Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[C:6]([NH2:21])[CH:5]=1.C(N(CC)CC)C.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36].C(=O)([O-])O.[Na+].[OH-].[Na+].Cl>C1COCC1.CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:22])=[CH:5][C:6]=2[NH:21][C:35]([C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)=[O:36])=[N:13]1
Reactant: COC(=O)c1ccc(C=Cc2n[nH]c3ccccc23)c(N)c1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)c(NC(=O)c2cccs2)c1
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A solution of 3-amino-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid methyl ester (0.51 g, 1.8 mmol) obtained in Step 1 of Example 217 and triethylamine (0.73 ml, 5.3 mmol) in THF (20 mL) was added with 2-thiophenecarbonyl chloride (0.20 g, 1.9 mmol) and stirred for 2 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain crude product. Further, the product was dissolved in methanol (10 mL) and 2 mol/L aqueous sodium hydroxide solution (2.0 mL) was added thereto, followed by stirring at 60° C. for 1 hour. The reaction mixture was acidified by hydrochloric acid (6 mol/L) and the precipitated crystal was collected by filtration to obtain (E)-4-[2-(1H-indazol-3-yl)vinyl]-3-[(thiophen-2-ylcarbonyl)amino]benzoic acid (0.28 g, 41%).
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:35][CH:36]([CH2:39][OH:40])[CH2:37][NH2:38]>CN(C=O)C.C(Cl)Cl>[OH:35][CH:36]([CH2:39][OH:40])[CH2:37][NH:38][C:1](=[O:22])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: NCC(O)CO
Reactant: CCCCCCCCC#CCC#CCC#CCCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCC#CCC#CCC#CCCCC(=O)NCC(O)CO

Procedure:
In the same manner as in the above example, 8 g of 5,8,11-eicosatriynoic acid in 40 cm3 of anhydrous DMF are treated initially with 5.62 g of carbonyldiimidazole. 4.1 cm3 of 2,3-dihydroxypropylamine are then added at 0° C. At the end of the reaction, the reaction mixture is poured into ice-cold water. The precipitated product is drained and dissolved in 300 cm3 of methylene chloride. The solution is dried over sodium sulphate and then concentrated under reduced pressure. The solid obtained is directly recrystallized in acetonitrile. 9 g of N-(2,3-dihydroxypropyl)-5,8,11-eicosatriynamide are thereby obtained in the form of very pate beige crystals of melting point 87° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:2]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:3][CH2:4][CH2:5][C:6]#[CH:7]
Reactant: C#CCCCCCl
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCCCN1CCCCC1
Yield: 54.8 %

Procedure:
A solution of 6-chlorohex-1-yne (5 mL, 41.3 mmol), piperidine (4.08 mL, 41.3 mmol) and sodium hydrogen carbonate (4.16 g, 49.5 mmol) in DMF (50 mL) was refluxed for 16 hours. The reaction was concentrated in-vacuo and the residue partitioned between ether (150 mL) and water (150 mL). The organic was separated and the aqueous back extracted with diethyl ether (50 mL). The combined organics were washed with brine (150 mL), dried (MgSO4), filtered and concentrated in vacuo to give a crude sample of the title compound (3.74 g). Oxalic acid (2.161 g, 24 mmol) was added to the crude product. The resultant solid was recrystallised from ethanol, collected by filtration and dried in-vacuo to give 1-(hex-5-yn-1-yl)piperidine oxalic acid salt (4.66 g). The solid was partitioned between diethyl ether (150 mL) and saturated aqueous sodium bicarbonate (150 mL). The organic was separated and dried (MgSO4) filtered and concentrated in vacuo to give the title compound as a yellow oil (1.93 g).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][CH2:17][C:18]([OH:25])([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:15]=1.CO.C(=O)([O-])[O-].[K+].[K+].O>C(O)(=O)C>[OH:25][C:18]([CH3:24])([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16][C:13]1[O:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])=[CH:15][CH:14]=1
Reactant: CCCCCC(C)(O)CCc1ccc(CCCCCCCC(=O)OC)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCC(C)(O)CCc1ccc(CCCCCCCC(=O)O)o1

Procedure:
A mixture of XIII (0.91 g, 0.0025 mole), methanol (10 ml), and 20% potassium cabonate (5 ml) was stirred and refluxed for 90 minutes. The clear yellow solution was mixed with water (15 ml) and acidified to pH 5-6 with acetic acid. The emulsion was extracted with two 15-ml portions of ether. The combined ethereal extracts were dried over magnesium sulfate. Ether was distilled off from a water bath (60°C), at last under 0.1 mm Hg. The yellow, oily residue (0.86 g) was purified by chromatography on three 20 × 20 cm preparative tlc plates (Merck silica gel 60F254 --2 mm layer), and the isolated crude XII herefrom was distilled at 175°-185°C and 0.03 mm Hg to give 0.63 g XII (71%) as a light yellow oil, nD25 1.4844.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I[CH2:17][CH3:18].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][N:10]([CH2:17][CH3:18])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: COC1(c2cccc(Cl)c2F)CCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCC(OC)(c2cccc(Cl)c2F)C1
Yield: 35.8 %

Procedure:
Preparation according to Example 2. (+3-(3-chloro-2-fluorophenyl)-3-methoxypyrrolidine (0.234 g, 1.02 mmol), tetrahydrofuran (20 ml), iodoethane (0.122 ml, 1.15 mmol) and triethylamine (0.285 ml, 2.04 mmol), the solution was stirred for 26 h. Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 65:35) gave the title compound 0.094 g (35.9%). [a]D=−16.1° (methanol). The amine was converted to the fumaric acid salt and recrystallized from 2-propanol/diisopropyl ether: M.p. 131-133° C. MS m/z (rel. intensity, 70 eV) 257 (M+, 4), 242 (38), 227 (20), 157 (31), 71 (bp).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccccn3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:36][CH:35]=2)=[O:9])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1C(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cn1nccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
A mixture of 1-methyl-1H-pyrazol-5-carboxylic acid (1.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.82 g), 1-hydroxybenzotriazole monohydrate (1.70 g) and chloroform (20 mL) was stirred at a room temperature for 15 minutes. Thereafter, 4-aminobenzotrifluoride (1.27 g) was added to the reaction solution, and the obtained mixture was then stirred for 24 hours. Thereafter, the reaction solution was concentrated under a reduced pressure, and the residue was then purified by column chromatography (chromatorex NH, hexane:ethyl acetate=4:1), so as to obtain the title compound (1.00 g) in the form of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:20]=[C:19](F)[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[N:6][C:7]=1[NH:8][CH3:9].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:20]=[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[N:6][C:7]=1[NH:8][CH3:9]
Reactant: CNc1ncc(Oc2cc(F)ccc2C(=O)OC)cc1Cl
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNc1ncc(Oc2cc(N3CCNCC3)ccc2C(=O)OC)cc1Cl

Procedure:
A solution of EXAMPLE 377E (0.230 g) and piperazine (0.255 g) in dimethylsulfoxide (3 mL) was heated to 85° C. for 1 hour. The reaction was cooled and diluted with ethyl acetate (75 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OCC)(=O)C>ClCCl>[C:32]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)CN(c1ccc2[nH]ccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(c1ccc2c(ccn2C(=O)c2ccccc2)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
50 mg tert.butyl [(3,5-dichloro-phenylsulphonyl)-(1H-indol-5-yl)-amino]-acetate are dissolved in 2 ml dichloromethane. 5 mg powdered sodium hydroxide and 19 μl benzoyl chloride are added. Then the mixture is stirred for 4 hours at ambient temperature, divided between 1 N sodium hydroxide solution and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried with magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1:2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:25]2[C:20](=[N:21][C:22]([S:27][CH3:28])=[N:23][C:24]=2[NH2:26])[NH:19][N:18]=1.C(NC(C)C)(C)C>S(Cl)(Cl)=O.O1CCCC1>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:25]2[C:20](=[N:21][C:22]([S:27][CH3:28])=[N:23][C:24]=2[NH:26][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[NH:19][N:18]=1
Reactant: O=C(O)c1ccccn1
Reactant: CSc1nc(N)c2c(-c3ccccc3Cl)n[nH]c2n1
Solvent: CC(C)NC(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CSc1nc(NC(=O)c2ccccn2)c2c(-c3ccccc3Cl)n[nH]c2n1
Temperature: 25 °C

Procedure:
Pyridine-2-carboxylic acid (78 mg, 0.64 mmol) was placed in 5 ml thionyl chloride and refluxed for 3 hours. Excess thionyl chloride was then removed in vacuo and the crude acid chloride was suspended in 2 ml anhydrous tetrahydrofuran. The solution of acid chloride was added to a mixture of 3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (190 mg, 0.64 mmol) and diisopropylamine (247 mg, 1.92 mmol) in 6 ml anhydrous tetrahydrofuran. The reaction mixture was refluxed for 15 h. After cooling to room temperature the resulting mixture was partition between 60 ml ethylacetate and 15 ml brine. The organic layer was washed 3 times with 3N HCl, next with saturated sodium bicarbonate solution and brine. After drying with sodium sulfate and solvent evaporation in vacuo, 140 mg of pyridine-2-carboxylic acid [3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amide, MS: 397.1 (M+H), was obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:44]1([CH2:50][C@H:51]([C:53]([OH:55])=[O:54])[NH2:52])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:52][C@@H:51]([C:53]([OH:55])=[O:54])[CH2:50][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.4 %

Procedure:
N-(tert-butoxycarbonyl)glycine (2.0 g, 11.4 mmol) and DIPEA (4.0 g, 31 mmol) were dissolved in methylene chloride (25 ml). TBTU (4.1 g, 12.8 mmol) was added and the mixture was stirred for 15 min at room temperature. 3-cyclohexyl-D-alanine (2.1 g, 12.2 mmol) was added and the reaction mixture was stirred over night at room temperature. The reaction mixture was transferred to a separation funnel and was then extracted with a water/acetic acid solution (100 ml 5% acetic acid). The organic layer was separated and evaporated under reduced pressure. The residue was dissolved in formic acid (20 ml) and the mixture was stirred over night at 40° C. The formic acid was removed under reduced pressure. The residue was washed with water (50 ml) and then stirred in aceton (25 ml) for 1 h at room temperature. The solid material was filtered off and washed with aceton (20 ml). 530 mg (20%) of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([NH:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:19]([O-])=O>CO.[Pd]>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[NH2:1])[O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)c1cccc(Oc2ccc(N)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cccc(Oc2ccc(N)c(N)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(4-Amino-3-nitro-phenoxy)-N-methyl-benzamide (Step B, 0.5 g, 1.7 mmol, 1.0 eq.) was dissolved in MeOH (10 mL) and the atmosphere was replaced by argon. A catalytic amount of 10% Pd/C was added and the argon was replaced by a H2 atmosphere. The mixture was stirred for 16 h at RT at atmospheric pressure. The Pd/C was filtered off and the obtained 3-(3,4-diamino-phenoxy)-N-methyl-benzamide was used crude in the next step.
Reaction SMILES: [S:1]([C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[CH:7][C:6]=1[OH:13])([OH:4])(=[O:3])=[O:2].[Cl:14]Cl>O.S(=O)(=O)(O)O>[S:1]([C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[C:7]([Cl:14])[C:6]=1[OH:13])([OH:4])(=[O:2])=[O:3]
Reactant: ClCl
Reactant: Cc1cc(O)c(S(=O)(=O)O)cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(Cl)cc(S(=O)(=O)O)c(O)c1Cl

Procedure:
According to the present invention there is provided a process for preparing 2-nitro-4,6-dichloro-5-methylphenol comprising sulphonation of 4-chloro-5-methyl-phenol with concentrated sulphuric acid at elevated temperature to form 2-sulpho-4-chloro-5-methylphenol, thereafter diluting the reaction mixture with water to a sulphuric acid content of 20 to 30%, chlorinating the resulting 2-sulpho-4-chloro-5-methylphenol with chlorine at elevated temperature and normal or elevated pressure to form 2-sulpho-4,6-dichloro-5-methylphenol and reacting the 2-sulpho-4,6-dichloro-5-methylphenol with nitric acid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])O.[Na+]>O1CCCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(I)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1ccc(I)cc1
Reaction time: 3 h

Procedure:
3-(4-iodophenyl)propanoic acid (Atlantic Research Chemicals Ltd.) (2.76 g, 10.00 mmol) were dissolved in tetrahydrofuran (100 mL) and added slowly to a suspension of lithium aluminium hydride (0.23 g, 6.00 mmol) in 100 mL tetrahydrofuran. The reaction was stirred for 3 h, then 1 N aqueous sodium hydrogen carbonate (150 mL) were added slowly and the resulting mixture was extracted with ethyl acetate (3×400 mL), the organic extracts were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([NH:13][CH:14]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29]C)[CH:27]=2)[NH:22][CH:21]=1)[C:15]([F:18])([F:17])[F:16])(=[O:12])=[O:11].B(Br)(Br)Br>ClCCl>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[S:10]([NH:13][CH:14]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=2)[NH:22][CH:21]=1)[C:15]([F:18])([F:16])[F:17])(=[O:12])=[O:11]
Reactant: COc1ccc2[nH]cc(CC(NS(=O)(=O)c3c(C)cc(C)cc3C)C(F)(F)F)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)NC(Cc2c[nH]c3ccc(O)cc23)C(F)(F)F)c(C)c1
Reaction time: 3 h
Yield: 58.6 %

Procedure:
To a stirred solution of 60 mg (0.14 mmol) of 2,4,6-trimethyl-N-[2,2,2-trifluoro-1-(5-methoxy-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide in 1 mL of anhydrous dichloromethane was slowly added 0.34 mL (0.34 mmol) of a 1 M solution of boron tribromide in dichloromethane. After 3 hours at room temperature, the reaction was cooled in ice, quenched with 0.5 mL of cold water and stirred for 5 minutes. The reaction mixture was diluted with 50 mL of dichloromethane, filtered through CELITE® filter aid, and concentrated in vacuo. The crude mixture was purified by preparative TLC eluting with dichloromethane-ethyl acetate (85:15) to afford 35 mg (60%) of the title compound as an off-white solid.
Reaction SMILES: [OH2:1].[Cl:2][C:3]1[C:8]([CH3:9])=[C:7](Cl)[N:6]=[C:5]([CH3:11])[N:4]=1.[OH-].[Na+].[Cl-].[Na+]>S(=O)(=O)(O)O>[CH3:11][C:5]1[N:6]=[C:7]([OH:1])[C:8]([CH3:9])=[C:3]([Cl:2])[N:4]=1
Reactant: Cc1nc(Cl)c(C)c(Cl)n1
Reactant: O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: Cc1nc(O)c(C)c(Cl)n1
Temperature: 23 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of water (5.6 mL) in sulfuric acid (21 mL) at 20° C. was added the 4,6-dichloro-2,5-dimethylpyrimidine (9.3 g, 52.5 mmol). The reaction mixture was stirred for 2 hours at 23° C. and then poured onto ice to which sodium hydroxide (16 g, 400 mmol) had been added. When the ice melted, sodium chloride (60 g) was dissolved in the solution which was then extracted with ethyl acetate. The combined ethyl acetate extracts were dried, filtered, and concentrated in vacuo to afford 7.8 g (94%) of product as a fluffy white solid. The recrystallization of the product from ethanol provided an analytically pure sample, m.p. 224°-225° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[Na].[CH3:22][SH:23].CN(C=O)C>O>[CH3:22][S:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2s1
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.30 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzothiazole, 0.14 g of methylmercaptan sodium salt and 3 ml of DMF was stirred at room temperature for 20 minutes. To the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate three times. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 2-[3-(methylthio)pyridin-4-yl]-5-(trifluoromethyl)benzothiazole (hereinafter, referred to as the present compound 5).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[N:31]=[N:32][N:33]([CH:38]2[CH2:41][CH:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:39]2)[C:34]=1[CH:35]1[CH2:37][CH2:36]1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>[Cl-].[Na+].O>[CH:35]1([C:34]2[N:33]([CH:38]3[CH2:39][CH:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:41]3)[N:32]=[N:31][C:30]=2[CH:21]([CH2:20][CH2:19][OH:18])[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:36][CH2:37]1
Reactant: CC(C)CC1CC(n2nnc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC1CC(n2nnc(C(CCO)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
tert-Butyl 5-(tert-butyldiphenylsilanyloxy)-3-[5-cyclopropyl-1-(3-isobutylcyclobutyl)-1H-[1,2,3]triazol-4-yl]valerate (233 mg) and tetrahydrofuran (3.0 mL) were mixed. To the mixture were added tetrabutylammonium fluoride (1 M in tetrahydrofuran) (0.444 mL) and 80 v/v % aqueous acetic acid (0.045 mL) at ice temperature. The mixture was stirred at RT overnight. After an addition of brine at ice temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/2) to give the title compound (107 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:20][N:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: CNc1ccccc1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(N(C)c3ccccc3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with N-methylaniline gave the title compound as a tan solid, mp 153-155° C.