Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]3[C:18]4[C:23]([CH2:24][CH2:25][C:14]=23)=[CH:22][C:21]([CH:26]=C)=[CH:20][CH:19]=4)=[CH:9][C:6]=1[C:7]#[N:8])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:32]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH:26]([C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:15]1=[N:16][O:17][C:13]([C:10]3[CH:11]=[CH:12][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([CH:9]=3)[C:7]#[N:8])=[C:14]1[CH2:25][CH2:24]2)=[O:32]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)c(C#N)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C#N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 71.3 %

Procedure:
To 2-isopropoxy-5-(7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazol-3-yl)benzonitrile (Preparation 15C, 0.088 g, 0.247 mmol) in THF (1.5 mL) was added N-methylmorpholine-N-oxide (50% in water) (0.17 mL, 0.370 mmol) followed by osmium tetroxide (0.039 mL, 4.94 μmol) at room temperature. The contents were stirred at room temperature for 3.5 h. Sodium periodate (0.106 g, 0.494 mmol) dissolved in 0.5 mL of water was added over a period of 2 min. at room temperature and the contents were stirred at room temperature for 1 h. The reaction mixture was concentrated and partitioned between ethyl acetate (15 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield 5-(7-formyl-4,5-dihydronaphtho[1,2-c]isoxazol-3-yl)-2-isopropoxybenzonitrile (0.090 g, 0.176 mmol, 71% yield) as an orange-yellow solid. LC/MS M+1=359.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([CH3:11])[CH2:5][NH:6][CH:7]1[CH2:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH:4]([CH3:11])[CH2:5][N:6]([C:16]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=1)[CH:7]1[CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)C(C)CNC1CCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC1
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a mixture of 1.71 g (0.010 mole) of (rac)-3-cyclobutylamino-2-methyl-propanoic acid methyl ester, 1.94 g (0.010 mole) of 2,4-dichloro-5-nitro-pyrimidine, 50 mL of ethyl acetate and 25 mL of water was added 3.0 g (0.030 mole) of potassium bicarbonate. The mixture was stirred for 3 hours then diluted with 50 mL of ethyl acetate and 50 mL of water. The aqueous layer was extracted with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (100:0-97:3) to give 2.54 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-2-methyl-propanoic acid methyl ester (IV-52) as a pale yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)N.[CH3:23][N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>C(N(CC)CC)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:11]2[C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=3[C:26]3[CH2:25][N:24]([CH3:23])[CH2:29][CH2:28][C:27]2=3)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(NN)cc1
Reactant: Clc1ccc(CCBr)cc1
Reactant: CN1CCC(=O)CC1
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cc(C(=O)O)ccc3n2CCc2ccc(Cl)cc2)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-4-chlorobenzene, methyl 4-hydrazinobenzoate, triethylamine and N-methyl-4-piperidone
Reaction SMILES: C([O:5][C:6](=[O:32])[CH:7]([CH2:26][O:27]C(C)(C)C)[NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:25])=[CH:16][N:17]=[C:18]2[NH:21][C:22]([NH2:24])=[NH:23])=[CH:13][CH:12]=1)=[O:10])(C)(C)C.[C:33]([C:37]([OH:39])=[O:38])([F:36])([F:35])[F:34]>C1(C)C=CC=CC=1>[F:34][C:33]([F:36])([F:35])[C:37]([OH:39])=[O:38].[Cl:25][C:15]1[C:14]2[C:19](=[CH:20][C:11]([C:9]([NH:8][CH:7]([C:6]([OH:32])=[O:5])[CH2:26][OH:27])=[O:10])=[CH:12][CH:13]=2)[C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[N:17][CH:16]=1
Reactant: CC(C)(C)OCC(NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC(CO)C(=O)O)cc12

Procedure:
A solution of O-t-butyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-serine t-butyl ester in CF3CO2H (1 mL) was stirred at room temperature for 1 h. The solution was diluted with PhMe, evaporated in vacuo, and the residue was recystallised twice from MeOH-EtOAc to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-serine trifluoroacetate (68 mg, 0.19 mmol) as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2([CH2:20][C:21]([OH:23])=O)[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:25]([O:29][NH2:30])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:29][NH:30][C:21](=[O:23])[CH2:20][C:15]1([S:14][C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:16][CH2:17][CH2:18][CH2:19]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCCC1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)ONC(=O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCCC1
Reaction time: 8 h

Procedure:
The 2-[1-(4-phenoxyphenylthio)-cyclopent-1-yl]-acetic acid obtained in Example 5 was dissolved in methylene chloride (8 ml) and treated with 4 -dimethylaminopyridine (180 mg), O-(tert-butyl) hydroxylamine hydrochloride (360 mg), triethylamine (540 μL), pyridine (400 μL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (750 mg). After stirring overnight the reaction mixture was partitioned between ethyl acetate and water, the organic layer separated, and the solvent removed under reduced pressure. Preparative TLC of the residue and elution with 2:1 hexane/ethyl acetate gave N-(tert-butoxy)-2-[1-(4-phenoxyphenylthio)cyclopent-1-yl]-acetamide (270 mg) as a white foam, which can be used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH2:11][O:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[BrH:22]>C(O)(=O)C>[Br:22][CH2:11][CH2:12][CH2:13][C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]([OH:10])=[O:14]
Reactant: Br
Reactant: O=C1OCCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CC(=O)O
Product: O=C(O)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 5.8 parts of 3,3-bis(4-fluorophenyl)tetrahydro-2H-pyran-2-one and 30 parts of a solution of hydrobromic acid in glacial acetic acid was stirred over week-end at room temperature. The reaction mixture was poured onto water. The precipitated product was filtered off and dissolved in 2,2'-oxybispropane. The organic phase was washed with water, dried, filtered and evaporated. The residue was boiled in a mixture of 42 parts of 2,2'-oxybispropane and 42 parts of petroleum ether. The product was filtered off and crystallized from 2,2'-oxybispropane, yielding 1.27 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetic acid; mp. 161° C. (intermediate 22).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=1)([O-:14])=[O:13].O>COCCOCCOC>[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[N:1]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: COCCOCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
2-Amino-4-nitrophenol (46.2 g, 0.3 mol) was dissolved in diglyme (1250 mL) and added to a 3-necked, 3-liter flask equipped with a condenser, a mechanical stirrer, and a hearer. 4-Nitrobenzoyl chloride (57 g, 0.3 mol) was dissolved in diglyme (250 mL) and added to the flask. The mixture was heated, with stirring, to 120° C. for 1 hour, whereupon polyphosphoric acid (90 g) was added. Heating was continued at 150° C. to 160° C. for an additional 1 hour. The reaction mixture was cooled to 110° C. to 120° C. and deionized water (500 mL) was added over a period of 15 to 30 minutes while the mixture was maintained at 100° C. The reaction mixture was cooled, and the precipitated product was filtered and washed with methanol (300 mL), then dried. The melting point was found to be 253° C. to 255° C. The overall yield was 95 percent with an assay of 100 percent by liquid chromatography.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[OH:36])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(N(CC)CC)C.[CH:45]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(Cl)Cl>[CH:45]1([C:51]([O:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:28]2[O:27][N:26]=[C:25]([C:23]3[N:24]=[C:20]([CH:17]4[CH2:16][CH2:15][N:14]([C:12](=[O:13])[CH2:11][N:5]5[C:6]([CH:8]([F:10])[F:9])=[CH:7][C:3]([CH:2]([F:1])[F:37])=[N:4]5)[CH2:19][CH2:18]4)[S:21][CH:22]=3)[CH2:29]2)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1)C1CCCCC1
Reaction time: 3 h

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (150 mg) and triethylamine (33 mg) in methylene chloride (10 ml) is added, at 0° C., a solution of cyclohexanecarbonyl chloride in methylene chloride (2 ml). The ice bath is removed and the reaction mixture is stirred at 0° C.-RT for 3 h. Then the mixture is admixed with dilute sodium hydrogencarbonate solution and extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl cyclohexanecarboxylate (150 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16]C(=O)OC(C)(C)C)=[C:12]([F:24])[CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C:25](OCC)(=[O:31])[C:26](OCC)=[O:27]>CCO>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[C:7]3[NH:8][C:25](=[O:31])[C:26](=[O:27])[NH:1][C:2]=3[N:3]=[CH:4][CH:5]=2)=[CH:11][C:12]=1[F:24]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)cc1F
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1F
Temperature: 25 °C

Procedure:
A solution of tert-butyl 4-(2,3-diaminopyridin-4-yloxy)-2-fluorophenylcarbamate (1.03 g, 3.08 mmol) was dissolved in dry EtOH (10 mL), diethyl oxalate (10 mL) was added and the solution was heated to reflux for 96 h, cooled to RT and filtered. The title compound was isolated as a white solid. Yield: 820 mg (92%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=5)[C:27](O)=[O:28])[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1>>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([C:23]3[N:18]4[N:17]=[C:16]([NH:15][C:12]5[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)=[CH:10][CH:11]=5)[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=3)[CH:25]=2)=[CH:37][CH:36]=1
Reactant: O=C(O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reactant: NCc1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Cl)cc1)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-benzoic acid (50 mg, 0.113 mmol), 4-chlorobenzylamine (27.5 μL, 0.226 mmol), EDC (44 mg, 0.226 mmol) and di-isopropylethylamine (98.5 μL, 0.564 mmol) was added HOBt (31 mg, 0.226 mmol). The mixture was stirred overnight at room temperature, and the desired product purified by preparatory HPLC. RT: 4.63 min, MI: 567.31, Method: basic. 1H NMR (DMSO, 300 MHz): 9.43 (s, 1H), 9.22 (t, 1H), 8.58 (s, 1H), 8.19 (t, 1H), 8.03 (d, 1H), 7.63 (m, 6H), 7.36 (s, 3H), 7.24 (dd, 1H), 6.84 (d, 2H), 4.50 (d, 2H), 3.99 (t, 2H), 2.81 (t, 2H), 2.50 (d, 2H), 2.36 (s, 2H), 1.69 (m, 4H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:37])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH2:35][OH:36])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:37])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH2:35][OH:36])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCO)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCCO)c1
Yield: 51 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10.0 mmol, 18 eq) of sodium hydroxide and 270 mg (0.55 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(3-hydroxypropoxy)biphenyl-4-yl]propanoate in 3 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from ethyl acetate/heptane, 135 mg of 3-[3′-(3-heptyl-1-methylureido)-2-(3-hydroxypropoxy)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=107° C.). Yield=51%
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:24][CH:23]=3)[C@H:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46]>O1CCCC1>[CH3:43][C:44]([CH3:49])([CH3:48])[C:45]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:24][CH:23]=3)[C@H:7]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1)=[O:46]
Reactant: Oc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of (±)-cis-7-hydroxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-3-(4-(trifluoromethyl)-phenyl)chromane (2.41 g, 4.98 mmol), triethylamine (3.40 ml, 24.4 mmol), 2,2-dimethylpropanoyl chloride (3.0 ml, 24.4 mmol) and tetrahydrofuran (150 ml) was stirred at room temperature for 4 days. The mixture was filtered to remove inorganic solids, the filter plug being washed with a little extra tetrahydrofuran. The solvents were then evaporated to give a colourless amorphous solid, which was recrystallised from 4:1 ethanol/water (20 ml) to give the product as colourless needles.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+]([O-])=O.FC1C=C(F)C=CC=1[N+:25]([O-:27])=[O:26].N1CCOCC1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:25]([O-:27])=[O:26])=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1F
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: O=[N+]([O-])c1ccc(F)cc1N1CCOCC1

Procedure:
4-(3-Fluoro-4-nitrophenyl)morpholine: A solution of 2,4-difluoronitrobenzene (10.0 mL, 91 mmol) and morpholine (17.4 mL, 200 mmol) in THF (100 mL) was stirred at RT under nitrogen for 2 h. The solvent was removed and the residue was partitioned between EtOAc and water. The organic layer was washed brine, dried over MgSO4, and concentrated. The resulting solid was purified by SiO2 chromatography with 20-50% EtOAc in hexane to give 4-fluoro-2-morpholinonitrobenzene (18.1 g) and 55a (1.81 g, 8% yield); [M+H]+=227.10.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][N:16]([S:22](Cl)(=[O:24])=[O:23])[CH2:17]2.[N:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[N:28][CH:27]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][N:16]([S:22]([NH:32][C:29]1[CH:30]=[CH:31][N:26]=[CH:27][N:28]=1)(=[O:24])=[O:23])[CH2:17]2
Reactant: Nc1ccncn1
Reactant: O=S(=O)(Cl)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Nc1ccncn1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A 15-mL round-bottom flask was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate D, 287.2 mg, 0.731 mmol) and triethylamine (224 μl, 1.609 mmol) in DCM (3.8 mL) to give a brown solution. The flask was cooled in an ice-bath for 10 min, then sulfuryl chloride (125 μl, 1.536 mmol) was added dropwise. Stirring was continued for 2 hours at which time the mixture was quenched with water, then extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on a 40 g silica gel column with 0 to 40% EtOAc/Heptane to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (253.01 mg, 0.556 mmol) as a clear, very viscous oil that was immediately used in the next step. A vial was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (40.045 mg, 0.088 mmol), pyrimidin-4-amine (41.9 mg, 0.440 mmol), chloroform (587 μl), and pyridine (71.2 μl, 0.881 mmol) and was placed into a 50° C. bath. The mixture was heated overnight before being allowed to cool to rt. The mixture was concentrated under a vacuum, and the residue was chromatographed on a 12 g silica gel column with 0 to 6% MeOH/DCM to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (29.77 mg, 0.058 mmol) as a yellow solid. [M+H]+=513.0. 1H NMR (400 MHz, DMSO-d6) δ ppm=9.55 (br. s., 1H), 9.07 (br. s., 1H), 8.57 (br. s., 1H), 8.13 (d, J=1.3 Hz, 1H), 7.99 (br. s., 1H), 7.83 (dd, J=1.1, 8.0 Hz, 1H), 7.55-7.44 (m, 1H), 7.35-7.21 (m, 2H), 7.02 (dd, J=2.0, 6.8 Hz, 1H), 4.71 (d, J=6.4 Hz, 1H), 4.32-4.17 (m, 2H), 3.24-3.07 (m, 2H), 2.45 (br. s., 2H).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[H-].[Na+].Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CN(C=[O:26])C>>[N:17]1[CH:18]=[CH:19][CH:20]=[N:21][C:16]=1[O:26][CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[C:8]1=[O:12]
Reactant: CN(C)C=O
Reactant: Clc1ncccn1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Product: O=C1c2ccccc2CCC1Oc1ncccn1
Temperature: 100 °C

Procedure:
6-Hydroxytetralone (31 mmol) was dissolved in dry DMF (50 mL), chilled in an ice/water bath and blanketed with a stream of nitrogen. NaH (60% in mineral oil, 31 mmol) was added slowly and in portions. Once gas evolution ceased, 2-chloropyrimidine (31 mmol) was added, the ice bath was removed and the solution heated at 100° C. for 1.5 hours. It was then cooled to room temperature and the solvent was removed in vacuo. The residue was treated with water and CH2Cl2 (200 mL each). Evaporation of the organic layer yielded crude material which was purified by flash chromatography (1:1 hexane:EtOAc) to afford 6-[(2-pyrimidinyl)oxyl-tetralone as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]#[CH:33])[CH2:27][CH2:26]1.CO>C(N(CC)CC)C.C1C=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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:33]#[C:32][CH2:31][N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: C#CCN1CCN(C)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(Nc2c(C#N)cnc3cc(C#CCN4CCN(C)CC4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.42 mmol), 1-methyl-4-prop-2-ynyl-piperazine (87.0 mg, 0.65 mmol), 9.7 mg of tetrakis(triphenylphosphine)palladium(0) and 2.0 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux for 5 hours. The mixture is cooled to room temperature and 2 mL of methanol are added. The solvents are removed in vacuo and the residue is purified by preparative thin layer chromatography developing with 12% methanol in dichloromethane to give a solid which is triturated with ether containing several drops of dichloromethane, to provide 89.6 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 172–173° C.; 1H NMR (DMSO-d6) δ 2.18 (s, 3H), 2.37 (s, 4H), 2.49 (s, 4H), 3.59 (s, 2H), 3.85 (s, 3H), 7.37 (s, 1H), 7.62 (s, 1H), 7.78 (s, 1H), 8.62 (s, 1H), 9.82 (s 1H); MS 486.1, 488.1 (M+H)+.