Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:12])[S:5][C:6]=1[CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9].[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.Cl>O>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:12][C:4]2[S:5][C:6]([CH2:7][C:8]([Cl:11])([Cl:9])[Cl:10])=[C:2]([CH3:1])[N:3]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1nc(N)sc1CC(Cl)(Cl)Cl
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: O
Product: Cc1nc(NS(=O)(=O)c2cccc(Cl)c2C)sc1CC(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 76 %

Procedure:
The title compound was prepared similar to EXAMPLE 6 according to METHOD A from 4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-ylamine (123 mg, 0.5 mmol) and 3-chloro-2-methylbenzenesulfonyl chloride (112.5 mg, 0.5 mmol). The solution was allowed to stand at r.t. overnight. Water (5 mL) was added and the resulted solution was made acidic with conc. HCl. The precipitate was filtered, washed with water and dried. Flash column chromatography of the precipitate on silica gel, eluted with a mixed solvents of ethyl ether and hexane (2:1) gave the title compound as a solid (165 mg, 76% yield). The product can be recrystallized from ethyl acetate and hexane: MS m/e: 439, 437, 435, 433.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO.CCCCCC.O.C1COCC1>[C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:10]([O:25][Si:37]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Analogously to Example 1i), 0.93 g (2.10 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-methoxy-phenylmethyl)-hexanoic acid in 20 ml of DMF is silylated with 1.4 g (9.64 mmol) of tert-butyldimethylchlorosilane and 1.17 g (17.2 mmol) of imidazole. The silyl ester function is hydrolysed with 1.7 g of potassium carbonate in methanol (23 ml)/THF (7 ml)/water (7 ml) and the crude product is stirred in hexane to give the title compound; tRet (I)=20.6 min; FAB-MS (M+H)+ =558.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[C:17]([Mg]Br)([CH3:19])=[CH2:18]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[N:6]=[CH:7][CH:8]=[C:9]3[CH:18]=[C:17]([CH3:19])[NH:1][C:4]=23)=[CH:11][CH:12]=1
Reactant: C=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1cccnc1-c1ccc(Cl)cc1
Product: Cc1cc2ccnc(-c3ccc(Cl)cc3)c2[nH]1
Yield: 32 %

Procedure:
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-(4-chlorophenyl)pyridine prepared in Preparation 12 and isopropenylmagnesium bromide, the titled compound was obtained as a white solid. (Yield: 32%)
Reaction SMILES: [CH2:1]([C:3]1[N:11]([CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[C:10]2[C:9](=[O:19])[N:8]([CH3:20])[C:7](=[O:21])[N:6](CC3C=CC(OC)=CC=3)[C:5]=2[N:4]=1)[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([C:3]1[N:11]([CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[C:10]2[C:9](=[O:19])[N:8]([CH3:20])[C:7](=[O:21])[NH:6][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCCC(CCC)n1c(CC)nc2c1c(=O)n(C)c(=O)n2Cc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCC(CCC)n1c(CC)nc2[nH]c(=O)n(C)c(=O)c21
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 8-ethyl-7-(4-heptyl)-3-(4-methoxybenzyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione in trifluoroacetic acid was heated at 100° C. in a sealed tube for 8 h. The mixture was cooled to r.t. and concentrated. The residue was transferred into a separatory funnel containing saturated aqueous NaHCO3 (20 mL) and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (5% methanol in CH2Cl2) to afford a colorless solid (645 mg, 91% yield): mp 152.5–153° C.; 1H NMR (300 MHz, CDCl3) δ 12.0 (s, 1H), 4.20–4.10 (m, 1H), 3.41 (s, 3H), 2.94 (q, J=7.3 Hz, 2H), 2.33–2.19 (m, 2H), 1.94–1.83 (m, 2H), 1.42 (t, J=7.4 Hz, 3H), 1.26–1.06 (m, 4H), 0.90 (t, J=7.3 Hz, 6H); LRMS (APCI) m/e 293.1 [(M+H)+, calcd for C15H25N4O2 293.2].
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]([NH2:12])[CH2:10][CH2:9][N:8]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH2:7]1)=[O:5])C.[OH-].[Li+]>C1COCC1.CO.O>[NH2:12][C@H:11]1[CH2:10][CH2:9][N:8]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH2:7][C@@H:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1CN(CCc2ccc(OC)c(OC)c2)CC[C@@H]1N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(CCN2CC[C@H](N)[C@@H](C(=O)O)C2)cc1OC
Yield: 37.5 %

Procedure:
(3R,4R) and (3S,4S)-4-Amino-1-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-3-carboxylic acid ethyl ester (262 mg) and lithium hydroxide (166 mg) in 5 ml THF, 5 ml MeOH and 1 ml H2O were stirred for 24 h at ambient temperature. The mixture was diluted with buffer pH 7 and extracted with AcOEt. The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography (Isolute SPE Flash NH2, AcOEt) and precipitated (AcOEt/heptane) to give 90 mg (37%) of the title compound as a white solid.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[S:23][CH:24]=[CH:25][C:18]=12>CN(C)C=O>[S:23]1[C:19]2=[N:20][CH:21]=[CH:22][C:17]([O:13][CH:10]3[CH2:9][CH2:8][CH:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH2:12][CH2:11]3)=[C:18]2[CH:25]=[CH:24]1
Reactant: OC1CCC(N2CCOCC2)CC1
Reactant: Clc1ccnc2sccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OC2CCC(N3CCOCC3)CC2)c2ccsc2n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-(morpholin-4-yl)cyclohexan-1-ol (164 mg, 0.89 mmol, 1.50 equiv) in N,N-dimethylformamide (15 mL), sodium hydride (47 mg, 1.96 mmol, 2.00 equiv). The resulting mixture was stirred at 80° C. for 30 minutes. Then 4-chlorothieno[2,3-b]pyridine (100 mg, 0.59 mmol, 1.00 equiv) was added to the mixture. The resulting solution was stirred for 4 h at 120° C. in an oil bath. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×15 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The crude product (120 mg) was purified by Prep-1-HPLC with the following conditions: Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, CH3CN and water with 0.05% HCOOH (10.0% water with 0.05% HCOOH up to 50.0% in 10 min, up to 100.0% in 2 min, down to 10.0% in 2 min); Detector, uv 254/220 nm. This resulted in 72.2 mg (32%) of 4-(4-[thieno[2,3-b]pyridin-4-yloxy]cyclohexyl)morpholine as a white semi-solid. MS: (ES,m/z): 319.10 [M+H]+NMR (400 MHz, D2O, ppm): δ 1.53-1.71 (m, 4H), 2.19-2.33 (dd, J1=29.7 Hz, J2=9.3 Hz, 4H), 3.24-3.30 (m, 3H), 3.51 (m, 2H), 4.07 (s, 2H), 4.60 (m, 1H), 6.98 (d, J=4.5 Hz, 1H), 7.37 (d, J=4.5 Hz, 1H), 7.52 (d, J=4.5 Hz, 1H), 8.33 (d, J=4.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.BrC1C=CC(NC)=NC=1.[NH2:23][CH2:24][CH2:25][OH:26]>>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([NH:23][CH2:24][CH2:25][OH:26])(=[O:12])=[O:11])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1
Reactant: CNc1ncc(Br)cc1S(=O)(=O)Cl
Reactant: NCCO
Agent: CNc1ccc(Br)cn1
Product: CNc1ncc(Br)cc1S(=O)(=O)NCCO

Procedure:
Prepared according to the methods described in reagent preparation 25 using 5-bromo-2-(methylamino)pyridine-3-sulfonyl chloride (prepared from 5-bromo-N-methylpyridin-2-amine using analogous conditions to those described in WO2008144463) and 2-aminoethanol in step 1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[CH2:21]1[C:24]2([CH2:27][CH2:26][CH2:25]2)[CH2:23][C:22]1=[CH:28][C:29]#[N:30].N1CCCN2CCCCCC=12>CC#N>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:22]4([CH2:28][C:29]#[N:30])[CH2:23][C:24]5([CH2:27][CH2:26][CH2:25]5)[CH2:21]4)[CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: N#CC=C1CC2(CCC2)C1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CC5(CCC5)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
7-(1-Methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation K-1; 0.050 g, 0.189 mmol), 2-(spiro[3.3]heptan-2-ylidene)acetonitrile (0.050 g, 0.377 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.014 mL, 0.094 mmol) were suspended in MeCN (3 mL) and stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure and the crude material purified by flash column chromatography, eluting with 1-4% (9:1 MeOH:NH4OH)/DCM to provide 2-(2-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)spiro[3.3]heptan-2-yl)acetonitrile (0.032 g, 0.080 mmol, 42% yield). MS (apci) m/z=399.2 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[CH2:23][OH:24]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:24][CH2:23][C:16]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=3[F:14])[CH:3]=2)[CH2:9][C@@H:10]1[CH3:13]
Reactant: OCc1cc(F)c(F)cc1F
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(F)cc3F)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,4,5-trifluorophenyl)methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].O.O(CCCC)CCCC>[Fe].CC(O)=O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCCCOCCCC
Solvent: O
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCCCc1ccccc1

Procedure:
A stirred mixture of 6-methoxy-4-methyl-8-nitro-5-(7-phenylheptoxy) quinoline [Example 1b] (2.0 g, 0.005 mol) de-greased 40 mesh Fe filings (5 g) H2O (20 ml), HOAc (4 ml) and n-Bu2O was heated at 80°-85° C. for 1 h, cooled and filtered. The solid was thoroughly extracted with Et2O (500 ml) and the extract was dried (Na2SO4) treated with charcoal and concentrated to an oil. Crystallization from pet ether gave 1.6 (85%) of 8-amino-6-methoxy-4-methyl-5-(7-phenylheptoxy) quinoline as yellow green crystals, mp 61°-63° C. A second crystallization from pet ether (Darco) provided the analytical sample as glistening yellow crystals, mp 64°-65° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1)#[N:21]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:15])([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][N:26]=3)=[O:29])[CH:3]=[C:4]([F:19])[C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)cc(F)c2F)N=C(N)OCC1(F)F
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#N)cn3)cc(F)c2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2,3-difluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as a light yellow solid. MS (ISP): m/z=408.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:38](=[CH2:40])=[N-:39]>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10](=[O:12])[CH:40]=[N+:38]=[N-:39])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)C=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
To a 0° C. solution of 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g, 4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4 mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol). The reaction mixture is stirred at 0° C. for 20 min and filtered. The filtrate is treated with an ether solution of diazomethane (˜16 mmol) at 0° C. The reaction mixture is stirred at room temperature for 3 hours and concentrated. The residue is dissolved in EtOAc and washed successively with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product as a slightly yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz, 2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd, J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz, 1H), 1.41 (s, 9H).
Reaction SMILES: [O:1]([CH3:3])[Na].C[O:5][C:6](=[O:36])[CH2:7][C@H:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C@H:18]3[C:26]4[C:21](=[C:22]([O:28][C:29]5[N:30]=[N:31][C:32](Cl)=[CH:33][CH:34]=5)[CH:23]=[CH:24][C:25]=4[F:27])[CH2:20][CH2:19]3)=[CH:16][C:11]=2[O:10][CH2:9]1.[OH-].[Na+]>O1CCCC1.CO>[F:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][C:29]2[N:30]=[N:31][C:32]([O:1][CH3:3])=[CH:33][CH:34]=2)=[C:21]2[C:26]=1[C@H:18]([O:17][C:15]1[CH:14]=[CH:13][C:12]3[C@H:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:9][O:10][C:11]=3[CH:16]=1)[CH2:19][CH2:20]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(Cl)nn5)ccc(F)c43)ccc21
Reactant: CO[Na]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaOCH3 (0.5 mol/L in methanol; 1.3 mL) is added to a solution of {(S)-6-[(R)-4-(6-chloro-pyridazin-3-yloxy)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester in tetrahydrofuran (3 mL) and methanol (0.1 mL) at room temperature. The solution is stirred at room temperature for 1 h, and then 4 M aqueous NaOH solution (0.21 mL) is added. The solution is stirred for 1 h and is then concentrated. The residue is purified by HPLC (acetonitrile/water/ammonia) to give the title compound. LC (method 2): tR=1.02 min; Mass spectrum (ESI−): m/z=451 [M−H]−.
Reaction SMILES: [C:1]12C(=CC=CC=1)NC(=O)OC2=O.[CH2:13]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[C:22]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:21]1=[O:36])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[N+](=C)=[N-]>CCOCC>[CH2:13]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([O:30][CH3:1])=[C:22]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:21]1=[O:36])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCCCn1c(=O)c(C(=O)OCC)c(OC)c2ccccc21

Procedure:
Following the procedure set forth in Preparation A, steps (2-3), isatoic anhydride was converted to 1-heptyl-4-hydroxy-3-ethoxycarbonyl-2(1H)-quinolinone, which upon reaction with excess diazomethane in ether gave the title compound. That the expected product was obtained was confirmed by the spectral data: MS: m/e 345 (M+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C(OC)(OC)OC.[C:36]1(=O)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: O=C1CCCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCCCCNC1CCCCCC1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (30.0 mg) obtained in Example 3-2 was dissolved in methanol (0.6 ml). This solution was added with trimethyl orthoformate (30.0 μl), acetic acid (30.0 μl), cycloheptanone (manufactured by Merck, Inc.) (18.7 μl), and sodium cyanoborohydride (14.9 mg), followed by stirring for 3 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. Then, the residue was dissolved in chloroform, washed with a 1 mol/l sodium hydroxide aqueous solution, and added with 1 mol/l hydrochloric acid to transfer the objective substance to the aqueous layer, followed by washing with chloroform. The 1 mol/l sodium hydroxide aqueous solution was added again to alkalinize the solution. The solution was subjected to extraction with chloroform and the extract was then washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was dried under vacuum and treated with hydrochloric acid, thereby obtaining hydrochloride (32.2 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:20]([CH3:23])=[N:21][S:22][C:10]=2[C:9]=1[OH:24])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]2[C:20]([CH3:23])=[N:21][S:22][C:10]=2[C:9]=1[O:24][C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(-c2ccccc2)c2c(C)nsc2c1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2c(C)nsc2c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A mixture of 7-Hydroxy-3-methyl-4-phenyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (1.15 mmol), trimethylacetyl chloride (1.39 mmol), Et3N (1.74 mmol), and CH2Cl2 (5.7 mL) was stirred at r.t. for 2 h. The mixture was then quenched with water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Eluting with 0-20% EtOAc/CH2Cl2 gave the title compound (392.8 mg) as a colorless oil: MS (m/z) 427.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](O[Si](C(C)(C)C)(C)C)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.Cl>O>[N:13]1[CH:12]=[CH:11][C:10]([C:9]2[C:31]3[C:26](=[N:27][CH:28]=[CH:29][N:30]=3)[NH:25][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:15][CH:14]=1
Reactant: Nc1cnccn1
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)c1ccc(F)cc1)c1ccncc1
Agent: Cl
Solvent: O
Product: Fc1ccc(-c2[nH]c3nccnc3c2-c2ccncc2)cc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
1-(4-Fluorophenyl)-2-t-butyldimethylsiloxy-2-(4-pyridyl) ethanone (16) (5.44 g, 15.77 mmol), 2-aminopyrazine (1.00 g, 10.5 mmol), and concentrated HCl (30 mL) were heated in a sealed tube to 190° C. behind an explosion shield. After 3 h at 190° C., the reaction was allowed to cool to 23° C. then diluted with water (100 mL). After further dilution with concentrated ammonium hydroxide to pH of 12, the reaction was extracted with methylene chloride (3×200 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by applying flash chromatography (100% ethyl acetate) to afford 3-(4-pyridyl)-2-(4-fluorophenyl)-4,7-diaza-indole (62): Mass Spectrum (CI) 291 (MH+).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]2[N:35]([CH:36]=1)[C:18]1[N:19]([C:28]3[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[C:20](=[O:27])[C:21]3[C:26]([C:17]=1[N:16]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3>ClCCl>[Cl:34][C:31]1[N:30]=[CH:29][C:28]([N:19]2[C:18]3[N:35]4[CH:36]=[C:12]([NH:11][CH:1]=[O:2])[CH:13]=[CH:14][C:15]4=[N:16][C:17]=3[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:27])=[CH:33][CH:32]=1
Reactant: Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Formic acid (5.0 equiv., 1.390 mmol, 0.064 g) was added to a cooled (0° C.) solution of acetic anhydride (2.0 equiv., 0.552 mmol, 0.050 g) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 1 h. Compound 53 (1.0 equiv., 0.276 mmol, 0.100 g) was added and the resulting suspension was stirred at room temperature for 6 h. The precipitate was filtered off and successively washed with isopropanol and isopropyl ether affording N-[6-(6-chloro-pyridin-3-yl)-5,6-dihydro-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-yl]-formamide (57) (0.060 g, yield=56%, purity (LC)=96%).