Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.N([O-])=[O:14].[Na+].[OH-].[Na+]>OS(O)(=O)=O.O>[OH:14][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2
Reactant: Cc1ccc2ncc(N)cc2c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2ncc(O)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
A solution of 3-Amino-6-methylquinoline [(1.21 g, 7.65 mmol), prepared according to J. Chem. Soc. 2024-2027 (1948) Morley et al.] in 6N H2SO4 (25 mL) was cooled in an ice bath. To the solution NaNO2 (560 mg, 8.10 mmol) in water (2 mL) was added and stirred for 30 min at 0° C. Separately 5% H2SO4 was refluxed and above Diazo reaction mixture was added to this refluxing solution. After 30 min the reaction mixture was cooled to room temperature, and was neutralized by 6N NaOH. The resulting insoluble material was collected by filtration. This solid was recrystallized by CHCl3/AcOEt to afford compound (92) (348 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ 7.34 (1H, dd, J=1.9, 8.6 Hz), 7.42 (1H, d, J=2.8 Hz), 7.55 (1H, s), 7.79 (1H, d, J=8.6 Hz), 8.50 (1H, d, J=2.8 Hz).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:12]([Cl:27])[C:11]2=[O:28])[CH:9]=1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32].C(N(CC)CC)C.[NH4+].[Cl-]>O1CCCC1>[Cl:27][C:12]1[C:11](=[O:28])[N:10]([C:8]2[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=2[F:29])[CH2:3][NH:2][C:30](=[O:33])[CH2:31][CH3:32])[C:15]([CH3:16])=[CH:14][C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CN)ccc1F
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)NCc1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one hydrochloride (250 mg, 0.56 mmol), propionyl chloride (49 μL, 0.56 mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4-0 mL). After stirring at 25° C. for 5 min the reaction was completed by LC-MS. The reaction mixture was poured into a saturated aqueous NH4Cl solution. The aqueous mixture was extracted with ethyl acetate. The organic phase was dried with Na2SO4 and concentrated in vacuo to obtain (240 mg, 91%) as a yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 8.3 (t, J=5.8 Hz, 1H), 7.6 (q, J=8.7 and 6.58 Hz, 1H), 7.38 (d, J=7.78 Hz, 1H), 7.3 (dd, J=2.6 and 7.6 Hz, 1H), 7.22 (d, J=7.51 Hz, 1H), 7.12 (td, J=2.0 and 6.5 Hz, 1H), 6.65 (s, 1H), 5.3 (s, 2H), 4.23 (d, J=3.6 Hz, 2H), 2.1 (q, J=7.7 Hz 2H), 1.98 (s, 3H), 0.98 (t, J=7.5 Hz, 3H) ppm. ES-HRMS m/z 465.1203 (M+H calcd for C23H21ClF3N2O3 requires 465.1187).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([O:30][CH:31]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])=[C:15](SC4SC5C=CC=CC=5N=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1C=C[CH:48]=[C:47]1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)CCCC)=C.O>O1CCCC1.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].[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([O:30][CH:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[O:29])=[C:15]([CH:47]=[CH2:48])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3nc4ccccc4s3)CS[C@H]12
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: 65 °C

Procedure:
A mixture of diphenylmethyl 7-phenylacetamido-3-[(benzothiazol-2-yl)thio]-3-cephem-4-carboxylate (IIc, 0.0973 g, 0.00015 mole), bis(dibenzylidene acetone)palladium (0.0044 g, 0.00000765 mole), tri(2-furyl)phosphine (0.006 g, 0.000026 mole), zinc chloride (0.042 g, 0.003 mole) and vinyl tributyl stannane (0.055 mL, 0.00018 mole) in dry tetrahydrofuran (3 mL) was heated under argon atmosphere at 65° C. for 18 h. After that period HPLC indicated no further conversion of compound IIc. Water and ethyl acetate was added to the reaction mixture, and the two phases were separated. The organic phase was separated, dried and concentrated. The crude product obtained was dissolved in acetonitrile and the acetonitrile solution was washed three times with equal volumes of pentane. Flash chromatography (5% dichloromethane in ethyl acetate) recovered starting compound IIc (0.041 g, 42%) and afforded product IIIa (0.0133 g, 17%, 29% when corrected for recovered starting material) as a yellow foam. Recrystallization from ethanol gave the analytical sample.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:29])=O)=[N:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:29])=[N:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCNC
Reactant: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)O)nc3)c(C)o2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cn1
Yield: 30.5 %

Procedure:
A solution of 5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridine-2-carboxylic acid (395 mg), ethyl 3-(methylamino)propanoate (157 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg), hydroxybenzotriazole monohydrate (184 mg) and triethylamine (168 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give ethyl 3-[{[5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate (155 mg). Ethyl 3-[{[5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.6 mL) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (100 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][S:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl>[Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][S:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH:8][CH:27]1[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1SCc1ccccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2SCc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-bromobenzyl)thioaniline (7.55 g) and 1-tert-butyloxycarbonylpiperidin-4-one (6.68 g) in 2-dichloroethane (100 ml) were added acetic acid (30 ml) and sodium triacetoxyborohydride (7.1 g), and the mixture was stirred at a room temperature for 2 hours. Additional amount of sodium triacetoxyborohydride (500 mg) was added, and the mixture was further stirred at a room temperature for 2 hours. The reaction was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water, a saturated aqueous sodium hydrogen carbonate solution, and water, dried over magnesium sulfate, and the solvent was removed. The residue thus obtained was purified by chromatography on a silica gel column (250 g) to give the title compound as a resinous product (11.2 g, 91%) from the fraction eluted with n-hexane:ethyl acetate=5:1.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC([CH2:31][C:32]([NH:34]CN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.C(N)C>CS(C)=O.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:23]=[C:22]([NH:34][CH2:32][CH3:31])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: CCN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CCNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 135 °C
Yield: 57 %

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (200 mg, 0.56 mmol) was dissolved in a mixture solution of dimethylsulfoxide (1 mL) and N,N-diisopropylethylamine (0.5 mL), ethylamine (2M tetrahydrofuran solution) (2 mL, 4 mmol) was added thereto, followed by heating in a sealed tube for 17 hours (oil bath temperature: 135° C.). The reaction mixture was allowed to room temperature, poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (117 mg, 0.32 mmol, 57%) was obtained.
Reaction SMILES: [Sn](Cl)Cl.[N:4]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[C@@H:6]([NH:12][C:13]([C:15]1[O:16][C:17]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:18]=3[CH:19]=1)=[O:14])[CH2:5]2.O.[OH-].[Na+]>CN(C=O)C>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11]1)[C@@H:6]([NH:12][C:13]([C:15]1[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:18]=3[CH:19]=1)=[O:14])[CH2:5]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2oc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1
Reaction time: 8 h

Procedure:
2.0 ml (4 mmol) of a 2 M tin(II) chloride solution in DMF are added to N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzofuran-2-carboxamide (100 mg, 0.32 mmol). The mixture is stirred overnight. The reaction mixture is poured into water and made basic using 1N aqueous sodium hydroxide solution. The aqueous phase is extracted six times with ethyl acetate. The combined organic phases are dried over magnesium sulfate, and the solvent is removed under reduced pressure using a rotary evaporator. The crude product is taken up in methanol and shaken together with acidic ion exchange resin (Dowex WX2-200) for about 20 min. The loaded ion exchanger is washed three times with in each ase 30 ml of methanol, then with water/methanol 8:2, again with methanol, with dichloromethane and finally again with methanol. The product is eluted using methanol/triethylamine 95:5. The solvent is removed under reduced pressure using a rotary evaporator. 52 mg (58% of theory) of the title compound are isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[OH-].[Na+].[C:14](Cl)(=[O:16])[CH3:15]>O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(CCN)c1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CCNC(C)=O)c1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
3-methoxyphenethylamine(50 g, 0.33 mol) was dissolved in a soultion of water(130 ml), dichloromethane(210 ml) and sodium hydroxide(17.6 g). Acetyl chloride(25.9 ml, 0.36 mol) was added dropwise at a room temperature to the mixture solution, which was then stirred for 1 hour. The separated dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure to give 63.6 g of the titled compound.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]1=[O:11].Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:22]1([N:19]2[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][N:7]3[CH2:8][CH2:9][C:10]4[NH:1][C:2](=[O:11])[CH:3]=[CH:4][C:5]=4[CH2:6]3)[CH2:17][CH2:18]2)[CH2:25][CH2:24][CH2:23]1
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Reactant: O=c1ccc2c([nH]1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCc2[nH]c(=O)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one (98 mg, 0.653 mmol), 1-(chloroacetyl)-4-cyclobutylpiperazine (142 mg, 0.653 mmol), K2CO3 (360 mg, 2.61 mmol) and KI (12 mg, 0.07 mmol) in CH3CN (15 mL) is stirred at rt overnight. The solvent is removed in vacuo and the residue is partitioned between water (10 mL) and EtOAc (20 mL). The layers are separated and the aqueous layer is extracted with EtOAc (2×10 mL) and the combined extracts are dried and evaporated. The resulting oil is purified by PTLC with DCM/MeOH/NH4OH (100:5:0.5) to give the title compound as a light yellow solid. MS (M+1): 331.2; 1H NMR (δ, CDCl3): 7.13 (d, 1H0, 6.38 (d, 1H), 3.60 (q, 4H), 3.44 (s, 2H), 3.35 (s, 2H), 2.79 (s, 2H), 2.63-2.75 (m, 1H), 2.26 (q, 4H), 1.63-2.06 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11].Br[CH2:21][C:22]([O:24]C)=[O:23]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:21][C:22]([OH:24])=[O:23])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:12]
Reactant: COc1ccccc1NS(=O)(=O)c1ncccc1C
Reactant: COC(=O)CBr
Product: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of 3-methyl-pyridine-2-sulfonic acid (2-methoxy-phenyl)-amide with methyl bromoacetate
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13].O>C(OCC)C>[Cl:11][C:4]1[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH:15][CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: CC(C)N
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)Nc1nc(Cl)c(C#N)c(Cl)n1
Yield: 51.5 %

Procedure:
A stirred solution of 4.2 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 100 ml of diethyl ether was cooled to between -5° and -10°, and a solution of 2.4 grams of isopropylamine in 100 ml of diethyl ether was added dropwise. Upon complete addition, water was added to the reaction mixture, and the ether layer was separated. The ethereal layer was dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was recrystallized from methylcyclohexane to give 2.4 grams of 4,6-dichloro-2-isopropylamino-5-pyrimidinecarbonitrile; mp, 179°-181°.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]2)=[O:24])=[CH:36][CH:35]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccc(Cl)cc1)N1CCN(C2CCCC2)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 4-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (34%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:18])[C@@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)([CH3:4])([CH3:3])[CH3:2].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH2:38]([O:40][C:41]([C@@H:43]([NH:53][C@H:54]([C:56](O)=[O:57])[CH3:55])[CH2:44][S:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:42])[CH3:39]>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:18])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:56](=[O:57])[C@H:54]([CH3:55])[NH:53][C@H:43]([C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:44][S:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Reactant: CCCCCCCSC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCSC[C@H](N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C

Procedure:
In 25 ml of DMF were dissolved 2.6 g of the β-isomer of N-[(R)-1-ethoxycarbonyl-2-heptylthioethyl]-alanine prepared in Reference Example 29, 2.5 g of (S)-prolyl-(S)-proline t-butyl ester prepared in Reference Example 28, 1.7 g of WSCD.HCl and 1.1 g of HOBt. To the solution was added 3.6 ml of triethylamine while being stirred with ice cooling. The solution was stirred overnight. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (a 30:1 mixture of chloroform and methanol as an eluent), giving the title compound as a colorless oil. Yield 3.5 g.
Reaction SMILES: [C:1]12([CH3:11])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].[H-].[Na+].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15]>C(COC)OC>[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[C:4]1[CH:5]2[C:8]([CH3:10])([CH3:9])[C:1]([CH3:11])([CH2:7][CH2:6]2)[C:2]1=[O:3])([O-:16])=[O:15]
Reactant: CC12CCC(CC1=O)C2(C)C
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC12CCC(C(=Cc3cccc([N+](=O)[O-])c3)C1=O)C2(C)C
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
The camphor (50.2 g, 0.33 mol), dimethoxyethane (180 ml) and sodium hydride (32 g at 50% in oil, 0.33 mol) washed with dimethoxyethane, are placed in a round-bottom flask. The mixture is heated under nitrogen to 80° C. and the meta-nitrobenzaldehyde (45.3 g, 0.3 mol) dissolved in dimethoxyethane (100 ml) is added dropwise over half an hour. The mixture is left stirring at 80° C. for 1.5 hours. The reaction mixture is allowed to cool and it is poured cautiously in 2 litres of acidified and ice cold water. The brown precipitate obtained is filtered, washed with water and dried. After recrystallisation in diisopropyl ether in the presence of vegetable black, 20 g of meta-nitrobenzylidenecamphor are obtained.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](Cl)=[O:13]>>[OH:13][C:12](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[C:8]1[N:7]([CH3:6])[CH:11]=[CH:10][CH:9]=1
Reactant: Cn1cccc1C(=O)Cl
Reactant: N#CCC#N
Product: Cn1cccc1C(O)=C(C#N)C#N

Procedure:
[Hydroxy(1-methylpyrrol-2-yl)methylene]methane-1,1-dicarbonitrile was synthesized in the same manner using malononitrile and 1-methylpyrrole-2-carbonylchloride. The ESI/MS data for this compound are shown below.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1>C(O)C>[CH:9]([C:11]1[CH:16]=[N:1][C:2]2[C:7]([CH:12]=1)=[CH:6][CH:5]=[C:4]([NH:8][C:9]([C:11]1[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=3)=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[CH:3]=2)=[O:10]
Reactant: Nc1cccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c1
Solvent: CCO
Product: O=Cc1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 200 %

Procedure:
A slurry of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (3-amino-phenyl)-amide (6.5 g, 18.2 mmol, 1 equiv) and 2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane bis(tetrafluoroborate) (19.5 g, 54.7 mmol, 3 equiv) in ethanol (200 mL, 30 volumes) was heated at reflux for 24 hours. The reaction became homogeneous after heating for 4 hours. The solution was concentrated and the residue was dissolved in THF (100 mL, 15 volumes) and 1 N HCl (100 mL, 15 volumes). The reaction mixture was stirred at room temperature for 3 hours, then poured into a saturated solution of sodium bicarbonate (100 mL), and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate, treated with activated charcoal, filtered, (6.5 g, 1 weight equiv) and concentrated to afford 4′-trifluoromethyl-biphenyl-2-carboxylic acid (3-formyl-quinolin-7-yl)-amide (7.65 g, 100% crude yield) as a yellow foam. The crude product was clean by 1H NMR and used in the next step without further purification.