Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:10]3[CH:14]=[C:13]([CH2:15][OH:16])[C:12]([CH3:17])=[N:11]3)=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[NH+]1C=CC=CC=1>ClCCl>[CH:1]1([C:4]2[C:5]([N:10]3[CH:14]=[C:13]([CH:15]=[O:16])[C:12]([CH3:17])=[N:11]3)=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1nn(-c2ncccc2C2CC2)cc1CO
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1nn(-c2ncccc2C2CC2)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
To a solution of [1-(3-cyclopropyl-pyridin-2-yl)-3-methyl-pyrazol-4-yl]-methanol (1.1 g, 5.0 mmol) in dry dichloromethane (15 mL) is added pyridinium chlorocromate (1.2 g, 5.5 mmol) under nitrogen atmosphere. The reaction mixture is stirred at room temperature for 2 h and then filtered through celite. The filtrate is concentrated under reduced pressure. The crude mixture is purified on silica gel eluting with hexane/ethyl acetate (90:10, 80:20) to yield 0.2 g (20%) of the title compound. MS (m/z): 228 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.Cl.ClCC1C(NCCOC)=NC2C(C=1)=CC(OC)=CC=2.[Li+].[OH-]>C1COCC1>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: ClCc1cnc2ccccc2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: COCCNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2cnc3ccccc3c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 47022 (436 mg, 1.9 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)quinoline hydrochloride SLA 47064B (400 mg, 1.9 mmol) and a 2 N aq. LiOH solution (1.90 mL, 3.80 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) provided 1-ethyl-6,7-dimethoxy-4-(quinolin-3-ylmethyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-(quinolin-3-ylmethyl)isoquinolin-3-ol dihydrochloride 78 as a yellow solid (87.5 mg, 10% yield).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>ClCCl>[N:18]1([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of a mixture of 3-chlorosulfonyl-5-trifluoromethylbenzoic acid (0.5 g) and pyrrolidine (0.72 ml) in dichloromethane (5 ml) was stirred at room temperature overnight. After evaporation to dryness, water (50 ml) was added to the residue and adjusted to pH 1.0 by 1N hydrochloric acid. The resulting precipitates were collected by filtration, and dried under reduced pressure at 45° C. to give 3-(pyrrolidinosulfonyl)-5-(trifluoromethyl)benzoic acid (0.514 g) as a powder.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([C:21]([OH:23])=[O:22])[O:12]1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(O)(C)C>[CH:24]([NH:27][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([C:21]([OH:23])=[O:22])[O:12]1)([CH3:26])[CH3:25]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: CC(C)N
Solvent: CC(C)O
Product: CC(C)Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@H]2OC(C)(C)O[C@H]21
Temperature: 25 °C

Procedure:
A mixture of (3aS,4S,6R,6aR)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (5.82 g) and isopropyl amine (7.27 ml) in isopropanol (20 ml) was heated under reflux for 40 h, cooled to room temperature and concentrated in vacuo. The resulting residue was partitioned between ethyl acetate (75 ml) and citric acid (0.5M, 75 ml). The layers were separated, and the organic phase washed with citric acid solution (2×50 ml). The combined organic extracts were washed with water (50 ml) and brine (80 ml), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a light brown foam (4.49 g).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15].O>CN(C)C=O>[CH3:3][C:2](=[CH2:4])[C:1]([O:6][CH2:10][CH2:11][CH2:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:22]2[CH2:23][CH2:24][CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27]2)[CH2:18][CH2:17]1)=[O:15])=[O:5]
Reactant: CCCCCC1CCC(C2CCC(C(=O)OCCCBr)CC2)CC1
Reactant: C=C(C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)C(=O)OCCCOC(=O)C1CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methacrylic acid (3.5 g, 40.7 mmol) in dimethylformamide (100 ml) is added dropwise to an ice cooled slurry of sodium hydride (60% suspension in paraffin oil) (1.6 g, 40.0 mmol) in dimethylformamide (100 ml). Once addition is complete, the mixture is allowed to warm to room temperature and is stirred for 1 h, the intermediate 4′-pentyl-bicyclohexyl-4-carboxylic acid 3-bromo-propyl ester (15.0 g, 37.4 mmol) in dimethylformamide (100 ml) is added dropwise. The mixture is stirred at 50° C. overnight. The mixture is cooled to room temperature, poured into icy water, and this is extracted three times with DCM. The DCM solution is washed with brine, water and then dried over sodium sulphate. The solution is evaporated to dryness and recrystallised from industrial methylated spirits to afford a white crystalline solid.
Reaction SMILES: C(OC([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=O)[CH:18]=2)[CH:13]=[CH:12]1)=O)C1C=CC=CC=1.[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([CH2:35][O:36][C:37]([NH:39][C:40]3[C:41]([NH2:46])=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:38])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(Cl)CCl.C(OCC)(=O)C>CN(C=O)C.O>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH:46][C:41]3[C:40]([NH:39][C:37]([O:36][CH2:35][CH:32]4[CH2:31][CH2:30][N:29]([C:26]5[CH:25]=[CH:24][N:23]=[CH:28][CH:27]=5)[CH2:34][CH2:33]4)=[O:38])=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:22])[CH:18]=2)[CH:13]=[CH:12]1
Reactant: Nc1ccccc1NC(=O)OCC1CCN(c2ccncc2)CC1
Reactant: O=C(O)c1ccc2ccn(C(=O)OCc3ccccc3)c2c1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: O=C(Nc1ccccc1NC(=O)c1ccc2cc[nH]c2c1)OCC1CCN(c2ccncc2)CC1
Reaction time: 18 h
Yield: 8.4 %

Procedure:
A solution of 1-benzyloxycarbonyl-6-indolecarboxylic acid (452 mg, 1.53 mmol), N1-[[1-(4-pyridyl)piperidin-4-yl]methoxycarbonyl]-1,2-benzenediamine (500 mg, 1.53 mmol), and EDC (294 mg, 1.53 mmol) in DMF (2.5 mL) was allowed to stir overnight (about 18 h). The mixture was poured into ethyl acetate and H2O, the aqueous layer was washed with EtOAc (3×), and the combined organic extracts were washed with 1 N NaOH (2×), H2O, brine, and dried (K2CO3). Concentration and purification of the residue by flash chromatography (SiO2) followed by recrystallization (MeOH/ether) yielded 60 mg (8%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:30]([C@H:13]1[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N+:31]=[N-:32]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](N=[N+]=[N-])C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of trans-tert-butyl 4-(benzyloxycarbonylamino)-3-(methylsulfonyloxy)piperidine-1-carboxylate (6.0 g, 14 mmol) in dimethyl sulfoxide (40 mL) was added sodium azide (9.11 g, 140 mmol), and the reaction mixture was stirred at 90° C. overnight under N2. The solution mixture was cooled to ˜30° C., diluted with ethyl acetate (˜300 mL), and washed with water (700 mL×3) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to the title compound (3.8 g, 72%) as a yellow oil. MS (ES+) C18H25N5O4 requires: 375, found: 276 [M+H−100]+, 373 [M+Na]+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:16](=[CH:17][CH:18]=1)[C:15]1[S:14][C:13]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]=3[C:30]([F:33])([F:32])[F:31])=[N:12][C:11]=1[CH2:10][CH2:9]2)[C:3]([OH:5])=O.C[N:35]1CC[O:38][CH2:37][CH2:36]1.NCCO.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(C(F)(F)F)=O>CN(C=O)C.CO.O>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:16](=[CH:17][CH:18]=1)[C:15]1[S:14][C:13]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]=3[C:30]([F:33])([F:31])[F:32])=[N:12][C:11]=1[CH2:10][CH2:9]2)[C:3]([NH:35][CH2:36][CH2:37][OH:38])=[O:5]
Reactant: O=C(O)C(O)c1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCO)C(O)c1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.4 %

Procedure:
To 2-hydroxy-2-(2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl)acetic acid (Preparation 84C, isomer 2, 0.035 g, 0.074 mmol) in DMF (1 mL) were sequentially added N-methylmorpholine (0.033 mL, 0.296 mmol), 2-aminoethanol (5.81 μl, 0.096 mmol) and HATU (0.042 g, 0.111 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with 0.5 mL of MeOH and subjected to preparative. HPLC (Waters Xbridge C18 19×100 mm; Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA). The desired fractions were collected, concentrated and freeze dried using MeOH (0.3 mL) and water (0.7 mL) to yield 2-hydroxy-N-(2-hydroxyethyl)-2-(2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl)acetamide (0.014 g, 0.024 mmol, 35% yield) as a pale yellow solid. The compound had an HPLC retention time=3.53 min. (condition C); LC/MS M+1=516; 1H NMR (500 MHz, C3D6O) δ ppm 6.91-6.97 (2H, m), 6.82-6.90 (4H, m), 6.69-6.77 (2H, m), 4.62 (1H, d, J=4.4 Hz), 4.36 (1H, d, J=3.9 Hz), 3.18 (1H, OH, br. s.), 2.87 (2H, m.), 2.57-2.65 (2H, m).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:30][CH2:31][Cl:32]>O>[Cl:32][CH2:31][CH2:30][O:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: ClCCBr
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCl)ccc21
Temperature: 70 °C

Procedure:
1-Ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(1.2 g) and potassium carbonate(0.95 g) were added to 50% hydrous acetonitrile(24 ml). The mixture was heated to 70° C. to be dissolved. 1-Bromo-2-chloroethane(1.9 ml) was added, and the mixture was heated under reflux for 7 hours. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried by sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=2:1→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound(1.4 g) as a colorless oily matter.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[OH:15][CH2:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.CCOC(C)=O.O>[OH:15][CH2:16][C:17]1[N:18]=[CH:19][N:20]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:4][CH:3]=2)[CH:21]=1
Reactant: OCc1c[nH]cn1
Reactant: O=c1ccccn1-c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1ccccn1-c1ccc(-n2cnc(CO)c2)cc1
Temperature: 130 °C

Procedure:
A mixture of 1-(4-iodophenyl)pyridin-2(1H)-one prepared in Example 19 (1.00 g, 3.37 mmol), 4-hydroxymethylimidazole II-1 (0.330 g, 3.37 mmol), 8-hydroxyquinoline (0.073 g, 0.50 mmol) and K2CO3 (1.00 g, 7.25 mmol) in DMSO (7 mL) was degassed with Ar before being charged with CuI (0.100 g, 0.52 mmol). The mixture in a sealed tube was heated at 130° C. overnight. Water and EtOAc were added. The mixture was filtered through CELITE. The organic layer was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give 1-(4-(4-(hydroxymethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one (335 mg). MS 268 (M+H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=O)=[CH:2]1.COC1C=CC(/C=[C:27]2/[C:28]([NH:30][C:31]([S:33]/2)=[NH:32])=[O:29])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[NH2:32][C:31]1[S:33]/[C:27](=[CH:10]\[C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)/[C:28](=[O:29])[N:30]=1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC1=NC(=O)/C(=C/c2c[nH]c3ncccc23)S1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
The suspension of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (example 1b, 200 mg, 1.4 mmol), pseudothiohydantoin (159 mg, 1.4 mmol), and sodium acetate (459 mg, 5.6 mmol) in acetic acid (2 mL) was stirred under reflux for 12 h. After cooling to room temperature, water was added. The solid was collected by filtration, washed with water and dried to obtain 2-amino-5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-meth-(Z)-ylidene]-thiazol-4-one (280 mg, 82%) as a slight yellow solid. LC-MS m/e 245 (MH+).
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:2]([C:14](O)=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[CH:5]=1.Cl.[NH2:25][C@@H:26]([C:34]([O:36][CH3:37])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:1]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[C@@H:2]([C:14]([NH:25][C@@H:26]([C:34]([O:36][CH3:37])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[CH:5]=1
Reactant: Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](Cc1cn(C)c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a mixture of Boc-D-Trp(CH3)-OH (1.59 g), HCl.H-D-Phe-OCH3 (1.08 g) and HOBT (0.81 g) in DMF (20 ml) was added WSCD (0.93 g) under ice-bath cooling. After being stirred for 2 hours at room temperature, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 0.5N hydrochloric acid (20 ml), water (20 ml), saturated sodium bicarbonate (20 ml) and water (20 ml×2) successively, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with ether to give Boc-D-Trp(CH3)-D-Phe-OCH3 (1.45 g).
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:7]2=[N:6][C:5]1=[O:17])([CH3:3])[CH3:2].C([O:22][CH:23]([CH3:25])[CH3:24])(=O)C>C(O)(C)C>[CH:23]([O:22][C:7]12[NH:6][C:5](=[O:17])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:18])[N:8]1[C:9](=[O:16])[C:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=1)([CH3:25])[CH3:24]
Reactant: CC(=O)OC(C)C
Reactant: CC(C)C1(C)C(=O)N=C2c3ncccc3C(=O)N21
Solvent: CC(C)O
Product: CC(C)OC12NC(=O)C(C)(C(C)C)N1C(=O)c1cccnc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 g of silica gel are added to a solution of 200 g of 3-isopropyl-3-methyl-2H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-2,5(3H)-dione in 900 ml of isopropyl acetate and 100 ml of absolute isopropanol, and the resulting suspension is then stirred at room temperature for about 16 hours. The mixture is subsequently filtered, the filtrate is evaporated to dryness and the residue is crystallized from ethyl acetate/n-hexane. There is obtained 1,9b-dihydro-9b-isopropoxy-3-isopropyl-3-methyl-2H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-2,5(3H)-dione as colorless crystals, m.p. 158°-160° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.[CH2:21](O)[CH3:22].S(=O)(=O)(O)O>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:3]1=2
Reactant: CCO
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2

Procedure:
5,6-Dihydro-11-oxodibenz[b,e]azepine-2-acetic acid was esterified with ethanol-sulfuric acid in a customary manner to obtain ethyl 5,6-dihydro-11-oxodibenz[b,e]azepine-2-acetate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:45][C@@H:46]1[NH:51][CH2:50][CH2:49][N:48]([S:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:47]1>CN(C=O)C>[CH3:1][C:2]1[C:7]([C:8]([N:51]2[CH2:50][CH2:49][N:48]([S:52]([C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=3)(=[O:53])=[O:54])[CH2:47][C@@H:46]2[CH3:45])=[O:10])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1ccc(C(=O)O)c(C)n1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)c(C)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 65.1 %

Procedure:
2,6-Dimethyl-3-pyridinecarboxylic acid (GSK1770624A, Atlantic) (98 mg, 0.65 mmol) and HATU (247 mg, 0.65 mmol) were suspended in DMF (2 ml) and DIPEA (0.170 ml, 0.97 mmol) was added. This mixture was stirred for 40 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (100 mg, 0.32 mmol) was added and stirring continued for 3 h. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (10 ml each). The layers were separated and the aqueous was washed with further DCM (2×5 ml). The combined organic layers were concentrated to leave a brown oil. This was purified by MDAP to give the title compound (92 mg) as an orange solid.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH2:12][N:13]=[C:14]=[S:15]>O1CCOCC1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH2:12][NH:13][C:14]([NH:2][NH2:3])=[S:15]
Reactant: NN
Reactant: Fc1ccc(Cl)c(CN=C=S)c1
Solvent: C1COCCO1
Solvent: O
Product: NNC(=S)NCc1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of hydrazine hydrate (80%, 13.4 g, 214 mmol) in 1,4-dioxane (100 mL) at 0° C. was added a solution of 1-chloro-4-fluoro-2-(isothiocyanatomethyl)benzene (26, 14.4 g, 71.6 mmol) in 1,4-dioxane (50 mL) The mixture was stirred at RT for 2 h. Ice cold water (300 mL) was added. The precipitated solid was collected by filtration, washed with water and dried over P2O5 overnight to provide N-(2-chloro-5-fluorobenzyl)hydrazinecarbothioamide (27). MS: m/z, 234 (100%, M+1), 236 (33%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:18][C:17]3([Br:20])[Br:19])=[CH:12][CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:18][C:17]3([Br:20])[Br:19])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: O=C(c1ccc(C2CC2(Br)Br)cc1)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Br)cc1Cc1ccc(C2CC2(Br)Br)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
Trifluoromethanesulfonic acid (0.5 g, 0.0033 mol) was added slowly to a stirred solution of Example 4B (104 g, 0.211 mol) and triethylsilane (66.8 g, 0.574 mol) in trifluoroacetic acid (300 mL) cooled to 30° C. in a water-bath. The reaction became refluxed. After 0.5 h, the water bath was replaced by an oil bath. The reaction mixture was heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was allowed to stir for another 1 h. The solid was filtered, washed with hexane (100 mL) and dried under vacuum at 30° C. to get the desired product as a pale gray solid (86.4 g, yield 85%) 1H NMR (CDCl3, 400 MHz): δ 7.28˜7.34 (m, 3H), 7.18˜7.25 (m, 4H), 4.08 (s, 1H), 2.93˜2.98 (m, 1H), 2.13˜2.17 (m, 1H), 2.00˜2.03 (m, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][NH:13][C:14]=1[N:15]=[CH:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1.[BH4-].[Na+]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][NH:13][C:14]=1[NH:15][CH2:16][C:17]1[NH:21][CH:20]=[CH:19][N:18]=1
Reactant: Nc1n[nH]c(N=Cc2ncc[nH]2)c1-c1nc2ccccc2s1
Agent: [BH4-]
Agent: [Na+]
Product: Nc1n[nH]c(NCc2ncc[nH]2)c1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A mixture of 4-benzothiazol-2-yl-N5-(1H-imidazol-2-ylmethylene)-1H-pyrazole-3,5-diamine (13 mg, 0.042 mmol) and NaBH4 (10 mg) was stirred at room temperature for 3 hrs. The solvent was then evaporated and the residue was purified by flash column chromatography eluting with a gradient of CH2Cl2 to CH2Cl2:MeOH=4:1 to yield 12 mg (84%) of the title compound. MS (m/z, ES+): 312.1 (M+1, 80%), 232.1 (100%).