Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C=Cc1ccc(Br)cc1

Procedure:
A solution of compound 2 (113.8 g, 0.5 mol) in thionyl chloride was refluxed for 1.5 h. Then the mixture was concentrated in vacuo and the crude product 3 was obtained (126.9 g, 93%).
Reaction SMILES: [O:1]([NH:19][C:20](=[O:50])[CH2:21][C@@H:22]([N:33]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)=[CH:40][CH:39]=2)=[CH:34]1)[C:23]([NH:25][C@H:26]([CH2:31][OH:32])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:24])[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].P([O-])([O-])([O-])=O>C1COCC1>[CH3:28][C:27]([CH3:30])([CH3:29])[C@H:26]([NH:25][C:23](=[O:24])[C@H:22]([N:33]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)=[CH:40][CH:39]=2)=[CH:34]1)[CH2:21][C:20]([NH:19][OH:1])=[O:50])[CH2:31][OH:32]
Reactant: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)NO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)NO)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Reaction time: 1.25 h
Yield: 41.6 %

Procedure:
To a solution of N4-t-butyldiphenylsiloxy-N1-[2,2-Dimethyl-1(S)-(hydroxymethyl)propyl]-2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamide (112 mg, 0.160 mmol) in THF (5 mL) was added a solution of tetra-n-butylanimonium fluoride (0.20 mL of 1M in THF). After 1.25 hours at ambient temperature, the mixture was added dropwise to 1M pH7 phosphate buffer (40 mL). The resultant precipitate was collected by filtration and washed with H2O. A solution in CH2Cl2/MeOH was passed through a 0.45μ syringe filter, and the filtrate was concentrated to give a solid which was triturated with EtOH to yield 30 mg (42%) of N1-[2,2-Dimethyl-1(S)-(hydroxymethyl)propyl]-N4-hydroxy-2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamide as an amorphous solid, which decomposed >200° C.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>ClCCl.C(Cl)(Cl)Cl>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:9]2[CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]2=3)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(-c2cccs2)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2cccs2)cc1)N1Cc2ccccc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
A mixture of 3 g of 4-(2-thienyl)benzoic acid and 30 ml of sulfonyl chloride is refluxed for 45 minutes and the solvent removed. The residue is dissolved in carbon tetrachloride and the solvent removed under vacuum (2-times) to give 4-(2-thienyl) benzoyl chloride. To a cooled (0° C.) solution of 2.0 g of 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine and 7 ml of N,N-diisopropylethylamine in 30 ml of dichloromethane is added dropwise a solution of 3.15 g of 4-(2-thienyl)benzoyl chloride in 30 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of chloroform. The solution is washed with 30 ml each of water, 2N HCl, saturated NaHCO3, water and dried (Na2 SO4). The solvent is removed under vacuum and the residue (3.1 g) chromatographed on silica gel (column) with hexane-ethyl acetate (2:1) as eluent to give 1.8 g of solid, m.p. 114° C.-116° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH3:22])[C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:50][CH:48]1[CH2:49][N:46]([C:19](=[O:21])[C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:22])[CH2:47]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(O)C1
Temperature: 25 °C
Yield: 84 %

Procedure:
DIPEA (8.53 mL, 49.0 mmol) was added to a mixture of (S)-2-(tert-butoxycarbonylamino)propanoic acid (3.089 g, 16.33 mmol), which is commercially available, and TBTU (5.24 g, 16.33 mmol) in DCM (30 mL). Upon stirring at rt the mixture gradually became a clear solution. Azetidin-3-ol hydrochloride (2.68 g, 24.5 mmol) was added and the mixture was stirred over night. NaHCO3 (8% aq., 20 mL) was added. The organic layer was washed with NaHCO3 (8% aq., 3×60 mL). DCM (100 mL) was used for back extraction of the combined aqueous phases. Toluene was added and the combined organic layers were concentrated on the rotavapor over night (45° C. in waterbath) to give the title product (3.35 g, 84%,) as a transparent oil which solidified upon standing. Mixture of rotamers: 1H NMR (500 MHz, CD3OD) δ 1.21-1.27, 1.41-1.49, 3.7-3.83, 3.98-4.27, 4.41-4.47, 4.56-4.64.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[N:11]3[CH:15]=[CH:16][N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O.C(N(CC)C1C=CC=CC=1)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([Cl:20])[N:11]3[CH:15]=[CH:16][N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cc2nccn12
Solvent: CCN(CC)c1ccccc1
Solvent: CC#N
Product: Clc1nc(-c2ccc(Br)cc2)cc2nccn12
Temperature: 50 °C
Yield: 39 %

Procedure:
To a flask charged with 7-(4-bromophenyl)imidazo[1,2-c]pyrimidin-5(6H)-one (25.00 g, 86.173 mmol), phosphoryl trichloride (31.554 mL, 344.69 mmol), and N,N-diethylaniline (27.420 mL, 172.35 mmol) was added acetonitrile (200 mL) and the mixture was heated to 50° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue diluted with water and DCM. The aqueous was neutralized with potassium carbonate and the bi-phasic mixture passed through a pad of celite to remove the insoluble material. The layers were separated and the aqueous extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude material was triturated with hexanes and the solids were collected by filtration to afford 7-(4-bromophenyl)-5-chloroimidazo[1,2-c]pyrimidine (10.369 g, 33.604 mmol, 38.997% yield). MS (apci) m/z=310.0 (M+H).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1O.[Cl-].[Al+3].[Cl-].[Cl-].[C:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:30][CH3:31])[C:25]=2Br)[CH:20]=1)(=[O:18])[CH3:17].BrC1C2C(=CC=CC=2)C=CC=1OC>>[C:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:30][CH3:31])[CH:25]=2)[CH:20]=1)(=[O:18])[CH3:17]
Reactant: COc1ccc2cc(C(C)=O)ccc2c1Br
Agent: COc1ccc2ccccc2c1Br
Agent: Oc1ccc2ccccc2c1
Agent: [Al+3]
Product: COc1ccc2cc(C(C)=O)ccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
42 Ml of β-naphthol and 16.2 g of anhydrous aluminum chloride are added to the solution of 2-acetyl-5-bromo-6-methoxynaphthalene obtained as in example 1a), while keeping the temperature at -10° C. The reaction mixture is kept for 48 hours under stirring at room temperature and then it is worked as in example 1 with the only difference that the product is crystallized by isopropyl alcohol. 19 Grams of product are obtained with a yield equal to 38.7% calculated on the basis of the starting material 1-bromo-2-methoxynaphthalene.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1nc(N)nc(SC)c1C#N
Temperature: 100 °C
Yield: 28.8 %

Procedure:
To a stirred solution of 250 mg (1.02 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 10 ml toluene at room temperature were added 310 mg (2.04 mmol) 2-methoxybenzeneboronic acid, 118 mg (0.10 mmol) tetrakis(triphenylphosphine) palladium(O) and 262 mg (2.04 mmol) potassium carbonate. The reaction mixture was heated at 100° C. for 16 h, then cooled to room temperature and partitioned between ethyl acetate and water. The phases were separated and the organic phase dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/4 then ethyl acetate/hexane 1/2) followed by trituration in hexane afforded 80 mg (29%) 2-amino-4-(2-methoxy-phenyl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 272 (M+, 32), 257 ([M—CH3]+, 100), 241 (17).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:27][C:28]1[S:32][C:31]([SH:33])=[N:30][N:29]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][S:33][C:31]2[S:32][C:28]([CH3:27])=[N:29][N:30]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: Cc1nnc(S)s1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CSc2nnc(C)s2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and 5-methyl-1,3,4-thiadiazole-2-thiol.
Reaction SMILES: C(O[C:4]([CH:6]1[C:12](=O)[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]1)=[O:5])C.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>C(O)(=O)C>[C:17]([O:16][C:14]([N:9]1[CH2:8][CH2:7][C:6]2=[C:4]([OH:5])[N:23]3[C:22]([N:21]=[C:12]2[CH2:11][CH2:10]1)=[CH:26][CH:25]=[N:24]3)=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(O)c2CC1
Temperature: 80 °C

Procedure:
To 13.3 g (46.61 mmol) 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 8 mL acetic acid was added 3.87 g (46.61 mmol) 3-aminopyrazole and the reaction mixture was heated at 80° C. for 15 minutes. The resulting solid was collected by filtration and washed with TBME (3×10 mL) to give the desired product.
Reaction SMILES: C([O:4][C:5]1[C:6]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:7][C:8]2[O:12][C:11]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)([CH3:13])[CH2:10][C:9]=2[C:23]=1[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:11]2([CH3:13])[CH2:10][C:9]3[C:23]([C:24]([CH3:27])([CH3:26])[CH3:25])=[C:5]([OH:4])[C:6]([C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:7][C:8]=3[O:12]2)=[CH:21][CH:20]=1
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COc1ccc(N)cc1)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(COc2ccc(N)cc2)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
Under a nitrogen atmosphere, 1.2 g of 5-acetoxy-2-(4-aminophenoxymethyl)-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran was dissolved in 30 ml of toluene. To the solution was added 11.3 ml of diisobutyl aluminum hydride (1.0 M in toluene) and the mixture was stirred at room temperature for 2 hours. After reaction, a saturated aqueous ammonium chloride solution was added and insoluble matters were filtered off on Celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 33% ethyl acetate to give 0.63 g of 2-(4-aminophenoxymethyl)-4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran as a pale yellow oil (yield 59%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]2[S:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Clc1nc2ccccc2s1
Solvent: Cc1ccccc1
Product: Fc1cc(Br)ccc1Nc1nc2ccccc2s1
Temperature: 130 °C
Yield: 99.9 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (1.00 g, 5.26 mmol) in toluene (25 mL) was added 2-chlorobenzothiazole (0.75 mL, 5.79 mmol). The purple solution was heated at 110-150° C. in a resealable tube for 66 h and then cooled to room temperature. The resulting brown solution was concentrated to give a purple solid which was triturated with heptane to afford N2-(4-bromo-2-fluorophenyl)-1,3-benzothiazol-2-amine (1.699 g, 99%) as a light purple powder. RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=13.82 min, 95%; m/z 325 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:16]([O:20][C:21]([NH:23][CH:24]([CH2:37][C:38]1([F:43])[CH2:42][CH2:41][CH2:40][CH2:39]1)[C:25]([NH:27][C:28]1([CH:32]([OH:36])[C:33](O)=[O:34])[CH2:31][CH2:30][CH2:29]1)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][CH:24]([C:25](=[O:26])[NH:27][C:28]1([CH:32]([OH:36])[C:33](=[O:34])[NH:1][C:2]2[CH:6]=[CH:5][NH:4][N:3]=2)[CH2:31][CH2:30][CH2:29]1)[CH2:37][C:38]1([F:43])[CH2:42][CH2:41][CH2:40][CH2:39]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(=O)O)CCC1
Reactant: Nc1cc[nH]n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(=O)Nc2cc[nH]n2)CCC1
Temperature: 0 °C
Reaction time: 0.04 h
Yield: 62.8 %

Procedure:
3-Aminopyrazole (92 mg, 1.08 mmol) and DIEA (110 μL, 1.08 mmol) were added to a solution of compound 57-b (0.31 mmol) in anh. DMF (3 mL). The solution was cooled to 0° C. and stirred for 2-3 minutes, then HATU (126 mg, 0.32 mmol) in anh. DMF (1 mL) was added. The reaction mixture was allowed to attain room temperature, stirred for 16 h and then diluted with DCM. The organic phase was extracted with NaHCO3 sat. aq. solution. The aqueous phase was extracted with ethyl acetate and the combined organics dried over anh. Na2SO4 and then concentrated. Purification by flash column chromatography (MeOH/DCM, 0:1-2:8) gave the title compound (91 mg g, 63%). MS m/z 468.3 (M+H)+.
Reaction SMILES: C(O[C:6](=[O:22])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:23]([O:25][C:26](=[O:38])[CH:27](C(OCC)=O)[C:28](OCC)=[O:29])[CH3:24]>>[CH2:23]([O:25][C:26]([C:27]1[C:6](=[O:22])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:28]=1[OH:29])=[O:38])[CH3:24]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)n2cccc2)cc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(OC)cc2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (4-methoxy-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 343 (M+H)+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:43])[C@H:16]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]=[CH:18][C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:21][CH:20]=1.CI>O1CCCC1>[CH3:13][O:14][C:15](=[O:43])[C@:16]([CH3:1])([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[N:17]=[CH:18][C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:21][CH:20]=1
Reactant: CCCCc1ncc(C=N[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCCCc1ncc(C=N[C@@](C)(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (1.27 g, 12.6 mmol) in tetrahydrofuran (50 ml) was added n-butyl lithium (5 ml of 2.5M in hexane, 12.6 mmol) at 0° C. After being stirred at 0° C. for 15 minutes, the solution was cooled to -78° C. and a solution of the imine, N [{1-[(2-chlorophenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}methylene]phenylalanine methyl ester (Example 3(i) Method B) (5.51 g, 12.6 mmol) in tetrahydrofuran (35 ml) was added dropwise. The mixture was stirred for 30 minutes at -78° C. under argon and methyl iodide (2.06 q, 14.5 mmol) in tetrahydrofuran (15 ml) was added at 78° C. The mixture was allowed to slowly warm to ambient temperature and then stirred for 18 hours. The solvent was evaporated, the residue dissolved in ethyl acetate, the insoluble materials were filtered and the concentrated product was used without purification to give 8N18 g of N-[{1-[(2-chlorophenyl)-methyl]-2-n-butyl-1H-imidazol-5-yl}methylene]-α-methylphenyl-alanine methyl ester.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([N+]([O-])=O)[CH:21]=1>CCO>[C:9]12([NH:8][C:24]3[CH:25]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=3[N+:26]([O-:28])=[O:27])[CH2:10][CH:11]3[CH2:17][CH:15]([CH2:14][CH:13]([CH2:12]3)[CH2:18]1)[CH2:16]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)cc1NC12CC3CC(CC(C3)C1)C2
Yield: 23.1 %

Procedure:
15.5 ml of triethylamine and then a suspension of 15 g of 1-aminoadamantane in 50 ml of 96° EtOH are added to a solution of 20 g of 4-chloro-1,2-dinitrobenzene in 80 ml of 96° EtOH. The mixture is refluxed for 7 hours and, after cooling, the precipitate formed is filtered off to give 7 g of the expected product. M.p.=146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1.[NH3:29]>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([NH2:29])=[O:27])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[N:16][CH:15]=[N:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COC(=O)c1cccc(Cc2c(-c3cncnc3)[nH]c3cc(OC)ccc23)n1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3cccc(C(N)=O)n3)c(-c3cncnc3)[nH]c2c1

Procedure:
A mixture of methyl 6-(6-methoxy-2-pyrimidin-5-yl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (466 mg), a solution of ammonia in methanol (about 7 mol/L, 18.6 mL) and tetrahydrofuran (6.2 mL) was stirred at room temperature for 48 hours. The precipitate was collected by filtration, washed with methanol, and then dried under reduced pressure to obtain the title compound (370 mg). 1H-NMR (DMSO-d6) δ ppm: 3.79 (3H, s), 4.44 (2H, s), 6.70 (1H, dd, J=2.3, 8.5 Hz), 6.89 (1H, d, J=2.3 Hz), 7.34-7.41 (1H, m), 7.51 (1H, d, J=8.5 Hz), 7.63-7.77 (2H, m), 7.79-7.86 (2H, m), 9.13 (1H, s), 9.14 (2H, s), 11.45 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10].[NH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.Cl>CCO>[Cl:8][C:6]1[CH:7]=[C:2]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=2)[C:3]([C:9](=[O:10])[NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:5]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Nc1cccnc1)c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(Nc2cc(Cl)ncc2C(=O)Nc2cccnc2)cc1
Temperature: 100 °C

Procedure:
To a suspension of 4,6-dichloro-N-(3-pyridyl)pyridine-3-carboxamide (500 mg, 1.9 mmol) in EtOH (5 mL) was added ethyl 4-aminobenzoate (340 mg, 2.1 mmol) and HCl (0.1 mL, 4M). The mixture was heated in a microwave for 10 min at 100° C. then heated again at 130° C. for 20 min. More ethyl 4-aminobenzoate (100 mg, 0.6 mmol) was added and the mixture heated again at 130° C. for 20 min. The mixture was evaporated to dryness and the residue purified by flash chromatography (40 g Reveleris silica cartridge, 0-10% MeOH in DCM) to afford ii as an off white solid (334 mg, 46%). A 10 mg sample of ii was dissolved in DMSO and purified further using reverse phase preparatory HPLC (20-60% MeCN in water, 0.1% formic acid) to afford 8.74 mg of ii as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.85 (d, J=2.2 Hz, 1H), 8.65 (s, 1H), 8.33 (d, J=3.7 Hz, 1H), 8.11 (ddd, J=8.3, 2.5, 1.5 Hz, 1H), 7.96 (d, J=8.6 Hz, 2H), 7.40 (dd, J=8.1, 4.4 Hz, 3H), 7.15 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 31-1). [M+H]+ m/z=397.09.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:6][CH:5]=1.[K].[OH-]>C(O)C.O>[CH2:14]([S:13][CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][CH:6]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCSCCOc1ccc(C(=O)OC)cc1
Agent: [K]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCSCCOc1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 94.1 %

Procedure:
A solution of 4-[2-(dodecylthio)ethoxy]benzoic acid methyl ester (11.29 g, 29.7 mmol) in 80% aqueous ethanol (100 ml) was treated with a solution of potassium, hydroxide, (6.0 g, 0.107 mol) in water (15 ml) and the resulting mixture was heated at 80° C. for 2 h. The solvent was then concentrated in vacuo and the residue was treated with 150 ml of 1N aqueous hydrochloric acid. The aqueous phase was extracted three times with dichloromethane and the combined organic extracts were washed with brine, dried (magnesium sulfate) and evaporated. The residue was recrystallized from dichloromethane to give 10.24 g (94%) of the title material as white needles: mp 97-98° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:3]1[NH:18]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:18][N:3]1[CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[CH2:5][CH2:6][CH2:7][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NN1C(=O)CCCC1c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: NN1C(=O)CCCC1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
tert-Butyl [2-oxo-6-(3-trifluoromethylphenyl)piperidin-1-yl]carbamate (210 mg) was dissolved in chloroform (4 mL), followed by addition of trifluoroacetic acid (2 mL). After stirring at room temperature for four hours, concentration under reduced pressure gave the title compound (119 mg). The property values of the compound are as follows.