Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:2].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1>C1C=CC=CC=1>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:3][CH:1]=[O:2])[CH:24]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccnc1
Solvent: c1ccccc1
Product: O=CCCc1cccnc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 6.08 g (20 mmol) (formylmethylene)triphenylphosphorane (Fluka; Buchs/Switzerland) and 2.14 g (20 mmol) freshly distilled 3-pyridinecarbaldehyde in 200 ml benzene is stirred for 3 h at 80° C. After the addition of a further 0.30 g (formylmethylene)triphenylphosphorane, the mixture is stirred for another 3 h at 80° C. The cooled benzene solution is extracted with 250 ml, 100 ml and finally 50 ml 0.1 N HCl. The acidic H2O phases are finally extracted with 150 ml ether and the organic phases discarded. The combined acidic H2O phases are covered with a supernatant 150 ml ether and adjusted to alkaline pH with 100 ml 1 N NaOH. The H2O phase is separated off and extracted 3 times with 150 ml EtOAc each time. Drying (Na2SO4) and partial evaporation of the organic phases yield 0.4 l of a solution of 3-(pyridin-3-yl)propen-1-one in EtOAc. Hydrogenation of the above solutions in the presence of 5% Pd/C, filtration of the catalyst, evaporation and column chromatography (SiO2; EtOAc) yield the title compound; TLC (EtOAc) Rf=0.30; FAB-MS (M+H)+=136.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@@H:4]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][CH:6]([C@H:4]2[CH2:5][C@H:3]2[CH2:2][O:1][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=2)[CH2:11][CH2:10]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CO)CC1
Reactant: BrCc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(Br)cc2)CC1

Procedure:
Using the conditions outlined in intermediate 5 (step C) tert-butyl 4-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]piperidine-1-carboxylate (intermediate 4) and 4-bromobenzyl bromide were reacted to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J 8.2 Hz, 2H), 7.22 (d, J 8.2 Hz, 2H), 4.53 (d, J 12.3 Hz, 1H), 4.44 (d, J 12.3 Hz, 1H), 4.17-3.18 (m, 2H), 3.58-3.51 (m, 1H), 3.43-3.37 (m, 1H), 2.73-2.58 (m, 2H), 1.84 (d, J 13.2 Hz, 1H), 1.70 (d, J 13.3 Hz, 1H), 1.49 (s, 9H), 1.34-1.24 (m, 2H), 1.24-1.17 (m, 1H), 0.94-0.85 (m, 1H), 0.77-0.66 (m, 2H), 0.03-0.02 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([NH:17][C:18](=[O:30])[C@@H:19]([NH2:29])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:16][C:9]([NH:17][C:18](=[O:30])[C@@H:19]([NH:29][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:8])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(NC(=O)[C@@H](N)COCc1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)[C@H](COCc1ccccc1)NC(=O)c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
3.2 g of an oily substance [which had been obtained by the treatment of the (2S)-N-(α,α-dimethylbenzyl)-3-benzyloxy-2-aminopropionamide trifluoroacetate (prepared as described in Preparation 5) with triethylamine] were dissolved, together with 1.5 g of triethylamine, in 150 ml of methylene chloride. 1.5 g of benzoyl chloride was dropped onto this solution in an ice bath, and the reaction solution was stirred for 30 minutes, after which the methylene chloride layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and recrystallization of the residue from a mixture of diethyl ether and hexane gave 4.1 g of the title compound melting at 88°-90° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:9]#[N:10])=[CH:4][CH:3]=1.[C:17]1(B(O)O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[C:26]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:22]=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[C:9]#[N:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N#CC(c1ccc(Br)cc1)C1CCCCC1
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC(c1ccc(-c2cccc3ccccc23)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of Example 1A (3.0 g, 10.8 mmol), 1-naphthylboronic acid (2.04 g, 11.9 mmol), Pd(PPh3)4 (249 mg, 0.22 mmol), and 3M Na2CO3 (9.0 mL, 27 mmol) in toluene (18 mL) was heated to 100° C. in a sealed tube, stirred for 14 hours, cooled to room temperature, and partitioned between water and diethyl ether. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20:1 to 10:1 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:25])([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[OH:10])=[CH:4][CH:3]=1.CO[C:28](OC)([CH3:30])[CH3:29].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O.CN(C)C=O.[Cl-].[Zn+2].[Cl-].C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:19][N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[O:10][C:28]([CH3:30])([CH3:29])[O:25]2)=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: OC(c1ccc(Cl)cc1Cl)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC1(C)OC(c2ccc(Cl)cc2Cl)C(Cn2cncn2)(c2ccc(Cl)cc2)O1
Yield: 20 %

Procedure:
To a solution of 500 mg of 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol in a mixture of 20 ml of acetone and 1 ml of dimethylformamide are added 2 ml of 2,2-dimethoxypropane, 100 mg of p-toluenesulfonic acid and about 50 mg of zinc chloride, and the resultant mixture is refluxed for 68 hours. The reaction mixture is poured into cold aqueous sodium hydrogencarbonate solution, and the mixture is shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, which is eluted with benzene and ethyl acetate (1:1 v/v). The eluate is concentrated and the residue is washed with isopropyl ether to give 110 mg of 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2,2-dimethyl-4-(1H-1,2,4-triazol-1-yl)methyl-1,3-dioxolane as crystals melting at 141° to 142° C. The yield is 20%.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]([OH:14])[CH2:11][O:12][CH3:13].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C(OCC)(=O)C>[CH2:15]([O:22][C:23]([NH:8][CH2:9][CH:10]([OH:14])[CH2:11][O:12][CH3:13])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COCC(O)CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
19.69 g of triethylamine are added to a solution of 10.23 g of 1-amino-3-methoxy-2-propanol in 100 ml of tetrahydrofuran. After the mixture is cooled, a solution of 16.60 g of benzyloxycarbonyl chloride in 50 ml of tetrahydrofuran is added dropwise thereto for 30 minutes. The mixture is stirred at room temperature for one hour. The reaction mixture is diluted with ethyl acetate, washed with water and dried. The residue is purified by silica gel column chromatography [solvent: ethyl acetate-hexane (2:1)]. 13.2 g of 1-benzyloxycarbonylamino-3-methoxy-2-propanol are obtained as colorless oil. ##STR24##
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)([Cl:21])=O>C(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2
Reactant: O=S(Cl)Cl
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CO)cc2C1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CCl)cc2C1
Temperature: 25 °C

Procedure:
(S)-N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (2.57 mmol, 692 mg) was dissolved in DCM (10 mL), thionyl chloride (5.14 mmol, 0.373 mL, 611 mg) added and the solution stirred at room temperature. After 45 min the mixture was concentrated then azeotroped with dichloromethane (4×10 mL) to give a yellow oil. This was used immediately in step f.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32]C)[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].ClCCl.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][OH:32])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCCl)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCCl)[nH]2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
N-(2-Chloroethyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (88 mg, 0.17 mmol) synthesized in Example (18b) was dissolved in dichloromethane (5 mL), and cooled to −78° C., and a 1.0 mol/L boron tribromide dichloromethane solution (0.19 mL, 0.19 mmol) was added under nitrogen atmosphere. The temperature was raised naturally, the solution was stirred at room temperature for 30 minutes, subsequently a saturated aqueous sodium hydrogencarbonate solution was added to neutralize the reaction solution, and extraction was carried out with dichloromethane (60 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-80%) to afford the desired product (55 mg, yield 64%) as a white solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(O[CH2:9][CH:10]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)(=O)=O>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:10]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:9][C:1]#[N:2])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC(COS(C)(=O)=O)c1ccc(Cl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CC#N)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Sodium cyanide (105 mg, 2.14 mmol) was added to 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)ethyl methanesulfonate (Intermediate 23) (300 mg, 0.86 mmol) in DMF (5 mL) at 20° C. The resulting suspension was stirred at 80° C. for 3 hours. The reaction mixture was evaporated to dryness and redissolved in water (10 mL), and washed sequentially with DCM 3× (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 1-(4-chlorophenyl)-2-cyanoethylcarbamate (209 mg, 87%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ1.38-1.42 (9H, s), 2.82-2.89 (2H, m), 4.89 (1H, d), 7.38-7.45 (4H, m), 7.76 (1H, d). m/z (ESI+) (M−H)−=279; HPLC tR=2.42 min.
Reaction SMILES: [C:1]([C:3]1[NH:16][C:6]2=[N:7][CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=[C:5]2[CH:4]=1)#[N:2].CO.O1CCCC1.[OH-].[Li+]>O>[C:1]([C:3]1[NH:16][C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:5]2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1cnc2[nH]c(C#N)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc2cc(C(=O)O)cnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To ethyl 2-cyano-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (36 mg, 0.17 mmol) was added methanol (1 mL), tetrahydrofuran (1 mL), and water (1 mL), followed by 2 N aqueous lithium hydroxide (0.17 mL, 0.33 mmol). The reaction was stirred at room temperature overnight and was then concentrated. The crude was taken up in water and the pH was adjusted to 4 using 1 N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (3×). The combined organics were dried over sodium sulfate, filtered, and concentrated to provide the 2-cyano-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid. The title compound was then prepared by a method analogous to that described in Example 1, using 2-cyano-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid. −ESI (M−H) 415.1.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].Cl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>CS(C)=O.O>[CH3:30][C:29]1[CH:28]=[C:27]([CH3:31])[NH:26][C:25](=[O:32])[C:24]=1[CH2:23][NH:22][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:3])[CH3:1])[C:8]=2[N:9]=[C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=1)=[O:15]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccccc3)nc21
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccccc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.25 mmol) and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone.HCl (56.3 mg, 0.3 mmol) in DMSO (3 mL). 1-hydroxy-7-azabenzotriazole (51 mg, 0.37 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. N-methylmorpholine (0.1 ml, 0.87 mmol) and EDC (72 mg, 0.37 mmol) were added, the vessel was sealed, and the bright yellow mixture was stirred at room temperature for 2 days. Next added 2 mL of water, and the contents were stirred for 10 min. Solids that precipitated were sonicated, and allowed to stand at room temperature for 10 min. The reaction contents were filtered and washed with water. The solid was treated with 2 mL of EtOH, sonicated and heated, and then allowed to cool to room temperature. The contents were filtered, washed with water and dried to afford the title compound (74 mg, 70%) as a white solid. LCMS E-S (M+H)=416.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (s, 1H), 8.98 (t, J=4.80 Hz, 1H), 8.38 (s, 1H), 8.25-8.30 (m, 2H), 8.17 (s, 1H), 7.49-7.59 (m, 3H), 5.91 (s, 1H), 5.30-5.38 (m, 1H), 4.42 (d, J=4.80 Hz, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 1.55 (d, J=6.57 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1>ClCCl>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:43])=[CH:37][CH:36]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 4-methoxyphenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 mins. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methoxy-phenyl)-amide as a white solid. (Yield 35 mg, 50%).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1[CH2:18]Br.[H-].[Na+]>CN(C)C=O>[C:1]1([S:7]([N:10]2[CH2:18][C:17]3[S:16][CH:15]=[N:14][C:13]=3[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: BrCc1ncsc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)N1Cc2ncsc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzenesulfonamide (638 mg) and 4,5-bis(bromomethyl)thiazole (M. Al. Hariri, O. Galley, F. Pautet, H. Fillion, Eur. J. Org. Chem., pp. 593-594 (1998)) (1.10 g) were dissolved in N,N-dimethylformamide (10 mL) under ice cooling, and sodium hydride (60% in oil, 357 mg) was added thereto at a time, followed by stirring at room temperature for 3 hours. The resultant mixture was partitioned between water and methylene chloride, and the organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=9:1), to thereby give the title compound (137 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:37][C:38]([NH:41][S:42]([C:45]1[S:49][C:48](Br)=[CH:47][CH:46]=1)(=[O:44])=[O:43])([CH3:40])[CH3:39].CCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:38]([NH:41][S:42]([C:45]1[S:49][C:48]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:12]=3)[CH:23]=2)=[CH:47][CH:46]=1)(=[O:43])=[O:44])([CH3:40])([CH3:37])[CH3:39]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.6) (0.46 g, 0.71 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.23 g, 0.78 mmol), tetrakis(triphenylphosphine)palladium (0.049 g, 0.042 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h, hexane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.34 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@:12]2([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:27]([O:29]C(C)(C)C)=[O:28])=[O:10])=[CH:7][C:6]=1[O:43][CH3:44])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@:12]2([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:27]([OH:29])=[O:28])=[O:10])=[CH:7][C:6]=1[O:43][CH3:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)N2[C@@H](c3nccs3)[C@@H](c3cnccn3)C[C@]2(Cc2ccccn2)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2[C@@H](c3nccs3)[C@@H](c3cnccn3)C[C@]2(Cc2ccccn2)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)=[CH:13][C:12]([Br:27])=[CH:11][C:10]=2[CH2:28]O)=[O:5])[CH3:2].S(Cl)([Cl:32])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)=[CH:13][C:12]([Br:27])=[CH:11][C:10]=2[CH2:28][Cl:32])=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(CO)cc(Br)cc2c1NCc1ccc(OC)c(Cl)c1
Product: CCOC(=O)c1cnc2c(CCl)cc(Br)cc2c1NCc1ccc(OC)c(Cl)c1

Procedure:
A solution of 1.73 mmole 6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl)amino)-8-hydroxymethylquinoline-3-carboxylic acid ethyl ester (i.e., Example 56) in 8 ml of thionyl chloride was stirred at RT for 1.5 hours. The solution was concentrated to give 0.86 g of the title compound as an orange foam. MS: 499; LC: 4.15′
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[C:4]([F:11])[CH:3]=1.C(B(CC)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)C.[OH-].[K+].C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Cl-].[Na+].O>[F:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:5]=1[N:6]([CH3:8])[CH3:7]
Reactant: CN(C)c1ccc(Br)cc1F
Reactant: CCB(CC)c1ccncc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(-c2ccncc2)cc1F
Temperature: 25 °C
Yield: 46.2 %

Procedure:
4-Bromo-2-fluoro-N,N-dimethyl aniline (2.83 g, 13 mmols), tetrakis triphenyl palladium (0) (0.508 g, 0.4 mmols), diethyl (4-pyridyl borane) (1.3 g, 9 mmols), potassium hydroxide (2.81 g, 50 mmols) and tetrabutylammonium bromide (1.42 g, 4 mmols) were combined in tetrahydrofuran (50 ml). The resulting mixture was heated at reflux for 18 hrs under nitrogen then cooled to ambient temperature. Ethyl acetate (100 ml) and brine (50 ml) were added and the organic solution was separated. This was dried over magnesium sulfate filtered and evaporated to yield a yellow solid. The product was purified by column chromatography on silica eluted with ethyl acetate:hexanes 50:50 to give 0.9 g of 2-Fluoro-N,N-dimethyl-4-(pyridin-4-yl)aniline (XII) in a 44% yield as a pale yellow solid.