Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1F.O.[NH2:16][NH2:17]>C(O)C>[N+:10]([C:7]1[CH:6]=[C:5]2[C:4]([C:3]([OH:2])=[N:16][NH:17]2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2c(O)n[nH]c2c1
Yield: 30.9 %

Procedure:
2-Fluoro-4-nitrobenzoic acid methyl ester (5 g, 25.11 mmol) and hydrazine hydrate (1.34 ml, 27.62 mmol) were dissolved in 250 ml of ethanol and heated under reflux for 11 h. A further 0.26 ml of hydrazine hydrate were added and heated under reflux for a further 6 h, and the mixture was concentrated and ethyl acetate and water were added. The precipitated residue was filtered off with suction and dried. Purification by preparative HPLC (PR18, acetonitrile/water 0.1% TFA) resulted in 1.39 g of product, M+H+: 180.05.
Reaction SMILES: [CH3:1][C@@H:2]([NH:13][CH2:14][C@@H:15]([C:17]1[CH:18]=[CH:19][C:20]2[N:21](N=N[N:25]=2)[CH:22]=1)[OH:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O.O.Cl[Sn]Cl.[C:31]([OH:43])(=[O:42])[CH2:32][C:33]([CH2:38][C:39]([OH:41])=[O:40])([C:35]([OH:37])=[O:36])[OH:34]>CO.C(O)C>[C:31]([OH:43])(=[O:42])[CH2:32][C:33]([CH2:38][C:39]([OH:41])=[O:40])([C:35]([OH:37])=[O:36])[OH:34].[NH2:25][C:20]1[N:21]=[CH:22][C:17]([C@H:15]([CH2:14][NH:13][C@H:2]([CH3:1])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[OH:16])=[CH:18][CH:19]=1
Reactant: C[C@H](Cc1c[nH]c2ccccc12)NC[C@H](O)c1ccc2nnnn2c1
Agent: Cl[Sn]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CO
Solvent: CCO
Product: C[C@H](Cc1c[nH]c2ccccc12)NC[C@H](O)c1ccc(N)nc1
Reaction time: 1 h

Procedure:
A solution of 0.5 g of this tetrazole in 15 ml of methanol is treated with 0.6 g of SnCl2.2H2O for 5 hours at reflux under nitrogen. The reaction mixture is partially concentrated and then poured into a mixture of 25 ml of CH2Cl2 and 15 ml of 1N NaOH solution. The layers are separated and the aqueous layer further extracted with CH2Cl2. The combined organic phases are backwashed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Concentration of this solution and chromatography on silica gel affords the product which is dissolved in ethanol and treated with one equivalent of an ethanolic solution of citric acid. The mixture is aged for approximately one hour and the citrate salt is collected by filtration.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[CH3:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=2[N:25]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][O:30][C:27]2[CH:28]=[CH:29][C:23]3[S:22][C:21]([CH3:20])=[N:25][C:24]=3[CH:26]=2)[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Reactant: Cc1nc2cc(O)ccc2s1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccc3sc(C)nc3c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 2-methyl-benzothiazol-5-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C21H23NO5S [M+H]+: 402.1.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([CH2:29][CH3:30])[CH:22]=2)=[N:18][CH:19]=1.Cl.[CH3:32][C:33]([C:36](OC)=[O:37])([CH3:35])[NH2:34].C[O-].[Na+]>CCOC(C)=O.CO>[CH3:32][C:33]1([CH3:35])[C:36](=[O:37])[N:13]([C:14]2[CH:15]=[N:16][C:17]([O:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([CH2:29][CH3:30])[CH:22]=3)=[N:18][CH:19]=2)[C:5](=[O:11])[NH:34]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(C)N
Reactant: CCc1cc(Oc2ncc(N)cn2)ccc1C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc(Oc2ncc(N3C(=O)NC(C)(C)C3=O)cn2)ccc1C#N
Temperature: 60 °C
Yield: 46.8 %

Procedure:
To a solution of triphosgene (20.8 mg, 0.07 mmol) in EtOAc (0.5 mL) at 0° C., a solution of 4-[(5-amino-2-pyrimidinyl)oxy]-2-ethylbenzonitrile (Intermediate 144, 35 mg)/TEA (0.037 mL, 0.27 mmol) in EtOAc (1.0 mL) was added dropwise under stirring. Then a solution of methyl 2-methylalaninate hydrochloride (Intermediate 107, 33.6 mg)/TEA (0.073 mL, 0.52 mmol) in 1.0 mL of EtOAc at 0° C. was slowly added and the reaction mixture was stirred at that temperature for 10 minutes. The mixture was quenched with an aqueous pH 3 buffer solution to pH 5-6 and extracted with EtOAc (three times). The collected organic were dried over Na2SO4, filtered and evaporated. The crude obtained was dissolved in MeOH (1.0 mL) and 3.0 mg (0.056 mmol) of sodium methoxide were added and the mixture was heated at 60° C. for 5 minutes. After cooling down to r.t., the mixture was evaporated, diluted with EtOAc and washed with NH4Cl (aqueous saturated solution) and the aqueous phase was extracted with EtOAc (three times). The collected organic were dried over Na2SO4, filtered and evaporated. The crude obtained was charged on a silica gel column and eluted with Cyclohexane/EtOAc (from 70:30 Cyclohexane/EtOAc to 60:40 in 20 CV, plateau at 60:40 in 20 CV) affording 11.5 mg of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:25][CH:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)=[O:24]>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:25][CH:26]1[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CCCCN2c2nc3ccccc3o2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCNCC1)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.4 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of tert-butyl 4-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)piperidine-1-carboxylate (1.631 g) [see Preparation 31] in dichloromethane (10 ml) at 0° C. The reaction mixture was then warmed to room temperature and stirred for 2 hours, after which time the solvent was removed under reduced pressure and the residue was dissolved in water. Sodium hydrogen carbonate was added until the solution reached a pH of 8 and the product was then extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-(4-piperidinyl)-2-piperidinecarboxamide (1.48 g) as a white foam.
Reaction SMILES: [CH3:1][C:2]([OH:5])(C)[CH3:3].O.C([O-])([O-])=[O:8].[K+].[K+].[Si:13]([O:20][CH2:21][C@@H:22]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[Cl:38])=[O:28])CC=C)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CC(O)(C)C.O.C(OCC)(=O)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3N=C(C4C=CC=CC=4)N=C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)C=3C3C=CC=CC=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>[Si:13]([O:20][CH2:21][C@@H:22]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[Cl:38])=[O:28])[CH2:1][C@@H:2]([OH:5])[CH2:3][OH:8])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)NCc1cccc(F)c1Cl
Reactant: CC(C)(C)O
Reactant: O=C([O-])[O-]
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nc(-c2ccccc2)nc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c1-c1ccccc1)c1ccnc2ccc(OC)cc12
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a mixture of t-BuOH (300 mL) and water (300 mL) were added K2CO3 (17.0 g, 123 mmol,), (DHQD)2Pyr (361 mg, 0.41 mmol), K2OsO2(OH)4(151 mg, 0.41 mmol), K3FeCN6 (40.5 g, 123 mmol) at RT The mixture was stirred at RT for 2 h and then cooled to 0° C. To the mixture was added a suspension of (S)-1-(1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl)-3-(2-chloro-3-fluorobenzyl)-1-methylurea (17.0 g, 41 mmol) in 100 mL of t-BuOH/water (1:1), and the reaction was stirred at 0° C. overnight. LC-MS indicted the reaction was completed, Na2S2O3.5H2O (30.6 g, 123 mmol) was added to the reaction, and the reaction was stirred at RT for 30 min. The mixture was diluted with ethyl acetate (1 L), washed with water (250 mL×2) and brine (250 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified on silica gel to give 1-((2S,4R)-1-(tert-butyldimethylsilyloxy)-4,5-dihydroxypentan-2-yl)-3-(2-chloro-3-fluorobenzyl)-1-methylurea (10.1 g, 55%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Cl:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>CCOCC.CCOC(C)=O>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:15]1[CH:16]=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: Clc1ncccn1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN(C)S(=O)(=O)n1ccnc1-c1ccnc(Cl)n1
Reaction time: 1 h
Yield: 4.5 %

Procedure:
N-BuLi [2.5M in hexane] (4 ml, 10 mmol) added at −78° C. to a solution of N,N-dimethyl imidazole-1-sulphonamide (1.75 g, 10 mmol) in dry ether (60 ml), stirred 1 hour, anion transferred to a suspension of 2-chloropyrimidine (1.48 g, 10 mmol) in ether (80 ml) keeping the temperature -30° C., temperature brought to 0° C. and held for 30 min. Reaction quenched with AcOH (0.64 ml) and water (0.1 ml), to the reaction was added THF (2 ml) then DDQ (2.27 g) in THF (10 ml) and stirred 0/N. Reaction diluted with EtOAc, solid filtered off and filtrate washed with water (3×) then ice cold 0.5% NaOH, organic layer dried over MgSO4, filtered and concentrated under reduced pressure, residue was purified by column chromatography to give the product (130 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](N=C=S)=[O:5])[CH3:2].[NH2:9][C:10]([NH2:12])=S.C([NH:16]CCC)CC>CN(C=O)C>[CH2:1]([O:3][C:4]([NH:9][C:10]([NH2:12])=[NH:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C=S
Reactant: CCCNCCC
Reactant: NC(N)=S
Solvent: CN(C)C=O
Product: CCOC(=O)NC(=N)N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.02 mol (4.10 g) of 3-amino-2-azocanopyridine and 0.02 mol of ethoxy-carbonyl isothiocyanate is stirred at ambient temperature for 3 hours in 100 ml of DMF, by which means the thiourea of formula (IV) is obtained, which it is not necessary to isolate. The solution is cooled to 0° C. and saturated with 2.5 eq. of di-n-propylamine, and 0.02 mol of mercuric chloride is added; at the end of 15 minutes, the ice bath is removed and the mixture is stirred at ambient temperature for 3 hours (the black precipitate caused by the formation of mercury sulphide will still be seen to appear). After having added 150 ml of ethyl acetate, the solution is filtered over Celite and the solvents are evaporated off under reduced pressure. The crude N-ethoxycarbonylguanidine thereby obtained is again dissolved in 50 ml of DMF and heated at reflux for 2 hours. After the hot solution has been filtered in order to remove the last remnants of mercury salt, the DMF is evaporated off under reduced pressure. The solid thereby obtained is taken up in a minimum of acetonitrile, filtered off over a frit under suction and then recrystallised from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[NH2:20])[C:15]#[N:16]>CS(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]1[NH:11][C:12]2[CH:13]=[C:14]([C:15]#[N:16])[CH:17]=[CH:18][C:19]=2[N:20]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: CS(C)=O
Product: N#Cc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 20 ml scint. vial was added 0.500 g (2.86 mmol) of 2,6-Dichloro-benzaldehyde, 0.3804 g (2.86 mmol) of 3,4-diamino-benzonitrile, and 6 mL DMSO. To the brown solution was added 0.1995 g (1.23 mmol) of FeCl3. Allowed stir at r.t. open to air for 18 h. Extracted with EtOAc and washed with water, and brine. Dried and purified on silica gel column chromatography (EtOAc/Hep, 1:9 to 7:3) to give of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.72 (m, 4H) 7.79 (br. s., 1H) 8.27 (br. s., 1H) 13.48 (br. s., 1H). MS (m/z) 288.1 M (+1), tR=1.18, Meth 10
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1>N1CCCCC1.C(O)C>[CH3:17][C:15]1[S:16][C:12]([CH:11]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:13][CH:14]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1ccc(C=O)s1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ccc(C=C2C(=O)Nc3ccccc32)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 151.42 mg of the 5-methylthiophene-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 237.8 mg (99%) of the title compound as a yellow solid.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[N:15]=[CH:14][NH:13][C:12]2=[N:16][CH:17]=[CH:18][C:11]=12.[CH3:19][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[C:31]3[C:35]([CH:36]=[C:37](B4OC(C)(C)CC(C)(C)O4)[CH:38]=2)=[N:34][N:33](C2CCCCO2)[CH:32]=3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:21].O>O1CCOCC1.CO>[CH3:21][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[CH:38]=[C:37]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:19]
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Reactant: Clc1nc[nH]c2nccc1-2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2ncnc3[nH]ccc23)cc2[nH]ncc12
Temperature: 120 °C

Procedure:
A microwave vial was charged with Solvias catalyst (8 mg), tripotassium phosphate (90 mg) and 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (available from ABCR, 24 mg). 1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (70 mg) in 1,4-dioxane (0.5 ml) was added followed by water (0.1 ml). The reaction was heated under microwave irradiation at 120° C. for 10 min. Solvias catalyst (8 mg) was added and the reaction heated under microwave irradiation at 120° C. for 10 min. Further Solvias catalyst (8 mg) and tripotassium phosphate (30 mg) were added and the reaction was heated under microwave irradiation at 120° C. for 30 min. Again further Solvias catalyst (8 mg) and tripotassium phosphate (90 mg) were added and the reaction was heated under microwave irradiation at 120° C. for 30 min. 4-Chloro-1H-pyrrolo[2,3-d]pyrimidine (12 mg) was added and the reaction was heated under microwave irradiation at 120° C. for 30 min. Addition of catalyst and base was repeated and the reaction was heated under microwave irradiation at 120° C. for 30 min. The reaction was passed through a silica cartridge preconditioned with methanol, washing with methanol, then dried under a stream of nitrogen. The residue was subjected to a DCM/water wash and then dried under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method A). The appropriate fraction was evaporated under a stream of nitrogen. The residue was dissolved in methanol, a few drops of 2M HCl (aq) were added and the mixture was left to stand briefly at room temperature, then evaporated under a stream of nitrogen. Sequential purification was carried out using the following system and the two gradients shown:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:6][CH:7]=1.[N:12]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:19].[OH-].[Na+]>Cl.O.Cl.CO.C1COCC1>[ClH:19].[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:6][CH:7]=1)[NH2:12]
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Reactant: Nc1ccc(S(N)(=O)=O)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NNc1ccc(S(N)(=O)=O)nc1
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a suspension of 5-amino-2-pyridinesulfonamide (7.0 g, 0.040 mol, C. Komfeld, J. Amer. Chem. Soc. 1695 (1942)) in conc HCl (60 mL) and H2O (20 mL), sodium nitrite (3.6 g, 0.052 mol) in H2O (50 mL) was added dropwise at 0° C. and the mixture was stirred for 30 min. The mixture changed to yellow brown solution and tin(II) chloride dihydrate (36 g, 0.16 mol) in conc HCl (30 mL) was added dropwise below 5° C. and stirred for 1 hour at 0° C. The mixture was made basic by addition of aqueous NaOH (pH=8). The resultant suspension was added THF (400 mL) and stirred for 10 min. The white precipitate was separated by celite filtration and washed with THF (100 mL×3). The filtrate was separated in two phase and organic phase was separated. Water phase was extracted with THF (150 mL×2), dried (MgSO4), and concentrated in vacuo gave brown oil. The oil was disolved in 10% HCl-MeOH (50 mL) and concentrated in vacuo gave brown amorphous solid. Crystallization from CH2Cl2 gave the titled compound as a brown solid (5.0 g, 56%).
Reaction SMILES: [N:1]1[N:2]([CH2:10][CH2:11]O)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[N:13]1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(OCC)C>[N:1]1[N:2]([CH2:10][CH2:11][NH2:13])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: c1ccncc1
Reactant: OCCn1nc2ccccc2n1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: NCCn1nc2ccccc2n1
Temperature: -50 °C
Yield: 44791.7 %

Procedure:
4.70 g Of the 2-(2-benzotriazolyl)ethanol (28.8 mmol) was dissolved in 200 ml diethyl ether and 2.28 g pyridine (28.8 mmol) was added. The mixture was cooled to -50° C., and 8.18 g triflic anhydride (29 mmol) was added. The mixture was removed from the cooling bath, and was allowed to reach room temperature. The mixture was filtered under dry conditions and added to a cold -40° C. solution of ca 150 ml ammonia in 50 ml diethyl ether. This mixture was allowed to reach room temperature, and ether was removed. 50 ml 2M HCl was added, and this mixture was washed with methylene chloride. The aqueous phase was made basic by addition of 50 ml 25% sodium hydroxide and extracted with 3×25 ml methylene chloride. Evaporation of the solvent gave 2.10 g 2-(2-benzotriazolyl)ethylamine (12.9 mol). This amine was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(OCC)(=O)C>O>[CH2:32]([O:31][C:29]([N:4]([CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N:16]2[CH:17]=[CH:18][CH:19]=[CH:20]2)[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2][OH:1])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc(CNCCO)cc(-n2cccc2)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cc(CN(CCO)C(=O)OCc2ccccc2)cc(-n2cccc2)c1
Reaction time: 2 h

Procedure:
To a mixture of methyl 3-(2-hydroxyethylaminomethyl)-5-(pyrrol-1-yl)benzoate (0.8 g) and triethylamine (0.48 ml) was added benzyl chloroformate (0.46 ml) under ice cooling. After stirring for 2 hours under ice cooling, the reaction mixture was poured into the mixture of ethyl acetate and water. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with the mixture of chloroform and methanol (15:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-[N-benzyloxycarbonyl-N-(2-hydroxyethyl)aminomethyl]-5-(pyrrol-1-yl)benzoate (1.11 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.O1CCCC1.[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=[CH2:27]>[OH-].[K+].C(O)C>[C:10]([C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:4]=1)([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH2:27][CH2:26][C:25]([O:29][CH2:30][CH3:31])=[O:28])#[N:11]
Reactant: C=CC(=O)OCC
Reactant: N#CC(c1cccc(C(F)(F)F)c1)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCC(C#N)(c1cccc(C(F)(F)F)c1)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of 5.0 g. of α-[3-(trifluoromethyl)phenyl]-4-morpholineacetonitrile in 200 ml. of tetrahydrofuran stirred at room temperature is added 30 drops of 30% potassium hydroxide in ethanol. To the mixture is added 10 ml. of ethyl acrylate. After one hour an additional 30 drops of 30% potassium hydroxide in ethanol and 10 ml. of ethyl acrylate is added. The mixture is stirred for 2 hours and the solvent removed under vacuum. Toluene is added several times and the solvent removed. The residue is stirred with ether, filtered and the solvent evaporated to give ethyl γ-cyano-γ-[3-(trifluoromethyl)phenyl]-4-morpholinebutanoate (5.6 g.) as an oil. The oil is heated with 70% glacial acetic acid for 2 hours and the solvent removed. The residue is dissolved in dichloromethane and washed with water. The organic layer is dried (Na2SO4) and the solvent removed to give an oil. A mixture of the oil and 300 ml. of 6 N hydrochloric acid is refluxed for 5 hours, cooled and extracted with dichloromethane. The organic layer is extracted with sodium bicarbonate. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with dichloromethane. The extract is dried (Na 2 SO4) and the solvent removed. The residue is crystallized from hexane to give 3-[3-trifluoromethylbenzoyl]propionic acid as crystals, mp. 80°-82° C.
Reaction SMILES: [CH:1]1([N:6]([C@@H:10]2[CH2:15][C:14]3[C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][CH:18]=[C:19]([F:20])[C:13]=3[O:12][CH2:11]2)[CH2:7][CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:36][OH:37].[C]=O.CN([CH:43]=[O:44])C>C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1([N:6]([C@@H:10]2[CH2:15][C:14]3=[C:16]([C:36]([O:44][CH3:43])=[O:37])[CH:17]=[CH:18][C:19]([F:20])=[C:13]3[O:12][CH2:11]2)[CH2:7][CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: CCCN(C1CCCC1)[C@H]1COc2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CO
Agent: [C]=O
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCN(C1CCCC1)[C@H]1COc2c(F)ccc(C(=O)OC)c2C1
Yield: 86 %

Procedure:
(R)-3-(N-Cyclopentyl-N-n-propylamino)-8-fluoro-5-trifluoromethylsulfonyloxy-3,4-dihydro-2H-1-benzopyran (3.7 g, 8.7 mmol), DMF (50 mL), triethylamine (2.5 g, 25 mmol), methanol (4 g, 130 mmol), palladium(ll)acetate (100 mg, 0.45 mmol) and 1,3-bis(diphenylphosphino)propane (200 mg, 0.48 mmol) were placed in a round-bottomed flask. The solution was stirred at 75° C. in an atmosphere of carbon monoxide for 4 h. After evaporation of the solvent in vacuo and subjecting the crude to flash chromatography, 2.5 g (86% yield) of the title compound as a colorless oil was isolated. GC/MS (70 eV) M=335 (20 %).