Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13]1[N:17]([CH2:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:16](=[O:24])[CH:15]([CH2:25][C:26](O)=[O:27])[S:14]1.[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:42][CH2:41][C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[NH:38][C:37]2=[O:47])[CH2:32][CH2:31]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:29][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13]1[N:17]([CH2:18][CH2:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C:16](=[O:24])[C@H:15]([CH2:25][C:26]([N:30]2[CH2:31][CH2:32][CH:33]([N:36]3[CH2:42][CH2:41][C:40]4[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=4[NH:38][C:37]3=[O:47])[CH2:34][CH2:35]2)=[O:27])[S:14]1
Reactant: CN(C)CCNc1c(F)cccc1C1SC(CC(=O)O)C(=O)N1CCC(C)(C)C
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C)CCNc1c(F)cccc1C1S[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N1CCC(C)(C)C
Yield: 22.8 %

Procedure:
2-(2-(2-(2-(dimethylamino)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (125.5 mg, 0.295 mmol), 4,5-dihydro-3-(piperidin-4-yl)-1H-benzo[d][1,3]diazepin-2(3H)-one (144.7 mg, 0.5900 mmol), EDC (113.1 mg, 0.5900 mmol), and HOBt (90.35 mg, 0.5900 mmol) in DMF (6 mL) were stirred at RT overnight. The mixture was transferred to a separatory funnel with water, extracted with EtOAc (3×), the organic layers were combined, dried over Na2SO4 and concentrated to a brown oil. Crude product was purified by ISCO flash chromatography on a 12 g Redisep column eluting with 5-15% MeOH in CH2Cl2. Obtained 44 mg of desired 3-(1-(2-((5S)-2-(2-(2-(dimethylamino)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetyl)piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][S:18]([C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:23][N:22]=1)(=[O:20])=[O:19].[CH2:36](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[CH3:36][C:11]([CH3:12])([CH3:13])[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[N:22][C:21]([S:18]([CH3:17])(=[O:19])=[O:20])=[N:26][CH:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:16]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CS(=O)(=O)c1ncc(N2C[C@H]3CC[C@H](N)[C@H]3C2)cn1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3cnc(S(C)(=O)=O)nc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-L-neopentylglycine for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(2-(methylsulfonyl)pyrimidin-5-yl)octahydrocyclopenta[c]pyrrol-4-amine from Step A for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.34 (s, 2H), 7.79 (ddd, J=3.5, 1.7, 0.7, 1H), 7.10-6.93 (m, 1H), 4.52 (td, J=8.2, 4.7, 1H), 4.27 (qd, J=7.1, 5.4, 1H), 3.90 (d, J=11.1, 3H), 3.85 (dd, J=8.1, 3.9, 1H), 3.77 (dd, J=12.1, 7.6, 1H), 3.67 (dd, J=11.8, 7.9, 1H), 3.42 (dd, J=11.8, 4.1, 1H), 2.79-2.63 (m, 2H), 2.16-2.02 (m, 2H), 1.97-1.83 (m, 1H), 1.72 (dd, J=14.3, 8.0, 1H), 1.68-1.56 (m, 1H), 1.49 (s, 9H), 1.44-1.30 (m, 1H), 0.99 (s, 9H); MS (ESI+) m/z 510 (M+H)+.
Reaction SMILES: C(#N)C.[Br:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][OH:19])[C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9].S([O-])([O-])(=O)=O.[Na+].[Na+].[F:27][C:28]([F:36])(S(F)(=O)=O)C(O)=O>O>[Br:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][O:19][CH:28]([F:36])[F:27])[C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Br)c(C)c(CCCO)c1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Br)c(C)c(CCCOC(F)F)c1
Temperature: 50 °C

Procedure:
To an acetonitrile (0.6 M) suspension of methyl 3-bromo-5-(3-hydroxypropyl)-4-methylbenzoate (1 eq.) from the previous step and sodium sulfate (0.2 eq.) was added dropwise at 50° C. difluoro(fluorosulfonyl)acetic acid (1 eq.) over a period of 10 min. After the completion of addition, the reaction suspension was heated at 50° C. for another 16 h. The reaction mixture was then cooled to RT, poured into water and extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:12]C)[C:8]=1[CH2:9][CH2:10][CH3:11].B(Br)(Br)Br.O.[OH-].[Na+]>C(Cl)Cl>[C:16]1([CH:15]=[CH:14][C:5]2[CH:4]=[C:3]([OH:2])[C:8]([CH2:9][CH2:10][CH3:11])=[C:7]([OH:12])[CH:6]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCc1c(OC)cc(C=Cc2ccccc2)cc1OC
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCc1c(O)cc(C=Cc2ccccc2)cc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To the crude 1-(3,5-dimethoxy-4-1-propylphenyl)-2-phenylethene (18.07 g) in dry CH2Cl2 (100 mL) at −78° C. under N2 was added BBr3 (5.2 mL, 55 mmol) dropwise. After the reaction was stirred at −78° C. for 1 h, the temperature was allowed to rise to room temperature and the reaction mixture was stirred at room temperature for 2 days. Water was added to quench the reaction, followed by 20% NaOH to adjust pH>12. The organic layer was removed and the aqueous layer was washed with hexane (2×100 mL). The aqueous layer was acidified with 6N HCl to pH 1 and extracted with ether (3×200 mL). The organic layer was separated and washed with water (50 mL) and brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of ether gave a red syrup. Recrystallization with chloroform yielded pure stilbene product 20B (6.92 g) as a white crystal. The mother liquid was concentrated and the residue was recrystallized once more to afford an additional 2.5 g of 20B (total 9.42 g, 67.7% over two steps). 1HNMR (CDCl3, ppm): δ 1.38 (d, J=7.3 Hz, 6H), 3.46 (hept., J=7.3 Hz, 1H), 4.80 (s, 2H), 6.50 (s, 2H), 6.92 (d, J=17.2 Hz, 1H), 6.97 (d, J=17.2 Hz, 1H), 7.25 (m, 1H), 7.34 (m, 2H), 7.52 (m, 2H).
Reaction SMILES: C(OC([NH:8][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=O)(C)(C)C.CC1C=CC(S(O[C:30]2[C:39]3[CH2:38][CH2:37][CH2:36][C:35]4([CH2:43][CH2:42][CH2:41][CH2:40]4)[C:34]=3[N:33]=[C:32]([NH2:44])[N:31]=2)(=O)=O)=CC=1>>[NH2:8][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11][N:12]([C:30]2[C:39]3[CH2:38][CH2:37][CH2:36][C:35]4([CH2:43][CH2:42][CH2:41][CH2:40]4)[C:34]=3[N:33]=[C:32]([NH2:44])[N:31]=2)[CH2:13][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Product: COC(=O)C1(N)CCN(c2nc(N)nc3c2CCCC32CCCC2)CC1

Procedure:
The title product was prepared using the procedures outlined in Examples 1G and 1H, substituting methyl 4-(tert-butoxycarbonylamino)piperidine-4-carboxylate (CAS# 115655-44-2) for the product from Example 1D. 1H NMR (300 MHz, CDCl3) δ 4.50 (s, 2 H), 3.74 (s, 3 H), 3.30-3.36 (m, 4 H), 2.45 (t, J=4.58 Hz, 2 H), 2.04-2.21 (m, 4 H), 1.79-1.92 (m, J=4.07 Hz, 2 H), 1.49-1.73 (m, 10 H). MS (DCI+) m/z 360 (M+H).
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[F:28][C:29]([F:36])([F:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1.[F-].[K+].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([N:31]4[CH2:32][CH2:33][CH2:34][C@H:30]4[C:29]([F:36])([F:35])[F:28])=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: FC(F)(F)[C@@H]1CCCN1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
To a vial was added 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 350 mg, 0.79 mmol), (S)-2-(trifluoromethyl)pyrrolidine (purchased from Sigma Aldrich) (219 mg, 1.57 mmol), potassium fluoride (229 mg, 3.93 mmol), DMSO (2.4 mL), and N,N-diisopropylethylamine (0.69 mL, 3.93 mmol). The vial was sealed and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C25H26ClF3N6 [M+H]+ 503. found 503.
Reaction SMILES: I[C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[CH2:29]([OH:34])[CH2:30][CH2:31][C:32]#[CH:33].[Cl-].C(#N)C>C(N(CC)CC)C.[Cu]I>[OH:34][CH2:29][CH2:30][CH2:31][C:32]#[C:33][C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Reactant: C#CCCCO
Agent: [Cu]I
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCCO)n(Cc3cccc4ccccc34)cc21
Temperature: 25 °C

Procedure:
5-Iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1 H-pyrrolo-[3,4-d]pyrimidine-2,4(3 H,6 H)-dione (100 mg), 4-pentyn-1-ol(0.080 ml), bis-triphenylphosphinepalladium (II) chloride (3 mg) and copper (I) iodide (1 mg) were dissolved in triethylamine (3 ml) and acetonitrile (1 ml) and heated to 90° C. in a sealed pressure tube of 3 hours. The reaction mixture was allowed to cool to room temperature and was then evaporated to leave a residue which was recrystallised from ethyl acetate. The resultant brown solid was chromatographed, eluting with ethyl acetate to give a white solid which was triturated with ethyl acetate to give the title compound (45 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:11][O:12]C(Cl)Cl.FC1C=C(F)C=C(OC)C=1C=O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[C:7]=1[CH:11]=[O:12]
Reactant: COC(Cl)Cl
Reactant: COc1cc(F)cc(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: COc1cc(F)cc(F)c1C=O
Solvent: ClCCl
Product: COc1cc(F)c(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(Intermediates 26A and 26B were prepared in a similar manner to the preparation described in WO 2004046133). To a stirred solution of 3,5-difluoroanisole (1.0 g, 7.0 mmol) in dichloromethane (6 mL) at 0° C. was added dropwise titanium tetrachloride (1.23 mL, 11.2 mmol) and dichloromethyl methyl ether (0.63 mL, 7.0 mmol). Upon completion of addition, the reaction mixture was stirred for 1 h and then poured into ice-water (50 mL). The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organics were washed with H2O (50 mL), brine (50 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide a residue. The residue was subjected to chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes to give 2,6-difluoro-4-methoxybenzaldehyde, Intermediate 26A [less polar material, 230 mg, 19%, 1H NMR (400 MHz, CDCl3) δ ppm 3.85 (s, 3H), 6.47 (d, J=10.55 Hz, 2H), 10.17 (s, 1H)] and 2,4-difluoro-6-methoxybenzaldehyde, Intermediate 26B [more polar material, 740 mg, 62%, 1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3H) 6.43-6.51 (m, 2H) 10.30 (s, 1H)], both as white solids.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:13]=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:22]=1[C:23]([NH2:25])=[O:24].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([C:13]3[NH:25][C:23](=[O:24])[C:22]4[C:21](=[CH:29][C:28]([O:30][CH3:31])=[CH:27][C:26]=4[O:32][CH3:33])[N:20]=3)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc(C=O)cc(N2CCN(C(C)C)CC2)c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc(N2CCN(C(C)C)CC2)c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 79.1 %

Procedure:
To a solution of 3-(4-isopropylpiperazin-1-yl)-5-methoxybenzaldehyde (1.23 g, 4.68 mmol) in N,N-dimethylacetamide (20 mL) was added 2-amino-4,6-dimethoxybenzamide (0.59 g, 3.00 mmol), NaHSO3 (58.5 wt %, 0.87 g, 4.80 mmol) and p-toluenesulfonic acid monohydrate (1.82 g, 9.60 mmol). The reaction mixture was stirred at 120° C. for 20 h under nitrogen. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with saturated Na2CO3 solution to adjust the pH to 12. The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 86:10:4 dichloromethane/ethyl acetate/methanol followed by 86:10:4 dichloromethane/ethyl acetate/7 N NH3 in methanol) and prep. HPLC to give 2-(3-(4-isopropylpiperazin-1-yl)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (1.04 g, 50%) as a white solid: mp 212-213° C.; 1H NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 7.36 (s, 1H), 7.20 (s, 1H), 6.76 (d, J=2.34 Hz, 1H), 6.60 (t, J=1.95 Hz, 1H), 6.53 (d, J=1.95 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.22 (t, J=4.29 Hz, 4H), 2.68 (quin, J=6.54 Hz, 1H), 2.58 (t, J=4.68 Hz, 4H), 1.01 (d, J=6.63 Hz, 6H); ESI MS m/z 437 [M−H]−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:31])([F:30])[F:29])=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38]>C(Cl)Cl.CO.CCOCC>[ClH:38].[N:11]1([C:14]2[N:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:29])([F:30])[F:31])=[O:22])=[CH:18][N:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1cnc(N2CCNCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester from above was suspended in methylene chloride and methanol. To this mixture was added hydrogen chloride in ether (4N, 3 mL). The mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was dried in vacuum. The resulting solid was triturated with dry ether and then filtered to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-piperazin-1-yl-pyrimidin-5-yl)-amide hydrochloride salt. LC-MS calcd for C19H17F3N6O2 (m/e) 418.39, obsd 419.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39]CCC[CH2:35]1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:35][CH2:34][CH2:39][C:4]3[CH:3]=[CH:10][CH:9]=[CH:8][C:5]=3[CH3:6])[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Product: Cc1ccccc1CCCN1C[C@H]2CC[C@H](NC(=O)C(c3ccccc3)C(C)C)[C@H]2C1

Procedure:
The title compound was prepared by substituting 3-o-tolylpropanal for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.57 (dd, J=7.2, 14.2, 1H), 7.68-7.62 (m, 2H), 7.34 (t, J=7.5, 2H), 7.29-7.23 (m, 2H), 7.23-7.22 (m, 1H), 7.17 (dd, J=2.6, 3.9, 2H), 4.42-4.31 (m, 1H), 3.23 (d, J=10.4, 1H), 2.98 (dd, J=2.3, 8.8, 0.5H), 2.69-2.64 (m, 2H), 2.64-2.59 (m, 2H), 2.58-2.51 (m, 0.5H), 2.51-2.45 (m, 0.5H), 2.45-2.39 (m, 0.5H), 2.39-2.34 (m, 2H), 2.32 (dd, J=2.7, 8.9, 1H), 2.28 (s, 1.5H), 2.25 (s, 1.5H), 2.19 (d, J=8.1, 0.5H), 2.17-2.11 (m, 1.5H), 1.93-1.85 (m, 1H), 1.84-1.77 (m, 0.5H), 1.73 (dd, J=7.6, 15.1, 1H), 1.66 (dt, J=7.4, 9.4, 1.5H), 1.43 (dt, J=7.5, 13.8, 1H), 1.38-1.30 (m, 1H), 1.23 (dd, J=6.5, 12.1, 3H), 0.71 (dd, J=2.8, 6.7, 3H); MS (ESI+) m/z 419 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:25](O)=[O:26])#[N:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:52]([NH2:56])[CH:53]([CH3:55])[CH3:54].C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[CH2:52]([NH:56][C:25]([C:7]1[N:6]([CH2:5][CH2:4][CH2:3][C:1]#[N:2])[C:14]2[C:9]([CH:8]=1)=[CH:10][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:12][CH:13]=2)=[O:26])[CH:53]([CH3:55])[CH3:54]
Reactant: N#CCCCn1c(C(=O)O)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Reactant: CC(C)CN
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
1-(3-Cyanopropyl)-5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid (0.10 g, 0.25 mmol), from Example 2(a), was dissolved in dimethylformamide (15 mL). PyBroP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) (0.13 g, 0.27 mmol) was added followed by isobutylamine (0.054 g, 0.74 mmol), diisopropylethylamine (0.13 g, 0.99 mmol), and a catalytic amount of N,N-dimethylaminopyridine. The reaction mixture was stirred for 18 h under argon at ambient temperature. The solution was diluted with dichloromethane and washed with water (3X) and brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 30% ethyl acetate/hexanes) yielded a white solid (0.076 g, 67%). MS(ES) m/e 458.2 [M +H]+.
Reaction SMILES: [CH3:1][C:2]([N+:12]([O-])=O)([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CC[OH:17]>[Pd].CO>[C:7]([OH:10])(=[O:17])[CH3:8].[NH2:12][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CCO
Reactant: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(=O)O
Product: CC(C)(N)Cc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A one-gallon high-pressure reactor was charged with 4(2-methyl-2-nitropropyl)phenol (120 g, 614 mmol), HOAC (35.2 mL, 614 mmol), 5% Palladium on carbon (24 g) wetted with 2B3 EtOH (60 mL), and MeOH (1230 mL). The mixture was heated to 50° C. with agitation (600 rpm), and the reactor was purged with N2 and pressurized to 50 psi with H2. After 15.5 h the reactor was purged with N2, and the cooled mixture was filtered. The filter cake was washed with MeOH and the filtrate was concentrated to 514 g of slurry on a rotary evaporator. To this slurry was added EtOAc (2 L) with vigorous agitation. After stirring for 1 h, the resulting crystals were filtered and washed with a small amount of EtOAc. The product was dried overnight in a 45° C. vacuum oven to yield 118.83 g (86%) of product as small white needles (mp 211-216° C. dec). This material was 99% pure by HPLC analysis, and while another 9.00 g of material was obtained from the mother liquor it was found to be only 88% pure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=O)[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1.Cl.[NH2:30][OH:31]>>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[N:30][OH:31])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: COC1(c2cc(OCc3ccc4c(c3)OCCC4=O)nc(N)n2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2cc(OCc3ccc4c(c3)OCCC4=NO)nc(N)n2)CCOCC1
Yield: 79 %

Procedure:
Using an analogous procedure to that described in Example 43, 7-[2-amino-6-(4-methoxytetrahydropyran-4-yl)pyrimidin-4-yloxymethyl]chroman-4-one was reacted with hydroxylamine hydrochloride to give 7-[2-amino-6-(4-methoxytetrahydropyran-4-yl)pyrimidin-4-yloxymethyl]chroman-4-one oxime in 79% yield, m.p. 224°-228° C.;
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:15](CC#N)=[N:14][N:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:12](=[O:25])[C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1.Cl.[C:27]([OH:30])(=[O:29])[CH3:28]>>[Br:1][C:2]1[C:3]2[C:4]3[C:15]([CH2:28][C:27]([OH:30])=[O:29])=[N:14][N:13]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:12](=[O:25])[C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)O
Reactant: Cn1c2cccc(Br)c2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Agent: Cl
Product: Cn1c2cccc(Br)c2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21

Procedure:
A solution of 4.8 g (12.2 mmol) of 9-bromo-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetonitrile in a mixture of 190 ml of acetic acid and of 50 ml of concentrated hydrochloric acid is heated at reflux for 6 h. The solution is concentrated under reduced pressure and the residue is taken up in a mixture of dichloromethane and of water. Basification is carried out with 30% sodium hydroxide solution, separation is carried out by settling and extraction is carried out with dichloromethane. The aqueous phase is acidified with concentrated hydrochloric acid while cooling with an ice bath. The precipitate is collected by filtration, washed with water and dried under reduced pressure. 3.1 g (7.5 mmol) of solid are obtained.