Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:10]([CH3:15])=[CH:11][CH:12]=[CH:13][CH:14]=1>ClCCl>[C:10]1([CH3:15])[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:5](=[O:7])[CH3:6]
Reactant: Cc1ccccc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.4 %

Procedure:
Acetic anhydride (33.0 mL, 350 mmol) was added to a stirred solution of o-toluidine (30.0 g, 280 mmol) in dichloromethane (500 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 h. The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine, then dried (MgSO4) and evaporated in vacuo. The residue was stirred in isohexane at 0° C. for 2 h, then filtered. The precipitate was washed with isohexane and dried under vacuum. The title compound (39.87 g, 95%) was obtained as a pale pink solid. δH (CDCl3) 7.80-7.78 (m, 1H), 7.26-7.20 (m, 2H), 7.13-7.08 (m, 1H), 6.92 (br s, 1H), 2.29 (s, 3H), 2.23 (s, 3H). LCMS (ES+) 150 (M+H)+, RT 0.85 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26][NH2:27])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26][NH:27][C:37](=[O:39])[CH3:38])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CN)c1nnc(C)n1-2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Temperature: 0 °C

Procedure:
To a solution of ((1S,2S)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-yl)methanamine (Compound 206; 50 mg, 0.126 mmol) in DCM (2 mL) was added N,N-diisopropylethylamine (43.9 μl, 0.251 mmol). Once the reaction was cooled to 0° C., a solution of acetic anhydride in DCM (140 mg/mL) (14.23 μl, 0.151 mmol) was added. The reaction was stirred at 0° C. for 15 min before an aqueous solution of NaHCO3(sat.) was added for the quench. The product was extracted with DCM (repeated 4 times). The organic layers were combined, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography (DCM/MeOH 10:0 to 9:1) to give the desired product as an off-white solid (33 mg). LRMS (M+H)+: 440 m/z. 1H NMR (two conformers detected in ˜1:1 ratio) (400 MHz, DMSO-d6) δ 8.08 (t, J=5.15 Hz, 0.5H), 7.75 (t, J=4.92 Hz, 0.5H), 7.44-7.56 (m, 4H), 3.45-3.51 (m, 1H), 2.78-2.86 (m, 0.5H), 2.64-2.72 (m, 0.5H), 2.56-2.63 (m, 3H), 2.35-2.42 (m, 3H), 2.13-2.22 (m, 0.5H), 2.00 (dd, J=5.04, 8.93 Hz, 0.5H), 1.86 (s, 1.5H), 1.71 (s, 1.5), 1.58 (m, 1.5H), 1.57 (m, 1.5H), 1.22-1.37 (m, 1H), 0.99 (dd, J=5.26, 9.16 Hz, 0.5H), 0.58 (t, J=5.95 Hz, 0.5H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Under inert gas atmosphere 5.00 g (23.3 mmol) 5-bromo-2-ethoxy-pyridine are added to a mixture of 7.19 g (23.3 mmol) 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, 95 mg (1.2 mmol) PdCl2(dppf)xCH2Cl2 and 15.2 g (46.5 mol) Cs2CO3 in 50 mL DMF and 10 mL H2O. The mixture is stirred for 12 h at 80° C. After that time, the solvent is evaporated, the residue taken up in DCM and washed with brine. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by column chromatography (silica gel; gradient PE/EtOAc 20:1→10:1) to yield the desired product which was directly used in the next step.
Reaction SMILES: [C:1]([O-:4])(O)=[O:2].[Na+].[N+:6]([C:9]1[C:14]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=1CO)([O-:8])=[O:7].[Na+].[Br-].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC(C)=O.CC1(C)N([O])C(C)(C)CCC1.CC(O)C>[Si:17]([O:16][CH2:15][C:14]1[C:9]([N+:6]([O-:8])=[O:7])=[C:10]([CH:11]=[CH:12][CH:13]=1)[C:1]([OH:4])=[O:2])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: [Br-]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 56 %

Procedure:
An aqueous solution of 15% NaHCO3 (18 mL) was added to a stirring solution of Compound 9 (1.80 g, 2.69 mmol) in acetone (60 mL) at 0° C. NaBr (133 mg, 1.29 mmol) and TEMPO (18.9 mg, 0.121 mmol) were then added followed by the slow addition of trichloroisocyanuric acid (2.81 g, 12.1 mmol). The resulting solution was allowed to warm to room temperature and stirring for 1 d after which time 2-propanol (3.63 mL) was added. The mixture was filtered over Celite, concentrated on a rotary evaporator, dissolved in 18 mL of saturated Na2CO3, washed with EtOAc (3×10 mL), acidified with 1 M HCl, and extracted with ethyl acetate (3×50 mL). The resulting organics were dried over Na2SO4, filtered, concentrated on a rotary evaporator and purified by silica gel chromatography (10% MeOH:CH2Cl2) to yield Compound 10 (1.05 g, 56%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][S:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)(=[O:35])=[O:34]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1Br
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3ccccc3Br)cc2)c2ccc3ccccc3c2N1
Yield: 46 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and (2-bromophenyl)methanesulfonyl chloride, the title compound (yield 46%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.C(=O)(O)[O-].[Na+]>C(O)C.[Fe]>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2ccncc2)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Nc1cccnc1Nc1cccc(/C=C/c2ccncc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A mixture of 3-nitro-2-[3-[(E)-2-(4-pyridyl)vinyl]phenylamino]pyridine (1.38 g), iron powder (1.0 g) and hydrochloric acid (35%, 3.0 ml) in ethanol (10 ml) was stirred at 80° C. for 2 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (8% methanol in chloroform) to give 3-amino-2-[3-[(E)-2-(4-pyridyl)vinyl]phenylamino]pyridine (1.14 g) as powder.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([CH:35](O)[CH3:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:36])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CC(O)c1ccccc1
Product: CC(Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccccc1

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and 1-phenyl-ethanol. MS (ESI) m/z 484.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].C(O)(=O)C.S(=O)(=O)(O)O.[H][H].[OH-].[Na+]>[Pt]>[CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12]
Reactant: [H][H]
Reactant: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Agent: [Pt]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Yield: 92.4 %

Procedure:
To 1-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime prepared as described in example P3 (54.2 g; assay 98.4%; 0.20 mol) in acetic acid (115 g; 1.92 mol) was added sulphuric acid (22.5 g; assay 96%; 0.22 mol) at such a rate that the mixture could be kept at 20-23° C. Platinum on charcoal (5.9 g; Evonik F101 N/W 5%, water wet; assay 2.32% Pt) was added. The resulting mixture was transferred to an autoclave, which then was sealed and pressurized with hydrogen (0.8 MPa). The agitator of the autoclave was started and hydrogen pressure is maintained at 0.8 MPa. When no more hydrogen is consumed (usually after 5 hours), hydrogenation was interrupted by stopping agitation. Pressure was released and the atmosphere in the autoclave changed to nitrogen. The hydrogenation mixture was filtered in order to remove the heterogenous catalyst. To the filtrate was added water (220 g) and a pH-probe was mounted. Aqueous sodium hydroxide (304 g; assay 30%; 2.28 mol) was fed until pH is above 9. The resulting mixture was extracted with tert-butyl methyl ether (300 ml). Phases were allowed to separate. The (lower) aqueous phase was separated and discarded. The organic phase was washed with water (2×250 g) and evaporated to dryness. Crude O-Methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (53.0 g; assay 93.7%; yield 92.4%) was obtained as clear oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.S(Cl)([Cl:13])=O>>[CH3:1][S:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([Cl:13])=[O:10])[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1nc(C(=O)O)cs1
Product: CSc1nc(C(=O)Cl)cs1
Temperature: 25 °C

Procedure:
2-(Methylthio)-1,3-thiazole-4-carboxylic acid (Intermediate 11; 1.0 g) in thionyl chloride (10 ml) was heated to reflux for 30 min. The solution was cooled to room temperature and concentrated in vacuo. The residue was washed with anhydrous THF and concentrated to yield a black solid which was dried and stored cold under nitrogen (1.2 g). NMR (CDCl3): 2.76 (s, 3H), 8.32 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[C:19]([C:20]5[N:25]=[CH:24][CH:23]=[CH:22][N:21]=5)=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:44].CCOC(C)=O>CO.C(Cl)Cl>[ClH:44].[C:1]1([C:7]2[C:8]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4([NH2:36])[CH2:35][CH2:34][CH2:33]4)=[CH:30][CH:31]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[C:19]([C:20]5[N:21]=[CH:22][CH:23]=[CH:24][N:25]=5)=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl {1-[4-(9-phenyl-3-pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6d) (71 mg, 0.125 mmol) in MeOH (2 mL) and DCM (3 mL) was added a 4N solution of HCl in EtOAc (3 mL, 12 mmol). The sealed reaction mixture was permitted to stir at room temperature. After 4 hours the reaction mixture was concentrated. After 4 hours the reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase column chromatography (Sunfire C18) eluting with 1 to 50% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were concentrated in vacuo. The resulting residue was then dissolved in DCM (5 mL) & MeOH (5 mL), then added a 4N solution of HCl in EtOAc (5 mL, 20 mmol), then concentrated in vacuo to give 1-[4-(9-phenyl-3-pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine hydrochloride (1-10) as a tan solid. HRMS (M+H)+: observed=470.2098, calculated=470.2088.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].CCN(C(C)C)C(C)C>C1COCC1>[CH3:19][O:20][CH2:21][C:22]([NH:11][C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:2]=2[CH3:1])[CH:10]=[CH:9][N:8]=1)=[O:23]
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2C)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 4-(2-methyl-4-nitrophenoxy)pyridin-2-amine [WO2007059257] (405 mg, 1.65 mmol) in THF (5.0 mL) at 0° C. was added 2-methoxyacetyl chloride (604 μL, 6.61 mmol) and DIPEA (1.44 mL, 8.26 mmol) and the reaction mixture warmed to RT for 30 min. The reaction was quenched by addition of a 1% solution of NH3 in MeOH (3.0 mL) and was kept at RT for 16 hr. A second aliquot of a solution of NH3 in MeOH (7M, 1.0 mL) was added and after 30 min at RT the resulting mixture was evaporated in vacuo. The residue was subjected to SCX capture and release to afford 2-methoxy-N-(4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)acetamide as an orange oil (357 mg, 92% pure, 63%); Rt 2.07 min (Method 2); m/z 318 (M+H)+ (ES+), which was used directly in the next step (below).
Reaction SMILES: [O:1]1[C:5]([C:6]2[N:7]=[C:8]([C:11]3[C:15](=[CH2:16])[S:14][CH:13]([C:17]([O:19][CH3:20])=[S:18])[CH:12]=3)[S:9][CH:10]=2)=[CH:4][CH:3]=[N:2]1.NC(=S)C1C=C(C(OC)=S)SC=1C.BrCC(C1ON=CC=1)=O.O1C(C(Cl)=O)=CC=N1>>[O:1]1[C:5]([C:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([O:19][CH3:20])=[S:18])[S:14][C:15]=3[CH3:16])[S:9][CH:10]=2)=[CH:4][CH:3]=[N:2]1
Reactant: C=C1SC(C(=S)OC)C=C1c1nc(-c2ccno2)cs1
Agent: COC(=S)c1cc(C(N)=S)c(C)s1
Agent: O=C(CBr)c1ccno1
Agent: O=C(Cl)c1ccno1
Product: COC(=S)c1cc(-c2nc(-c3ccno3)cs2)c(C)s1
Yield: 83 %

Procedure:
Methyl 4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5-methlylthiothiophene-2-carboxylate: Methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (872 mg, 2.51 mmol) was allowed to react with 2-bromo-1-isoxazol-5-ylethan-1-one (737 mg, prepared from isoxazole-5-carbonyl chloride [Maybridge Chemicals, Cornwall, UK] as described in Example 177, step (a) as described in Example 154, step (a) to give 704 mg (83% yield) of methyl 4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate. 1H NMR (DMSO-d6, 300 MHz) δ 2.75 (s, 3H), 3.85 (s, 3H), 6.93 (d, 1H, J=1.8 Hz), 8.22 (s, 1H), 8.38 (s, 1H), 8.70 (d, 1H, J=1.8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[S:13])[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O>C(O)(C)(C)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[S:13][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1CCCCC1Cl
Reactant: NC(=S)Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1ccc(Cc2nc3c(s2)CCCC3)cc1
Yield: 67.2 %

Procedure:
A mixture of 2-(4-nitrophenyl)ethanethioamide (7.0 g), 2-chloro-cyclohexanone (7.28 g) and tert-butanol (100 mL) was heated under reflux for 3 days. The reaction mixture was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(4-nitrobenzyl)-4,5,6,7-tetrahydro-1,3-benzothiazole as pale-brown crystals (6.58 g, yield 66%) from a fraction eluted with hexane-ethyl acetate (3:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 118-119° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](/[N:8]=[C:9](/[NH2:35])\[C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:34])([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:22][N:21]=2)[CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]>C1(C)C(C)=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[O:7][N:35]=[C:9]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([CH3:34])([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:22][N:21]=3)[CH:17]([CH3:19])[CH3:18])=[CH:14][CH:15]=2)[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)/N=C(/N)c1ccc(C(C)(c2ccc(OCc3ccccn3)cn2)C(C)C)cc1
Solvent: Cc1ccccc1C
Product: CC(=O)OCc1nc(-c2ccc(C(C)(c3ccc(OCc4ccccn4)cn3)C(C)C)cc2)no1
Temperature: 25 °C

Procedure:
A stirred solution of 3b (0.896 mmol) in xylene (6.00 mL) was heated to 110° C. for approximately 1 h. After cooling to rt, the reaction mixture was concentrated in vacuo to afford the title compound 3c, which was used without further purification in the subsequent reaction. m/z (ES) 473 (MH)+.
Reaction SMILES: CC1(C)CC=C(C2SC=CN=2)C2C=C(C#CC3C=CC=CC=3C(O)=O)C=CC1=2.[CH3:29][C:30]1([CH3:59])[CH2:39][CH:38]=[C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]2[CH:35]=[C:34]([C:46]#[C:47][C:48]3[CH:58]=[CH:57][C:51]([C:52]([O:54]CC)=[O:53])=[CH:50][CH:49]=3)[CH:33]=[CH:32][C:31]1=2>>[CH3:29][C:30]1([CH3:59])[CH2:39][CH:38]=[C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]2[CH:35]=[C:34]([C:46]#[C:47][C:48]3[CH:49]=[CH:50][C:51]([C:52]([OH:54])=[O:53])=[CH:57][CH:58]=3)[CH:33]=[CH:32][C:31]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2)=CCC3(C)C)cc1
Agent: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccccc3C(=O)O)ccc21
Product: CC1(C)CC=C(c2ccccc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6-dihydro-5,5-dimethyl-8-(2- thiazolyl)-2-naphthalenyl)ethynyl]benzoic acid (Compound 30a), 27.0 mg (0.07 mmol) of ethyl 4-[(5,6- dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl)ethynyl]benzoate (Compound 1a) was converted into the title compound (colorless solid) using 5.9 mg (0.14 mmol) of LiOH in H2O. PMR (d6-DMSO): δ 1.31 (6H, s), 2.35 (2H, d, J=4.5 Hz), 6.05 (1H, t, J=J=J=4.5 Hz), 7.00 (1H, s), 7.33 (2H, d, J=6.2 Hz), 7.44 (4H, m), 7.59 (2H, d, J=8.1 Hz), 7.90 (2H, d, J=8.1 Hz).
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:17])[O:15][CH3:16])[CH:10]=[CH:11][CH:12]=1)=O.C(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl>O>[CH3:1][C:2]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14](=[O:17])[O:15][CH3:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1
Reactant: COC(=O)Nc1cccc(CCNC(C)=O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1ccc2c(c1)CCN=C2C
Reaction time: 16 h

Procedure:
A mixture of 4.13 g (17.5 mmol) methyl N-[3-(2-methylcarbonylamino-ethyl)phenyl]carbamate and 35 ml chloroform is slowly combined with 8.00 g (38.4 mmol) phosphorus pentachloride and the mixture is stirred for 16 h. Then the mixture is carefully poured into water and stirred for 45 min. It is extracted 3× with methylene chloride and then the aqueous phase is made basic with 4N NaOH. The crystals precipitated are suction filtered and dried.
Reaction SMILES: F[B-](F)(F)F.[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7].[FH:17].[FH:18].F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:6]([CH:10]1[CH2:15][CH2:14][C:13]([F:18])([F:17])[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: F
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C1CCC(F)(F)CC1
Reaction time: 4 h
Yield: 52.4 %

Procedure:
To a suspension of diethylaminosulfinium tetrafluoroborate (593 mg, 2.6 mmol) in dichloromethane (10 mL) at room temperature is added 4-tert-butylcyclohexanone (200 mg, 1.3 mmol) and triethylamine trihydrofluoride (266 μl, 1.3 mmol). The reaction mixture is stirred for 4 hours, then an aqueous solution of sodium bicarbonate (5%) is added and stirring is continued for 30 minutes. The organic phase is isolated and dried with magnesium sulphate. The solution is diluted with pentane (10 mL) and the solution is passed through a pad of silica gel with pentane elution. Solvent are evaporated in vacuo to provide 4-t-butyl-1,1-difluorocyclohexane (120 mg, 53%) as a clear liquid, admixed with 3% of the corresponding vinyl fluoride. Major compound: 1H NMR (CDCl3) 2.09-1.95 (m, 2H), 1.76-1.67 (m, 2H), 1.65-1.51 (m, 2H), 1.30-1.15 (m, 2H), 1.02-0.97 (s, 1H), 0.80 (s, 9H); 19F NMR (CDCl3)-91.9 (d, J=232.6 Hz, 1F), −103.5 (dm, J=232.6 Hz, 1F).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][O:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[Cl:18])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:26][O:27][C:28]([C:30]1[C@@H:31]2[N:45]([CH3:46])[C@H:34]([CH2:35][C:36]=1OS(C(F)(F)F)(=O)=O)[CH2:33][CH2:32]2)=[O:29].CCOC(C)=O>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH3:26][O:27][C:28]([C:30]1[C@@H:31]2[N:45]([CH3:46])[C@H:34]([CH2:35][C:36]=1[C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][O:9][C:10]3[C:15]([Cl:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[Cl:18])=[CH:4][CH:3]=1)[CH2:33][CH2:32]2)=[O:29]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(Br)cc2)c(Cl)c1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@@H]2CC[C@H]1N2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C[C@@H]2CC[C@H]1N2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
1-[2-(4-Bromo-phenoxy)-ethoxy]-2,6-dichloro-4-methyl-benzene (10.5 g, 28.0 mmol) was dissolved in THF (90 mL), and the sol. was cooled to −78° C. BuLi (1.6M in hexane, 18.2 mL, 29.1 mmol) was added, and the sol. was stirred at −78° C. for 1 h. ZnCl2 (1M in THF, 30.8 mL, 30.8 mmol) was added, and the mixture was allowed to warm to rt. A sol. of (rac.)-(1R*,5S*)-8-methyl-3-trifluoromethanesulfonyloxy-8-aza-bicyclo[3.2.1]oct-2-ene-2-carboxylic acid methyl ester (WO 2004/096799; 4.60 g, 14.0 mmol) in THF (10 mL), and then Pd(PPh3)4 (324 mg, 0.280 mmol) were added. The mixture was heated rapidly to 55° C., and stirred at this temperature for 30 min. The mixture was cooled to 0° C., and EtOAc (250 mL) was added. This mixture was washed with cold aq. 1M NaOH (1×), and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 5:95) yielded the title compound (5.77 g, 87%). LC-MS: tR=0.86 min; ES+: 476.26.