Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:27]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:20])=[O:21])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:24])[F:25])[C:9]=2[Cl:27])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Reaction time: 18 h
Yield: 62.6 %

Procedure:
To a solution of 5-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (350 mg, 0.783 mmol) in N,N-dimethylformamide (12 ml) was added N-chlorosuccinimide (1.05 g, 7.83 mmol) at room temperature. After the mixture was stirred for 18 hr, 1.05 g of N-chlorosuccinimide was added. The resulting mixture was stirred for further 36 hr. 20 nm of saturated aqueous sodium thiosulfate and 50 nm of diethyl ether were added and the two-phase-mixture was stirred for 0.5 hr. The separated organic layer was washed with water (20 ml×3) and dried over magnesium sulfate. Removal of solvent gave a pale yellow gum, which was chromatographed on a column of silica gel (50 g) eluting with ethyl acetate/hexane (1:3) to afford 236 mg (63%) of the title compound as a white solid.
Reaction SMILES: [CH3:1]I.[NH:3]1[C:10](=[O:11])[CH2:9][C:7](=[O:8])[NH:6][C:4]1=[S:5]>CCO.[OH-].[Na+].O>[CH3:1][S:5][C:4]1[N:6]=[C:7]([OH:8])[CH:9]=[C:10]([OH:11])[N:3]=1
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc(O)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (32.64 g, 220 mmol) was added dropwise to a suspension of thiobarbituric acid (29 g, 200 mmol) in EtOH (300 ml) and 2M NaOH solution in water (110 ml) at room temperature. The mixture was stirred at room temperature overnight and then stirred for two hours at 60° C. The ethanol was removed, water was added and the mixture was allowed to stay for 2 hours on an ice bath. The solid title compound was filtered of, washed with ice cold water and dried (30 g, 95%).
Reaction SMILES: [C:1]([C:4]1[C:31]([CH3:32])=[CH:30][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH2:22][C:23]4([CH3:29])[CH2:28][O:27][CH2:26][O:25][CH2:24]4)[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C([O-])(O)=[O:34].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>C(Cl)Cl.O>[C:1]([C:4]1[C:31]([CH3:32])=[CH:30][C:7]2[NH:8][C:9]([S:11]([CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH2:22][C:23]4([CH3:29])[CH2:24][O:25][CH2:26][O:27][CH2:28]4)[CH:16]=[CH:15][N:14]=3)=[O:34])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1c(OCC2(C)COCOC2)ccnc1CSc1nc2cc(C(C)=O)c(C)cc2[nH]1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1c(OCC2(C)COCOC2)ccnc1CS(=O)c1nc2cc(C(C)=O)c(C)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred mixture of 5-acetyl-6-methyl-2-[[(3-methoxy-4-(5-methyl-1,3-dioxan-5-yl-methoxy)-2-pyridinyl)methyl]thio]-1H-benzimidazole (87 mg, 0.19 mmol) in 20 ml CH2Cl2 and NaHCO3 (32 mg, 0.38 mmol) in 5 ml H2O was cooled to 0° C. and treated with 3-chloro-perbenzoic acid (47 mg 70%, 0.19 mmol). After reacting for 10 min the layers were separated (the aqueous layer was washed once more with 5 ml CH2Cl2) and the organic layer extracted with 10 ml H2O containing NaOH (15 mg, 38 mmol). The alkaline aqueous layer was collected and treated with several portions of methyl formate (each 23 μl, 38 mmol) until the solution turned opaque. The aqueous layer was extracted with 25+10 ml CH2Cl2. The two latter organic layers were combined, dried over MgSO4 and evaporated. The residue was chromatographed (SiO2, CH2Cl2 /MeOH saturated with NH3(g), 93/7) yielding 40 mg (44%) pure solfoxide.
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:10](Cl)([Cl:13])([Cl:12])=[S:11]>CCOCC>[CH2:1]([N:8]([CH3:9])[P:10]([Cl:13])([Cl:12])=[S:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccccc1
Reactant: S=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CN(Cc1ccccc1)P(=S)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A solution of N-benzyl-N-methylamine (2.81 g, 0.32 mol) in 47 mL of ether was added dropwise with stirring to 78.6 g (0.47 mol) of thiophosphoryl chloride in 375 mL of ether at 0° C. under an argon atmosphere. After the addition was complete, the resultant slurry was stirred for 30 min at 0° C., and then for 1 h at 25° C. The amine hydrochloride was removed by filtration and the solvent was concentrated at reduced pressure to provide 28.5 g (92.5%) of a red colored oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9]C)=[O:8].[C:14]([N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][CH:24]([O:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=2[C:7]([OH:9])=[O:8])[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(OC)cc1O
Product: COc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
Using methyl 4-methoxysalicylate and 1-Boc-piperidin-4-ol, the acid is obtained using procedures similar to those described at Example 1-G and 1-H.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](O)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([Cl:23])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Yield: 92.9 %

Procedure:
2-Butyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (444 mg, 1.58 mmol) was dissolved in dry DCM (15 mL) at rt and under an atmosphere of nitrogen. Oxalyl chloride (0.15 mL, 1.73 mmol) was added dropwise and the reaction mixture was refluxed for 1.5 h. DMF (0.08 mL) was added followed by the addition of oxalyl chloride (0.15 mL, 1.73 mmol) in 2 portions and the reaction mixture was refluxed for another 6 h. The solvents were evaporated and the residue was partitioned between water and DCM. The combined organic layers were washed with water and the two phases were separated using a phase separator. Evaporation of the organic phase gave the title compound (440 mg, 88%) as a brown oil with approximately 95% purity according to 1H-NMR and was used without further purification; 1H-NMR (400 MHz, CDCl3): δ 7.96-8.00 (m, 2H), 7.53-7.62 (m, 3H), 3.74-3.80 (t, 2H), 1.78-1.87 (m, 2H), 1.39-1-50 (m, 2H), 0.98 (t, 3H); 13C-NMR (100 MHz, CDCl3): δ 156.3, 137.1, 132.7, 129.6, 129.2, 127.6, 123.7, 40.9, 30.1, 20.1, 13.7.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([F:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:24][C:25](=[O:42])[C:26]1[CH:31]=[C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH:29]=[CH:28][C:27]=1[N+:39]([O-])=O.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].O.C(O)C>[NH2:39][C:27]1[CH:28]=[CH:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:31][C:26]=1[C:25]([NH:24][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:2]=1[Cl:1])[C:6]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[C:11]([F:21])[CH:10]=1)=[O:7])=[O:42]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(C(=O)Nc3cc(C(=O)Nc4cc(F)cc(N5CCOCC5)c4)ccc3Cl)c2)CC1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(C(=O)Nc3cc(C(=O)Nc4cc(F)cc(N5CCOCC5)c4)ccc3Cl)c2)CC1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
Iron powder (0.726 g) was added to a stirred suspension of 4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-[5-(4-methylpiperazin-1-yl)-2-nitrobenzamido]benzamide (0.76 g), water (2 ml), acetic acid (0.5 ml) and ethanol (15 ml) and the resultant mixture was stirred and heated to reflux for 1 hour. The mixture was cooled to ambient temperature. Water (80 ml) was added and the mixture was basified by the addition of sodium carbonate. The resultant mixture was filtered through diatomaceous earth and the separated solids were washed in turn with methylene chloride and methanol. The combined filtrates were evaporated and the residue was triturated under ethyl acetate. The mixture was filtered and the filtrate was evaporated to give 3-[2-amino-5-(4-methylpiperazin-1-yl)benzamido]-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide (0.385 g); Mass Spectrum: M+H+ 567.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:51]2[N:52]=[C:53]([NH:56]C(OC(C)(C)C)=O)[S:54][CH:55]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42]C(OC(C)(C)C)=O)[C:38]([CH3:50])=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:42][CH2:41][C:39]1[C:38]([CH3:50])=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:51]3[N:52]=[C:53]([NH2:56])[S:54][CH:55]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1
Reactant: Cc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)nc1CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nc1CN
Yield: 59.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (155 mg, 0.170 mmol), DCM (1.70 mL), anisole (37 μL, 0.34 mmol) anf TFA (0.787 mL, 10.2 mmol). The crude material was purified by reverse phase preparative HPLC (XSELECT C18, 5μ, 30×100 mm, ACN—H2O w/0.1% formic acid buffer, 60 mL/min), affording the title compound (55 mg, 57%) as an off-white solid. LCMS: Rt=0.49 min, m/z=544.1 (M+1) Method 2m_acidic_polar. 1H NMR (400 MHz, D2O) δ 7.04 (s, 1H), 5.46 (d, J=5.6 Hz, 1H), 4.91-4.84 (m, 1H), 4.84-4.76 (m, 1H), 4.62-4.56 (m, 1H assumed; obscured by solvent residual peak), 4.13 (s, 2H), 2.16 (s, 3H), 1.32-1.18 (m, 2H), 1.18-1.00 (m, 2H).
Reaction SMILES: N.Cl[CH:3]([F:22])[C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)=[O:5].[NH2:23]C1C=CC(Cl)=CC=1C(C1C=CC=CC=1)=O.ClC(F)C(Cl)=O>CS(C)=O>[F:22][CH:3]1[N:23]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=2[NH:6][C:4]1=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(F)Cl
Agent: N
Agent: O=C(Cl)C(F)Cl
Solvent: CS(C)=O
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F
Reaction time: 16 h

Procedure:
NH3 is passed into a solution of 3.26 g. of 2-(α-chloro-α-fluoro-acetamido)-5-chloro-benzophenone, obtainable from 2-amino-5-chlorobenzophenone and α-chloro-α-fluoroacetyl chloride, in 15 ml. of DMSO at 50° for one hour. After stirring for 16 hours, the mixture is evaporated; 35 ml. of chloroform and 35 ml. of 13% NHO3 are added and the resulting salt is filtered off. The product is suspended in ethanol and neutralized with ammonia. Dilution with water gives 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one, m.p. 235° (decomposition).
Reaction SMILES: [C:1]([O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:9]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[C:1]([O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([OH:16])=[O:15])[CH2:9]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)OC[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)OC[C@H]1CCCN(C(=O)O)C1
Reaction time: 0.5 h

Procedure:
170 mg of dimethylaminopyridine and 3.4 mg of pyridine are added to 3.0 g of t-butyl (S)-3-hydroxymethyl-1-piperidinecarboxylate. 1.66 ml of isobutyryl chloride are added dropwise thereto. The reaction mixture is then concentrated. The residue is taken up in ether and the ether phase is washed in succession with 20 ml of citric acid, water, sodium bicarbonate solution and water. After drying and evaporation of the ether phase there are obtained 3.9 g of t-butyl (S)-3-isobutyroxymethyl-1-piperidinecarboxylate, Rf=0.87 (ether). 3.09 g of this ester are dissolved in 80 ml of methylene chloride and treated with 20 ml of trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated. 30 ml of methanol are added to the residue and saturated sodium bicarbonate solution is then added dropwise. The aqueous phase is extracted with methylene chloride and the methylene chloride extracts are dried and concentrated. There are obtained 2.82 g of (S)-3-iso- butyroxymethyl-1-piperidinecarboxylic acid trifluoroacetic acid salt, Rf=0.4 (Takeda solution).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:17])[C:8]=1[CH3:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][F:31]>>[C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:29][CH2:30][F:31])=[CH:12][C:11]=2[CH3:17])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)cc2C)c1C
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(OCCF)cc2C)c1C

Procedure:
As outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (20 mg) reacted with 1-bromo-2-fluoro ethane (50 μL), in the presence of K2CO3 powder (50 mg), to afford 1-{4-acetyl-1-[4-(2-fluoro-ethoxy)-2-methyl-phenyl]-2,5-dimethyl-1H-pyrrol-3-yl}-ethanone: MS (ESI) 332 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone and hydrazine reacted to give 6-[4-(2-fluoro-ethoxy)-2-methyl-phenyl]-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.06 (d, 1H), 6.94 (s, 1H), 6.90 (m, 1H), 4.12 (q, 2H), 2.81 (s, 6H), 2.38 (s, 6H), 1.80 (s, 3H), 1.50 (t, 3H); MS (ESI) 310 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]N(C=O)C>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:13])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Product: Cn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-bromo-1H-indole (2.5 g, 12.8 mmol) in DMF (10 ml) was slowly added NaH (354 mg, 14.0 mmol) at room temperature. The resulting mixture was stirred for 20 min at RT after which Mel (956 μl, 15.4 mmol) was added. The mixture was stirred for 1 hour at room temperature and then partitioned between DCM and brine. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to provide 6-Bromo-1-methyl-1H-indole CXLII in quantitative yield (2.7 g).
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH2:10])=O)[N:6]=1.O1CCCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1.O>C(OCC)(=O)C>[SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH2:10])=[S:25])[N:6]=1
Reactant: NC(=O)Cc1csc(S)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=S)Cc1csc(S)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 197.8 %

Procedure:
To a mixture of 2-mercaptothiazol-4-yl-acetamide (174 mg) and tetrahydrofuran (10 ml) was added Lawesson's reagent (202 mg) at room temperature. After stirring at room temperature overnight, the solution was poured into a mixture of water and ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate) to give 2-mercaptothiazol-4-yl-thioacetamide (188 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.ClC1C=CC(C(=O)C)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:30][C:31]1[CH:32]=[C:33]([O:37][CH2:38][CH2:39]Br)[CH:34]=[CH:35][CH:36]=1>C(N(CC)CC)C.O.C1(C)C=CC=CC=1>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:39][CH2:38][O:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[CH:32]=2)[CH2:5][CH2:4]1
Reactant: NCC1CCNCC1
Reactant: Clc1cccc(OCCBr)c1
Agent: CC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: NCC1CCN(CCOc2cccc(Cl)c2)CC1

Procedure:
In a similar manner to Example 7, a mixture of 4-aminomethylpiperidine (2.9 g), 4'-chloroacetophenone (3.94 g), toluene (100 ml) and a catalytic amount of p-toluenesulphonic acid was boiled under reflux for five hours with removal of the water formed using a Dean and Stark apparatus. The mixture was cooled and treated with 2-bromoethyl 3-chlorophenyl ether (6.0 g) followed by triethylamine (3.54 ml). The mixture was boiled under reflux for 6 hours and then evaporated to dryness. 6M Hydrochloric acid (50 ml) was added and the mixture heated on a steam bath for 16 hours to give 4-aminomethyl-1-[2-(3-chlorophenoxy)ethyl]piperidine, as an oil. The oil, obtained on work up, was treated with 98% formic acid (5.0 ml) and formaldehyde (5.0 ml, 38% aqueous solution). The mixture was heated on a steam bath for 4 hours. After extractive work up as described in Example 7, the oil obtained was distilled at 120° C. at 0.13 mbar. The distillate was treated with ethereal hydrogen chloride to give 1-[2-(3-chlorophenoxy)ethyl]-4-(dimethylaminomethyl)piperidine dihydrochloride, m.p. 258°-260° C., after recrystallisation from absolute ethanol.
Reaction SMILES: C([O-])(O)=O.[Na+].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH3:18])=[C:11]([S:13](Cl)(=[O:15])=[O:14])[CH:12]=1.O.[C:20]1([OH:28])[CH:27]=[C:25]([CH3:26])[CH:24]=[C:22]([OH:23])[CH:21]=1>C(OCCCC)CCC.O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH3:18])=[C:11]([S:13]([O:23][C:22]2[CH:21]=[C:20]([OH:28])[CH:27]=[C:25]([CH3:26])[CH:24]=2)(=[O:15])=[O:14])[CH:12]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Yield: 349.1 %

Procedure:
Saturated aqueous NaHCO3 (70 mL) was added to a solution of 5-chloro-2-methoxybenzenesulfonyl chloride (3.83 g, 15.9 mmol) and orcinol monohydrate (3.39 g, 23.9 mmol) in di-n-butyl ether (53 mL) and tetrahydrofuran (17 mL). The biphasic solution was mixed vigorously at 50° C. for 7 h and then at ambient temperature overnight. The reaction mixture was combined with that from a previous reaction (which used 4.53 g [18.8 mmol] of 5-chloro-2-methoxybenzenesulfonyl chloride), the layers were separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (250 mL), dried over Na2SO4, filtered, and evaporated to give 18.25 g of a clear brown oil. The product was purified by flash column chromatography (1% to 4% ethyl acetete in dichloromethane) to give the title compound (9.86 g, 86%) as a pale yellow oil which crystallized upon standing. 1H-NMR (300 MHz, CDCl3) δ 7.81 (d, 1 H, J =2.6 Hz), 7.55 (dd, 1 H, J=2.6, 8.9 Hz), 7.02 (d, 1 H, J=8.9 Hz), 6.53 (m, 2H), 6.41 (t, 1 H, J=2.2 Hz), 3.99 (s, 3 H), 2.24 (s, 3 H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C14H13ClO5S: 351.0 (M+Na). Found: 351.1.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([SH:13])[N:6]=1.Cl[C:15]1[S:16][CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>O.C(O)C>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[N:6]=[C:7]([S:13][C:15]2[S:16][CH:17]=[CH:18][C:19]=2[N+:20]([O-:22])=[O:21])[N:8]=1
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: COc1cc(OC)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)nc(Sc2sccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
Sodium hydroxide (1.2 g) was dissolved in water (50 ml), 4,6-dimethoxy-2-mercaptopyrimidine (5.3 g) was added, and the mixture was stirred at room temperature for 15 minutes. 2-Chloro-3-nitrothiophene (5.0 g) dissolved in ethanol (50 ml) was added with stirring, the mixture being stirred at room temperature for 6 hours. The resulting precipitate was filtered, washed with water and dried, to give 7.6 g of the desired product, mp 199°-201° C.
Reaction SMILES: [C:1]1([C:7](=[O:19])[CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O1CCCC1.O>C(OCC)(=O)C>[C:13]1([CH:11]([OH:12])[CH2:10][CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(CCCC(=O)c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OC(CCCC(O)c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
While cooled by an ice-bath and stirred intensely, 0.0 mol 1,5-diphenyl-1,5-pentandione was added dropwise slowly to a mixture of 3 g LiAlH4 and 100 ml anhydrous tetrahydrofuran. The mixture was heated refluxing for 5 hours, then cooled. Excess LiAlH4 was decomposed with water. After mixing completely the reaction mixture with ethyl acetate, the mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate. The solvent was removed. Column chromatography gave 1,5-diphenyl-1,5-pentanediol as a white solid, and the yield was 85%. mp: 64-67° C. IR spectrum had a strong —OH absorption peak at 3400 cm−1, and had no —CO— absorption peak at about 1700 cm−1. This demonstrated that the reduction reaction was carried out completely.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]#[C:31][CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33]>C(OCC)C>[C:34]1([C:32](=[O:33])[C:31]#[C:30][C:26]2[O:25][CH:29]=[CH:28][CH:27]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: OC(C#Cc1ccco1)c1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(C#Cc1ccco1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place pyridinium dichromate (0.75 g, 2 mmol) and methylene chloride (15 mL) under argon atmosphere and cool to 0° C. Add α-[(2-furanyl)ethynyl]-benzenemethanol (297 mg, 1.5 mmol). Stir overnight while slowly warming to room temperature. Dilute with ethyl ether and filter the chromium salts. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH2:12].O=[CH:16][C:17]([OH:19])=[O:18].[BH3-]C#N.[Na+]>CO>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH:12][CH2:16][C:17]([OH:19])=[O:18]
Reactant: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Reactant: O=CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNc1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-(trifluoromethyl)-1H-indazol-3-amine (as prepared in the previous step, 50 mg, 0.25 mmol, 1.00 equiv) in MeOH (10 mL), 2-oxoacetic acid (80% in water) (27.6 mg, 0.37 mmol, 1.20 equiv) and NaBH3CN (105 mg, 0.50 mmol, 2.00 equiv). The reaction mixture was stirred for 2 h at room temperature, then concentrated under vacuum to give 2-(5-(trifluoromethyl)-1H-indazol-3-ylamino)acetic acid as a yellow solid. LC-MS-(ES, m/z) 261[M+H]+