Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1N2N=NN=C2C2N=C(CCC)N(CCCS(C3C=CC(C(Cl)=O)=CC=3)(=O)=O)C=2C=1C.C(N)CCC.N1CCOCC1.[CH2:44]([NH:48][C:49](=[O:79])[C:50]1[CH:55]=[CH:54][C:53]([S:56]([CH2:59][CH2:60][CH2:61][N:62]2[C:70]3[C:69]([CH3:71])=[C:68]([CH3:72])[N:67]4N=N[N:75]=[C:66]4[C:65]=3[N:64]=[C:63]2[CH2:76][CH2:77][CH3:78])(=[O:58])=[O:57])=[CH:52][CH:51]=1)[CH2:45][CH2:46][CH3:47]>ClCCl>[NH2:75][C:66]1[C:65]2[N:64]=[C:63]([CH2:76][CH2:77][CH3:78])[N:62]([CH2:61][CH2:60][CH2:59][S:56]([C:53]3[CH:54]=[CH:55][C:50]([C:49]([NH:48][CH2:44][CH2:45][CH2:46][CH3:47])=[O:79])=[CH:51][CH:52]=3)(=[O:58])=[O:57])[C:70]=2[C:69]([CH3:71])=[C:68]([CH3:72])[N:67]=1
Reactant: CCCCNC(=O)c1ccc(S(=O)(=O)CCCn2c(CCC)nc3c2c(C)c(C)n2nnnc32)cc1
Agent: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCS(=O)(=O)c1ccc(C(=O)Cl)cc1
Solvent: CCCCN
Solvent: C1COCCN1
Solvent: ClCCl
Product: CCCCNC(=O)c1ccc(S(=O)(=O)CCCn2c(CCC)nc3c(N)nc(C)c(C)c32)cc1
Reaction time: 8 h

Procedure:
The general methods described in Example 101 were followed with the following modifications. To one-third of the crude solution of 4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]benzoyl chloride in dichloromethane, described in Part B of Example 101, was added butylamine (0.49 mL, 4.9 mmol) in lieu of morpholine, and the reaction was stirred overnight. Additional butylamine (0.5 mL) was added, and the reaction was stirred for two hours. Dichloromethane (100 mL) was added to the reaction mixture, and the resulting solution was washed with saturated aqueous sodium carbonate (3×25 mL), water (3×25 mL), 10% by volume acetic acid in water (3×30 mL), and water (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was dried for three hours in a vacuum oven at 100° C. and then triturated with ethyl acetate to provide a solid that was isolated by filtration and dried for three hours in a vacuum oven at 90° C. N-Butyl-4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]benzamide (830 mg, 1.62 mmol) was treated as described in Part C of Example 101. The crude product was purified by column chromatography on silica gel (eluting sequentially with chloroform and 90:10 chloroform:methanol) to provide the product as an oil, which was recrystallized from ethyl acetate:hexane with a few drops of methanol to yield crystals. The crystals were isolated by filtration, washed with hexanes, and dried in a vacuum oven at 80° C. to provide 0.18 g of 4-[3-(4-amino-6,7-dimethyl-2-propyl-1II-imidazo[4,5-c]pyridin-1-yl)propane-1-sulfonyl]-N-butylbenzamide as a white powder, mp 147.0–149.0° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21]1([C:31](Cl)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>ClCCl>[C:21]1([C:31]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc2ccccc12)N1CCN(c2ccc(O)cc2)CC1
Reaction time: 3 h

Procedure:
To a stirring mixture of 4-(1-piperazinyl)phenol (5.54 g) and triethylamine (10.83 ml) in dichloromethane (140 ml) was added dropwise, 1-naphthalenecarbonyl chloride (9.83 ml). The resulting reaction mixture was stirred under a nitrogen atmosphere for 3 h. The mixture was partitioned between dichloromethane and water and the organic phase was washed with saturated brine, dried (MgSO4) and evaporated to dryness. The residue was suspended in 6:4 tetrahydrofuran-methanol (370 ml) and treated with a saturated solution of potassium carbonate in methanol (45 ml). The mixture was stirred at room temperature under a nitrogen atmosphere for 20 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic phase was washed with saturated brine, dried (MgSO4) and evaporated to give an oil (15.5 g), part of which (14.5 g) was purified by chromatography on a silica SPE bond elut cartridge eluting with 10% -80% ethyl acetate-cyclohexane gradient to give the title compound (8.9 g). LCMS RT=2.97 min.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:31]Cl>O>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:31]([C:30]3[CH:33]=[CH:34][C:35]([Cl:36])=[C:28]([Cl:27])[CH:29]=3)=[O:2])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Temperature: 25 °C

Procedure:
35 ml of nitrobenzene are cooled in an ice-bath and then treated in succession with 5.2 g of aluminum chloride and 5.0 g of 4-methyl-biphenyl. The mixture is brought to room temperature and then treated with 7.7 g of 3,4-dichlorobenzyl chloride. The mixture is stirred at room temperature, poured into water and extracted with methylene chloride. The extracts are washed with 2N hydrochloric acid and water, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel with toluene/ethyl acetate 9:1. 3,4Dichlorophenyl 4'-methyl-4-biphenylyl ketone is obtained.
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+]([C:7]1[CH:14]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])([O-])=O>CC(C)=O>[CH3:1][S:2][C:7]1[CH:14]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: C[S-]
Reactant: N#Cc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CSc1cc(S(F)(F)(F)(F)F)ccc1C#N
Temperature: 20 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
Sodium thiomethoxide (8.97 g) was added to a solution of 2-nitro-4-pentafluorosulphanylbenzonitrile (11.7 g) in acetone and stirred at 20° C. overnight, then evaporated and purified by column chromatography on silica gel eluting with ethyl acetate/hexane (3:97) to give 2-methylthio-4-pentafluorosulphanylbenzonitrile (4.65 g), m.p.101-102° C.
Reaction SMILES: [CH3:1][C@H:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][C@@H:4]([C:15]([OH:17])=[O:16])[N:3]1[C:18]([S:20][CH3:21])=[S:19].[N+](=[CH2:24])=[N-]>CCOCC>[CH3:1][C@H:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][C@@H:4]([C:15]([O:17][CH3:24])=[O:16])[N:3]1[C:18]([S:20][CH3:21])=[S:19]
Reactant: C=[N+]=[N-]
Reactant: CSC(=S)N1[C@H](C(=O)O)Cc2c([nH]c3ccccc23)[C@@H]1C
Solvent: CCOCC
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](C)N1C(=S)SC
Yield: 81.6 %

Procedure:
A mixture of (1S,3S)-1-methyl-2-[(methylthio)thiocarbonyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1.28 g), diazomethane [prepared from N-nitrosomethylurea (3.0 g) and 40% NaOH (9 ml)] and ether (100 ml) is allowed to stand under ice-cooling overnight. The resulting precipitates are collected by filtration and dried to give the title compound (1.09 g, 82%), m.p. 229°-230° C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:36])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:36][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1NC(=O)Cc1ccc(-n2cnc3cccnc32)cc1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-o-tolyl-2H-pyrazol-3-ylamine. Title compound: ES-MS: 465.07 [M+H]+; tR=3.1 min (System 3).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:18][C:19]1[CH:39]=[CH:38][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:37]=[CH:36][C:31]3[NH:32][C:33]([CH3:35])=[N:34][C:30]=3[CH:29]=2)=[O:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:37]=[CH:36][C:31]3[N:32]([C:8]4[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=4[C:1]#[N:2])[C:33]([CH3:35])=[N:34][C:30]=3[CH:29]=2)=[O:27])=[CH:38][CH:39]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:37]=[CH:36][C:31]3[N:32]=[C:33]([CH3:35])[N:34]([C:8]4[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=4[C:1]#[N:2])[C:30]=3[CH:29]=2)=[O:27])=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: Cc1nc2cc(C(=O)NCCc3ccc(Cl)cc3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nc2cc(C(=O)NCCc3ccc(Cl)cc3)ccc2n1-c1ccc(CC(=O)O)cc1C#N
Product: Cc1nc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2n1-c1ccc(CC(=O)O)cc1C#N
Reaction time: 4 h
Yield: 59.7 %

Procedure:
A mixture of tert-butyl 2-(3-cyano-4fluorophenyl)acetate (0.0825 g, 0.351 mmol), N-(4-chlorophenethyl)-2-methyl-1H-benzo[d]imidazole-5carboxamide (0.100 g, 0.319 mmol) and potassium carbonate (0.0661 g, 0.478 mmol) was stirred together in 3 mL of DMSO at 85° C. After stirring for 4 hours, the reaction was loaded onto a silica gel samplet and the product eluted using a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes. The resulting oil was dissolved in DCM (1 mL) and treated with TFA (1 mL). After 2 hours, the reaction was concentrated, and the residue was loaded onto silica gel. The product was eluted using a gradient of 0.5% MeOH/DCM containing 0.5% AcOH to 10% MeOH/DCM containing 0.5% AcOH to provide 2-(4-(5-(4-chlorophenethylcarbamoyl)-2-methyl-1H-benzo[d]imidazol-1yl)3-cyanophenyl)acetic acid and 2-(4-(6-(4-chlorophenethylcarbamoyl)-2-methyl-1H-benzo[d]imidazol-1-yl)-3-cyanophenyl)acetic acid (0.045 g, 29.9% yield) as a 2:1 mixture. 1H NMR (400 MHz, CD3OD) δ 8.49 (t, J=5.5 Hz, NH), 7.77-7.82 (m, 2H), 7.68 (s, 1H), 7.52-7.54 (m, 1H), 7.20-7.32 (m, 4H) 7.00-7.08 (m, 2H), 3.71 (s, 2H), 3.58 (q, J=6.8 Hz, 2H), 3.30 (s, 3H), 2.90 (t, J=7.3 Hz, 2H). MS(APCI)=473.5 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>>[C:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1c(OC)cc(C(C)=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C(C)=O)cc(OC)c1OCCCC(=O)O
Yield: 86 %

Procedure:
Following the method of Preparation 3, 0.179 g (0.577 mmol) of 4-(4-acetyl-2,6-dimethoxyphenoxy)-butanoic acid, ethyl ester is treated with potassium carbonate, producing an off-white solid. Recrystallization from ethyl acetate/hexane gives 4-(4-acetyl-2,6-dimethoxyphenoxy)butanoic acid as white crystals (0.14 g, 88%): m.p. 122°-24° C.; IR (KBr) 1735, 1660 cm-1 ; 1H-NMR (CDCl3) is consistent with the desired product; MS (FAB) m/e 283 (M+ +H). Analysis calculated for C14H18O6 : C, 59.57; H, 6.43; O, 34.01. Found: C, 59.34; H, 6.40; O, 34.26.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)=[C:2]([CH:9]=1)[NH2:1]
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nnn[nH]2)c(N)c1
Temperature: 100 °C
Yield: 42.2 %

Procedure:
To a mixture of 2-amino-4-methylbenzonitrile (500 mg, 3.3 mmol), sodium azide (4.3 mmol, 1.3 eq.), and triethylamine hydrochloride (4.3 mmol, 1.3 eq.) in a sealed tube, 8 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with another 10 mL of toluene, transferred to a separatory funnel and washed 3×20 mL with water. The aqueous layer was collected and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 244 mg of 5-methyl-2-(1H-tetrazol-5-yl)aniline. MS (EI) for C8H9N5: 176 (M+H). Step 2: N-[5-Methyl-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a solution of 5-methyl-2-(1H-tetrazol-5-yl)aniline (240 mg, 1.4 mmol) in 6 mL of DCM was added DIPEA (7.5 mmol, 5.5 eq.) followed by thiophene-2-carbonyl chloride (6.8 mmol, 5 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The basic aqueous extractions and final brine extraction were combined and acidified to a pH of 4 with concentrated HCl. The resulting solid was collected by filtration. This crude material was further purified by redissolving the material into minimum volume of aqueous NaOH (0.1 M), and then reacidified with concentrated HCl. The solid was collected by filtration, washed with EtOAc, and dried under vacuum to afford 26.8 mg of the desired product. 1H-NMR (400 MHz, d6-DMSO): δ 11.60 (s, 1H), 8.35 (s, 1H), 7.98-7.94 (m, 2H), 7.90 (d, 1H), 7.33 (t, 1H), 7.20 (d, 1H), 2.42 (s, 3H). MS (EI) for C13H11N5OS: 286 (M+H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:20][CH:21]=3)[N:15]=2)[CH2:6]1)=[O:4].B.O1CCCC1.Cl.C(O)C>O1CCCC1>[F:29][C:2]([F:1])([F:28])[CH:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:20][CH:21]=3)[N:15]=2)[CH2:6]1)[OH:4]
Reactant: O=C(N1CCCC(c2nc(-c3cnc(-c4ccccc4)nc3)c[nH]2)C1)C(F)(F)F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: OC(N1CCCC(c2nc(-c3cnc(-c4ccccc4)nc3)c[nH]2)C1)C(F)(F)F
Temperature: 65 °C

Procedure:
To a room temperature solution of (±)-2,2,2-trifluoro-1-(3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)ethanone (18 mg, 0.04 mmol) in tetrahydrofuran (1 mL) was added borane-tetrahydrofuran (1 M, 0.13 mL, 0.13 mmol). The reaction mixture was heated at 65° C. for four hours, cooled, treated carefully with 6 mL of 6N HCl and 2 mL of ethanol and heated at 65° C. for one hour. The cooled reaction mixture was extracted four times with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered, and rotovapped. The residue was chromatographed on silica (4 g) and eluted with 1:20:80 to 5:30:70 triethylamine-isopropanol-hexanes to give the title compound as a bright yellow solid. white solid; Rf 0.15 with 1:20:80 v/v triethylamine-isopropanol-hexanes; MS (ESI+) m/z 404 (M+1); H-PGDS FPBA IC50: 10 μM.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[N:15][C:14]([NH2:17])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:2]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1>>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([NH:17][C:14]2[N:15]=[CH:16][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)=[N:20][CH:21]=1
Reactant: Nc1ncc(-c2cccnc2)c2cccnc12
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(Nc2ncc(-c3cccnc3)c3cccnc23)nc1

Procedure:
The title compound, MS: m/e=314.0 (M+H+), was prepared in accordance with the general method of example 6 step 3 from 5-pyridin-3-yl-[1,7]naphthyridin-8-ylamine and 2-bromo-5-methylpyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:37])([F:36])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:36])[F:37])=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)Cn1ccc2ccc(N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2ccc(NCCCC#Cc3ccc(OC(F)(F)F)cc3)cc21
Temperature: 70 °C
Reaction time: 14 h
Yield: 13 %

Procedure:
A suspension of (6-amino-indol-1-yl)-acetic acid ethyl ester (50 mg, 0.23 mmol, WO 2003041714 A1), methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (148 mg, 0.46 mmol) and potassium carbonate (63 mg, 0.46 mmol) in DMF (1 ml) was stirred for 3 h at ambient temperature and for 14 h at 70° C. The reaction mixture was poured onto ethyl acetate/ice water 1/1, the layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica gel, heptane/AcOEt) to give 16 mg (0.03 mmol, 15%) of the title compound as yellow oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1.C(Cl)Cl>[CH3:21][S:22]([O:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(C#N)=NO)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#N)=NOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
20 g (0.114 mol) of α-hydroxyimino-4-methoxybenzylcyanide are dissolved in 100 ml of tetrahydrofuran (THF) and charged with 17.2 g (0.17 mol) of triethylamine. To this mixture are added dropwise and with cooling 14.3 g (0.0.12 mol) of methanesulfonyl chloride dissolved in 50 ml of THF. This mixture is then warmed to room temperature and stirred for 12 hours. Subsequently, the reaction solution is diluted with 300 ml of CH2Cl2, washed with water, dilute hydrochloric acid and again with water and is then dried over magnesium sulfate. After filtration, the solvent is distilled off on a rotary evaporator and the brownish crude product is recrystallised from toluene, giving 23.9 g (83%) of α-(methyl-sulfonyloxy-imino)-4-methoxybenzylcyanide in the form of beige crystals having an m.p. of 124-125° C. The 1H-NMR spectrum of the compound shows the product to be a pure stereoisomer.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O=S(Cl)Cl.[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccccc1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (2-hydroxyphenyl)acetic acid (11 g, 72.3 mmol) in 100 mL of MeOH was added SOCl2 (17.2 g, 144.7 mmol) at 0° C. The mixture was stirred at 50° C. overnight. The reaction was concentrated. The residue was purified column chromatography to give methyl(2-hydroxyphenyl)acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](=[O:14])(=[O:13])[NH2:12])[CH3:2].C(Cl)(=O)[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:12]=[C:17]=[O:18])(=[O:13])=[O:14])=[O:15])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1ccccc1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1S(=O)(=O)N=C=O
Temperature: 95 °C

Procedure:
At 85° C., 68.76 g (0.3 mol) 2-sulfamylbenzoic acid ethylester are added to 57.9 g (0.45 mol) oxalylchloride and 0.4 g diazadicyclo(2,2,2,)octane in 500 ml absolute toluene. The reaction mixture is heated yet three hours to an interior temperature of 95° C., until no gas development is observed.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1.[C:23]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CN(C=O)C.CCOC(C)=O.C(Cl)Cl>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:21]2[CH:22]=[C:18]([CH3:17])[N:19]=[CH:20]2)=[C:3]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=1)#[CH:23]
Reactant: Cc1c[nH]cn1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#Cc1ccc(-n2cnc(C)c2)c(Oc2ccccc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A mixture of 4-fluoro-3-phenoxybenzaldehyde (1.0 g, 4.6 mmol) in 10 mL of DMF was treated with 4-methylimidazole (1.0 g, 12 mmol) and warmed to 100° C. Stirred overnight. Diluted with EtOAc, washed with sat'd NaHCO3, dried (Na2SO4), concentrated. Dissolved in 10 mL of MeOH, treated with K2CO3 (1.0 g, 7.2 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.0 g, 5.2 mmol) and stirred overnight. Diluted with DCM and washed with water. Dried (Na2SO4), conc. Chromatography on silica (0-20% MeOH/DCM) gave the desired alkyne (1.1 g; 87% overall yield):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc3cc[nH]c23)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc3cc[nH]c23)CC1
Reaction time: 8 h
Yield: 63.4 %

Procedure:
4-Hydroxy-4-(1-H-indol-7-yl)-piperidine-1-carboxylic acid tert-butyl ester XVI (1.17 g, 3.7 mmol) was combined with pyridine (20 mL) and phosphorus oxychloride (0.7 mL, 7.4 mmol) at room temperature under nitrogen, and was stirred overnight. The reaction was partitioned between ethyl acetate (55 mL) and water (55 mL). The ethyl acetate layer was washed with water (2×30 mL) and brine (55 mL), then dried (MgSO4), filtered and concentrated to afford (700 mg, 64%) of 4-(1H-indol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester XVII.
Reaction SMILES: N[C@H](C=O)CCSC.[Na].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br-].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC(O)C>[Br:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: CSCC[C@H](N)C=O
Agent: [Br-]
Agent: [Na]
Solvent: CC(C)O
Product: BrCCC/C=C/c1ccccc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Metal sodium (303 mg) was added to dry 2-propanol (30 mL), and the mixture was stirred at 70° C. After the sodium was dissolved, benzaldehyde (1.0 g) was added to the solution at 0° C., 4-bromobutyltriphenylphosphonium bromide (5.4 g) was then added, and the mixture was gradually warmed to room temperature. After 5 hours, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the resultant mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (hexane) to obtain the title compound.