Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([O:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[Cl-].[NH4+].[N-:35]=[N+:36]=[N-:37].[Na+].Cl.N([O-])=O.[Na+]>CN(C)C=O.O.CCCCCC>[NH:35]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([O:17][CH:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:13][CH2:12]3)=[CH:31][CH:32]=2)=[N:2][N:37]=[N:36]1
Reactant: N#Cc1ccc(OCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: c1ccc(C(OC2CCN(CCCOc3ccc(-c4nnn[nH]4)cc3)CC2)c2ccccc2)cc1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
1.67 g (3.92 mmol) of 1-[3-(4-cyanophenoxy)propyl]-4diphenylmethoxypiperidine dissolved in 15 ml of dimethylformamide was added 1.26 g (23.6 mmol) of ammonium chloride, and the mixture was stirred at 45° C. for 15 minutes. Subsequently, 1.02 g (15.7 mmol) of sodium azide was added to the mixture, and the mixture was stirred at 100° C. to 110° C. for 12 hours. After completion of the reaction, the reaction mixture was allowed to cool to 70° C., and a solution of 1.6 ml of conc. hydrochloric acid diluted with 50 ml of water was added. After the mixture was allowed to cool to 35° C., 10 ml of n-hexane and 1.35 g (19.6 mmol) of sodium nitrite in 5 ml of water were added to the mixture to give vigorous gas evolution and then an amber viscous product was liberated. After the supernatant was removed by decantation, 50 ml of ethyl acetate was added to the residual amber viscous product, and the mixture was shaken vigorously. The precipitated crystals were filteref off and washed sufficiently with ethyl acetate to obtain 1.20 g (yield: 65%) of 1-{3-[4-(1,2,3,4-tetrazol-5-yl)phenoxy]propyl)-4-diphenylmethoxypiperidine as pale brown crystals.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Sn](CCCC)(CCCC)CCCC)[N:31]=1.[Cl-].[Li+].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([Cl:29])[N:31]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(Cl)n1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (241.41 mg, 0.5 mmol) in DMF (2 mL) was added 2-chloro-6-(tributylstannyl)pyridine (241.55 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium (28.89 mg, 0.03 mmol), copper (I) iodide (9.52 mg, 0.05 mmol), and lithium chloride (21.2 mg, 0.5 mmol). The reaction mixture was stirred at 95° C. for 4 h. Brine was added (5 mL) and EtOAc (10 mL). The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by CombiFlash (EtOAc/Hexanes) to give (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(6-chloropyridin-2-yl)-5-methylbenzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C26H25Cl2N2O3S: 515.1 (M+H+); Found: 515.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[Cl:16][C:17]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:25]([Cl:33])[C:24]2[C:19](=[C:20]([CH3:36])[CH:21]=[C:22]([CH:34]=[O:35])[CH:23]=2)[N:18]=1>C(Cl)Cl.C(Cl)Cl.CO.O=[Mn]=O>[Cl:16][C:17]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:25]([Cl:33])[C:24]2[C:19](=[C:20]([CH3:36])[CH:21]=[C:22]([C:34]([C:2]3[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][CH:3]=3)=[O:35])[CH:23]=2)[N:18]=1
Reactant: Cc1cc(C=O)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Reactant: Cc1ccc(Br)cn1
Agent: O=[Mn]=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C(=O)c2cc(C)c3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-bromo-2-methylpyridine (380 mg, 2.21 mmol) in DCM (2.2 mL) was stirred on an ice bath while iPrMgCl—LiCl (1.84 mL, 1.2 M in THF, 2.21 mmol) was added dropwise over 1-2 min under argon. After 30 min stirring at room temperature, the dark brown Grignard solution was added dropwise over 1-2 min to a slurry of 2,4-dichloro-8-methyl-3-phenylquinoline-6-carbaldehyde (460 mg, 1.46 mmol, Intermediate 47, step b) in LaCl3-2LiCl (2.60 mL, 0.56 M in THF, 1.46 mmol) on an ice bath under argon. The homogeneous reddish-amber reaction was removed from the ice bath immediately following Grignard addition and stirred at room temperature overnight. The resulting homogeneous brown amber solution was diluted with 9:1 DCM/MeOH (14 mL) and 5 M NH4Cl (0.72 mL), shaken with Celite® and filtered, and the filter cake was washed with 9:1 DCM/MeOH (1×5 mL). The combined clear amber filtrates were dried (Na2SO4), filtered, and concentrated repeatedly from DCM. The residue was taken up in DCM (15 mL) and the resulting slurry was stirred with MnO2 (1.27 g, 14.5 mmol) under air (capped) at 40° C. for 32 hours. The reaction was diluted with 9:1 DCM/MeOH (10 mL) and Celite®, and filtered on a bed of Celite®. The filtrate was concentrated and flash chromatographed with a DCM to 30% EtOAc/DCM gradient to provide the title compound as a colorless film.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1.[Na+].[Cl-:19]>O.OP(O)(O)=O.[O-]S([O-])(=O)=O.[Cu+2]>[Cl:19][C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: [Cl-]
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=P(O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A solution of NaNO2 (3.18 g, 46.1 mmol) in water was slowly added to a solution of 2-amino-6-nitro-benzothiazole (3.00 g, 15.4 mmol) in 85% H3PO4 over a period of 30 min at 0° C. The reaction solution was stirred for 1 hour and was gradually added to a solution of CuSO4 (7.61 g, 76.8 mmol) and NaCl (13.5 g, 230 mmol) in water over a 30 min period at 0° C. The resultant suspension was allowed to warm to room temperature, stirred until gas evolution ceased, diluted with water and extracted with CH2Cl2. The extracts were combined, dried over Na2SO4 and concentrated in vacuo to provide the title compound (3.15 g, 95%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:17](=O)[CH:16]3[NH:19][CH:12]([CH2:13][CH2:14][CH2:15]3)[C:11]2=O)=[CH:6][CH:5]=1.S(C)C.FC(F)(F)C1C=CC(C2CCNCC=2)=CC=1.[OH-].[Na+]>C1COCC1>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:17][CH:16]3[NH:19][CH:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C1C2CCCC(N2)C(=O)N1c1ccc(OC(F)(F)F)cc1
Agent: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(N2CC3CCCC(C2)N3)cc1
Reaction time: 0.67 h

Procedure:
A solution of 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione (80 mg, 0.25 mmol) and THF (4 mL) was heated at 70° C. under N2. A solution of BH3.SMe2 (2M in THF, 0.4 mL, 0.8 mmol) was added dropwise. After 40 min, 6N HCl (1.0 mL) was added dropwise (Caution: H2 evolution). After an additional 30 min, the reaction was poured into 1N NaOH (8 mL) and extracted with dichloromethane (30 mL×2). The combined organic extracts were dried, filtered and concentrated to give 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane: MS (ESI): 287.5 (M+H).
Reaction SMILES: [C:1]1([CH2:7][C:8](C(S)C(O)=O)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[NH:17]([C:19]([O:21][CH3:22])=[O:20])[NH2:18]>O>[C:1]1([CH2:7][C:8]([NH:18][NH:17][C:19]([O:21][CH3:22])=[O:20])=[S:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)NN
Reactant: O=C(O)C(S)C(=S)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)NNC(=S)Cc1ccccc1
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 86.0 g of 2-(2-phenyl-1-thioxoethyl)thioglycolic acid, 195 ml of 2N sodium hydroxide and 100 ml of water was added dropwise to a suspension of 50 g of methyl hydrazinocarboxylate in 200 ml of water with vigorous stirring. Stirring was continued overnight, then the mixture was extracted twice with ether. The extracts were combined, washed successively with 5% aqueous sodium bicarbonate (twice), water and saturated aqueous sodium chloride, dried and concentrated in vacuo. The dark orange oil was purified by percolation through a bed of hydrous magnesium silicate with dichloromethane. The resulting pale yellow oil was chromatographed on a 70×850 mm dry column of silica gel, eluting with dichloromethane. The resulting oil was crystallized from toluene-hexane, giving 42.6 g of the desired compound as yellow crystals, mp 93.5°-94° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90 MHz: 3.79 (s, 3H, OCH3); 4.11 (s, 2H, CH3CS); 7.33 (bs, 5H, C6H5); 8.65 (bs, 1H, NH); 9.55 (bs, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][OH:14])=[N:10][C:9]=2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[F:18][C:19]1[C:27]2[N:26]=[C:25]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)[NH:24][C:23]=2[CH:22]=[CH:21][C:20]=1[F:35].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)C.CO.ClCCl>[F:18][C:19]1[C:27]2[N:26]=[C:25]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30]3[C:15]([C:9]3[N:10]=[C:11]([CH2:13][OH:14])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:17])[NH:24][C:23]=2[CH:22]=[CH:21][C:20]=1[F:35]
Reactant: Fc1ccc2[nH]c(CC3CCCCN3)nc2c1F
Reactant: O=C(O)c1nc(CO)sc1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(c1nc(CO)sc1-c1ccc(F)cc1)N1CCCCC1Cc1nc2c(F)c(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
A stirring solution of 5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid (320 mg, 1.0 mmol, 80% pure) and (RS)-4,5-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D21 (250 mg, 1.0 mmol) in DMF (10 ml) was treated with EDC.HCl (194 mg, 1.0 mmol) and 1-hydroxybenzotriazole (50 mg, 0.4 mmol). The reaction mixture was stirred at room temperature, under argon for 16 h. The resulting solution was diluted with diethyl ether then washed with saturated aqueous NaHCO3, water (3×) and brine. Drying (MgSO4) and removal of the solvent in vacuo afforded an orange gum. Chromatography (silica gel, 0-2% methanol-dichloromethane) afforded the title compound as an orange powder (160 mg, 33%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH:27]([F:29])[F:28])[CH:23]=[CH:22][C:21]=1B(O)O.CCOC(C)=O.O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([O:26][CH:27]([F:28])[F:29])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: OB(O)c1ccc(OC(F)F)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1c(-c2ccc(OC(F)F)cc2Cl)ccnc1OCc1ccccc1
Yield: 68 %

Procedure:
To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (6.59 g, 24.9 mmol) in DME/H2O, was added 2-chloro-4-difluoromethoxy-phenylboronic acid (Wilde, et al. WO 99/01454) (5.54 g, 24.9 mmol), Ba(OH)2 8H2O (7.86 g, 24.9 mmol), and Pd(PPh3)2Cl2 (1.01 g, 1.45 mmol) and the mixture was heated at reflux for 5 h. The reaction was cooled and poured into EtOAc and H2O (500 mL). The EtOAc layer was washed with H2O, brine, dried Na2SO4, filtered and concentrated in vacuo to give 6.9 g (68%) of 2-benzyloxy-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridine as a viscous oil; MS(AP) m/z 408.9 [(M+H)+, 100].
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH:37]([NH2:47])CC2C=CC(OC)=CC=2)[CH:6]=1.NCCCO[C:53]1[CH:81]=[C:80]([O:82][CH3:83])[CH:79]=[CH:78][C:54]=1[C:55](NC1C=C([N+]([O-])=O)C=CC=1C(NC1C=CC(OC)=CC=1)=O)=O.COC1C=CC(C=O)=CC=1>>[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH2:37][NH:47][CH2:55][C:54]2[CH:53]=[CH:81][C:80]([O:82][CH3:83])=[CH:79][CH:78]=2)[CH:6]=1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCN)cc1
Reactant: COc1ccc(CC(N)CCOc2cc(OC)ccc2C(=O)Nc2cc([N+](=O)[O-])ccc2C(=O)Nc2ccc(OC)cc2)cc1
Agent: COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(CNCCCOc2cc(OC)ccc2C(=O)Nc2cc([N+](=O)[O-])ccc2C(=O)Nc2ccc(OC)cc2)cc1

Procedure:
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[4-methoxy-2-[3-(4-methoxybenzyl)-aminopropoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (48 mg, 0.078 mmol, 52%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 4-methoxybenzaldehyde.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.[NH2:42][C:43]1[CH:47]=[C:46]([CH3:48])[NH:45][N:44]=1>C(Cl)Cl>[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:42][C:43]4[CH:47]=[C:46]([CH3:48])[NH:45][N:44]=4)=[O:32])=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:9])[CH3:10]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: Cc1cc(N)n[nH]1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2ccc(C(=O)N3CCN(c4ncccc4NC(C)C)CC3)nc2)n[nH]1
Temperature: 5 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Triethylamine (0.8 ml) was added to 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid (2 g) in methylene chloride (30 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (0.7 ml) at 0° C.˜5° C., the mixture was stirred at 5° C. for 1 hour. With the addition of triethylamine (0.9 ml) and 3-amino-5-methylpyrazole (0.56 g), the mixture was stirred at 5° C.˜10° C. for 3 hours. The solution was slowly heated and stirred at 15° C.˜20° C. for 30 minutes. The solution was washed with an aqueous sodium bicarbonate and water twice. The separated organic layer was concentrated under reduced pressure. The concentrated residue was chromatographed on column (chloroform/isopropanol=10/1, v/v). The purified solution was recovered and concentrated under reduced pressure. The residue was treated with ether for crystallization and with the addition of isopropyl ether (20 ml), and stirred for 2 hours, filtered and washed to give a desired compound of 1.77 g (yield: 73%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[C:31](Cl)(=[O:34])[O:32][CH3:33].C(N(CC)CC)C>O1CCCC1>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:30]=[C:2]([NH:1][C:31](=[O:34])[O:32][CH3:33])[N:3]=2)[N:6]=1)=[O:29]
Reactant: COC(=O)Cl
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 60.9 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), methyl chlorocarbonate (33 μL, 0.435 mmol), triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (3 mL) as starting materials and in the same manner as in Example 388, the title compound (104 mg, 61%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:18].[I:19]I>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[I:19])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:18]
Reactant: II
Reactant: CN1Cc2cncn2-c2ccc(F)c(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(I)ncn2-c2ccc(F)c(Cl)c2C1=O

Procedure:
6.08 g (22.8 mmol) of 7-chloro-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at 100° for 4 hours with 20 g (79.5 mmol) of iodine in 50 ml of N,N-dimethylformamide. The reaction mixture was evaporated, the residue was taken up in methylene chloride and water, decolorized with sodium thiosulphate and neutralized with sodium bicarbonate. The aqueous phase was separated and extracted four times with methylene chloride. The combined organic phases were dried over magnesium sulphate, evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate/hexane (1:1). There was obtained 7-chloro-8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 218°-219°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:17])[CH3:16].Cl.CCN(CC)CC>CC#N.C(Cl)Cl>[CH2:15]([NH:17][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13])[CH3:16]
Reactant: CCN
Reactant: CC(C)c1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CCNc1cc(C(C)C)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 4-chloro-6-isopropyl-3-nitro-1H-pyridin-2-one (Example 28, step 6) (500 mg, 2.31 mmol) in CH3CN at room temperature is added EtNH2.HCl (565 mg, 6.92 mmol) followed by Et3N (1.29 mL, 9.23 mmol). The reaction mixture is then stirred in a sealed tube at 100° C. for 1.5 h. After cooling, the reaction mixture is diluted with CH2Cl2 and washed with H2O (2×25 mL). The aqueous washes are reextracted once with CH2Cl2, and the combined extracts are dried over Na2SO4 and concentrated to provide 4-ethylamino-6-isopropyl-3-nitro-1H-pyridin-2-one as a yellow-orange solid. The material is sufficiently pure to be used without further purification. 1H NMR (DMSO-d6, 400 MHz) δ 11.1 (br, 1H), 8.93 (m, 1H), 5.73 (s, 1H), 3.37 (dq, J=7.4, 6.8 Hz, 2H), 2.67 (sept, J=6.8 Hz, 1H), 1.17 (t, J=7.4 Hz, 3H), 1.15 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:38]([CH:40]2[CH2:42][CH2:41]2)=[O:39])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:36]=[CH:35][C:24]([O:25][CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=3)=[O:20])[C@@H:11]([CH3:37])[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:38]([CH:40]2[CH2:41][CH2:42]2)=[O:39])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][C:28]([CH3:33])([CH3:34])[C:29]([OH:31])=[O:30])=[CH:35][CH:36]=3)=[O:20])[C@@H:11]([CH3:37])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)C3CC3)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H]1C[C@@H](N(C(=O)C2CC2)c2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(OCCC(C)(C)C(=O)O)cc1
Temperature: 40 °C
Yield: 86.9 %

Procedure:
Methyl 4-(4-{[(2S,4R)-4-[(4-chlorophenyl)(cyclopropylcarbonyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoate (100 mg, 0.17 mmol, 1 equ.) was dissolved in methanol/tetrahydrofuran (2/1) (1 ml). A solution of sodium hydroxide (21 mg, 0.51 mmol, 3 eq.) in water (0.5 ml) was added and reaction mixture heated to 40° C. for 2 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude acid. Purification by silica gel chromatography (methylene chloride/methanol 98/2) gave pure 4-(4-{[(2S,4R)-4-[(4-chlorophenyl)(cyclopropylcarbonyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoic acid (85 mg, 87%).
Reaction SMILES: [CH2:1]([C:3]1([C@@H:7]([OH:11])[CH2:8][CH2:9]O)[CH2:6][CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C:25]1([N:31]2[C:35]([SH:36])=[N:34][N:33]=[N:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([C:3]1([C@@H:7]([OH:11])[CH2:8][CH2:9][S:36][C:35]2[N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:32]=[N:33][N:34]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCC1([C@@H](O)CCO)CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1([C@@H](O)CCSc2nnnn2-c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of (1S)-1-(1-ethylcyclobutyl)-propane-1,3-diol (8.90 g) in toluene (110 mL) were added tetrabutylammonium chloride (1.56 g) and a 2N aqueous sodium hydroxide solution (170 mL). At an inner temperature about 25° C., tosyl chloride (11.3 g) was added to the reaction solution, which was stirred at 25° C. for 1 hour. 1-Phenyl-1H-tetrazol-5-thiol (11.0 g) was added to the reaction solution, which was stirred at 60° C. for 1 hour. After cooling, water was added to the reaction solution, which was separated. The water layer was extracted with t-butyl methyl ether. The mixed organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (17.9 g) having the following physical data.