Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[C:28]([CH3:35])[CH:27]=1.[NH2:36][CH2:37][C:38]([NH2:40])=[O:39]>>[NH2:40][C:38](=[O:39])[CH2:37][NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:30]=[CH:31][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:27][C:28]=1[CH3:35])=[O:7])=[O:18]
Reactant: NCC(N)=O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cc(-c2ccccc2C)ccc1C(=O)O
Product: CON=C1C[C@@H](C(=O)NCC(N)=O)N(C(=O)c2ccc(-c3ccccc3C)cc2C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and 2-aminoacetamide, the title compound was obtained in 85% purity by HPLC. MS(ESI+): m/z=423.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:21])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][C:23]=1[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH2:10][C:11]3[C:2]([O:38][C:35]4[CH:36]=[CH:37][C:32]([C:23]5[CH:24]=[N:25][C:26]6[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=6)[N:22]=5)=[CH:33][CH:34]=4)=[CH:3][CH:4]=[N:5][C:6]=3[NH:7][C:8]2=[O:21])=[CH:14][CH:15]=1
Reactant: Oc1ccc(-c2cnc3ccccc3n2)cc1
Reactant: COc1ccc(CN2Cc3c(Cl)ccnc3NC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3c(Oc4ccc(-c5cnc6ccccc6n5)cc4)ccnc3NC2=O)cc1
Temperature: 130 °C
Yield: 42.7 %

Procedure:
A suspension of 5-chloro-3-(4-methoxy-benzyl)-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-2-one (100.00 mg; 0.33 mmol; 1.00 eq.), 4-quinoxalin-2-ylphenol (91.46 mg; 0.41 mmol; 1.25 eq.), and cesium carbonate (214.54 mg; 0.66 mmol; 2.00 eq.) in DMF (2.00 ml) was heated in a microwave at 130° C. for 4 hours. The reaction was concentrated, redissolved in DMSO, syringe filtered, and purified via prep HPLC to afford 69 mg of 280 as an off-white solid. LC-MS (M+H=490, obsd.=490).
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].[B:17]([Cl:20])(Cl)Cl.[CH2:21]([NH:24][CH2:25][CH:26]=[CH2:27])[CH:22]=[CH2:23].C(N(CC)CC)C>CCCCCC>[CH2:3]([B:17]([Cl:20])[N:24]([CH2:25][CH:26]=[CH2:27])[CH2:21][CH:22]=[CH2:23])[CH:2]=[CH2:1]
Reactant: C=CCNCC=C
Reactant: ClB(Cl)Cl
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: C=CCB(Cl)N(CC=C)CC=C
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A solution of allyltributyltin (62.2 g, 0.19 mol) in 50 mL of hexane was added dropwise to a solution of BCl3 (24.8 g, 0.21 mol) in 120 mL of hexane at −78° C. After the reaction mixture was stirred at −78° C. for 1 hour, it was allowed to warm to 25° C. for 2 hours followed by recooling to −78° C. Then diallylamine (23.5 mL, 0.19 mol) was added dropwise followed by triethylamine (26.7 mL, 0.19 mol). The mixture was stirred for 12 hours while it slowly warmed to 25° C. The solvent was removed under reduced pressure and the product (33.1 g, 95 percent) was obtained by distillation (bp=38° C. at 0.1 torr).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][C:7]2[C:8](=[CH:12][CH:13]=1)[N:9]=[N:10][N:11]=2)=[O:4].[H-].[Na+].CI.[CH3:18]COC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([CH3:18])[C:7]2[C:8](=[CH:12][CH:13]=1)[N:9]=[N:10][N:11]=2)=[O:4]
Reactant: COC(=O)C1=CC=C2N=NN=C2C1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1=CC=C2N=NN=C2C1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1 g of Benzotriazole-5-carboxylic acid methyl ester (5.64 mmol) was dissolved in 20 ml DMF at 0° C. To this solution was added 1 eq. of NaH (60%) at 0° C. The mixture was stirred for 30 min at 0° C., 801 mg (1 eq.) of Methyliodide were slowly added, and the resulting reaction mixture was stirred for 2 h at rt. EtOAc was added and the organic layer was washed extensively with brine and water, dried over MgSO4 and filtered to afford 1 g of crude Methyl-benzotriazole-5-carboxylic acid methyl ester as three different regioisomers. The separation was performed on silica gel using EtOAc/CH 3:7 as eluents.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([O:15][C:16](=[O:38])[CH:17]([O:35][CH2:36][CH3:37])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:21][CH:20]=1)[CH3:14].Cl>ClCCl>[CH2:13]([O:15][C:16](=[O:38])[CH:17]([O:35][CH2:36][CH3:37])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][S:9]([CH3:8])(=[O:11])=[O:10])=[CH:32][CH:33]=2)=[CH:21][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NS(C)(=O)=O)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.9 %

Procedure:
Triethylamine (0.544 g; 2.99 mmole) and thereafter methanesulfonyl chloride (0.392 g; 2.99 mmole) were added to a solution of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester (0.89 g; 2.49 mmole) in dichloromethane (8.9 ml) at 0° C. After stirring at room temperature for 20 hours the reaction mixture was poured onto a mixture of hydrochloric acid and ice. Dichloromethane was added, the phases were separated and the organic phase was washed with water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane:ethyl acetate (3:2) as eluant gave 0.78 g (yield 72%) of 2-ethoxy-3-{4-[2-(4-methanesulfonylaminophenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:15]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]3[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[O:17])=[CH:25][CH:24]=1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)O)ccc12
Reactant: COC(=O)c1ccc(N)cc1
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccc(C(=O)OC)cc3)ccc12
Yield: 91.4 %

Procedure:
This compound was prepared according to the method of Example 11, using 300 mg (1.16 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid and 193 mg (1.28 mmol, 1.1 equiv) methyl-4-amino-benzoate as starting materials to give 415 mg (91%) of white crystals: mp 129-132° C.; Anal. calcd for C23H25N3O3: C, 70.56; H, 6.44; N, 10.73. Found: C, 70.36; H, 6.43; N, 10.61.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:31][CH2:32][CH3:33])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:34](Cl)([Cl:36])=[O:35]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:34]([Cl:36])=[O:35])[CH:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:31][CH2:32][CH3:33])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1([CH2:15][OH:16])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:21](OCC)(=O)C>O1CCCC1.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1([CH2:15][O:16][CH3:21])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CO)COCCN1Cc1ccccc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COCC1(C)COCCN1Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 4-benzyl-3-hydroxymethyl-3-methylmorpholine (1 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of sodium hydride (60% oil suspension; 0.27 g) in tetrahydrofuran (20 ml) at room temperature under nitrogen atmosphere and the whole was stirred at 70° C. for 1 hour. After cooling, methyl iodide (0.34 ml) was added to the mixture and the whole was stirred at 40° C. for 1 hour. After cooling, ethyl acetate and water were added to the mixture and the organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1:4) as an eluent to give 4-benzyl-3-methoxymethyl-3-methylmorpholine (0.77 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]1[CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[O:13]1>>[CH2:12]1[CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:16]([NH:17][C:2]3[N:7]=[C:6]([NH:17][C:16]4[CH:18]=[CH:19][C:20]5[O:21][CH2:22][CH2:12][O:13][C:14]=5[CH:15]=4)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=3)=[CH:15][C:14]=2[O:13]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)OCCO2
Product: O=[N+]([O-])c1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-nitropyrimidine with 3,4-ethylenedioxyaniline gave N2,N4-bis-(3,4-ethylenedioxyphenyl)-5-nitro-2,4-pyrimidinediamine. LCMS: ret. time: 30.78 min.; purity: 100%; MS (m/e): 424 (MH+); 1H NMR (CDCl3): δ 10.21 (1H, s), 9.10 (1H, s), 7.40 (1H, s), 7.11-6.71 (6H, m), 4.29 (4H, s), 4.25 (4H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=3)[C:14]=2[CH3:23])[CH:7]=1)[CH3:2]
Reactant: CCCn1cc(Br)cn1
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)OCC)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 4-bromo-1-propylpyrazole.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH2:23]([C:25]([OH:30])([CH2:28][CH3:29])[C:26]#[CH:27])[CH3:24].C1COCC1>C(OCC)(=O)C.[Cu](I)I>[CH2:26]([C:25]([C:23]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=4)=[CH:10][C:11](=[O:15])[O:12]3)=[CH:7][CH:6]=2)[CH:24]=1)([OH:30])[CH2:28][CH3:29])[CH3:27]
Reactant: Cc1cccc(-c2cc(=O)oc3cc(CN=[N+]=[N-])ccc23)c1
Reactant: C#CC(O)(CC)CC
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)(CC)c1cn(Cc2ccc3c(-c4cccc(C)c4)cc(=O)oc3c2)nn1
Reaction time: 8 h

Procedure:
To a solution of 7-(azidomethyl)-4-(3-methylphenyl)-2H-chromen-2-one (100 mg, 0.34 mmol) and 3-ethyl-1-pentyn-3-ol (46 mg, 0.41 mmol) in THF (4 mL) N,N-diisopropylethylamine (296 uL, 1.7 mmol) and copper iodide (97 mg, 0.51 mmol) were added. After overnight stirring, the reaction was diluted with ethyl acetate, filtered and washed with water and brine. The organic layer was then dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (acetone/CH2Cl2 20:80) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.90 (s, 1H), 7.54 (d, 1H), 7.47 (t, 1H), 7.43-7.33 (m, 4H), 7.25 (d, 1H), 6.33 (s, 1H), 5.78 (s, 2H), 3.70 (s, 1H), 2.45 (s, 3H), 1.95-1.75 (m, 4H), 0.79 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[H-].[Na+].Cl[S:21]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:34])[CH:25]=1)(=[O:23])=[O:22].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:21]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:34])[CH:25]=1)(=[O:22])=[O:23]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1F
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2nccs2)cc1F
Temperature: 25 °C
Yield: 102.2 %

Procedure:
To an ice cooled solution of N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 9.0 g, 35.9 mmol, 1 eq) in THF (80 ml) was added 60% sodium hydride (2.15 g, 53.9 mmol, 1.5 eq) portionwise. The mixture was stirred for 30 minutes before the addition of methyl 4-(chlorosulfonyl)-2-fluorobenzoate (Preparation 13, 9.06 g, 35.9 mmol, 1 eq) then stirred for a further hour at room temperature. The reaction mixture was added to water (20 ml) and the THF evaporated in vacuo. The residue was diluted with water (200 ml), extracted into DCM (3×200 ml), dried over sodium sulphate, filtered and evaporated in vacuo to yield the title compound as an orange solid (17.1 g, 36.7 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]1[CH2:8][C:7](=[O:9])[CH2:6]1.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C@H:5]1[CH2:8][C@@H:7]([OH:9])[CH2:6]1
Reactant: COC(=O)CC1CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (3-oxo-cyclobutyl)-acetic acid methyl ester (700 mg, 4.92 mmol) in MeOH (20 ml), NaBH4 (205 mg, 5.41 mmol) is added at 0° C. The mixture is stirred at room temperature for 5 hours. To the mixture, H2O is added and a portion of MeOH is removed under reduced pressure. The mixture is extracted with AcOEt and the organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give cis (3-hydroxy-cyclobutyl)-acetic acid methyl ester (578 mg, 80%); TLC (hexane/AcOEt, 1:1) Rf 0.38, 1H NMR (400 MHz, chloroform-d) δ ppm 1.56-1.65 (m, 1H), 1.76 (m, 1H), 2.08-2.16 (m, 2H), 2.44 (d, 2H), 2.51-2.59 (m, 2H), 3.66 (s, 3H), 4.16 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:13])([CH3:12])[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:12])([CH3:13])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[CH2:8][CH2:7]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)C(C)(C)CC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 140 °C
Yield: 79.4 %

Procedure:
2,2-Dimethyl-3-(piperidine-4-yl)-propionic acid methyl ester (156 mg, 0.78 mmol) from above was mixed with 2-chloro-5-nitropyridine (124 mg, 0.78 mol) in tetrahydrofuran (2 mL) containing triethylamine (0.24 mL). The mixture was heated in a microwave at 140° C. for 30 minutes. The mixture was extracted with ethyl acetate and water. The organic layer was washed with brine and dried. Solvents were evaporated and the residue was triturated with ether to give 2,2-dimethyl-3-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid methyl ester (199 mg) as a crystalline material. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[CH3:16][N:17]([CH2:19][CH2:20][CH2:21][O:22][NH2:23])[CH3:18].C(O)(=O)/C=C/C([O-])=O>>[CH3:16][N:17]([CH2:19][CH2:20][CH2:21][O:22][N:23]=[C:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:18]
Reactant: CN(C)CCCON
Reactant: O=C1CCCCCCCCCCC1
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)O
Product: CN(C)CCCON=C1CCCCCCCCCCC1

Procedure:
Starting from 18.23 g. (0.1 moles) of cyclododecanone and 21.0 g. (0.11 moles) of dimethylaminopropoxyamine dihydrochloride the title compound is prepared as in Example 13. Yield: 20.9 g. (74%). Hydrogen fumarate, m.p.: 117°-118° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19]C2.ClC1C=CC(C2CCNCC2)=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[NH:15][N:14]=[C:22]4[CH2:21][CH2:20][CH2:19][C:17]=34)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: Clc1ccc(C2CCNCC2)cc1
Product: Cc1ccc(N2CCN(CCCc3[nH]nc4c3CCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(2,4,5,6-tetrahydrocyclopentapyrazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 4 and 1-(4-methylphenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-2,4,5,6-tetrahydrocyclopentapyrazole was obtained, m.p. 101-102° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[SH2:10]>N1C=CC=CC=1>[N:1]1[S:10][C:8]([NH2:9])=[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]=12
Reactant: S
Reactant: N#Cc1cccnc1N
Solvent: c1ccncc1
Product: Nc1snc2ncccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-amino-3-cyanopyridine (1.00 g, 8.40 mmol) in pyridine (8 mL) and TEA (0.8 mL) in a sealed tube, H2S gas was bubbled through for 5 min. It was then stirred at room temperature for 20 h. The mixture was concentrated in vacuo to dryness. The residue was dissolved in MeOH (10 mL). To the solution, aq. H2O2 (30%, 3 mL) was added. The mixture was then stirred at room temperature for 5 h, during which time, solids precipitated out. The solids were collected by filtration, dried on vacuum to give isothiazolo[3,4-b]pyridin-3-amine (860 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:26]=[C:9]2[CH2:10][N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[N:8]2[N:7]=1)=O)C.[NH3:27]>C(O)C>[C:20]1([C:12]2[C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[N:8]3[N:7]=[C:6]([C:4]([NH2:27])=[O:3])[N:26]=[C:9]3[CH2:10][N:11]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: N
Solvent: CCO
Product: NC(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 24 h

Procedure:
An amount of 3.67 g (0.010 mole) of 6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]-benzodiazepine-2-carboxylic acid ethyl ester is dissolved at 40° in 300 ml of ethanol, and 50 ml of conc. aqueous ammonia solution is then added. The clear solution is allowed to stand for 24 hours at room temperature and thereupon concentrated at 40° in vacuo. The red residue is suspended in 100 ml of water, filtered under suction, and the filter residue subsequently washed with water. The resulting product is recrystallised from methanol and dried at 100°-120° in vacuo to obtain 6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide, M.P. 252°-254°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10](O)=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:10]([N:43]1[CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41][CH2:42]1)(=[O:11])[CH3:9]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 16 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and acetyl chloride as starting materials in 16% yield. LCMS for C26H28ClN6O2 (M+H)+: m/z=491.2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([Cl:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.O[CH2:13][C:14]1[O:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4]([CH:13]([C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:11])[N:2]([CH3:1])[CH:3]=1)[C:14]1[O:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=1)=[CH:3][N:2]2[CH3:1]
Reactant: Cn1ccc2c(Cl)cccc21
Reactant: O=Cc1ccc(CO)o1
Product: Cn1cc(C(c2ccc(CO)o2)c2cn(C)c3cccc(Cl)c23)c2c(Cl)cccc21

Procedure:
The compound Bis(4-chloro-1-methylindol-3-yl)-(5-hydroxymethyl-2-furyl)methane was prepared following procedure A, starting from N-methyl 4-chloro indole and 5-hydroxy methyl furfural. LC: Tr 2.73 min, MS: 439 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.CS[C:17](=[NH:22])[NH:18][N+:19]([O-:21])=[O:20]>>[N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][C:6]=1[CH2:5][S:4][CH2:3][CH2:2][NH:1][C:17]([NH:18][N+:19]([O-:21])=[O:20])=[NH:22]
Reactant: NCCSCc1nc2ccccc2[nH]1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCSCc1nc2ccccc2[nH]1)N[N+](=O)[O-]

Procedure:
Reacting 2-[(2-aminoethyl)thiomethyl]benzimidazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-[2-(2-benzimidazolylmethylthio)ethyl]-N'-nitroguanidine. Treatment with hydrochloric acid gives the hydrochloride salt.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][CH2:14][N:15]([CH2:20][CH2:21]Cl)[C:16]([CH3:19])([CH3:18])[CH3:17]>CS(C)=O.Cl>[C:16]([N:15]1[CH2:20][CH2:21][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:8]#[N:9])[CH2:13][CH2:14]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N(CCCl)CCCl
Reactant: N#CCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)N1CCC(C#N)(c2ccccc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of phenyl acetonitrile (1.0 g, 8.54 mmol) in DMSO (8 mL) was treated with sodium hydride (0.717 g, 29.88 mmol) portionwise. The resulting-suspension was stirred at 23° C. for 30 minutes. N,N-bis(2-chloroethyl)-2-methylpropan-2-amine (2.20 g, 9.39 mmol) was then slowly added over 5 minutes, then the suspension was heated at 65° C. overnight. The reaction was then diluted with 1N hydrochloric acid and washed with ethyl acetate (2×). The aqueous phase was basified with sat. aq. sodium carbonate and extracted with ethyl acetate (3×). The combined extracts were washed with water (5×), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil (1.40 g, 68%) which solidified on standing and was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ ppm: 2.10-2.17 (3H, m), 2.31-2.37 (1H, m), 2.42 (3H, s), 2.47-2.57 (2H, m), 3.01 (2G, d, J=12.6 Hz), 7.45 (2H, dd, J=4.55 and 1.52 Hz), 8.68 (2H, dd, J=4.55 and 1.77 Hz).