Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: Clc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(Cl)cc3)CC2)C1
Temperature: 120 °C
Yield: 50 %

Procedure:
Sodium t-butylate (4.99 mmol, 3.0 eq.) was added to a stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.66 mmol, 1.0 eq.) and 1-chloro-4-iodobenzene (1.66 mmol, 1.0 eq.) in toluene (12 ml) and the reaction mixture was degassed with N2. BINAP (0.099 mmol, 0.06 eq.) and Pd(OAc)2 (0.03 mmol, 0.02 eq.) were added and the reaction mixture obtained was heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 10% ethyl acetate in hexane), so that the desired product was achieved. Yield: 50%
Reaction SMILES: [OH:1][P:2]([CH:17]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7])=[O:3].[OH-].[Na+].Cl>CO>[OH:3][P:2]([CH:17]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:4][CH:5]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]([OH:8])=[O:7])=[O:1]
Reactant: COC(=O)C(Cc1ccccc1)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 10 h
Yield: 100 %

Procedure:
To a solution of 1 g (2.02 mmol) of methyl 3-[hydroxy[2-phenyl-1-[[(phenylmethoxy)carbonyl)amino]ethyl]phosphinyl]-2-(phenylmethyl)propanoate in 20 ml of methanol are added 20 ml of 1N sodium hydroxide. After stirring for 10 hours, the medium is acidified with 2N hydrochloric acid, the methanol is then evaporated off and the residue is extracted three times with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulphate and evaporated. 0.97 g of product is recovered (yield=100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:17]=[CH:16]3)=[N:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)=[N:3]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(-c3ccccc3C3=NC(C)(C)CO3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2-c2ccc3[nH]ccc3c2)=N1
Reaction time: 3 h
Yield: 74.5 %

Procedure:
5-[2-(4,4-Dimethyloxazolin-2-yl) phenyl ]-1-triisopropylsilylindole (1.48 mmoles, 661 mg) in 5 ml THF was treated at 0°C. with tetrabutylammonium fluoride (2.22 mmoles, 2.22 ml of 1.0N solution in THF). The solution was stirred for 3 hours, poured into 30 ml water, and extracted with ether. The organic layer was dried and concentrated. The oil was triturated with ether/hexane, and the solid was isolated by filtration. The reaction yielded 320 mg of 5-[2-(4,4-dimethyloxazolin-2yl)phenyl]indole. (MS)
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH:5][CH3:6])=[O:4].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]2[C:28]3[C:29]([CH3:33])=[C:30]([CH3:32])[S:31][C:27]=3[CH2:26][CH2:25][NH:24]2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]2[C:28]3[C:29]([CH3:33])=[C:30]([CH3:32])[S:31][C:27]=3[CH2:26][CH2:25][N:24]2[CH:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([NH:5][CH3:6])=[O:4])=[CH:17][CH:16]=1
Reactant: CNC(=O)C(Br)c1ccccc1
Reactant: COc1ccc(CCC2NCCc3sc(C)c(C)c32)cc1
Product: CNC(=O)C(c1ccccc1)N1CCc2sc(C)c(C)c2C1CCc1ccc(OC)cc1

Procedure:
(MS(m/e): 449.1 (MH+)), were prepared from 2-bromo-N-methyl-2-phenyl-acetamide (commercially available) and 4-[2-(4-methoxy-phenyl)-ethyl]-2,3-dimethyl-4,5,6,7-tetrahydro-thieno [3,2-c]pyridine both as light brown solid.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[CH3:7][C:2]([C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CC(C)(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To cooled (0° C) concentrated H2SO4 (18.5 mL), was added 3-methyl-3- phenylbutanoic acid (10 g, 56 mmol). Next, a cooled solution of HNO3 (3 mL) in H2SO4 (6.2 mL) was added dropwise and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 30 min more. The mixture was poured into ice and the resulting solution was allowed to stand in the refrigerator overnight. The precipitate was filtered, washed with H2 0 and dried, to afford a crude product (14.5 g). This was purified by chromatography on silica gel (CHCl3 :MeOH, 3%) to give the title compound (5.9 g, 47%). 1H NMR (80MHz, CDCl3) δ (TMS): 8.16 (d, J=6.5 Hz, 2H), 7.55 (d, J=6.5 Hz, 2H), 3.5 (m, 1H), 2.70 (s, 2H), 1.50 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:22]=[C:21]([CH2:23]O)[CH:20]=[CH:19][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:3].P(Br)(Br)[Br:26]>C(Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([C:4]1[CH:22]=[C:21]([CH2:23][Br:26])[CH:20]=[CH:19][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:3]
Reactant: BrP(Br)Br
Reactant: COC(=O)C(Oc1ccc(CO)cc1C(C)C)c1cccc(Cl)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1C(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
To a solution of 0.110 g (0.31 mmol) of the product of Step A dissolved in 1.0 mL of carbon tetrachloride was added 0.03 mL (1.6 mmol) of phosphorous tribromide and the reaction mixture was stirred at room temperature for 10 minutes. Carbon tetrachloride was evaporated from the reaction mixture several times to remove the hydrogen bromide, then the residue was purified on a silica gel flash chromatography column eluted with 15% EtOAc-hexane. The purified fractions were evaporated in vacuo affording 0.104 g (80%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)[O:4][N:3]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>O1CCOCC1.O>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[O:4][N:3]=1
Reactant: Cc1noc(-c2ccccc2[N+](=O)[O-])n1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: C1COCCO1
Product: Cc1noc(-c2ccccc2N)n1
Reaction time: 0.75 h
Yield: 62.1 %

Procedure:
3-methyl-5-(2-nitrophenyl)-1,2,4-oxadiazole (1.0 g, 4.8 mmol) in dioxane (11 mL) at 80°0 C. was treated with 11 mL of an aqueous solution of sodium sulfide nonahydrate (2.55 g, 10.6 mmol), also at 80° C. After stirring at that temperature for 45 minutes, the reaction was diluted with water (15 mL) and cooled in an ice bath. The resulting precipitate was collected by filtration and rinsed with water to afford 3-methyl-5-(2-aminophenyl)-1,2,4-oxadiazole (522 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=5)=[O:9])[CH:43]=[CH:42][CH:41]=4)=[CH:31][N:30]3[N:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cn1nccc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cn1nccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 75.3 %

Procedure:
In the same manner as in Example 18-4 and using 1-methyl-1H-pyrazole-5-carboxylic acid (114 mg, 0.904 mmol), tetrahydrofuran (8 mL), oxalyl chloride (118 μL, 1.36 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (71.0 mg, 75%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]3[C:29]([O:30][CH2:31][CH2:32][OH:33])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[CH:19]=[CH:18][C:17]=1[F:36])[C:11](=[O:37])[NH:10]2)=[O:5])[CH3:2].N1C=CC=CC=1.Cl[C:45]([O:47][CH2:48][CH3:49])=[O:46].Cl>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]3[C:29]([O:30][CH2:31][CH2:32][O:33][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[CH:19]=[CH:18][C:17]=1[F:36])[C:11](=[O:37])[NH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1scc2[nH]c(=O)n(-c3cc(OCc4c(OCCO)ccc(F)c4F)ccc3F)c(=O)c12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)OCCOc1ccc(F)c(F)c1COc1ccc(F)c(-n2c(=O)[nH]c3csc(C(=O)OCC)c3c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5-ethoxycarbonyl-3-{2-fluoro-5-[2,3-difluoro-6-(2-hydroxyethoxy)benzyloxy]phenyl}thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (80 mg) in ethyl acetate (2 mL) were added pyridine (0.036 mL) and ethyl chloroformate (0.021 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give the title compound (38 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[S:18]>O1CCCC1.C(N(CC)CC)C>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]1[CH2:2][OH:1])=[S:18]
Reactant: S=C=Nc1ccccc1Cl
Reactant: OCC1CCCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCC1CCCCN1C(=S)Nc1ccccc1Cl
Reaction time: 12 h

Procedure:
3.4 g 2-Hydroxymethylpiperidine in 50 ml absolute tetrahydrofuran was treated with 1 drop of triethylamine and 5 g 2-chlorophenyl isothiocyanate. After 12 hours at room temperature, the reaction solution was cooled in an ice bath. The crystals were suction filtered and recrystallised from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:14])[N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: CCNCC
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Product: CCN(CC)C(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with diethyl amine gives “A87”; method 1: HPLC/MS: 1.36 min, [M+H]=390;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.CO.[OH-].[K+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CN(c2ncnc(C)c2Cc2ccc(F)cc2)CCO3)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ncnc(N2CCOc3ccc(-c4ccc(C(=O)O)cc4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.3 %

Procedure:
To a solution of methyl 4-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate (1.0 g, 2.0 mmol) in 1:1 methanol and THF (10 mL) was added drop wise 2N aqueous potassium hydroxide (8 mL). The reaction mixture was stirred at room temperature for 18 h and then refluxed for 90 min. The mixture was cooled by adding ice, and the pH adjusted to 6 with 2N aqueous hydrochloric acid. The precipitate was filtered, washed with water, azeotroped with toluene (20 mL), and dried to afford 4-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoic acid (0.97 g, 100% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=O)=[CH:7][C:6]=1[F:20].ClC1N=C[C:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33](OC3CCCCO3)=[CH:32][CH:31]=2)=O)=[CH:24]C=1>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH3:24])=[CH:7][C:6]=1[F:20]
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCBr)c(F)c1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCBr)c(F)c1)c1ccccc1
Yield: 74.3 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, (4-(2-bromoethoxy)-3-fluorophenyl)(4-hydroxyphenyl)methanone (150 mg, 0.442 mmol) was reacted with 1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (94 mg, 0.533 mmol, made by example 1, step A) to give 145 mg desired product (68%, Z/E=1/1) as a gray solid.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[S:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][N:22]=1>N1C=CC=CC=1>[CH2:27]([O:26][C:24]([CH2:23][C:20]1[S:19][C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)=[N:22][CH:21]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)Cc1cnc(N)s1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cnc(N=C2SC[C@@H]3Cc4ccccc4CN23)s1
Temperature: 0 °C
Reaction time: 48 h
Yield: 77.2 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo-[3,4-b]isoquinolinium iodide (10 g) is added to a solution of ethyl (2-aminothiazol-5-yl)acetate (5.1 g) in pyridine (150 cc). After 48 hours at a temperature of the order of 20° C., the solution is concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa). The residue is dissolved in a mixture of methylene chloride (200 cc) and N sodium hydroxide solution (100 cc). The organic phase is decanted off, washed with water (3×50 cc), dried over sodium sulphate and then concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C. The residue is crystallised by dissolving it in boiling ethanol (100 cc) and cooling to 0° C. The resulting crystals are filtered off, washed with ethanol (30 cc) and diethyl ether (20 cc) and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield (S)-3-[(5-ethoxycarbonylmethylthiazol-2-yl)imino-]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (7.9 g) m.p.=132° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(Cl)Cl.S(=O)(=O)(O)O.[C:25](O)([CH3:28])([CH3:27])[CH3:26]>[Cl-].[Na+].O>[C:25]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:2]([CH3:1])[CH2:3][N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[CH:12][CH:13]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(Cc1ccccc1)CN1CCCCC1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1
Temperature: 20 °C

Procedure:
100 g of 1-(2-methyl-3-phenyl-propyl)-piperidine are added to 375 ml of methylene chloride. 255 g of 95-96% sulfuric acid are then added dropwise over a 1.5 hour period with rapid stirring while cooling with brine to an internal temperature of 10° C. The mixture is warmed to 20° C. and 42.5 g of tert.-butanol are added dropwise. The mixture is reacted at room temperature for 2 hours. The work-up is analogous to that described in Example 1. The crude product is purified by fractional distillation on a Goodloe silver column to yield pure 1-[3-(p-tert.butyl-phenyl)-2-methyl-propyl]-piperidine, b.p. 118° C./0.07 Torr.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:32]=[C:31]([C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH2:34])[N:30]=[CH:29][C:28]=3[N:41]=2)=[C:21]([F:42])[CH:20]=1>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:32]=[C:31]([C:33]4([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:1][CH2:34]4)[N:30]=[CH:29][C:28]=3[N:41]=2)=[C:21]([F:42])[CH:20]=1
Reactant: CC(C)(C)[O-]
Reactant: C=C(c1ccccc1)c1cc2sc(-c3ccc(C4OCCCO4)cc3F)nc2cn1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2cnc(C3(c4ccccc4)CC3)cc2s1
Reaction time: 4 h

Procedure:
To a clear solution of potassium tert-butoxide (0.201 g, 1.79 mmol) and trimethylsulfoxonium iodide (0.394 g, 1.79 mmol) in 5 mL DMSO was added a cloudy mixture of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenylvinyl)thiazolo[4,5-c]pyridine (0.500 g, 1.19 mmol) in 20 mL THF rapidly. After 4 h, the reaction mixture was partitioned between EA and sat'd aq NH4Cl, and the organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting material was taken up in DCM and was filtered. The filtrate was collected and adsorbed onto 2 g silica gel and dried in vacuo. The resulting material was purified by silica gel chromatography, 40 g, 0-100% EA/hexanes to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenylcyclopropyl)thiazolo[4,5-c]pyridine as a white solid. MS (ESI) m/z: calculated: 432.1; Observed: 433.0 (M++1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)Cl.S(Cl)(Cl)=O.[CH2:21]([O:28][C:29](=[O:44])[NH:30][C:31]1[C:32]([NH2:43])=[N:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][CH:36]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:28][C:29](=[O:44])[NH:30][C:31]1[C:32]([NH:43][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=2)=[N:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][CH:36]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1nc(-c2ccccc2)ccc1NC(=O)OCc1ccccc1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)Nc2nc(-c3ccccc3)ccc2NC(=O)OCc2ccccc2)cc1

Procedure:
A solution of 4-(acetylamino)benzoic acid (33.6 mg, 0.188 mmol) and methylene chloride (0.190 mL) was cooled to 0° C. and treated with thionyl chloride (41 uL, 0.563 mmol) and a drop of DMF. The cold bath was removed, and the reaction progress was checked via piperidine quench and LCMS. The reaction was thoroughly concentrated and dissolved in methylene chloride:THF (1:1, 0.240 mL) and benzyl(2-amino-6-phenylpyridin-3-yl)carbamate (20 mg, 0.0626 mmol) added. After 2 days the reaction was concentrated, taken into DMF and purified via reversed phase HPLC, 20-80% MeCN in water with 0.05% TFA to afford the requisite compound which was taken to the next reaction. MS cal'd 481 (M+H)+, exp 481 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[C:1]([NH:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NC1(c2ccccc2Cl)CCC=CC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1(c2ccccc2Cl)CCC=CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (142 μl, 1.8 mmol) was added to a solution of 6-amino-6-(2-chlorophenyl)-2-cyclohexene-1-one (R. F. Parcell and J. P. Sanchez, J. Org. Chem., 46: 5055 [1981]), (200 mg, 0.9 mmol) and triethylamine (1.0 ml) in dichloromethane (10 ml), and the reaction stirred at room temperature for 1 h. Analysis by TLC indicated complete reaction, and the mixture was partitioned between ethyl acetate and 1N HCl. The organic phase was washed with brine, dried (MgSO4), and the solvent removed by evaporation. Flash chromatography on silica gel eluted with 1:1 ethyl acetate/hexane afforded 6-acetylamino-6-(2-chlorophenyl)-2-cyclohexen-1-one which crystallized on standing, m.p. 144°-145° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1.N1C=CC=CC=1.S(Cl)([Cl:28])(=O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Cl:28][C:5]1[S:4][C:3]([CH:7]2[CH2:16][C:15]3[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=3[C:9](=[O:18])[CH2:8]2)=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1ccsc1C1CC(=O)c2c(C)ccnc2C1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)sc1C1CC(=O)c2c(C)ccnc2C1
Reaction time: 4 h
Yield: 74.3 %

Procedure:
To a solution of 7-(3-methyl-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.38 g) in ethyl acetate (10 ml) were added pyridine (0.023 g) and sulfuryl chloride (0.3 g) at room temperature, and the mixture was stirred at the same temperature for 4 hours. To the reaction solution was added sodium hydrogen carbonate solution, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give 7-(5-chloro-3-methyl-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.32 g), which was dissolved in ethanol (20 ml). To the solution were added aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.27 ml) and water (0.27 ml), and the mixture was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 7-(5-chloro-3-methyl-2-thienyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 122) (0.32 g) as colorless crystals.