Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-])=O)=[C:6]([CH:22]=1)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1c(Nc2cc(Cl)ccc2[N+](=O)[O-])sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(Cl)ccc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(5-chloro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-5-chloroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Mn]([O-])(=O)(=O)=[O:22].[K+]>C1C=CC=CC=1>[C:7]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:22])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=C(c1ccccc1)c1cccc(C(C)C(=O)O)c1
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 18 h

Procedure:
α-(3-(1-Phenylethenyl)phenyl)propionic acid (35 g) obtained in Example 2 was dissolved in 250 ml of benzene and 250 ml of water was further added thereto with vigorous stirring to prepare a suspension. Then, 2 liter of 2% aqueous solution of potassium permanganate was dropped little by little over 1.5 hours. After the dropping, stirring was continued for 18 hours at room temperature. After the reaction, it was acidified by adding concentrated sulfuric acidand was treated by adding 35 g of sodium sulfite. After that, 500 ml of water was added and extraction was carried out three times with 150 ml of ether. The ether solution was washed with water and it was extracted three times with 200 ml of 5% aqueous solution of sodium hydroxide. The aqueous layer was then acidified by adding hydrochloric acid and extracted again three times with 150 ml of ether, which was followed by washing with water, drying with anhydrous magnesium sulfate, and filtration. The ether was then removed by reduced-pressure evaporation. Finally, 20 g of α-(3-benzoylphenyl)propionic acid (ketoprofen) was obtained by re-crystallization from benzene/petroleum ether mixture. The melting point and spectrum were the same as those of an authentic sample.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(O)cc2C(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccc(OCC3CC3)cc2C(O)C1

Procedure:
1.50 g (5.65 mmol) 4,6-Dihydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example XLII), 840 mg (6.22 mmol) (bromomethyl)cyclopropane and 1.60 g (11.3 mmol) K2CO3 in 10 mL DMF are stirred at 80° C. over night. The reaction mixture is diluted with water and extracted with DCM. The organic layer is concentrated by evaporation and the residue is purified by HPLC.
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[O:4].Cl.[CH3:22][NH:23][CH3:24].C(N(CC)CC)C>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH:2]([N:23]([CH3:24])[CH3:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)#[N:14]
Reactant: N#Cc1ccc(CNC(=O)C(Br)c2ccccc2)cc1
Reactant: CNC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(C(=O)NCc1ccc(C#N)cc1)c1ccccc1
Reaction time: 19 h
Yield: 92.6 %

Procedure:
To a stirred solution of (RS)-2-bromo-N-(4-cyano-benzyl)-2-phenyl-acetamide (200 mg) in THF (10 ml) at rt under an Ar atmosphere were added dimethylamine, hydrochloride (149 mg), triethylamine (0.42 ml) and tetrabutylammonium iodide (34 mg). The reaction mixture was stirred for 19 hrs, then treated with additional dimethylamine, hydrochloride (149 mg) and triethylamine (0.42 ml). After another 8 hrs stirring at rt, the solids were filtered off and washed with EtOAc. The filtrate was washed with water and brine, dried over MgSO4 and concentrated. The product was isolated by chromatography (silica gel, gradient dichloromethane=>dichloromethane/MeOH 9:1) to give (RS)-N-(4-cyano-benzyl)-2-dimethylamino-2-phenyl-acetamide (165 mg). Orange solid. MS 294.3 ([M+H]+)
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.C(O)(=O)C.[Cl:29]N1C(=O)CCC1=O>ClCCl>[Cl:29][C:6]1[S:5][C:4]([C@H:3]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[O:11])[CH2:2][OH:1])=[CH:8][CH:7]=1
Reactant: O=C(Nc1ccc(-c2ccncc2)cc1)N[C@H](CO)c1cccs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1ccc(-c2ccncc2)cc1)N[C@H](CO)c1ccc(Cl)s1
Yield: 36.3 %

Procedure:
To a solution of 1-[(1R)-2-hydroxy-1-(2-thienyl)ethyl]-3-[4-(4-pyridinyl)phenyl]urea (700 mg) and acetic acid (734 mg) in dichloromethane (10 mL) were added N-chlorosuccinimide (303 mg) and the mixture was refluxed for 3 hours. The mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with chloroform/methanol (9:1) and crystallized from ethanol to afford 1-[(1R)-1-(5-chloro-2-thienyl)-2-hydroxyethyl]-3-[4-(4-pyridinyl)phenyl]urea (280 mg) as a crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:21])[CH:11]=[N:12][C:13]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](O)=[O:29])[CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:21][C:28](=[O:29])[C:24]3[CH:25]=[CH:26][CH:27]=[N:22][CH:23]=3)[CH:11]=[N:12][C:13]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccnc1
Reactant: C[C@H](Oc1ncc(N)cc1-c1ccc(Cl)cc1)C(F)(F)F
Product: C[C@H](Oc1ncc(NC(=O)c2cccnc2)cc1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-ylamine (example 420 and 3-pyridine carboxylic acid (CAN 59-67-6) as starting materials; MS (EI) 422.0 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:12].C(=O)(O)[O-].[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(O)C>[CH2:22]([O:21][C:19]([NH:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:12])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H]1Cc2ccccc2C[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(N[C@@H]1Cc2ccccc2C[C@H]1O)OCc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of trans 3-amino-2-hydroxy-1,2,3,4-tetrahydronaphthalene (2.2 g, 72% pure) in ethanol (135 mL) stirring at room temperature under nitrogen was added sodium bicarbonate (2.2 g) and benzyl chloroformate (2.12 mL). After 4 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography eluting with a step-wise gradient of 30-70% ethyl acetate in hexane to provide the title compound (2.0 g) as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:41]([NH2:49])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:41]([NH:49][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 40 °C

Procedure:
A mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (50 mg, 0.22 mmol) (from Example 11), HOBt (74 mg, 2.5 eq.), EDAC (105 mg, 2.5 eq.), phenethylamine (106 mg, 4 eq.) and TEA (0.5 mL) in DMF (1 mL) was heated at 40° C. for overnight. The reaction was concentrated and purified on a silica gel column to give the titled compound as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:8]2[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[C:22]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:8]2[N:13]=[C:12]([CH:14]=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cccc(CO)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cccc(C=O)n1
Reaction time: 24 h
Yield: 95.5 %

Procedure:
100 g of manganese dioxide is added in portions to a solution of 20 g of 6-(diphenyl-tert-butylsilyloxymethyl)-2-hydroxymethylpyridine in 236 ml of toluene at 24° C. under nitrogen and stirred for 24 hours. It is filtered on Celite, rewashed well with toluene and concentrated by evaporation in a vacuum. 19.0 g of the title compound is obtained as colored liquid, which is further used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][C:58]1=[O:63].ClCl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:60]1[CH2:61][CH2:62][N:57]([CH3:56])[C:58](=[O:63])[CH2:59]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CN1CCNCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CC1=O
Yield: 9 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, TBTU, diisopropylethylamine, and 1-methylpiperazin-2-one in DMF. Yield: 9%; C21H19C12N5O3 (460.32); mass spectrum: (M+H)+=460/462/464 (chlorine isotope).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)=[O:17])[CH:11]=[CH:12][C:13]=1[CH3:14])=[O:6].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38]Cl)[CH2:33][CH2:32]1>>[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][O:1][C:2]2[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=2)[C:5]([NH:7][C:8]2[CH:9]=[C:10]([NH:15][C:16]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)=[O:17])[CH:11]=[CH:12][C:13]=2[CH3:14])=[O:6])[CH2:33][CH2:32]1
Reactant: ClCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1cccc(O)c1
Product: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1cccc(OCCN2CCOCC2)c1
Temperature: 40 °C
Yield: 41 %

Procedure:
Using an analogous procedure to that described in Example 7 except that the reaction mixture was heated to 70° C. rather than 40° C., N-[3-(3-hydroxybenzamido)-4-methylphenyl]quinoline-6-carboxamide was reacted with 2-morpholinoethyl chloride to give the title compound in 41% yield, m.p. 216-217° C.; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 2.47 (m, 4H), 2.73 (t, 2H), 3.59 (t, 4H), 4.18 (t, 4H), 7.17 (m, 1H), 7.24 (d, 1H), 7.42 (t, 1H), 7.54 (s, 2H), 7,61 (m, 2H), 7.87 (s, 1H), 8.15 (d, 1H), 8.23 (m, 1H), 8.52 (m, 1H), 8.61 (s, 1H), 9.0 (d, 1H), 9.9 (s, 1H), 10.49 (s, 1H); Mass Spectrum: M+H+ 511.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][CH:5]=[O:6].[N:8]([O-])=[O:9].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3](=[O:7])[C:4](=[N:8][OH:9])[CH:5]=[O:6]
Reactant: COC(=O)CC=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(C=O)=NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the respective 3-oxo-propionic acid methyl ester derivative (4.8 mmol, 1.0 eq.) in glacial acetic acid (1.9 mL) was cooled to 10° C. and at this temperature was added a solution of NaNO2 (5.6 mmol, 1.16 eq.) in water (0.68 mL). After the addition was complete (15 min), the solution was allowed to warm to room temperature and stirred for 2 h. Then the solution was poured into water (10 mL) and after a few minutes crystals begun to appear. This suspension was cooled in an ice-bath and crystals were collected by filtration. The cake was washed several times with cold water and the water was removed by the azeotrope of toluene-water in vacuo to give 2-hydroxyimino-3-oxo-propionic acid methyl ester derivatives which were dissolved in a mixture of acetic anhydride (1.375 mL) and glacial acetic acid (1.8 mL). To this solution was added sodium acetate (0.296 mmol, 0.06 eq.) and HgCl2 (0.01 mmol, 0.002 eq.). The mixture was refluxed for 1 h, then cooled to room temperature and filtered. The solid was rinsed with ether, the organic filtrate was recovered, washed 3 times with water and one time with 1M aq. K2CO3. The organic layer was dried over MgSO4, filtered and concentrated. The crude products were purified by flash chromatography to afford the corresponding 2-acetylamino-3-oxo-propionic acid methyl ester derivatives.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=O)C.[I:41][CH2:42][CH2:43][CH2:44][CH2:45]I>O1CCCC1>[CH2:9]([N:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH:24]([CH2:45][CH2:44][CH2:43][CH2:42][I:41])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:21]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ICCCCI
Reactant: CCOC(=O)CCCN1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CCCCI)CCN1CCN(Cc2ccccc2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of lithium diisopropylamide (2 M, 32.0 ml, 6.36 mmol) in tetrahydrofuran (420 ml) was added ethyl 4-(4-benzyl-1-piperazinyl)-butanoate (6.47 g, 21.2 mmol) (Preparation 1) at −78° C. and the mixture was stirred for 1 h at the same temperature. To this mixture was added HMPA (19.4 ml) and the resultant mixture was added to a solution of 1,4-diiodobutane (13.2 g, 4.25 mmol) in tetrahydrofuran (22 ml) at −78° C. After 1 h, the temperature was raised to −50° C. and the mixture was stirred for 1 hour. The reaction was quenched by adding AcOH (0.230 ml). After the mixture was basified with aq. saturated NaHCO3, then the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 200-350 mesh/500 g/hexane:ethyl acetate=2:1) to provide a yellow oil (6.3 g/63%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([Sn](C)(C)C)=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:17][CH:16]=1
Reactant: Brc1ccccc1-c1ccccc1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Product: Cc1ccc(-c2ccccc2-c2ccccc2)cc1

Procedure:
Prepared from 2-bromobiphenyl and 4-methylphenyltrimethylstannane by the procedure described in Example 69, Step B.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][OH:19])[CH2:8][O:7][CH:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[O:5][CH2:4]1)[CH3:2].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.Cl>[CH3:27][S:28]([O:19][CH2:18][C:3]1([CH2:1][CH3:2])[CH2:4][O:5][CH:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[O:7][CH2:8]1)(=[O:30])=[O:29]
Reactant: CCC1(CO)COC(c2c([N+](=O)[O-])cnn2C)OC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(COS(C)(=O)=O)COC(c2c([N+](=O)[O-])cnn2C)OC1
Temperature: 25 °C

Procedure:
To a solution of (5-ethyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methanol (trans isomer) (610 mg, 2.25 mmol, intermediate 66) in dry DCM (15 mL) at 0° C. was added Et3N (0.45 mL, 3.38 mmol) followed by methanesulfonyl chloride (0.21 mL, 2.70 mmol). The reaction mixture was slowly warmed to room temperature over 1.5 hr. The mixture was re-cooled to 0° C. and diluted with aqueous 1 M HCl (10 mL) and DCM (20 mL). The organic layer was washed with aqueous saturated NaHCO3 (15 mL) and water (15 mL), separated, dried over Na2SO4 and concentrated under reduced pressure to give (5-ethyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl methanesulfonate as a white solid (816 mg, quantitative). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 6.38 (s, 1H), 4.14 (s, 3H), 4.05-3.88 (m, 6H), 3.22-2.92 (m, 3H), 1.96 (q, J=7.6 Hz, 2H), 1.03 (t, J=7.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:24]([C:23]3[CH:26]=[CH:27][C:20]([O:19][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:21][CH:22]=3)[NH:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CCCCCCOc1ccc(C=O)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCOc1ccc(-c2nc3ccc(C(=O)OC)cc3[nH]2)cc1
Temperature: 145 °C
Reaction time: 48 h
Yield: 48.9 %

Procedure:
A mixture of Methyl 3,4-diaminobenzoate (1.84 g) and 4-hexyloxy benzaldehyde (2.30 g) in nitrobenzene (40 ml) was stirred for 48 hours at 145° C. After cooling, the mixture was evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel eluted with (n-hexane:ethyl acetate=2:1) gave 5-Methoxycarbonyl-2-(4-hexyloxyphenyl)benzimidazole (1.91 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH2:12][OH:13].Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:11]2[CH2:12][O:13][C:23](=[O:25])[NH:10]2)=[CH:20][CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(CO)Cc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1NC(Cc2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Diisopropylethylamine (0.78 ml, 4.5 mmol, 2.25 eq) is added to a solution of 2-amino-3-(4-chlorophenyl)propan-1-ol a93 (0.37 g, 2 mmol, 1 eq) in dichloromethane (75 ml). The mixture is cooled (ice bath) and triphosgene a89 (0.30 g, 1 mmol, 0.5 eq) is added. The mixture is stirred overnight at room temperature, washed with water, with 0.1 N aqueous hydrochloric acid, dried over magnesium sulfate and concentrated in vacuo to give 0.47 g of 4-(4-chlorobenzyl)-1,3-oxazolidin-2-one a94 as a yellow oil. This oil is used in the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:4][CH:5]=[N:6][CH:7]=1.[N:22]([O-])=O.[Na+]>C(O)(=O)C.O>[N:1]1[C:2]2[CH:7]=[N:6][CH:5]=[N:4][C:3]=2[N:8]([CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:22]=1
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ncncc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1nnc2cncnc21
Reaction time: 1 h
Yield: 114.7 %

Procedure:
1,1-Dimethylethyl (2S)-2-{[(5-amino-4-pyrimidinyl)amino]methyl}-1-pyrrolidinecarboxylate (1.6633 g, 5.67 mmol) and sodium nitrite (469 mg, 6.80 mmol) were dissolved in a mixture of acetic acid (5 mL) and water (8 mL), and the mixture was stirred vigorously for 1 h. The solution was concentrated in vacuo to provide 1,1-dimethylethyl (2S)-2-(3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-1-pyrrolidinecarboxylate (1.98 g, >99%). LCMS: (M+H)+: 305.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].CN(C)C=O.[NH2:17][C:18]1[C:33]([Cl:34])=[CH:32][C:21]([C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]2[OH:31])=[O:23])=[C:20]([O:35][CH3:36])[CH:19]=1>C(N(CC)CC)C>[NH2:17][C:18]1[C:33]([Cl:34])=[CH:32][C:21]([C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][C:5](=[O:6])[N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:27][C@H:26]2[OH:31])=[O:23])=[C:20]([O:35][CH3:36])[CH:19]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CCNC[C@H]1O
Reactant: O=C(CCCCl)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CCN(CCCC(=O)N2CCCC2)C[C@H]1O
Temperature: 70 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
To a stirred solution of 3.00 parts of 1-(4-chloro-1-oxobutyl)pyrrolidine in 67.5 parts of N,N-dimethylformamide were added 1.93 parts of trans-4-amino-5-chloro-N-(3-hydroxy-4-piperidinyl)-2-methoxybenzamide and 1.5 parts of N,N-diethylethanamine and the whole was stirred for 18 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in a sodium carbonate solution in water. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.1 parts (47.8%) of trans-4-amino-5-chloro-N-[3-hydroxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]-2-methoxybenzamide; mp. 174.7° C. (compound 15).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:11][CH:10]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[CH:11][CH:10]=1)=[O:1]
Reactant: O=C(Nc1ccc(C2=C(CO)CCCC2)cc1)c1c(F)cccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.9 %

Procedure:
To the solution of Compound 22 (55 mg, 0.16 mmol) in DCM (4 mL) was added Dess-Martin reagent (100 mg, 0.24 mmol). The solution was stirred at room temperature for 20 min before it was concentrated and chromatographed to afford Compound 100 (42 mg, 78%). 1H NMR (300 MHz, CDCl3) δ 9.52 (s, 1 H), 7.68-7.65 (m, 3 H), 7.47-7.41 (m, 1 H), 7.25 (d, J=8.4 Hz, 2 H), 7.02 (t, J=8.1 Hz, 2 H), 2.55-2.51 (m, 2 H), 2.37-2.31 (m, 2 H), 1.79-1.71 (m, 4 H); ESMS cacld (C20H17F2NO2): 341.1; found: 342.1 (M+H).