Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C)C=O>[CH3:34][O:33][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH3:7])=[C:9]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:32]
Reactant: COC(=O)CCCCCCCBr
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(-c2cccnc2)c(C)c2ccccc21
Temperature: 25 °C

Procedure:
Dimethylformamide (1640 ml) is charged into a 20 gallon glass kettle along with 430g of potassium t-butoxide. This solution is stirred under nitrogen and cooled to -8°. A solution of 682 g of 3-methyl-2-(3-pyridyl)indole in 3280 ml of dimethylformamide is added over 0.75 hour while the temperature is maintained below 0°. After 2 hours of stirring of -10°, 1640 ml of a solution of 780 g of methyl 8-bromooctanoate in dimethylformamide is added over 1 hour. Reaction temperature is maintained below 0°. After 2 hours stirring, the reaction mixture is allowed to warm to room temperature overnight. The rust-colored mixture is then cooled to about 5° and treated with 19.7 L of ice water. The temperature rises to 25°. After 0.5 hour stirring, the mixture is extracted with 2×8 L of ether. The extracts are dried (MgSO4) and concentrated in vacuo to give 1-(7-methoxycarbonylheptyl)-3-methyl-2-(3-pyridyl)indole as an oil; 1293 g of this oil is treated with 6.53 L of 1N NaOH and warmed over steam to 90° for 2.5 hours. After cooling to room temperature, the solution is washed with 3×3 L of ether. The aqueous layer is cooled to 10° and acidified to pH 3.5 with 3.4 L of 2N HCl. The heavy suspension which results is extracted with 4×4 L of methylene chloride. The combined extracts are washed once with 4 L of water and dried (MgSO4). After filtration and evaporation of solvent in vacuo at 60°, the residue is triturated with ether (2.0 L) and dried to give 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)indole, m.p. 113°-115°. Recrystallization from ethanol raises melting point to 114°-116°.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10](OC(C)(C)C)=O)[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4].Cl.[C:29]1(B(O)O)[CH:34]=[CH:33]C=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]2[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=2)[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:20])[CH3:21])=[O:4]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1C(=O)OC)C(C)C
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.2 %

Procedure:
3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (0.20 g, 0.515 mmol) was dissolved in dichloromethane (1.0 mL) and HCl (4M dioxane, 1 mL) was added. The resultant suspension was stirred at room temperature for 60 minutes, after which all volatiles were removed in vacuo. The crude material was combined with phenyl boronic acid (188 mg, 1.545 mmol) and DCM (15 mL) was added. Triethylamine (1.2 mL, 8.89 mmol) was added, followed by copper(II) acetate and molecular sieves 4 Å. The reaction was stirred at room temperature. After 24 hrs, the reaction was quenched with aqueous ammonium hydroxide solution (10%) and the organic layer was isolated. The organic layer was washed with aqueous HCl solution (0.5 M), brine, and was dried over sodium sulfate. Filtration and evaporation gave crude material. Purification via flash chromatography on silica gel (eluent: EtOAc/hexanes) yielded the desired product 3-(2-Methoxycarbonylamino-3-methyl-butyryl)-1-phenyl-imidazolidine-4-carboxylic acid methyl ester (51.0 mg, 0.14 mmol): LCMS-ESI+: calc'd for C18H25N3O5: 363.4 (M+). Found: 364.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[PH:11](=[O:14])([OH:13])[OH:12].[CH2:15]([C:17]([CH2:45][CH3:46])([CH:19](Br)[C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1)[CH3:18])[CH3:16].C(O)(=O)C>C(O)C>[PH:11](=[O:12])([OH:14])[OH:13].[CH2:45]([C:17]([CH2:15][CH3:16])([CH:19]([O:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1)[CH3:18])[CH3:46]
Reactant: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NO
Agent: O=[PH](O)O
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCC(C)(CC)C(ONC(=O)OC(C)(C)C)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Yield: 104.4 %

Procedure:
A stirred solution of t-butyl-N-hydroxycarbamate (0.25 g) in ethanol (10 ml) was treated with postassium hydroxide (0.10 g), then diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 29) added. The mixture was allowed to stand for twenty hours, poured into ice-water, neutralized with a little acetic acid and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate, and evaporated under reduced pressure to give crude diethyl 3-t-butoxycarbonylaminoxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.14 g) as a colourless gum. NMR (CDCl3): δ 1.3(6H,t), 1.4(9H,s), 1.5-1.8(2H,m), 2.2-2.3(2H,m), 4.1(4H,m), 5.0(1H,t), 7.1(6H,m), 7.3(9H,m), 7.95(1H,s). M/S: M+ 620.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[B:18]([O:35]CC1C=CC=CC=1)([O:27]CC1C=CC=CC=1)[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C1C=CC=CC=1>>[CH2:20]([C:7]1[CH:6]=[C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])[CH:4]=[CH:3][C:2]=1[OH:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[B:18]([O-:35])([O-:27])[O-:19]
Reactant: c1ccc(COB(OCc2ccccc2)OCc2ccccc2)cc1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: OCc1ccccc1
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)c(Cc2ccccc2)c1
Product: [O-]B([O-])[O-]

Procedure:
34g Of bisphenol-A and 100g of tribenzyl borate were stirred under a pressure of 0.5-10mm Hg at a temperature of 120° C. During the reaction benzyl alcohol (28g) was distilled over. The residue was a clear viscous liquid. The compound has a Tg-value below 0° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:33])=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[C:21]=3[Cl:31])[CH:17]=1)[N:5]=2.N1C=CC=CC=1.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1.C(=O)([O-])O.[Na+]>O1CCCC1.C1(C(Cl)=O)CC1.O>[Cl:31][C:21]1[C:22]([C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:43]([CH:40]4[CH2:42][CH2:41]4)=[O:44])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=[CH:14][C:15]=1[F:33])=[O:32]
Reactant: O=C(Cl)C1CC1
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)ccc3F)c2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (9.0 g, 18.8 mmol) and pyridine (2.3 mL, 28.1 mmol) in tetrahydrofuran (90 mL) was added dropwise cyclopropanecarbonyl chloride (1.89 mL, 20.8 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Cyclopropanecarbonyl chloride (63 μL, 0.69 mmol) was further added and the mixture was stirred at room temperature for 12 hr. Water (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) were added to the reaction mixture to give a suspension, and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, repeatedly washed with water, and dried under reduced pressure to give the title compound (9.85 g, 96%) as a white powder.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.C([Mg][Cl:15])(C)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]([C:30]2[C:31]([CH:37]=[O:38])=[N:32][CH:33]=[C:34](C)[CH:35]=2)COC)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:39]([F:42])([F:41])[F:40]>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:30]2[C:31]([CH:37]([OH:38])[C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][N:9]=[CH:10][C:3]=34)=[N:32][CH:33]=[C:34]([Cl:15])[CH:35]=2)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:39]([F:42])([F:41])[F:40]
Reactant: Ic1ccnc2[nH]ncc12
Reactant: COCN(c1cc(C)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)cnc1C(O)c1ccnc2[nH]ncc12)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution of 4-iodo-1H-pyrazolo[3,4-b]pyridine (174.2 mg, 0.71 mmol) in THF (3 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 1.06 mL, 2.13 mmol). The resulting yellow suspension was then stirred for 30 min at 0° C. followed by the addition of a solution of 4-chloro-N-(2-formyl-5-methyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (300 mg, 0.71 mmol) in THF (2 mL) at 0° C. The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-{5-chloro-2-[hydroxy-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methyl]-pyridin-3-yl}-3-trifluoromethyl-benzene sulfonamide (192 mg) in 50% yield. ESMS m/z (relative intensity): 542 (M+H)+ (100), 564 (M+Na)+ (10).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[O:23][CH3:24])[CH:10]=[CH:9][N:8]=1)=[O:5].[H][H]>CO.CC(O)=O.[Pt]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[C:15]([O:23][CH3:24])[CH:16]=1
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2OC)ccn1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: COCC(=O)Nc1cc(Oc2ccc(N)cc2OC)ccn1

Procedure:
A solution of 2-methoxy-N-(4-(2-methoxy-4-nitrophenoxy)pyridin-2-yl)acetamide (232 mg, 696 μmol) in a mixture of MeOH (30 mL) and AcOH (2.0 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 50° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo to afford the title compound, Intermediate H4 as an impure oily liquid; Rt 1.08 min (Method 2); m/z 304 (M+H)+ (ES+). This material, containing residual acetic acid was used directly, without further purification, in the next step (below).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4]1)[CH3:2].C([Si:22]([CH3:25])([CH3:24])[CH3:23])#C.O.[CH2:27](N(CC)CC)[CH3:28]>CN(C)C=O.[Cu]I>[CH2:27]([C:2]#[C:1][N:3]1[C:12]2[C:7](=[CH:8][C:9]([Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:10][CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4]1)[CH3:28]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cn(CC)c2ccc(Br)cc2c1=O
Reactant: CCN(CC)CC
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Product: CCC#Cn1cc(C(=O)OCC)c(=O)c2cc([Si](C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 9 h
Yield: 80 %

Procedure:
A mixture of ethyl 1-ethyl-6-bromo-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Example 13h)), 1.94 ml of ethynyltrimethylsilane, 70 mg of bis-trimethylphosphine-palladium dichloride and 2.5 mg of copper(I) iodide in 7 ml of triethylamine and 7 ml of dimethylformamide is stirred at 60° for 9 hrs. After cooling to room temperature the reaction mixture is treated with 100 ml of water and extracted twice with 50 ml of methylene chloride each time. The combined organic phases are washed twice with 250 ml of water each time and once with 250 ml of a saturated, aqueous sodium chloride solution and dried over magnesium sulphate. The crude product is chromatographed on aluminium oxide (neutral, grade III) with n-hexane/ethyl acetate 1:1. 1.27 g (80%) of ethyl 1-ethyl-6-trimethylsilyl-ethynyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]([CH3:37])[C:7](=[O:36])[CH:8]([CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][CH:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:17][CH:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:39]=[CH:38][C:5]=3[N:6]([CH3:37])[C:7](=[O:36])[CH:8]([CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[N:9]=2)[CH2:16][CH2:15]1
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(NC(=O)OC(C)(C)C)CC2)c2cc(Cl)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(N)CC2)c2cc(Cl)ccc21
Yield: 28 %

Procedure:
5,7-Dichloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (170 mg, 0.44 mmol) and tert-butyl piperidin-4-ylcarbamate (89 mg, 0.44 mmol) were coupled according to the corresponding procedure described in Example 14 to yield intermediate tert-butyl 1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-ylcarbamate. (85 mg, 35%). Tert-butyl 1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-ylcarbamate (85 mg, 0.16 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) and stirred at ambient temperature for 2 hours. The solution was concentrated, redissolved in ethyl acetate and extracted into 1 M aqueous hydrochloric acid (3×10 mL). The extracts were neutralized with saturated sodium bicarbonate, extracted with dichloromethane (3×25 mL), then dried with sodium sulfate, filtered, and concentrated to yield 5-(4-aminopiperidin-1-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (20 mg, 29% yield). MS (M+H)+447.2.
Reaction SMILES: Cl.[OH:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7].C(N(CC)CC)C.[C:22]([C:24]1[CH:64]=[CH:63][C:27]([CH2:28][C@@:29]2([CH3:62])[N:33]3[C:34]([S:37](N4CCC[C@H]4C(N[C@H](C)C(O)=O)=O)(=[O:39])=[O:38])=[CH:35][N:36]=[C:32]3[N:31]([C:53]3[CH:58]=[C:57]([Cl:59])[CH:56]=[C:55]([Cl:60])[CH:54]=3)[C:30]2=[O:61])=[CH:26][CH:25]=1)#[N:23].CN(C=O)C>C(Cl)Cl>[OH:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[S:37]([C:34]1[N:33]2[C@@:29]([CH2:28][C:27]3[CH:63]=[CH:64][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)([CH3:62])[C:30](=[O:61])[N:31]([C:53]3[CH:54]=[C:55]([Cl:60])[CH:56]=[C:57]([Cl:59])[CH:58]=3)[C:32]2=[N:36][CH:35]=1)(=[O:38])=[O:39])=[O:7]
Reactant: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: CC(C)(O)CNC(=O)C1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(O)CNC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Pyrrolidine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide hydrochloride (0.241 g, 1.082 mmol) was dissolved in CH2Cl2 and triethylamine (0.206 mL, 1.513 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 10 min. (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl chloride (see Example 5) (0.3 g, 0.605 mmol) in CH2Cl2 was added to the reaction mixture and stirred for 1 h. DMF (0.5 mL) was then added to the reaction mixture and stirred for another 30 min. The reaction solution was washed with 1N HCl and saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica gel preparative thin layer chromatography using CH2Cl2-MeOH (10:1) as an eluent to afford 0.28 g of the title compound (M+1, 644.98).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>ClCCl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=1[Cl:21])=[O:13]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1Cl)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(Cl)cc1Cl
Yield: 18.5 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2,4-dichloroaniline (1.89 g, 11.7 mmol) in 15 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate, ethanol and methanol (1:1:1) and filtered to yield 0.64 g of the title compound, mp 227°-228° C.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:12])=[CH:6][CH:5]=1)([O-])=O>C1(C)C=CC=CC=1>[C:7]1([NH:10][C:11]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:9][CH:8]=1.[N:15]1[CH:16]=[CH:21][CH:22]=[CH:13][CH:14]=1
Reactant: Cn1c(=O)c(C(=O)Nc2ccc([N+](=O)[O-])cc2)c(O)c2ccccc21
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(C(=O)Nc2ccccc2)c(O)c2ccccc21
Product: c1ccncc1

Procedure:
A mixture consisting of 34.5 parts of N-(4-nitrophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (1:20), 0.3 parts of platinic oxide, and 330 parts of toluene is hydrogenated at 50° C. and at 5 atm. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue crystallizes to give N-(4-aminophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (1). M.p. 300° C.
Reaction SMILES: [BH3-]C#N.[Na+].[N:5]1([C:10]2[N:15]=[C:14]([CH:16]3[CH:20]([C:21]([NH:23][CH3:24])=[O:22])[CH2:19][CH2:18][NH:17]3)[CH:13]=[C:12]([CH3:25])[N:11]=2)[CH:9]=[CH:8][N:7]=[CH:6]1.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH2:35][N:36]([CH2:44][CH:45]=O)[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:34][C:29]=2[O:28][CH2:27]1.C(OC)(OC)OC>C(O)(=O)C.O>[N:5]1([C:10]2[N:15]=[C:14]([CH:16]3[CH:20]([C:21](=[O:22])[NH:23][CH3:24])[CH2:19][CH2:18][N:17]3[CH2:45][CH2:44][N:36]([CH2:35][C:33]3[CH:32]=[CH:31][C:30]4[O:26][CH2:27][O:28][C:29]=4[CH:34]=3)[C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH:13]=[C:12]([CH3:25])[N:11]=2)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CC(C)(C)OC(=O)N(CC=O)Cc1ccc2c(c1)OCO2
Reactant: CNC(=O)C1CCNC1c1cc(C)nc(-n2ccnc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)C1CCN(CCN(Cc2ccc3c(c2)OCO3)C(=O)OC(C)(C)C)C1c1cc(C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
NaBH3CN (76 mg, 1.2 mmol) was added all at once to a stirred solution of 2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-N-methylpyrrolidine-3-carboxamide (230 mg, 0.80 mmol), tert-butyl benzo[d][1,3]dioxol-5-ylmethyl(2-oxoethyl)carbamate (280 mg, 0.95 mmol), acetic acid (100 μL, 1.59 μmol) and trimethyl orthoformate (20 ml). The reaction mixture stirred at rt for 16 h then water (20 mL) was added. The solution was extracted with EtOAc (2×20 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified using column chromatography (20:1 CHCl3/MeOH) to afford 100 mg (22%) of tert-butyl 2-(2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-3-(methylcarbamoyl)pyrrolidin-1-yl)ethyl(benzo[d][1,3]dioxol-5-ylmethyl)carbamate as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4]Cl.[N-:12]=[N+]=[N-].[Na+].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4][NH2:12]
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)c(CN)c(C)c1
Temperature: 60 °C
Yield: 60.9 %

Procedure:
To a solution of 2,4,6-trimethylbenzyl chloride (5 g, 29.7 mmol) in DMSO (20 mL) was added sodium azide (2.9 g, 44.6 mmol). The mixture was heated at 60° C. for 3 h before it was allowed to cool to rt and poured to water (200 mL). The resulted precipitate was filtered dissolved in wet THF (50 mL) followed by the addition of triphenylphosphine (15.6, 59.4 mmol). The mixture was heated under reflux for 3 h and the volatiles were evaporated. The residue was added to 1 N HCl (200 mL) and the solids were filtered off. The filtrate was basified and the resulted precipitate was filtered, dried under vacuum to give 2,4,6-trimethylbenzylamine (2.7 g, 61% yleld).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:4]=1[CH:5]=[CH:6][CH:7]=[O:8].C(C1C(=O)C(Cl)=C(Cl)[C:21](=[O:22])C=1C#N)#N.CO>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:4]=1[CH:5]=[CH:6][C:7]([O:22][CH3:21])=[O:8]
Reactant: COc1cc(OC)c(OC)cc1C=CC=O
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1cc(OC)c(OC)cc1OC
Yield: 84 %

Procedure:
A homogeneous mixture containing 2,4,5-trimethoxycinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of AMBERLITE® IR 120 (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl 2,4,5-trimethoxycinnamate (from formula I where X1═OCH3, X2═H, X3═OCH3, X4═OCH3, X5═H, R═CH3) is isolated in 84% yield. 1H-NMR (CDCl3, 300 MHz) δ7.91 (1H, d, J=16.10 Hz), 7.01 (1H, s), 6.50 (1H, s), 6.37 (1H, d, J=16.10 Hz), 3.93 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.80 (3H, s); 13C-NMR (CDCl3, 75.4 MHz) δ168.2, 153.9, 151.9, 143.4, 139.7, 116.6, 115.4, 112.6, 96.9, 56.5, 56.4, 56.1, 51.5.