Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11](=[O:24])[N:10]([CH2:25][CH2:26][CH2:27][CH3:28])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.CC1(C)OC(=O)[C:35]2([CH2:37][CH2:36]2)[C:34](=O)[O:33]1.[Cl-].[NH4+]>CN(C)C=O.O>[CH2:17]([N:12]1[C:13](=[O:16])[C:14]2[NH:15][C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([N:1]4[CH2:37][CH2:36][CH2:35][C:34]4=[O:33])=[CH:30][CH:29]=3)=[N:8][C:9]=2[N:10]([CH2:25][CH2:26][CH2:27][CH3:28])[C:11]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(N4CCCC4=O)cc3)nc21
Temperature: 100 °C
Yield: 51.3 %

Procedure:
To a solution of 8-(4-amino-benzyl)-1-benzyl-3-butyl-3,7-dihydro-purine-2,6-dione (60 mg) in N,N-dimethylformamide (2 mL) was added 6,6-dimethyl-5,7-dioxa-spiro[2.5]octane-4,8-dione (Lancaster) (34 mg) and the mixture heated to 100° C. under argon for 16 hrs. The reaction mixture was cooled to RT and poured into saturated aqueous ammonium chloride, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purification by chromatotron using a 2 mm silica plate eluted with 95:5 chloroform/methanol gave the desired product as a pale yellow solid (36 mg). MS, m/z(M+)=471.2272.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][C:18]=3[Cl:32])=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1)(=O)=O>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:42]4[C:43]5[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=5)[CH2:39][CH2:40][CH:41]=4)=[CH:19][C:18]=3[Cl:32])=[O:16])[CH2:6][C:5]=12
Reactant: CC1(C)OB(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)OC1(C)C
Reactant: O=S(=O)(Oc1cccc2ccccc12)C(F)(F)F
Product: O=C(c1ccc(C2=CCCc3ccccc32)cc1Cl)N1Cc2cccn2Cc2ccccc21
Yield: 96.3 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 10, Step B (0.300 g, 0.668 mmol) and naphthalen-1-yl trifluoromethanesulfonate (0.205 g, 0.735 mmol) were reacted by the procedure described in Example 1, Step F. The crude product was purified by flash column chromatography on silica gel, eluting with 30% ethyl acetate in hexane to afford a clear oil. The oil was recrystallized from diethyl ether/petroleum ether to afford white crystals (0.290 g), m.p. 174–176° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:36])=[CH:27][CH:26]=1
Reactant: NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)thio]phenyl}propan-1-ol (450 mg, 1.51 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (287 mg, 1.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (435 mg, 2.27 mmol) and 1-hydroxybenzotriazole hydrate (231 mg, 1.51 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (447 mg, 57%).
Reaction SMILES: [CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:39][NH:38][CH2:37]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:45])[CH3:44])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].[CH3:58][N:59]=[C:60]=[O:61].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:37][N:38]([C:60]([NH:59][CH3:58])=[O:61])[CH2:39]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:44])[CH3:45])[NH:31][CH:32]=4)=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5]
Reactant: CN=C=O
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CNC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CNC(=O)N1CC2(CC(c3nc(-c4ccc(-c5ccc(-c6c[nH]c([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)n6)cc5)cc4)c[nH]3)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[6-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,6-diazaspiro[3.4]oct-7-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate (Example 24) (45 mg, 0.06 mmol) in anhydrous CH2Cl2 (0.6 mL) was added methyl isocyanate (0.01 mL, 0.17 mmol) and the reaction stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue dissolved in methanol (1 mL) and potassium carbonate (40 mg, 0.29 mmol) was added and the reaction stirred at room temperature for 18 h. The reaction was partitioned between CH2Cl2 (10 mL) and water (5 mL), the aqueous layer was extracted with CH2Cl2 (5 mL), the organic layers were combined and dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow solid (34 mg, 70% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.64 (br. s., 10H) 7.33 (br. s., 2H) 5.06-5.22 (m, 1H) 4.03-4.46 (m, 3H) 3.73-4.04 (m, 8H) 3.54-3.73 (m, 6H) 3.46 (q, J=7.0 Hz, 2H) 2.52-2.76 (m, 5H) 2.10-2.53 (m, 4H) 2.02 (br. s., 3H) 0.70-1.09 (m, 12H). HRMS for C44H57N10O7 (M+H)+ calc: 837.4412. found: 838.4416. Purity (LC-MS): 91%.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[CH3:19][CH:20]([NH2:35])[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[O:22][N+:23]([O-:25])=[O:24].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:35][CH:20]([CH3:19])[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[O:22][N+:23]([O-:25])=[O:24])#[N:2]
Reactant: CC(N)C(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)OC(=NC#N)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: CC(N=C(NC#N)c1ccncc1)C(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5 %

Procedure:
Isopropyl N cyano-4-pyridinecarboximidate (0.31 g, 1.6 mmol) was dissolved in methanol (15 ml), and 1-methyl- 2-(4-nitrophenyl)-2-nitroxyethylamine nitrate (0.50 g, 1.8 mmol) and sodium methoxide (0.09 g, 1.7 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (60:1). The eluted fractions were concentrated under reduced pressure and crystallized from diethyl ether to give the title compound (0.03 g, 0.08 mmol, yield 5%) as colorless crystals.
Reaction SMILES: CO[C:3](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[NH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[C:13]([C:10]([C:11]#[N:12])=[C:3]([NH:15][CH2:16][CH2:17][NH:18][C:19]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:25])[C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)#[N:14]
Reactant: COC(=C(C#N)C#N)c1cccn1C
Reactant: CC(C)(C)OC(=O)NCCN
Product: Cn1cccc1C(NCCNC(=O)OC(C)(C)C)=C(C#N)C#N

Procedure:
N-(2-{[2,2-dicyano-1-(1-methylpyrrol-2-yl)vinyl]amino}ethyl)(tert-butoxy)carboxamide was synthesized in the same manner using [methoxy(1-methylpyrrol-2-yl)methylene]methane-1,1-dicarbonitrile and tert-butyl N-(2-aminoethyl)carbamate. The ESI/MS data for this compound are shown below.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:35][C:36]1([F:41])[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C:36]([F:41])([F:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: FC1(F)CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC(F)(F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3,3-difluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.61 (s, 1H), 4.01 (m, 2H), 3.80 (m, 2H), 3.45 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 460 [M+H]
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]2([CH2:1][C:2](=[O:3])[C:4]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=3[O:11]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1cc(O)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(O)ccc1O2
Yield: 82.6 %

Procedure:
A solution of 2,5-dihydroxyacetophenone (15 g, 98 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g, 100 mmol) and pyrrolidine (21 mL, 260 mmol) in methanol (146 mL) was stirred at reflux for 23 h and concentrated under vacuum to produce a red oily crude material. The oily crude material was purified by ISCO (330 g column) chromatography using 27 to 80% ethyl acetate in hexane to afford the product of step 1 (27 g, 82%), mp 72-74° C. (ethyl acetate, ether and hexane), MS m/z=332 (M−H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[CH:12]=[C:11]([CH2:30][CH2:31][O:32][CH3:33])[N:10]=1)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl>[C:5]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([NH:29][C:1](=[O:3])[CH3:2])[CH2:27][CH2:28]3)[CH2:17][CH2:16]2)[CH:12]=[C:11]([CH2:30][CH2:31][O:32][CH3:33])[N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(=O)Cl
Reactant: COCCc1cc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)nc(C(C)(C)C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1cc(N2CCN(CC[C@H]3CC[C@H](NC(C)=O)CC3)CC2)nc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of acetyl chloride (181 mg, 2.308 mmol), trans-4-(2-{4-[2-tert-Butyl-6-(2-methoxy-ethyl)-pyrimidin-4-yl]-piperazin-1-yl}-ethyl)-cyclohexylamine (690 mg, 1.539 mmol) and triethylamine (778 mg, 7.69 mmol) in DCM (15 ml) was stirred at room temperature for about 3 h. The solution was concentrated to dryness. The residue was transferred neat onto a 50×250 mm silica gel column and eluted with 5% MeOH/CH2Cl2. Fractions were collected and the solvent removed under reduced pressure to provide the title compound (468 mg, 1.040 mmol, 67.6% yield) as a white powder.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[C:8]([OH:16])[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[C:17]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOC(=O)c1c(O)cccc1CC=C
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOC(=O)c1c(CC=C)cccc1OC
Temperature: 25 °C
Reaction time: 40 h
Yield: 98 %

Procedure:
To a solution of allyl 6-allyl-2-hydroxybenzoate (v) (1.2 g, 5.5 mmol) in acetone (12 mL) was added K2CO3 (0.84 g, 6.05 mmol) and Mel (1.04 mL, 16.5 mmol) and the mixture was stirred for 40 h at rt. After filtration of the mixture through a short plug of silicagel, the filtrate was concentrated in vacuo and the residue purified by FC (3% Et2O/pentane) to give 1.25 of allyl 6-allyl-2-methoxybenzoate (via) (98%) as a colorless oil. via: IR 2918, 2850, 1733, 1715, 1585, 1363, 1244, 1223,914,733 cm−1; 1H NMR (400 MHz, CDCl3) o 7.29 (1H, app:t, J=8.0 Hz), 6.83 (1H, d, J=7.6 Hz), 6.79 (1H, d, J=8.4 Hz), 5.97-6.06 (1H, m), 5.86-5.96 (1H, m), 5.42 (1H, br d, J=17.2 Hz), 5.28 (1H, br d, J=10.4 Hz), 5.05 (1H, br d, J=16.8 Hz), 5.04 (1H, br d, J=10.0 Hz), 4.82 (2H, br d, J=6.0 Hz), 3.82 (3H, s), 3.36 (2H, d, J=6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 167.8, 156.6, 138.7, 136.4, 132.1, 130.6, 123.6, 121.8, 118.8, 116.5, 109.2, 66.0, 56.1, 37.9; MS (El) 232 (M+, 18), 191 (28), 175 (34), (147 (50), 132 (100), 115 (58). Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.10; H, 6.87. vib (MOM): IR 2956, 2928, 2853, 1732, 1636, 1589, 1466, 1256, 1153, 1031, 919 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.26 (1H, dd, J=7.6, 8.4 Hz), 7.01 (1H, d, J=7.6 Hz), 6.88 (1H, d, J=8.4 Hz), 6.01 (1H, ddt, J=5.6, 10.0, 17.2 Hz), 5.90 (1H, ddt, J=6.8, 10.4, 16.8 Hz), 5.42 (1H, br d, J=17.2 Hz), 5.28 (1H, br d, J=10.0 Hz), 5.17 (2H, s), 5.06 (1H, br d, J=16.8 Hz), 5.05 (1H, br d, J=10.4 Hz), 4.81 (2H, d, J=5.6 Hz), 3.46 (3H, s), 3.37 (2H, d, J=6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 167.8, 154.2, 138.8, 136.5, 132.2, 130.7, 124.7, 123.0, 118.9, 116.6, 112.9, 94.9, 66.0, 56.4, 37.8. HRMS Calcd for C15H18O4Li (MLi+): 269.1365. Found: 269.1371.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2cccc(C)c2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(-c2cccc(CBr)c2)c1
Yield: 15.7 %

Procedure:
3-Bromomethyl-3'-methyl[1,1'-biphenyl] was prepared by treating 3,3'-dimethyl[1,1'-biphenyl] (20.0 g, 0.11 mole) with N-bromosuccinimide (18.9 g, 0.11 mole) in the presence of 0.1 g of benzoyl peroxide in 130 ml of carbon tetrachloride. Irradiation of the reaction mixture with white light afforded 3-bromomethyl-3'-methyl[1,1'-biphenyl] (4.5 g). The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:10]([CH3:9])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cncc(Br)c1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-Bromo-3-pyridinamine (200 mg) was dissolved in pyridine (5 ml), cooled to 0° C. and stirred for 10 min. Methanesulfonyl chloride (0.05 ml) was added dropwise and the reaction continued stirring for 1 hr. 2M HCl (aq) (5 ml) was added and the reaction was extracted with DCM, passed through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DCM and adsorbed onto fluorosil and purified by column chromatography on silica, eluting with 50% ether/cyclohexane then 0-10% MeOH/DCM to give the title compound (96 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([NH2:12])[NH:10][N:11]=2)[CH2:3][CH2:2]1.[Br:13][CH:14]([CH:17]=O)[CH:15]=O>>[Br:13][C:14]1[CH:15]=[N:12][C:9]2[N:10]([N:11]=[C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[CH:8]=2)[CH:17]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1cc(C2CCOCC2)n[nH]1
Product: Brc1cnc2cc(C3CCOCC3)nn2c1

Procedure:
The title compound, light brown solid, MS: m/e=284.0 (M+H+), can be prepared in accordance with the general method of example 9, step 1 from 5-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-ylamine (example 26, step 1) and 2-bromomalonaldehyde.
Reaction SMILES: S[C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.ClCC(O)=[O:18].Cl>O>[OH:18][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: O=C(O)CCl
Reactant: Oc1cc(-c2ccccc2)nc(S)n1
Agent: Cl
Solvent: O
Product: Oc1cc(-c2ccccc2)nc(O)n1
Yield: 83.5 %

Procedure:
2-Mercapto-4-hydroxy-6-phenylpyrimidine (8.6 g, 42 mmol) and chloroacetic acid (8.5 g, 90 mmol) were slurried in water (100 mL). After refluxing the mixture for 24 hours, hydrochloric acid was added and the precipitate was isolated by filtration. The solid was dried in a vacuum oven to give 6.6 g (83%) of 2,4-dihydroxy-6-phenylpyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:17]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)ccc1O
Yield: 94.8 %

Procedure:
A mixture of 5-chloro-2-hydroxybenzoic acid (100 g, 0.57 mol), 20 ml of conc. H2SO4 and 200 ml of dry methanol was heated under reflux for 22 hours. An additional 5 ml of conc. H2SO4 was then added and the solution heated for an additional 24 hours. The solvent was evaporated under reduced pressure and the resulting residue poured into aqueous saturated Na2CO3 and then extracted with CH2Cl2 (2×400 ml). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated to give the desired compound as a white solid (100.5 g, 94.8% yield), mp 44°-46° C. IR (nujol) 1680 (ester) cm-1. NMR (CDCl3) δ 10.60 (s, 1H, OH), 7.73 (d, 1H, JBC =3 Hz HC), 7.33 (d of d, 1H, JAB =9 Hz, HB), 6.87 (d, 1H, HA), and 3.92 (s, 3H, CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:22]([OH:24])=[O:23]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]([OH:24])=[O:23])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccc(-c2ccc(F)cc2)cc1
Reactant: O=CO
Agent: O=S(=O)(O)O
Product: O=C(O)C(c1ccccc1)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 6 %

Procedure:
Compound 12 (600 mg, 2.16 mmol) was dissolved in a 25:1 mixture of concentrated sulfuric acid:formic acid (19.76 mL) and left without stirring for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified via prep-HPLC (ISCO) in silica gel column with a gradient of ethyl acetate (20-80%) in hexanes to afford compound 13 as an orange oil (40 mg, 6%). 1H NMR (DMSO-d6) δ (ppm): 7.68-7.64 (m, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.40-7.21 (m, 9H), 5.09 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:12][NH:13][S:14]([OH:17])(=[O:16])=[O:15].[I:18]Cl>O.O1CCCC1.Cl>[OH:1][C:2]1[C:7]([I:18])=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:12][NH:13][S:14]([OH:17])(=[O:16])=[O:15]
Reactant: ClI
Reactant: CC(C)(C)c1ccc(O)c(CNS(=O)(=O)O)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(I)c(O)c(CNS(=O)(=O)O)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-5-(1,1-dimethylethyl)phenylmethanesulfamic acid (2.6 g., 0.01 mole) in water-tetrahydrofuran (5:1; v:v; 90 ml.) is added a freshly prepared solution of iodine monochloride (1.64 g., 0.01 mole) in 3 N hydrochloric acid (12 ml.) portionwise over 5 minutes providing a dark reaction solution which is stirred at 20° C. for 2 hours and then cooled to 0°-5° C. The resulting insoluble solid is collected, washed with 12 N hydrochloric acid, dried with aspiration at 20° C. and washed with water to give crude 2-hydroxy-3-iodo-5-(1,1-dimethylethyl)phenylmethanesulfamic acid (3.3 g., 85.9%), m.p. 172°-180° C. with dec. Recrystallization from water-ethanol (10:1; v:v) provides pure 2-hydroxy-3-iodo-5-(1,1-dimethylethyl)phenylmethanesulfamic acid as colorless crystals, m.p. 180°-182° C. with dec.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][O:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][O:11][CH3:12]
Reactant: COCCl
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1Br
Temperature: 80 °C
Yield: 67 %

Procedure:
To a solution of 2-bromophenol (5.0 g, 28.90 mmol) and chloro(methoxy)methane (3.4 g, 43.35 mmol) in DMF (50 mL) was added sodium carbonate (18.7 g, 57.8 mmol). The reaction mixture was heated at 80° C. for 12 h. After completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (3×100 mL), dried over sodium sulfate and concentrated under reduced pressure to yield desired 1-bromo-2-(methoxymethoxy)benzene (4.2 g, 67.7%) as a clear liquid, which was used without further purification.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([CH:15]([CH3:18])[CH:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC.C1COCC1>[CH:1]1([CH:16]([OH:17])[CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CC(C=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(c1ccccc1)C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 70.4 %

Procedure:
To a solution of cyclohexylmagnesium chloride (50 mmol) in 25 mL of Et2O and 40 mL of THF at −5° C. was added a solution of 2-phenylpropanaldehyde (5.36 g, 40 mmol) in 10 mL of THF. The reaction mixture exothermed to 5° C. After stirring at room temperature for 75 min, the solution was poured onto ice cold 1 N HCl, extracted with toluene, dried over MgSO4, and concentrated to give the title compound as a colorless oil (6.15 g, 70%): 1H NMR (d6-DMSO): δ 7.23-7.30 (m, 2H, phenyl CH), 7.15-7.22 (m, 3H, phenyl CH), 4.17-4.51 (brs, 1H, —OH), 3.23-3.33 (m, 1H, R2CHOH), 2.78 (dq, J=7.0 Hz, J=7.1 Hz, 1H, —CH(CH3)Ph), 1.23-1.83 (m, 6H, cyclohexyl CH), 1.20 (d, J=6.9 Hz, 3H, —CH(CH3)Ph), 0.88-1.18 (m, 5H, cyclohexyl CH).