Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Cl[CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[K+].[Br-]>CO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][CH2:11][N:5]2[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]2=[O:9])=[CH:14][CH:15]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: COc1ccc(SCCl)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(SCn2cc(Cl)cnc2=O)cc1
Reaction time: 2 h

Procedure:
The title compound was prepared from 5-chloropyrimidin-2-one hydrochloride (10 mmol) and 1-chloromethylthio-4-methoxy benzene [see Preparation 1] (10 mmol) in a manner similar to that described in Example 2. The reaction time was 2 h. Yield: 2.46 g (87%) of the N- and O-isomers in the ratio 7:5. The N-isomer was isolated by its lower solubility in methanol; m.p. 140° C. (MeOH). (Found C41.23; H4.00 Calc. for C12H11ClN2O2S: C50.97; H3.93) 1H NMR (DMSO-d6): δ 3.77 (OMe), 5.12 (CH2), 6.8-7.4 (Ph), 7.90 and 8.56 (H-4 and H-6, respectively, J 4 Hz). IR (KBr): 1660 cm-1 (CO. MS (70 eV, m/z % rel. int.)]: 282/284 (5/2,M), 143/145 (100/33).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:9]=[C:10]([CH:12]=[CH:13][C:14]3[N:18]([CH3:19])[N:17]=[C:16]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:15]=3)[N:11]=2)[C:7]=1[CH3:8].C(N(CC)CC)C>[Pd].C(O)C>[CH3:8][C:7]1[N:6]2[N:9]=[C:10]([CH2:12][CH2:13][C:14]3[N:18]([CH3:19])[N:17]=[C:16]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:15]=3)[N:11]=[C:5]2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1c(Cl)ccc2nc(C=Cc3nc(N4CCCC4)nn3C)nn12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cccc2nc(CCc3nc(N4CCCC4)nn3C)nn12
Reaction time: 1 h
Yield: 110.7 %

Procedure:
A mixture of 6-chloro-5-methyl-2-(2-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyridine (5 mg, 14.5 μmol, Eq: 1.00), palladium on carbon (10.0 mg, 94.0 μmol, Eq: 6.46) and triethylamine (0.02 ml) in ethanol (3 ml) was stirred 1 h under hydrogen (1 atm). The mixture was filtered over Celite and then concentrated to an oil. The residue was dissolved in DCM (15 ml) and Na2CO3 (50 mg) was added. The mixture was stirred for 5 min and then filtered over Celite and concentrated to give the desired product (5 mg) as a colorless oil. MS: m/z=312.3 (M+H+)
Reaction SMILES: [K+].[Br:2][C:3]1[C:8]2[N:9]=[C:10]([S-:12])[S:11][C:7]=2[CH:6]=[C:5]([C:13]#[N:14])[CH:4]=1.[K].S[C:17]1SC2C(N=1)=NC=C(C(OCC)=O)C=2>>[Br:2][C:3]1[C:8]2[N:9]=[C:10]([S:12][CH3:17])[S:11][C:7]=2[CH:6]=[C:5]([C:13]#[N:14])[CH:4]=1
Reactant: CCOC(=O)c1cnc2nc(S)sc2c1
Reactant: N#Cc1cc(Br)c2nc([S-])sc2c1
Agent: [K+]
Agent: [K]
Product: CSc1nc2c(Br)cc(C#N)cc2s1

Procedure:
4-Bromo-2-(methylthio)benzo[d]thiazole-6-carbonitrile was synthesized as a yellow solid (1.0 g, 12%) using a procedure analogous to that described in Step 2 of Example 114, substituting 4-bromo-6-cyanobenzo[d]thiazole-2-thiolate potassium salt from the previous step for ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt used in Example 114. LCMS (ESI) m/z 284, 286 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH:12]([C:14]1[O:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:17]2[O:18][C:14]([CH:12]=[O:13])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2ccc(C=O)o2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.2 %

Procedure:
To a round bottom flask containing 1-bromo-4-tert-butyl-benzene (1.5 g, 7.04 mmol) and 5-formyl-2-furan-boronic acid (1.47 g, 10.56 mmol) in dimethoxyethane (80 mL) and ethanol (20 mL) was added an aqueous solution of sodium carbonate (2.24 g, 21.12 mmol) m water (30 mL). The reaction mixture was stirred at room temperature for 5 minutes, followed by the addition of tetrakis(triphenylphosphine)palladium (404 mg, 0.35 mmol). The reaction mixture was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (500 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 20% ethyl acetate in hexanes to afford 5-(4-tert-butyl-phenyl)-furan-2-carbaldehyde (1.16 g, 72%) as a dark brown solid. 1H NMR (400 MHz, CDCl3): δ 1.35 (9H, s), 6.80 (1H, d, J=3.6 Hz), 7.31 (1H, d, J=3.6 Hz), 7.44-7.7.48 (2H, m), 7.74-7.77 (2H, m), 9.64 (1H, s); APCI-MS: 228.34.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)=[O:23])[CH3:20].CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH2:19]([O:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=[CH:13][C:12]=2[N+:15]([O-:17])=[O:16])=[N:26][C:25]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)=[O:23])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reactant: CCOC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(Nc2cc(OCc3ccccc3)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
To a mixture of 2.57 g (10 mmole) of 4-benzyloxy-2-fluoro-1-nitro-benzene, 2.83 g (10 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester and 20 mL of dimethylformamide was added 16.25 g (50 mmole) of cesium carbonate. The mixture was heated at 100 degrees for 1 hour. The reaction was allowed to cool to room temperature and then 500 mL of water was added. The mixture was stirred for 15 minutes and the resulting yellow solid collected by filtration to give 5.09 g of 2-(5-benzyloxy-2-nitro-phenylamino)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (VI.25).
Reaction SMILES: [F-].[Cs+].Br[C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].[CH3:23][N:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:27]2=[CH:39][N:40]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:41]=[C:26]2[C:25]1=[O:50]>C(O)CCC.O.C(OCC)(=O)C.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.Cl[Pd]Cl>[NH2:8][C:7]1[CH:9]=[CH:10][C:4]([C:28]2[C:27]3[C:26](=[N:41][N:40]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:47])([CH3:49])[CH3:48])[CH:39]=3)[C:25](=[O:50])[N:24]([CH3:23])[CH:29]=2)=[C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(Br)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2cn(COCC[Si](C)(C)C)nc2c1=O
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cs+]
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(N)c([N+](=O)[O-])c2Oc2ccc(F)cc2F)c2cn(COCC[Si](C)(C)C)nc2c1=O
Temperature: 100 °C
Yield: 50 %

Procedure:
A solution of 4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1) (22.3 mg, 0.0314 mmol), cesium fluoride (1.11 g, 7.34 mmol), 4-bromo-3-(2,4-difluorophenoxy)-2-nitroaniline (724 mg, 2.10 mmol), and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (850 mg, 2.097 mmol) in 1-butanol (9.5 mL) and water (2.2 mL) was degassed with nitrogen for 5 min and heated at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with brine, dried with magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (50% EtOAc/hexanes to 100% EtOAc) gave the desired product (0.57 g, 50%). LCMS calculated for C25H28F2N5O5Si (M+H)+: m/z=544.2. found: 544.1.
Reaction SMILES: [CH2:1]([C@@H:8]([C:20](=[O:74])[NH:21][CH2:22][CH2:23][CH2:24][NH:25][C@@H:26]([C@H:34]([CH:36]1[C@@H:40]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:39]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C@H:38]([N:57]2[CH:62]=[CH:61][C:60](=[O:63])[N:59]([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=3)[C:58]2=[O:73])[O:37]1)[OH:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:9]C(=O)OCC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[NH2:9][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:20]([NH:21][CH2:22][CH2:23][CH2:24][NH:25][C@@H:26]([C@H:34]([CH:36]1[C@@H:40]([O:41][Si:42]([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:43])[CH3:44])[C@@H:39]([O:49][Si:50]([C:53]([CH3:54])([CH3:55])[CH3:56])([CH3:52])[CH3:51])[C@H:38]([N:57]2[CH:62]=[CH:61][C:60](=[O:63])[N:59]([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=3)[C:58]2=[O:73])[O:37]1)[OH:35])[C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])=[O:74]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](Cc4ccccc4)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](N)Cc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 70.4 %

Procedure:
By using an analogous procedure to that described for Example 2, tert-butyl (5S,12S)-5-benzyl-12-[(R)-[(3R,4R,5R)-3,4-bis{[tertbutyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (Example 12) (49 mg, 0.046 mmol) was hydrogenated in methanol (1.5 ml) using 10% palladium on carbon (12 mg) to provide tert-butyl (2S,3R)-2-[(3-{[(2S)-2-amino-3-phenylpropanoyl]amino}propyl)amino]-3-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate (30 mg, 70%) as a white amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]=[C:13]([NH:15]CC2C=CC(OC)=CC=2)[CH:12]=[CH:11][CH:10]=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCCc1cccc(NCc2ccc(OC)cc2)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCc1cccc(N)n1

Procedure:
The ester 16-3 (5.7 g) in TFA (75 mL) was heated at 60° C. for 2 hours then cooled and the excess TFA removed in vacuo. The residue was diluted with water, made basic with NaHCO3 and extracted with ether (3×). After washing the ether layer with saturated NaHCO3 then brine, it was dried (Na2SO4) and concentrated to give a viscous oil. Purification by silica gel chromatography (hexane:EtOAc 3:7) afforded the title compound 16-4 as an oil.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:11][CH3:12]>>[CH2:11]([S:8][C:1](=[NH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: NC(=S)c1ccccc1
Reactant: CCI
Product: CCSC(=N)c1ccccc1

Procedure:
As depicted in Scheme 4, cyclic aridines of the invention can be prepared by reacting 2-substituted benzonitrile with hydrogen sulfide to form a thiobenzamide. The resulting thiobenzamide is then treated with iodoethane to give a thiobenzimidic acid ethyl ester. In the presence of hydrochloric acid, the thiobenzimidic acid ethyl ester is suspended in tetrahydrofuran and treated with hydrogen sulfide. The resulting dithiobenzoic acid ethyl ester is then heated with various diamines, in the presence or absence of an added catalyst such as silver trifluoroacetate, to give cyclic amidines.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]1[O:13][CH2:12][CH2:11][O:5]1
Reactant: OCCO
Reactant: O=Cc1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C2OCCO2)c(F)c1

Procedure:
A stirred solution of 2,4-difluorobenzaldehyde (15.4 ml) in toluene (200 ml) was treated with ethylene glycol (23.2 ml) and p-toluene sulfonic acid (0.53 g). The reaction mixture was heated to reflux during 5 hrs (Dean-Stark trap), then it was cooled to r.t and poured onto ice. The organic layer was separated off, washed with 10% KHCO3-solution and brine, dried over MgSO4, filtered and concentrated to give 2-(2,4-difluoro-phenyl)-[1,3]dioxolane (26.8 g) as a light yellow oil. MS 186.1 ([M]+)
Reaction SMILES: C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:12]1[CH:13]=[C:14]([C:28]([F:31])([F:30])[F:29])[CH:15]=[C:16]([NH:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25](O)=[O:26])[CH:17]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:30][C:28]([F:29])([F:31])[C:14]1[CH:15]=[C:16]([NH:18][C:19]2[C:20]([CH2:25][OH:26])=[CH:21][CH:22]=[CH:23][N:24]=2)[CH:17]=[CH:12][CH:13]=1
Reactant: O=C(O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cccnc1Nc1cccc(C(F)(F)F)c1
Yield: 85 %

Procedure:
500 ml of anhydrous ethyl ether are run gently onto 26 g of lithium aluminum hydride, and 100 g of niflumic acid, dissolved in 250 ml of anhydrous tetrahydrofuran, are then added dropwise. The mixture is then brought to reflux for 3 hours. After cooling, it is hydrolyzed with 150 ml of ethyl acetate and 100 ml of saturated sodium sulfate solution. After filtration, the filtrate is concentrated to obtain the expected compound in the form of a yellow solid.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C:16]1[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][C:11]=1[CH2:10][CH2:9]3.[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>C(O)C>[CH3:21][O:20][C:13]1[CH:14]=[CH:15][C:16]2[C@@H:17]3[C@H:8]([C@H:5]4[C@@:3]([CH2:19][CH2:18]3)([CH3:4])[C:2](=[CH2:1])[CH2:7][CH2:6]4)[CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCO
Solvent: O
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12C
Yield: 68.5 %

Procedure:
To a stirred suspension of 17-methylenestra-1,3,5(10)-trien-3-ol (5.37 g, 20.0 mmol) and potassium carbonate (50.82 g, 0.3678 mol) at reflux in 90% ethanol (500 mL) was added dimethyl sulfate (5.0 mL, 53 mmol). After ½ h reflux additional dimethyl sulfate (36 mL, 0.38 mol, in three 12 mL aliquots) was added over the period of 1 h. See FIG. 17. The reaction was refluxed a further hour, following which 360 mL of water were added and the mixture was placed in the refrigerator overnight. The resulting suspension was filtered and washed with 80 mL of 60% methanol+three 80 mL portions of 5% (w/w) sodium hydroxide+three 80 mL portions of water. The residue was recrystallized from aqueous methanol to give white crystals (3.88 g, 13.7 mmol, 69%), m.p. 59-62° C. TLC (20% ethyl acetate/hexanes on silica gel) showed product (Rf 0.63) with trace contaminants at Rf 0.37 and at the origin.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[N:27]=[C:28]=[O:29])([CH3:17])[CH3:16]>CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][NH:10][C:28]([NH:27][C:19]2[C:18]([CH:15]([CH3:16])[CH3:17])=[CH:23][CH:22]=[CH:21][C:20]=2[CH:24]([CH3:26])[CH3:25])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCC(CN)c1cccc(C)c1
Solvent: CCCCCC
Product: CCCCC(CNC(=O)Nc1c(C(C)C)cccc1C(C)C)c1cccc(C)c1
Reaction time: 8 h
Yield: 50 %

Procedure:
To 20 ml of n-hexane was added 1.81 g (9.5 mmol) of 2-(3-methylphenyl)hexylamine. An 18 ml of 0.52M hexane solution of 2,6-diisopropylphenyl isocyanate was added dropwise to the mixture under ice cooling. The resulting mixture was stirred overnight and the precipitated crystals were collected by filtration to give 1.87 g (50% yield) of 1-(2-(3-methylphenyl)hexyl)-3-(2,6-diisopropylphenyl)urea.
Reaction SMILES: C(OC(=O)[N:7]([CH2:20][CH2:21][NH:22][S:23]([C:26]1[C:27]2[CH:28]=[CH:29][N:30]=[CH:31][C:32]=2[CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)[CH:35]=1)(=[O:25])=[O:24])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)(C)(C)C.[ClH:44]>C(Cl)Cl.CO>[ClH:44].[ClH:44].[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][NH:7][CH2:20][CH2:21][NH:22][S:23]([C:26]2[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][C:32]=3[CH:33]=[C:34]([C:36]3[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=3)[CH:35]=2)(=[O:25])=[O:24])=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc([N+](=O)[O-])cc1)CCNS(=O)(=O)c1cc(-c2ccc(O)cc2)cc2cnccc12
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccc(CCCNCCNS(=O)(=O)c2cc(-c3ccc(O)cc3)cc3cnccc23)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To {2-[7-(4-hydroxy-phenyl)-isoquinoline-5-sulfonylamino]-ethyl}-[3-(4-nitro-phenyl)-propyl]-carbamic acid tert-butyl ester, (0.090 g, 0.148 mmol) in 6 ml (1:1) CH2Cl2/MeOH bubble HCl (g) for several minutes, then stir for 1 h and filter to give 0.0859 g of 7-(4-hydroxy-phenyl)-isoquinoline-5-sulfonic acid {2-[3-(4-nitro-phenyl)-propylamino]-ethyl}-amide dihydrochloric acid in 100% yield. ES Positive Ion MS [M+H]+ ion observed: m/z 507. 1H-NMR (DMSO-d6) δ9.62 (s, 1H), 8.93 (br s, 2H), 8.75 (s, 1H), 8.69-8.71 (m, 2H), 8.61 (s, 1H), 8.52 (d, J=6.2 Hz, 1H), 8.15 (d, J=8.8 Hz, 2H), 7.75 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 3.10-3.15 (br m, 2H), 2.90-3.00 (br s, 2H), 2.87 (br s, 2H), 2.75 (t, J=7.5 Hz; 2H), 1.87-1.90 (m, 2H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:22]=[CH:21][C:14]([CH2:15][N:16]([OH:20])[C:17]([NH2:19])=[O:18])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[NH4+]>Cl>[OH:20][N:16]([CH2:15][C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[CH:22][CH:21]=1)[C:17]([NH2:19])=[O:18]
Reactant: NC(=O)N(O)Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)N(O)Cc1ccc(N2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.7 %

Procedure:
A mixture of N-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzyl]-N-hydroxyurea (2.2 g, 7.16 mmol) (which was obtained in Example 53) and hydrochloric acid (concentrated, 10 mL) was stirred at room temperature for three days. The mixture was then neutralized with ammonium hydroxide, and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (ethyl acetate) gave a white solid (1.86 g, 98% yield); mp 138–140° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.41 (m, 4H), 3.60 (m, 4H), 4.43 (s, 2H), 6.37 (brs, 2H), 7.03 (m, 2H), 7.21 (m, 2H), 9.31 (s, 1H); MS (ES) m/z: 264 (MH+);
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[NH:30]1[CH2:35][CH2:34][S:33][CH2:32][CH2:31]1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:30]2[CH2:35][CH2:34][S:33][CH2:32][CH2:31]2)=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: C1CSCCN1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Product: CS(=O)(=O)c1ccc(N2CCSCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example 202 from (2-Chloro-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (example BO) and thiomorpholine to yield the title compound as a pale yellow solid. MS (m/e): 514.5 (M+H, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].CS([C:14]1[N:19]=[C:18]([N:20]2[CH:24]=[CH:23][N:22]=[C:21]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]=[CH:16][N:15]=1)(=O)=O>C1COCC1>[C:25]1([C:21]2[N:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[N:19]=3)[CH:24]=[CH:23][N:22]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccccn1
Reactant: CS(=O)(=O)c1nccc(-n2ccnc2-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(-c2nccn2-c2ccnc(Nc3ccccn3)n2)cc1

Procedure:
To a solution of 2-aminopyridine (31 mg, 0.33 mmol) in dry THF (0.5 mL) was added NaH (32 mg, 1.33 mmol) at room temperature. Once the resulting bubbling had ceased, 2-(methylsulfonyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine (0.100 g, 0.33 mmol) was added all at once. After 1.5 hours the mixture was concentrated in vacuo, diluted with water and the pH of the resulting solution was adjusted to 7 with 1M HCl (aq). The resulting precipitate was filtered and purified by reverse phase HPLC (5-100% CH3CN/H2O+0.1% TFA). 1H-NMR (300 MHz, CDCl3) δ 8.44 (d overlapping with s, J=5.4 Hz, 2H), 8.33 (d, J=4.1 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.55 (m, 4H), 7.40 (m, 3H), 7.33 (m, 1H), 6.95 (dd, J=4.9, 7.1 Hz, 1H), 6.45 (d, J=5.3 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][NH:3]1.Cl>C1COCC1>[OH:17][C:14]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:13][CH2:12][CH:11]([N:10]2[C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=3[C:8]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)=[N:9]2)[CH2:16][CH2:15]1
Reactant: NC(=O)c1cc(-c2nn(C3CCC(=O)CC3)c3cc[nH]c(=O)c23)cs1
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2nn(C3CCC(O)(c4ccccc4)CC3)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of 4-(4-oxo-1-(4-oxocyclohexyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (30.0 mg) obtained in Example 170 in THF (10 mL) was added dropwise 1.6 M phenyllithium butyl ether solution (0.210 mL) at −78° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added dropwise 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (cis/trans mixture, 11.2 mg).