Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[C:8]([C:3]1([CH2:2][O:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC1(CO)CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(C#N)CCCC2)cc1
Reaction time: 3 h

Procedure:
At 0° C., to a solution of 1-hydroxymethyl-cyclopentanecarbonitrile (10 g, 79.9 mmol) in CH2Cl2 (100 mL) was added pyridine (6.3 g, 79.9 mmol) and p-toluenesulfonyl chloride (12.18 g, 63.9 mmol). After stirred for 3 h, the solution was concentrated and the residue was used for next step reaction without further purification.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([OH:21])=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22]CCl>CN(C)C=O>[C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([Cl:22])=[O:21])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a suspension of 3-(4-phenylsulfamoyl-phenyl)-acrylic acid (43a) (0.25 g, 0.82 mmol) in dichloromethane (4.7 ml) oxalyl chloride (0.32 ml, 3.68 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.24 g, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:22][C:16]3([CH3:23])[CH2:17][C:18]([OH:21])([CH2:20][C:14]([CH3:24])([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:22][C:16]3([CH3:23])[CH2:17][C:18]([O:21][C:29]([CH2:28][CH2:27][CH2:26][Br:25])=[O:30])([CH2:20][C:14]([CH3:24])([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCBr
Reactant: CC12CC3(C)CC(O)(C1)CC(NC(=O)OCc1ccccc1)(C2)C3
Solvent: CN(C)C=O
Product: CC12CC3(C)CC(NC(=O)OCc4ccccc4)(C1)CC(OC(=O)CCCBr)(C2)C3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(benzyloxy-carbonyl)amino-3,5-dimethyl-7-hydroxyadamantane (100 mg) in DMF (0.4 mL) was added 4-bromobutyryl chloride (0.3 mL). The reaction mixture was stirred for 2 h at room temperature. The mixture was purified by thin layer chromatography eluting with ethyl acetate and hexane (1/2, v/v) to afford an oily product. 1H NMR (DMSO-d6, ppm): 7.38-7.29 (m, 5H, C6H5), 7.12 (brs, 1H, NH), 4.95 (s, 2H, OCH2), 3.53-3.49 (t, 2H, J=6.6 Hz, COCH2), 2.36-2.32 (t, 2H, J=7.7 Hz, CH2Br), 2.10 (s, 2H), 2.00-1.96 (m, 2H, CH2CH2CH2), 1.66 (s, 4H), 1.59-1.41 (dd, 4H, J=11.5, 51.7 Hz), 1.08-1.07 (d, 2H, J=3.8 Hz), 0.87 (s, 6H, 2×CH3).
Reaction SMILES: [C:1]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][C:9]=2[S:8][C:7]=1[N:16]=[C:17](OCC)[CH3:18])([O:3]CC)=O.[NH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH2:27][CH2:26]1>C(O)C>[CH3:18][C:17]1[N:22]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])[CH2:29][CH2:30]2)[C:1](=[O:3])[C:6]2[C:14]3[CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][C:9]=3[S:8][C:7]=2[N:16]=1
Reactant: COc1ccccc1N1CCN(CCN)CC1
Reactant: CCOC(=O)c1c(N=C(C)OCC)sc2c1CCN(C)C2
Solvent: CCO
Product: COc1ccccc1N1CCN(CCn2c(C)nc3sc4c(c3c2=O)CCN(C)C4)CC1
Yield: 28.4 %

Procedure:
1.9 g (6.2 mmol) of ethyl N-(3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)ethanimidate in 30 ml of ethanol were mixed with 1.5 g (6.2 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine and refluxed for 7 h. The mixture was then concentrated in a rotary evaporator, and the residue was taken up in 20 ml of ethyl acetate. 2.1 g of crude product crystallized out overnight and were filtered off with suction and purified by column chromatography (silica gel, mobile phase methylene chloride/methanol 92/8). 0.8 g (29%) of product was isolated.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8]OS(C)(=O)=O)[CH:6]=1.CN(C)C=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:6]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOS(C)(=O)=O)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCN2CCCC2)CC1
Temperature: 50 °C
Yield: 98 %

Procedure:
Combine tert-butyl 4-(4-bromo-1-(2-(methylsulfonyloxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (4.45 g, 9.84 mmol), dimethylformamide (25 mL), and pyrrolidine (2.46 mL, 3.0 eq) under nitrogen. Heat the reaction mixture at 50° C. overnight, then allow to cool to room temperature. Dilute with ethyl acetate. Wash with water followed by saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give the title compound (4.12 g, 98%). MS (ES) m/z=427 [M]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.CCN(CC)CC.O>CS(C)=O>[C:21]1([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:6]2[CH:7]=[C:3]([CH:2]=[O:1])[N:4]=[CH:5]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 110 °C

Procedure:
The product from Step 8.a. (2.04 g, 6.00 mmol) was suspended in DMSO (10.0 ml) and Et3N (3.34 ml, 24.0 mmol) and SO3-pyridine complex (2.39 g, 15.0 mmol) were added at room temperature. The mixture was warmed at about 110° C. for about 1 hour and then allowed to cool. The mixture was poured into 150 ml H2O and the product was filtered off. The residue was treated with saturated NaHCO3 solution (50 ml) and extracted 2×100 ml CH2Cl2. The combined CH2Cl2 layers were washed with 5% citric acid solution (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was crystallized from MeOH and H2O. Yield=1.08 g (53%).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>C1C=CC=CC=1>[Br:1][CH2:4][C:3]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[O:13])=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(=O)c1ccc(OCC(=O)OC(C)C)cc1
Reactant: BrBr
Solvent: c1ccccc1
Product: CC(C)OC(=O)COc1ccc(C(=O)CBr)cc1
Reaction time: 0.25 h

Procedure:
Bromine (12g.) was added dropwise to a stirred solution of isopropyl 4-acetylphenoxyacetate (17.6g.) in benzene (200ml.) over 30 minutes. The solution was stirred for a further 15 minutes and then evaporated. The residue was crystallised from ether/hexane to give isopropyl 4-(bromoacetyl)phenoxyacetate, m.p. 60°-61° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>ClCCl.O>[CH2:12]([NH:20][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCNS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.07 h
Yield: 95 %

Procedure:
A solution of toluene-4-sulfonyl chloride (5.0 g, 0.026 mol) in dry dichloromethane (150 ml) was cooled to 0° C. during the dropwise addition of n-octylamine (9.6 ml, 0.058 mol) with stirring over 4 minutes. The reaction mixture was then allowed to stir for 30 minutes before being diluted with dichloromethane (200 ml) and water (200 ml). The organic layer was separated and washed consecutively with 1M HCl, 0.5 M Na2CO3 and brine before being dried over anhydrous Na2SO4. The solution was filtered and concentrated in vacuo to a crude solid which was purified by flash chromatography (silica gel, 11% ethyl acetate in hexane) to give the title compound as a white solid (7.0 g, 94%). This material was then used immediately in the next step.
Reaction SMILES: O1C2C=CC=CC=2C=C1C(O)CN.C(CCCOC1C=CC(CC(=O)C)=CC=1)(OC)=O.[C:32]([C:36]1[CH:37]=[C:38](C=CC=1)[O:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2C=CC=[CH:48][C:47]2([NH:53][CH2:54][CH:55]([C:57]2[O:58][C:59]3[CH:65]=[CH:64][CH:63]=[CH:62][C:60]=3[CH:61]=2)[OH:56])C)=[CH:42][CH:41]=1)([O:34][CH3:35])=[O:33]>CCOCC>[C:32]([CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH:47]([NH:53][CH2:54][CH:55]([C:57]2[O:58][C:59]3[CH:65]=[CH:64][CH:63]=[CH:62][C:60]=3[CH:61]=2)[OH:56])[CH3:48])=[CH:42][CH:41]=1)([O:34][CH3:35])=[O:33]
Reactant: COC(=O)c1cccc(Oc2ccc(C3C=CC=CC3(C)NCC(O)c3cc4ccccc4o3)cc2)c1
Agent: COC(=O)CCCOc1ccc(CC(C)=O)cc1
Agent: NCC(O)c1cc2ccccc2o1
Solvent: CCOCC
Product: COC(=O)CCCOc1ccc(CC(C)NCC(O)c2cc3ccccc3o2)cc1

Procedure:
By a method analogous to that described in Example 2 but using 2-(2-benzofuranyl)-2-hydroxyethanamine (4.54 g) and 1-(4-[3-carbomethoxypropoxy]phenyl)propan-2-one (6.41 g), N-[2-(4-(3-carbomethoxyphenoxy)phenyl)-1-methylphenyl]-2-(2-benzofuranyl)-2-hydroxyethanamine was prepared, m.p. 63°-70° (Et2O) as a 37:63 mixture of diastereoisomers.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[N:22][OH:23])[CH:7]=[C:8]([C:12]3[N:13]=[CH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]1([C:37]#[CH:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:12]([C:8]2[O:9][C:10]3[C:5]([C:6](=[N:22][OH:23])[CH:7]=2)=[CH:4][CH:3]=[C:2]([C:38]#[C:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:11]=3)[N:13]=1
Reactant: C#Cc1ccccc1
Reactant: ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3ccccc3)ccc12
Temperature: 90 °C
Yield: 13.2 %

Procedure:
A solution of 7-bromo-2-isoquinolin-3-yl-chromen-4-one oxime (52 mg, 0.142 mmol), trans-dichlorobis(triphenylphosphine)palladium (10 mg, 0.014 mmol), copper iodide (5.3 mg, 0.028 mmol) in dimethylformamide (3 ml) was degassed with argon for 10 min and then treated with triethylamine (30 μl, 0.213 mmol) and phenyl acetylene (19 μl, 0.170 mmol). The solution was warmed to 90° C. for 18 hours and then poured onto a 0.5N aqueous solution of hydrogen chloride, extracted with ethyl acetate and purified by preparative HPLC (gradient 25-10% Water/acetonitrile+0.05% trifluoroacetic acid) to yield 2-isoquinolin-3-yl-7-phenylethynyl-chromen-4-one oxime (7.3 mg, 13%) as a yellow solid and a 80/20 mixture of Z/E oxime isomers.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:16]=[CH:15][C:10]2[NH:11][C:12](=[S:14])[S:13][C:9]=2[CH:8]=1)[CH3:6])C.[OH-].[Na+].CC(O)=O>C1COCC1.O>[S:14]=[C:12]1[NH:11][C:10]2[CH:15]=[CH:16][C:7]([CH:5]([CH3:6])[C:4]([OH:17])=[O:3])=[CH:8][C:9]=2[S:13]1
Reactant: CCOC(=O)C(C)c1ccc2[nH]c(=S)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2[nH]c(=S)sc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(2-Thioxo-2,3-dihydro-benzothiazol-6-yl)-propionic acid ethyl ester (587 mg) in THF (4 mL) and H2O (4 mL) was added NaOH (229 mg) at room temperature. After stirred for 14 h at room temperature, the reaction mixture was acidified with AcOH (pH=4) and diluted with water. The resulting mixture extracted with dichloromethane and the combined organic layer was dried magnesium sulfate, filtered and concentrated in vacuo. (511 mg, 97%, pale yellow solid)
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[Cl:11][C:12]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:12]=2[Cl:11])[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: Clc1cccc(CBr)c1Cl
Reactant: Nc1cc(O)nc(S)n1
Solvent: O
Product: Nc1cc(=O)[nH]c(SCc2cccc(Cl)c2Cl)n1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (2.22 g) with 2,3-dichlorobenzyl bromide (3.30 g) to afford the subtitle compound as a white solid. Yield: 3.25 g.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:20][C@H:19]2[CH2:21][OH:22])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C@@H:18]2[CH2:20][C@H:19]2[CH:21]=[O:22])=[CH:16][CH:17]=1
Reactant: OC[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C[C@@H]1C[C@H]1c1ccc(Br)cc1
Reaction time: 0.08 h

Procedure:
The above alcohol (1.07 g) was suspended in hexane (50 ml) at room temperature and cooled to -20° C. under nitrogen Diethyl zinc (ex Aldrich) (22.7 ml of a 1.1M solution in hexane) was added dropwise, followed by diiodomethane (ex Aldrich) (4.1 ml). The mixture was allowed to warm to 25° slowly, then stirred for 18 hours. Saturated ammonium chloride was added and the mixture extracted with ether. The combined ethereal extracts were washed with saturated sodium thiosulphate solution dried over magnesium sulphate and the solvents removed under vacuum. Purification by chromatography (silica, ether/hexane) gave (±)-trans-2-(4-bromophenyl)-1-hydroxymethyl cyclopropane (0.53 g). NMR 1H: 7.38(2H,d), 6.95(2H,d),3.65 (2H,d),1.8 (1H,m), 1.55 (1H,s), 1.44(1H,m), 0.95 (2H,m). p (iv) Oxalyl chloride (ex Aldrich)(0.22 ml) was dissolved in dichloromethane (3 ml) and cooled to -70° under nitrogen. Dimethylsulphoxide (ex BDH) (0.36 ml) in dichloromethane (1 ml) was added dropwise. After five minutes, the above alcohol (0.53 g) in dichloromethane (4 ml) was added and the suspension stirred at -70° for 30 minutes. Triethylamine (ex Aldrich) (1.6 ml) was added and the mixture allowed to warm to 0° over one hour. Work-up in the conventional manner gave (±)-trans-[2-(4-bromophenyl)cyclopropyl]-methanal which was used directly. NMR 1H: 9.4 (1H,d), 7.33 (2H,d), 6.9 (2H,d), 2.54(1H,m), 2.20 (1H,m), 1.0-1.9(2H,m).
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH:12]=[C:11]([O:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:10]=[CH:9][C:6]=2[S:7][CH:8]=1)(=[O:3])C.C1(S(OC2C=CC(SCC#C)=CC=2)(=O)=[O:30])C=CC=CC=1.Cl[O-].[Na+].Cl>O1CCOCC1>[C:17]1([S:14]([O:13][C:11]2[CH:10]=[CH:9][C:6]3[S:7][CH:8]=[C:4]([C:1]([OH:30])=[O:3])[C:5]=3[CH:12]=2)(=[O:15])=[O:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C#CCSc1ccc(OS(=O)(=O)c2ccccc2)cc1
Reactant: CC(=O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Temperature: 11 °C
Reaction time: 7 h
Yield: 82.4 %

Procedure:
The compound (9) (6.65 g, 20 mmol) prepared in above (2) was dissolved in dioxane (50 ml), and 10% sodium hypochlorite (46.2 ml) was added over 20 minutes with stirring while maintaining the temperature at 10-12° C. After 7 hours, the reaction mixture was diluted with ice-water (80 ml) and acidified with conc. hydrochloric acid (5.2 ml). The deposited crystals were filtered, washed with water, dried to provide 5.84 g of crude crystals. The 5.84 g of the crude crystals were recrystallized from methanol (66 ml) and water (16 ml) to provide 5.51 g of the title compound (6). Yield: 82.4%. mp 203-204° C.
Reaction SMILES: [CH3:1][C:2]1([NH:22][C:23]2[N:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25]N=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8]([C:10]1[C:15]([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].[CH3:33]C1(NC2C=CC(C(F)(F)F)=CN=2)CCCC1N.N1C=CC=NC=1C1C(C(O)=O)=NC=CC=1.C(N(CC)CC)C>>[CH3:1][C:2]1([NH:22][C:23]2[CH:33]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][N:28]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8]([C:10]1[C:15]([C:16]2[N:17]=[CH:18][CH:19]=[CH:20][N:21]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9]
Reactant: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-c1ncccn1
Reactant: CC1(Nc2ccc(C(F)(F)F)cn2)CCCC1N
Agent: O=C(O)c1ncccc1-c1ncccn1
Solvent: CCN(CC)CC
Product: CC1(Nc2ccc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-c1ncccn1

Procedure:
Prepared according to the procedure for N-(2-methyl-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl)-3-(pyrimidin-2-yl)pyridine-2-carboxamide (Example 153) from 1-methyl-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine (Intermediate 51; 91 mg, 0.35 mmol), 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 85 mg, 0.42 mmol) and triethylamine (0.147 ml, 1.06 mmol) except after work-up the organics were loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM then with 2M ammonia in methanol and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (C18 silica, 5-100% water (0.05% ammonia)/acetonitrile) then recrystallised from MTBE/heptane to afford the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.Br[C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH:15]([CH3:34])[N:16]([C:20]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[N:23]=[C:22]([NH2:33])[N:21]=3)[CH2:17]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].N#N>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[CH3:32][N:29]1[CH2:28][CH2:27][N:26]([C:24]2[CH:25]=[C:20]([N:16]3[CH:15]([CH3:34])[CH2:14][C:13]4[C:18](=[CH:19][C:10]([C:3]5[CH:4]=[CH:5][NH:1][N:2]=5)=[CH:11][CH:12]=4)[CH2:17]3)[N:21]=[C:22]([NH2:33])[N:23]=2)[CH2:31][CH2:30]1
Reactant: OB(O)c1cc[nH]n1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(-c3cc[nH]n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 1H-pyrazol-3-ylboronic acid (64.3 mg, 0.575 mmol, Frontier Scientific, Cat. No. P1638), 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.20 g, 0.48 mmol) (Peak 2, Example 49, Step 7), dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (10.2 mg, 0.0144 mmol), and sodium carbonate (0.102 g, 0.958 mmol) in 1,4-dioxane (2.2 mL) and water (0.3 mL) was vacuumed and refilled with N2 for 3 times and then stirred at 90° C. overnight. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=405.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12](=O)N(C)C)=[C:7]([Cl:17])[CH:6]=1.C[O-].[Na+].BrC[CH2:24][CH2:25][O:26][C:27]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]2[C:30]([CH:31]=[C:32]([CH2:41][CH3:42])[C:33](=[O:40])[O:34]2)=[CH:29][CH:28]=1>CO>[Cl:17][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:18])[CH:10]=[CH:9][C:8]=1[S:11][CH2:12][CH2:24][CH2:25][O:26][C:27]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]2[C:30]([CH:31]=[C:32]([CH2:41][CH3:42])[C:33](=[O:40])[O:34]2)=[CH:29][CH:28]=1
Reactant: COC(=O)Cc1ccc(SC(=O)N(C)C)c(Cl)c1
Reactant: CCCc1c(OCCCBr)ccc2cc(CC)c(=O)oc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc2cc(CC)c(=O)oc12
Temperature: 70 °C

Procedure:
To a solution of 3-chloro-4-dimethylcarbamoylthiophenylacetic acid methyl ester (54 mg, 0.1656 mmol) in 0.50 mL methanol was added a 0.5M solution of sodium methoxide (0.33 mL, 0.1656 mmol) in methanol. This mixture was heated to 70° C. for 90 minutes. After cooling to ambient temperature, a solution of 7-(3-bromopropoxy)-3-ethyl-8-propylcoumarin (Step D; 54 mg, 0.1656 mmol) in 1.2 mL methanol was added dropwise. The mixture was heated to 70° C. for several hours. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate. The organic mixture was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (20% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: [CH2:1]([SH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([O-:20])=[O:19].N1C=CC=CC=1>C(#N)C>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:29])[S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCS
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCSC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, n-hexadecanethiol (165 g) was dissolved in acetonitrile (1000 ml). To the solution, p-nitrophenyl isocyanate (100 g) was gradually added, then pyridine (4 ml) was added dropwise, and the mixture was stirred at room temperature for 10 minutes, and then heat-refluxed for 30 minutes. When the reaction mixture was cooled to room temperature, crystals precipitated. The crystals were collected by filtering and washed with acetonitrile. S-n-hexadecyl p-nitrophenylthiocarbamate (250 g) was obtained at a yield of 97%.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:28](N(CC)CC)[CH3:29].ClC(OCC)=O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:1]1([CH2:6][CH:7]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:28][CH3:29])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCN(CC)CC
Reactant: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCCCCOC(COCc1ccc(OC)cc1)Cn1ccnc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A stirred solution of 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoic acid (Example 1c) (10 g, 0.026 mol) and triethylamine (3.0 g, 0.03 mol.) in dichloromethane (100 ml, dried over 4 A molecular sieves) at -50° C. was treated dropwise with ethyl chloroformate (3.2 g, 0.029 mol.). The solution was allowed to warm up to 0° C. over 0.5 hours, cooled back to -50° C. and treated with ethanol (6 ml, 0.1 mol). The solution was allowed to warm up and then stirred for 15 hours at 18° C. The mixture was then shaken with an aqueous solution of saturated sodium carbonate (500 ml). The organic layer was separated, dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crude product which was purified by column chromatography (silica gel, 5% ethanol in chloroform) to give ethyl 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoate as a pale-yellow oil.