Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[Cl:23])[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>C1COCC1>[Cl:23][C:14]1[CH:15]=[CH:16][C:17]([C:19]([F:20])([F:21])[F:22])=[CH:18][C:13]=1[C:12]([NH:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([CH2:3][OH:2])[CH2:6][CH2:7]1)=[O:24]
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@H](CO)CC1)c1cc(C(F)(F)F)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-(2-chloro-5-trifluoromethyl-benzoylamino)-cyclohexane carboxylic acid methyl ester (step 1) (95.2 g, 0.26 mol) in dry THF (1 L) under nitrogen at 0° C. is added lithium aluminium hydride pellets (20 g, 0.53 mol) portion wise over 3 hours. The reaction mixture is stirred at 0° C. for a further 2 hours and then carefully quenched at 0° C. by the addition of water (40 mL) in THF (60 mL) followed by further THF (500 mL) to maintain a mobile suspension. Finally, 1M sodium hydroxide solution (80 mL) is added at 0° C. resulting in a yellow solution containing a colourless suspension. The reaction is filtered through a Celite® pad (filter material) to remove inorganic salts. The Celite® pad/salts are washed with EtOAc (500 mL) then with EtOAc:THF (1:1; 300 mL). The organics are combined and diluted with further EtOAc (600 mL) and then washed with saturated brine (600 mL). The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure until a slurry is obtained. Et2O is added to the slurry, which is then stirred for 5 minutes before being filtered to recover a colourless solid. The solid is washed with isohexane and then dried at 35° C. under vacuum to give the required product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][Cl:30])[CH:7]=[CH:6][CH:5]=3)[C:16]=12
Reactant: CC(C)n1nc(-c2cccc(N)c2)c2c(N)ncnc21
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)n1nc(-c2cccc(NC(=O)CCl)c2)c2c(N)ncnc21
Reaction time: 1 h
Yield: 13 %

Procedure:
A solution of THF (20 mL), compound 22 (200 mg, 0.75 mmol) and DIPEA (143 μL, 0.821 mmol) was cooled to 0° C. Chloroacetylchloride (54 μL, 0.67 mmol) was added and the reaction was allowed to proceed for 1 hour and afterwards concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL) and washed with saturated sodium bicarbonate (20 mL). The aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The product was purified by preparative RP-HPLC and lyophilized (30.4 mg, 13% yield): 1H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 8.41 (s, 1H), 7.95 (s, 1H), 7.67 (d, J=7.6, 1H), 7.53 (t, J=7.9, 1H), 7.41 (d, J=7.7, 1H), 5.11 (hept, J=6.7, 1H), 4.30 (s, 2H), 1.51 (d, J=6.7, 6H); 13C NMR (100 MHz, DMSO) δ 165.06, 154.82, 151.89, 150.90, 144.68, 139.03, 132.62, 128.28, 123.81, 120.02, 119.24, 96.92, 48.84, 43.55, 21.77; [M+H]+ calculated for C16H17ClN6O 345.1, found 345.4.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]([CH:15]2[CH2:17][CH2:16]2)=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([F:18])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[CH:42]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH2:44][CH2:43]1.Cl>O1CCCC1>[CH2:1]([O:5][C:6]1[C:14]([CH:15]2[CH2:17][CH2:16]2)=[CH:13][C:9]([C:10]([NH:48][S:45]([CH:42]2[CH2:44][CH2:43]2)(=[O:47])=[O:46])=[O:12])=[C:8]([F:18])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NS(=O)(=O)C1CC1
Reactant: CCCCOc1cc(F)c(C(=O)O)cc1C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCOc1cc(F)c(C(=O)NS(=O)(=O)C2CC2)cc1C1CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
To a stirred solution of 4-butoxy-5-cyclopropyl-2-fluorobenzoic acid (0.039 g, 0.15 mmol) in tetrahydrofuran (1 mL) and under an atmosphere of nitrogen was added carbonyldiimidazole (0.030 g, 0.18 mmol) and the reaction mixture was stirred at 70° C. for 1 hour. The mixture was cooled down to room temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.02 mL, 0.02 mmol) was added followed by cyclopropanesulfonamide (0.024 g, 0.20 mmol) and the stirring continued at ambient temperature for 18 hours. 5% aqueous hydrochloric acid solution (0.15 mL) was added and the mixture was concentrated and directly purified by column chromatography (0 to 30% gradient ethyl acetate in hexanes) to afford the title compound (0.011 g, 20%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.82-8.57 (m, 1H), 7.57 (d, J=9.24 Hz, 1H), 6.58 (d, J=14.42 Hz, 1H), 4.04 (t, J=6.30, 6.30 Hz, 2H), 3.16-3.05 (m, 1H), 2.18-1.74 (m, 3H), 0.72-0.61 (m, 2H), 1.71-0.84 (m, 13H), 0.74-0.60 (m, 2H); MS (ES+) m/z 356.1 (M+1); MS (ES−) m/z 354.2 (M−1).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([N:11]2[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[C:17]([C:20]([OH:22])=O)[CH:18]=3)[CH:13]=[CH:12]2)[CH2:10][CH2:9]1.Cl.[O:26]=[C:27]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]3[CH:43]=[N:44][CH:45]=[C:46]([CH:50]=3)[C:47]([OH:49])=[O:48])[CH:40]=2)[O:35][C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28]1.Cl>CN(C=O)C.O>[CH:8]1([N:11]2[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[C:17]([C:20]([N:32]4[CH2:33][CH2:34][C:29]5([CH2:28][C:27](=[O:26])[C:41]6[C:36](=[CH:37][CH:38]=[C:39]([C:42]7[CH:43]=[N:44][CH:45]=[C:46]([CH:50]=7)[C:47]([OH:49])=[O:48])[CH:40]=6)[O:35]5)[CH2:30][CH2:31]4)=[O:22])[CH:18]=3)[CH:13]=[CH:12]2)[CH2:9][CH2:10]1
Reactant: O=C(O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Reactant: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
N,N′-carbonyldiimidazole (130 mg) and triethylamine (0.446 mL) were added to a solution of 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylic acid (185 mg) in DMF (4 mL), and stirred at 70° C. for 20 hours. To the reaction mixture was added 5-(4-oxo-spiro[chroman-2,4′-piperidin]-6-yl)nicotinic acid hydrochloride (370 mg), which was further stirred at that temperature for 6 hours. 1 N hydrochloric acid and water were added to the reaction mixture, and the formed solid was collected by filtration. The solid was purified through silica gel column chromatography (chloroform/methanol) to obtain the intended compound. 1H-NMR (400 MHz, DMSO-d6) δ: 9.04-9.00 (2H, m), 8.40 (1H, s), 8.06-8.00 (2H, m), 7.30-7.22 (3H, m), 6.58 (1H, s), 6.40 (1H, d, J=3.2 Hz), 4.47-4.01 (1H, m), 3.88 (3H, s), 3.79-3.09 (4H, m), 2.96 (2H, s), 2.15-1.71 (4H, m), 1.09-1.01 (2H, m), 0.96-0.89 (2H, m); MS [M+H]+=552.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:12])[CH2:10][CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br-:13].[Br-].O1CCOCC1>O1CCOCC1>[Br:13][CH:10]([CH3:11])[C:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)=[O:12]
Reactant: [Br-]
Reactant: CCC(=O)c1cc(F)cc(F)c1
Solvent: C1COCCO1
Product: CC(Br)C(=O)c1cc(F)cc(F)c1
Yield: 102.1 %

Procedure:
To 3',5'-difluoropropiophenone (56.0 g. 0 33 mole) was added a solution of dioxane dibromide (81.8 g. 0.33 mole) in dioxane (500 ml) The reaction mixture was worked up as in Example 1 to yield crude 2-bromo-3',5'-difluoropropiophenone (83.9 g).
Reaction SMILES: [S:1]1[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31]([O:33][CH3:34])=[O:32])[CH:30]=1)[NH:27][CH:26]=[CH:25]2.C([SiH](CC)CC)C>C(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31]([O:33][CH3:34])=[O:32])[CH:30]=1)[NH:27][CH:26]=[C:25]2[CH:4]1[CH2:5][CH2:6][CH2:7][S:1][CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: O=C1CCCSCC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c(C3CCCSCC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
To a flask under argon in an ice-bath, the 4-thiepanone (200 mg, 1.536 mmol) in 6 mL of dried CH2Cl2 was first dried w/4 A sieves and then transferred via a double needle tubing (cannula). TMS-OTf (278 uL, 1.536 mmol) was added dropwise and the reaction was stirred for 10 min. A solution of methyl 5-bromo-1H-indole-7-carboxylate (390 mg, 1.536 mmol) in 7 mL of CH2Cl2 was dried with 4 A sieves and then added into above solution dropwise. Stirring continued for 4 hours and the reaction was warmed to room temperature. The mixture was cooled to 0° C. and triethylsilane (245 uL, 1.536 mmol) was added as one portion. The mixture was stirred overnight then warmed to room temperature. The mixture was quenched water and sat. NaHCO3, then diluted water/AcOEt and washed with H2O and brine. 194 mg of crude product was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([C:29]1[S:30][CH:31]=[C:32]([C:34]([OH:36])=O)[N:33]=1)[CH2:26][CH2:27][CH3:28].[Si:37]([O:44][CH2:45][CH2:46][C:47]1[C:48]([F:65])=[C:49]([CH:62]=[CH:63][CH:64]=1)[CH2:50][N:51]1[CH2:61][CH2:60][C:54]2([O:59][CH2:58][CH2:57][NH:56][CH2:55]2)[CH2:53][CH2:52]1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].C(N(CC)CC)C>CN(C=O)C>[Si:37]([O:44][CH2:45][CH2:46][C:47]1[C:48]([F:65])=[C:49]([CH:62]=[CH:63][CH:64]=1)[CH2:50][N:51]1[CH2:52][CH2:53][C:54]2([O:59][CH2:58][CH2:57][N:56]([C:34]([C:32]3[N:33]=[C:29]([CH2:25][CH2:26][CH2:27][CH3:28])[S:30][CH:31]=3)=[O:36])[CH2:55]2)[CH2:60][CH2:61]1)([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CCCCc1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO[Si](C)(C)C(C)(C)C)c4F)CC3)C2)cs1
Reaction time: 1 h

Procedure:
2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.378 g) was added to a stirred solution of 2-butylthiazole-4-carboxylic acid (example 78, step g) (0.193 g), 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.4 g), and triethylamine (0.383 g) in DMF (4 mL). After 1 h, the reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water and brine, dried over magnesium sulphate, filtered and evaporated in vacuo. Purification by silica gel chromatography eluting with 7:1:0.5, isohexane:ethyl acetate:triethylamine gave the subtitled compound as a gum. Yield 0.35 g.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([CH2:29]Cl)=[CH:26][CH:27]=5)[C:22]([C:31]#[N:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[I-:33].[K+]>CC(C)=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([CH2:29][I:33])=[CH:26][CH:27]=5)[C:22]([C:31]#[N:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(CCl)ccc54)ccc3o2)n1
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(CI)ccc54)ccc3o2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.9 %

Procedure:
A mixture of 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(chloromethyl)indole-3-carbonitrile (0.65 g) and potassium iodide (0.91 g) in acetone (5 ml) was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure and the residue was dissolved with dichloromethane. After removal of the resulting insolble mass by filtration, and the filtrate was evaporated under reduced pressure to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(iodomethyl)indole-3-carbonitrile (0.88 g). Methyl magnesium bromide (1M) in tetrahydrofuran solution (15 ml) was added dropwise to diethyl malonate (5.41 g) under ice-cooling. After the mixture was stirred at room temperature for 1.5 hours, 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(iodomethyl)indole-3-carbonitrile (0.88 g) was added to the mixture. After several hours, the resulting mixture was partitioned between diluted hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give ethyl 3-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-3-cyanoindol-5-yl}-2-(ethoxycarbonyl)propionate (0.78 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:9]=[C:8]([CH3:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:6]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[CH:32][CH:33]=[C:28]3[N:27]=[CH:26]2)[CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C)C=O>[Cl:18][C:13]1[CH:12]=[C:11]([N:7]2[C:8]([CH3:10])=[CH:9][C:5]([O:4][CH2:3][CH2:2][N:19]3[CH2:20][CH2:21][CH:22]([N:25]4[C:29]5=[N:30][CH:31]=[CH:32][CH:33]=[C:28]5[N:27]=[CH:26]4)[CH2:23][CH2:24]3)=[N:6]2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: c1cnc2c(c1)ncn2C1CCNCC1
Reactant: Cc1cc(OCCCl)nn1-c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCN2CCC(n3cnc4cccnc43)CC2)nn1-c1ccc(Cl)c(Cl)c1
Yield: 43.7 %

Procedure:
3-(2-chloroethoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole (0.2 g, 0.65 mmol), 3-(piperidin-4-yl)-3H-imidazo[4,5-b]pyridine (0.145 g, 0.72 mmol), K2CO3 (270 mg, 1.96 mmol) and NaI (98 mg, 0.65 mmol) in dry dimethylformamide (6 ml) was warmed overnight at 85° C., and then an additionally 16 hrs at 95° C., in a dry nitrogen atmosphere. Solvents were evaporated in vacuo and the crude residue partitioned in water/ethyl acetate. The combined organic extracts were washed with water, dried on Na2SO4 and concentrated in vacuo to obtain a yellow crude oil, which was purified by column chromatography on silica gel (eluent: ethyl acetate 100% and ethyl acetate/MeOH 98/2 and 95/5) yielding 134 mg of 3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridine as a white solid with m.p.=104-107° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C>[Si:16]([O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
A solution of tert-butyl 3-hydroxyphenylcarbamate (12-2, 6.40 g, 30.6 mmol, 1 equiv), t-butyldimethylsilyl chloride (4.61 g, 30.6 mmol, 1.00 equiv), and imidazole (2.71 g, 39.8 mmol, 1.30 equiv) in DMF (50 mL) was stirred at 23° C. for 16 h. The reaction mixture was partitioned between half-saturated sodium bicarbonate solution and ethyl acetate (200 mL). The organic layer was washed successively with half-saturated ammonium chloride solution (100 mL), saturated sodium bicarbonate solution (100 mL), and brine (100 mL), then dried over sodium sulfate and concentrated to give tert-butyl 3-{[tert-butyl(dimethyl)silyl]oxy}phenylcarbamate (12-3) as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.92 (t, 1H, J=7.8 Hz), 6.73 (m, 2H), 6.31 (ddd, 1H, J=7.8, 1.9, 0.7 Hz), 6.20 br s, 1H), 1.32 (s, 9H), 0.78 (s, 9H), −0.02 (s, 6H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(N(CC)CC)C.[Si:14]([O:21][C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[C:25]([O:27][CH2:28][CH2:29][CH2:30][Cl:31])=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[CH:35]12[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[C:36]1=O)[CH2:42]2>C1COCC1.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[Si:14]([O:21][C:22]1[CH:23]=[C:24]([C:25](=[C:36]2[CH:37]3[CH2:43][CH:41]4[CH2:40][CH:39]([CH2:44][CH:35]2[CH2:42]4)[CH2:38]3)[O:27][CH2:28][CH2:29][CH2:30][Cl:31])[CH:32]=[CH:33][CH:34]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCCCl)c1
Agent: [Ti+3]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(OCCCCl)=C2C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C

Procedure:
Titanium trichloride (25.8 g, 0.167 mol) was added to dry THF (500 mL) in a dried 3 L three-necked flask under a head of Ar at 0° C. Lithium aluminum hydride (3.01 g, 0.084 mol) was added in small portions with vigorous stirring. The reaction mixture was warmed to room temperature and 23.3 mL of triethylamine was added dropwise. After the addition was completed, the reaction mixture was refluxed for 2 h. Heating was stopped and a solution of 3-chloropropyl 3-(tert-butyldimethylsilyloxy)benzoate (5.28 g, 0.016 mol) and adamantanone (7.23 g, 0.048 mol) in 100 mL of dry THF was added dropwise to the refluxing mixture over a 45 min period. The reaction mixture was stirred over night at room temperature. The black mixture was diluted with water and extracted with 3×300 mL of hexane. The combined organic solutions were filtered, dried over sodium sulfate and concentrated under reduced pressure. The residue was partially purified by flash chromatography (2% ethyl acetate/hexane) to give the product as a viscous oil which was taken on to the next step. 1H NMR (CDCl3) δ0.200 (S, 6H), 0.988 (S, 9H), 1.66-2.01 (m, 14H), 2.63 (br s, 1H), 3.23 (br s, 1H), 3.538 (t, 2H, J=5.7 Hz), 3.640 (t, 2H, J=6.6 Hz), 6.75-7.22 (m, 4H). ##STR23##
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.CO.[N+](C1C=CC(OC(=O)[NH:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH:55]([CH3:57])[CH3:56])=[CH:50][CH:49]=2)=CC=1)([O-])=O>>[CH:55]([O:54][C:51]1[CH:52]=[CH:53][C:48]([NH:47][C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:21][CH:22]=4)[N:17]=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:49][CH:50]=1)([CH3:57])[CH3:56]
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCOS(C)(=O)=O)ccc23)CC1
Agent: Cl
Solvent: CO
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4cc(OCCCOS(C)(=O)=O)ccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To 4-[7-(3-methanesulfonyloxy-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 115, was added 3M HCl/MeOH (2 mL) and the mixture was stirred at rt for 2 h and then concentrated in vacuo and the residue was dissolved in a 1:1 mixture of DCM:MeOH, neutralized with excess Et3N and treated with (4-isopropoxy-phenyl)-carbamic acid 4-nitrophenyl ester (0.11 mmol), which was prepared as described in Example 1a. The mixture was stirred at rt overnight and then concentrated in vacuo and partitioned between water and DCM. DCM layer was drawn off, washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by Preparative TLC (silica gel; DCM:MeOH; 9.5:0.5) to obtain 40 mg (75%) of the title compound. 1H-NMR (300 MHz, CDCl3): 9.12 (s, 1H), 8.05 (d, 1H), 7.32-7.20 (m, 4H), 6.81 (d, 2H), 6.53 (s, 1H), 4.50-4.40 (m, 3H), 4.25 (t, 4H), 3.72-3.59 (m, 1H), 3.16-3.03 (m, 2H), 3.01 (s, 3H), 2.36-2.26 (m, 2H), 2.18-2.00 (m, 2H), 1.99-1.87 (m, 2H), 1.29 (d, 6H). LC/MS (ESI): 543.1 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: OCCC(c1ccccc1)c1ccccc1
Product: CCC(=O)Nc1ccc(C2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
Prepared by Procedure O and Scheme W using 3,3-diphenyl-1-propanol and N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 427.0 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:15][C:12]1[CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH2:14])=[N:10][CH:11]=1
Reactant: BrBr
Reactant: Nc1ncccc1Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1ncc(Br)cc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A 3 L flask was charged with 3-phenoxypyridin-2-amine (63.6 g, 342 mmol) and CHCl3 (1500 mL). The reaction was cooled to 0° C. and bromine (21.0 mL, 410 mmol) was added dropwise. The reaction was stirred for 1 hour. Another 1 mL of bromine was added and the reaction was poured into saturated aqueous NaHCO3 (1500 mL) and extracted with CH2Cl2. The organic layer was dried with sodium sulfate and 25 g charcoal. The mixture was filtered through Celite and concentrated in vacuo. The residue was dissolved in CH2Cl2 and passed through a plug of silica (1 L) eluting with 30% EtOAc/Hexanes to afford 5-bromo-3-phenoxypyridin-2-amine (64.02 g, 70.70% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3]F.[C:5]([O:9][C:10](=[O:30])[N:11]([C:13]1[CH:18]=CC(C2C=CC3C(C=2)=NON=3)=[C:15]([O:28][CH3:29])[CH:14]=1)[CH3:12])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:5]([O:9][C:10](=[O:30])[N:11]([C:13]1[CH:18]=[CH:3][C:2]([Br:1])=[C:15]([O:28][CH3:29])[CH:14]=1)[CH3:12])([CH3:8])([CH3:7])[CH3:6]
Reactant: COc1cc(N(C)C(=O)OC(C)(C)C)ccc1-c1ccc2nonc2c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(N(C)C(=O)OC(C)(C)C)ccc1Br
Temperature: 52.5 °C
Reaction time: 12 h

Procedure:
0.63 mL (1.25 eq.) 1-bromo-2-fluoroethane are added at room temperature to a stirred suspension of 2 g (6.6 mmol) (4-benzo[1,2,5]oxadiazol-5-yl-3-methoxy-phenyl)-methyl-carbamic acid tert-butyl ester and 3.2 g (1.5 eq.) cesium carbonate in 50 mL DMF. After stirring for 12 hours at 50 to 55° C., the reaction mixture is cooled to rt. And extracted with water/ethyl acetate. The combined organic phases are washed with brine, dried over magnesium sulfate and evaporated to yield the desired product as a yellow oil, which is used without further purification.