Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C:16]([OH:24])(=[O:23])[C:17]([CH2:19][C:20](O)=[O:21])=[CH2:18]>O>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([N:6]2[CH2:18][CH:17]([C:16]([OH:24])=[O:23])[CH2:19][C:20]2=[O:21])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Product: O=C(O)C1CC(=O)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 20 °C
Yield: 70.9 %

Procedure:
229 g (1 mole) of 3,5-bis-(trifluoromethyl)-aniline and 136.5 g (1.05 moles) of itaconic acid are stirred in 55 ml of water during 24 hours at 200° C in an autoclave. The reaction mixture is subsequently cooled to 20° C and 2 liters of cold water are added. Two liters of water are then evaporated, and the reaction mixture is again cooled to 20° C. The crystals that have precipitated are filtered off, dried, dissolved in 400 ml of diethyl ether and precipitated with 600 ml of n-hexane. There is obtained 242 g (71% of theory) of 1-(3,5-bis-trifluoromethylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid; m.p. 108°-9° C.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH2:8]([C@H:10]1[CH2:19][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:24][CH3:25])[N:16]=2)[NH:11]1)[CH3:9].N1C=CC=CC=1.Cl>ClCCl>[CH:5]([O:4][C:2]([N:11]1[C:12]2[C:17](=[N:16][C:15]([O:24][CH3:25])=[CH:14][CH:13]=2)[C@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH2:19][C@@H:10]1[CH2:8][CH3:9])=[O:3])([CH3:7])[CH3:6]
Reactant: CC(C)OC(=O)Cl
Reactant: CC[C@H]1C[C@@H](NC(C)=O)c2nc(OC)ccc2N1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H]1C[C@@H](NC(C)=O)c2nc(OC)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
Add isopropyl chloroformate (3.10 mL, 2.82 mmol, 1.0 M in toluene) dropwise to a solution of (+/−)-cis-N-(2-ethyl-6-methoxy-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide (702 mg, 3.102 mmol) and pyridine (0.677 mL, 8.46 mmol) in dichloromethane (15 mL) at 0° C. under an atmosphere of nitrogen and stir at room temperature for 10 min. Add 1 M HCl and separate the layers. Extract the aqueous layer with dichloromethane. Dry the organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure, to afford the title compound (895 mg, 95%). MS (ES+): 336 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[CH:15]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([S:25](Cl)(=[O:27])=[O:26])[C:19]=2[CH:18]=[CH:17][N:16]=1>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][S:25]([C:20]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:24]=2[CH:23]=[CH:22][CH:21]=1)(=[O:26])=[O:27]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CN(C)CCCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)CCCNS(=O)(=O)c1cccc2cnccc12
Reaction time: 4 h
Yield: 71 %

Procedure:
In 50 ml of a chloroform solution containing 1.4 g of 3-dimethylaminopropylamine and 1.4 g of triethylamine was added dropwise 30 ml of a chloroform solution containing 2.6 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 2° C. to 10° C. for four hours, and the reaction mixture solution was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom, the residue obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 2.38 g of N-(3-dimethylaminopropyl)-5-isoquinolinesulfonamide, i.e., Compound (17) in a yield of 71%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:28][C:29]([NH2:31])=[S:30])[CH:19]=[CH:20][C:21]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1>C(OCC)C>[Br:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH3:13])=[C:5]([C:3]2[N:31]=[C:29]([NH:28][C:18]3[CH:19]=[CH:20][C:21]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:16]([O:15][CH3:14])[CH:17]=3)[S:30][CH:2]=2)[CH:10]=1
Reactant: COc1ccc(Br)cc1C(=O)CBr
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCOCC
Product: COc1ccc(Br)cc1-c1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 102 mg (0.33 mmol) 2-bromo-1-(5-bromo-2-methoxyphenyl)ethanone and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude reaction was diluted with diethyl ether and stirred for 15 minutes at room temperature. The product was filtered off and dried to yield 147 mg (99%) [4-(5-bromo-2-methoxy-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a white solid. MS ISP (m/e): 472.8/470.9 (100/93) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.74 (s, 1H), 9.30 (s, 1H), 8.34 (dd, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.51 (d, 1H), 7.47 (d, 1H), 7.13 (d, 1H), 7.05 (d, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:9][NH:8][C:7]1=[O:15].[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Cl)[CH3:17]>CS(C)=O>[C:19]([CH2:20][N:8]1[CH2:9][CH2:10][N:11]([C:12](=[O:14])[CH3:13])[CH:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:7]1=[O:15])([O:18][CH2:16][CH3:17])=[O:22]
Reactant: CC(=O)N1CCNC(=O)C1c1cccs1
Reactant: CCOC(=O)CCl
Solvent: CS(C)=O
Product: CCOC(=O)CN1CCN(C(C)=O)C(c2cccs2)C1=O
Reaction time: 12 h
Yield: 83.9 %

Procedure:
12 g (0.053 mol) of 3-(2-thienyl)-4-acetylpiperazin-2-one, prepared in accordance with Example 17, are stirred with 6.6 g (0.059 mol) of potassium tert.-butylate in 100 ml of dimethyl sulphoxide. After removing 10 ml of dimethyl sulphoxide by distillation in vacuo, 6.4 g (0.059 mol) of ethylchloroacetate are added dropwise at room temperature and the mixture is stirred for a further 12 hours. The dimethyl sulphoxide is removed by evaporation in vacuo, the residue is stirred with water and taken up in ethyl acetate, and the organic phase is separated off. Distilling off the ethyl acetate gives 13.8 g of the title product, 88% of theory (molecular weight 296), in the form of a viscous oil.
Reaction SMILES: CCO.[NH2:4][N:5]1[C:9]([C:10]#[N:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([F:21])[CH:13]=2)[C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:6]1.C(O)(=O)C.[CH:31](N)=[NH:32].O>CCOCC>[NH2:11][C:10]1[C:9]2=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([F:21])[CH:13]=3)[C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:6][N:5]2[N:4]=[CH:31][N:32]=1
Reactant: N=CN
Reactant: CCOC(=O)c1cn(N)c(C#N)c1-c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])c(F)c1
Temperature: 80 °C
Yield: 66.7 %

Procedure:
To a solution of EtOH (75 mL) was added ethyl 1-amino-5-cyano-4-(3-fluoro-4-nitrophenyl)-1H-pyrrole-3-carboxylate (1.68 g, 5.28 mmol) and formamidine acetate (5.49 g, 52.8 mmol). The solution was heated to 80° C. for 17 h. Upon cooling to rt the solution was treated with water and a precipitate formed which was filtered and washed with additional water. The solid was then suspended in DCM and Et2O. The solid was collected and washed with Et2O yielding 1.22 g of an orange-yellow solid (3.52 mmol, yield 67%). 1H-NMR (DMSO-d6) δ 8.20 (s, 1H), 8.18 to 8.14 (t, J=8.2 Hz, 1H), 7.97 (s, 1H), 7.66 to 7.63 (d, J=12.4 Hz, 1H), 7.41 to 7.39 (d, J=8.4 Hz, 1H), 4.12 to 4.07 (q, J=7.0 Hz, 2H), 1.13 to 1.10 (t, J=7.0 Hz, 3H); MS [M+H]+=346.2; LCMS RT=2.77 min.
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[Cl:9][C:10]1[C:11](=[O:24])[CH:12]=[CH:13][C:14]2[C:23]=1[S:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:15]=2>O.CN(C=O)C>[Cl:9][C:10]1[C:23]2[S:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:24]
Reactant: O=c1ccc2nc3ccccc3sc-2c1Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2c(c1Cl)Sc1ccccc1N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of Na2S2O4 (70 g) in water (500 ml) was added to a solution of 4-chloro-3H-phenothiazin-3-one (50 g) in DMF (1200 ml). The reaction mixture was stirred at room temperature for 3 hours and then poured in 5 liters of water. The resulting precipitate was then filtered to give the 4-chloro-3-hydroxy-10H-phenothiazine (95%). m.p.: 110° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[C:8]([CH3:14])[CH:7]=1.CN(C)C=O>CC1C=CC=CC=1>[Cl:3][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=1[CH3:14]
Reactant: Cc1cc(F)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To 14.3 parts of thionyl chloride is added dropwise a solution of 14 parts of 4-fluoro-2-methylbenzenemethanol and 0.9 parts of N,N-dimethylformamide in 45 parts of methylbenzene while cooling in ice-water. Then there are added 135 parts of methylbenzene and stirring is continued for 1 hour at room temperature. The reaction mixture is evaporated, yielding 17 parts (100%) of 1-(chloromethyl)-4-fluoro-2-methylbenzene as a residue.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[O-][C:15]#[N:16].[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Cl:13][C:4]1[C:3]([CH2:2][C:15]#[N:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: N#C[O-]
Reactant: COC(=O)c1cccc(CBr)c1Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CC#N)c1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of methyl 3-(bromomethyl)-2-chlorobenzoate (748 mg, 2.84 mmol) in N,N-dimethylformamide (7 mL) was added sodium cyanate (412 mg, 8.41 mmol), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was diluted with a mixed solvent of ethyl acetate/hexane (1:1). The solution was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/98→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (470 mg, 79%) as white crystals.
Reaction SMILES: [CH2:1]([Cl:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].Cl>O>[Cl:10][CH2:1][C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(CCl)c1ccccc1
Agent: Cl
Solvent: O
Product: O[C@H](CCl)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
After preparing the reducing agent by the same method as described in Example 1. 1.55 g (10 mmol) of phenacyl chloride was added to the reducing agent and the mixture was stirred at 50° C. for 2 hours. To the mixture were added 2 ml of 1N hydrochloric acid and 20 ml of water to conduct hydrolysis. The mixture was extracted with ethyl acetate and concentrated to obtain an oily product. The obtained oil was analyzed by HPLC.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][C:6]=1[Cl:13]>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[CH:7][C:6]=1[Cl:13]
Reactant: [C-]#N
Reactant: Clc1cc(CBr)ccc1Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#CCc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
Sodium cyanide (10.91 g, 222.52 mmol) in water (10 mL) was added to a solution of chloroform (20 mL) of N-benzyl-N,N-diethylethanaminium chloride (25.3 g, 111.26 mmol). 1-Bromo-4-(bromomethyl)-2-chlorobenzene (31.64 g, 111.26 mmol) in chloroform (5 mL) was added dropwisely at room temperature. The mixture was stirred at room temperature for 1 h then heated to 45° C. for additional 2 h. The reaction mixture was cooled, separated into two layers and the organic layer was washed with 0.5 N NaOH then brine. The chloroform layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash Silica chromatography {CombiFlash Companion—Presearch Ltd}, column size=330 g, flow rate=100 mL/min, elution gradient 0 to 100% EtOAc in isohexane over 40 minutes. Pure fractions were evaporated to dryness to afford 2-(4-bromo-3-chlorophenyl)acetonitrile (2.430 g, 9.48%) as a orange/yellow oil which solidified on standing.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH3:20])[CH2:17][NH:18][CH3:19])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[CH:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1)=O.C(O)(=O)C>CO>[C:5]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([CH3:20])[CH2:17][N:18]([CH2:21][C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[CH3:19])=[CH:13][CH:14]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CNCC(C)Cc1ccc(C(C)(C)C)cc1
Reactant: Cn1cc(C=O)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN(C)Cc1cnn(C)c1
Reaction time: 8 h

Procedure:
Route B-2: After suspending 200 mg (3.2 mmol) of sodium cyanoborohydride in 2 ml of absolute methanol, 380 mg (1.7 mmol) of 3-(4-t-butylphenyl)-N,2-dimethylpropylamine (IV-1) was added thereto. Subsequently, to this was added a solution of 170 mg (1.6 mmol) 4-formyl-1-methylpyrazole/2 ml absolute methanol by portions, the pH was adjusted to 7 with acetic acid, and then stirring was conducted at room temperature for 8 h.
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[CH2:8]([O:10][CH:11]([O:14][CH2:15][CH3:16])[CH2:12][NH2:13])[CH3:9]>C(O)C>[CH2:8]([O:10][CH:11]([O:14][CH2:15][CH3:16])[CH2:12][NH:13][C:2](=[NH:7])[CH3:3])[CH3:9]
Reactant: CCOC(CN)OCC
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: CCOC(CNC(C)=N)OCC

Procedure:
N-(2,2-Diethoxyethyl)acetamidine was synthesized in the same manner as in Reference Example 2. That is, ethyl acetimidate hydrochloride (25.0 g, 0.202 mol) was reacted with aminoacetaldehyde diethyl acetal (31 mL, 0.21 mol) in ethanol (150 mL) to give 44.1 g of a pale-green oil containing the target compound.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[C:27]([F:40])=[CH:28][C:29]([F:39])=[C:30]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[C:27]([F:40])=[CH:28][C:29]([F:39])=[C:30]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCCO)c1cc(Br)c(F)cc1F
Product: O=S(=O)(NCCO)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (337 mg, 1.0 mmol) and 5-bromo-2,4-difluoro-N-(2-hydroxy-ethyl)-benzenesulfonamide (example B.37) (411 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (100 mg, 17%). MS (ISP) 573.1 [(M+H)+]; mp 149-150° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:33]=[CH:32][C:31]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[CH:30][CH:29]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 29.9 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 4-acetylphenylboronic acid (available from Combi-Blocks Inc.; 66 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-acetyl-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (28 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.23 (br s, 1H), 8.48 (s, 1H), 8.40 (d, J=1.5 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (dd, J=8.3, 2.0 Hz, 1H), 8.03 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.3 Hz, 2H), 2.63 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:17]([O:16][C:13](=[O:15])[CH2:14][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: BrCCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CCCCCCBr
Reaction time: 0.25 h

Procedure:
To 6.94 ml of diisopropylamine in 100 ml of anhydrous tetrahydrofuran was added dropwise 34 ml of a 1.45 M solution of n-butyl lithium in hexane at -70° C. and the mixture was stirred for 15 minutes. To the solution was added dropwise a solution of 6.63 ml of t-butyl acetate in 30 ml of anhydrous tetrahydrofuran and the mixture was stirred for 30 minutes, and then 8 ml of 1,5-dibromopentane in 10 ml of anhydrous tetrahydrofuran were added thereto and the mixture was stirred for 5 minutes. To it was added 17 ml of hexamethylphosphamide, the mixture was stirred at -78° C. for 1 hour and at from -40° C. to -30° C. for 30 minutes. To the reaction mixture was added an aqueous solution of ammonium chloride, and was separated aqueous layer from organic layer. The aqueous layer was extracted with diethyl ether, and the extract was added that organic layer and washed with water, a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and cyclohexane (1:1) as an eluent to give 8.5 g of the title compound having the following physical characteristic:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OC)=O)[C:9](OC)=[O:10])=[C:4]([N+:17]([O-])=O)[CH:3]=1.[Cl-].[Li+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][C:9](=[O:10])[NH:17]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Product: O=C1Cc2ccc(Br)cc2N1
Reaction time: 3 h

Procedure:
A solution of 17.4 g of dimethyl 2-(4-bromo-2-nitrophenyl)malonate and 4.6 g of lithium chloride in 150 ml of dimethyl sulfoxide was placed in an oil bath at 100° C. After 3 hours, the reaction mixture was
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]1([N:29]2[C:33]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)=[CH:32][C:31]([C:44]([CH3:50])([CH3:49])[C:45]([F:48])([F:47])[F:46])=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:33]2[N:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:30]=[C:31]([C:44]([CH3:50])([CH3:49])[C:45]([F:48])([F:47])[F:46])[CH:32]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1)C(F)(F)F
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 59.7 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3 ml) was added DMAP (23 mg, 0.18 mmol) and phenyl 1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-ylcarbamate (117 mg, 0.3 mmol) described in Example 306A to afford 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)urea (109 mg, 60%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.57 (s, 6H), 4.04 (s, 6H), 6.55 (s, 1H), 7.25 (d, J=6 Hz, 1H), 7.33-7.49 (m, 5H), 7.55-7.60 (m, 4H), 7.80 (s, 1H), 8.59 (s, 1H), 8.69 (s, 1H), 9.29 (s, 1H); LC-MS (ESI) m/z 609 (M+H)+.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH2:52][C:53]([N:56]1[CH:60]=[C:59]([C:61]2[N:66]=[C:65]([C:67](=[O:70])[NH:68][CH3:69])[C:64]([NH:71][C:72]3[C:77]([C:78]([F:81])([F:80])[F:79])=[CH:76][N:75]=[C:74]([NH:82][C:83]4[CH:97]=[CH:96][C:86]([CH2:87][P:88](=[O:95])([O:92]CC)[O:89][CH2:90][CH3:91])=[CH:85][C:84]=4[O:98][CH3:99])[N:73]=3)=[CH:63][CH:62]=2)[CH:58]=[N:57]1)([CH3:55])[CH3:54]>>[OH:50][CH2:51][CH2:52][C:53]([N:56]1[CH:60]=[C:59]([C:61]2[N:66]=[C:65]([C:67](=[O:70])[NH:68][CH3:69])[C:64]([NH:71][C:72]3[C:77]([C:78]([F:81])([F:79])[F:80])=[CH:76][N:75]=[C:74]([NH:82][C:83]4[CH:97]=[CH:96][C:86]([CH2:87][P:88](=[O:92])([OH:95])[O:89][CH2:90][CH3:91])=[CH:85][C:84]=4[O:98][CH3:99])[N:73]=3)=[CH:63][CH:62]=2)[CH:58]=[N:57]1)([CH3:54])[CH3:55]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C(C)(C)CCO)c4)nc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C(C)(C)CCO)c4)nc3C(=O)NC)n2)c(OC)c1
Yield: 78.5 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({6-[1-(4-hydroxy-2-methylbutan-2-yl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 50B, 117 mg, 0.163 mmol) to afford 88.6 mg of the title compound (79%). 1H NMR (400 MHz, CD3OD) δ 8.76 (s, 1H), 8.35 (s, 1H), 8.11 (d, J=8.6 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 6.85 (s, 1H), 6.52 (d, J=8.1 Hz, 2H), 3.72-3.98 (m, 7H), 3.15-3.25 (m, 2H), 2.94 (s, 3H), 2.30-2.43 (m, 2H), 1.77 (s, 6H), 1.11 (t, J=7.1 Hz, 3H). MS (ESI): m/z=693.61 [M+H]+. UPLC: tR=1.18 min (UPLC-TOF: polar—2 min).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]([NH2:15])([CH3:14])[CH3:13]>C(O)CCC>[CH:12]([NH:15][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])([CH3:14])[CH3:13]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Solvent: CCCCO
Product: CC(C)Nc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.6 %

Procedure:
Heat a mixture of 2,4-dibromonitrobenzene (3.50 g, 12.5 mmol), isopropylamine (4.42 g, 6.40 ml, 74.8 mmol) and n-butanol (20 ml) in a sealed reaction vessel to 117° C. overnight. Cool to room temperature and concentrate under reduced pressure. Partition the residue between ethyl acetate and saturated aqueous sodium chloride, dry the organic layer over sodium sulfate, and concentrate under reduced pressure to provide the desired compound as a yellow solid (3.0 g, 94%).