Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[N:16]1[N+:20]([O-])=[C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]2=[N:17]1.C1(C)C=CC=CC=1.N12CCCCC1CNCC=C2.[H][H]>[Ni].CC(O)CC>[OH:1][C:2]1[C:7]([C:8]([CH3:10])([CH3:11])[CH3:9])=[CH:6][C:5]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]2=[N:17]1
Reactant: CC(C)(C)c1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Ni]
Agent: C1=CN2CCCCC2CNC1
Solvent: CCC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 78.8 %

Procedure:
37.4 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole-N-oxide, 0.25 g of Raney nickel catalyst, 150 ml of toluene, 100 ml of 2-butanol and 0.5 g of 1,5-diazabicyclo[5.4.0]undecene were charged into a 500-ml stainless autoclave equipped with an agitator. After the air in the autoclave had been replaced by nitrogen, hydrogen was charged to a pressure of 8 kg/cm2. The temperature of the resultant mixture was increased to 60° C. under agitation, and reaction was been effected while agitation being continued until no hydrogen gas was absorbed by the mixture. After the reaction had been completed, after treatment was performed in the same way as that employed in Example 9 to obtain 28.2 g of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole as a target substance (yield, 79%; melting point, 153° to 155° C.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C@H:12]1[O:16][C:15](=[O:17])[C@H:14]([CH2:18][CH2:19][CH3:20])[CH2:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([O:11][S:29]([CH3:28])(=[O:31])=[O:30])[C@@H:12]1[CH2:13][C@@H:14]([CH2:18][CH2:19][CH3:20])[C:15](=[O:17])[O:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@@H]1C[C@@H]([C@H](O)COCc2ccccc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@@H]1C[C@@H]([C@@H](COCc2ccccc2)OS(C)(=O)=O)OC1=O
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 12.1 g of (3R,5S)-5-[(R)-2-benzyloxy-1-hydroxyethyl]-3-propyldihydrofuran-2-one obtained in Example (116c) (43.5 mmol) in methylene chloride (300 ml) was cooled in an ice bath. Then, 13.2 g of triethylamine (131 mmol) and 7.30 g of methanesulfonyl chloride (63.7 mmol) were added thereto, and the mixture was stirred at the same temperature for one hour. 500 ml of water was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=4/1-1/1) to obtain 15.2 g of the title compound (yield: quant.).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]#[C:13][NH2:14].[Na].O.Cl>CN1CCCC1=O>[CH3:11][O:10][C:4]1[N:3]=[C:2]([NH:14][C:13]#[N:12])[C:7]([O:8][CH3:9])=[CH:6][N:5]=1
Reactant: N#CN
Reactant: COc1ncc(OC)c(Cl)n1
Agent: Cl
Agent: [Na]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ncc(OC)c(NC#N)n1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 76.4 %

Procedure:
4-Chloro-2,5-dimethoxypyrimidine (CDMP; 15 g, 0.086 mol) was dissolved in N-methyl-2-pyrrolidinone (NMP; 62.5 g) at ambient temperature. Sodium hydrogen cyanamide (12.1 g, 2.2 eq) was added all at once, and the mixture was heated to 50° C. with stirring for 2.5 h. The resulting slurry was cooled to 25° C., and 150 mL of water was added. Concentrated hydrochloric acid was added drop-wise until a pH of 5.5 was reached. The thick slurry was filtered and washed twice with 10 mL of water to afford 2,5-dimethoxy-4-cyanoamino-pyrimidine (2) as a white solid (11.83 g, 76% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:16]([CH3:17])[C:3]=12.[OH-].[Na+].C(O)(=O)C>CS(C)=O.O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:16]([CH3:17])[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc(-c3cccnc3)c(C)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1nc2sc(-c3cccnc3)c(C)c2c(N)c1C(=O)O
Temperature: 120 °C
Yield: 89.2 %

Procedure:
A mixture of ethyl 4-amino-3,6-dimethyl-2-(3-pyridinyl)thieno[2,3-b]pyridine-5-carboxylate (120 mg, 0.367 mmol) (Description 32) in DMSO (3 mL) and 2M NaOH (0.916 mL, 1.833 mmol) was heated at 120° C. for 1 h. After cooling to RT, the mixture was diluted with water (20 mL), acidified with acetic acid to pH 6. The mixture was extracted with 10% MeOH in DCM (5×30 mL). The combined organics were dried and concentrated. The residue was passed through a C18 solid phase extractor cartridge, eluted with water (4×30 mL) followed by MeOH (4×30 mL). The combined organics were concentrated and dried at 55° C. in a vacuum oven, to afford the title compound (98 mg). LCMS (A) m/z: 300 [M+1]+, Rt 0.58 min (acidic).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16].C(N(CC)C(C)C)(C)C>C(OCC)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([NH:17][CH3:18])=[O:16])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Yield: 49 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-nitropyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in ethyl ether (no microwave—20° C., 3 hours) to afford 2-(2-chloro-5-nitro-pyrimidin-4-ylamino)-N-methyl-benzamide as a yellow solid in 49% yield. Mp: 201-3° C. (dec); MS: 308.09 (M+H); 1H NMR (d6-dmso): δ 12.43 (s, 1H), δ 9.20 (s, 1H), δ 8.75 (br s, 1H), δ 8.19 (d, J=9 Hz, 1H), δ 7.71 (d, J=8 Hz, 1H), δ 7.58 (t, J=8 Hz, 1H), δ 7.33 (t, J=8 Hz, 1H), δ 2.78 (d, J=5 Hz, 3H).
Reaction SMILES: [C:1]1([N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N(C2C=CC=CC=2)/[C:28](/[C:36]2[CH:41]=[CH:40]C=CC=2)=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C=CC=CC=1>C(OCC)(=O)C.CO>[C:15]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:40][C:41]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]=[CH:28][CH:36]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Reactant: C(=C(\c1ccccc1)N(c1ccccc1)c1ccccc1)\c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: C(=C(c1ccccc1)N(c1ccccc1)c1ccccc1)c1cccc2ccccc12

Procedure:
This compound was synthesized from diphenylbenzylamine and N-phenyl-1-naphthaldimine under the same conditions outlined for (E)-1-(diphenylamino)-1-phenyl-2-phenylethylene above. Recrystallizatiom from ethyl acetate/methanol gave small crystals mp 170-2° C. 1H NMR (200 MHz, CDCl3) δ (assignment): 6.60-6.90 (m, 2 H, aromatic), 6.80-7.38 (m, 15 H, aromatic), 7.52-7.85 (m, 6 H, aromatic). MS [m/e (70 eV, % of base peak] C10H7CHCPhNPh2 397 (M+., 43.1), 180 (PhCNPh+, 100), 77 (Ph+, 43.2); HRMS (m/z) for C30H23N (M+.), calcd. 397.183 found 397.195.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[F:11][CH:12]([F:25])[O:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[F:25][CH:12]([F:11])[O:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=1
Reactant: Oc1ccc2ccoc2c1
Reactant: Fc1ccc(C(F)(F)F)cc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)Oc1cc(C(F)(F)F)ccc1Oc1ccc2ccoc2c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-benzofuran-6-ol (13.4 g, 100 mmol) and 2-(difluoromethoxy)-1-fluoro-4-trifluoromethylbenzene (29.9 g, 130 mmol) in DMF (300 mL) was added cesium carbonate (65.2 g, 200 mmol). The reaction mixture was stirred at 75° C. for 16 hours (or at 110° C. for 2 hours). After cooling to room temperature, it was diluted with ethyl acetate, washed with water (2×) and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified on a silica gel column, eluting with ethyl acetate (0-20%) in hexanes. The final product was collected as a colorless oil. 1H NMR (CDCl3, δ ppm): 6.7 (t, 1H, J=74 Hz), 6.8 (s, 1H), 7.0 (m, 2H), 7.2 (s, 1H), 7.4 (d, 1H), 7.6 (m, 3H).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[C:9]2[C:10](=[CH:17][C:18]3[C:23]=2[CH2:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[N:11]([CH2:13][CH:14](O)[CH3:15])[N:12]=1.C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:33]([CH:14]([CH3:15])[CH2:13][N:11]1[C:10]2=[CH:17][C:18]3[C:23]([CH2:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[C:9]2[C:8]([O:7][CH3:6])=[N:12]1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=C2C=c3c(c(OC)nn3CC(C)O)=C2CC=C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C2C=c3c(c(OC)nn3CC(C)N=[N+]=[N-])=C2CC=C1
Yield: 48.8 %

Procedure:
1.21 ml (15.2 mmol) of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0% of 2.08 g (7.6 mmol) of (RS)-1-(3,7-dimethoxy-1,4-dihydro-indeno[2,1-c]-pyrazol-1-yl)-propan-2-ol and 4.3 ml (30.4 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 110 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 1 g (15.4 mmol) of sodium azide and the reaction mixture was heated to 70° for 20 hours while stirring. After cooling, the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 80 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.11 g (49%) of (RS)-1-(2-azido-propyl)-3,7-dimethoxy-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2].[CH3:27][O:28][CH2:29][C:30]([OH:32])=O>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[C:30](=[O:32])[CH2:29][O:28][CH3:27])[CH:11]=1)[CH3:2]
Reactant: COCC(=O)O
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)COC)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester and methoxyacetic acid were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-ethyl-N-(2-methoxy-acetyl)-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 30, Step 2.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[S:4]([NH2:7])(=[O:6])=[O:5].[C:22](OC)(OC)(OC)[O:23][CH3:24].C(O)(=O)C>O1CCOCC1>[CH3:22][O:23][C:24]1[O:1][C:2]([CH3:21])([CH3:20])[CH:3]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:12][CH:13]=2)[S:4](=[O:5])(=[O:6])[N:7]=1
Reactant: COC(OC)(OC)OC
Reactant: CC(C)(O)C(c1ccc(N2CCOCC2)cc1)S(N)(=O)=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(c2ccc(N3CCOCC3)cc2)C(C)(C)O1

Procedure:
2-Hydroxy-2-methyl-1-(4-morpholin-4-ylphenyl)propane-1-sulfonamide (41 mg) was stirred with tetramethyl orthocarbonate (0.2 ml), glacial acetic acid (0.01 ml) and dioxane (0.1 ml) at 90° C. for 4 hours. The solvents were removed under reduced pressure and the residue was used further without further purification.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Ca+2].[Cl-].Cl.C([O:27][CH2:28][CH3:29])(=O)C>O>[OH:19][C:13]1[CH:18]=[CH:17][C:16]([C:4]2([C:1]3[CH:6]=[CH:29][C:28]([OH:27])=[CH:3][CH:2]=3)[CH2:5][CH2:6][CH:1]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)=[CH:15][CH:14]=1
Reactant: CCOC(C)=O
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: Oc1ccc(C2(c3ccc(O)cc3)CCC(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
(1st step): To a mixture of 51.6 g of 4-phenylcyclohexane, 111.5 g of phenol and 65.7 g of calcium chloride, 24.7 ml of concentrated hydrochloric acid was slowly added dropwise by vigorous stirring of the mixture at room temperature. Then, the mixture was stirred for eight hours and left for more 168 hours at room temperature. 0.3 liters of warm water and one liter of ethyl acetate were added to the mixture to dissolve by heating, and the mixture was washed with a saturated sodium chloride solution (warm water of 40°-50° C. was used). After drying with MgSO4, the mixture was filtered and concentrated. The resultant concentrate was recrystallized with toluene to obtain 64.9 g of white 1,1-bis(4-hydroxyphenyl)-4-phenylcyclohexane. The melting point was 262.1°-263.3° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH3:28].[K+].[Br-].C(O)(C(F)(F)F)=O>C(#N)C.O>[CH3:28][C:7]1[CH:8]=[C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:29])=[O:2]
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccccn3)cc2)cc1C
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cc(SCc2ccc(OCc3ccccn3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 60A. mp 150° C.; IR (KBr) cm−1: 2917, 1723, 1605, 1511, 1490, 1217; 400 MHz 1HNMR (DMSO-d6): δ 12.95 (brs, 1H), 8.49-8.55 (s, 1H), 7.73-7.81 (m, 1H), 7.40-7.48 (m, 1H), 7.24-7.33 (m, 1H), 7.00-7.19 (m, 4H), 6.83-6.93 (m, 2H), 6.69 (d, 1H, J=8.5 Hz), 5.08 (s, 2H), 4.62 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H); HPLC: area %=96.24, r.t.=1.95 min., γ=214 nm, mobile phase=acetonitrile/water with 0.10% TFA; MS m/z 396 (M+1). Anal. Calc'd for C22H21NO4S: C, 66.82; H, 5.35; N, 3.54. found: C, 66.12; H, 5.09; N, 3.44.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].[C:12]([Cl:15])(=[O:14])[CH3:13]>C(O)(=O)C>[C:12]([C:6]([CH2:7][C:8](=[O:10])[O-:9])([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[OH:11])(=[O:14])[CH3:13].[Cl-:15]
Reactant: CC(=O)Cl
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Product: [Cl-]
Temperature: 50 °C
Reaction time: 48 h

Procedure:
2 grams of carnitine chloride were dissolved in 20 ml of glacial acetic acid, and acetyl chloride (10 ml) was added thereto. The reaction mixture was kept at room temperature for 48 hours. The excess of acetyl chloride and the solvent were removed under vacuum, by heating on a water bath at 50° C. The residue was crystallized from isopropanol-ethyl ether, and a pure product was thus obtained.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=CC(F)=C[C:24]=3F)[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.C(OC(N1CC(C2C=CC3C4C(CCOC=3C=2)=CN(C2N(C(C)C)N=CN=2)N=4)C1)=O)(C)(C)C>>[ClH:1].[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([CH:23]([CH3:28])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Agent: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(C3CN(C(=O)OC(C)(C)C)C3)cc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(C3CNC3)cc1OCC2

Procedure:
8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was prepared similarly to 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride from 3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester. LCMS: RT=2.86 min, M+H+=351 (20%), M+H+-iPr=308 (100%).
Reaction SMILES: Cl[N:2]1[C:7](=[O:8])[C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=[N:3]1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C(Cl)[Cl:18]>>[Cl:9][C:6]1[C:7](=[O:8])[N:2]([CH:16]2[CH:15]([Cl:18])[CH2:14][CH2:13][CH2:12][O:11]2)[N:3]=[CH:4][C:5]=1[Cl:10]
Reactant: ClCCl
Reactant: C1=COCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1Cl
Product: O=c1c(Cl)c(Cl)cnn1C1OCCCC1Cl
Reaction time: 0.5 h

Procedure:
In 20 ml of methylene chloride were dissolved 4 g of 2,4,5-trichloro-3(2H)-pyridazinone, and thereto dropwise added 2.5 g of 2,3-dihydro-pyran under ice-cooling. The solution was stirred for 30 minutes and the by-produced 4,5-dichloro-3(2H)-pyridazinone was filtered off. The filtrate was distilled off under reduced pressure. The oil thus obtained was separated by means of column chromatography (on silica gel, eluting with benzene) to give 1.5 g of trans-form as the first fraction (m.p.: 136°-137° C.) and 1.3 g of cis-form as the second fraction (m.p.: 109°-110° C.).
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(OC([N:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][S:22][CH2:21]1)=O)(C)(C)C.N1C(C)=CC=CC=1C>C(Cl)Cl.CO>[NH:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][S:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CSCc2ccccc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: c1ccc2c(c1)CSCN2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.47 ml of trimethylsilyl trifluoromethanesulfonate are added dropwise to a solution of 1.0 g of N-tert-butoxycarbonyl-3,4-dihydro-1H-2,4-benzothiazine in 35 ml of methylene chloride at room temperature, and 1.41 ml of 2,6-lutidine is added. The reaction mixture is stirred at room temperature for 20 minutes and then diluted with 5 ml of methanol and concentrated. The crude product is purified by means of FC (30 g of silica gel, mobile phase G). This gives the pure title compound: Rf (D)=0.26; Rt (I)=19.5 min; anal. calc. for C8H9NS: C 63.54%, H 6.00%, N 9.26%; found C 63.22%. H 6.01%, N 8.99%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:28])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:28][C:35](=[O:37])[CH3:36])[C:24]([F:25])([F:26])[F:27])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
A solution of 6-(1-Azido-2,2,2-trifluoroethyl)-9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (68.2 mg, 0.143 mmol) and triphenylphosphine (56.3 mg, 0.215 mmol) in tetrahydrofuran (5.0 mL) and water (0.10 mL) was stirred at 60° C. for 20 hr. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture to give 1-[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine as a white solid (67.2 mg). To a solution of 1-[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (67.9 mg) and pyridine (0.12 mL, 1.48 mmol) in tetrahydrofuran (5.0 mL) was added acetyl chloride (0.051 mL, 0.717 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. Aqueous sodium hydrogen carbonate was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 25-80% ethyl acetate/n-hexane gradient mixture to give the title compound (33.1 mg, 0.067 mmol, 47%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:37]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)#[N:38]>O1CCOCC1>[NH2:1][C:2]1[N:3]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:4](=[O:23])[C@@:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:43]4[CH:44]=[C:39]([CH:40]=[CH:41][CH:42]=4)[C:37]#[N:38])[CH:14]=3)[O:9][C@@H:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[NH2:1][C:2]1[N:3]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:4](=[O:23])[C@@:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:43]4[CH:44]=[C:39]([CH:40]=[CH:41][CH:42]=4)[C:37]#[N:38])[CH:14]=3)[O:9][C@H:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)[C@@]2(C[C@@H](c4ccccc4)O3)N=C(N)N(Cc3ccccc3)C2=O)c1
Product: N#Cc1cccc(-c2ccc3c(c2)[C@@]2(C[C@H](c4ccccc4)O3)N=C(N)N(Cc3ccccc3)C2=O)c1
Temperature: 130 °C
Yield: 33 %
Yield: 4.8 %

Procedure:
To a solution of 2′-amino-1′-benzyl-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (17.3 mg, 0.04 mmol) in 1,4-dioxane (1.5 mL) there is added Cs2CO3 (excess), 3-cyanophenylboronic acid (excess), and catalytical amount of PdCl2dppf. After degassing, the resulting mixture is heated in a CEM microwave reactor at 130° C. for 30 min. Solvent is removed in vacuo and the residue is purified by reversed phase HPLC to give 3-((2R,4R)-2′-amino-1′-benzyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (6.0 mg, 33%) as a TFA salt (135a) and 3-((2S,4R)-2′-amino-1′-benzyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (0.86 mg, 4.8%) as a TFA salt. (135b).