Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br)#[N:26].C1CCCCC1>C(OCC)(=O)C>[C:25]([C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][O:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1)#[N:26]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@]12CCNC2=O
Reactant: N#Cc1ccccc1CBr
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3C#N)cc2)CC[C@]12CCNC2=O
Yield: 90.4 %

Procedure:
The title compound (102 mg, 90%) was prepared using a similar procedure as set out earlier in Description 11 starting from 1,1-dimethylethyl (2R,5R)-2-(4-hydroxyphenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D25, 84 mg, 0.252 mmol) and 2-cyanobenzyl bromide (74 mg, 1.5 eq); Rt (HPLC): 5.37 min; Rf (cyclohexane:ethyl acetate=1:1): 0.07; MS: (ES/+) m/z: 470 [M+Na+]. C26H29N3O4 requires 447.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[C:31]1([CH2:37][S:38]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1ccccc1)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.628 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of α-toluenesulfonylchloride (143 mg, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound (207 mg, 69%). 1H NMR (400 MHz, CDCl3) δ7.27-7.22 (m, 3H), 7.16-7.14 (m, 2H), 7.07 (d, 2H), 6.83 (d, 2H), 4.05 (s, 2H), 3.95 (t, 2H), 3.68-3.63 (m, 2H), 3.55 (t, 1H), 3.49-3.44 (m, 2H), 3.01 (d, 2H), 2.57 (t, 2H), 2.47 (s, 4H), 2.02-1.93 (m, 4H), 1.78-1.72 (m, 6H).
Reaction SMILES: [CH2:1]1[C@@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Cl[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].CC(C)CC(=O)C>[CH2:1]1[C@@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNC[C@H]21
Reactant: CCOC(=O)COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
32.48 g of (S)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine (prepared as described in Preparation 3), 22.7 g of ethyl 2-choroethoxyacetate, 48.9 g of sodium carbonate and 0.79 g of sodium iodide were added to 340 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 16 hours. At the end of this time, it was cooled to room temperature and was filtered using a Celite filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel eluted with a 1:1 by volume mixture of ethyl acetate and hexane, to give 44.85 g (yield 91%) of the title compound as a pale yellow oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([Cl:31])[N:24]=[C:23]2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([Cl:31])[N:24]=[C:23]2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:19][CH:20]=1)(=[O:8])=[O:7]
Reactant: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Yield: 100.8 %

Procedure:
1-((2'-((tert-butylamino)sulfonyl)(1,1'-biphenyl)-4yl)methyl)-2-butyl-4-chloro-imidazole-5-carboxylic acid, methyl ester (75.0 mg, 0.145 mmol) was stirred in trifluoroacetic acid (1.0 ml) containing anisole (20 μl) under nitrogen at room temperature for 24 hours. The trifluoroacetic acid was removed in vacuo and the residue chromatographed (silica gel, 35% ethyl acetate-hexane) to afford 1-((2'-(aminosulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-butyl-4-chloro-imidazole-5-carboxylic acid, methyl ester (67.5 mg, 100%) as a white solid; 1H NMR (300 MHz, CD3OD/CDCl3) δ8.08 (d, J=7.7 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.26 (d, J=7.7 Hz, 1H), 7.04 (d, J=8.1 Hz, 2H), 5.57 (s, 2H), 3.80 (s, 3H), 2.64 (t, J=7.4 Hz, 2H), 1.62 (quin, J=7.4 Hz, 2H), 1.31 (sext, J=7.4 Hz, 2H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[CH3:14][O:13][C:3]1[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:12])[CH:9]=2)[N:4]=1
Reactant: COc1nc2ccc(C)cc2nc1N
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 98 %

Procedure:
3-Amino-2-methoxy-6-methylquinoxaline (568 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with n-hexane:ethyl acetate (3:1) mixture and concentration gave 768 mg of the titled compound (yield, 98%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[C:9]([NH:12][CH2:13][C:14]([OH:16])=[O:15])(=O)[CH3:10].CC([O-])=O.[Na+]>CC(OC(C)=O)=O.[OH-].[Na+].C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([CH:7]=[C:13]2[C:14](=[O:15])[O:16][C:9]([CH3:10])=[N:12]2)=[CH:4][CH:3]=1
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1ccc(Cl)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC1=NC(=Cc2ccc(Cl)s2)C(=O)O1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A mixture consisting of 5-chlorothiophene-2-carboxaldehyde (1.00 g, 6.82 mmol), N-acetylglycine (0.96 g, 8.18 mmol), NaOAc (0.67 g, 8.18 mmol) in Ac2O (5 mL) is warmed at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and diluted with dilute aqueous NaOH (0.5 M, 100 mL) and CH2Cl2 (100 mL). The layers are separated and the organic phase is washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to provide 1.5 g (100%) of the title compound as a colorless oil which is used without further purification in the next reaction. 1H NMR (300 MHz, CDCl3) δ2.39 (s, 3H), 6.94 (d, J=4.0 Hz, 1H), 7.21 (s, 1H), 7.26 (d, J=4.0 Hz, 1H) ppm.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[O:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C>[S:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:21][CH2:20][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NCC1CCOCC1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(C(=O)NCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Sulfamoylbenzoic acid (201 mg), (tetrahydro-2H-pyran-4-yl)methanamine (144 mg), 1-hydroxybenzotriazole hydrate (230 mg), and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (288 mg) were combined in acetonitrile. The mixture was stirred at room temperature overnight. The solids were filtered off and reaction mixture was concentrated. The crude material was purified by flash chromatography eluting with a gradient of 2% methanol/dichloromethane to 10% methanol/dichloromethane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:7][CH2:8][N:9]([C:35](=[O:37])[CH3:36])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1(NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)CCNCC1
Solvent: ClCCl
Product: CCOC(=O)C1(NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)CCN(C(C)=O)CC1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
To a solution of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-4-carboxylic acid ethyl ester (0.7 g, 1.44 mmol) in CH2Cl2 (10 mL) and TEA (0.4 mL, 2.89 mmol) at 0° C. was added acetyl chloride (0.113 mL, 1.59 mmol). The reaction was allowed to warm to 25° C. over 19 h. The reaction was then taken up in CH2Cl2 (50 mL) and washed with 1N HCl (5 mL) and water (5 mL). The organics were washed with saturated aqueous sodium chloride (30 mL), dried over MgSO4, filtered and concentrated. The residue was purified by Biotage Flash 40S chromatography, eluting with 2:1 ethyl acetate-hexanes, to provide 1-acetyl-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-4-carboxylic acid ethyl ester as a white solid (0.4 g, 53%). MS: 526 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:3]=1[O:4][CH:5]([CH3:9])[C:6]([NH2:8])=O.F[B-](F)(F)F.C[O+](C)C.C(Cl)Cl.[CH2:27](N)[CH2:28][NH2:29]>C(O)C>[Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:3]=1[O:4][CH:5]([C:6]1[NH:29][CH2:28][CH2:27][N:8]=1)[CH3:9]
Reactant: CC(Oc1c(Cl)cccc1Cl)C(N)=O
Reactant: NCCN
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CC(Oc1c(Cl)cccc1Cl)C1=NCCN1
Temperature: 0 °C

Procedure:
A mixture of 25 (25 g, 106.8 mmol), trimethyloxonium tetrafluoroborate (16.6 g, 110 mmol) and CH2Cl2 (600 mL) was stirred for 36 hours, during which the coarse suspension changed to a clear, colorless solution. Cooling of this solution of 0° C. was followed by a dropwise addition of ethylene diamine (7.00 g, 1.1 equiv) over 10 minutes. The resulting solution was warmed to room temperature, diluted with absolute ethanol (200 mL) and then evaporated to dryness. The pasty white residue was partitioned between 5% aqueous K2CO3 (200 mL) and CH2Cl2 (500 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure. Recrystallization of the residue from boiling hexanes (500 mL) afforded pure 3 as white needles that were removed by filtration and dried in air (23.52 g, 85%). 1H NMR (300 MHz, d6-DMSO) δ ppm 7.46-7.44 (m, 2H, Ar), 7.14 (t, J=7.8 Hz, 1H, Ar), 6.45 (s, 1H, NH), 4.79 (q, J=6.6 Hz, 1H), 3.43-3.37 (s, br, 4H), 1.47 (d, J=6.6 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ ppm 166.3, 150.0, 130.0, 129.6, 129.5, 129.2, 126.6, 77.3, 50.4 (very broad), 19.2; mp=129-130° C. (hexanes); [α]23D=−80.2° (c 1.0, EtOH) (lit.4 [α]20D=−76.4° (c 1.0, EtOH).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.[C:8]([C:14](OC)=[O:15])#[C:9][C:10]([O:12][CH3:13])=[O:11]>C(O)C>[OH:15][C:14]1[N:6]2[C:5]([SH:7])=[N:4][N:3]=[C:2]2[N:1]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=1
Reactant: Nc1n[nH]c(S)n1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCO
Product: COC(=O)c1cc(O)n2c(S)nnc2n1
Yield: 98.6 %

Procedure:
A mixture of 15.1 g of 3-amino-5-mercapto-s-triazole, 18.9 g of dimethyl acetylenedicarboxylate and 100 ml of ethanol was refluxed for 90 minutes. The objective compound (29 g) was obtained by collecting the crystals separated out upon cooling the reaction mixture.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:25])=[CH:17][CH:16]=1
Reactant: O=C(O)COc1ccc(-c2ccccc2F)nc1
Reactant: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(-c2ccccc2F)nc1)N1CCCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.277 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 47.1 mg (0.554 mmol) of piperidine. Yield: 72 mg.
Reaction SMILES: Br[CH2:2][C:3](CBr)=[O:4].[C:7]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH3:24])=[O:21])[CH:17]([CH3:19])[CH3:18])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:36][C:37]1[C:45]([F:46])=[C:44]([F:47])[C:43]([F:48])=[C:42]([F:49])[C:38]=1[C:39]([OH:41])=[O:40]>>[CH3:2][C:3]([O:40][C:39](=[O:41])[C:38]1[C:37]([F:36])=[C:45]([F:46])[C:44]([F:47])=[C:43]([F:48])[C:42]=1[F:49])=[O:4].[C:7]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH3:24])=[O:21])[CH:17]([CH3:18])[CH3:19])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(CBr)CBr
Agent: CCCC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C)C(=O)O
Product: CC(=O)OC(=O)c1c(F)c(F)c(F)c(F)c1F

Procedure:
(Electrospray MS m/z 614 [MH+ ]) from of N-benzoyl-L-valyl-L-alanyl-L-norleucine bromomethyl ketone and 2,3,4,5,6-pentafluorobenzoic acid.
Reaction SMILES: O[C@H:2]([CH3:40])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[N:23][C:22]([C:25]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[O:26])=[CH:21]N=3)[CH:15]=[C:14]([O:34][C@@H:35]([CH3:39])[CH2:36][O:37][CH3:38])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+:54]>O1CCCC1>[CH3:38][O:37][CH2:36][C@H:35]([CH3:39])[O:34][C:14]1[CH:15]=[C:16]([CH:17]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C@@H:2]([CH3:40])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:13]=1)[O:18][C:19]1[CH:24]=[N:23][C:22]([C:25]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])=[CH:21][N:54]=1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCN(C)CC3)cn2)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Reactant: [NH4+]
Agent: CS(=O)(=O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCN(C)CC3)cn2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
N-[(2R)-2-Hydroxypropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}oxy)phenyl}-1H-pyrrole-2-carboxamide (447 mg, 0.81 mmol) synthesized in Example (131c) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (282 mg, 1.62 mmol) and triethylamine (0.34 mL, 2.43 mmol) were added, followed by stirring at 50° C. for 4 hours under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out twice with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (279 mg, yield 65%) as a pale yellow solid.
Reaction SMILES: C1(S(C2(SC)[CH2:15][C@H:14]3[C@:12]([C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][CH:17]=4)([CH2:13]3)[CH2:11]2)(=O)=O)C=CC=CC=1.[CH3:28][OH:29].Cl>C(OCC)(=O)C.CCCCCC>[C:16]1([C@:12]23[CH2:13][C@H:14]2[CH2:15][C:28](=[O:29])[CH2:11]3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CSC1(S(=O)(=O)c2ccccc2)C[C@@H]2C[C@]2(c2cccc3ccccc23)C1
Reactant: CO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1C[C@@H]2C[C@]2(c2cccc3ccccc23)C1
Yield: 99 %

Procedure:
(1S,5S)-3-Benzenesulfonyl-1-(1-naphthyl)-3-methylsulfanyl-bicyclo[3.1.0]hexane (3 g, 7.6 mmol), methanol (18 mL) and concentrated hydrochloric acid (5.4 mL) were heated to reflux for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (20:80)).The reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the reaction mass was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether (300 mL). The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 3 g of crude oil, which was purified by preparative HPLC to give 1 g (62%) of 99% pure product. 1H NMR δ(300 MHz,CDCl3): 0.75-0.78 (1H,t, J=4 Hz), 1.37 (1H,m), 1.98-2.04 (1H,m), 2.49-2.55 (1H,d ,J=18 Hz), 2.77-2.79 (2H,d,J=6 Hz), 3.03-3.11 (2H,dd,J=18,6 Hz), 7.39-7.44 (1H,m), 7.48-7.57 (3H,m),7.76-7.78 (1H,d,J=6 Hz), 7.87-7.90 (1H,m), 8.12-8.15 (2H,d ,J=9 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[Cl:21].CC([O-])(C)C.[K+]>CS(C)=O.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:22][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCCSc1ccc(Cl)nc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCSc1ccc(Oc2ccc(Cl)c(Cl)c2)nc1C#N

Procedure:
6-Chloro-3-propylthio-2-pyridinecarbonitrile (12.8 g) was mixed with 10.6 g of 3,4-dichlorophenol in the presence of 7.3 g of t-BuOK in DMSO (10 ml) and THF (100 ml). The desired, 6-(3,4-dichlorophenoxy)-3-propylthio-2-pyridinecarbonitrile was recovered, m.p. 67°-69° C.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:3].[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35]2[CH:34]=[C:33]([CH3:36])[N:32]=[C:31]([NH2:37])[C:30]=2[N:29]=[C:28]1[CH2:38][O:39][CH2:40][CH3:41]>>[NH2:37][C:31]1[C:30]2[N:29]=[C:28]([CH2:38][O:39][CH2:40][CH3:41])[N:27]([CH2:26][CH2:25][CH2:24][CH2:23][NH:22][S:18]([C:15]3[CH:16]=[CH:17][C:12](/[N:11]=[N:10]/[C:7]4[CH:8]=[CH:9][C:4]([N:2]([CH3:3])[CH3:1])=[CH:5][CH:6]=4)=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:35]=2[CH:34]=[C:33]([CH3:36])[N:32]=1
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNS(=O)(=O)c1ccc(/N=N/c2ccc(N(C)C)cc2)cc1

Procedure:
Using the method of Examples 32-46, 4-dimethylaminoazobenzene-4′-sulfonyl chloride was reacted with 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 565.2720.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(I)cc1
Reactant: Sc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Sc2ccccc2)cc1

Procedure:
A mixture of 6.04 g of methyl α-(p-chlorophenoxy)(p-iodophenyl)acetate, 3.36 g of cuprous phenylmercaptide, and 800 mg of thiophenol in 150 ml of pyridine is heated under Argon overnight. The mixture is poured into 300 ml of water and extracted with two 100 ml portions of chloroform. The combined organic layers are washed with two 50 ml portions of 5% NaOH, two 50 ml portions of water, 50 ml of saturated brine and dried over MgSO4. Evaporation of the solvent at reduced pressure yields an oil. After column chromatography (benzene) and bulb-to-bulb distillation (173° C. @ 0.01 mm) there is obtained the product as a yellow oil.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][NH:13][C:14]([N:16]1[CH:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:27]=2[S:34][CH3:35])[C:24]2[C:23](=[O:36])[CH2:22][CH2:21][CH2:20][C:19]=2[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=2)[C:17]1=[O:47])=[O:15]>ClCCl>[CH3:12][NH:13][C:14]([N:16]1[CH:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:27]=2[S:34]([CH3:35])=[O:6])[C:24]2[C:23](=[O:36])[CH2:22][CH2:21][CH2:20][C:19]=2[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:45])([F:44])[F:46])[CH:38]=2)[C:17]1=[O:47])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1SC
Solvent: ClCCl
Product: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)=O
Reaction time: 1.5 h

Procedure:
3-Chloroperoxybenzoic acid (77%, 24 mg, 0.107 mmol) is added at room temperature to a solution of 4-(4-cyano-2-methylsulfanyl-phenyl)-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,4,5,6,7,8-hexahydro-2H-quinazoline-3-carboxylic acid methylamide (INTERMEDIATE 8, 63 mg, 0.122 mmol) in dichloromethane (2 mL), and the mixture is stirred for 90 min. The reaction mixture is concentrated under reduced pressure and purified by reversed phase HPLC (X-Bridge C18, gradient of acetonitrile in water, 0.1% NH4OH) yielding the two diastereomers of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[CH2:13][CH2:14][O:9][CH2:10][CH:11]=2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Solvent: O
Solvent: C1COCCO1
Product: Brc1cnc(C2=CCOCC2)nc1
Temperature: 80 °C

Procedure:
5-bromo-2-iodo-pyrimidine (250 mg; 0.88 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (196 mg, 0.92 mmol) were dissolved in 1,4-dioxane-H2O (10:1; 10 mL) and degassed with a stream of N2 for 10 min. Pd(Ph3)2Cl2 (30 mg, 0.04 mmol) was introduced and the reaction sealed and heated in a microwave reactor for 30 min at 80° C. The reaction was concentrated in vacuo, re-dissolved in DCM, filtered and purified over silica (gradient elution, 0-50% EtOAc-n-heptane) yielding i (105 mg, 50%). MS: 241.1 & 243.0; 1:1 [M+H]+.