Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]1[C:13](=[O:15])[O:18][C@H:16]1[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCOC(=O)N[C@H]1C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 15 h
Yield: 36.1 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of employing (2R,3S)-2-(heptoxycarbonylamino)-3-hydroxy-butanoic acid (0.3 g, 1.14 mmol) in dry CH2Cl2 (30 mL), Et3N (0.48 mL, 3.44 mmol) and subsequently TBTU (0.44 g, 1.37 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy:EtOAc (from 100:0 to 0:100) to afford the title compound (0.10 g, 37%), as white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][NH:12][CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH:16](O)=O>C=O.O.[OH-].[Na+]>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][N:12]([CH3:16])[CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=CO
Reactant: Clc1ccc(C23CNCC2C3)cc1Cl
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1CC2CC2(c2ccc(Cl)c(Cl)c2)C1
Temperature: 90 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
To a stirred solution of 1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride (30.0 g, 132 mmol) in 37% aqueous formaldehyde (25.8 mL) was added formic acid (32.4 mL). The resulting solution was stirred at 90° C. for 6 h. The reaction was then diluted with water (100 mL) and 2N aqueous sodium hydroxide added until the pH was greater than 9. The resulting mixture was extracted with CH2Cl2 (2×200 mL) and the combined organic extracts were washed with brine (200 mL), dried (MgSO4) and concentrated under vacuum to provide the title compound (25.0 g, 79% yield) as an orange oil: LC (ELS)/MS: >99%, m/z 242.1 [C12H13Cl2N+H]+; 1H NMR (300 MHz, CDCl3): δ 0.94 (dd, 1H, J=5.3 Hz, J=7.9 Hz), 1.73 (t, 1H, J=4.7 Hz), 1.80 (m, 1H), 2.55 (s, 3H), 2.78 (d, 2H, J=9.2 Hz), 3.35 (d, 1H, J=9.6 Hz), 3.54 (d, 1H, J=9.3 Hz), 6.99 (dd, 1H, J=2.1 Hz, J=8.3 Hz), 7.24 (d, 1H, J=2.1 Hz), 7.35 (d, 1H, J=8.3 Hz).
Reaction SMILES: [O:1]=[C:2]([C:22]1[CH:27]=[CH:26][C:25]2[O:28][CH2:29][O:30][C:24]=2[CH:23]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]([CH2:19][CH3:20])[C:11]2=[O:21])[CH2:6][CH2:5]1.[BH4-].[Na+]>CO>[OH:1][CH:2]([C:22]1[CH:27]=[CH:26][C:25]2[O:28][CH2:29][O:30][C:24]=2[CH:23]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]([CH2:19][CH3:20])[C:11]2=[O:21])[CH2:6][CH2:5]1
Reactant: CCn1c(=O)n(C2CCN(CC(=O)c3ccc4c(c3)OCO4)CC2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCn1c(=O)n(C2CCN(CC(O)c3ccc4c(c3)OCO4)CC2)c2ccccc21
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
1.25 g of the product obtained in Example 26 is dissolved in 50 ml of methanol. 300 mg of sodium borohydride is added thereto over 30 minutes at room temperature, and the mixture is stirred for one hour at the same temperature. Then, the same post-treatment as in Example 11 is conducted to obtain a crude product. Recrystallization thereof from ethanol yields 0.9 g of 1-[2-hydroxy-2-(3,4-methylenedioxyphenyl)-1-ethyl]-4-(3-ethyl-2-keto-1-benzimidazolinyl)-piperidine.
Reaction SMILES: [OH-].[K+].C(=O)([O-])[O-].[K+].[K+].[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:17]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=4)[NH:21][CH:20]=3)=[CH:18][C:11]=12.[Cl:42][CH2:43][CH2:44]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:17]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=4)[N:21]([CH2:44][CH2:43][Cl:42])[CH:20]=3)=[CH:18][C:11]=12
Reactant: ClCCCl
Reactant: COc1cc2[nH]cc(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCl)c2cc1OC
Reaction time: 5 h

Procedure:
0.79 g of potassium hydroxide and 0.61 g of potassium carbonate are added to a solution of 1 g of 4-chloro-2-(5,6-dimethoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.013 g of tetrabutylammonium bromide in 25 ml of 1,2-dichloroethane. The suspension obtained is brought to around 50° C. for approximately 5 hours. After returning to a temperature in the region of 20° C. and agitating at this temperature for approximately 16 hours, the reaction mixture is filtered through celite; the insoluble material is washed with three times 10 ml of dichloromethane. The filtrate is washed with three times 50 ml of water, dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (75/25 by volume)]. 0.62 g of 4-chloro-2-[1-(2-chloroethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[N-:39]=[N+:40]=[N-:41].[Li+]>CS(C)=O>[N:39]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a stirred suspension of 11.15 g (20 mmole) of 5-[4'-(bromomethyl)biphenyl-2-yl]-N-trityltetrazole [P. E. Aldrich, M. E. Pierce, and J. J. V. Duncia, European Patent Application 291,969 (1988)]in 55 ml of dry DMSO was added 1.23 g (25 mmole) of freshly pulverized lithium azide, and the mixture was stirred at room temperature under N2. Within a few minutes virtually all of the solid had dissolved, accompanied by a mild exotherm, and this was followed immediately by precipitation of product. After 4 hours the solid was collected on a filter and washed with some methanol, then with a relatively large volume of H2O, and finally again with methanol. The solid was air-dried overnight and-then dried further in a vacuum oven at 70° C. (<1 mm) to give 8.60 g (83%) of white crystals, mp 139°-140.5° C. dec., satisfactory purity by TLC (9:1 hexane-ethyl acetate) for use in the next step. From the combined filtrate and washes was recovered a less pure second crop (1.68 g of cream-colored crystals, mp 129°-132° C. dec.), which was also usable in the next step. Mass spectrum (FAB) m/e 243 (trityl cation); IR (Nujol) 2100 cm-1.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][S:11]([NH2:14])(=[O:13])=[O:12].CN(C)CC(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CCOC(C)=O.[Cu](I)I>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:14][S:11]([CH3:10])(=[O:13])=[O:12])=[CH:3][CH:4]=1)=[O:7]
Reactant: CS(N)(=O)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(C=O)cc1
Yield: 57.7 %

Procedure:
A mixture of 4-bromobenzaldehyde (0.250 g, 1.40 mmol), methanesulfonamide (0.154 g, 1.62 mmol), copper iodide (0.0510 g, 0.270 mmol), N,N-dimethylglycine (0.0280 g, 0.270 mmol), and potassium phosphate tribasic (0.716 g, 3.38 mmol) in DMF (5.00 mL) was stirred at reflux for 16 hours. The mixture was diluted with EtOAc (50 mL), washed with water (50 mL), and then saturated aqueous LiCl (5 mL). The combined aqueous layers were then back-extracted with EtOAc (50 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure, to provide N-(4-formylphenyl)methanesulfonamide (0.161 g, 58%) as a yellow oil.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[N+]=[N-].C1CC=CCC=1>[Pd].C(O)C>[NH2:1][CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To an ice-cooled suspension of (R)-5-(2-azido-1-(tert-butyldimethylsilyloxy)-ethyl)-8-(benzyloxy)quinolin-2(1H)-one (5.77 g, 12.8 mmol) and palladium on activated charcoal (5.8 g, 10% w/w wet) in ethanol (50 mL), 1,4-cyclohexadiene (12.0 mL, 126 mmol) was added dropwise. After stirring at this temperature for 30 minutes, the coolant was removed and replaced with a water bath at 30° C. The reaction was stirred at this temperature for 1 hour. The suspension was filtered and the filter cake washed with further ethanol. The filtrate was evaporated under reduced pressure to dryness. The resulting solid was suspended in acetonitrile and stirred for 1 hour. The suspension was filtered and the resulting solid air-dried under vacuum to afford the title compound (2.90 g, 87%).
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:17]([CH2:18][C:19]([OH:21])=O)=[CH:16][N:15]=[CH:14]1.[CH3:22][O:23][C:24](=[O:36])[CH:25]([NH2:35])[CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=C2C(N(O)N=NC2=CC=1)=O.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:22][O:23][C:24](=[O:36])[CH:25]([NH:35][C:19](=[O:21])[CH2:18][C:17]1[N:13]([CH2:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=2)[CH:14]=[N:15][CH:16]=1)[CH2:26][NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29]
Reactant: COC(=O)C(N)CNC(=O)OC(C)(C)C
Reactant: O=C(O)Cc1cncn1Cc1ccc2ccccc2c1
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)C(CNC(=O)OC(C)(C)C)NC(=O)Cc1cncn1Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl]acetic acid hydrochloride (3.83 g, 12.7 mmol), 3-t-butoxycarbonylamino-2(R,S)-aminopropionic acid methyl ester (3.33 g, 15.3 mmol), HOOBT (2.30 g, 14.1 mmol), and triethylamine (5.80 ml, 42.0 mmol) in DMF (150 ml) at 0° C., was added EDC (2.67 g, 13.9 mmol). The reaction was stirred at room temperature for 18 hrs, diluted with EtOAc and the organic layer washed with sat. aq NaHCO3, brine, dried (Na2SO4), and the solvent evaporated in vacuo. The residue was chromatographed (SiO2, 5% MeOH in CH2Cl2) to afford the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][N:17]([CH3:19])[CH3:18])[N:9]=[CH:10]2.[NH3:21]>CO>[Cl:15][C:14]1[C:5]([CH2:4][C:3]([NH2:21])=[O:2])=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][C:8]([CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7]2
Reactant: N
Reactant: COC(=O)Cc1c(Cl)ccc2cnc(CN(C)C)cc12
Solvent: CO
Product: CN(C)Cc1cc2c(CC(N)=O)c(Cl)ccc2cn1
Temperature: 70 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of (6-chloro-3-dimethylaminomethyl-isoquinolin-5-yl)-acetic acid methyl ester (515 mg, 1.76 mmol) in a mixture of methanol (10 mL) and liquid ammonia (10 mL) was stirred for 16 h in an autoclave at 70° C. After careful evaporation of the ammonia, the remaining solvent was evaporated in vacuo to afford the title compound as a brown solid (410 mg, 1.48 mmol, 84%). MS (ES+): 278 (M(C14H1635ClN3O)+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]1[N:13]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-])=O)=[CH:18][C:19]=3[C:6]1=[N:5]2.[H][H].C(Cl)Cl>CC(N(C)C)=O.[Pd]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]2[N:13]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:7]3[C:6]([C:19]=2[CH:18]=1)=[N:5][C:4]1[C:9](=[CH:10][C:11]([CH3:12])=[C:2]([CH3:1])[CH:3]=1)[N:8]=3
Reactant: Cc1cc2nc3c4cc([N+](=O)[O-])ccc4n(CCN(C)C)c3nc2cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1cc2nc3c4cc(N)ccc4n(CCN(C)C)c3nc2cc1C
Yield: 84 %

Procedure:
A suspension of 3.63 9 (10 mmol) of (2d) and 0.36 g 10% Pd/C in 160 ml DMA was left under 2.7 atm hydrogen pressure for 24 h. The product was soluble in DMA. Pd/C was filtered away with celite. The filtrate was poured onto ice-water and pH was increased to basic with 20% KOH, which resulted in a brown precipitate. The precipitate was chromatographied in 20% MeoH/CH2Cl2, which resulted in 2.80 g of the product (3d).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:19]1[C:24]([I:25])=[CH:23][N:22]=[CH:21][N:20]=1>C(O)(C)C>[I:25][C:24]1[C:19]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[N:20][CH:21]=[N:22][CH:23]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1cccc(N)c1
Reactant: Clc1ncncc1I
Solvent: CC(C)O
Product: Cc1ccc(C(=O)O)cc1-c1cccc(Nc2ncncc2I)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3′-Amino-6-methylbiphenyl-3-carboxylic acid (3.00 g, 0.0132 mol) was mixed with 4-chloro-5-iodopyrimidine (3.30 g, 0.0137 mol) and isopropyl alcohol (60 mL). The resulting mixture was heated to 80° C., at which temperature solution occurred. A short time later, the product began to precipitate. After 2 h, HPLC showed 95% conversion of to product. HPLC Method: Zorbax SB C18, 5 μm, 15 cm, 35 C, flow 1.2 mL/min, 25% CH3CN—H20 (0.05% TFA), to 100% CH3CN in 8.0 min; stop time 11 min; detector 254 &220 nm; retention time starting material, 2.8 min (UVmax 205 & 230 nm); pyrimidine, 4.8 min (UVmax 240 & 270 nm); product, 4.9 min (UV max 204, 228, & 290 nm). The reaction was cooled to 20° C. The product was isolated by filtration, rinsed with iPrOH, then vacuum dried. Yield 5.35 g of a light tan powder. The product is believed to be the HCl salt or partial salt. 1H NMR (300 MHz, DMSO) δ 9.62 (br s, 1H, NH); 8.83 (s, 1H); 8.69 (s, 1H); 7.83 (dd, 1H); 7.76 (d, 1H); 7.42-7.58 (m, 4H); 7.25 (dt, 1H); 2.33 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:14]([C:12]#[N:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3]1
Reactant: CCOC(=O)CC#N
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C1CC(C)(C)CC(C)(C)C1
Yield: 47.2 %

Procedure:
The mixture of 3,3,5,5-tetramethylcyclohexanone (2-13) (2.64g, 17 mmol), ethyl cyanoacetate (1.93, 17 mmol), acetic acid (0.2 ml) and ammonium acetate (0.2 g) in benzene (6.4 ml) was refluxed with a Dean-Stark aparatus for 10 h. To this benzene (30 ml) and saline (30 ml) was added, organic layer separated, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography, eluting with hexane to give 2.0 g (50%) of (16) as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[S:21]1[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:26]([C:23]2[CH:24]=[CH:25][S:21][CH:22]=2)=[O:27])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccsc1
Agent: Cl
Product: O=C(CNC(=O)c1ccsc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 3-thiophenecarboxylic acid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[H-].[Na+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Ic1ccc(N(Cc2ccccn2)c2ncccn2)cc1
Yield: 71.9 %

Procedure:
In the same manner as in Reference Example 22, N-(4-iodophenyl)pyrimidin-2-amine (300 mg) and 2-bromomethylpyridine hydrobromide (307 mg) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-N-((pyridin-2-yl)methyl)pyrimidin-2-amine (282 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[N:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1.[C:22]([NH:25][NH2:26])(=O)[CH3:23]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22]([CH3:23])=[N:25][N:26]=[C:10]3[N:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NN1C
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NN2C

Procedure:
A mixture of 7.25 grams (23.0 m moles) of 7-chloro-3-methyl-(methylthio)-5-phenyl-3H-1,3,4-benzotriazepine (Example 27), 4.8 grams (65 moles) of acethydrazide, and 100 ml of n-butanol was stirred and refluxed under nitrogen for about 17 hours. The solvent was removed in vacuo on a rotary evaporator. The residue was dissolved in methylene chloride. The resulting solution was washed with water, dried with magnesium sulfate, and concentrated in vacuo. The residue was dissolved in a minimum amount of warm carbon tetrachloride. The solution was cooled and seeded with product. The precipitate was collected, washed with cold carbon tetrachloride, and air dried to yield the title compound as a yellow solid. The melting point was found to be 225.5°-227.5° C. The structure was confirmed by elemental analysis.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH3:11][C:12]1[CH:21]=[CH:20][C:15]([CH2:16][N:17]=[C:18]=[O:19])=[CH:14][CH:13]=1>>[CH3:11][C:12]1[CH:21]=[CH:20][C:15]([CH2:16][NH:17][C:18]([N:2]2[C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1]2)=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(CN=C=O)cc1
Reactant: O=c1[nH]sc2ccccc12
Product: Cc1ccc(CNC(=O)n2sc3ccccc3c2=O)cc1

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 61 (54% yield) was synthesized from benzo[d]isothiazol-3-one and 4-methylbenzyl isocyanate as a white solid. mp 171-173° C.; IR(KBr) 3281, 1711, 1650, 1538 cm−1; 1H-NMR (DMSO-d6) δ2.27 (s, 3H), 4.48 (d, J=5.8 Hz, 2H), 7.14 (d, J=8.2 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 7.48 (t, J=7.8 Hz, 1H), 7.78 (t, J=8.2 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 8.01 (d, J=8.2 Hz, 1H), 9.22 (br t, J=5.8 Hz, 1H); ESIMS m/e 299 (M++1).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>>[F:10][C:8]1[CH:9]=[C:2]([C:22]2[N:18]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:19]=[CH:20][CH:21]=2)[CH:3]=[C:4]([F:11])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(F)cc(Br)cc1F
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: N#Cc1c(F)cc(-c2ccnn2C2CCCCO2)cc1F
Yield: 108.8 %

Procedure:
The title compound was prepared from 4-bromo-2,6-difluorobenzonitrile (2.5 g, 11.47 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.51 g, 12.61 mmol) using the method of Example 34(a) producing 3.61 g of title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.52-1.67 (m, 3H), 1.81-1.87 (m, 1H), 1.95-1.99 (m, 1H), 2.33-2.41 (m, 1H), 3.59-3.65 (m, 1H), 3.94-3.98 (m, 1H), 5.36-5.39 (m, 1H), 6.77 (d, 1H), 7.62 (s, 1H), 7.64 (s, 1H), 7.66 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:5]2=[N:6][CH:7]=1.CC(N=NC(C#N)(C)C)(C#N)C.[Cl:25]C1C=CC=CC=1>>[Cl:25][CH2:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1ccccc1
Reactant: Cc1cnc2c(c1)C(=O)OC2=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: O=C1OC(=O)c2ncc(CCl)cc21
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
106.8 g (0.65 mol) of 5-methyl-2,3-pyridine dicarboxylic acid anhydride were dissolved in 427 g chlorobenzene and heated up to 85° C. A solution of 0.64 g (0.004 mol) AIBN in 99.0 g (0.66 mol) SO2Cl2 was added during 45 min. The mixture was stirred for additional 90 min at 85° C. Chlorobenzene was partly distilled off and the solution was cooled to 10° C. via 10 h ramp. The precipitate was filtered off and washed with chlorobenzene/hexane.
Reaction SMILES: [OH-].[Na+].O.Cl.[CH2:5]([NH2:7])[CH3:6].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13]>CO>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:7][CH2:5][CH3:6])=[O:13]
Reactant: CCN
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNC(=O)c1cccc(Br)c1
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
To a solution of sodium hydroxide (3.80 g) in methanol (50 ml)—water (15 ml) was added by portions ethylamine hydrochloride (7.80 g) at 0° C. and the mixture was stirred for 5 min. 3-Bromobenzoyl chloride (5.53 g) was added dropwise and the mixture was stirrd at room temperature for 1 h. Methanol was evaporated under reduced pressure, and ethyl acetate was added to the residue for partitioning. The organic layer was washed with water and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (5.47 g) as colorless powder crystals.