Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[C:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[C:16]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:15][C:11]=2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:18]=[C:17]([C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])[C:16]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:15][C:11]=2[C:12]([NH:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccc(F)cc3)cc2C(=O)N2CCOCC2)cn1
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(C(=O)Nc3cccnc3)c(OCc3ccc(F)cc3)cc2C(=O)N2CCOCC2)cn1
Reaction time: 18 h

Procedure:
To a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)benzoic acid (may be prepared as described in Description 29; 12 mg, 0.02 mmol) in N,N-dimethylformamide (4 ml), was added diisopropylethylamine (4.15 μL, 0.02 mmol), 3-aminopyridine (2.23 mg, 0.02 mmol) and HATU (9.03 mg, 0.02 mmol). The reaction stirred for 18 hours, then the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a gum. 4.8 mg.
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[N:9]([C:10](=C(C)C)[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:30])[C@@H:7]1[NH:31][C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]([CH3:4])=[O:3].[O:41]=O>C(Cl)Cl>[CH2:1]([O:5][C@H:6]1[N:9]([C:10](=[O:41])[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:30])[C@@H:7]1[NH:31][C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(C(=O)OC(c1ccccc1)c1ccccc1)=C(C)C
Reactant: O=O
Solvent: ClCCl
Product: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(=O)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diphenylmethyl α-[4(R)-acetonyloxy-3(R)-phenylacetamido-2-oxo-azetidin-1-yl]-α-isopropylideneacetate (2.342 g; 4.33 mmoles) in methylene chloride (40 ml) is introduced ozonized oxygen for 25 minutes at -78° C. Excess ozone is purged with nigrogen gas, and the mixture is mixed with dimethyl sulfide (3 ml), and stirred at -78° C. for 30 minutes, and at room temperature for 30 minutes. The reaction mixture is mixed with three drops of acetic acid, washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give the product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[CH2:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:21][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CC(C)(C)CN
Reactant: O=S(=O)(Cl)c1ccc(OCCCCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CNS(=O)(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3.5 g (13 mmol) of 4-(3-chloropropoxy)-benzenesulfonyl chloride in 100 ml of CH2Cl2, a solution of 1.62 g (18.56 mmol) of neopentyl amine in 15 ml of CH2Cl2 and 2.59 ml (18.56 mmol) of triethyl amine are added dropwise at 0-5° C. After stirring for 2.5 h at r.t., the reaction mixture is neutralized with 1N aqueous HCl and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 4-(3-chloropropoxy)-N-(2,2-dimethyl-propyl)benzenesulfonamide; NMR (CDCl3): 0.879 (s, 9H), 2.20-2.35 (m, 2H), 2.66 (d, 2H, J=6.88 Hz), 3.76 (t, 2H, J=6.28 Hz), 4.20 (t, 2H, J=5.84 Hz), 4.35-4.465 (m, 1H), 6.98 (d, 2H, J=8.88 Hz), 7.77 (d, 2H, J=8.88 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH2:13]=[CH:14][CH3:15]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:14]([CH3:15])[CH3:13])[CH:9]=2)[CH:4]=1
Reactant: COc1ccc2ccccc2c1
Reactant: C=CC
Product: COc1ccc2cc(C(C)C)ccc2c1
Temperature: 225 °C
Reaction time: 8 h

Procedure:
A 450 ml autoclave was charged with 158 g 2-methoxynapthalene and 3.2 g dealuminized mordenite catalyst. The autoclave was pressurized to 670 kPa with propylene then heated to 225° C. with agitation. Propylene was added as it was consumed to maintain pressure. In 8 hours, the conversion was 12% with 34% selectivity to 2-methoxy-6-isopropylnaphthalene (as confirmed by gas chromatography). Repetition of the reaction at 275° C. gave 19% conversion in 3 hours with 31% selectivity.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH3:25][NH:26][CH3:27]>CN(C)C=O>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([N:26]([CH3:27])[CH3:25])[N:3]=[CH:4][C:5]=3[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]=2[CH:16]=1
Reactant: CNC
Reactant: Fc1ccccc1C1=NCc2cnc(Cl)nc2-c2ccc(Cl)cc21
Solvent: CN(C)C=O
Product: CN(C)c1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 4.0 g (0.0112 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine in 15 ml of N,N-dimethylformamide was cooled in an ice bath and saturated with dimethylamine. After 18 hr at room temperature, 80 ml of ice water was added and the precipitate was collected by filtration and recrystallized twice from methanol to give the end product as white rods, mp 175°-179°.
Reaction SMILES: O1B([C@@H](NC(=O)[C@@H](NC(C2C=NC=CN=2)=O)CC2C=CC=CC=2)CC(C)C)[O:5][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:36])[CH3:35])[O:3]B1[C@@H](NC(=O)[C@@H](NC(C1C=NC=CN=1)=O)CC1C=CC=CC=1)CC(C)C.[C:82](O)(=[O:89])[C@@H:83]([CH2:85][C:86]([OH:88])=[O:87])O>CC(C)=O>[CH3:35][CH:34]([CH3:36])[CH2:33][C@@H:32]([B:4]1[O:5][C@H:83]([CH2:85][C:86]([OH:88])=[O:87])[C:82](=[O:89])[O:3]1)[NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]1[CH:55]=[N:54][CH:53]=[CH:52][N:51]=1)=[O:49])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)O1
Reactant: O=C(O)C[C@@H](O)C(=O)O
Solvent: CC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OC(=O)[C@@H](CC(=O)O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N,N′,N″-(boroxin-2,4,6-triyltris{[(1R)-3-methylbutane-1,1-diyl]imino[(2S)-1-oxo-3-phenylpropane-1,2-diyl]})tripyrazine-2-carboxamide (0.305 g, 0.278 mmol) and D-malic acid (130.3 mg, 0.33 mmol) were mixed in acetone (3 mL). The mixture was heated to form a solution. The solution was cooled uncontrolled until the internal temperature was about 25° C. White solid precipitated out and the resultant slurry was agitated at ambient temperature for 3 h. The slurry was filtered to collect solid 2-((R)-2((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)-5-oxo-1,3,2-dioxaborolan-4-yl)acetic acid (0.410 g, 100%). [M+H] calculated for C23H28BN4O7, 483.2051. found, 483.2.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([C:37]1([CH3:45])[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:30]2=[O:46].CCOC(C)=O>CN(C)C=O>[CH3:45][C:37]1([N:31]2[C:30](=[O:46])[C:29]3[C:33](=[CH:34][CH:35]=[C:27]([CH2:26][NH:25][C:9]([C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=4)=[O:11])[CH:28]=3)[C:32]2=[O:36])[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44]
Reactant: CSc1ccc(C(=O)O)nc1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A stirred mixture of 5-methylsulfanyl-pyridine-2-carboxylic acid (0.34 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (0-5% gradient, MeOH/CH2Cl2, 0-5% gradient, product eluted after 4.7 min). The product fractions were combined, concentrated and the residue was triturated in MeCN (50 mL) for 1.5 h. The product was isolated by filtration and dried in vacuo to give 5-methylsulfanyl-pyridine-2-carboxylic acid [2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.52 g, 57% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.89 min (98.54%); mp: 210-212° C.; 1H NMR (DMSO-d6) δ 1.88 (s, 3H), 1.97-2.12 (m, 1H), 2.53-2.78 (m, 6H), 4.62 (d, J=6.2 Hz, 2H), 7.68-7.90 (m, 4H), 7.91-8.04 (m, 1H), 8.52 (d, J=1.7 Hz, 1H), 9.51 (t, J=6.3 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 13.93, 21.02, 28.57, 29.09, 42.35, 58.73, 121.75, 122.05, 123.15, 129.59, 131.34, 133.53, 133.82, 139.65, 145.00, 145.90, 147.39, 164.07, 167.73, 167.88, 172.15; LCMS: MH=453; Anal Calcd for C22H20N4O5S: C, 58.40; H, 4.46; N, 12.38. Found: C, 58.24; H, 4.33; N, 12.16.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:5]=[CH:6][CH:7]=O.[C:13]([CH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:17])#[N:14]>>[N:23]1[CH:24]=[CH:25][C:20]([CH2:19][NH:18][C:16](/[C:15](=[CH:7]/[CH:6]=[CH:5]/[C:4]2[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=2)/[C:13]#[N:14])=[O:17])=[CH:21][CH:22]=1
Reactant: O=CC=Cc1ccc(O)c(O)c1
Reactant: N#CCC(=O)NCc1ccncc1
Product: N#C/C(=C\C=C\c1ccc(O)c(O)c1)C(=O)NCc1ccncc1

Procedure:
The compound was prepared as described in Example 3 by adding 3,4-dihydroxycinnamaldehyde (32 mg, 0.2 mmol) to 2-cyano-N-pyridin-4-ylmethylacetamide (33 mg, 0.2 mmol). After refluxing for 2 h and recrystallization from ethanol-water an orange solid was obtained (44 mg, 69%). The product gave the following analytical data:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][CH2:16][C:17]1([OH:20])[CH2:19][CH2:18]1.C(O[K])(C)(C)C.O>CN(C=O)C>[Cl:12][C:8]1[C:9]([Cl:11])=[N:10][C:2]([O:13][CH2:14][CH2:15][CH2:16][C:17]2([OH:20])[CH2:19][CH2:18]2)=[C:3]([CH:7]=1)[C:4]([NH2:6])=[O:5]
Reactant: OCCCC1(O)CC1
Reactant: NC(=O)c1cc(Cl)c(Cl)nc1Cl
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Cl)c(Cl)nc1OCCCC1(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A mixture of compound 2,5,6-trichloronicotinamide (0.6 g, 2.7 mmol), 1-(3-hydroxypropyl)cyclopropanol (370 mg, 3.2 mmol) and tert-BuOK (363 mg, 3.2 mmol) in DMF was stirred at room temperature overnight and the reaction mixture was then poured into cold water, the mixture was extracted twice with ethyl acetate, the combined organic layers were washed with brine twice, dried over Na2SO4 and concentrated, the residue was purified by column chromatography (silica gel, Petroleum ether: EtOAc=1:0 to 5:1) to give the 5,6-dichloro-2-(3-(1-hydroxycyclopropyl)propoxy)nicotinamide (0.72 g, 73%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.65 (s, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 5.48 (s, 1H), 4.82 (t, 2H, J=6.4 Hz), 2.36 (m, 2H), 1.97 (m, 2H), 0.94 (t, 2H), 0.73 (t, 2H).
Reaction SMILES: C1(COC([S:8][CH:9]2[N:12]([C:13](=[C:18]([O:21]C(OCC3CC3)=O)[CH2:19][Br:20])[C:14]([O:16][CH3:17])=[O:15])[C:11](=[O:29])[CH:10]2[N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])=O)CC1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[SH:8][CH:9]1[N:12]([C:13](=[C:18]([OH:21])[CH2:19][Br:20])[C:14]([O:16][CH3:17])=[O:15])[C:11](=[O:29])[CH:10]1[N:30]1[C:31](=[O:40])[C:32]2=[CH:39][CH:38]=[CH:37][CH:36]=[C:33]2[C:34]1=[O:35]
Reactant: COC(=O)C(=C(CBr)OC(=O)OCC1CC1)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1SC(=O)OCC1CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(=C(O)CBr)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of methyl α-[4-cyclopropylmethoxycarbonylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-(2-bromo-1-cyclopropylmethoxycarbonyloxyethylidene)-acetate (500 mg) in methylene chloride (20 ml) is added aluminum chloride (510 mg) at once and the mixture is stirred at room temperature. After 1 hour, the mixture is poured into cold 3% hydrochloric acid (20 ml), and extracted with methylene chloride. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give methyl α-[4-mercapto-3-phthalimido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)-acetate (252 mg). Yield: 72.5%. IR: νmaxCHCl3 1790, 1783, 1728, 1670, 1620 cm-1. NMR: δCDCl3 1.80d(11 Hz)1H, 3.87s3H, 4.22+4.56AB2(10 Hz)2H, 5.38dd (11; 5 Hz)1H, 5.70d(5 Hz)1H, 7.76m4H, 12.3s1H.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>CCO.C(Cl)(Cl)Cl>[CH2:12]([NH:19][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[OH:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: OC(CNCc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a cooled (0° C.) suspension of 2-bromo-1-(4-bromophenyl)ethanone (40.24 g; 0.14 mol) in EtOH (500 mL) and CHCl3 (100 mL) was added benzylamine (63 mL; 0.58 mol). After 30 minutes the ice-bath was removed and the mixture stirred for another 2 hours at RT. Subsequently the reaction mixture was cooled again to 0° C. and NaBH4 (6.26 g; 165.5 mmol) was added in small portions. The resulting mixture was stirred at 0° C. for 1 hour and thereafter another 4 hours at RT. The reaction mixture was quenched with 1M aqueous HCl (750 mL) at 0° C. and stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 1M aqueous NaOH. The organic layer was dried (Na2SO4), filtered, concentrated in vacuo. The residue was crystallized from tert-butyl methyl ether/heptanes to afford 2-benzylamino-1-(4-bromo-phenyl)-ethanol (18.8 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:16]2[N:15]3[CH2:17][N:18]=[C:19]([CH3:20])[C:14]3=[CH:13][C:12]3[CH:21]=[N:22][CH:23]=[N:24][C:11]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>CCO>[CH3:20][C:19]1[C:14]2=[CH:13][C:12]3[CH:21]=[N:22][CH:23]=[N:24][C:11]=3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:16]=3[N:15]2[CH2:17][N:18]=1
Reactant: CCOC(=O)c1cccc2c1N1CN=C(C)C1=Cc1cncnc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1=NCN2C1=Cc1cncnc1-c1cccc(C(=O)O)c12
Temperature: 0 °C
Yield: 75.3 %

Procedure:
To a solution of 6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester (1.6 g, 5 mmol) in EtOH (20 mL) was added sodium hydroxide (0.22 g, 5.5 mmol) and water (3.5 mL) and the resulting mixture was heated under reflux for 20 min. The mixture was then cooled to 0° C. and then hydrochloric acid (4 N, 1.32 mL) was added and the mixture was cooled in an ice-bath for 1 h. A solid formed and was filtered off and then dried under vacuum to leave the product (1.1 g, 77%) as off-white crystals, mp 285-287° C., m/z 292 (M).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8](N(OC)C)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:8]([C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)=[O:9])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)c1nccnc1Cl
Reactant: Br[Mg]c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-N-methoxy-N-methylpyrazine-2-carboxamide (2.05 g) in THF (50 mL) was added dropwise [4-(benzyloxy)phenyl]magnesium bromide in THF (12 mL) at 0° C. After stirring at 0° C. for 2 h, the mixture was quenched with water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (2.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH2:11][C:12](O)([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=3)[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 93.6 %

Procedure:
A mixture of 2-(3-chloro-4-methylphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole from Step 2 (725 mg, 1.7 mmol) and p-toluenesulfonic acid monohydrate (150 mg) in toluene (40 mL) was heated to reflux for 48 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture (860 mg) was chromatographed on silica gel using toluene/ethyl acetate 1/1 to give pure 2-(3-chloro-4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole (660 mg, 95%) as a white solid: mp(DSC) 206° C. Anal. Calc'd. for C18H14N2SO2F3Cl: C, 52.12, H, 3.40, N, 6.75, S, 7.73. Found: C, 52.24, H, 3.45, N, 6.64, S, 7.83.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[Cl:10][C:4]1[CH:3]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH2:11][CH3:12])[CH:19]=2)[CH:8]=[C:7]([Cl:9])[C:5]=1[NH2:6]
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1cccc(-c2cc(Cl)c(N)c(Cl)c2)c1
Yield: 88.6 %

Procedure:
The title compound (0.550 g) was prepared from 4-Bromo-2,6-dichloroaniline (0.5 g, 2.2 mmol) and 3-ethoxyphenylboronic acid (0.447 g, 2.7 mmol) as a yellow liquid which was about 70% pure as adjudged by 1H-NMR data. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.56 (s, 2H), 7.28 (s, 1H), 7.16-7.08 (m, 2H), 6.83 (dd, J 2, 8.1, 1H), 5.62 (s, 2H), 4.10 (q, J 7, 2H), 1.32 (t, J 7, 3H).
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:22].[F:40][C:41]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][C:42]=1[C:43](O)=[O:44]>>[F:40][C:41]1[CH:49]=[CH:48][C:47]([C:50]([F:51])([F:52])[F:53])=[CH:46][C:42]=1[C:43]([NH:19][CH2:20][C:21](=[O:22])[NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:44]
Reactant: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1F)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the EDCI coupling of 2-amino-N-[1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-acetamide TFA salt (as prepared in the previous step) and 2-fluoro-5-trifluoromethyl-benzoic acid (Aldrich) using the procedure described in Step F of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13](=[O:15])[NH:14][C:7]=23)[CH:3]=1)=[O:27])([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: CC(C)(C)c1cccc(C(=O)Cl)c1
Product: CC(C)(C)c1cccc(C(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)[nH]c34)c2)c1
Yield: 54 %

Procedure:
Method H was used Method H was used with 7-(3-Aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-tert-butylbenzoyl chloride to afford the title compound as a light pink solid (90 mg, 54%). 1H-NMR (δ, ppm, DMSO-d6): 1.32 (s, 9H, tBu), 6.49 (d, 1H, HPy,5, J=5.9 Hz), 6.91 (d, 1H, Harom, J=6.7 Hz), 7.41-7.46 (m, 2H, Harom), 7.62-7.66 (m, 3H, Harom), 7.75 (d, 1H, Harom, J=7.6 Hz), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 7.89 (s, 1H, Harom,), 10.35 (s, 1H, NHamide), 11.26 (s, 1H, NHurea), 11.44 (s, 1H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 30.98 (C(CH3)3), 34.55 (C(CH3)3), 106.41, 110.83, 113.60, 114.40, 116.31, 124.30, 124.78, 128.09, 128.67, 130.11, 134.42, 140.84, 141.31, 144.67, 147.06, 150.90, 154.17, 154.58, 166.06. HRMS (EI): m/z [M+H] calculated for C23H22N4O3: 403.1765; found: 403.1762.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9]C(C#N)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:2].CC[O:16][C:17]([CH3:19])=[O:18]>S(=O)(=O)(O)O.O>[CH:1]([C:3]1[CH:10]=[CH:9][C:19]([C:17]([OH:16])=[O:18])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:2]
Reactant: N#Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
A mixture of 4-formyl-2-nitrobenzonitrile (150 mg, 0.85 mmol) in conc. sulfuric acid (2 mL) and water (4 mL) was heated at 100° C. for 13 hours. Followed standard aqueous/EtOAc workup to give Intermediate 73.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][N:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH:33]=O)=[C:28]([O:35][CH3:36])[CH:27]=2)[CH:23]=[N:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C1[N:42]=[CH:43][C:44]2[CH:50]=[CH:49][N:48]=[C:47]([NH:51][CH:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[C:45]=2[N:46]=1)(=O)=O>>[CH3:36][O:35][C:28]1[CH:27]=[C:26]([C:24]2[CH:23]=[N:22][N:21]([CH2:20][CH2:19][OH:18])[CH:25]=2)[CH:31]=[CH:30][C:29]=1[NH:32][C:33]1[N:42]=[CH:43][C:44]2[CH:50]=[CH:49][N:48]=[C:47]([NH:51][CH:52]3[CH2:53][CH2:54][O:55][CH2:56][CH2:57]3)[C:45]=2[N:46]=1
Reactant: COc1cc(-c2cnn(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)ccc1NC=O
Reactant: CS(=O)(=O)c1ncc2ccnc(NC3CCOCC3)c2n1
Product: COc1cc(-c2cnn(CCO)c2)ccc1Nc1ncc2ccnc(NC3CCOCC3)c2n1

Procedure:
The title compound was prepared according to Example 43 using N-(4-(1-(2-(tert-butyldiphenylsilyloxy)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide (Preparation 67) and 2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 45). The intermediate silyl ether was purified using silica gel column chromatography eluting with 0 to 55% EtOAc in cyclohexane and the title compound was purified using silica gel column chromatography eluting with 0 to 5% MeOH in EtOAc (6 mg, 85%).