Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:9][O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16](O)=[CH:17][CH:18]=1)=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C1COCC1>[CH3:9][O:10][C:11](=[O:12])[C:13]1[CH:14]=[CH:15][C:16]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCc1ccccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 146.5 %

Procedure:
To a solution of THF (50 mL) of 2-(hydroxymethyl)pyridine (1.5 g), methyl p-hydroxybenzoate (2.1 g), and triphenylphosphine (5.0 g) was added diisopropyl azodicarboxylate (3.9 g) at 0° C., which was stirred for 20 minutes at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The solvent was evaporated from the organic layer under a reduced pressure, and the residue was purified by NH silica gel chromatography (heptane:ethyl acetate=2:1), then purified by silica gel chromatography (heptane:ethyl acetate=1:1) to obtain the titled compound (4.9 g).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:39])[CH2:15][N+:16]23[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]2)[C@H:18]([NH:24][C:25]([NH2:38])=[N:26][C:27]([C:29]2[C:34]([NH2:35])=[N:33][C:32]([NH2:36])=[C:31]([Cl:37])[N:30]=2)=[O:28])[CH2:17]3)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[Cl-:40]>>[ClH:37].[Cl-:40].[C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:39])[CH2:15][N+:16]23[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]2)[C@H:18]([NH:24][C:25]([NH2:38])=[N:26][C:27]([C:29]2[C:34]([NH2:35])=[N:33][C:32]([NH2:36])=[C:31]([Cl:37])[N:30]=2)=[O:28])[CH2:17]3)[CH2:10][CH2:9]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)C[N+]23CCC(CC2)[C@H](NC(N)=NC(=O)c2nc(Cl)c(N)nc2N)C3)CC1
Agent: [Cl-]
Product: Cl
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)N[C@@H]1C[N+]2(CC(=O)N3CCC(C(=O)O)CC3)CCC1CC2

Procedure:
Starting from 120 mg (0.20 mmol) of (S)-1-[2-(4-tert-butoxycarbonyl-piperidin-1-yl)-2-oxo-ethyl]-3-[N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-1-azonia-bicyclo[2.2.2]octane; chloride (Intermediate 67).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1(C(C2C=CC=CC=2)(O)[C@H](C2C=CC=CC=2)O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[NH:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N:14]=2)=[O:24])=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of omeprazole (500 mg, 1.45 mmol) and (S)-1,1,2-triphenyl-1,2-ethanediol (630 mg, 2.17 mmol, 99.3% e.e. recovered according to Example 24) was dissolved in a minimum volume of toluene (18 ml) at 90° C. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with toluene (2×5 ml) and was dried in vacuo to afford (S)-omeprazole.2[(S)-1,1,2-triphenyl-1,2-ethanediol] inclusion complex (627 mg, 94%, 93.7% e.e.) as an off-white powder.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[O:5]2.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[O:26][C:25]3=CSC=[C:24]3[C:23](=O)[NH:22][C:21]=2[CH:31]=1.[CH3:32][O-:33].[Na+].CI>C(O)C>[CH3:16][N:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[O:5][C:4]2=[CH:3][S:2][CH:1]=[C:10]2[C:9]1=[O:11].[CH3:16][C:17]1[C:18]2[C:19]([C:32](=[O:33])[SH:2]([CH3:1])[CH:3]=2)=[C:20]2[O:26][CH2:25][CH:24]=[CH:23][N:22]=[C:21]2[CH:31]=1
Reactant: C[O-]
Reactant: O=C1Nc2ccccc2Oc2cscc21
Reactant: Cc1ccc2c(c1)NC(=O)c1cscc1O2
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CN1C(=O)c2cscc2Oc2ccccc21
Product: Cc1cc2c(c3c1=C[SH](C)C3=O)OCC=CN=2

Procedure:
The starting material, thieno[3,4-b][1,5]benzoxazepin-10(9H)-one (I) or 7-methyl-thieno[3,4-b][1,5]benzoxazepin-10(9H)-one (II) in ethanol is treated with sodium methoxide and methyl iodide and extracted with methylene chloride to yield 9-methyl-thieno[3,4-b][1,5]benzoxazepin-10(9H)-one (III) and 7,9-dimethyl-thieno[3,4][1,5]benzoxazepin-10(9H)-one (IV) respectively. The above compounds III and IV are refluxed with 5 N sodium hydroxide for 16 hours, diluted with water, adjusted to pH 4-5 with hydrochloric acid and extracted with methylene chloride. The base compounds thus obtained are dissolved in ether and treated with alcoholic hydrochloric acid to give the corresponding 4-(o-methylaminophenoxy)-3-thiophenecarboxylic acid hydrochloride (V) and 4-(2-methylamino-p-tolyloxy)-3-thiophenecarboxylic acid hydrochloride (VI) compounds.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([O:19]CC)=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:24]([Mg][Cl:28])[CH2:25][CH3:26].[CH2:29]1[CH2:33]OC[CH2:30]1>>[ClH:28].[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]([OH:19])([CH2:30][CH2:29][CH3:33])[CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: C1CCOC1
Reactant: CCC[Mg]Cl
Product: CCCC(O)(CCC)CCN1CCC(c2noc3cc(F)ccc23)CC1
Product: Cl
Reaction time: 17 h
Yield: 45 %

Procedure:
To a solution of ethyl 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (4.5 g, 14.0 mmol) in THF (120 ml) was added propylmagnesium chloride (21.1 ml, 42.0 mmol, 2.0M in ether) at room temperature under nitrogen (mild exotherm). The reaction mixture was stirred for 17 hours at which time it was carefully quenched with NH4Cl (sat., 30 ml). The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organics were washed with brine and dried (Na2SO4). Filtration and concentration gave the crude product which was purified via flash column chromatography (silica gel, 2% Et3N/ether). After flushing the product through alumina with ether, the hydrochloride salt was prepared in ether/EtOAc (1:1, 40 ml, 1 drop IPA) with ethereal HCl to give 2.5 g (45%) of the desired product as a white solid, m.p.=163°-164° C.
Reaction SMILES: [C:1]1([C:7]2C=CC(C(=O)CCl)=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg:24][Cl:25])C1C=CC=CC=1>C(OCC)C>[Mg:24].[CH2:7]([Cl:25])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCl)c1ccc(-c2ccccc2)cc1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: CCOCC
Product: ClCc1ccccc1
Product: [Mg]

Procedure:
115.3 g (0.5 mol) of 4-phenylphenacyl chloride are added portions to a solution of benzyl-magnesium chloride, obtained from 24.3 g (1 mol) of magnesium and 115 ml (1 mol) of benzyl chloride in 150 ml of diethyl ether. The reaction mixture is warmed under reflux for 90 minutes and then poured onto aqueous ammonium chloride solution. The ether phase is separated off, washed with water, dried over sodium sulphate and concentrated. The oil which remains is made to crystallise by stirring with petroleum ether. 50 g (31% of theory) of 2-(4-biphenylyl)-3-chloro-1-phenylpropan-2-ol of melting point 96° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:38](=[O:45])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].O>C(Cl)Cl>[CH2:15]([NH:14][C:12]1[C:11]2=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=[CH:24][N:10]2[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:45])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:7]=[N:6][CH:5]=2)[N:13]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)Nc1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 62.2 %

Procedure:
2-(5-Aminopyridin-3-yl)-N-benzyl-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.500 g, 1.27 mmol) was dissolved in CH2Cl2 (10 mL) and pyridine (0.103 mL, 1.27 mmol) was added, followed by the addition of ethyl 3-chloro-3-oxopropanoate (0.192 g, 1.27 mmol). The reaction mixture was stirred at room temperature for 14 h. Water (10 mL) was added to the reaction mixture followed by addition of CH2Cl2 (10×4 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 3% methanol in CH2Cl2) to afford ethyl 3-((5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)amino)-3-oxopropanoate (0.400 g, 62.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.2 Hz, 3H), 3.54 (s, 2H), 4.15 (q, J=7.2 Hz, 2H), 4.82 (d, J=5.6 Hz, 2H), 6.66 (t, J=5.6 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 7.27-7.55 (m, 10H), 7.91 (d, J=2.8 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 8.87 (dd, J=2.4 Hz, J=1.6 Hz, 1H), 9.09 (d, J=1.6 Hz, 1H), 10.52 (s, 1H). LCMS Condition B-49: retention time 1.91 min, [M+1]=507.2. HPLC Condition B-32: retention time 10.36 min, Purity 98.80%.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([NH:13][C:14](=[O:36])[CH:15]([S:32]([OH:35])(=[O:34])=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([O-])(=O)C.[NH4+].C=O.[H][H]>[Ni].C(O)C>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH3:37])[C:9]([NH:13][C:14](=[O:36])[CH:15]([S:32]([OH:35])(=[O:34])=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)[O-]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCC(C(=O)NC1=NN(c2ccccc2)C(=O)C1)S(=O)(=O)O
Agent: [Ni]
Agent: C=O
Agent: [NH4+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC(C(=O)NC1=NN(c2ccccc2)C(=O)C1C)S(=O)(=O)O
Temperature: 75 °C

Procedure:
An autoclave was charged with 52.1 g (0.1 mole) of 1-phenyl-3-(α-sulphostearoylamino)-2-pyrazolin-5-one, 15.4 g (0.2 mole) of ammonium acetate, 4.5 g (0.15 mole) of paraformaldehyde, 10 g of Raney nickel and 535 ml of ethanol. The mixture was heated to 75° C whereupon hydrogenation started at a hydrogen pressure of 700 psi. After 30 min the hydrogen pressure was released and another 4.5 g of paraformaldehyde were added whereupon hydrogenation was continued. After having filtered off the catalyst, the filtrate was acidified with 100 ml of concentrated hydrochloric acid. The precipitate was filtered off. Yield: 41 g (75%). Melting point: 240° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[CH:3]1.C(Cl)Cl.ClN1C(=[O:28])CCC1=O>C(OCC)C.C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][C:3]1=[O:28]
Reactant: Cn1ccc2cccc(C(=O)c3ccccc3)c21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CN1C(=O)Cc2cccc(C(=O)c3ccccc3)c21
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6.17 g. (26.25 mmoles) of 1-methyl-7-benzoylindole in 62 ml. of methylene chloride was added 3.58 g. (26.25 mmoles) of 98% N-chlorosuccinimide and the mixture allowed to stir for 90 minutes. An additional 720 mg. of N-chlorosuccinimide was added and stirring continued for 2 hours. The reaction mixture was concentrated in vacuo and 52 ml. of acetic acid added. The mixture was heated to 80° C. and 27 ml. of 85% phosphoric acid was added. The temperature was raised to reflux for 90 minutes and the reaction was cooled and poured into 200 ml. of ice and water. The precipitate was filtered, dissolved in methylene chloride and the solution dried with magnesium sulfate. Removal of the solvent gave a residue which was dissolved in 5% diethyl ether-methylene chloride and filtered through silica gel. The fractions were collected, combined and concentrated to give 4.0 g. of the product as a viscous oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N:20]1([C:26]2[N:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:32]([C:29]3[CH:28]=[CH:27][C:26]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:31][CH:30]=3)=[O:33])[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CCOCC2)nc1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Yield: 78.2 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 1) (80 mg, 0.272 mmol) in DMF (5 ml) were added 6-(4-morpholinyl)-3-pyridinecarboxylic acid (56.6 mg, 0.272 mmol), HOBT.H2O (41.6 mg, 0.272 mmol), HBTU (103 mg, 0.272 mmol) and DIPEA (0.142 ml, 0.816 mmol) and the reaction mixture was stirred at room temperature for 2 h. The DMF was evaporated in vacuo then 5 ml of DCM were added and washed with saturated aqueous NaHCO3 solution (5 ml), dried on a phase separation cartridge and evaporated in vacuo. The crude material was dissolved in MeCN/DMSO 1:1 and purified by MDAP. The desired fractions were collected and concentrated under vacuo giving the title compound (103 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])[CH:13]=2)[NH:8][CH:7]=1)[CH3:2].[CH3:31][C:32](C)([O-])C.[K+].C(I)C.O>CS(C)=O>[CH2:29]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]([CH2:31][CH3:32])[S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:17])=[O:18])[CH:13]=2)[NH:8][CH:7]=1)[CH3:30]
Reactant: CCN(CC)CCc1c[nH]c2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCI
Solvent: O
Product: CCN(CC)CCc1c[nH]c2ccc(N(CC)S(=O)(=O)c3ccc4ccccc4c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 285 mg (0.7 mMol) of N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide (example 17) and 80 mg (0.7 mMol) of potassium t-butoxide in 3 ml of DMSO are stirred for 30 minutes at ambient temperature. Then are added 105 mg (0.7 mMol) of ethyl iodide and left with stirring for 3 hours. Water is added and is extracted with ethyl acetate. The organic solution is evaporated to dryness and the resulting crude is purified by chromatography on silica gel, using as an eluent mixtures of methylene chloride/methanol/ammonia, yielding N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-N-ethyl-naphthalene-2-sulphonamide as a solid with m.p.=49–50° C.
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][C:19]=1[CH3:28]>>[NH2:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:14]([C:10]2[CH:9]=[C:8]([O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[N:13]=[CH:12][N:11]=2)=[O:16])=[C:19]([CH3:28])[CH:20]=1)(=[O:25])=[O:26]
Reactant: O=C(O)c1cc(OC2CCCCC2)ncn1
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(OC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting 6-(cyclohexyloxy)pyrimidine-4-carboxylic acid (Intermediate 32) and 4-amino-3-methylbenzenesulfonamide (Biofine), the title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH3:8])[NH:4][N:3]=1.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[O:12]>C(Cl)Cl>[CH3:8][S:7][C:5]1[NH:4][N:3]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:11]([O:10][CH3:9])=[O:12])(=[O:21])=[O:20])=[O:24])[N:6]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CSc1nc(N)n[nH]1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1n[nH]c(SC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5.0 grams (0.0385 mole) 3-amino-5-methylthio-1H-1,2,4-triazole (Aldrich Chemicals) and 75 ml of dry methylene chloride stirring in a 200 ml RB single neck flask, 10.5 grams of 2-(methoxycarbonyl)benzenesulfonylisocyanate was added at ambient temperature; a clear solution gradually formed. After stirring overnight at room temperature, the white solid which precipitated was filtered and washed with methylene chloride, yield 11.7 grams, m.p.147°-153°.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.O[N:35]=[C:36]([NH2:44])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:44]=[C:36]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:35]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: NC(Cc1ccccc1)=NO
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](c2nc(Cc3ccccc3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and N′-hydroxy-2-phenylethanimidamide, the title compound was obtained in 86% purity by HPLC. MS(ESI+): m/z=453.2.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(CN)CC1>C(O)(=O)C>[CH:6]1([CH2:1][N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:4][CH2:5]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NCC1CC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1CC1CC1
Yield: 62.6 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), cyclopropanemethylamine (0.086 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 76 mg (0.27 mmol, 62.6% yield) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C@H:3]1/[CH:17]=[CH:18]/[C@@H:19]([OH:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.C([O-])([O-])=O.[K+].[K+].I[CH:40]([CH3:42])[CH3:41].O>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH:40]([CH3:42])[CH3:41])=[O:15])[C@H:3]1/[CH:17]=[CH:18]/[C@@H:19]([OH:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=1
Reactant: CC(C)I
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A solution of crude Travoprost acid (1.1 g from Example 9) in DMF (11 mL) was treated with K2CO3 (0.90 g, 6.5 mmol) and 2-iodopropane (0.74 g, 4.4 mmol). This mixture was then stirred at 80° C. for 2 hr under an atmosphere of nitrogen (TLC monitoring). Water (30 mL) and ethyl acetate (30 mL) were added and the mixture was stirred for 10 min. The aqueous layer was separated and extracted with ethyl acetate (30 mL), and the combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 1.2 g of crude Travoprost. The crude Travoprost was dissolved in 10 mL ethyl acetate in 25 mL round-bottom flask, followed by addition of imidazole (0.82 g, 12 mmol) at room temperature. Chlorotriethylsiliane (1.6 g, 10.6 mmol) was added into this flask and stirred for 10 minutes. White solid was produced and filtered off and washed with 50 mL ethyl acetate twice. All organic solvent was combined and washed with 15 mL saturated NaHCO3 aqueous solution twice. The organic layer was dried over anhydrous MgSO4, solid was filtered off and solvent was evaporated under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield of the title compound was 1.85 g. (91.6%)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:18][CH2:19][CH3:20]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH3:20])[CH2:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(C2=CCNCC2)c1
Reactant: CCCI
Product: CCCN1CC=C(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)-1,2,3,6-tetrahydro-pyridine and iodopropane: MS m/z (relative intensity, 70 eV) 279 (M+, 26), 250 (bp), 171 (6), 128 (12), 115 (8).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33].N#N>C(Cl)Cl.CCOC(C)=O>[Br:33][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:2]=1[F:1]
Reactant: BrC(Br)(Br)Br
Reactant: OCCOc1ccc(F)cc1F
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Fc1ccc(OCCBr)c(F)c1
Reaction time: 0.5 h

Procedure:
To a cool solution 2-(2,4-difluoro-phenoxy)-ethanol (0.48 g, 2.77 mmol.) in CH2Cl2 (15 ml), triphenyl phosphine (1.3 g, 5 mmol)) was added. Carbon tetrabromide (1.65 g, 5 mmol.) in CH2Cl2 (3 ml) was added to the solution dropwise under N2. The solution was stirred for 30 minutes. EtOAc was added, then the solvent was evaporated under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[C-:18]#[N:19].[Na+].[C-]#N>CN(C=O)C.C(O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:18]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12)#[N:19]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(cnn2CC)c1C#N
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a solution of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (10.0 g, 39.5 mmol) in DMF (50 mL) and ethanol (10 mL) was added either sodium cyanide (3.9 g, 80.0 mmol) or tetrabutylarimonium cyanide (11.8 g, 1.1 eq) or tetrabutylammonium chloride (14.7 g, 1.0 eq) and sodium cyanide (2.4 g, 1.2 eq) together. This solution or suspension was warmed up to 60° C. until reaction was completed as judged by TLC. The reaction mixture was then diluted with water (200 mL) and stirred gently at rt for 10 min. A large amount of precipitate formed. The solid was filtered and rinsed thoroughly with water to afford the title compound as an off-white solid after drying: 40-80% yield. This material was >95% pure as judged by HPLC and was used directly without further purification.