:42]=[CH:41][CH:40]=[N:39]1
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C2CC2)cc1O
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C2CC2)cc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of methyl 4-cyclopropyl-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.36 g) in a mixed solvent of DME (5.70 mL)-water (1.90 mL) were added 1-(4-(bromomethyl)phenyl)-1H-pyrazole (0.27 g), tetrakis(triphenylphosphine)palladium(0) (0.07 g) and sodium carbonate (0.24 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][O:36][C:37](=[O:40])[CH2:38]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:40])[CH2:38][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: COC(=O)CBr
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 8 mg of sodium hydride and stirred for 30 minutes at 20° C. 50 mg of bromoacetic acid methyl ester was added, allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].ClCCl.[CH3:11][NH:12][CH2:13][C:14]([O:16][CH:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24](=[O:42])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:27][C:26]=2[CH3:41])[C:19]2[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:18]1=2)=[O:15].CN1CCOCC1>C(OCC)(=O)C>[Cl:7][CH:5]([O:4][C:2]([CH2:11][NH:12][CH2:13][C:14]([O:16][CH:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24](=[O:42])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:27][C:26]=2[CH3:41])[C:19]2[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:18]1=2)=[O:15])=[O:3])[CH3:6]
Reactant: CNCC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CNCC(=O)OC(C)Cl)c3cc(Cl)ccc32)c(C)c1
Yield: 89.1 %

Procedure:
1-Chloroethyl chloroformate (0.12 ml, 1.2 mmol) was added dropwise to a dichloromethane (10 ml) solution of 7-chloro-1-[2-methyl-4-(2-methylbenzamido)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl methylaminoacetate (0.60 g, 1.2 mmol), and the mixture was cooled with ice. Then N-methylmorpholine (0.15 ml, 1.4 mmol) was gradually added dropwise thereto. After the resultant mixture was stirred at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate, washed with water and an aqueous saturated sodium chloride solution, dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel chromatography (n-hexane:ethyl acetate) to obtain 0.67 g (93%) of 7-chloro-1-[2-methyl-4-(2-methylbenzamido)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl [(1-chloroethoxycarbonyl)methylamino]acetate as amorphous.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]1[CH:13]([C:14]([O:16]CC)=[O:15])[CH:7]12.[OH-].[Na+]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]1[CH:13]([C:14]([OH:16])=[O:15])[CH:7]12
Reactant: CCOC(=O)C1C2CCc3c(F)ccc(F)c3C21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1C2CCc3c(F)ccc(F)c3C21

Procedure:
4,7-Difluoro-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic acid was synthesized analogously to Example 72e from ethyl 4,7-difluoro-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate (0.45 g, 1.8 mmol) by stepwise hydrolysis first with excess of NaOH at r.t. and then with the excess of NaOH at heating (60° C., 1.5 h) to give 80 mg of product as white crystals (cis/trans ratio 78:22 according to HPLC).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH3:6][C:7]1([CH3:27])[C:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[CH:12]=[CH:11][C:10]=2[N+:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]1[CH3:26].C(OCC)C.[OH-].[K+]>C1C=CC=CC=1.O>[CH3:6][C:7]1([CH3:27])[C:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[CH:12]=[CH:11][C:10]=2[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]1=[CH2:26]
Reactant: CC1=[N+](c2ccccc2)c2ccc3ccccc3c2C1(C)C
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: C=C1N(c2ccccc2)c2ccc3ccccc3c2C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1,2-Trimethyl-3-phenyl-1H-benzo[e]indolium perchlorate (11) (0.386 g) was suspended in 50 ml of benzene or diethyl ether and a solution 0.1 g potassium hydroxide in 2 ml water was added. The mixture was stirred at room temperature under nitrogen for one hour. The organic solvent layer was separated and washed with water and filtered through silica gel and then dried and evaporated. The resultant oily product (0.2 g) was sufficiently pure for the next synthetic step. 1H NMR (400 MHz, DMSO) δ 8.05 (d, 1H, J=8.5), 7.81 (d, 1H, J=8.1), 7.67 (d, 1H, J=8.8), 7.59 (t, 2H, J=7.8), 7.43 (dt, 4H, J=6.9, 20.3), 7.22 (t, 1H, J=7.3), 6.75 (d, 1H, J=8.7), 4.05 (d, 1H, J=1.7), 3.88 (d, 1H, J=1.7), 1.71 (s, 6H).
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=3[OH:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C=O)C.C(N(CC)CC)C.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C1C=CN=CC=1)C.O>[C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=3[O:18][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Yield: 64152.2 %

Procedure:
A 2.0 L three-neck flask attached with a power-stirrer was charged with 2-adamantan-1-yl-4-bromophenol (102.8 g, 0.334 mol, 1.0 eq), DMAP (3.67 g, 0.0301 mol), anhydrous DMF (1.0 L) and triethylamine (76.1 g, 0.753 mol, 1.25 eq). Stirring was initiated and to the resulting solution at room temperature was added t-butyl-dimethylsilyl chloride (99.8 g, 0.662 mmol, 1.10 eq). The resulting mixture was allowed to stir overnight, poured into water, and extracted with diethyl ether (2×). The combined organics were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified on silica gel (hexane) to give 179 g (70%) of 3-adamantan-1-yl-4-t-butyldimethylsilanyloxybromobenzene as a white powder. 1H NMR (300 MHz; CDCl3): δ 0.33 (s, 6H), 1.03 (s, 9H), 1.75 (brs, 6H), 2.06 (s, 9H), 6.65 (d, J=8.4 Hz, 1H), 7.14 (dd, J1=8.4 Hz, J2=2.1 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[C:7]([C@H:13]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]([CH3:24])=[CH:5]2.C(N(C(C)C)CC)(C)C.Cl[Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])=[C:7]([C@H:13]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]([CH3:24])=[CH:5]2
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1O[Si](CC)(CC)CC
Reaction time: 1 h

Procedure:
To a solution of (S)-ethyl 2-(6-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (238 mg, 0.6 mmol) in anhydrous DCM (20 mL) at 0° C. was added diisopropylethylamine (0.21 mL, 1.2 mmol), followed by chlorotriethylsilane (0.12 mL, 0.72 mmol) and the resulting mixture stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with DCM and organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give the desired compound. 1H NMR (400 MHz, CDCl3): δ 7.82 (m, 2H), 7.42 (m, 1H), 7.08 (s, 1H), 5.98 (s, 1H), 4.19 (m, 2H), 2.43 (s, 3H), 1.21 (s, 9H), 0.98 (t, 9H), 0.83 (m, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][O:45][CH3:46]>CN(C=O)C.C(Cl)Cl>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:43][CH2:44][O:45][CH3:46])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: COCCBr
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COCCN1CCC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 47.5 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt (300 mg, 0.61 mmol) in DMF (3.5 mL) were added potassium carbonate (290 mg, 2.10 mmol) and 1-bromo-2-methoxy-ethane (93 mg, 0.67 mmol). The resultant reaction mixture was stirred at 60° C. for 4 hours before being cooled to RT and diluted with DCM. The mixture was washed sequentially with sodium hydrogen carbonate solution (sat. aq.), water and brine then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-8% MeOH in DCM) and triturated with petroleum ether to afford 286 as a white solid (127 mg, 0.29 mmol, 48%). LCMS: RT=3.02 min, [M+H]+=437. 1H NMR δ (ppm) (DMSO-d6): 8.28 (1H, d, J=8.28 Hz), 7.86 (1H, d, J=0.62 Hz), 7.85 (1H, s), 7.01 (1H, dd, J=8.36, 1.77 Hz), 6.85 (1H, d, J=1.72 Hz), 5.90-5.80 (1H, m), 4.45 (4H, m), 3.40 (2H, t, J=5.89 Hz), 3.20 (3H, s), 2.93 (2H, d, J=11.11 Hz), 2.01 (2H, dd, J=12.41, 10.21 Hz), 1.70 (2H, d, J=12.52 Hz), 1.58 (2H, ddd, J=24.42, 12.21, 3.61 Hz), 1.44 (6H, d, J=6.60 Hz). 3H obscured by solvent.
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1.[CH3:15][C:16]([CH3:18])=[O:17].[H-].[Na+].Cl>C1(C)C=CC=CC=1.O>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([C:1](=[O:13])[CH2:15][C:16](=[O:17])[CH3:18])[CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Reactant: CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc(C(=O)CC(C)=O)c1
Temperature: 100 °C
Yield: 13.1 %

Procedure:
A solution of dimethyl isophthalate (12 g, 61.85 mmole) and acetone (5 mL, 68 mmole) in a mixture of toluene/dimethoyethane (90 mL/30 mL) was added to a suspension of NaH 60% (2.97 g, 74.23 mmole) in dry toluene (30 mL) under argon. The mixture was heated at 100° C. for 4 hours. The reaction mixture was cooled to rt and 25 mL of water were added. The mixture was poured into water (250 mL) and the pH was adjusted to 3-4 with HCl 2N. The aqueous mixture was extracted with ethyl acetate (2×250 mL), washed with brine, dried over sodium sulphate and evaporated to afford a yellow solid which was purified by column cromatography (n-Hex/EtOAc 9:1 to 8:2) to afford the title compound (1.78 g, 11% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:28]=4)[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 40 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 2H), 7.42–7.36 (m, 2H), 7.30–7.20 (m, 2H), 7.05–6.96 (m, 3H), 6.85–6.79 (m, 1H), 3.28 (q, 2H, J=6.3 Hz), 2.95–2.87 (m, 2H), 2.57–2.41 (m, 2H), 2.36–2.28 (m, 4H), 2.06 (s, 1H), 1.96–1.84 (m, 4H), 1.83–1.75 (m, 2H), 1.71–1.54 (m, 9H), 1.24 (d, 6H, J=7.1 Hz); ESMS m/e: 508.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)=[C:9]([F:22])[CH:8]=1)=[O:5])[CH3:2].F[C:24]1C=C(C=CC=1B1OC(C)(C)C(C)(C)O1)N.C1(N=C=O)CC1>>[CH:1]1([NH:3][C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([B:13]3[O:14][C:15]([CH3:21])([CH3:20])[C:16]([CH3:19])([CH3:18])[O:17]3)=[C:9]([F:22])[CH:8]=2)=[O:5])[CH2:24][CH2:2]1
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: O=C=NC1CC1
Product: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Yield: 100 %

Procedure:
Prepared as 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 28) using 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and cyclopropyl isocyanate as starting materials. The crude reaction mixture was then partitioned between DCM and water. The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo to yield a light orange solid (3.2 g, 10 mmol, 100%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([C:21]([OH:23])=[O:22])[CH:12]([C:18]([OH:20])=[O:19])[C:13]([C:15]([OH:17])=[O:16])=[CH2:14].OS(O)(=O)=O>O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH:12]([C:18]([OH:20])=[O:19])[CH2:11][C:21]([OH:23])=[O:22]
Reactant: C=C(C(=O)O)C(CC(=O)O)C(=O)O
Reactant: Sc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CC(C(=O)O)C(CSc1nc2ccccc2s1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.45 g of 2-mercaptobenzthiazole, and 5 g of but-3-ene-1,2,3-tricarboxylic acid are ground with one another in a mortar. The powdered mixture is introduced in portions and with stirring into 60 ml of 70% H2SO4 at 48°-50°, in the course of one hour. After a further 3 hours at 48°-50°, the reaction mixture is cooled to room temperature and diluted with 250 ml of water at 25°-30°, with stirring. The aqueous solution is decanted from a little tacky deposit and is diluted with a further 200 ml of water. After being stirred for 1 hour the precipitate is filtered off and dried. The 4-(benzthiazol-2-ylthio)-butane-1,2,3-tricarboxylic acid obtained melts at 188°-190° after recrystallisation from methanol/water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([NH2:23])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][C:20]([NH:23][S:38]([CH3:37])(=[O:40])=[O:39])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2
Reactant: CS(=O)(=O)Cl
Reactant: NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-amine (8.4 mg, 0.016 mmol, 1 eq.) in 2 mL of THF was added methanesulfonyl chloride (0.01 mL) and triethylamine (0.02 mL). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 8 mg (82%) of N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-yl}methanesulfonamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.22 (s, 3 H) 2.30-2.44 (m, 2H) 2.47-2.66 (m, 2H) 4.20 (br. s., 2 H) 4.75 (s, 2 H) 7.08-7.64 (m, 13 H) 8.38 (s, 1 H), [M+H]+ 593.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:11](=[O:25])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:29][C:30]1[CH:34]=[C:33]([CH3:35])[O:32][N:31]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13]3)[C:11](=[O:25])[N:10]([CH2:29][C:30]3[CH:34]=[C:33]([CH3:35])[O:32][N:31]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCC2c1ccc(F)cc1
Reactant: Cc1cc(CBr)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CN2CC(c3ccc(F)cc3)C3(CCCN(C(=O)OC(C)(C)C)C3)C2=O)no1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Tert-butyl 4-(4-fluorophenyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (200 mg; 0.574 mmol) was solubilised in DMF (5 ml) and cooled to 0° C. 60% Sodium hydride dispersion in mineral oil (46 mg, 1.148 mmol) was added and the mixture stirred at 0° C. for 45 minutes. 3-(Bromomethyl)-5-methylisoxazole (101 mg; 0.574 mmol) was solubilised in DMF (0.7 ml) and added. The reaction was stirred at 0° C. for 30 minutes then warmed to RT for 3 hr. The mixture was quenched with water and extracted with EtOAc. The organics were combined and washed with brine and dried over magnesium sulphate, filtered and concentrated in vacuo. The resultant oil was purified by chromatography on silica eluting with 50-100% TBME in iso-hexane to yield tert-butyl 4-(4-fluorophenyl)-2-((5-methylisoxazol-3-yl)methyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[N:21][OH:22])[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C[Si]([N:27]=[C:28]=[O:29])(C)C.N1C=CC=CC=1>C1COCC1>[C:28]([O:22][N:21]=[C:17]([C:16]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12)[CH:18]([CH3:19])[CH3:20])(=[O:29])[NH2:27]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)C(=NO)c1c(-c2ccc(Cl)cc2)nn2ccccc12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)C(=NOC(N)=O)c1c(-c2ccc(Cl)cc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.6 %

Procedure:
To a solution of 783 mg (2.5 mmol) of 1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature over 48 hrs, followed by addition of 500 μl pyridine. After stirring for another 4 hours, the solvent was removed and the residue was extracted by ethyl acetate three times. The combined organic layers were washed with 1N HCl twice, brine and dried over MgSO4. After evaporation of the solvent under vacuum, 935 mg of crude product was obtained. Purification on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant furnished 621 mg (69.6%) of 1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime. Compound 1026.