Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH:30]1[C:43]2[C:42](=[O:44])[CH2:41][C:40]([CH3:46])([CH3:45])[CH2:39][C:38]=2[O:37][C:36]2[CH2:35][C:34]([CH3:48])([CH3:47])[CH2:33][C:32](=[O:49])[C:31]1=2.[CH3:50][S:51]([NH2:54])(=[O:53])=[O:52].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27]([NH:54][S:51]([CH3:50])(=[O:53])=[O:52])=[O:29])[CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH:30]1[C:43]2[C:42](=[O:44])[CH2:41][C:40]([CH3:46])([CH3:45])[CH2:39][C:38]=2[O:37][C:36]2[CH2:35][C:34]([CH3:47])([CH3:48])[CH2:33][C:32](=[O:49])[C:31]1=2
Reactant: COc1ccc(-c2cccc(C(=O)O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: CS(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2cccc(C(=O)NS(C)(=O)=O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 2 h
Yield: 56.1 %

Procedure:
1,1′-Carbonyldiimidazole (54.6 mg, 0.34 mmol) was added to a solution of the 6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylic acid produced in Example 1-2 (130 mg, 0.26 mmol) in DMF (2.6 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 2 hours. Thereafter, methanesulfonamide (32.1 mg, 0.34 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.050 ml, 0.34 mmol) were added to the resulting solution at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 71 hours. Thereafter, an aqueous solution of citric acid (249 mg, 1.30 mmol) was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (methanol:dichloromethane=0:1 to 1:9, v/v). Ethanol was added to the fraction thus obtained, and the generated solid was then collected by filtration and dried to obtain the title compound (84.4 mg, yield: 56%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:43])[CH3:44])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Cl)cn4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Cl)cn4)ccc3Oc3ccc(N)cc3)ncnc2n1
Yield: 76.3 %

Procedure:
The product of Example 199D (162.2 g, 0.2591 mmol) was treated with trifluoroacetic acid (2 mL) in methylene chloride (2 mL) at room temperature for 30 minutes. The solvents were removed by rotary evaporation and the residual oil taken up in ethyl acetate (75 mL) and washed with saturated aqueous sodium bicarbonate (30 mL), water (2×30 mL), and brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography eluting with 4% methanol/methylene chloride afforded the title compound (104 mg, 76%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.32 (d, J=6.99 Hz, 6 H) 3.09-3.30 (m, 1 H) 5.04 (s, 2 H) 6.57 (d, J=8.82 Hz, 2 H) 6.78 (d, J=8.83 Hz, 1 H) 6.79 (d, J=8.82 Hz, 2 H) 7.60 (d, J=8.46 Hz, 1 H) 7.94-7.98 (m, 2 H) 8.20-8.27 (m, 2 H) 8.43 (d, J=2.94 Hz, 1 H) 8.62 (s, 1 H) 8.85 (d, J=8.46 Hz, 1 H) 9.97 (s, 1 H) 10.91 (s, 1 H); MS (ESI+) m/z 526/528 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14]>>[NH2:14][C:13]1[CH:12]=[C:11]([CH3:10])[C:17]([CH3:18])=[CH:16][C:15]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: Cc1ccc(N)cc1C
Reactant: O=Cc1ccccc1Cl
Product: Cc1cc(N)c(C(=O)c2ccccc2Cl)cc1C

Procedure:
(2-amino-4,5-dimethylphenyl)-(2-chlorophenyl)-methanone (Xw) was prepared by reacting 2-chlorobenzaldehyde with 0.123 moles of 3,4-dimethyl aniline in a manner analogous to Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C@@H:20]1([NH2:30])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>>[C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH2:13][NH:30][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CC(C)(C)c1ccc(Oc2cccc(C=O)c2)cc1
Product: CC(C)(C)c1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
3-(4-tert-Butylphenoxy)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [OH:1]O.[C:3]([CH2:6][S:7][C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([F:19])=[CH:14][CH:15]=2)[N:10]([CH3:20])[CH:9]=1)([OH:5])=[O:4]>C(O)(=O)C.O>[C:3]([CH2:6][S:7]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([F:19])=[CH:14][CH:15]=2)[N:10]([CH3:20])[CH:9]=1)=[O:1])([OH:5])=[O:4]
Reactant: OO
Reactant: Cn1cc(SCC(=O)O)c(=O)c2ccc(F)cc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(S(=O)CC(=O)O)c(=O)c2ccc(F)cc21
Temperature: 55 °C
Reaction time: 4 h

Procedure:
50% hydrogen peroxide (57ml, 33.6 mg, 0.988 mmol) was added to a solution of 3-carboxymethylthio-7-fluoro-1-methyl-4-quinolone (4) in acetic acid (3.6 ml) at 60° C. and the mixture was stirred at 55° C. for 4 h. The hot mixture was diluted with water (12ml) and cooled to 0° C. A white solid that precipitated was filtered off and dried under high vacuum. The yield of 3-Carboxymethylsulfinyl-7-fluoro-1-methyl-4-quinolone was 185 mg (72.7%) (5).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[OH:34][C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37]>CN(C=O)C>[OH:34][C:35]([CH3:40])([CH3:39])[C:36]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=[O:37]
Reactant: CC(C)(O)C(=O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C(C)(C)O)C3)ccc1-2
Yield: 21 %

Procedure:
Following the procedure for 318, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and 2-hydroxyisobutyric acid were reacted in DMF. Purification by trituration with ether then reverse phase preparative HPLC (Gemini C18 column, gradient 40-98% MeOH in H2O+0.1% HCO2H) gave 444 as a white solid (39 mg, 21%). LCMS: RT=11.04 min, [M+H]+=454. 1H NMR δ (ppm) (CDCl3): 8.36 (1H, d, J=8.19 Hz), 7.90 (1H, s), 7.11 (1H, dd, J=8.22, 1.90 Hz), 7.00-6.96 (1H, m), 5.92-5.83 (1H, m), 4.74 (1H, d, J=9.42 Hz), 4.46 (1H, t, J=9.76 Hz), 4.39 (3H, t, J=5.47 Hz), 4.14 (1H, s), 3.87-3.78 (1H, m), 3.65 (1H, s), 3.40 (2H, t, J=5.00 Hz), 1.60 (6H, d, J=6.63 Hz), 1.43 (6H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]1([N:21]=[C:22]=[S:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[S:23])=[CH:13][CH:14]=1
Reactant: S=C=Nc1ccccc1
Reactant: Clc1ccc(CNC2CCCC2)cc1
Product: S=C(Nc1ccccc1)N(Cc1ccc(Cl)cc1)C1CCCC1
Yield: 92.8 %

Procedure:
Analogously to Example 1, 21 grams (0.1 mole) of N-4-chlorobenzyl-N-cyclopentylamine were reacted with 13.5 grams (0.1 mole) of phenylisothiocyanate. 32 grams of N-4-chlorobenzyl-N-cyclopentyl-N'-phenylthiourea were obtained. Yield: 92%, Melting point: 129°-132° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[C:14]2[S:13](=[O:16])(=[O:15])[N:12]=[C:11]([CH2:17][C:18]([OH:20])=O)[NH:10][C:9]=2[S:8][CH:7]=1.C([O:23][C:24]([C@H:26]1[C@@H:31]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C@H:30]2[CH2:41][C@@H:27]1[CH2:28][CH2:29]2)=O)C.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:32]2[C:18](=[O:20])[C:17]([C:11]3[NH:10][C:9]4[S:8][CH:7]=[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])[C:14]=4[S:13](=[O:15])(=[O:16])[N:12]=3)=[C:24]([OH:23])[C@H:26]3[C@@H:31]2[C@H:30]2[CH2:41][C@@H:27]3[CH2:28][CH2:29]2)=[CH:39][CH:38]=1
Reactant: COCOCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCOCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 75 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a solution of (7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-acetic acid (0.38 g, 1.20 mmol) and (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.42 g, 1.44 mmol) in N,N-dimethylformamide (4 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.34 g, 1.80 mmol). The reaction was stirred at 25° C. for 15 min before triethylamine (1 mL, 7.20 mmol) was added. The reaction was then stirred at 75° C. overnight. The reaction was cooled to 25° C. and quenched with 1.0 M aqueous hydrochloric acid solution (5 mL). The resulting mixture was extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-50% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.44 g, 0.80 mmol, 67%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.18-1.78 (6H, m), 2.55-2.56 (1H, m), 2.82-2.86 (2H, m), 3.45 (3H, s), 4.21 (1H, d, J=15.6 Hz), 4.79 (2H, s), 4.82 (2H, s), 5.15 (1H, d, J=15.2 Hz), 7.00-7.07 (3H, m), 7.20 (2H, dd, J=5.6, 8.8 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:23]=[CH:24][CH:25]=5)[N:18]=4)[N:13](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:23]=[CH:24][CH:25]=5)[N:18]=4)[NH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)Nc1cccc(-c2cnc3c(n2)c(-c2cc4ccc(C)cc4[nH]2)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C=CC(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cc5ccc(C)cc5[nH]4)c3n2)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of Compound 9 (20 mg, 0314 mmol) in chloroform was added trifluoro acetic acid. The reaction was stirred overnight at 45° C. The reaction was completely distilled and diluted with water, adjust the pH to 9-10 with 1 molar NaOH solution at 20-25° C. The aqueous layer was extracted with DCM (25 mL) twice. The organic layer was dried over sodium sulphate, filtered and concentrated to get the crude. The resulting oil was purified via silica gel chromatography using gradient of 50% Ethyl acetate:hexane afforded Compound 10. MS-ES +393.16; 1H NMR (400 MHz, DMSO-D6-d6) 10: 12.29 (d, 1H),11.17 (d, 1H), 10.39 (d,1H), 8.84 (d,1H), 8.54 (d,1H),7.94 (d, 2H),7.55 (d, 2H), 7.49 (d, 2H),7.26(d, 2H), 6.83 (d, 1H), 6.54 (d,1H), 6.36 (d, 1H) 5.81 (d, 1H), 4.45 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH:10]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([F:36])[CH:31]=2)[CH2:11][C:12](=O)[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[CH:6]=[CH:7][CH:8]=1.[NH2:40][NH2:41].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCO>[F:38][C:2]([F:39])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:40]=[N:41][C:12]([CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:18]3)=[CH:11][C:10]=2[C:30]2[CH:35]=[CH:34][N:33]=[C:32]([F:36])[CH:31]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NN
Reactant: O=C(CC(C(=O)c1cccc(C(F)(F)F)c1)c1ccnc(F)c1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(c2cc(-c3ccnc(F)c3)c(-c3cccc(C(F)(F)F)c3)nn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
Under Ar, a solution of 19 (8.8 g, 14.1 mmol) in EtOH (270 mL) was stirred at room temperature and treated with hydrazine (1.4 g, 42.1 mmol). After 2 h, the reaction was concentrated to dryness. The reaction was partitioned between H2O and EtOAc (3×). The organic extracts were backwashed with brine, dried, filtered and concentrated to dryness. The residue was dissolved in toluene (400 mL) and treated with DDQ (3.4 g, 14.9 mmol). After stirring at room temperature for 3 h, the reaction was concentrated to dryness. The residue was chromatographed on a Still column (100 mm) and the product eluted with 60% EtOAc-hexanes to yield 5.5 g of 20.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[O:7]1[CH2:12][CH2:11]C(C(O)=O)[CH2:9][CH2:8]1>CN(C=O)C.C(Cl)Cl>[O:7]1[CH2:12][CH2:11][CH:1]([C:2]([Cl:4])=[O:3])[CH2:9][CH2:8]1
Reactant: O=C(O)C1CCOCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCOCC1
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (170 μL, 1.94 mmol) and DMF (2 drops) were added to a solution of tetrahydro-2H-pyran-4-carboxylic acid (84 mg, 0.64 mmol) in DCM (4 mL) and stirred for 1.5 hours. The reaction was concentrated under vacuum affording tetrahydro-pyran-4-carbonyl chloride. This was used with no further purification or analysis.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])[CH3:3].C(N1C=CN=C1)([N:21]1C=CN=C1)=O.N>O1CCCC1>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([NH2:21])=[O:9])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(N)=O)cc(C(C)(C)C)c1O
Temperature: 26 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
In a 22 L Morton flask, 749 g (3.0 mol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, 533 g (3.3 mol) carbonyldiimidazole and tetrahydrofuran (THF) were combined and heated slowly to reflux and allowed to reflux for 2.5 hours. The reaction mixture was cooled to 26° C. and concentrated aqueous ammonia was added. Stirring was continued for 2 hours and the reaction mixture was allowed to stand overnight. The contents were transferred to a flask and rinsed with tetrahydrofuran (250 mL). The mixture was stirred, layers were separated, and the aqueous layer was saved. The organic layer was washed with brine (2.5 L) followed by brine/deionized (DI) water (1 L/1.5 L). The organic layer was washed with 9.7 M hydrochloric acid (HCl)/deionized water (0.25 L/2.25 L), followed by 9.7 M hydrochloric acid/deionized water (0.5 L/2.8 L), and 9.7 M hydrochloric acid/deionized water/brine (0.5 L/1.5 L/1.5 L). The organic layer was set aside while the combined aqueous layers were washed with tetrahydrofuran. The combined organic layers were washed with brine, dried with sodium sulfate (855 g) and filtered. The filtrate was evaporated to 1011 g of a wet (water), white solid. Methylene chloride was added and removed in vacuo. This procedure was repeated with ethyl acetate (6 L, then 2 L) to produce a solid residue (779 g). The residue was slurried in ethyl acetate and heptane, filtered, and dried in a vacuum oven to yield the desired amide (736 g, 98.7%) as a white solid.
Reaction SMILES: C(OC([NH:8][N:9]([CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:10])=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[C:18]([Si:15]([CH3:16])([CH3:17])[O:14][CH2:13][CH2:12][CH2:11][N:9]([CH3:10])[NH2:8])([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(CCCO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(N)CCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N′-[3-(t-Butyl-dimethyl-silanyloxy)-propyl]-N′-methyl-hydrazinecarboxylic acid t-butyl ester (120 mg, 377 μmol) was at 0° C. combined with dichloromethane (2 mL) and trifluoroacetic acid (2 mL) to give a light yellow solution. The reaction mixture was stirred for 2 h at 0° C. and subsequently concentrated in vacuo to give the title compound as yellow oil, which was used without further purification in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][N:12]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:21][CH:20]=4)[C:16]([C:17]#[N:18])=[C:11]3[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:36]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][N:12]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:21][CH:20]=4)[C:16]([C:17]([NH2:18])=[O:36])=[C:11]3[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(c1cccc(O)c1)C2
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(c1cccc(O)c1)C2

Procedure:
The desired product was prepared from 6-(3-hydroxyphenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. MS (ESI) m/e [M+1]+ 426.9.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:3])[CH3:2].O.[N+:12]([CH:15]([CH:18]=O)[CH:16]=O)([O-:14])=[O:13].[Na].C(O)(=O)C>O>[CH:1]([NH:4][C:5]1[C:9]2[C:8](=[N:10][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:18]=2)[NH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: CC(C)Nc1cc(N)[nH]n1
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Nc1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A solution of N3-isopropyl-1H-pyrazole-3,5-diamine (0.231 g, 1.85 mmol) and sodium nitromalonaldehyde monohydrate (0.307 g, 1.95 mmol) in water (20 mL) was heated to 100° C. overnight. The reaction mixture was cooled to room temperature, and the pH was adjusted to about 6 with acetic acid. The resulting solids were collected by filtration, washed with water and dried in vacuo to give N-isopropyl-5-nitro-1H-pyrazolo[3,4-b]pyridin-3-amine (0.243 g, 59%). m/z (APCI-neg) M−1=220.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].CCOC(C)=O>CN(C=O)C>[N:13]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CBr)nc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 6-(bromomethyl)nicotinate from Example G1 (2.0 g, 8.60 mmol) in DMF (15 ml) was added sodium azide (0.84 g, 12.9 mmol). The mixture was stirred at room temperature for 18 h. EtOAc (100 ml) was added and the mixture was washed with water (3 times), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet ether 20:80) to give a yellow gum; yield 1.55 g (93%).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:25]I>CN(C)C=O.Cl>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]=[C:10]2[N:14]([CH3:25])[C:13]([CH3:15])=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:11]2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CI
Reactant: CCOC(=O)c1sc(NC(=O)c2ccc(C#N)cc2)nc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(=NC(=O)c2ccc(C#N)cc2)n(C)c1C
Temperature: 25 °C

Procedure:
Ethyl 2-(4-cyanobenzoylamino)-4-methylthiazole-5-carboxylate (22.07 g) was added to a suspension of 60% oily sodium hydride (3.08 g) in N,N-dimethylformamide (hereinafter referred to as DMF) (300 ml) under ice-cooling, followed by stirring at room temperature for an hour. A solution of methyl iodide (4.8 ml) in DMF (50 ml) was added dropwise to the reaction mixture, followed by further stirring at room temperature for an hour. The reaction mixture was taken up in 3% hydrochloric acid, and the precipitated crystals were collected by filtration, and the resulting crude crystals were recrystallized from a mixture of methylene chloride and methanol to give ethyl 2-(4-cyanobenzoylimino)-3,4-dimethylthiazoline-5-carboxylate (15.97 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12].[Cl:14][S:15](O)(=[O:17])=[O:16]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[CH:4][C:5]([S:15]([Cl:14])(=[O:17])=[O:16])=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)c1ccc(C(C)C)c(Br)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cc(S(=O)(=O)Cl)c(C(C)C)cc1Br

Procedure:
To a one-liter flask containing 80 parts of 2-bromo-1,4-diisopropylbenzene in 320 parts of carbon tetrachloride, there is added over 15 min. 154 parts of chlorosulfonic acid. After stirring thirty min. longer, the reaction mixture is poured onto 1000 parts of ice. The organic layer is separated and washed with 200 parts of water and then dried over magnesium sulfate. Removal of the solvent under reduced pressure gives 105 parts of 4-bromo-2,5-diisopropylbenzenesulfonyl chloride which can be recrystallized from n-hexane, m.p. 80°-83°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>C1COCC1>[O:16]=[C:12]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[C:32]([O:31][C:30]([F:29])([F:41])[F:42])[CH:33]=4)[CH:19]=[CH:18][CH:17]=3)[C:15]=2[N:14]=[CH:13]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
Method G1: 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one (43 mg, 0.169 mmol) and diisopropylethylamine (44 μL, 0.254 mmol) were mixed in dry THF (5.0 mL) and 3-trifluoromethoxybenzoyl chloride (57 mg, 0.254 mmol) was added. This mixture was heated to reflux for 17 h. After cooling at RT, the solvent was removed in vacuo. The obtained oily residue was dissolved in DCM and washed with water and dried over MgSO4. After evaporation of DCM, the residue was retaken in Et2O, triturated and filtered off to afford the title compound as a white solid (45 mg, 60%).