Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9](=[N:16][OH:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)c1ccc(Br)cc1
Temperature: 1 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
Crude ethyl 3-(4-bromophenyl)-3-oxopropanoate (24.5 g, 0.0884 mol) is dissolved in acetic acid (250 mL) at 23° C. under nitrogen, and water (60 mL) is added. The mixture is cooled to 1° C., and a solution of sodium nitrite (7.63 g, 0.111 mol) in water (60 mL) is added dropwise while maintaining the reaction temperature between 1 to 3° C. The mixture is allowed to stir at 1° C. for 3 hours. Water (100 mL) is added dropwise to the cooled reaction mixture to precipitate the product. The cold (about 5° C.) mixture is suction filtered and the collected solids are rinsed with cold 1:1 (v/v) HOAc/water (50 mL), followed by water (2×50 mL). The solids are suction dried overnight to give 18.3 g of crude title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[CH:16]=[C:15]3[CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=2[O:32][CH3:33])=[O:8])[CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH2:44])(=[O:43])=[O:42]>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[CH:16]=[C:15]3[CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH:44][S:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[Cl:34])(=[O:43])=[O:42])=[O:29])=[CH:25][C:24]=2[O:32][CH3:33])=[O:8])[CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(CCNC(=O)N3CCOCC3)cc12
Reactant: NS(=O)(=O)c1ccccc1Cl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2Cl)ccc1Cc1cn(C)c2ccc(CCNC(=O)N3CCOCC3)cc12

Procedure:
Using a similar procedure to that described in Example 2, part c, except starting from 4-[5-[2-[(morpholinocarbonyl)amino]ethyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoic acid, and using 2-chlorophenylsulfonamide instead of 2-methylphenylsulfonamide, the title compound was obtained (45%) as a white solid; mp 175°-181° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].Cl[C:17](=[N+:19]([CH3:21])[CH3:20])Cl.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]1([S:7]([CH2:10][C:11]2[O:12][C:17]([N:19]([CH3:21])[CH3:20])=[N:14][N:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)CS(=O)(=O)c1ccccc1
Reactant: C[N+](C)=C(Cl)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)c1nnc(CS(=O)(=O)c2ccccc2)o1

Procedure:
To 3.0 g (14.0 mmol) of benzenesulfonyl-acetic acid hydrazide in 100 mL of CHCl3, 3.41 g (21.0 mmol, 1.5 eq) of dichloromethylene-dimethyl-ammonium chloride and 3.90 mL (28.0 mmol, 2 eq) of triethyl-amine were added. The solution was stirred at reflux for 1 hour, partitioned between aqueous NaOH 0.5M and EtOAc. The combined organic phases were dried over Na2SO4, filtered, evaporated, and column chromatography on silica gel with CH2Cl2/MeOH 100:1 afforded 0.59 g /15%) of (5-benzenesulfonylmethyl-[1,3,4]oxadiazol-2-yl)-dimethyl-amine as a white solid, MS: 268 (MH+).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=1[Cl:20])=O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][CH2:2][CH2:3][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]([CH3:16])([CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=1[Cl:20]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(=O)CBr)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(CCBr)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of ethyl 2-[4-(2-bromoacetyl)-3-chloro-phenoxy]-2-methylpropionate (209 mg) in trifluoroacetic acid (445 μl ) was added triethylsilane (300 μl), and the mixture was stirred for 1 hour at 60° C. After the reaction mixture was concentrated under reduced pressure, purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=30/1) gave ethyl 2-[4-(2-bromoethyl)-3-chlorophenoxy]-2-methylpropionate (171 mg).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:27])=[CH:9][C:8]=1[CH3:28])C.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:28][C:8]1[CH:9]=[C:10]([S:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:35]4[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=4)=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:27])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:3])=[O:29]
Reactant: CCOC(=O)COc1ccc(SCc2sc(-c3ccc(Br)cc3)nc2C)cc1C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(SCc2sc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)nc2C)ccc1OCC(=O)O
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of {4-[2-(4-Bromo-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (53 mg, 0.1076 mmol) in toluene:ethanol (1:1, 2.0 mL) is added palladium tetrakis triphenylphosphine (5.0 mg, 0.0053 mmol), 4-(trifluoromethyl)-phenyl boronic acid (22.5 mg, 0.1184 mmol), and a solution of sodium carbonate (0.216 mL, 1.0M in water, 0.216 mmol). The reaction is purged with nitrogen and heated to reflux. The reaction is monitored by HPLC, and upon completion is allowed to cool to room temperature. The reaction is diluted with EtOAc and then washed with 0.1N sodium hydroxide, water, and brine. The organic layer is dried over anhydrous sodium sulfate, then concentrated. The product is purified by flash column chromatography. The pure ester compound is then diluted with THF and 1N sodium hydroxide is added. The reaction is allowed to stir at room temperature, and monitored by TLC. Upon completion, 1N hydrochloric acid is added to neutralize the solution. The reaction is diluted with EtOAc and then washed with water. The organic layer is dried over anhydrous sodium sulfate and concentrated to the pure acid, 50 mg or 94% yield. MS (ES): 530.7 (M++1), the structure is also confirmed by proton NMR.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:24]2[CH2:25][CH2:26][N:21]([C:16]3[N:15]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:22][CH2:23]2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Reactant: c1cnc(N2CCNCC2)nc1
Product: Clc1nnc(N2CCN(c3ncccn3)CC2)cc1-c1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 86.7 %

Procedure:
A mixture of 3,6-dichloro-4-phenylpyridazine (1.35 g, 6 mmol), 1-(2-pyrimidyl)piperazine (1.2 g, 6.0 mmol) in 10 ml of 1-BuOH was heated with stirring at 80° C. for 12 h. The solvent was removed by evaporation in vacuo, the residue was treated with water to give a suspension. The solid was then filtered off, washed with water, dried over filter funnel in vacuo to give white solid (1.8 g, 5.2 mmol, yield 86.0%). ESI-MS: m/z 353.9.
Reaction SMILES: [O-2:1].[O-2].[O-2].[U+6:4].[N+:5]([O-])([O-])=[O:6].[NH4+:9]>>[NH4+:5].[NH4+:9].[O-2:6].[O-2:1].[O-2:6].[O-2:6].[O-2:6].[O-2:6].[O-2:6].[U:4].[U:4]
Reactant: O=[N+]([O-])[O-]
Reactant: [U+6]
Agent: [NH4+]
Agent: [O-2]
Product: [U]

Procedure:
reacting solid uranium trioxide with aqueous ammonium nitrate to form an insoluble ammonium uranate
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12]O)[C:5]([CH3:14])=[CH:4][CH2:3]1.S(Cl)([Cl:17])=O>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][Cl:17])[C:5]([CH3:14])=[CH:4][CH2:3]1
Reactant: CC1=CCN(C)c2c(CO)cccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1=CCN(C)c2c(CCl)cccc21
Yield: 81 %

Procedure:
1,4-Dimethyl-8-hydroxymethyl-1,2-dihydroquinoline (0.9 g) was dissolved in dichloromethane (30 ml). To this solution was added dropwise thionylchloride (0.6 g) with stirring under ice-cooling, and the mixture was stirred for 30 minutes. After completion of the reaction, dichloromethane was distilled off under reduced pressure, and n-hexane was added to the residue. The mixture was concentrated under reduced pressure to give 1,4-dimethyl-8-chloromethyl-1,2-dihydroquinoline (0.8 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:9][CH2:8][CH2:7][O:6]1.[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:19]=1[OH:31].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:9][CH2:8][CH2:7][O:6]1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(C2(CCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)OCCO2)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
2.0 g of 2-(3-chloro-propyl)-2-(4-fluoro-phenyl)-[1,3]dioxolane are added to a suspension of 2.36 g of 2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenol, 1.7 g of potassium carbonate and 120 mg of potassium iodide in 50 ml of acetone. The mixture is then stirred for 48 hours at 60° C. The reaction mixture is concentrated and the residue is taken up in water and extracted with ethyl acetate. After concentration of the organic phase and purification over silica gel, 2-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl}-2-(4-fluoro-phenyl)-[1,3]dioxolane is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCCC1.O.[Cl-].[Zn+2].[Cl-]>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH:1][C:2]2[C:15]3[C:10]([N:9]=[C:8]4[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]4)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1c2ccccc2nc2ccccc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(C=Cc2c3ccccc3nc3ccccc23)cc1
Temperature: 130 °C
Yield: 35 %

Procedure:
A mixture of 9-methylacridine (4.83 g, 25.0 mmol), 4-nitrobenzaldehyde (4.23 g, 31.25 mmol) and zinc chloride (5.06 g, 31.25 mmol) is heated at 130° C. for 3 hours with an oil bath. The solid recovered is heated in a solution of sodium metabisulfite in order to eliminate the excess aldehyde and the hot mixture is filtered. Precipitates obtained are dissolved in a minimum amount of tetrahydrofuran and water is added to the solution so as to obtain the product in the form of precipitates. These precipitates are recovered by filtration and dried. The product can be recrystallized from ethanol. The yield is 35%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][Si](C(C)C)(C(C)C)C(C)C)=[CH:24][N:23]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cn2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(O)cn2)c1

Procedure:
3-(triisopropylsilyloxy)pyridine (2.66 mmol) was used in Procedure J with hexamethyldistannane to yield 5-(triisopropylsilyloxy)-2-(trimethylstannyl)pyridine. The crude material (˜0.55 mmol) was used in Procedure K with N-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.17 mmol). Purified by silica gel chromatography (0-40% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-(triisopropylsilyloxy)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a yellow oil. N-(4-chloro-3-(5-(triisopropylsilyloxy)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (1 mmol) was treated with TBAF (2 mL, 1 M in THF) in THF (1 mL) at 23° C. for thirty minutes, concentrated, redissolved in ethyl acetate, washed with brine, dried (MgSO4), and concentrated. The crude solid was purified by silica gel chromatography (0-10% isopropanol/dichloromethane) to yield N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid: TLC Rf=0.59 (10% ethyl acetate/hexanes); MS (Q1) 408 (M)+.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClC(Cl)C.[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:33].[C:35]1([S:41]([C:44]2[CH:48]=[CH:47][S:46][C:45]=2[CH:49]=O)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(=O)([O-])O.[Na+]>[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[C:25]([CH2:49][C:45]2[S:46][CH:47]=[CH:48][C:44]=2[S:41]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:43])=[O:42])=[C:24]1[CH3:33]
Reactant: COC(=O)Cn1c(C)cc2cc(Cl)ccc21
Reactant: O=Cc1sccc1S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A mixture of triethylsilane (2.7 g), trifluoroacetic acid (1.6 g) and dichloroethane (8.0 mL) at −20° C. was treated dropwise with a mixture of (5-chloro-2-methylindol-1-yl)acetic acid methyl ester (0.36 g), 3-phenylsulphony-2-thiophenealdehyde (0.39 g) and dichloroethane (8.0 mL), and the resulting mixture was warmed to room temperature over a period of 1.5 hours. The mixture was treated with additional triethylsilane (2.7 g) and trifluoroacetic acid (1.6 g) and then stirred at room temperature for 1 hour. The mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 0:1 by volume) to afford the title compound (0.55 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH2:12])[CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:19][C:20](Br)=[O:21]>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:19][C:20](=[O:21])[NH:12][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(O)c(N)c1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-Methylsulfonyl-2-aminophenol (Intermediate 102) (690 mg, 3.68 mmol) was dissolved in chloroform (30 mL) and saturated sodium bicarbonate (20 mL). The biphasic reaction mixture was cooled to 0° C. and bromoacetyl bromide (889 mg, 4.42 mmol) was added dropwise. The reaction was stirred overnight at room temperature. The layers were separated and the aqueous layer was filtered to yield the desired product as a solid, 280 mg (33%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:15][CH:16]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C(Cl)[Cl:29].CO.[ClH:33]>O1CCOCC1>[ClH:29].[ClH:33].[Br:1][C:2]1[CH:3]=[C:4]([O:15][CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1
Reactant: ClCCl
Reactant: Cc1csc(Nc2ncc(Br)cc2OC2CCN(C(=O)OC(C)(C)C)C2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1csc(Nc2ncc(Br)cc2OC2CCNC2)n1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
A mixture of tert-butyl 3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidine-1-carboxylate (prepared according to Example 61; 550 mg, 1.21 mmol) and CH2Cl2 (10 mL) and MeOH (2 mL) was stirred at room temperature. 4N HCl in dioxane (5 mL) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was concentrated and dissolved in small amount of CH2Cl2/methanol and added to vigorously stirred ether and filtered to afford N-(5-bromo-3-(pyrrolidin-3-yloxy)pyridin-2-yl)-4-methylthiazol-2-amine dihydrochloride (478 mg, 92.4% yield) as a white solid. 1H NMR (d6-DMSO) δ 11.18 (bs, 1H), 9.80 (bs, 1H), 9.27 (bs, 1H), 8.09 (d, 1H), 7.83 (d, 1H), 6.80 (s, 1H), 5.42 (m, 1H), 3.62-3.30 (m, 4H), 2.31 (s, 3H), 2.22 (m, 2H); Mass spectrum (apci) m/z=357.0 (M+H-2HCl).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH2:15])[CH:11]=[CH:12][C:13]=2[F:14])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[H][H]>[Pd]>[F:14][C:13]1[CH:12]=[CH:11][C:10]([NH2:15])=[CH:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[CH:2][N:7]=1
Reactant: [H][H]
Reactant: Nc1ccc(F)c(-c2ccnc(Cl)n2)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Product: Nc1ccc(F)c(-c2ccncn2)c1

Procedure:
To the solution of 3-(2-chloro-pyrimidin-4-yl)-4-fluorophenylamine from above was added triethylamine (0.48 mL, 3.15 mmol) and palladium on active carbon (100 mg, 10% palladium) and the mixture was reduced under 40 p.s.i. hydrogen for 30 minutes. The mixture was filtered and the solvent removed to give 4-fluoro-3-pyrimidin-4-yl-phenylamine as a yellow solid: m/z (ES+) 190 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][C:9]=2[O:8][C:7]=1[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:5])[CH3:2].[CH3:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.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>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:38]3[CH:39]=[C:34]([CH3:33])[CH:35]=[CH:36][CH:37]=3)=[CH:14][C:9]=2[O:8][C:7]=1[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:5])[CH3:2]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(OS(=O)(=O)C(F)(F)F)ccc12
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: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(C)c3)ccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
To a solution of 2-(2,4-Dichloro-benzoyl)-6-trifluoromethanesulfonyloxy-benzofuran-3-carboxylic acid ethyl ester from step 4 (162 mg, 0.32 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 mL) were sequential added 3-methyl benzene boronic acid (64.6 mg, 0.63 mmol, 1.5 eq), potassium carbonate (87.6 mg, 0.63 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (73.2 mg, 0.06 mmol, 0.2 eq) under argon. The reaction mixture was degassed for 5 min. The reaction was then stirred at 80° C. for 4 h followed by stirred at rt for 12 h. The mixture was cooled to room temperature then poured into ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). Combined the organic layer was washed by water (2×10 mL), dried over Na2SO4, filtrated, and evaporated in vacuo. The residue was purified by pre-HPLC to afford an yellow solid (91.3 mg, 63%) as product. 1H-NMR (CDCl3): δ 8.04 (d, J=8.3 Hz, 1H), 7.73 (s, 1H), 7.64 (dd, J=1.5, 8.3 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H), 7.41 (m, 2H), 7.36 (dd, J=1.9, 8.3 Hz, 1H), 7.34 (t, 1H), 7.19 (d, J=8.3 Hz, 1H), 4.245 (q, 2H), 2.43 (s, 3H), 1.28 (t, 3H); LC-MS (MH+=453/455).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[N:17]=[CH:16][NH:15][C:14]=1[CH:18]=O>>[Cl:1][C:2]1[C:3]2[C:10](=[CH:18][C:14]3[NH:15][CH:16]=[N:17][C:13]=3[CH3:12])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1nc[nH]c1C=O
Reactant: O=C1Cc2c(Cl)ncnc2N1
Product: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Yield: 76.9 %

Procedure:
4-Chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1 eq.) was condensed with 5-methyl-3H-imidazole-4-carbaldehyde (1 eq.) at room temperature to give (76.9%) of 4-chloro-5-(5-methyl-3H-imidazol-4-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.BrN1C(=O)CCC1=O.C(Cl)[Cl:20]>>[Cl:20][C:8]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: ClCCl
Reactant: Fc1ccc2nncn2c1
Agent: O=C1CCC(=O)N1Br
Product: Fc1ccc2nnc(Cl)n2c1
Temperature: 45 °C
Yield: 63 %

Procedure:
Intermediate 14a (908 mg, 6.60 mmol) was dissolved in DCM (50 mL) and N-bromosuccinimide (1.29 g, 7.26 mmol) added. The reaction was heated to 45° C. for 4 h, then cooled and partitioned between DCM (150 mL) and saturated aqueous NaHCO3 (150 mL), and extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo. Purification by FCC, using 0-5% [2M NH3 in MeOH] in DCM, gave the title compound (900 mg, 63%). LCMS (Method 1): Rt 1.94 min, m/z 216/218 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:14])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C=O)C>[Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2cc(O)ccc2nc1Cl
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cc2cc(OCC3CC3)ccc2nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A mixture of 2-chloro-6-hydroxyquinoline-3-carbaldehyde SLA 47016 (1.00 g, 4.8 mmol), cesium carbonate (3.14 g, 9.6 mmol) and (bromomethyl)cyclopropane (0.94 mL, 9.6 mmol) in dry DMF (30 mL) in a 50 mL round-bottomed flask equipped with a magnetic stirrer was stirred overnight at RT. DMF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave 2-chloro-6-(cyclopropylmethoxy)quinoline-3-carbaldehyde SLA 47086 as a pale brown solid (513 mg, 41% yield).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Si]([N:14]=[N+:15]=[N-:16])(C)(C)C>CCOCC>[CH2:7]([C:8]1[N:14]=[N:15][NH:16][CH:9]=1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#CCCCCCCC
Solvent: CCOCC
Product: CCCCCCCc1c[nH]nn1
Temperature: 150 °C

Procedure:
##STR8## 1-Nonyne (5.0 g) and Me3SiN3 (6.2 g) were sealed into a heavy-walled glass reactor at -70° C. and 0.6 mm Hg. The mixture was heated at 150° C. for 34 hours, cooled and dissolved in Et2O. The Et2O solution was washed successively with 5 percent aq. HCl, 7 percent aq. NaHCO3, saturated aq. NaCl, dried over MgSO4, filtered and distilled to give 3.89 g (58%) pale yellow oil, bp 110-130/0.05 mm whose NMR spectrum and elemental analysis confirm its structure.