Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[S:31][C:32]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:33]=4[N:34]=3)=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:9][CH:8]([CH3:10])[C@H:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[S:31][C:32]4[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:35][C:33]=4[N:34]=3)=[O:29])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])[C:6]([OH:43])=[O:5]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4cc(C(F)(F)F)ccc4s3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4cc(C(F)(F)F)ccc4s3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To (S)-3-methyl-2-{4′-[(5-trifluoromethyl-benzothiazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester (210 mg) was added 3 mL of TFA/CH2Cl2 (1:1). The solution was stirred at room temperature for 3 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 181 mg of (S)-3-methyl-2-{4′-[(5-trifluoromethyl-benzothiazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid as a yellow solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.83 (dd, J=12.63, 6.82 Hz, 6 H) 1.92-2.00 (m, 1 H) 3.56 (dd, J=9.35, 6.06 Hz, 1 H) 7.80-7.86 (m, 4 H) 7.88-7.92 (m, 2 H) 7.97 (dd, J=8.59, 1.52 Hz, 1 H) 8.05-8.07 (m, 1 H) 8.09 (d, J=2.78 Hz, 1 H) 8.49 (s, 1 H) 8.57 (d, J=8.59 Hz, 1 H) 11.41 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCC[C@H]1C(O)=O)(OC(C)(C)C)=O.[N+:29]([C:32]1[CH:33]=[C:34](O)[CH:35]=[CH:36][CH:37]=1)([O-:31])=[O:30].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH:37]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cccc([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 40 %

Procedure:
A 2.25 g (1.2 mmol) sample of (R)-1-t-butoxycarbonyl-2-azetidinemethanol (prepared as in Example 1b above, except replacing the N-BOC-L-proline thereof with N-BOC-S-azetidinecarboxylic acid) and 2.25 g (18 mmol) of 3-nitrophenol (Aldrich) were added to a complex of TPP and DEAD (prepared as in Example 1 above, 18.1 mmol of each)in 80 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was chromatographed on silica gel, eluting with a gradient of 1:1, 1:2, 1:3, 1:4 chloroform:hexane to give 1.5 g (40%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][NH:37]3)O1>>[NH:37]1[C:38]2[C:34](=[C:33]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][C:6]=4[N:7]=3)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CS(=O)(=O)CCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CS(=O)(=O)CCNCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(2-methanesulfonyl-ethyl)-amine was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in General Procedure A. Purification by column chromatography yielded 383. NMR: CDCl3: 2.95 (3 H, s, Me), 3.18-3.21 (4 H, m, CH2), 3.82-3.85 (4 H, m, CH2), 4.01-4.04 (4 H, m, CH2), 4.12 (2 H, s, CH2), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1 H, s, Ar). MS: (ESI+): MH+ 473.22
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:15]([CH3:24])[N:14]=[N:13][C:12]=1[CH3:25].C(OCC)(=O)C>CN(C=O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[C:11]([N:5]3[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]3)=[C:12]([CH3:25])[N:13]=[N:14][C:15]=2[CH3:24])=[CH:22][CH:21]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2c(C)nnc(C)c2-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
70 mg of sodium hydride (55% oil dispersion) was added to 1 ml of N,N-dimethylformamide (hereinafter, described as DMF) To this was added 0.17 g of 3,5-dimethylpyrazole, and the mixture was stirred for 1 hour at room temperature. To the resultant mixture was added a solution of 0.15 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine in 2 ml of DMF, and the mixture was stirred for 7 hours on an oil bath of 60° C. To the reaction mixture was added ethyl acetate and the mixture was washed with brine five times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. To 0.33 g of the resultant residue was added 50 ml of ethyl acetate, and washed with 50 ml of 1 mol/L hydrochloric acid and brine sequentially, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.21 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.12 g of 5-(4-chloro-phenyl)-4-(3,5-dimethyl-1-pyrazolyl)-3,6-dimethylpyridazine (hereinafter, described as compound (3) of the present invention).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:37]1(=[O:47])(=[O:46])[N:41]2[CH2:42][CH2:43][NH:44][CH2:45][CH:40]2[CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:44]3[CH2:43][CH2:42][N:41]4[S:37](=[O:47])(=[O:46])[CH2:38][CH2:39][CH:40]4[CH2:45]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=S1(=O)CCC2CNCCN21
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3C(CCS3(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 34.8 %

Procedure:
A 8 ml sealed vial was charged with 100 mg (0.187 mmol) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 98 mg (0.561 mmol) of hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide (D10), 52 mg (0.374 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with dichloromethane; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to cyclohexane/ethyl acetate 1:1 and affording 44 mg (0.065 mmol) of the title compound as pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH2:33][CH2:34][NH:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].CO.[Li+].[OH-].Cl>C1COCC1>[CH:39]([O:38][C:36]([NH:35][CH2:34][CH2:33][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:42])=[O:2])=[O:37])([CH3:41])[CH3:40]
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(N4CCOCC4)cc3)oc2C)cc1CCNC(=O)OC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccc(N3CCOCC3)cc2)nc1CCOc1ccc(CCC(=O)O)c(CCNC(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
This ester intermediate was dissolved in THF (0.6 mL) and MeOH (0.4 mL) and treated with aqueous 2M LiOH (1.0 mL, 2.0 mmol). The mixture was stirred for 16 h at ambient temperature, neutralized with HCl (1.0 mL, 2.0 M), and concentrated. The residue was extracted with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified using silica gel chromatography column (hexanes/EtOAc/HOAc, 5/5/0.02) to afford the title compound (10 mg, 18%). MS (ES+) m/z 566.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[CH2:14][C:13]=2[C:12]([C:20]([OH:22])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[CH3:19][N:15]1[C:16](=[O:18])[C:17]2[C:13](=[C:12]([C:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:11]=[CH:10][C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14]1
Reactant: C1CCNC1
Reactant: CN1Cc2c(C(=O)O)ccc(NC(=O)OC(C)(C)C)c2C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1Cc2c(C(=O)N3CCCC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-[(Tert-butoxycarbonyl)amino]-2-methyl-1-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (Compound 116C, 45 mg, 0.15 mmol), pyrrolidine (123 uL, 1.47 mmol), TBTU (236 mg, 0.734 mmol), DIPEA (128 uL, 0.734 mmol) and DMF (1 mL) were mixed and stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed with water (2×) and brine. The crude product was purified by column chromatography. MS (ES+): m/z 360.34 (100) [MH+]; HPLC: tR=1.20 min (UPLC, Analytical).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[OH-].[K+].[F:12][C:13]([F:17])=[C:14]([F:16])Cl>C1S(=O)(=O)CCC1>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]2[O:6][C:13]([F:17])([F:12])[CH:14]([F:16])[O:9][C:4]=2[CH:3]=1
Reactant: FC(F)=C(F)Cl
Reactant: Cc1ccc(O)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Product: Cc1ccc2c(c1)OC(F)C(F)(F)O2

Procedure:
124 g of 4-methylpyrocatechol were initially introduced into 300 ml of tetramethylene sulphone, together with 110 g of potassium hydroxide, at 110° C. 170 g of trifluorochloroethylene were then passed in in the course of 4 hours. The mixture was then distilled over a column under 15 mm Hg, the distillate being removed up to a transition temperature of 85° C. After separating off the aqueous phase in the receiver, the product was again distilled. 133 g ( 65% of theory) of 6-methyl-2,2,3-trifluoro-1,4-benzodioxene were obtained at a boiling point 70°-72° C./12 mm Hg (nD20 : 1.4565).
Reaction SMILES: CS(C)=O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([C@H](N)C(O)=O)CC(N[C@H](C(NCC(O)=O)=O)CS)=O.[CH3:45][CH2:46][CH2:47][CH2:48][CH2:49][C@H:50]([OH:69])/[CH:51]=[CH:52]/[C@@H:53]1[C@@H:57]([CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][C:64]([OH:66])=[O:65])[C@H:56]2[O:67][O:68][C@@H:54]1[CH2:55]2>C(O)(C)C>[CH3:45][CH2:46][CH2:47][CH2:48][CH2:49][C@H:50]([OH:69])/[CH:51]=[CH:52]/[C@@H:53]1[C@@H:57]([CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][C:64]([OH:66])=[O:65])[C:56](=[O:67])[CH2:55][C@H:54]1[OH:68]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H]2C[C@H]1OO2
Agent: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CS(C)=O
Solvent: CC(C)O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 0.01 h

Procedure:
Prostaglandin E synthase microsomal fractions are prepared from CHO-K1 cells transiently transfected with plasmid encoding the human mPGES-1 cDNA. Microsomes are then prepared and the PGES assay begins with the incubation of 5 μg/ml microsomal PGES-1 with compound or DMSO (final 1%) for 20-30 minutes at room temperature. The enzyme reactions are performed in 200 mM KPi pH 7.0, 2 mM EDTA and 2.5 mM GSH-reduced form. The enzymatic reaction is then initiated by the addition of 1 μM final PGH2 substrate prepared in isopropanol (3.5% final in assay well) and incubated at room temperature for 30 seconds. The reaction is terminated by the addition of SnCl2 in 1N HCl (1 mg/ml final). Measurement of PGE2 production in the enzyme reaction aliquots is done by EIA using a standard commercially available kit (Cat #: 901-001 from Assay Designs).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[C:52]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[NH:62][CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)([CH3:55])([CH3:54])[CH3:53]>CN(C=O)C.O>[C:52]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[NH:62][CH:63]1[CH2:68][CH2:67][N:66]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:65][CH2:64]1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)c1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1NC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.088 g, 0.00036 mol) in DMF (2 mL) was added DIPEA (0.211 g, 0.0016 mol), HOBt (0.048 g, 0.00036 mol) and EDCI.HCl (0.125 g, 0.000655 mol) at ambient temperature. After 2 minutes (2-tert-butyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00033 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.07 g (49%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-tert-butyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 460.26 (M+1)+, 89.75%, 1H NMR (DMSO-d6): δ 13.8 (s, 1H), 8.1 (s, 1H), 7.8 (d, 2H), 7.6-7.4 (m, 3H), 7.2-7.0 (m, 3H), 6.8 (d, 1H), 6.6 (t, 1H), 4.3 (d, 1H), 4.2 (d, 2H), 3.9 (m, 2H), 3.7 (s, 1H), 3.2 (t, 1H), 2.8 (t, 1H), 2.0 (t, 3H), 1.4 (s, 9H), 1.0 (bs, 1H).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[OH-].[Na+].[C:14](=[O:16])=[O:15]>>[NH2:1][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C=O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 180 °C
Yield: 75 %

Procedure:
p-Acetaminophenol 15 g, sodium hydroxide 37.5 g, and Y-type molecular sieve 15 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 2.0 MPa and heated to 180° C., maintained for 3 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve sodium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% of hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 99.5% and the yield is 75%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[CH2:7][N:8]([CH2:14][CH3:15])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10].[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:24]=[C:25]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=2[CH2:7][N:8]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH2:14][CH3:15])[C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH3:19]
Reactant: CCN(Cc1cc(Br)ccc1I)C(=O)C1CC1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: cyclopropanecarboxylic acid (5-bromo-2-iodo-benzyl)-ethyl-amide and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](NCC(CN(C)C)=O)[CH2:9][N:8]=[C:7](C3C=CC=CC=3)[C:6]=2[CH:26]=1>C(O)COCCO>[NH:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:26][C:6]=2[CH:7]=[N:8][CH:9]=[CH:10]1
Reactant: CN(C)CC(=O)CNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: OCCOCCO
Product: C1=CNc2ccccc2C=N1

Procedure:
A suspension of 7-chloro-5-phenyl-2-[[3-(dimethylamino)acetonyl]amino]-3H-1,4-benzodiazepine, ethylene ketal (1.5 mmole) is heated to 110 to 120° in diethylene glycol under nitrogen for 20 hours. The above mixture is cooledand evaporated to dryness in vacuo leaving behind a white oil. This is crystallized from ethyl acetate/hexane to give 8-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-imidazo]1,2-a][1,4]benzodiazepine of melting point 181°--182° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]([CH:11]=[O:12])=[CH:9][N:10]=1.[CH3:13][C@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](O)=[O:16].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[CH:11]([C:8]1[S:7][C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:15](=[O:16])[C@@H:14]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH3:13])=[N:10][CH:9]=1)=[O:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCCNc1ncc(C=O)s1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76.2 %

Procedure:
Following the procedure as described in Example 24, except using the material from Example 68 (254 mg, 0.984 mmol), N-alpha-t-BOC-L-Alanine (201 mg, 1.06 mmol), 1-hydroxy-7-azabenzotriazole (70.0 mg, 0.514 mmol), CH2Cl2 (15 mL), N-methylmorpholine (224 μlit, 2.04 mmol), and EDC (229 mg, 1.21 mmol), and stirring at room temp for 45 min., 267.3 mg (76%) of the title compound is obtained as a yellow solid. Purification is done by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 100% EtOAc, over 8.5 column volumes, with a hold at 100% EtOAc for 15 column volumes. LC/MS (Condition A): ret. T=2.54 min, (M+H)+ 357.20.
Reaction SMILES: [CH3:1][C:2]1([CH:8]=[CH:9][C:10](O)=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[N+:13]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:32])([F:31])[F:30])[CH:19]=[CH:20][C:21]=1[NH2:22])([O-])=O>>[CH3:1][C:2]1(/[CH:8]=[CH:9]/[C:10]2[NH:22][C:21]3[CH:20]=[CH:19][C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])=[CH:17][C:16]=3[N:13]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC1(C=CC(=O)O)CCOCC1
Product: CC1(/C=C/c2nc3cc(-c4ccccc4C(F)(F)F)ccc3[nH]2)CCOCC1

Procedure:
(E)-2-[2-(4-Methyl-tetrahydro-pyran-4-yl)-vinyl]-5-(2-trifluoromethyl-phenyl)-1H-benzimidazole was prepared from the acid chloride of 3-(4-methyl-tetrahydro-pyran-4-yl)-acrylic acid (prepared as in STEP B above) and 3-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (prepared as described in Example 3, STEP A) following the procedure as described in Example 8, STEP C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]=2[CH:21]=1.[OH:24][CH2:25][C:26]([NH:28][NH2:29])=O>C(O)CCC>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:26]([CH2:25][OH:24])=[N:28][N:29]=[C:11]3[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]=2[CH:21]=1
Reactant: NNC(=O)CO
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Solvent: CCCCO
Product: OCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-7-trifluoromethyl-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butyl alcohol is refluxed to give 8-trifluoromethyl-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 5 1-(Hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[C:3]=1[C:10](Cl)=[O:11].C(=O)([O-])[O-:14].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[C:3]=1[C:10]([OH:11])=[O:14]
Reactant: O=C(Cl)c1c(Cl)nc(Cl)nc1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1c(Cl)nc(Cl)nc1Cl

Procedure:
A solution of 12.35 parts of trichloropyrimidine-5-carbonyl chloride in 200 parts by volume of acetone is stirred into a suspension of 12.12 parts of γ-(β-sulfatoethylsulfonyl)-propylamine in 250 parts by volume of acetone at 0° C. The reaction is carried out at 5° to 10° C., while maintaining a pH of 6.5 by means of 15% strength aqueous sodium carbonate solution. The trichloro-pyrimidine-5-carboxylic acid compound thus obtained of the formula ##STR25## is isolated by evaporation of the solution under reduced pressure. The compound is a solid substance; it is characterized by the following 13C-NMR spectroscopy values in hexadeutero-dimethyl sulfoxide: δ (in ppm)=21.7; 37.9; 51.2; 52.3; 60.0; 129.4; 157.5; 159.4; 160.6 compared with tetramethylsilane as the internal standard.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.[C:16](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:16])[C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1
Reactant: O=C1CCCc2[nH]c3ccc(F)cc3c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1c2c(c3cc(F)ccc31)C(=O)CCC2
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
The product of Stage (ii) (7.28 g), potassium carbonate (9.90 g), acetone (70 ml), and dimethylsulphate (5.1 ml) were vigorously stirred at room temperature overnight under nitrogen. The mixture was concentrated to one half of its volume and then stirred with water (350 ml) for 30 min. The mixture was filtered off, washed with water (50 ml), air-dried for 1 h, and dried in vacuo over phosphorus pentoxide to give the title compound as needles (7.59 g), m.p. 157.5°-158.5°.