Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([CH3:24])[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([CH3:24])[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[N:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(N=C=Nc2ccc(C)cc2)cc1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: Cc1ccc(N=C(Nc2ccc(C)cc2)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
1.05 mmol of 1-methylpiperazine was dissolved in 10 ml of N,N′-dimethylformamide (DMF), and 1.0 mmol of 1,3-di-p-tolylcarbodiimide was added. After 0.5 h. of stirring at room temperature, a small precipitation was removed by filtration and washed twice with 1 ml of DMF. The filtrates were collected and kept at room temperature overnight. 50 ml of water was added to the solution. An oil precipitated after 0.5 h which transformed into a solid. The solid residue was collected by filtration, washed twice with water and dissolved in 20 ml of methanol. 0.2 ml of conc. HCl was added was added to the methanol solution. After evaporation of the methanol, the residue was redissolved in methanol, and pure product was precipitated from the solution with ethyl ether. Yield=78%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].FC1C=CC(C2C=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=2)=CC=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)nc1
Reactant: CC(=O)c1cccc(F)c1F
Product: O=C(O)c1ccc(-c2cccc(F)c2F)nc1

Procedure:
The title compound was prepared from 2′,3′-difluoroacetophenone using the procedures outlined for 6-(4-fluorophenyl)nicotinic acid (D1-D3).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19]C(N)=O>>[NH2:19]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: NC(N)=O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 55 %

Procedure:
Prepared as in Example 41 from 2-benzoyl-benzo[b]thiophen-3-ol, but using urea instead of ammonium acetate, with a yield of 55% of theory; m.p. 121°-122° C. (petroleum ether/ethyl acetate 2:1). The product was identical to that of Example 1, based on its TLC, mixed melting point and IR-spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH2:10])=[O:4].C(=O)([O-])O.[Na+].[Cl:16][CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27](Cl)=[O:28])[N:25]=1)=[O:19].O>O1CCCC1>[CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:27](=[O:28])[C:26]([C:24]1[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][Cl:16])[S:22][CH:23]=1)=[N:30][O:31][CH3:32])=[O:4]
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Reactant: CON=C(C(=O)Cl)c1csc(NC(=O)CCl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C(=O)OC)c1csc(NC(=O)CCl)n1

Procedure:
Under ice-cooling and stirring, 6 ml of an aqueous solution containing 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester and 561 mg of sodium hydrogen carbonate is added to a suspension of 1.18 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride (syn isomer) in 10 ml of tetrahydrofuran. After the mixture is stirred for 2 hours at room temperature, the solvent is distilled off in vacuo to leave a residue, which solidifies. Water is added to the solid, followed by filtration, and the collected crystals are washed successively with water and ethanol to give cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), m.p. 270°-275° C. (dec.).
Reaction SMILES: [CH2:1]([N:4]([CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[C:5](=[O:43])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3([C:35](=[O:42])[NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])[C:34]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:28]4[C:23]3=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:14][CH2:13]2)=[N:8][CH:7]=1)[CH:2]=[CH2:3]>CO.C(Cl)Cl.[Pd]>[CH:44]1([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:43])[C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]4([C:35](=[O:42])[NH:36][CH2:37][C:38]([F:41])([F:39])[F:40])[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=5[C:29]5[C:34]4=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:14][CH2:13]3)=[N:8][CH:7]=2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: C=CCN(C(=O)c1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc1)C1CCCCC1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCCN(C(=O)c1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc1)C1CCCCC1
Reaction time: 4 h
Yield: 84.6 %

Procedure:
The compound (50 mg, 0.07 mmol) prepared in Example 113 was dissolved in 1 ml of methanol and 0.5 ml of methylene chloride. 10% Pd—C (5 mg) was added to the solution. The mixture was subjected to catalytic reduction under the atmospheric pressure at room temperature for 4 hr. The reaction solution was filtered, and the solution was concentrated under the reduced pressure to give the title compound (40 mg, yield 80%) as a white foam.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:18]([C:19](OC)=[O:20])=[CH:17][C:16]([O:23][CH2:24][CH3:25])=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:14]1[C:18]([CH2:19][OH:20])=[CH:17][C:16]([O:23][CH2:24][CH3:25])=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOc1cc(C(=O)OC)n(Cc2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(CO)n(Cc2ccccc2)n1
Temperature: 0 °C
Yield: 67.4 %

Procedure:
11.1 mg of lithium aluminium hydride are added to a solution of 76 mg of methyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate in 0.75 ml of tetrahydrofuran, cooled to a temperature in the region of 0° C. by an ice bath. After 3 hours at a temperature in the region of 0° C., 22.2 mg of lithium aluminium hydride are added and the reaction medium is allowed to warm to a temperature in the region of 20° C. After 30 minutes at a temperature in the region of 20° C., 10 ml of ice-cold water are added and the reaction mixture is then filtered through Celite. After separation of the phases by settling, the aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated under reduced pressure. 45.7 mg of (2-benzyl-5-ethoxy-2H-pyrazol-3-yl)methanol are thus obtained in the form of a brown lacquer, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=2[NH:20][C:21](=[O:28])[CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=O)[CH:5]=[CH:6][CH:7]=1.CC([O-])(C)C.[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:10]3[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=3)[NH:20][C:21](=[O:28])[C:22]=2[C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(NC(=O)Cc2cccs2)c(C(=O)c2cccc(Br)c2)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc2[nH]c(=O)c(-c3cccs3)c(-c3cccc(Br)c3)c2cc1OC
Reaction time: 1 h

Procedure:
To a solution of N-{2-[(3-bromophenyl)carbonyl]-4,5-dimethoxyphenyl}-2-(thiophen-2-yl)acetamide (8 g, 17.4 mmol) in dry THF (80 mL) was added t-BuOK (6 g 52.1 mmol) in portions at 0° C. The reaction mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuum to afford 4-(3-bromophenyl)-6,7-dimethoxy-3-(thiophen-2-yl)quinolin-2(1H)-one. MS (M+H)=442 and 444.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:22]([F:30])[CH:23]=1
Reactant: N#Cc1cc(Br)c2cc[nH]c2c1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(Br)c2ccn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 4-bromo-6-cyanoindole (900 mg, 4.1 mmol) in dichloromethane (30 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (2.0 g, 8.1 mmol), triethylamine (1.2 mL, 8.6 mmol), copper (II) acetate (1.5 g, 8.2 mmol) and powdered 4A molecular sieves (2.0 g). The reaction mixture was stirred at room temperature in the presence of air for 16 hours. Further quantities of 4-benzyloxy-3-fluorobenzeneboronic acid (500 mg), triethylamine (0.3 mL) and copper acetate (375 mg) were added and the mixture stirred at room temperature in the presence of air for a further 16 hours. The mixture was filtered and the solid washed with dichloromethane. The filtrate was concentrated at reduced pressure. The product was purified by silica gel chromatography eluting with 2-40% ethyl acetate in hexane to yield the title compound (D13), (1.09 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>CC#N>[Cl:11][C:4]1[N:3]=[C:2]([NH:27][C@H:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[CH3:26])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.8 %

Procedure:
To a mixture of 2,6-dichloro-3-nitropyridine (2.26 g, 10.8 mmol) and potassium carbonate (1.29 g, 9.34 mmol) in anhydrous CH3CN (20 ml), was added (S)-1-(4-fluoro-phenyl)-ethylamine (1.00 g, 7.19 mmol) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 17 hrs. The solid was removed by filtration and the resulted cake was washed with EtOAc (20 ml). The combined filtrate was concentrated and purified by column chromatography (hexane-EtOAc=10:1) to give the title compound as a yellow solid (1.74 g, 82%). 1H NMR (400 MHz) δ 8.65 (d, J=7.6 Hz, 1H), 8.43 (d, J=8.4 Hz, 1H), 7.51 (m, 2H), 7.16 (m, 2H), 6.81 (d, J=8.8 Hz, 1H), 5.37 (m, 1H), 1.59 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[C:27]([NH2:32])[CH:26]=1>C(OCC)(=O)C>[NH2:32][C:27]1[CH:26]=[C:25]([Cl:24])[CH:30]=[CH:29][C:28]=1[S:31][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: Nc1cc(Cl)ccc1S
Reactant: COC(=O)/C(=C/c1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccc(Cl)cc1N)c1ccccc1
Yield: 28 %

Procedure:
Using a procedure similar to that described in Example 10, part b, except using methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-phenylacrylate (9a) (4.0 g, 12.9 mmol) as the olefin component, and 4-chloro-2-aminothiophenol (10 g, 62.7 mmol) as the thiol component (stirred for 6 days), the product was obtained as a crude oil. Flash column chromatography (5:1 hexanes:ethyl acetate) returned the title compound (1.7 g, 28%). Recrystallization from ethyl acetate-hexanes afforded the title compound (13a) (1.4 g) as a white solid (>98% erythro). MS APCI, m/z=471 (M+1). LC/MS: 2.90 min.
Reaction SMILES: C([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([CH2:28][S:29][C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH2:11]1)(=O)C1C=CC=CC=1.C[O-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[SH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:12]([CH2:28][S:29][C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH2:11]1
Reactant: Cn1nnnc1SC[C@@H]1C[C@H](SC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: Cn1nnnc1SC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a solution of (2S,4S)-4-benzoylthio-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.60 g) in methanol (30 ml) was added sodium methoxide (28% solution in methanol) (0.78 ml) under ice-cooling. After stirring at the same temperature for 30 minutes, to this solution was added glacial acetic acid (1 ml). The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (100 ml). The solution was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (20:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-mercapto-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.78 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=O)=[CH:5][CH:4]=1.Cl.[CH3:14][NH:15][C:16](=NC)[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>>[CH3:14][N:15]1[C:16]([CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])=[N:10][N:9]=[C:7]1[C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: C=CCCCC(=NC)NC
Agent: Cl
Product: C=CCCCc1nnc(-c2ccc(OC)cc2)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.12 g yield starting from 4-methoxybenzhydrazide (0.5 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.48 g). MS (m/z): 258 [MH]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:36]=[CH:35][C:8]2[S:9][C:10]([C:12](=[O:34])[NH:13][O:14][C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][C:7]=2[CH:6]=1)=[O:4]>C1COCC1.[OH-].[Na+]>[C:15]([O:14][NH:13][C:12]([C:10]1[S:9][C:8]2[CH:35]=[CH:36][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH:11]=1)=[O:34])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc2sc(C(=O)NOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2sc(C(=O)NOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A solution of 2-trityloxycarbamoyl -benzo[b]thiophene-5-carboxylic acid methyl ester (4.439 g, 8.99 mmol) in THF (50 mL) and 2M aqueous NaOH (50 mL) was allowed to stir at rt for six days. After removal of THF, the aqueous phase was acidified with HOAc/H2O (1:1) to pH≈4. The solid formed was filtered, collected and dried to give 2-trityloxycarbamoyl-benzo[b]thiophene-5-carboxylic acid as a white solid. 1H NMR (DMSO-d6, 200 MHz) δ 11.33 (brs, 1H), 8.47 (s, 1H), 8.10-7.80 (m, 3H), 7.56-7.14 (m, 15H). MS (EI): cal'd 243.1 (M-benzothiophene moiety+H+,) exp 243.1 (M-benzothiophene moiety+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[C:10]([CH3:22])([CH3:21])[CH:11](CC)[C:12]3[CH:13]=[N:14][C:15](N)=[N:16][C:17]=3[C:8]=2[N:7]([CH3:23])[N:6]=1)=[O:4].[I-:24].[Cs+].II.N(OCCC(C)C)=O>[Cu]I.C(COC)OC>[CH3:1][NH:2][C:3]([C:5]1[C:9]2[C:10]([CH3:22])([CH3:21])[CH2:11][C:12]3[CH:13]=[N:14][C:15]([I:24])=[N:16][C:17]=3[C:8]=2[N:7]([CH3:23])[N:6]=1)=[O:4]
Reactant: CCC1c2cnc(N)nc2-c2c(c(C(=O)NC)nn2C)C1(C)C
Reactant: [I-]
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: COCCOC
Product: CNC(=O)c1nn(C)c2c1C(C)(C)Cc1cnc(I)nc1-2
Temperature: 70 °C

Procedure:
In a round bottom flask maintained under argon atmosphere, ethyl 8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methylamide (13.00 g, 45.400 mmol) was dissolved into anhydrous dimethoxyethane (800 mL); cesium iodide (11.795 g, 45.400 mmol), bisublimated iodine (5.761 g, 22.698 mmol), copper(I) iodide (2.594 g, 13.621 mmol), and iso-amyl nitrite (9.107 mL, 68.100 mmol) were added in that order and the mixture was heated to 70° C. for 22 hours.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[O:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1)#[N:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[OH:11][CH2:10][C:8]1[O:9][C:5]([C:3]#[N:4])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C=O)o1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(CO)o1
Temperature: -30 °C
Reaction time: 2 h
Yield: 8800 %

Procedure:
2.34 g (62 mmol) of sodium borohydride were added in portions to a solution of 30 g (0.25 mol) of 5-cyanofuran-2-carbaldehyde in 500 ml of absolute ethanol at -30° C. The solution was stirred at -30° C. for 2 hours and, while cooling, was adjusted to pH 7 with a 5% strength citric acid solution in water. The reaction mixture was concentrated under water pump vacuum, saturated sodium chloride solution was added to the residue, the mixture was extracted several times with 150 ml of diethyl ether each time, the combined organic phases were dried over magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under water pump vacuum at room temperature. This resulted in 27 g (22 mol, 88%) of the title compound as a dark red oil, which was employed without further purification in the following reactions. 1H-NMR (250 MHz, d6 -DMSO): δ=4.4 (m, 2H), 5.6 (bs, 1H), 6.6 (d, 1H), 7.5 (d, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)C3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=O)C3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-cyclohexylcarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Br.CCCCCC.C(OCC)(=O)C>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[F:33])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: Fc1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccccc2F)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 5.0 g (16.37 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 21 D) 1)b)] dissolved in 75 ml of THF are deprotonated at -75° C. with 32.7 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated starting at -75° C. with 2.1 ml (18.0 mmol) of o-fluorobenzyl bromide (Fluka; Buchs/Switzerland) (warming up during 60 min up to max. -60° C.). Column chromatography (SiO2, hexane/ethyl acetate 3:1) yields the title compound: TLC Rf (D)=0.61.
Reaction SMILES: [CH3:1][C:2]([C:4]1([CH3:7])[CH2:6][CH2:5]1)=[O:3].[CH:8]1[C:13]([CH:14]=O)=[CH:12][C:11]2[O:16][CH2:17][O:18][C:10]=2[CH:9]=1>>[CH3:7][C:4]1([C:2]([CH:1]=[CH:14][C:13]2[CH:8]=[CH:9][C:10]3[O:18][CH2:17][O:16][C:11]=3[CH:12]=2)=[O:3])[CH2:6][CH2:5]1
Reactant: CC(=O)C1(C)CC1
Reactant: O=Cc1ccc2c(c1)OCO2
Product: CC1(C(=O)C=Cc2ccc3c(c2)OCO3)CC1

Procedure:
2-(3,4-Methylenedioxyphenyl)vinyl 1-methylcyclopropyl ketone [III; Ar is 3,4-methylenedioxyphenyl, R is CH3 ] was prepared from 25.6 g. of 1-methylcyclopropyl methyl ketone and 9.3 g. of piperonal according to the procedure described above in Preparation A1, affording 29.5 g. of crystalline product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[CH:14][NH:13][N:12]=2)=[CH:3]1.[H-].[Na+].Br[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>C1COCC1>[C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:13]1[CH:14]=[N:15][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[N:12]1)(=[O:21])[CH3:19]
Reactant: Cn1cc(-c2nc[nH]n2)c2ccccc21
Reactant: O=C(CBr)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CCCCC1n1cnc(-c2cn(C)c3ccccc23)n1
Reaction time: 4 h
Yield: 25.8 %

Procedure:
3-(1-Methyl-1H-indol-3-yl)-1,2,4-triazole (0.190 g, 0.960 mmol) was dissolved with stirring in dry THF (5 ml) and was treated with sodium hydride (80%) (0.032 g, 1.05 mmol), followed by 1-(bromoacetyl)piperidine (Bull. Soc, Chim. Fr. 1964, 5, 1063-9) (0.232 g, 1.05 mmol) in dry THF (1 ml). After 4 h, the reaction mixture was evaporated under reduced pressure and partitioned between EtOAc and water. The organic layer was then dried (Na2SO4) and evaporated under reduced pressure to give a yellow oil, which was purified by silica-gel chromatography (EtOAc→EtOAc:MeOH 100:1 as eluant) to give the title compound (D5b) as a white solid (0.080 g, 26%).