Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH:3]=1.[Li]CCCC.C[Si](C)(C)[O:31][C@@H:32]1[C@@H:37]([O:38][Si](C)(C)C)[C@H:36]([O:43][Si](C)(C)C)[C@@H:35]([CH2:48][O:49][Si](C)(C)C)[O:34][C:33]1=O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.O1CCCC1.C1(C)C=CC=CC=1.C(#N)C.ClCCl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:33]2[C@H:32]([OH:31])[C@@H:37]([OH:38])[C@H:36]([OH:43])[C@@H:35]([CH2:48][OH:49])[O:34]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CCC2)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4CCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-(2-cyclobutoxyethoxy)benzyl)benzene (110 mg, 0.3 mmol) in anhydrous toluene/tetrahydrofuran (v/v=2/1, 2 mL) was added n-BuLi (0.17 mL, 2.5 M) dropwise at −78° C. The mixture was stirred for 30 min and then transferred to a solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (195 mg, 0.4 mmol) in anhydrous toluene (1 mL) at −78° C. The mixture was stirred at −78° C. for 2 h until starting material was consumed. The reaction was quenched with methanesulfonic acid (54 μL in 1.4 mL methanol), and the mixture was allowed to warm to room temperature and stirred overnight. Then water was added, the organic phase was separated, and the water phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate, then with water and then with brine, and then dried over anhydrous sodium sulfate, filtered and concentrated to get the crude product. The crude product was dissolved in acetonitrile/dichloromethane (1.2 mL), triethylsilane (0.3 mL, 1.9 mmol) was added, the mixture was cooled to −40° C., and boron trifluoride diethyl etherate (1.8 μL, 1.4 mmol) was added quickly. After addition, the mixture was stirred for 2 h at 0° C. The reaction was quenched with saturated aqueous sodium bicarbonate. The volatiles were removed under reduced pressure and the residue was extracted with ethyl acetate, washed with water and then with brine, and then dried over anhydrous sodium sulfate. The residue was filtered, concentrated, and purified by preparative LC-MS to obtain 16 mg of pure product. 1H NMR (CD3OD, 400 MHz): δ 7.25-7.34 (m, 3H), 7.09-7.11 (m, 2H), 6.81-6.83 (m, 2H), 4.01-4.09 (m, 6H), 3.85-3.88 (m, 1H), 3.65-3.70 (m, 3H), 3.37-3.44 (m, 3H), 3.26-3.28 (m, 1H), 2.18-2.23 (m, 2H), 1.90-1.95 (m, 2H), 1.55-1.72 (m, 1H), 1.48-1.53 (m, 1H); MS ES− (m/z): 523 (M+45)−; MS ES+ (m/z): 479 (M+1)+, 496 (M+18)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(O)C.[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].N12CCCC=C1CCCCN2>C1(C)C=CC=CC=1>[CH2:25]([O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)=[N:4][CH:3]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCI
Reactant: CCCCCCCCc1ccc(-c2ncc(O)cn2)cc1
Agent: C1=C2CCCCNN2CCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCOc1cnc(-c2ccc(CCCCCCCC)cc2)nc1
Yield: 70 %

Procedure:
To 5-hydroxy-2-(4-octylphenyl)pyrimidine (5 g, 0.018 mol) were added ethanol (50 ml), octyl iodide (12.6 g, 0.053 mol) and diazabicyclo[5.4.0]undec-7-ene (0.053 mol), followed by refluxing the mixture for 4 hours, dissolving the reaction mixture in toluene, sufficeiently washing the solution with 2N--NaOH aqueous solution, further washing it with water, distilling off toluene and recrystallizing the residue from ethanol (75 ml) to obtain 5-octyloxy-2-(4-octylphenyl)pyrimidine (5 g). This product exhibited liquid crystalline properties and its phase transition points were as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:16][CH2:15]1.[Br-].[CH2:30]([Zn+])[CH2:31][CH3:32]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[CH2:30]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH:21]=[CH:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:18][CH2:19]1)[CH2:31][CH3:32]
Reactant: CCC[Zn+]
Reactant: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Product: CCCc1ccc2oc(=O)cc(NC3CCN(CC=Cc4ccccc4)CC3)c2c1
Temperature: 160 °C
Yield: 73.4 %

Procedure:
Into a dry microwave vial under nitrogen was added 6-bromo-4-[1-(3-phenyl-allyl)-piperidine-4-ylamino]-chromen-2-one (20 mg, 0.046 mmol), Pd(dppf)Cl2 (about 5 mol %), and CuI (about 6 mol %) in dry THF (0.5 mL) followed by n-propyl zinc bromide (0.273 mL, 0.138 mmol (0.5M in THF)) dropwise. The solution was heated in the microwave for 10 minutes at 160° C., filtered, and was purified by Prep HPLC to give 13.6 mg (57%) of the desired compound as the TFA salt. MS (ESI(+)Q1MS m/z 403 (M+H)+; 1H NMR (300 MHz, MeOH) δ ppm 0.96 (t, 3H), 1.70 (m, 2H), 1.98-2.01 (m, 2H), 2.39 (br d, 2H), 2.69 (t, 2H), 3.23 (br t, 2H), 3.72 (m, 2H), 3.88-3.98 (m, 3H), 5.42 (s, 1H), 6.30-6.40 (m, 1H), 6.95 (d, 1H), 7.24-7.54 (m 0.8H), 7.85 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)([O-:3])=[O:2].B(F)(F)F.CCOCC.[CH2:31]=[C:32]([CH3:34])[CH3:33]>C(#N)C>[CH3:31][C:32]1([CH3:34])[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:10]=2)[NH:7][CH:6]([C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:33]1
Reactant: O=[N+]([O-])c1ccccc1C=Nc1ccc(C(F)(F)F)cc1
Reactant: C=C(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CC1(C)CC(c2ccccc2[N+](=O)[O-])Nc2ccc(C(F)(F)F)cc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a suspension of N-(2-nitrobenzylidene)-4-(trifluoromethyl)aniline (2.7 g, 9.18 mmol) and Borontrifluoride etherate (289 μL) in anhydrous acetonitrile was added isobutene (16 mL, pre-cooled to −78° C.) at ice-bath. After addition, the resulting mixture was stirred at 90° C. in sealed tube overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 4,4-dimethyl-2-(2-nitrophenyl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (2.56 g, yield 80%). LC/MS m/e obsd. (ESI+) [(M+H)+] 351.1.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21]([CH3:22])=[O:33])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Solvent: ClC(Cl)Cl
Product: CS(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C

Procedure:
To a stirred solution of 1.0 g of 9-fluoro-11β-hydroxy-17-(methylthio)androsta-1,4,16-trien-3-one (see Example 1B) in chloroform (500 ml) is added a solution of 85% m-chloroperbenzoic acid (552 mg) in chloroform (10 ml) in the course of 3.0 minutes. In less than 10 minutes, the peracid and the starting steroid disappear. The solution is then washed with a dilute potassium carbonate solution and water, dried, concentrated (to about 10 ml) and diluted with ethyl acetate resulting in the precipitation of small, light needles of the analytical specimen of the title compound, (1.0 g), melting point 268°-269° C (dec.). This is a mixture of the two sulfinyl isomers.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1>>[C:1]([O:5][C:6](=[O:22])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH:23]3[CH2:25][CH2:24]3)[CH2:28][CH2:29]2)=[O:34])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(CC2CC2)CC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 1 (step f), the title compound rac-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester using 1-(1-cyclopropylmethyl)-piperidine-4-carboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a brown oil which was directly used in the next step without purification.
Reaction SMILES: COC1C=CC2SC(C(O)=O)=C(OC(C)C)C=2C=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=1[O:30][CH3:31]>CO>[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31]
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1N

Procedure:
Following a procedure analogous to Example 12, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (230 mg, 0.86 mmol) and methyl 4-amino-3-methoxybenzoate (310 mg, 1.38 mM) [obtained by esterification of 4-amino-3-methoxybenzoic acid (Aldrich) with MeOH/AcC1]provides 269 mg (73%) of product; mp 278° C. dec. Saponification of 100 mg of methyl 3-methoxy-4-[[[5-methoxy-3-(1-methylethoxy)benzo [b]thien-2-yl]carbonyl]amino]benzoate gives 48 mg (50%) of product; mp 278°-281° C. dec.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][S:18][CH3:19])=[CH:11][N:10]=2)=CC=1>FC(F)(F)C(O)=O>[CH3:19][S:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[N:14][C:9]([NH2:8])=[N:10][CH:11]=1
Reactant: COc1ccc(CNc2ncc(OCCSC)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CSCCOc1cnc(N)nc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 32.6 %

Procedure:
N-(4-Methoxybenzyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (172 mg) was dissolved in trifluoroacetic acid (3 mL) at room temperature, and the solution was stirred at 60° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative silica gel thin layer chromatography (chloroform:methanol=15:1) to obtain 5-[2-(methylthio)ethoxy]pyrimidin-2-amine (34 mg, 18% in 2 steps) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([OH:21])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N1CCOCC1)C.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:30]([NH:37][C:19]([C:12]1[C:13]([C:15]([F:17])([F:18])[F:16])=[N:14][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:10][CH:11]=1)=[O:21])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reactant: NCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 2-(3-chlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid (35 mg) in dimethylformamide (2 ml) was added successively N-ethylmorpholine (42 μl), benzylamine (15 μl), 1-hydroxybenzotriazole hydrate (23 mg) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (25 mg). The solution was stirred for 3 h and allowed to stand overnight. Dimethylformamide was removed under reduced pressure and ethyl acetate (5 ml) added. The solution was washed sequentially with 5% sodium bicarbonate solution (2.5 ml), water (2.5 ml), 5% citric acid solution (2.5 ml) and brine (2×2.5 ml), dried (MgSO4) and evaporated to afford the title compound (45 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].[OH-].[Na+]>CN(C=O)C.O>[F:16][CH:12]([F:17])[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)F)cc1
Temperature: 125 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
4-Nitrophenol (0.10 g, 0.72 mmol, Aldrich), sodium chlorodifluoroacetate (0.11 g, 0.72 mmol, Alfa Products) and sodium hydroxide (0.03 g, 0.72 mmol) were combined in dry DMF (1 mL) under an atmosphere of argon. After stirring at 125° C. for 1 h, the mixture was cooled to RT, was diluted with water and was extracted twice with ether. The combined organic extracts were washed twice with brine, were dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 25% ethyl acetate/hexanes ) to provide the title compound as a white solid (0.10 g, 73%). mp 33°-35° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1C=CC=CC=1>[N:1]1([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)CCCn1ccnc1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
Part A. A solution of imidazole (17.0 g, 0.25 mole) in benzene (200 mL) at room temperature was treated with sodium hydride (60% w/w oil dispersion; 8.0 g, 0.20 mole) and heated at reflux for 1 hour. After cooling to room temperature, a solution of ethyl 4-bromobutyrate (30.0 g, 0.20 mole) in benzene (50 mL) was added. The resulting mixture was again heated at reflux for 20 hours. After cooling to room temperature, the solution was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residual yellow oil was subjected to kugelrohr distillation at 125°-135° under rotary vacuum pump pressure to provide ethyl 4-(1-imidazolyl)butyrate as a colorless liquid (11.0 g, 30% yield). NMR(CDCl3) 7.44(1H,s) 7.04(1H,s) 6.90(1H,s) 4.12(2H,q,J=7 Hz) 4.02(2H,t,J=8 Hz) 2.24(2H,t,J=8 Hz) 2.08(2H,m) 1.31(3H,t,J=7 Hz).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH2:30][C:31]#[N:32])[CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[CH3:43].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C.O.CS(C)=O>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:3]=[C:4]([O:29][CH2:30][C:31]#[N:32])[C:5]([N:9]3[C:18]4[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]5[CH:27]=[CH:26][O:25][N:24]=5)(=[O:21])=[O:20])=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]3=[O:28])=[CH:6][C:7]=2[F:8])=[CH:36][C:35]=1[CH3:43]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: N#CCOc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2cc(OCC#N)c(-n3c(=O)ccc4cc(S(=O)(=O)Nc5ccon5)ccc43)cc2F)ccc1Cl
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 25.9 %

Procedure:
To a solution of 1-(4-bromo-2-(cyanomethoxy)-5-fluorophenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.020 g, 0.039 mmol) and (4-chloro-3-methylphenyl)boronic acid (9.84 mg, 0.058 mmol) in DMF (0.154 ml) and water (0.039 ml) was added potassium carbonate (0.016 g, 0.116 mmol) followed by PdCl2dppf, DCM adduct (1.409 mg, 1.926 μmol). The resulting mixture was heated to 50° C. and stirred for 3.5 hours. The solution was then cooled to RT, dissolved in 1.5 ml of DMSO and passed through a 0.20 Micron filter. An additional 0.5 ml was used to rinse the reaction vial and the solution was passed through the same filter. The resulting. DMSO solution was purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 30 to 95% MeCN in water (containing 0.1% trifluoroacetic acid as an additive), flow rate 40 mL/min to yield 1-(4′-chloro-5-(cyanomethoxy)-2-fluoro-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (5.7 mgs, 26% yield). 1H NMR (500 MHz, DMSO-d6) □=ppm 2.45 (s, 3 H) 5.17-5.27 (m, 2 H) 6.79-6.91 (m, 1 H) 7.00 (br. s., 1 H) 7.10 (br. s., 1 H) 7.20 (br. s., 1 H) 7.54 (d, J=8.04 Hz, 2 H) 7.58-7.66 (m, 2 H) 7.69 (br. s., 1H) 7.87 (d, J=8.89 Hz, 1 H) 8.25 (d, J=7.98 Hz, 1 H) 8.39 (s, 1 H) 8.72 (s, 1 H). m/z (ESI) 565.0 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CNCCN1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A suspension of 0.70 g (2.50 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.86 g (10.0 mmol) of anhydrous piperazine and 20 mL of acetonitrile was refluxed for 5 hours, then stirred at room temperature overnight. The precipitate was collected by filtration, washed with water and acetonitrile, and dried in vacuo to give 0.85 g of the title compound, mp 226°-228 ° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][N:3]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C=O.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:18][N:6]1[CH2:7][C@H:2]([CH3:1])[N:3]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][C@@H:5]1[CH3:8]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccccc2)[C@@H](C)CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of (2S,5S)-2,5-dimethyl-1-(phenylmethyl)piperazine (J. Med. Chem. 2006, 49, 716-726) (770 mg, 3.77 mmol) in dichloromethane (25 mL) at 0° C. was added formaldehyde (0.396 mL, 37% water solution, 5.28 mmol) followed by sodium triacetoxyborohydride (959 mg, 4.52 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were washed with brine, dried (MgSO4) and evaporated to yield (2S,5S)-1,2,5-trimethyl-4-(phenylmethyl)piperazine (782 mg, 95%). LCMS: (M+H)+: 219.1.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1.Br[CH2:13][C:14]([OH:16])=[O:15]>>[CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[C:9]([S:10][CH2:13][C:14]([OH:16])=[O:15])=[N:8][N:7]=[N:6]1
Reactant: CN(C)CCn1nnnc1S
Reactant: O=C(O)CBr
Product: CN(C)CCn1nnnc1SCC(=O)O

Procedure:
2-{1-[2-(dimethylamino)ethyl]-1,2,3,4-tetraazol-5-ylthio}acetic acid was prepared from commercially available 1-(2-dimethylaminoethyl)-5-mercapto-1,2,3,4-tetrazole and bromo acetic acid according to the procedures described in Russian J. Org. Chem. 2000, 761
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:9](=[N:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)O[C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:4]1[N:5]=[CH:6][N:7]=[C:2]2[C:3]=1[N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:9]([NH:19][CH:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:25]1)=[N:1]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)N1CCC(N=c2oc3ncnc(N)c3n2Cc2ccc(F)cc2)CC1
Product: CCOC(=O)N1CCC(Nc2nc3ncnc(Cl)c3n2Cc2ccc(F)cc2)CC1
Reaction time: 1.5 h
Yield: 41.5 %

Procedure:
A mixture of 50.7 parts of ethyl 4-[[7-amino-1-[(4-fluorophenyl)-methyl]oxazolo[5,4-d]pyrimidin-2(1H)-yliden]amino]-1-piperidinecarboxylate and 3050 parts of phosphoryl chloride was stirred for 90 minutes at reflux temperature. The reaction mixture was evaporated. The residue was poured into ice water. The whole was treated with ammonium hydroxide. The product was extracted with 4-methyl-2-pentanone. 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, (95:5 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 21.6 parts (41.5%) of ethyl 4-[[6-chloro-7-[(4-fluorophenyl)methyl]-7H-purin-8-yl]amino]-1-piperidinecarboxylate; mp. 126.6° C. (compound 25).
Reaction SMILES: C1CCC(P(C2C(C3C=CC=CC=3)=CC=CC=2)C2CCCCC2)CC1.Cl[C:27]1[N:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([NH2:54])[CH:45]=[CH:46][C:47]=1[N:48]1[CH:52]=[C:51]([CH3:53])[N:50]=[CH:49]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:40][O:41][C:42]1[CH:43]=[C:44]([NH:54][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:32]=2)[CH:45]=[CH:46][C:47]=1[N:48]1[CH:52]=[C:51]([CH3:53])[N:50]=[CH:49]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1cccc(Nc2ccccc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2cccc(Nc3ccccc3)n2)ccc1-n1cnc(C)c1
Yield: 22.6 %

Procedure:
A mixture of palladium(II)acetate (4 mg; 0.02 mmol) and (2-biphenyl) dicyclohexylphosphine (14 mg; 0.04 mmol) in dioxane (5 mL) was stirred under argon for 10 min at 20° C. (6-Chloro-pyridin-2-yl)-phenyl-amine (100 mg; 0.5 mmol), 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (99 mg; 0.5 mmol), and potassium carbonate (1.35 g; 10 mmol) were added and the mixture was refluxed under argon for 3 h. After quenching the reaction by addition of water, the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane/0-20% methanol as eluent to give the title compound (42 mg, 23%) as a light yellow solid.