Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[Br:19].[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCl>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([O:18][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:10]([F:11])([F:12])[F:13])[C:14]([F:17])([F:15])[F:16])=[CH:4][C:3]=1[Br:19]
Reactant: Nc1c(Cl)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1Br
Reactant: O=C(O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1c(Cl)cc(C(OC(=O)c2ccccc2)(C(F)(F)F)C(F)(F)F)cc1Br
Temperature: 25 °C
Yield: 42 %

Procedure:
To a solution of 2-(4-amino-3-bromo-5-chlorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Example 3.3) (3.725 g, 10.0 mmol) and benzoic acid (1.28 g, 10.5 mmol) in dichloromethane (30 ml) was added pyridine (4.18 ml, 30 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”) (2.80 g, 11 mmol). The reaction mixture was heated to reflux for 24 hours. The reaction mixture was cooled to ambient temperature and quenched by addition of aqueous hydrochloric acid (1N) (50 ml). The mixture was then extracted three times with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (Buchi fraction collector C-660, prepacked cartridges Silicagel 60, particle size: 40-63 μm, D 40×150 mm, Gradient 99 to 1% methanol in toluene over 15 min, 60 mL/min, fraction 20 mL) to give benzoic acid 1-(4-amino-3-bromo-5-chlorophenyl)-2,2,2-trifluoro-1-trifluoromethylethyl ester (2 g, 42% yield). 1H NMR (400 MHz, CDCl3): 8.18 (d, 1H), 8.11 (d, 1H), 7.68 (m, 1H), 7.53 (m, 2H), 7.41 (s, 1H), 7.29 (s, 1H), 4.74 (bs, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[S:6][CH:7]=1.S(Cl)([Cl:13])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([Cl:13])=[O:10])[S:6][CH:7]=1
Reactant: COc1csc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: COc1csc(C(=O)Cl)c1

Procedure:
24.0 g (152 mmol) 4-methoxy-2-thiophenecarboxylic acid were suspended in 250 ml thionyl chloride and heated for two hours under reflux. The excess thionyl chloride was then distilled off under vacuum. The crude product was quickly distilled off and crystallised out in the receiver.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][C:15]1([CH3:23])[C:19](=[O:20])[CH:18]([CH3:21])[NH:17][C:16]1=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:11][C:10]([F:13])([F:12])[C:4]1[CH:3]=[C:2]([N:17]2[CH:18]([CH3:21])[C:19](=[O:20])[C:15]([CH3:23])([CH3:14])[C:16]2=[O:22])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Reactant: CC1NC(=O)C(C)(C)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using 4-iodo-2-(trifluoromethyl)benzonitrile (957 mg), 5 3,3,5-trimethylpyrrolidine-2,4-dione (350 mg), cesium carbonate (1.21 g), tris(dibenzylideneacetone)dipalladium(0) (227 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (287 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 452 mg, 59%).
Reaction SMILES: [Na].C([N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22])[C:12]=2[CH:11]=[CH:10]1)C1C=CC=CC=1.N>C1COCC1>[NH:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22])[C:12]=2[CH:11]=[CH:10]1
Reactant: CCOC(=O)Nc1nccc2c1ccn2Cc1ccccc1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nccc2[nH]ccc12
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 99.1 %

Procedure:
Sodium metal (0.067 g, 2.9 mmol, 10 eq) was added to a solution of ethyl 1-benzyl-1H-pyrrolo[3,2-c]pyridin-4-ylcarbamate (0.086 g, 0.29 mmol, 1.0 eq) in a mixture of liquid NH3 (5 mL) and THF (1 mL) at −78° C. The dark blue reaction mixture was stirred at −78° C. for 5 minutes and then was quenched with solid NH4Cl. The clear solution was allowed to warm to room temperature, treated with 10% NaHCO3 and extracted with 10/1 CHCl3/MeOH. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the product (0.059 g, 100%) as a solid. 1H NMR (CD3OD) δ 7.74 (d, 1H, J=6.0 Hz), 7.21 (d, 1H, J=3.4 Hz), 7.09 (d, 1H, J=5.7Hz), 6.59 (d, 1H, J=3.4Hz), 4.15 (q, 2H, J=7.1 Hz), 1.25 (t, 3H, J=7.1 Hz); MS(ESI+) m/z 206 (M+H)+. Calculated: 206.0930, found: 206.0932.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].[O:31]1[C:36]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.ClCCl>[O:31]1[C:36]2[CH:37]=[CH:38][C:39]([CH2:41][N:21]3[CH2:20][CH2:19][C:18]([CH2:17][N:15]([CH3:16])[C:8]4[N:7]=[C:6]([NH2:30])[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:23][CH2:22]3)=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(Cc4ccc5c(c4)OCCO5)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (250 mg) and 1,4-benzodioxan-6-carboxaldehyde (105 mg) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (140 mg) in one portion. The mixture was stirred at room temperature for two days. Aqueous NaOH (1N, 5 ml) was added and stirring was continued for one hour. The product was isolated by extraction with dichloromethane and purified by flash chromatograpy, to yield N2-[1-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-phenyl-piperidin-4-ylmethyl]-6,7-dimethoxy-N2-methyl-quinazoline-2,4-diamine 16, MS: 556 ([M+H]+). Treatment of the product with HCl in methanol/ethyl acetate gave 320 mg of the dihydrochloride salt.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[C:9]([C:16]#[C:17][Si](C)(C)C)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[C:9]([C:16]#[CH:17])[CH:8]=1
Reactant: C[Si](C)(C)C#Cc1cc(C2OCCCO2)c2occc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(C2OCCCO2)c2occc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A mixture of 7-[1,3]dioxan-2-yl-5-trimethylsilylethynyl-benzofuran (330 mg), and potassium carbonate (40 mg) in anhydrous methanol (10 ml) was stirred at room temperature for 1 h. The solvent was removed in vacuo, the residue treated with water (50 ml), and extracted with ether (3×75 ml). The combined organic extracts were washed with sodium hydroxide (50 ml; 2M), dried, and evaporated in vacuo to give the title compound as a brown oil (247 mg).
Reaction SMILES: [O:1]=[C:2]1[C:5]([CH3:6])=[C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH2:18][CH2:19][CH2:20][OH:21])[C:3]1=[O:22].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl.C1COCC1>[O:1]=[C:2]1[C:5]([CH3:6])=[C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH2:18][CH2:19][CH2:20][O:21][S:31]([CH3:30])(=[O:33])=[O:32])[C:3]1=[O:22]
Reactant: Cc1c(NCc2ccc3[nH]cc(CCCO)c3c2)c(=O)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(NCc2ccc3[nH]cc(CCCOS(C)(=O)=O)c3c2)c(=O)c1=O
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
To a solution of 5-(1,2-dioxo-4-methyl-3-cyclobuten-3-yl)aminomethyl-3-(3-hydroxypropyl)indole (0.48 g, 0.0016 mol) in 45 mL of dichloromethane-THF (4:1), cooled at -20° C. under Ar, was added triethylamine (0.28 mL, 0.002 mol) followed by methanesulfonyl chloride (0.16 mL, 0.002 mol). The resulting solution was stirred at -20° C. for 1.5 h and then it was washed (brine), dried (Na2SO4) and evaporated to give a brown gum. This material was chromatographed (SiO2 /ethyl acetate) to give the title compound (0.50 g, 83%) as a beige foam: IR (neat) 3320 (br), 1785, 1727, 1600 (br), 1350 (br) cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ 10.86 (s, 1H), 9.45 (m, 0.5H), 9.21 (m, 0.5H), 7.48 (s, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.17 (s, 1H), 7.03 (d, J=8.3 Hz, 1H), 4.78 (d, J=5.9 Hz, 1.2H), 4.62 (d, J=6.0 Hz, 0.8H), 4.23 (m, 2H), 3.80 (s, 3H), 3.06 (m, 2H), 2.76 (m, 2H), 2.14 (s, 1.2H), 2.05 (s, 1.8H).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].CS[C:17]1[NH:18][CH2:19][C:20]([CH3:27])([CH3:26])[CH2:21][C:22]=1[N+:23]([O-:25])=[O:24]>>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:18][CH2:19][C:20]([CH3:27])([CH3:26])[CH2:21][C:22]=2[N+:23]([O-:25])=[O:24])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CSC1=C([N+](=O)[O-])CC(C)(C)CN1
Product: CC1(C)CNC(NCCSCc2csc(NC(=N)N)n2)=C([N+](=O)[O-])C1

Procedure:
The title compound is prepared from 2-(2-guanidino-4-thiazolylmethylthio)ethylamine and 2-methylthio-3-nitro-5,5-dimethyl-1,4,5,6-tetrahydropyridine by a process analogous to that of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[S:12])[N:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]2=[O:19].[C:20]([O-])([O-])=O.[K+].[K+].CI>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:20])[N:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]2=[O:19]
Reactant: O=C([O-])[O-]
Reactant: O=c1c2cccc(Br)c2[nH]c(=S)n1-c1ccccn1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nc2c(Br)cccc2c(=O)n1-c1ccccn1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A mixture of 8-bromo-3-(pyridin-2-yl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (330 mg, 0.987 mmol, 415b), K2CO3 (59.6 mg, 0.987 mmol), and THF (9.9 mL) was set stirring under nitrogen at RT. MeI (61.3 pt, 0.987 mmol) was added, and the mixture was set stirring at 75° C. for 4 h. The reaction was cooled to RT and filtered, rinsing with chilled THF. The filtrate was concentrated under reduced pressure to give 310 mg of a waxy yellow-brown solid that contained the product. m/z (ESI, +ve) 349.7 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[NH2:12][OH:13].[OH-].[Na+].[Cl-].[Na+]>C(O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:12][OH:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: NO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc(N)cc1
Reaction time: 18 h
Yield: 30 %

Procedure:
To a mixture of 1-(4-amino-phenyl)-ethanone (2.75 g, 20.3 mmol) and hydroxylamine hydrochloride salt (2.1 g, 30.5 mmol) in ethanol (200 ml) was added sodium hydroxide (4.1 g, 101.7 mmol) in water (50 ml). After stirring for 18 hours, the mixture was treated with saturated aqueous sodium chloride solution (100 ml) and extracted with dichloromethane (200 ml). The organic extract was concentrated under reduced pressure to afford 1-(4-amino-phenyl)-ethanone-oxime (30% yield).
Reaction SMILES: [H-].[Na+].CN([C:6]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[C:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)[CH:8]=O)C.[C:25]([CH2:27][C:28]([NH2:30])=[O:29])#[N:26].P([O-])(O)(O)=O.[Na+]>CN(C)C=O.CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[NH:30][C:28](=[O:29])[C:27]([C:25]#[N:26])=[CH:8][C:7]=2[C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: CSc1ccc(C(C=O)=C(c2ccc(F)cc2)N(C)C)cc1
Reactant: N#CCC(N)=O
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To 1.45 g of 60% dispersion of sodium hydride in mineral oil (containing 869 mg, 36.2 mMol), washed once with hexane, in 20 ml of dry dimethylformamide, was added dropwise a solution of 9.42 g (29.9 mMol) of 1-(N,N-dimethylamino)-1-(4-fluorophenyl)-2-(4-methylthiophenyl)prop-1-en-3-one from Step 4, cyanoacetamide (2.59 g, 30.3 mMol), and 2.9 ml of methanol in 50 ml of dimethylformamide. After the addition was complete, the resulting dark solution was stirred overnight at 70°-80° C. After cooling, the mixture was added in portions to 500 ml of 1M aqueous sodium dihydrogen phosphate, producing a yellow solid. The solid was filtered, washed with water, and dried to give 9.24 g of 1,2-dihydro-6-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-2-oxo-pyridine-3-carbonitrile.
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH2:11]([NH2:13])[CH3:12]>[Pt]=O.C(O)C>[CH2:11]([NH:13][CH:2]([CH3:10])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:12]
Reactant: CC(=O)CCn1ccnc1
Reactant: CCN
Agent: O=[Pt]
Solvent: CCO
Product: CCNC(C)CCn1ccnc1

Procedure:
A mixture of 1-(3-oxobutyl)imidazole, ethylamine and ethanol is hydrogenated using platinum oxide as catalyst, by the procedure of Example 3, to give 1-(3-ethylaminobutyl)imidazole.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:26])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19](O)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[CH:42]1([NH2:46])[CH2:45][CH2:44][CH2:43]1>C(Cl)Cl.CN(C=O)C>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:26])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19]([NH:46][CH:42]3[CH2:45][CH2:44][CH2:43]3)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(C)c2ccc(OCCCl)cc2c1=O
Reactant: NC1CCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CCC2)cc1-n1cc(C)c2ccc(OCCCl)cc2c1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A suspension of 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoic acid (550 mg) in methylene chloride (10 ml) was cooled to 0° C. and oxalyl chloride (0.26 ml) was added followed by DMF (10 μl) and the reaction mixture was left to stir at room temperature for 1 hour when N,N′-diisopropylethylamine (1.03 ml) and cyclobutylamine (0.51 ml) were added. The reaction mixture was stirred at room temperature for 4 hours and concentrated. The residue was diluted with ethyl acetate and washed with water (×3), brine, dried (magnesium sulfate) and concentrated to a brown foam which was purified by column chromatography on a silica column eluting using a gradient of iso-hexane to ethyl acetate to give 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-cyclobutyl-4-methylbenzamide as a pale yellow solid (397 mg); NMR Spectrum: (DMSOd6) 1.66 (m, 2H), 2.06 (m, 2H), 2.12 (s, 3H), 2.21 (m, 2H), 2.28 (s, 3H), 4.01 (t, 2H), 4.38-4.46 (m, 3H), 7.12 (s, 1H), 7.49-7.54 (m, 2H), 7.74-7.76 (m, 2H), 7.81 (s, 1H), 7.89 (d, 1H), 8.60 (d, 1H); Mass Spectrum: M+ 425.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[N:9]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>CCCCC.C1COCC1>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][N:19]=3)[CH:14]=2)[N:9]=1
Reactant: COc1ccc2cc(Br)ccc2n1
Reactant: c1cnccn1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(-c3cnccn3)ccc2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
t-Butyl lithium (4.6 cm3 of a 2.6M solution in pentane) was added dropwise to a stirred solution of 2-methoxy-6-bromoquinoline (1.43 g) in THF (10 cm3) at -70° under nitrogen. After 20 minutes a solution of pyrazine (0.48 g) in THF (5 cm3) was added and after stirring for a further 20 minutes a stream of dry air was bubbled through the solution for 0.5 hour at -70° and then for a further 1 hour as the mixture warmed to room temperature. Chloroform (50 cm3) was added and the solution was washed with water (10 cm3), dried (MgSO4) and concentrated in vacuo to afford a residue which was chromatographed on silica (Merck "MK 60.9385") eluting with ethyl acetate:hexane, 1:1, to give a solid. Recrystallisation from ethyl acetate gave 2-methoxy-6-(2-pyrazinyl)quinoline. 1/4H2O, m.p. 130°-132°, (0.22 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[S:15]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)(=[O:17])=[O:16])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(OCC)(=O)C>CN(C)C=O.O>[CH2:32]([O:31][P:27]([CH2:26][N:14]([S:15]([C:18]1[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=1)(=[O:17])=[O:16])[C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([C:3](=[O:4])[CH2:2][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[CH:6]=[CH:7]2)(=[O:34])[O:28][CH2:29][CH3:30])[CH3:33]
Reactant: CCOP(=O)(CN(c1ccc2c(ccn2C(=O)CCl)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(CN(c1ccc2c(ccn2C(=O)CN2CCOCC2)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
125 mg diethyl {[[1-(2-chloro-acetyl)-1H-indol-5-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-methyl}-phosphonate are dissolved in 2 ml dimethylformamide, combined with 34 mg potassium carbonate and 22 μl morpholine and stirred overnight at ambient temperature. The mixture is divided between ethyl acetate and water. The organic phase is washed with saturated sodium chloride solution and dried on magnesium sulphate. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (ethyl acetate/methanol 30:1 to 10:1).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5]([O:9][CH2:10][CH3:11])(=[O:8])[CH:6]=[CH2:7].[CH2:12]=[CH:13]C=C.C(OC)(=O)C(C)=C>>[CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:8])[CH:6]=[CH2:7]
Reactant: C=CC(=O)OCC
Agent: C=C(C)C(=O)OC
Agent: C=CC=C
Product: C=CC(=O)OCCCC

Procedure:
The 1,3-butadiene-butyl acrylate copolymer prepared according to Example 19 is hydrogenated and isolated according to Example 18 with the exception that 1 ml. of 30% aqueous hydrogen peroxide is added to the aqueous citric acid solution to speed up isolation. Both IR and NMR spectra of the final copolymer show no olefinic absorptions (no unsaturation). GPC gives Mw=9.3×105, Mn=1.6×105, and Mw/Mn=5.7 (relative to polymethylmethacrylate). The performance of this copolymer as a VI improver is illustrated in Table II. The hydrogenated 1,3-butadiene-butyl acrylate copolymer exhibited high VIe comparable to 1,3-butadiene-ethyl acrylate copolymer of Example 18 and the 1,3-butadiene-methyl methacrylate copolymer of Example 11 at a slightly lower use level in base oil.
Reaction SMILES: [C:1]([N:4](C(=O)C)[C:5]1[O:10][C:9]2[C:11]3[C:16]([CH:17]=[CH:18][C:8]=2[CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:6]=1[C:28]#[N:29])=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[O:10][C:9]2[C:11]3[C:16]([CH:17]=[CH:18][C:8]=2[CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:6]=1[C:28]#[N:29])=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)C1=C(C#N)C(c2cccc([N+](=O)[O-])c2)c2ccc3ccccc3c2O1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)c2ccc3ccccc3c2O1
Reaction time: 24 h

Procedure:
2-Diacetylamino-4-(3-nitrophenyl)-4H-naphtho[1,2-b]pyran-3-carbonitrile (3.62 g) was dissolved in chloroform (200 ml) and mechanically stirred in the presence of Grade III alumina (36 g) for 24 hours at ambient temperature. The suspension was filtered, the alumina pad was washed through with 5% methanol in chloroform, the combined filtrates were evaporated and the residue was triturated with a little chloroform. The white solid was dissolved in dioxan (50 ml) and left to stand for 24 hours. An impurity precipitated out and this was filtered off. Water was added (200 ml) to the filtrate and the solid produced was filtered off, washed with water and dried. This solid was passed through a chloroform--`flash` silica column. The fractions containing product were bulked, evaporated to dryness and triturated with methanol to give yellow crystals of 2-acetamido-4-(3-nitrophenyl)-4H-naphtho[1,2-b]pyran-3-carbonitrile, m.p. 234.5°-236° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[C@@H:15]([NH:16]C(=O)OC(C)(C)C)[CH2:14][C@@H:13]([N:24]2[CH2:31][C:30]3[C:26](=[N:27][N:28]([S:32]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)(=[O:34])=[O:33])[CH:29]=3)[CH2:25]2)[CH2:12][O:11]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[C@@H:15]([NH2:16])[CH2:14][C@@H:13]([N:24]2[CH2:31][C:30]3[C:26](=[N:27][N:28]([S:32]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)(=[O:34])=[O:33])[CH:29]=3)[CH2:25]2)[CH2:12][O:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CCCC4)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CCCC4)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate obtained in Step A above (93 mg, 0.16 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3 mL) at room temperature. After 1.5 h, the reaction was concentrated to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:18][S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNS(=O)(=O)c1ccc(C#N)cc1
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To 4-cyano-benzenesulfonyl chloride in dichloromethane (10 mL) was added amino-acetic acid methyl ester hydrochloride (250 mg, 2 mmol) and triethylamine (1.01 g, 10 mmol). The mixture was stirred for 20 min at r.t and was washed with water. The crude was triturated in methanol to give (4-cyano-benzenesulfonylamino)-acetic acid methyl ester (240 mg, 47%). This material was dissolved in NH3 in methanol (30 mL) followed by addition of Raney Ni (3 g). The mixture was hydrogenated under H2 (60 psi, 1 h, r.t) to provide the title compound (1:5, 230 mg).