Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=1.C([O-])(O)=O.[Na+]>CN(C)C(=O)C>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([O:19][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=4)[CH2:15][CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=C([C@H]1CC[C@H](O)CC1)N1CCN(C2CCC2)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(O[C@H]2CC[C@H](C(=O)N3CCN(C4CCC4)CC3)CC2)nc1
Reaction time: 0.5 h

Procedure:
To a mixture of 115 mg (0.43 mmol) of trans-(4-Cyclobutyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone (Intermediate 3) in 1 ml of N,N-dimethylacetamide (DMA), 19 mg (0.44 mmol) of sodium hydride was added at room temperature and stirred for 30 min. To the mixture, 100 mg (0.72 mmol) of 6-chloronicotinonitrile (commercially available) was added and stirred at 160° C. for 14 h. The mixture was poured into saturated NaHCO3 solution., extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO4, and evaporated. The residue was purified by column chromatography on silica eluting with CH2Cl2 and methanol=from 98:2 to 95:5. The combined product fractions were evaporated to dryness to yield 30 mg (11%) of the title compound. MS (m/e): 369.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.C([Li])CCC.[O:21]1CCC[CH2:22]1.C=O>C(OCC)C.CCCCCC>[OH:21][CH2:22][CH2:8][C:6]1[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Agent: C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(CCO)nc(-n2c(C)ccc2C)c1
Temperature: -17.5 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of 2.97 mg (14.8 mmol) of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (from Example 53, Step A) in 15 mL of ethyl ether was added to a -20° C. solution prepared from 30 mL of ethyl ether and 12 mL (17 mmol) of 1.4 M n-butyllithium in hexane. The mixture was stirred for 1 h at -20 to -15° C. with the formation of a precipitate. Tetrahydrofuran (10 mL) was added, giving an orange-red solution of the intermediate anion. Paraformaldehyde in a separate flask was heated to 150-160° C., generating formaldehyde gas. The formaldehyde, diluted with nitrogen, was introduced as a gas stream impinging on the anion solution (kept at -15 to -10° C.) until the anion color had faded (20-30 min). The mixture was stirred an additional 15 min, quenched by the addition of 50 mL of saturated aqueous ammonium chloride, and extracted with 50 mL of ethyl acetate. The organic layer was washed with 30 mL of saturated aqueous sodium choride, dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on 90 g of silica gel eluting with 2 L of 30% ethyl acetate in hexane to give 1.55 g (45% yield) of 6-(2-hydroxyethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine as a colorless oil.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[OH:15])[C:9]([OH:11])=[O:10].[CH3:19]O>>[OH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[OH:15])[C:9]([O:11][CH3:19])=[O:10]
Reactant: CO
Reactant: O=C(O)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Yield: 71.4 %

Procedure:
Thionyl chloride (6.07 mL, 83 mmol) was added drop wise to a stirred solution of 3,4-dihydroxy-5-nitrobenzoic acid (14.4 g, 72.3 mmol) in MeOH (70 mL) at room temperature for 1 h. The reaction mixture was refluxed for 3 h and concentrated. The residue was recrystallized from water and vacuum-dried to afford the desired ester (11.0 g, 51.6 mmol, 71.4% yield).
Reaction SMILES: Cl.C([NH:6][S:7]([C:10]1[C:11]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]3[CH:25]=[N:26][C:27](C)=[C:28]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=4)[C:29]=3[CH2:30][OH:31])=[CH:18][CH:17]=2)=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])(C)(C)C.[NH3:43].CO>C(O)C>[OH:31][CH2:30][C:29]1[C:24]([CH2:23][NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:7](=[O:9])(=[O:8])[NH2:6])=[CH:17][CH:18]=2)=[CH:25][N:26]=[CH:27][C:28]=1[O:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=1)[C:40]([NH2:41])=[NH:43]
Reactant: Cc1ncc(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(CO)c1OCc1cccc(C#N)c1
Reactant: N
Agent: Cl
Solvent: CO
Solvent: CCO
Product: N=C(N)c1cccc(COc2cncc(CNc3ccc(-c4ccccc4S(N)(=O)=O)cc3)c2CO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Hydrogen chloride gas was bubbled into a suspension of 4′-{[5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-biphenyl-2-sulfonic acid tert-butylamide (13) (100 mg, 0.17 mmol) in absolute ethyl alcohol (30 mL) at 0° C. for 30 minutes. The septum was replaced and the reaction mixture was stirred at room temperature overnight. Hydrogen chloride gas was purged with nitrogen gas for 2 hours and the solvent evaporated to give the crude amide ester as a solid. Ammonia in methyl alcohol (30 mL, 7 M, 350 mmol) was added to the crude amide ester and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the product purified on a silica gel column using a mixture of dichloromethane:methyl alcohol (4:1) as eluant to give the corresponding 3-{4-hydroxymethyl-5-[(2′-sulfamoyl-biphenyl-4-ylamino)-methyl]-pyridin-3-yloxymethyl}-benzamidine (14) (90 mg, 97% yield) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([NH2:16])(=O)[CH2:11][C:12]([CH3:14])=O.[NH2:17][C:18]([NH2:20])=[O:19].C1COCC1>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[NH:20][C:18](=[O:19])[NH:17][C:12]([CH3:14])=[C:11]2[C:10]#[N:16])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)CC(N)=O
Reactant: NC(N)=O
Reactant: O=Cc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(C#N)C(c2cccc(Br)c2)NC(=O)N1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
A mixture of 3-bromobenzaldehyde (13.0 g, 70 mmol), acetoacetamide (7.08 g, 70 mmol), urea (5.26 g, 87.5 mmol), polyphosphate ester (9.1 g, 21 mmol) and THF (150 mL) was heated in a sealed tube for 18 h at 75° C. This mixture was cooled to room temperature; more polyphosphate ester (60.6 g, 140 mmol) was added and heating resumed for another 5 h. The reaction mixture was cooled to room temperature, poured into water (800 mL) and stirred for 18 h. The resulting precipitates were collected by vacuum filtration, washed with water and with ether, and air dried to yield 6-(3-bromophenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-(2H)-pyrimidine as a light yellow solid (16.25 g; 79%): 1H NMR (DMSO-d6, 400 MHz) δ 9.60 (s, 1H), 7.87 (s, 1H), 7.55 (m, 1H), 7.48 (m, 1H), 7.39 (t, 1H, J=7.9 Hz), 7.32 (d, 1H, J=7.9 Hz), 5.14 (s, 1H), 2.02 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:26]=[C:23]([CH:24]=[O:25])[C:22]([OH:27])=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:27][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:26][C:23]=1[CH:24]=[O:25]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3ccc(OC(F)(F)F)cc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-trifluoromethoxysalicylaldehyde (412 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-trifluoromethoxybenzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
METHOD 2 N-tert-butoxycarbonyl L-proline (3.04 g, 14.1 mmol) and L-proline methyl ester hydrochloride (2.34 g, 14.1 mmol) were dissolved in CH2Cl2 (25 mL). N,N-diisopropylethylamine (1.82 g, 14.1 mmol) was added and the solution cooled to 0° C. (icebath). HOBt hydrate (2.16 g, 14.1 mmol) and then EDC hydrochloride (2.97 g, 15.5 mmol) were added together with 15 mL CH2Cl2. The icebath was removed and the reaction mixture stirred for 16 h 15 min at room temperature. The reaction mixture was diluted with CH2Cl2 (60 mL) and the solution washed with 1M HCl(3×25 mL), 7.5% (w/w) K2CO3 solution (3×25 mL) and saturated brine (25 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a very pale yellow, almost clear oil, which was dried under high vacuum overnight. The compound (3.67 g, 79%) showed spectral characteristics in accordance with published data1; δH (200 MHz; d6-DMSO) 4.56-4.31 (2H, m, CαH(Pro1)/CαH(Pro2)), 3.78-3.28 (4H, m, CδH2(Pro1)/CδH2(Pro2)), 3.67 (3H, s, OCH3, rotomer 1), 3.65 (3H, s, OCH3, rotomer 2), 2.26-1.65 (8H, m, CH2), 1.40/1.34/1.22 (9H, s, (CH3)3, all rotomers); δC (75 MHz; CDCl3) 172.8, 172.5, 171.5, 171.0, 154.4, 153.6, 79.3, 58.5, 57.6, 57.5, 53.3, 52.0, 51.9, 46.7, 46.5, 46.3, 29.8, 28.9, 28.7, 28.6, 28.3, 28.2, 24.9, 24.8, 23.9, 23.4
Reaction SMILES: [CH2:1]([O:15][CH:16]([CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:17]N1C(=O)C2=CC=CC=C2C1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O.[NH2:46]N>C(O)C>[CH2:31]([O:30][CH:29]([NH2:46])[CH:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:17])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCCCOCC(CN1C(=O)c2ccccc2C1=O)OCCCCCCCCCCCCCC
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCOC(C)C(N)OCCCCCCCCCCCCCC
Yield: 86 %

Procedure:
Crude N-(2,3-dimyristyloxypropyl)phthalimide 4 (20.0 g, 25.0 mmol) was dissolved in ethanol (300 ml). Hydrazine monohydrate (20 ml, 412.3 mmol) was added and the reaction was left to reflux overnight. The ethanol was removed on the rotary evaporator and the residue was redissolved in chloroform (200 ml). The precipitate was filtered off and the chloroform was removed on the rotary evaporator. TLC (10% MeOH—CHCl3, developed in Molybdate) indicated that most of the starting material had reacted to form product. This resulting product was further purified by flash column chromatography (0-5% MeO—CHCl3) to yield 10.4 g (89.7% over three steps from 1,2-dimyristyloxypropan-3-ol 2) of 1,2-dimyristyloxypropylamin 5.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:9]([O:11][CH3:12])=[O:10])(=O)C>CO>[OH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(COC(C)=O)c1
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(CO)c1
Temperature: 25 °C

Procedure:
In a 5-liter three-necked round-bottomed flask equipped with a reflux condenser, overhead stirrer and nitrogen inlet, was placed 318 g of the previously prepared methyl 3-acetoxymethyl-4-nitrobenzoate and 3.2 l of anhydrous methanol. To the resulting solution was bubbled in 40 g of hydrogen chloride and the resulting mixture was refluxed for 3 hours. After cooling to room temperature the solvent was removed using a rotary evaporator yielding 273 g of methyl 3-hydroxymethyl-4-nitrobenzoate as a yellow solid containing traces of methanol, which was used as such in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:10][CH:9]=[C:8]([CH:19]2[CH2:21][CH2:20]2)[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>CCO>[CH:19]1([C:8]2[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]([NH:12][C:13]3[CH:18]=[N:17][CH:16]=[N:15][CH:14]=3)=[CH:10][CH:9]=2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc(C2CC2)ccc1Nc1cncnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A suspension of 6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester (1.85 g, 6.5 mmol) from example A-2 in EtOH (15 ml) was treated with 1N NaOH (13 ml). The reaction mixture was stirred at r.t. overnight. The compact suspension was brought to pH 6 by addition of 1N HCl. The solid was collected by filtration, washed with EtOH and dried to give the product (1.29 g, 77%) as off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]2[S:11][C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:9]=2[CH:8]=1.I([O-])(=O)(=O)=[O:22].[Na+]>C(O)C.O>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][S:5]([CH2:6][C:7]1[CH:19]=[CH:18][C:10]2[S:11][C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:9]=2[CH:8]=1)=[O:22]
Reactant: CN(C)CCSCc1ccc2sc(S(N)(=O)=O)cc2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)CCS(=O)Cc1ccc2sc(S(N)(=O)=O)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a partial solution of 5-[2-(dimethylamino)ethylthiomethyl]-2-sulfamoylbenzo[b]thiophene (1.32 g, 0.004 mol) in 20 ml of ethanol and 40 ml of water was added sodium metaperiodate (0.94 g, 0.0044 mol) and the mixture was stirred at room temperature for 16 hours over night. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The white solid residue was recrystallized twice from 4/1 (V/V) water/ethanol and chromatographed on silica gel eluting with 7.5% (V/V) methanol/CHCl3. There was recovered 0.88 g of white solid, m.p. 180°-183° C., dec. (Yield 64%).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH3:5][C:6]([Si:9](Cl)([CH3:11])[CH3:10])([CH3:8])[CH3:7].N#N.Cl>N1C=CC=CC=1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:4][Si:9]([C:6]([CH3:8])([CH3:7])[CH3:5])([CH3:11])[CH3:10])[C:2]#[CH:3]
Reactant: C#CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCO[Si](C)(C)C(C)(C)C
Reaction time: 72 h

Procedure:
To a solution of 5.82 mL of propargyl alcohol in 20 mL of pyridine and 30 mL of CH2Cl2 was added 0.122 g of DMAP and 16.88 g of TBDMSCl in a N2 atmosphere. After stirring 3 days, the reaction was poured into 100 mL of 1N HCl, and diluted with CH2Cl2. The layers were separated and the organic layer washed with 100 mL of 1N HCl (2×), 10% NaHCO3, H2O and brine and dried (MgSO4). Filtration and concentration provided 15.07 g of an oil which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[NH2:24][CH:25]([CH2:28][CH3:29])[CH2:26][OH:27]>>[OH:27][CH2:26][CH:25]([NH:24][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])[CH2:28][CH3:29]
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: CCC(N)CO
Product: CCC(CO)NC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)cn1
Yield: 70 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using rac-2-amino-1-butanol instead of isopropylamine, to the title compound (87 mg, 70%), which was obtained as a white solid. MS: m/e=383.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:3][CH2:2]1.[Li+].[OH-]>O1CCOCC1.CCOC(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:33])[F:34])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(OCC4CC4)c(C(F)(F)F)c3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(OCC4CC4)c(C(F)(F)F)c3)cc21
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (22.9 mg, 0.047 mmol) in dioxane was added 1M LiOH (0.188 mL, 0.188 mmol). The reaction mixture was stirred 3 h, taken up in EtOAc and washed with 1 M HCl. The EtOAc extract was dried over MgSO4 and concentrated. The residue was purified by preparative HPLC/MS to give the title compound as a solid. LCMS m/z=460.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.30-0.38 (m, 2H), 0.52-0.59 (m, 2H), 1.17-1.27 (m, 1H), 2.03-2.13 (m, 1H), 2.35 (dd, J=15.98, 8.91 Hz, 1H), 2.59-2.76 (m, 4H), 3.99 (d, J=6.69 Hz, 2H), 5.05 (s, 2H), 6.69 (dd, J=8.84, 2.40 Hz, 1H), 6.91 (d, J=2.53 Hz, 1H), 7.19 (d, J=8.72 Hz, 1H), 7.24 (d, J=8.46 Hz, 1H), 7.62-7.71 (m, 2H), 10.45 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.[CH:14](OCC)(OCC)OCC.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(O)=O>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=2)[CH:14]=[N:26][N:25]=[N:24]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)Cc1ccc(N)cn1
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(-n2cnnn2)cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of ethyl (5-aminopyridin-2-yl)acetate (1.0 g, 5.5 mmol), CH(OEt)3 (1.31 g, 8.80 mmol) in AcOH (10 mL) was added NaN3 (0.54 g, 8.3 mmol) at room temperature. The mixture was heated to 80° C. and stirred for 3 hours. The mixture was concentrated under reduce pressure. Water was added, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatography via silica gel to give ethyl [5-(1H-tetrazol-1-yl)pyridin-2-yl]acetate. 1H-NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.90 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.96 (s, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[K].[CH3:26][S:27]([CH3:30])(=[NH:29])=[O:28]>COCCOC>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([N:29]=[S:27]([CH3:30])([CH3:26])=[O:28])=[O:11]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CS(C)(=N)=O
Agent: [K]
Solvent: COCCOC
Product: CS(C)(=O)=NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 38.01 g of 5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrobenzoyl chloride in 125 ml of absolute 1,2-dimethoxyethane is added dropwise at 10°-15° C. while stirring during 30 minutes to a suspension of the dimethyl sulphoximine potassium salt in 250 ml of absolute 1,2-dimethoxyethane. The mixture is stirred at room temperature for 24 hours and subsequently evaporated to dryness under reduced pressure. The resinous residue is dissolved in 1.25 l of diethyl ether, the solution is filtered through Celite and the filtrate is evaporated to dryness. The residue is subsequently purified by chromatography on silica gel with methylene chloride. There is obtained N-[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrobenzoyl]-S,S-dimethyl-sulphoximine as colourless crystals, m.p. 126°-127° C.; 1H-NMR (CDCl3): 7.99 (d,1H), 7.80 (d,1H), 7.60 (q,1H), 7.23 (d,1H) 7.14 (d,1H), 7.02 (q,1H) and 3.40 (s,6H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:3].[Br:14][CH2:15][CH2:16][CH2:17][Cl:18].CO>CCCCCC.C(OC)(C)(C)C>[Br-:14].[Cl:18][CH2:17][CH2:16][CH2:15][N+:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([CH3:1])[CH3:3]
Reactant: ClCCCBr
Reactant: CCCCCCCCCCN(C)C
Solvent: CCCCCC
Solvent: COC(C)(C)C
Solvent: CO
Product: CCCCCCCCCC[N+](C)(C)CCCCl
Product: [Br-]
Temperature: 65 °C

Procedure:
Into a 1000 mL, round-bottomed flask equipped with air condensers and a magnetic stirring plate was charged N,N-dimethyldecylamine (200.0 grams, 1.08 moles), 1-bromo-3-chloropropane (170 grams, 1.08 moles) and methanol (200 mL). The reaction was maintained at 65° C. for 18 hours. Solvent was removed by rotary evaporation under reduced pressure and furthermore with high vacuum distillation to yield brown oil. The oil was placed in a beaker and stirred with hexane/t-butylmethylether 1:1 solution (400 mL) causing a white precipitate The solids were collected by vacuum filtration. Solids were dried in a vacuum oven at 30° C. overnight. Yield 305.0 grams (0.089 moles, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH3:9])=[N:6][CH:7]=1
Reactant: Clc1ccc(Br)cn1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1nccn1-c1ccc(Br)cn1
Temperature: 150 °C

Procedure:
A mixture of 5-bromo-2-chloro-pyridine (Aldrich, Buchs, Switzerland, 392 mg, 2.04 mmol), 2-methyl-1H-imidazole (Aldrich, Buchs, Switzerland, 251 mg, 3.06 mmol) and cesium carbonate (1.33 g, 4.08 mmol) in DMA (10 ml) was heated by microwave irradiation for 20 min at 100° C. and 2.5 h at 150° C. The reaction mixture was quenched with diluted brine (200 ml) and cooled. The precipitate was filtered, washed with water and dried to give the title compound as off-white solid. (HPLC: tR 2.03 min (Method A); M+H=238, 240 MS-ES).