Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:40])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:39])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](\[CH3:38])/[CH:22]=[CH:23]/[CH:24]=[C:25](\[CH3:37])/[CH:26]=[CH:27]/[C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32]C[CH2:30][C:29]=1C.Cl([O-])(=O)=[O:42].[Na+].[C:46]([OH:49])(=O)[CH3:47]>C(Cl)(Cl)Cl.O.II>[CH3:1][C:2]1[C:7](=[O:42])[CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:40])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:39])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](\[CH3:38])/[CH:22]=[CH:23]/[CH:24]=[C:25](\[CH3:37])/[CH:26]=[CH:27]/[C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:47][C:46](=[O:49])[C:29]=1[CH3:30]
Reactant: CC(=O)O
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Reactant: [O-][Cl+2]([O-])[O-]
Agent: II
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)CCC2(C)C)C(C)(C)CCC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
10 g of β-carotene are dissolved in 500 ml of chloroform under a nitrogen atmosphere, and 60 g of sodium chlorate in 80 ml of water are added. The pH of the aqueous phase was brought to 3-4 with glacial acetic acid. 200 mg of iodine, dissolved in 100 ml of chloroform, are then added and the mixture is stirred for 20 hours at 25° C. The organic phase is then washed with four 200 ml portions of water and is dried, and the solvent is stripped off under reduced pressure. 500 ml of ethanol are added to the oily residue and the mixture is left to stand for 25 hours at -10° C. 8.2 g of crude canthaxanthin of 80.5% purity are obtained by filtration. Yield, 78.5%.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)[N:17]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl>[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37]([N:39]1[CH2:40][CH2:41][N:42]([C:27]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:18]3[N:17]=[C:16]([C:13]4[CH:14]=[CH:15][C:10]([S:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)(=[O:9])=[O:8])=[CH:11][CH:12]=4)[CH:21]=[CH:20][N:19]=3)=[CH:31][CH:30]=2)=[O:28])[CH2:43][CH2:44]1)=[O:38]
Reactant: O=C(O)c1ccc(Nc2nccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)n2)cc1
Reactant: O=C(c1ccco1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1ccc(Nc2nccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)n2)cc1)N1CCN(C(=O)c2ccco2)CC1
Reaction time: 12 h
Yield: 51.5 %

Procedure:
4-{4-[4-(Morpholine-4-sulfonyl)-phenyl]-pyrimidin-2-ylamino}-benzoic acid (0.25 g, 0.57 mmol) was dissolved in THF (5 mL). To this solution was added 1-furoylpiperazine (0.123 g), EDCI (0.131 g), and HOBt (0.092 g). The mixture was stirred 12 h. The mixture was then diluted with CH2Cl2 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude solid was subjected to preparatory HPLC (20-70 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na2SO4), filtered, and concentrated to afford [4-(furan-2-carbonyl)piperazin-1-yl](4-{4-[4-(morpholine-4-sulfonyl)-phenyl]pyrimidin-2-ylamino}phenyl)methanone (0.177 g, 52%): HPLC Retention Time; 9.62 min. (Method B) M+H=603.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][NH2:37])[CH:32]=[CH:33][CH:34]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH:37][CH2:36][CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=2)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCC(=O)O)cc1OC
Reactant: Cc1cccc(CCN)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)NCCc2cccc(C)c2)cc1OC
Reaction time: 0.83 h
Yield: 87.4 %

Procedure:
A solution of 3-(3,4-dimethoxyphenyl) propionic acid (21 g, 0.10 mol) and 16.4 g (0.101 mol) of carbonyldiimidazole in dry THF was stirred for 1 h in a flask protected from moisture. To this solution was added 2-(3-methylphenyl)ethylamine (14.2 g, 0.105 mol) and stirring was continued for 50 min. The solvent was evaporated and the residue was triturated with water and collected by filtration. The crude amide was recrystallized from methanol-water to give 28.6 g (88%) of the title compound mp 100-103°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:22])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(N)CO
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 57 %

Procedure:
As described for example 10b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (94 mg, 0.29 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (65 mg, 57%) which was obtained as a white solid. MS: m/e=400.3 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([F:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)(=O)=O)=CC=1.[C:28]12([CH2:38][NH2:39])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>CS(C)=O.C(OCC)(=O)C.CCCCCC>[C:28]12([CH2:38][NH:39][CH2:11][CH:12]3[O:26][C:16]4=[C:17]5[C:21](=[C:22]([F:24])[CH:23]=[C:15]4[O:14][CH2:13]3)[NH:20][C:19](=[O:25])[CH2:18]5)[CH2:35][CH:34]3[CH2:33][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH2:29]1)[CH2:37]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(F)c4c(c3O2)CC(=O)N4)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: O=C1Cc2c(c(F)cc3c2OC(CNCC24CC5CC(CC(C5)C2)C4)CO3)N1
Temperature: 85 °C
Yield: 72.5 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-6-fluoro-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.0 g, 2.5 mmole) and 1-adamantylmethylamine (1.6 g, 10 mmole) were combined in 30 ml of dry DMSO and heated at 80-90° C. for 4 hours under an argon atmosphere. After cooling to room temperature, the mixture was diluted with 500 ml of 1:1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate and with two 250 ml portions of water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel using 0.5% methanol/CHCl3 as eluant to give 0.70 g of the free base of the title compound as a colorless oil. This was crystallized from ethanol with the addition 4 N isopropanolic HCl to give 0.54 g of the (S) enantiomer of the title compound as a fluffy white solid hydrochloride, m.p.>260° C.
Reaction SMILES: C(OCC)(C(C(C(F)(F)F)(F)F)(F)F)(F)F.C([C:19](C(F)=O)([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])C.C(OC=C)=C.C(N(CC)CC)C>COCCOCCOC>[C:20]([CH2:19][C:24]([F:27])([F:26])[F:25])([F:23])([F:22])[F:21]
Reactant: CCC(C(=O)F)(C(F)(F)F)C(F)(F)F
Agent: C=COC=C
Agent: CCOC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: FC(F)(F)CC(F)(F)F

Procedure:
Using essentially the procedure as in Example 1, a mixture of perfluorobutyric acid fluorides (3.77 g with acyl fluoride content of 81%, 14 mmol), KF (1.02 g ,17 mmol), the ethoxyisobutene (4.56 g with purity 88%, 0.18 mmol) in 8.33 g diglyme was agitated at room temperature for four days. The reactor was vented to yield 0.67 g liquid which comprised (GC %): 88% starting acyl fluorides mixture and 8% C4F9OC2H5. The reaction solution remaining in the reactor was vacuum distilled to yield 3.0 g of a mixture which comprised (GC %): 75% C4F9OC2H5, 1.5% C2H5C(CF3)2C(O)F and 7.6% starting vinyl ether. After decarboxylation by treatment with triethylamine, the remaining diglyme solution yielded 1.45 g CF3CH2CF3 (purity 98% contaminated with 1.5% C4F9OC2H5 and 0.5% (CF3)CC2H5C(O)F). Triethylamine recovery gave 2.5 g organic liquid material with b.p. up to 101° C., consisting of (GC %): 2.5% CF3CH2CF3, 42% triethylamine, 9% starting vinyl ether and 29% diglyme. Calculated yields were: C4F9OC2H5, 72% on the consumed acid fluoride mixture, CF3CH2CF3, 75% on consumed vinyl ether.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]O)[N:6]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[N:26][CH:25]=[C:24](Cl)[N:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[OH-].[K+].C1OCCOCCOCCOCCOCC[O:33]C1>C1(C)C=CC=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[N:26][CH:25]=[C:24]([O:33][CH2:1][C:2]3[S:3][CH:4]=[C:5]([CH3:7])[N:6]=3)[N:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Reactant: Cc1nc(CO)cs1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1csc(COc2cncc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Temperature: 25 °C

Procedure:
(2-Methyl-thiazol-4-yl)-methanol I-3t (155 mg, 1.2 mmol) was dissolved in dry toluene (5 mL) under dry nitrogen and 6′-chloro-2,3,5,6-tetrahydro-[1,2′]-bipyrazinyl-4-carboxylic acid tert-butyl ester (I-1a) (299 mg, 1.00 mmol), powdered KOH (191 mg, 3.4 mmol), and 18-crown-6 (13.2 mg, 50 μmol) were added with stirring. The mixture was heated at reflux with vigorous stirring. The mixture was stirred at reflux for 3 h then cooled to room temperature. The toluene was removed in vacuo. The residue was purified by preparative thin layer chromatography (10% methanol/90% CH2Cl2) to give the title compound I-3u as a viscous amber oil (375 mg, 96% yield).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[C:13]([CH3:20])[CH:12]=1>O1CCOCC1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1]2)=[O:19])=[C:13]([CH3:20])[CH:12]=1
Reactant: Cc1cc(Cl)ccc1N=C=O
Reactant: c1ccc2c(c1)CNC2
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1NC(=O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of isoindoline (238 mg, 2.0 mmol) in dry 1,4-dioxane (10 mL) was added 4-chloro-2-methylphenyl isocyanate (335 mg, 2.0 mmol) under argon at room temperature. The reaction mixture was then stirred at RT overnight. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization from ethanol to give the title compound (540 mg, 94%) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 2.24 (s, 2H), 4.76 (s, 4H), 7.20 (dd, J=2.5, 8.5 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.30-7.32 (m, 2H), 7.34-7.37 (m, 2H), 7.42 (d, J=8.5 Hz, 1H), 7.84 (s, 1H); 13C NMR (DMSO-d6): δ 17.7, 51.9, 122.8, 125.6, 126.8, 127.3, 128.1, 129.5, 134.7, 136.8, 154.2; MS(MH+, 287); EA calc'd for C16H15ClN2O: C, 67.02; H, 5.27; N, 9.77; Found C, 66.82; H, 5.41; N, 9.92.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:17]([CH:18]=[CH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH2:16][CH2:15][C:10]21OCC[O:11]2>Cl>[O:21]=[C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:19]=[CH:18][CH:17]1[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[C:10](=[O:11])[CH2:15][CH2:16]1
Reactant: O=C(C=CC1CCC2(OCCO2)C1CCCCCCCO)c1ccccc1
Agent: Cl
Product: O=C(C=CC1CCC(=O)C1CCCCCCCO)c1ccccc1
Reaction time: 1 h
Yield: 18.1 %

Procedure:
A suspension of 6-(7-hydroxyheptyl)-7-(3-phenyl-3-oxoprop-1-enyl)-1,4-dioxaspiro[4,4]nonane [1.0 g; prepared as hereinafter described in Example 9(ii)] at dilute hydrochloric acid (2N; 30 ml.) was stirred in 60°-65° C. for 1 hour. The mixture was extracted with diethyl ether and then the combined ethereal extracts were washed with aqueous sodium bicarbonate solution (10% w/v) and then with water, and then dried over anhydrous magnesium sulphate. The solution was evaporated and the residue was purified by preparative thin layer chromatography on silica gel, using a mixture of diethyl ether, n-hexane and ethyl acetate (2:1:1 by volume) as eluant, to give 7-[5-(3-oxo-3-phenylprop-1-enyl)-2-oxocyclopentyl]heptanol (0.16 g.), in the form of a yellow oil. [Elemental analysis: Found: C, 76.9; H, 8.9%; C21H28O5 requires C, 76.8; H, 8.6%, νmax 990 cm-1, 1620 cm-1, 1665 cm-1, 3400 cm-1. N.M.R. (approximately 10% w/v solution in deuterochloroform): triplet at 3.6δ (J = 6 cycles/second), multiplets at 7.85-8.05δ, 7.4-7.65δ, 6.85-7.15δ, 2-2.9δ and 1.1-2.0δ].
Reaction SMILES: C[O-:2].[Na+].[Cl:4][C:5]1[C:15]([Cl:16])=[C:14]([C:17](=O)[CH2:18][CH2:19]N(C)C)[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10].[C:24](OCC)(=O)[CH2:25][C:26](C)=O>C(O)C>[Cl:4][C:5]1[C:15]([Cl:16])=[C:14]([C:17]2[CH2:26][CH2:25][CH2:24][C:19](=[O:2])[CH:18]=2)[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CN(C)CCC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: C[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)COc1ccc(C2=CC(=O)CCC2)c(Cl)c1Cl

Procedure:
To a stirred solution of sodium methoxide (0.5 g, 0.009 moles) in ethanol (40 ml) and ethyl acetoacetate (0.9 ml) was added [2,3-dichloro-4-(3-dimethylamino-1-oxopropyl)phenoxy]acetic acid (0.95 g, 0.0027 mole). The reaction mixture was heated at reflux for 21/2 hours then the solvent was distilled at reduced pressure. The residue was dissolved in water, acidified with hydrochloric acid, extracted with ether, washed with water, dried over magnesium sulfate and evaporated at reduced pressure to give 50 mg of [2,3-dichloro-4-(3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid which melted at 197°-198° C. after purification by thin layer chromatography on silica gel (CH2Cl2 :THF:methanol; 50:1:1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([CH:31]([CH3:33])[CH3:30])[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccn1)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)=O
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccn2)CC1
Yield: 69.7 %

Procedure:
Using alkylation method A, 3-chloro-N-[1-(2-pyridinyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (170 mg, 0.41 mmol) and acetone (1.2 mL, 16.8 mmol) afforded 130 mg (70%) of the title compound.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.C([Sn](Cl)(Cl)CCCC)CCC.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C1([SiH3])C=CC=CC=1>COCCOC.CO.O>[O:34]1[CH2:35][CH2:36][N:31]([CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=3)[CH2:3]2)[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(=O)C2)cc1
Reactant: C1COCCN1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(N3CCOCC3)C2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A mixture of ketone 267 (0.40 g, 1.53 mmol), dibutyltin dichloride (0.35 g) and morpholine (0.27 mL) in ethyleneglycol dimethylether (3.5 mL) was stirred at room temperature for 6 h, then cooled to 0° C. for the addition of neat phenyl silane (0.60 mL, 4.72 mmol). The reaction mixture was stirred at room temperature for 18 h then diluted with MeOH (3 mL) and H2O (0.5 mL), stirred for additional 4 h and concentrated. The residue was purified by flash chromatography (eluent: 5% MeOH in DCM) to provide title compound 268 (0.56 g, >100% yield, crude, used without additional purification).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[CH2:44][OH:45].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22]([N:39]3[CH2:43][CH2:42][CH2:41][C@H:40]3[CH2:44][OH:45])=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@H]3CO)c2C1)Cc1cc(F)c(F)cc1F
Yield: 116.9 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), (S)-pyrrolidin-2-ylmethanol (54.62 mg, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 10 mL of dichloromethane under stirring, and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.14 g, 0.54 mmol) was then added to the solution. The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-((S)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 30a (0.2 g) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:17](=[O:18])[N:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)[C:15]([CH2:34][CH2:35][CH3:36])=[N:14][C:13]=3[CH3:37])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl.[NH2:39]O.[C:41](=[O:44])([O-])[OH:42].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:17](=[O:18])[N:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]5[NH:39][C:41](=[O:44])[O:42][N:33]=5)=[CH:22][CH:21]=4)[C:15]([CH2:34][CH2:35][CH3:36])=[N:14][C:13]=3[CH3:37])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: NO
Reactant: CCCc1nc(C)c(-c2ccc(OCC3CC3)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)c(-c2ccc(OCC3CC3)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
4′-{[5-[4-(Cyclopropylmethoxy)phenyl]-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.56 g) was dissolved in dimethyl sulfoxide (5 mL), and hydroxylamine hydrochloride (0.79 g) and sodium hydrogen carbonate (1.2 g) were added. The mixture was stirred overnight at 90° C. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.28 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added. After stirring for 30 min, the reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 78%).
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:33]([CH2:35][C:36]([NH2:38])=[O:37])#[N:34].C(O)(=O)C.N1CCCCC1>C(O)C>[C:33]([C:35](=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([NH:16][C:13]2[N:14]=[C:15]3[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]3=[N:11][CH:12]=2)=[CH:18][CH:19]=1)[C:36]([NH2:38])=[O:37])#[N:34]
Reactant: N#CCC(N)=O
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(N)=O)cc3)nc12
Yield: 96.4 %

Procedure:
To a 50 ml three necked round bottom flask 4-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.25 g, 0.0005 mole) and 2-cyanoacetamide (0.094 g, 0.0011 mole) was taken in ethanol (20 ml). To this reaction mixture, piperidine acetate (3.3 M solution in water) (1.0 ml) was added drop wise at RT. After completion of the addition, reaction mixture was refluxed for 2 hr. After completion of the reaction, the ethanol was distilled out and water was added to residue. The aq. layer was extracted with ethyl acetate, the organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was purified by triturated with n-pentane, pentane layer was decanted and solid was dried under vacuum to yield 0.25 g of 2-cyano-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:10]=1[Cl:11])=[O:5])C.[OH-].[Li+]>CO.O>[Cl:11][C:10]1[N:9]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(CCOCCOC)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOCCn1ncc(C(=O)O)c1Cl
Yield: 86 %

Procedure:
To a solution of 5-chloro-1-[2-(2-methoxyethoxy)-ethyl]-1H-pyrazole-4-carboxylic acid ethyl ester (3.43 g, 12.39 mmol) in methanol (12 mL) and water (12 mL) was added lithium hydroxide (415 mg, 17.3 mmol). The reaction mixture was stirred at reflux for 3 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was then acidified carefully with 6.0 N aqueous HCl. The resulting mixture was extracted with methylene chloride (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 5-chloro-1-[2-(2-methoxyethoxy)-ethyl]-1H-pyrazole-4-carboxylic acid as a white solid (2.65 g, 86%). Mass spectrum: m/z: 249.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[N:1]2
Reactant: COc1ccc(C=O)cc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1ccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1
Yield: 44 %

Procedure:
5,7-Dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-methoxy benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 5,7-Dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one (106 mg, 44%) was isolated as an off-white solid. Selected data: MS (m/z): 312.99; MP 276-277° C.