Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[CH:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[OH-].[Na+].O1CCOCC1>O>[F:3][CH:2]([O:11][C:10]1[CH:5]=[C:6]([CH3:12])[CH:7]=[CH:8][CH:9]=1)[F:4]
Reactant: Cc1cccc(O)c1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(OC(F)F)c1
Temperature: 68 °C
Reaction time: 0.75 h
Yield: 64.5 %

Procedure:
260 parts by weight of chlorodifluoromethane are passed over 10 hours, whilst stirring, into a mixture of 221 parts by weight of m-cresol, 412 parts by weight of sodium hydroxide, 600 parts by volume of 1,4-dioxane and 500 parts by volume of water, at 67°-70° C. After stirring for 45 minutes at 68° C., the reaction mixture is cooled, diluted with 1,000 parts by volume of water and extracted four times with 200 parts by volume of diethyl ether. After drying, concentrating under reduced pressure and distilling, 209 parts by weight (yield: 64.5% of theory) of 3-tolyl difluoromethyl ether of boiling point 64°-67° C./24.7 mbar are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10][NH:11][C:12](=[O:18])[C:13](OCC)=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:9][C:3]1[C:2]2[N:1]=[C:13]([C:12](=[O:18])[NH:11][CH3:10])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(N)c1N
Reactant: CCOC(=O)C(=O)NC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1nc2c(C)cccc2[nH]1
Temperature: 175 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of 2,3-diaminotoluene (2.0 g) and ethyl N-methyloxamate (2.36 g) in N,N-dimethylformamide (10 ml) was stirred at 175° C. for 8 hours. After being cooled to ambient temperature, the mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. The organic layer was washed with brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (50:1) to give 4-methyl-2-(N-methylcarbamoyl)-1 H-benzimidazole (1.17 g) as a powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH2:12][CH2:13][OH:14])[CH3:2].N1C2C(=CC=CC=2)C(CCO)=C1.[C:27]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][C:27]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH2:12][CH2:13][O:14]1)=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:1][CH3:2])[CH3:40]
Reactant: CCc1cccc2c(CCO)c[nH]c12
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: OCCc1c[nH]c2ccccc12
Product: CCOC(=O)CC1(c2ccccc2)OCCc2c1[nH]c1c(CC)cccc21

Procedure:
Following the procedure of example 22.A. except using 2-(7-ethyl-1H-indol-3-yl)-ethanol as the 3-indolethanol component and ethyl benzoylacetate as ketone component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 10.05 (br, 1H), 7.42 (d, 1H), 7.28 (m, 5H), 7.12 (m, 2H), 3.96 (m, 3H), 3.60 (m, 1H), 3.43 (d, 1H), 3.22 (d, 1H), 3.05 (m, 3H), 2.65 (dd, 1H), 1.42 (d, 3H), 1.03 (t, 3H); ESI (−) MS m/e=362 (MH−).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)[CH3:20].O>CN(C)C=O>[C:2]([C:4]1[CH:12]=[CH:11][C:9]([O:10][CH2:25][CH2:24][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:27])=[C:6]([O:7][CH3:8])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(C)=O)cc1OC
Reaction time: 17.5 h
Yield: 98.1 %

Procedure:
Acetovanillone (16.6 g, 0.10 mol), potassium carbonate (30.0 g, 0.22 mol) and ethyl-4-bromobutyrate (17 mL, 0.12 mol) were combined in dimethylformamide (50 mL) and stirred under Argon for 17.5 h. The reaction was poured into water (800 mL) and stirred for 24 h. The product was isolated by filtration to yield ethyl 4-(4-ethanoyl-2-methoxyphenoxy)butanoate (27.5 g, 98%) as a white powder. 1H NMR (δ, ppm): 1.28 (t, CO2CH2CH3), 2.21 (p, ArOCH2CH2CH2), 2.56 (t, ArOCH2CH2CH2), 2.60 (s, ArCOCH3), 3.92 (s, ArOCH3), 4.13 (t, ArOCH2), 4.18 (q, CO2CH2), 6.92 (d, aromatic H ortho to ArOCH2), 7.54 (s, aromatic H ortho to ArOCH3), 7.58 (d, aromatic H ortho to ArCOCH3).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].Cl.O.[N:46]1([CH2:52][CH:53]=O)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C([BH3-])#N>CO>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH:23]2[CH2:27][CH2:26][N:25]([CH2:53][CH2:52][N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: O=CCN1CCOCC1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CC2CCNC2)cn1
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CC2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
A vial was charged with ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate (Example 239, 700 mg, 1.14 mmol), morpholin-4-yl-acetaldehyde monohydrate hydrochloride (260 mg, 1.39 mmol) and methanol (10 mL). MP-cyanoborohydride beads (730 mg, 1.71 mmol) were added and the resulting mixture was allowed to stir at room temperature overnight. The reaction went to completion based on LC. The mixture was filtered and the beads were washed with methanol. The filtrate was concentrated under reduced pressure and purified by Analogix SF15-24 g column eluting with dichloromethane/methanol system to give a light yellow solid (310 mg, 37.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A mixture of 3-fluoro-4-methoxyaniline (56.4 g; 400 mmol) and triethylamine (56 ml; 400 mmol) in dichloromethane (400 ml) is cooled down using an ice bath. Acetic anhydride (57 ml; 600 mmol) is added dropwise and the reaction mixture is agitated for 3 hours at ambient temperature. The reaction medium is then washed successively with water, with an aqueous solution of 10% sodium bicarbonate then with an aqueous solution saturated in sodium chloride. The organic fraction is dried over sodium sulphate and concentrated under reduced pressure. The residue is recrystallized from an ethyl acetate/pentane mixture in order to produce 66.5 g (91%) of a white solid, m.p. 120° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:3]1.CC[O:31]C(C)=O.[ClH:35]>CO>[OH2:31].[ClH:35].[CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:3]1
Reactant: CCOC(C)=O
Agent: CC1CC(c2ncc3ncc(-c4ccccc4)c-3[nH]2)CC(c2ccccc2)N1
Agent: Cl
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing (1,2-diphenylvinyl)pyrrolidine (freshly prepared before use) (1.83 g, 7.35 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.50 g, 7.35 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (1.3 mL, 7.35 mmol), piperidine (1.2 mL, 11.8 mmol), NEt3 (Aldrich Chemical Company) (2.0 mL) and SnCl2 (Aldrich Chemical Company) (22 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 110 mg (4%) of the free base as a pale yellow colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.65 (br s, 6), 2.42 (s, 3), 3.72 (br s, 4), 7.19 (m, 1), 7.28 (m, 2), 7.39-7.44 (m, 7), 11.20 (s, 1). MS m/z: 369 (M+1). To a solution of 2-methyl-6,7-diphenyl-4-piperidylpyrrolo[3,2-d]pyrimidine (148 g, 0.40 mmol) in 1:1 EtOAc:MeOH (50 mL) was added 1M etheral HCl (Aldrich Chemical Company) (400 mL, 0.40 mmol). The solvent was removed under reduced pressure and then dried under vacuum to give 83 mg (51%) of the title compound as a beige colored solid. Mp: 169-171° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.72 (br s, 6), 2.56 (s, 3), 4.06 (br s, 4), 7.29 (dd, 2, J=1.7, 6.0), 7.37-7.45 (m, 8), 12.26 (s, 1), 13.40 (s, 1). MS m/z: 369 (M+1). Anal. Calcd. for C24H24N4.HCl.H2O: C, 68.25; H, 6.40; N, 13.27; Cl, 8.29. Found C, 68.33; H, 6.41; N, 13.15; Cl, 8.50.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C1(C)C(C)=CC=CC=1>[CH:4]1[CH:5]=[CH:6][C:1]([C:7]([OH:8])([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:2][CH:3]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Solvent: Cc1ccccc1C
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Temperature: 170 °C
Reaction time: 17 h
Yield: 86 %

Procedure:
A 1.4 L hydrogenation shaker bomb was charged with 43.00 grams (0.165 moles) diphenyl-4-pyridylcarbinol, 8.00 grams 50% H2O wet 5% Pd on carbon (4 grams dry) and 350 ml xylene. The bomb was sealed, pressurized with 900 psi H2, and heated with shaking to 170° C. After 17 hours, the pressure was 1075 psi (at 170° C.) and the bomb was allowed to cool. The contents are poured out, heated to 70° C. and suction filtered carefully to remove the catalyst. GC analysis of the filtrate and washes at this point indicated 6.9% azacyclonol and 0.05% diphenyl-4-pyridylcarbinol. The filtrate was topped off on a rotary evaporator to a constant weight (42.65 grams). The sticky crude azacyclonol was removed and recrystallized from 200 ml heptane and 165 ml xylene. After chilling, filtration and over drying (2 hours, 100° C., 15 mm) a yield of 37.84 grams or 86.0% of azacyclonol was obtained, having a melting point of 163°-166° C.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:41][CH:42]3[CH2:45][CH2:44][CH2:43]3)=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=4[F:40])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:42]1([NH:41][C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[F:40])[CH2:27][CH2:26]2)[CH2:43][CH2:44][CH2:45]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CNCC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-benzyl-N-cyclobutyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (103.4 mg, 0.164 mmol) and Pd(OH)2 on carbon (10 mg, 0.014 mmol) in THF (818 μL) was stirred at rt under an atmosphere of hydrogen gas (balloon) for 4 h. The mixture was filtered through a pad of Celite™, washing with MeOH, and concentrated to afford the title compound as its TFA salt (89 mg, 100%) as a yellow solid. ESI-MS m/z [M+H]+ 428.4.
Reaction SMILES: ClC(OCC)=O.[N:7]1([CH2:12][C:13]([OH:15])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:16][N:17]1[C:26]2[C:25](=[O:27])[NH:24][C:23]3[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=3[NH:21][C:20]=2[C:19]([CH3:32])=[CH:18]1.[OH-].[Na+]>O1CCCC1>[CH3:16][N:17]1[C:26]2[C:25](=[O:27])[NH:24][C:23]3[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=3[N:21]([C:13](=[O:15])[CH2:12][N:7]3[CH2:8][CH2:9][CH2:10][CH2:11]3)[C:20]=2[C:19]([CH3:32])=[CH:18]1
Reactant: Cc1cn(C)c2c1Nc1ccccc1NC2=O
Reactant: O=C(O)CN1CCCC1
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cn(C)c2c1N(C(=O)CN1CCCC1)c1ccccc1NC2=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
1.1 g of ethyl chloroformate are added dropwise at 0° C. to a suspension of 1.29 g of pyrrolidin-1-ylacetic acid in 20 ml of tetrahydrofuran. 2.28 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one are added to the obtained suspension. The mixture is stirred 1 hour at 0° C. and a further 4 hours at room temperature. It is then poured onto 160 ml of 2 N sodium hydroxide solution and extracted with toluene. The organic phase is concentrated to dryness. The residue is chromatographed over a silica gel column by means of a mixture of dioxane/methanol (1:1) to yield 2.1 g of the title compound of m.p. 210° to 212° C. (from isopropanol).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([Cl:25])[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[N:6]3[C:7]4[C:12]([N:13]=[C:14]([CH3:15])[C:5]3=[C:4]([CH3:17])[N:3]=2)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=4)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(-c2cc(Cl)cc(Cl)c2)n2c1c(C)nc1ccc(F)cc12
Yield: 77.7 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 3,5-dichlorophenylboronic acid (58 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (70 mg, 78% yield). EIMS 360.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.Cl[C:9]1[N:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:9]2[N:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:2]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Oc1cccnc1
Product: N#Cc1cccnc1Oc1cccnc1

Procedure:
Pyridin-3-ol was treated with 2-chloronicotinonitrile and processed according to the method of Example 128B to provide the product. MS (ESI+) m/z 198 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.[CH3:30][C:31]([CH3:33])=[O:32]>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([C:31]([OH:32])([CH3:33])[CH3:30])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CC(C)=O
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C(C)(C)O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, acetone was added and the resulting mixture was stirred at −78° C. for 30 min. The dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound.1H NMR(CDCl3) d 7.17(s,2H), 6.08(s,1H), 3.73(d,1H), 3.33(m,1H), 2.19(s,3H), 2.15(s,3H), 2.12(s,6H), 1.4-1.7(m,4H), 1.26(s,6H), 0.96(t,6H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][CH2:20][CH:21]=[CH:22][CH2:23]Br.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:23][CH:22]=[CH:21][CH2:20][Br:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)OCc1ccccc1
Reactant: BrCC=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N(CC=CCBr)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of N-benzyloxycarbonylbenzylamine (50 g), 1,4-dibromo-2-butene (44 g) and NaH (10.7 g, 60% in oil) in 350 ml of DMF is stirred at 0° C. for 1 h and then at 25° C. for 3 h. The reaction mixture is subjected to aqueous workup and the residue obtained is purified by chromatography over SiO2. The title compound is obtained as an oil having characterization data as indicated below.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[C:7]([CH3:9])[CH:8]=1)=O.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.ClC(Cl)C.C([O-])(O)=O.[Na+]>[C:18]([N:21]1[CH2:26][CH2:25][N:24]([CH2:1][C:3]2[CH:4]=[C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[C:7]([CH3:9])[CH:8]=2)[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: Cc1cc(C=O)cc(NC(=O)OC(C)(C)C)c1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(Cc2cc(C)cc(NC(=O)OC(C)(C)C)c2)CC1

Procedure:
To a solution of tert-butyl 3-formyl-5-methylphenylcarbamate (200 mg, 0.85 mmol) and acetylpiperazine (131 mg, 1.02 mmol) in 0.1 mL HOAc and 4 mL dichloroethane was added NaBH(OAc)3 (216 mg, 1.02 mmol) at room temperature. After 2 hours additional acetylpiperazine (131 mg, 1.02 mmol) and NaBH(OAc)3 (216 mg, 1.02 mmol) were added. After 2 hours the mixture was diluted with saturated NaHCO3. The layers were separated and the aqueous extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (5% MeOH/CH2Cl2) gave tert-butyl 3-[(4-acetylpiperazin-1-yl)methyl]-5-methylphenylcarbamate as a white foam:
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[N:38]=[C:37]([O:39][CH3:40])[C:36](B(O)O)=[CH:35][N:34]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:36]4[C:37]([O:39][CH3:40])=[N:38][C:33]([O:32][CH3:31])=[N:34][CH:35]=4)=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[C:14]2[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=2)=[CH:24][C:25]=1[F:30]
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)c(F)c1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)c(F)c2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-3-fluoro-phenyl)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate AZ) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1.S(Cl)(Cl)=O>N1C=CC=CC=1.Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1)=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(OCc2ccccc2C(=O)O)cc(C(C)(C)C)c1
Reactant: Nc1nnn[nH]1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(OCc2ccccc2C(=O)Nc2nnn[nH]2)cc(C(C)(C)C)c1
Yield: 31.9 %

Procedure:
A solution of 3.40 g (0.01 mole) of 2-(3,5-di-t-butylphenoxymethyl)benzoic acid and 1.03 g (0.01 mole) of 5-aminotetrazole in 30 ml of pyridine was treated with a dropwise addition of 2.36 g (0.02 mole) of thionyl chloride. The resulting solution was stirred for forty minutes before being diluted with 300 ml of 5% hydrochloric acid to give a gum which slowly crystallized. The solid was collected, rinsed with water and recrystallized from aqueous dimethylformamide to give 1.3 g of white solid 2-(3,5-di-t-butylphenoxymethyl)-N-(tetrazol-5-yl)benzamide, m.p. 251°-254° C.. Analysis: Calculated for C23H29N5O2 : %C, 67.8; %H, 7.2; %N, 17.2; Found: %C, 67.7; %H, 7.1; %N, 17.2.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([O:5][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1

Procedure:
While cooling on ice, Boc-D-Pro-OH (17.2 g, 80 mmol) and benzyl bromide (14.3 ml, 120 mmol) were reacted in DMF (160 ml) in the presence of triethylamine (16.8 ml, 120 mmol) to obtain Boc-D-Pro-OBzl as an oily product. This product was reacted with 2 N HCl/dioxane (5 eq.) for 3 hours to obtain H-D-Pro-OBzl-HCl.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1.II>C(OCC)(=O)C>[C:9]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH:5]=[CH:6][O:1]1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1CCC=CO1
Agent: II
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1CCC=CO1
Temperature: 0 °C
Yield: 86 %

Procedure:
A mixture of (±)-3,4-dihydro-2H-pyran-2-methanol (514 g, 4.51 mol, 1 eq) and acetic anhydride (621 g, 6.09 mol, 1.35 eq) was cooled to 0° C. To the resultant mixture was added pyridine (35.6 g, 0.45 mol, 0.1 eq) and the resultant reaction mixture was allowed to warm to room temperature with stirring. The resultant reaction mixture was allowed to stir for an additional 8 hours after reaching room temperature and was shown to be complete by thin-layer chromatography (2:1 hexanes:ethyl acetate, I2 staining). The reaction mixture was concentrated in vacuo at 35° C. and the resultant residue was diluted using ethyl acetate (2 L). The resultant mixture was transferred to a separatory funnel and sequentially washed with deionized water (3×1 L), saturated aqueous NaHCO3 (2×10 L), and brine (1.0 L). The organic layer was dried over sodium sulfate and concentrated in vacuo at 35° C. to provide (±)-3,4-dihydro-2H-pyran-2-yl-methyl acetate as a clear liquid (605.9 g, 86% yield). 1H NMR (300 MHz, CDCl3) δ 1.6-2.2 (m, 4H), 2.1 (s, 3H), 4.2 (m, 3H), 4.8 (m, 1H), 6.4 (m, 1H).