Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([C:10](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[N:4]2[C:3]=1[CH3:20].C1COCC1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([CH:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[OH:11])[N:4]2[C:3]=1[CH3:20]
Reactant: Cc1sc2ncc(C(=O)/C=C/c3ccccc3)n2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1sc2ncc(C(O)C=Cc3ccccc3)n2c1C

Procedure:
A solution of 2,3-Dimethyl-α-(2-phenyl-E-ethenyl)imidazo[2,1-b]thiazole-5-methanone (FIG. D-2) (0.34 g) in 1:1 ethanol:THF (40 mL) was treated with a solution of NaBH4 (0.35 g) in ethanol (5 mL). The solution was reacted for 2.5 hours, evaporated in vacuo, and the residue was diluted with water. The precipitated 2,3-Dimethyl-α-(2-phenylethenyl)imidazo[2,1-b]thiazole-5-methanol (FIG. D-5) was extracted into ethyl acetate, the extract was dried and evaporated to a viscous residue. The residue was triturated with ethyl acetate to yield 2,3-Dimethyl-α-(2-phenylethenyl)imidazo[2,1-b]thiazole-5-methanol (FIG. D-5), 0.28 g, m.p. 149-151° after crystallization from acetonitrile.
Reaction SMILES: C([O-])=O.[K+].[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[CH3:6]>[Ru].CO>[C:8]1([C@H:5]([OH:7])[CH3:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccccc1
Agent: [Ru]
Agent: O=C[O-]
Agent: [K+]
Solvent: CO
Product: C[C@@H](O)c1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A ruthenium complex RuCl[(R,R)-Tsdpen] (p-cymene) (6.4 mg, 0.01 mmol), potassium formate (1.0 g, 12 mmol) and acetophenone (1.20 g, 10 mmol, substrate/catalyst ratio=1000) were set in a 20 mL glass Schlenk-type reaction tube under an argon atmosphere. Methanol (6 mL) was added thereto and stirred at 50° C. for 24 hours to give (R)-1-phenylethanol at 100% yield and 96.2% ee optical purity.
Reaction SMILES: C([NH:4][C:5]1[C:6]2[C:13](Br)=[CH:12][N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29]C(=O)C)[C@@H:21]([O:22]C(=O)C)[C@@:16]3([CH3:33])[O:17]C(=O)C)[C:7]=2[N:8]=[CH:9][N:10]=1)(=O)C.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:49])(=O)=O)=CC=1.[Cl-].[NH4+]>C1COCC1.ClCCl>[NH2:4][C:5]1[C:6]2[C:13]([F:49])=[CH:12][N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:21]([OH:22])[C@@:16]3([CH3:33])[OH:17])[C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(=O)Nc1ncnc2c1c(Br)cn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@]1(C)OC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(F)c2c(N)ncnc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a pre-cooled (−78° C.) solution of the compound from Step B (529 mg, 1.00 mmol) in THF is added butyl lithium (2M in hexanes) (0.5 mL, 1.00 mmol). The resulting solution is stirred at −78° C. for 30 min and then quenched with N-fluorobenzensulfonimide (315 mg, 1.00 mmol) in THF. The resulting solution is very slowly allowed to come to ambient temperature and then poured into a stirred mixture of saturated aqueous ammonium chloride and dichloromethane. The organic phase is evaporated in vacuo and treated with ammonium hydroxide at 55° C. in a closed container overnight. The resulting crude mixture is purified on silica gel using dichloromethane/methanol as the eluent. Fractions containing the desired product are pooled and evaporated in vacuo to give the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]O)[CH2:14][C@@H:13]1[C:21]([O:23][CH3:24])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Cl:29])(=O)=O.C(N(CC)CC)C.CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O.[Cl-]>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][Cl:29])[CH2:14][C@@H:13]1[C:21]([O:23][CH3:24])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(CCCl)CC[C@H]1NC(=O)OCc1ccccc1

Procedure:
Methyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-hydroxyethyl)piperidine-3-carboxylate (Intermediate 37) (650 mg, 1.93 mmol) was reacted with methanesulfonyl chloride (0.18 mL, 2.32 mmol) in the presence of triethylamine (0.38 mL, 2.7 mmol) as described for Intermediate 6. The crude chloride was used without delay for the next step.
Reaction SMILES: [C:1]([NH:4][CH:5](/[CH:13]=[C:14](\[CH3:26])/[CH2:15][CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH2:6][P:7](=[O:12])([O:10]C)[O:8]C)(=[O:3])[CH3:2].N1C(C)=CC(C)=CC=1C.C[Si](Br)(C)C>ClCCl.C1(C)C=CC=CC=1.[OH-].[NH4+]>[C:1]([NH:4][CH:5](/[CH:13]=[C:14](\[CH3:26])/[CH2:15][CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH2:6][P:7](=[O:8])([OH:10])[OH:12])(=[O:3])[CH3:2]
Reactant: COP(=O)(CC(/C=C(\C)CC/C=C(\C)CCC=C(C)C)NC(C)=O)OC
Agent: C[Si](C)(C)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)NC(/C=C(\C)CC/C=C(\C)CCC=C(C)C)CP(=O)(O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of dimethyl [2-acetamido-(E,E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]phosphonate (39 mg, 0.101 mmol) and 2,4,6-collidine (0.054 ml, 0.404 mmol) in dichloromethane (2.5 ml) under argon at 0° C., was added trimethylsilyl bromide (0.054 ml, 0.404 mmol) and the resulting mixture stirred at 0° C. for 30 min and then at r.t. for 5 hr. The resulting white suspension was diluted with toluene (10 ml) and the solvent evaporated in vacuo. The resulting white solide was dissolved in ethylacetate and water and the pH was adjusted to 3 by the addition of 1M HCl solution. The organic layer was separated, dried (Na2SO4) and evaporated to afford a clear oil, which was dissolved in hexanes and treated with 10 drops of ammonium hydroxide, the precipitate was removed by filtration and dried in vacuo to afford the title compound as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][N:5]2[C:9]([CH:10]=1)=[C:8]([C:11]([OH:13])=O)[C:7]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH3:22])=[C:6]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:11]([C:8]2[C:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=3[CH3:22])=[C:6]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:5]3[C:9]=2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4]3)=[O:13])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(F)cccc1Cc1c(C(=O)O)c2cc(Br)ccn2c1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1c(F)cccc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cc(Br)ccn2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of the crude compound obtained in step 2 (219 mg, 0.50 mmol), 1-tert-butoxycarbonyl-piperazine (98 mg, 0.55 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol) and 1-hydroxybenzotriazole (88 mg, 0.58 mmol) in DMF (5 ml) was added N-methyl-morpholine (330 μl, 3.00 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (HEP/EA). 300 mg of the title compound were obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([NH:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.O>COCCOC>[Si:1]([O:8][CH2:9][C@H:10]([NH:17][C:18](=[S:36])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](NC(=O)c1cccc(I)c1)c1ccccc1
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H](NC(=S)c1cccc(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of N-(1-tert-butyldimethylsilyloxy-2(R)-phenylethan-2-yl)-3-iodobenzamide (13.1 g, 27.2 mmol) in 1,2-dimethoxyethane (80 ml) was added Lawesson's reagent (8.2 g, 20 mmol). The reaction mixture was stirred at ambient temperature for 1 h and then at 60° C. for 2 hours, cooled and poured into water (100 ml). The mixture was extracted with CH2 Cl2 (2×50 ml), washed with brine (100 ml), dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (=1:7) to afford N-(1-tert-butyldimethylsilyloxy-2(R)-phenyl-ethan-2-yl)-3-iodobenzthiamide (4.99 g, 50%) as a yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([P:10](=[O:17])([O:14]CC)[O:11]CC)=[CH:6][CH:5]=1)([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([P:10](=[O:11])([OH:14])[OH:17])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=[N+]([O-])c1ccc(P(=O)(O)O)cc1
Yield: 100 %

Procedure:
A solution of diethyl (4-nitrophenyl)phosphonate (60 g, 230 mmol) in 250 mL of concentrated HCl (aq) was stirred at reflux overnight. The excess HCl was removed under reduced pressure and the product used in further chemistries without purification (46.8 g, yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:17]=[CH:16][N:15]=[C:14]3[C:10]=2[N:11](COCC[Si](C)(C)C)[CH:12]=[N:13]3)[C:5](=[O:26])[N:4]2[C:27]3([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[NH:28][C:29](=[O:30])[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:17]=[CH:16][N:15]=[C:14]3[C:10]=2[NH:11][CH:12]=[N:13]3)[C:5](=[O:26])[N:4]2[C:27]3([NH:28][C:29](=[O:30])[C:3]=12)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3
Reactant: C[Si](C)(C)CCOCn1cnc2ncnc(Nc3cc(Cl)c4n(c3=O)C3(CCCCC3)NC4=O)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC2(CCCCC2)n2c1c(Cl)cc(Nc1ncnc3nc[nH]c13)c2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Chloro-6-[[7-(2-trimethylsilylethoxy)purin-6-yl]amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione (5, 0.6 g, 1.2 mmol) was dissolved in dichloromethane (10 mL) in a flask and trifluoroacetic acid (1.36 g, 11.95 mmol) was added dropwise and stirred the mixture at room temperature overnight. After completion, evaporated the solvent under reduced pressure and the crude was basified by saturated aqueous solution of sodium bicarbonate to pH 8 and extracted with dichloromethane (2×50 mL). The organic layer was dried over any. Sodium sulfate and concentrated to afford crude. The crude was purified by flash column chromatography eluting with 2.5% methanol in dichloromethane. The desired fractions were concentrated to dryness under vacuum to afford 8-chloro-6-(7H-purin-6-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione (Cpd. No. 117) as a yellow solid. Yield: 0.06 g, 13%; MS (ESI) m/z 386.39 [M+1]+; 1H NMR: (400 MHz, DMSO-d6) δ 10.43 (m, 1H), 10.37 (s, 1H), 8.88 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 2.94 (t, J=2.32 Hz, 2H), 1.77 (m, 2H), 1.63 (m, 3H), 1.57 (d, J=12.8 Hz, 2H), 1.23 (m, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=O)C.P(Cl)(Cl)(Cl)=O.N1C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36](C(=O)C)[CH2:35][CH2:34]2)=[C:29]([F:42])[CH:28]=1.C(=O)([O-])O.[Na+].[OH-].[Na+]>O1CCCC1.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:5]([OH:4])=[C:6]([CH:10]=1)[C:7]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]2)=[C:29]([F:42])[CH:28]=1)=[O:9]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2F)CC1
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(N2CCNCC2)c(F)c1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 4.9 %

Procedure:
2-Acetoxy-5-chlorobenzoic acid (0.257 g, 1.20 mmol), phosphorus oxychloride (0.184 g, 1.20 mmol) and pyridine (0.095 g, 1.20 mmol) were added to a solution of 1-[4-(4-amino-2-fluorophenyl)piperazin-1-yl]ethanone (compound of Reference Example 85; 0.237 g, 1.00 mmol) in tetrahydrofuran (3 ml) under ice cooling, and the mixture was stirred under ice cooling for 3 hours. The reaction mixture was neutralized by addition of saturated aqueous sodium hydrogencarbonate, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. 6N Hydrochloric acid (6 ml) was added to the residue obtained by evaporation of the solvent under reduced pressure, and the mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature and neutralized by addition of 2N aqueous sodium hydroxide. The precipitated solid was collected by filtration, washed with water, and purified by column chromatography on silica gel (methanol:chloroform=1:10) to give the title compound (0.017 g, 5%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:12][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a mixed solution of methyl 2,5-dihydroxybenzoate (10.0 g), potassium carbonate (12.3 g) and acetone (100 ml) was added benzyl bromide (7.43 ml), and the mixture was stirred overnight at room temperature. After the insoluble material was removed by filtration, the mother solution was concentrated. The obtained residue was purified by column chromatography (LL, Biotage cartridge, ethyl acetate:n-hexane=1:9→1:5) to give methyl 5-benzyloxy-2-hydroxybenzoate (9.63 g, 63%) as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:35][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)[C:7]=2[C:6]=1[CH3:36])=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:31]([O:30][C:28]([N:24]1[CH2:25][CH2:26][CH2:27][C@@H:22]([O:21][C:15]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=2[NH:13][C:12]2[C:7]3[C:6]([CH3:36])=[C:5]([C:3]([OH:4])=[O:2])[S:35][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:23]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c12

Procedure:
A mixture of 4-[2-((R)-1-tert-Butoxycarbonyl-piperidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (1.65 g) in MeOH/THF (1:1; 20 ml) was treated with NaOH (2M; 8 ml) and heated at reflux for 10 mins. Organic solvent was removed in vacuo. HCl (2M; 8 ml) was added to pH 1 and water was added. The suspension was filtered and washed with water. The solid was suspended in EtOH and evaporated. The residue was triturated with Acetonitrile to give the desired product.
Reaction SMILES: S.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)=[O:20])=[O:11])=[N:7][CH:8]=1.CI.[N:37]1C=CC=CC=1>CCN(CC)CC.CC(C)=O.C(O)(=O)C.CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([NH2:37])=[NH:34])=[CH:23][CH:22]=2)=[O:20])=[O:11])=[N:7][CH:8]=1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: c1ccncc1
Agent: S
Solvent: CO
Solvent: CI
Solvent: CC(=O)O
Product: N=C(N)c1ccccc1-c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
A stream of H2S (g) was bubbled through a 0° C. solution of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(2-cyanophenyl)phenyl]carboxamide (100 mg, 0.22 mmol, 1.0 equiv.) in 9 mL pyridine and 1 mL NEt3 until saturation. The mixture was stirred at rt for 1 day and evaporated. The resulting residue was treated with MeI (94 mg, 0.663 mmol, 3.0 equiv.) in 10 mL acetone at reflux temperature for 1 hr and concentrated to dryness. The resulting residue was treated with a mixture of NH4OAc (340 mg, 4.42 mmol, 20 equiv.) in 0.5 mL acetic acid and 2 mL methanol at 50° C. for 2 days. The solvent was removed at reduced pressure and the crude benzamidine was purified by HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN to give 2-[4-(N-{2-[N-(5-chloro-2-pyridyl)carbamoyl]phenyl}carbamoyl)phenyl]benzenecarboxamidine (15 mg, 15%).
Reaction SMILES: [K].[CH3:2][C:3](C)([O-:5])[CH3:4].[CH3:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:25][CH3:26])=[CH:13][CH:14]=2)[C:9]1=[O:27]>CS(C)=O>[CH3:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:2][CH:3]3[O:5][CH2:4]3)=[CH:20][CH:19]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:25][CH3:26])=[CH:13][CH:14]=2)[C:9]1=[O:27]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2cc(-c3ccc(O)cc3)n(C)c(=O)c2c1
Agent: [K]
Solvent: CS(C)=O
Product: COc1ccc2cc(-c3ccc(OCC4CO4)cc3)n(C)c(=O)c2c1

Procedure:
1.35 gm (10 mmols+20%) of potassium-tert.butoxide were added to a solution of 2.8 gm (10 mmols) of 2-methyl-3-(4-hydroxy-phenyl)-7-methoxy-isoquinolin-1(2H)-one in 20 ml of dimethylsulfoxide, while stirring; the potassium salt precipitated out after a short time. 2.8 ml of epibromohydrin were now added, and the mixture was stirred at room temperature until the reaction had gone to completion. The reaction mixture was then poured into ice water, and the cristalline precipitate was collected by suction filtration, washed and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:12]1[S:25][C:15]2[C:16]3[CH:24]=[N:23][CH:22]=[CH:21][C:17]=3[O:18][CH2:19][CH2:20][C:14]=2[CH:13]=1)=[N:10][NH2:11].[CH2:26](OC(OCC)OCC)C>>[S:25]1[C:15]2[C:16]3[CH:24]=[N:23][CH:22]=[CH:21][C:17]=3[O:18][CH2:19][CH2:20][C:14]=2[CH:13]=[C:12]1[C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:26]=[N:11][N:10]=1
Reactant: CCOC(OCC)OCC
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cnccc1OCC2
Product: Clc1ccccc1-n1cnnc1-c1cc2c(s1)-c1cnccc1OCC2
Temperature: 85 °C
Yield: 38 %

Procedure:
A mixture of N-(2-chlorophenyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine-2-carbohydrazonamide (44 mg, 0.12 mmol) and 3 ml of triethylorthoformate was heated at 85° C. for 4 hours. The mixture was concentrated in vacuum and triturated with diethylether. The precipitate was collected, washed with diethylether and purified by flash chromatography eluting with 60% of ethyl acetate in hexane to give 320 (17 mg, 38%). MS: (ESI+) 381.1
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:19]2[CH:18]=[CH:17][C:16]([S:13]([NH:12][C:6]3([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]3)(=[O:14])=[O:15])=[CH:21][CH:20]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Yield: 9.8 %

Procedure:
A solution of 4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid ethyl ester (34.19 grams, 0.807 mole) in ethanol (330 mL) was treated with aqueous 3 M sodium hydroxide solution (330 mL, 0.990 mole) and heated to reflux overnight. The solvent was evaporated under vacuum and the residue partitioned between water and diethyl ether. The aqueous layer was washed with diethyl ether, acidified to pH 1 with 3N aqueous hydrochloric acid solution and extracted with ethyl acetate. After washing with water, the organic extract was dried over sodium soulfate, and concentrated to give 4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid (31.26 grams, 98%) as a white crystalline solid. 1HNMR (CDCl3) δ 7.73 (d, 2H), 7.03 (t, 2H) 6.96 (m, 2H), 6.91 (d, 2H), 3.56 (m, 2H), 3.43 (br m, 3H), 2.01 (m, 2H), 1.80 (br d, 2H). MS Atmospheric Pressure Chemical Ionization Mass Spectra: 394 (M+ -1) (-ion).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][N:5]=[N+:6]=[N-:7].[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=O)[S:13][C:14]=1[CH3:15].C[O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:8])[C:4]([N:5]=[N+:6]=[N-:7])=[CH:16][C:12]1[S:13][C:14]([CH3:15])=[C:10]([Br:9])[CH:11]=1
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: Cc1sc(C=O)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=Cc1cc(Br)c(C)s1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of azido-acetic acid methyl ester (25 g, 220 mmol) and 4-bromo-5-methyl-thiophene-2-carbaldehyde (15 g, 73 mmol) in 50 ml of MeOH cooled at −25° C. was added a solution NaOMe in MeOH (51 ml, 4.36 M). The resulting mixture (slush) was stirred with a mechanical stirrer for 2 h at 0° C. and the 200 g of ice was added. The yellow solid was collected by filtration and air-dried to give 18 g of the title product which was used for the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[NH:17][NH2:18]>>[C:21]([O:20][C:16]([NH:17][N:18]=[C:12]1[CH2:13][CH2:14][CH:9]([C:7]2[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=2)[CH2:10][CH2:11]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)c1noc(C2CCC(=O)CC2)n1
Reactant: CC(C)(C)OC(=O)NN
Product: CC(C)c1noc(C2CCC(=NNC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexanone (Intermediate 11; 1.6 g, 7.7 mmol) and tert-butyl carbazate (1.12 g, 8.5 mmol) in hexanes (3 mL) was heated at reflux for 3 h, then allowed to cool to room temperature and stand overnight. The white solid was filtered off, washed with hexanes and held under high vacuum to give N′-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)cyclohexylidene]-hydrazinecarboxylic acid tert-butyl ester (1.9 g, 77%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, 6H, J=6.9 Hz), 1.41 (s, 9H), 1.60-1.76 (m, 2H), 1.98-2.20 (m, 2H), 2.25-2.36 (m, 2H), 2.75-2.84 (m, 1H), 2.96-3.06 (m, 1H), 3.24-3.35 (m, 2H), 9.62 (br s, 1H).