Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[NH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH:26]([CH3:28])[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:26]([CH3:28])[CH3:27])[CH:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)I
Reactant: O=C(c1ccnc(Cl)c1)c1c[nH]c2ccncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)c2ccnc(Cl)c2)c2cnccc21
Reaction time: 18 h
Yield: 19.8 %

Procedure:
To a mixture of (2-chloropyridin-4-yl)-(1H-pyrrolo[3,2-c]pyridin-3-yl)methanone (Preparation 49, 34 g, 0.13 mol) in DMF (700 mL) was added Cs2CO3 (65 g, 0.2 mol) and 2-iodopropane (34 g, 0.2 mol) at room temperature and the reaction stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate from 10:1 to 1:1 to afford the title compound as a yellow solid (7.7 g, 23.6%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([OH:11])[CH2:7][C@H:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:4].[CH3:22][O:23][C:24]1[C:33]([CH3:34])=[C:32]2[C:27]([C:28](O)=[CH:29][C:30]([C:35]3[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=3)=[N:31]2)=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:28]2[C:27]3[C:32](=[C:33]([CH3:34])[C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[N:31]=[C:30]([C:35]3[S:36][CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[N:39]=3)[CH:29]=2)[CH2:7][C@H:6]1[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:4]
Reactant: COC(=O)[C@@H]1CC[C@@H](O)C[C@H]1C(=O)OCc1ccccc1
Reactant: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC[C@@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a stirred solution of compound 34d (2.18 g, 1.2 eq.), compound 203b (1.58 mg, 1 eq.), and PPh3-PS (polystyrene supported triphenylphosphine) (3.34 g, 2 eq.) in THF (50 mL) was added DIAD (2.1 mL, 2 eq.) under nitrogen. The reaction mixture was stirred at room temperature for 16 hrs. The mixture was filtered, and the filtrated was concentrated in vacuo and purified by chromatography on silica gel (DCM/MeOH) to yield compound 34e as a beige solid in 65% yield. MS (ESI, EI+): m/z=617 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][CH2:37][NH:38]3)=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][CH2:44][OH:45]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:18][CH:19]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:43][CH2:44][OH:45])=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC3CC3)cc2)[C@@H](OCc2ccc3c(c2)NCCC3)C1
Reactant: OCCCBr
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC3CC3)cc2)[C@@H](OCc2ccc3c(c2)N(CCCO)CCC3)C1

Procedure:
In analogy to the procedure described in example 4(a), the (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was reacted with 1-bromo-3-hydroxy-propane to yield the (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-[1-(3-hydroxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 609 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH3:36].CO>>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: N
Solvent: CO
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Temperature: 90 °C

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (196 mg, 0.364 mmol) and ammonia in methanol 7M (8 ml, 56.0 mmol) and heating to 90° C. for 24 h, the title compound, N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide was obtained (94 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1H), 7.93 (d, J=5.2 Hz, 1H), 7.55-7.70 (m, 1H), 7.35-7.43 (m, 1H), 7.31 (t, J=6.3 Hz, 1H), 7.14-7.27 (m, 3H), 6.70 (s, 2H), 5.79 (d, J=5.13 Hz, 1H), 1.35 (s, 9H). MS (ESI): 519.9 [M+H]+.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][C@@H:10]([CH2:15][O:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:11]([O:13][CH3:14])=[O:12].N1C=CN=C1>CN(C=O)C>[Si:5]([O:9][C@@H:10]([CH2:15][O:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:11]([O:13][CH3:14])=[O:12])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC[C@@H](C)OC[C@H](O)C(=O)OC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC[C@@H](C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Temperature: 40 °C
Reaction time: 5 h
Yield: 21.5 %

Procedure:
tert-Butylchlorodimethylsilane (7.09 g, 47.01 mmol) was added to (S)-methyl 2-hydroxy-3-((R)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y6) (7.53 g, 39.18 mmol) and 1H-imidazole (5.33 g, 78.35 mmol) in DMF (50 mL) at room temperature under nitrogen. The resulting solution was stirred at 40° C. for 5 hours. The reaction mixture was evaporated to dryness and re-dissolved in ethyl acetate (125 mL), and washed sequentially with water (50 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% ethyl acetate in isohexane to afford the product (2.58 g, 21.5%). 1H NMR (400 MHz, DMSO) δ −0.01 (d, 6H), 0.81 (s, 9H), 0.97 (d, 3H), 3.13-3.29 (m, 5H), 3.49-3.64 (m, 6H), 4.26-4.31 (m, 1H); m/z (ESI+) M-C4H9=249; GC tR=10.92 min.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[H-].[Na+].[C:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15](=[O:18])[CH2:16]Br)=[CH:13][CH:12]=1)#[N:10]>C1COCC1>[F:1][C:2]([F:6])([F:5])[CH2:3][S:4][CH2:16][C:15]([C:14]1[CH:19]=[CH:20][C:11]([C:9]#[N:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: FC(F)(F)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)CSCC(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of 2,2,2-trifluoroethanethiol (1.5 mL, 17.2 mmol) in anhydrous THF (28 mL) at 0° C. under nitrogen, add sodium hydride (629 mg, 15.7 mmol) and stir for 15 min. Then, add 4-cyanophenacyl bromide (3.2 g, 14.3 mmol) and stir at ambient temperature overnight. Quench with water and extract with EtOAc. Dry the combined organics extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (7:3) to obtain the desired intermediate (3.1 mg, 84%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[N:8][C:9]([NH2:12])=[N:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[CH:14]([C:17]1([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)[CH2:19][CH2:18]1)[CH:15]=O>C(O)(C)C>[N:1]1([C:6]2[CH:7]=[N:8][C:9]3[N:10]([C:14]([C:17]4([C:20]5[CH:21]=[C:22]6[C:27](=[CH:28][CH:29]=5)[N:26]=[CH:25][CH:24]=[CH:23]6)[CH2:19][CH2:18]4)=[CH:15][N:12]=3)[CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Nc1ncc(-n2cccn2)cn1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CC(C)O
Product: c1cnc2ccc(C3(c4cnc5ncc(-n6cccn6)cn45)CC3)cc2c1
Temperature: 90 °C

Procedure:
A mixture of 5-(1H-pyrazol-1-yl)pyrimidin-2-amine (0.08 g, 0.5 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.1 g, 0.5 mmol) in isopropanol (15 mL) was heated at 90° C. overnight. After cooling, the mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=353.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:21]([OH:23])=[O:22])=[C:7]2[C:11]=1[O:10][C:9]([CH:12]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:13])=[CH:8]2.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:22][C:21]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]3[O:10][C:9]([CH:12]([O:14][CH:15]4[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)[CH3:13])=[CH:8][C:7]=23)=[O:23])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: COc1ccc(C(=O)O)c2cc(C(C)OC3CCNCC3)oc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(C)OC3CCNCC3)oc12
Yield: 27.5 %

Procedure:
Prepared from 7-methoxy-2-(1-methyl-piperidin-4-yloxymethyl)-benzofuran-4-carboxylic acid (1.9 g), 4-nitrophenol (835 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15 g) and 4-dimethylaminopyridine (catalytic amount) in dichloromethane (40 ml). Purification by column chromatography eluting with 10% methanol in dichloromethane afforded the desired product as a pale yellow solid (720 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1.O>CN(C=O)C>[F:30][C:29]([F:31])([F:32])[CH:28]([CH3:33])[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:7]2[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=[CH:5][C:6]2=[O:9])=[CH:21][CH:20]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Reactant: CCOC(=O)C(c1ccc(CBr)cc1)C(C)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc(Cn2cc(C(F)(F)F)ccc2=O)cc1)C(C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
1.80 g (11.04 mmol) of 5-(trifluoromethyl)pyridin-2(1H)-one were initially charged in 2.5 ml of DMF, and 0.44 g (11.04 mmol, 60% pure) of sodium hydride was added. The mixture was stirred for 30 min, and 3.0 g (8.49 mmol) of ethyl 2-[4-(bromomethyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate were then added. After a further 2 h at RT, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 4:1). This gave 2.89 g (78.2% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17]O)=[CH:11][CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17][Br:48])=[CH:11][CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)NC1CCc2ccc(CCO)cc2C1Cc1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)NC1CCc2ccc(CCBr)cc2C1Cc1cccc(Cl)c1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of [1-(3-chloro-benzyl)-7-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]carbamic acid ethyl ester (554 mg, 1.428 mmol) in 15 ml dry CH2Cl2 cooled to 0° C. was added triphenylphosphine (562 mg, 2.142 mmol) and carbon tetrabromide (0.208 ml, 2.142 mmol). The mixture was stirred for 1 h, after which solvents were evaporated. The residue was purified by chromatography to obtain 277 mg of product as a white solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:12]=2[N:13]=[CH:14][N:15]=1>C(Cl)Cl>[Br:1][C:18]1[C:11]2[C:10]([Cl:9])=[N:15][CH:14]=[N:13][C:12]=2[N:16]([Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ncnc21
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2c(Cl)ncnc21
Yield: 71.3 %

Procedure:
N-Bromosuccinimide (60.3 g, 338 mmol) was added to a solution of 4-Chloro-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (100 g, 323 mmol) in CH2Cl2 (1 L). After 12 h 15 the reaction was quenched with saturated aqueous NaHCO3 (500 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (4×500 mL). The combined organic layers were filtered through silica gel and concentrated in vacuo. Purification by flash column chromatography (ethyl acetate/hexanes 1:99) afforded the title compound as a clear solid (89.5 g, 72%). MS: 388.8/390.8 (MH+); HPLC Rf: 9.84 min. (HPLC method 4).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Li]CCCC.[CH3:16][S:17]SC.CI>C1COCC1>[Cl:1][C:2]1[C:3]2[S:10][C:9]([S:17][CH3:16])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2ccsc12
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CSc1cc2ncnc(Cl)c2s1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 20 (shown in the scheme 4) (200 mg, 1.18 mmol) in THF (11 mL) was added n-BuLi (566 μL, 1.42 mmol, 2.5M in THF) very slowly at −78° C. and the mixture was stirred for 15 min at the same conditions. A solutions of dimethyl disulfide (160 uL, 1.77 mmol) and MeI (110 μL, 1.77 mmol) in THF (1 mL) was added drop wise. The reaction mixture was stirred for 2 h at −78° C., quenched with saturated aqueus NH4Cl solution, and extracted with DCM. The extract was dried over anhydrous Na2SO4 and concentrated to afford the title compound 280 (210 mg, 82% yield) as a yellowish solid. MS (m/z): 217.0(M+H) (found).
Reaction SMILES: C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=O)[CH2:31]1.[NH2:39][OH:40]>O1CCCC1>[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([NH:39][OH:40])=[O:38])[CH2:31]1
Reactant: COCOc1ccc(C2CCCC(C(=O)O)C2)c(OCOC)c1
Reactant: NO
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCOc1ccc(C2CCCC(C(=O)NO)C2)c(OCOC)c1
Reaction time: 0.5 h

Procedure:
Triethylamine (11 μl) and isobutylchloroformate (10 μl) were added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanecarboxylic acid in anhydrous tetrahydrofuran (2 ml) at 0° C. under argon. After 30 min, aqueous hydroxylamine solution (0.5 ml, 50 wt %) was added. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a solid (26 mg, quant.) and a mixture of diastereoisomers; m/z (ES+) 340 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.C[Si](C)(C)[O:15][C:16](O)(O)[CH2:17][CH2:18]O[Si](C)(C)C>C(Cl)Cl>[CH2:16]1[O:15][C:7]2([CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH2:8]2)[O:12][CH:17]1[CH3:18]
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: C[Si](C)(C)OCCC(O)(O)O[Si](C)(C)C
Solvent: ClCCl
Product: CC1COC2(CCc3cc(Br)ccc3C2)O1

Procedure:
The ketone group of the tetralone is first protected as a ketal. Preferably, ketalization is afforded by slowly adding 1,3-bis-trimethylsilyloxy propandiol to a solution of trifluromethanesulfonate in methylene chloride. Temperatures from about -70° C. to about -60° C. are employed using standard cooling procedures. For example, 6-bromo-2-tetralone is slowly added to a solution of 1,3-bis-trimethylsilyloxy propandiol and trifluromethanesulfonate in methylene chloride to yield 6-bromo-2-tetralone propylene ketal.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)[N:13]=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:11]=2)[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(NC3CC3)c3cc(N4CCCCC4)ccc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropylamine in step E. MS (ESI/CI): predicted mass C20H22N6O2, 378.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]4[N:13]=[C:12]3[CH2:22][CH3:23])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:26]1(=[O:36])[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>CN(C=O)C>[C:29]([C:28]1[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=1[C:26]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]4[N:13]=[C:12]3[CH2:22][CH3:23])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:36])([OH:31])=[O:30]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2C(=O)c2ccccc2C(=O)O)c1
Reaction time: 16 h
Yield: 46.9 %

Procedure:
To a solution of the product of Step A (75 mg, 0.25 mmol) in 3 mL of DMF was added 11 mg (0.27 mmol, 1.1 eq) of 60% NaH, followed by 45 mg (0.30 mmol, 1.2 eq) of phthalic anhydride. This mixture was stirred for 16 hours and the DMF removed in vacuo. The resultant oil was flash column chromatographed with 15% of (10/1) mixture of methanol/NH4OH in CHCl3 to yield the titled compound (53 mg, 47%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:21]1(=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][OH:3])=[CH:8][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOC(=O)COc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a cold (5° C.) solution of ethyl({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)acetate (190) (0.200 g, 0.53 mmol) in THF (10 mL) was added 1 M solution of LiAlH4 (1.3 mL, 2.5 mmol). The reaction mixture was stirred at that temperature for 0.5 h. Reaction mixture was quenched with EtOAc (5 mL) and stirred for an additional 10 min before pouring into 20% aqueous HCl (50 ml). The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organics washed with brine (1×25 ml), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using hexanes and EtOAc (4:1 to 3:2) as an eluent to afford 155 mg (86%) of compound 224 as a white solid. 1H NMR (300 MHz, CD3OD): δ 7.04 (d, J=8.7 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 4.03 (t, J=5.1 Hz, 2H), 3.86 (t, J=5.1 Hz, 2H), 2.32 (d, J=4.5 Hz, 4H), 1.60 (br s, 8H). LCMS (ESI): m/z 337 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([CH2:23][CH3:24])[C@H:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:14][NH:13][CH2:12]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:59]([C:61]1[CH:62]=[CH:63][C:64]([N:67]2[CH2:72][CH2:71][CH:70]([C:73](O)=[O:74])[CH2:69][CH2:68]2)=[N:65][CH:66]=1)#[N:60]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:14][N:13]([C:73]([CH:70]3[CH2:69][CH2:68][N:67]([C:64]4[CH:63]=[CH:62][C:61]([C:59]#[N:60])=[CH:66][N:65]=4)[CH2:72][CH2:71]3)=[O:74])[CH2:12]2)[CH2:23][CH3:24])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(F)cc1
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: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A mixture of 125 mg (0.36 mmol) ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid 4-fluoro-phenyl ester, 137 mg (0.36 mmol) HATU, 63 uL (0.36 mmol) DIPEA and 69.4 mg (0.3 mmol) 5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid in 4 mL DMF was shaken for 2 h at room temperature. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 106 mg (63%) of the title compound as off-white solid. MS m/e: 560.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH:15]=1>>[N:20]1([C:16]2[CH:15]=[C:14]([CH:13]3[C:3]4[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=4[NH:1][C:2]4[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]3=4)[CH:19]=[CH:18][CH:17]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: COC(OC)c1cccc(-n2ccnc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(-n2ccnc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-(1-imidazolyl)-benzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 gave 3,4,6,7,9,10-hexahydro-9-[3-(1-imidazolyl)-phenyl]-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from methanol/water gave a yellow crystalline solid of melting point 286-288° C.