Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOC(=O)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(C#N)C(=O)C(F)(F)F)cc1OC
Temperature: 25 °C
Yield: 30.9 %

Procedure:
To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (2.0 g, 11 mmol) and ethyl trifluoroacetate (1.7 mL, 14 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 8.4 mL, 23 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-4,4,4-trifluoro-3-oxobutanenitrile as a brown oil (0.8 g, 3.4 mmol, 30% yield), MS (EI) for C12H10F3NO3: 274 (MH+).
Reaction SMILES: [P:1]([O-:47])([O-:46])([O:3][C:4](C(C)(C)C)(C(C)(C)C)[N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:13]=[C:8]2[C:7]([C:21](=[O:37])[C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:23]=2[F:36])=[CH:6]1)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[P:1]([OH:46])([OH:47])([O:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:13]=[C:8]2[C:7]([C:21](=[O:37])[C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:23]=2[F:36])=[CH:6]1)=[O:2]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(OP(=O)([O-])[O-])(C(C)(C)C)C(C)(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COP(=O)(O)O)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of di-tert-butyl((5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propyl sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl) phosphate (1 g, 1.4 mmol) in DCM (25 mL) was added TFA (1.6 mL, 2.4 g, 21 mmol). The reaction was stirred at rt for 2 h, and then concentrated in vacuo. The residue was washed with 20 mL of EtOAc to give the title compound as a white solid (0.56 g, 66.5%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:17]O>>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)CCc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1ccccc1

Procedure:
A mixture of 3-phenylpropionic acid (50g.), methanol (250ml.) and concentrated sulphuric acid (12ml.) was heated under reflux for 12 hours, and then the excess of methanol was evaporated under reduced pressure. The residue was added to saturated aqueous sodium bicarbonate solution (100ml.) containing ice (400g.) and the pH adjusted to 9 by the addition of more sodium bicarbonate solution. The mixture was extracted with ether (5 × 100ml.), and the extracts combined, washed with brine (2 × 50ml.), dried and evaporated to give methyl 3-phenylpropionate as an oil with a peak at 1740 cm-1 in its I.R. spectrum.
Reaction SMILES: [N:1]([C@H:4]1[C:7](=[O:8])[NH:6][C@H:5]1[CH2:9][CH:10](OC)[O:11]C)=[N+:2]=[N-:3]>Cl.O1CCOCC1.O>[N:1]([C@H:4]1[C:7](=[O:8])[NH:6][C@H:5]1[CH2:9][CH:10]=[O:11])=[N+:2]=[N-:3]
Reactant: COC(C[C@@H]1NC(=O)[C@@H]1N=[N+]=[N-])OC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: [N-]=[N+]=N[C@H]1C(=O)N[C@H]1CC=O
Reaction time: 0.5 h

Procedure:
A mixture of 500 mg (2.5 mmole) of cis-3-azido-2-(2,2-dimethoxyethyl)-4-oxoazetidine in 10 ml of 5% HCl and 10 ml of dioxane was stirred at 35° for 1/2 hour. The mixture was diluted with water and extracted with 50 ml of benzene. The aqueous phase was saturated with brine and extracted 10 times with 50 ml of ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and evaporated to dryness. The residue was titurated with ether to give the desired aldehyde, 235 mg (60%), mp 73°-78°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[N:19]=2)=[CH:11][C:10]=1[C:26]#[N:27])C1C=CC=CC=1>C1COCC1.C(O)C.[C].[Pd]>[C:26]([C:10]1[CH:11]=[C:12]([C:15]2[S:16][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[N:19]=2)[CH:13]=[CH:14][C:9]=1[OH:8])#[N:27]
Reactant: CCOC(=O)c1sc(-c2ccc(OCc3ccccc3)c(C#N)c2)nc1C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2ccc(O)c(C#N)c2)nc1C
Temperature: 25 °C

Procedure:
Ethyl 2-[4-(benzyloxy)-3-cyanophenyl]-4-methyl-1,3-thiazole-5-carboxylate was suspended in a mixture of THF and ethanol, then palladium-carbon was added thereto, and the mixture was stirred under a hydrogen atmosphere at room temperature to obtain ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate. APN: 287.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:21]=[N:22][C:16]=2[CH:15]1[C:29](O)=[O:30])=[O:13].Cl.[CH3:33][NH:34][CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:21]=[N:22][C:16]=2[CH:15]1[C:29]([N:34]([CH3:35])[CH3:33])=[O:30])=[O:13]
Reactant: O=C(O)C1c2ncn(-c3ccccn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1c2ncn(-c3ccccn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Yield: 54.4 %

Procedure:
A solution of 5-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-pyridin-2-yl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-4-carboxylic acid (0.05 g, 0.10 mmol), dimethylamine hydrochloride (0.01 g, 0.10 mmol), HATU (0.04 g, 0.11 mmol), and DIPEA (0.05 mL, 0.26 mmol) in DMF (2 mL) was stirred for 30 min. The reaction was diluted with EtOAc (15 mL) and washed with H2O (3×10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (26 mg, 53%). 1H NMR (500 MHz, CDCl3) δ 8.60-8.35 (m, 1H), 8.09-7.69 (m, 3H), 7.65-7.27 (m, 4H), 6.64-6.46 (m, 1H), 4.17 (tt, J=19.0, 5.6 Hz, 1H), 3.72-3.53 (m, 3H), 3.33-2.85 (m, 6H). MS (ESI): mass calculated for C22H19ClF3N5O2, 477.12. m/z found, 478.1 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O.[CH:14]([C:17]1[S:18][CH:19]=[C:20]([C:22]([N:24]2[CH2:29][C:28]3([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[O:27][CH2:26][CH2:25]2)=[O:23])[N:21]=1)([CH3:16])[CH3:15].CS([O:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49]O)=[CH:44][CH:43]=1)(=O)=O>C(#N)C.O>[OH:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][N:32]2[CH2:31][CH2:30][C:28]3([O:27][CH2:26][CH2:25][N:24]([C:22]([C:20]4[N:21]=[C:17]([CH:14]([CH3:16])[CH3:15])[S:18][CH:19]=4)=[O:23])[CH2:29]3)[CH2:34][CH2:33]2)=[CH:44][CH:43]=1
Reactant: CS(=O)(=O)OCCc1ccc(CCO)cc1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO)cc4)CC3)C2)cs1
Temperature: 60 °C

Procedure:
Potassium carbonate (0.634 g) was added to a solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Example 1, step b] (0.971 g) and 4-(2-hydroxyethyl)phenethyl methanesulfonate [Aromatic Intermediate 10] (0.56 g) in acetonitrile (20 mL) and water (0.3 mL). The reaction mixture was heated at 60° C. for 1 day. The solvent was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate and the combined organic phases were dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, using 2% methanol in dichloromethane with 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.68 g.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](O)(=[O:34])/[CH:13]=[CH:14]\[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl.O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][C:12](=[O:34])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)Oc1ccc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To a solution of vanillin (330 mg, 2.17 mmol), cis-docosahexaenoic acid (870 mg, 2.65 mmol) and catalytic amount of 4-(dimethylamino)pyridine in dichloromethane (15 mL) was added a solution of N,N′-dicyclohexylcarbodiimide (720 mg, 3.50 mmol) in DCM (5 mL) for 5 min at ice cold temperature. The mixture was stirred at rt for 16 h and diluted with water. DCM layer was separated and the aqueous layer was extracted with DCM (3×100 mL). The combined DCM layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the residue was chromatographed over silica gel column using hexane-ethyl acetate (95:5) mixture as an eluent to give the product as an oil (800 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 9.94 (1H, s, —CHO), 7.49 (1H, d, J=1.6 Hz, H-2), 7.47 (1H, dd, J=8.0, 1.6 Hz, H-6), 7.20 (1H, d, J=8.0 Hz, H-5), 5.30-5.48 (12H, m, H-4′, 5′, 7′, 8′, 10′, 11′, 13′, 14′, 16′, 17′, 19′, 20′, 3.89 (3H, s, —OCH3), 2.80-2.88 (10H, m, H-6′, 9′, 12′, 15′, 18′), 2.58-2.67 (2H, m, H-2′), 2.22-2.25 (2H, m, H-21′), 2.05-2.11 (2H, m, H-3′), 0.97 (3H, t, J=7.4 Hz, H-22′).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:24]=[N:25][N:26]([CH2:28][C@H:29]([OH:33])[C:30]([NH2:32])=[O:31])[CH:27]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1>O1CCOCC1.O>[F:9][CH:8]([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:15][C:16]2[CH:17]=[C:18]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][C@H:29]([OH:33])[C:30]([NH2:32])=[O:31])[CH:27]=3)[CH:19]=[C:20]([CH3:22])[CH:21]=2)[N:7]=1
Reactant: FC(F)c1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(-c2cnn(C[C@H](O)C(N)=O)c2)c1
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(C[C@H](O)C(N)=O)c2)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
2-Chloro-4-(difluoromethyl)pyrimidine (24.8 mg, 0.12 mmol) and acetic acid (0.0074 mL, 0.130 mmol) were added to an oven-dried flask containing (2S)-3-[4-(3-amino-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanamide (46.2 mg, 0.12 mmol) dissolved in dioxane (0.41 mL). The mixture was stirred for 3 hours at 120° C. The mixture was then cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2 to 100% EtOAc/hexanes) to afford (2S)-3-[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanamide. MS ESI calcd. for C18H19F2N6O2 [M+H]+ 389. found 389. 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.68 (d, J=4.9 Hz, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 7.32 (s, 1H), 7.04 (d, J=4.9 Hz, 1H), 7.01 (s, 1H), 6.87 (t, J=54.4 Hz, 1H), 5.86 (d, J=5.9 Hz, 1H), 4.41-4.33 (m, 1H), 4.24-4.18 (m, 1H), 4.17-4.13 (m, 1H), 2.28 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]([OH:19])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[N:28]=1>CC(CC(C)C)=O>[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])([OH:19])[CH2:1][CH3:2])=[CH:9][CH:8]=2)[N:28]=1
Reactant: CCC(O)(c1ccc(O)cc1)c1ccccc1OC
Reactant: Cc1cccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCC(O)(c1ccc(OCc2cccc(C)n2)cc1)c1ccccc1OC

Procedure:
7.8 g of α-ethyl-α-(2-methoxyphenyl)-4-hydroxybenzyl-alcohol are dissolved in 65 ml. of methylisobutyl ketone, 9.1 g. of anhydrous potassium carbonate are added, and the reaction mixture is brought up to a boil. Thereafter, a solution of 4.7 g. of 2-methyl-6-chloromethyl-pyridine in 20 ml. of methylisobutyl ketone is added dropwise, and the reaction mixture is slightly boiled for 4 additional hours. After cooling, the reaction mixture is filtered off, and the filtrate is evaporated under reduced pressure. The residue is dissolved in benzene, the solution is washed with a 5% aqueous potassium hydroxide solution and then with water, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The crude product is crystallized from a mixture of ethyl acetate and cyclohexane. Melting point: 110° to 111° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.Br[CH2:15][CH2:16][CH2:17][NH2:18].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CCO>[NH2:18][CH2:17][CH2:16][CH2:15][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: NCCCN1CCN(c2ccccc2)CC1
Yield: 56.3 %

Procedure:
4-Phenylpiperazine (5.00 g, 30.8 mmol, 1.00 equiv, Aldrich), 3-bromopropylamine hydrobromide (8.09 g, 37.0 mmol, 1.20 equiv) and potassium carbonate (8.51 g, 61.6 mmol, 2.00 equiv) were stirred in refluxing acetone (200 mL) and EtOH (40 mL) for 14 hours. After removal of the solvents, water (250 mL) was added and the pH was adjusted to 11-12 by addition of 1N aqueous NaOH. The mixture was extracted with CH2 Cl2 (4 ×250 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, CHCl3 -MeOH-NH3 (2M in MeOH) 100:10:5 to 100:20:10) to give 3.80 g (56%) of yellow oil, which was characterized spectroscopically.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8](C)[CH3:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([O:22]C)[CH:16]=[C:15]([O:24]C)[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([OH:22])[CH:16]=[C:15]([OH:24])[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cc(N(C)C)ccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CNc1ccc(Cl)c(-c2cc(=O)c3c(O)cc(O)c([C@@H]4CCN(C)[C@H]4CO)c3o2)c1

Procedure:
Compound of example 101 (0.25 g, 0.53 mmol) was demethylated using pyridine hydrochloride (2.5 g, 21.6 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)[CH3:5].[CH2:17]([OH:20])[CH2:18][OH:19]>O>[CH3:1][O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:19][CH2:18][CH2:17][OH:20])=[O:15])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(N=C=O)cc1
Reactant: OCCO
Solvent: O
Product: COC(=O)C(C)Oc1ccc(NC(=O)OCCO)cc1
Reaction time: 16 h
Yield: 50.76 %

Procedure:
2-(4-Isocyanatophenoxy)-propionic acid methyl ester 11 (20 g, 90.49 mmol) was added to ethylene glycol (40 ml) at room temperature. The reaction was exothermic and the temperature rose to 58° C. This was followed by stifling at room temperature for 16 hours. Water (150 ml) was added and crude 12 was extracted in to chloroform, washed with water (2×50 ml), dried over sodium sulphate and distilled. Crude 12 was purified by column chromatography on silica gel using chloroform as eluant to get pure 12 (13 g, 50.76%) as a syrup which crystallized in 48 hours as a white powder with an m.p between 90.5-92.8° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1.[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:25]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)[CH:27]=1)=[O:25]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: FC(F)(F)c1cc(Cl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2cc(C(F)(F)F)nc3ccccc23)c2ccccc12
Temperature: 100 °C
Reaction time: 20 h
Yield: 54 %

Procedure:
1.04 g (7.5 mmol) of potassium carbonate and 0.695 g (3 mmol) of 4-chloro-2-(trifluoromethyl)quinoline are added to 0.526 g (3 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm3 of dimethylformamide under an argon atmosphere. After stirring at a temperature in the region of 100° C. for 20 hours, the reaction mixture is cooled and diluted with 100 cm3 of ethyl acetate and 100 cm3 of water. The organic phase is separated off by settling and washed with twice 100 cm3 of water and 100 cm3 of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in an orange-coloured oil. This oil is triturated in 20 cm3 of isopropyl ether and the resulting precipitate is filtered off, giving 0.6 g of 3-methoxycarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 370 (M+•), m/e 339.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C@@H:43](OS(C)(=O)=O)[CH:44]([CH3:46])[CH3:45])[CH2:10]2)=[CH:5][CH:4]=1.[C:52](#[N:54])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)(=[O:33])=[O:34])[C@@H:11]([CH2:42][C@@H:43]([CH:44]([CH3:46])[CH3:45])[C:52]#[N:54])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@@H](OS(C)(=O)=O)C(C)C)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@H](C#N)C(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 19c, 370 mg of methanesulfonic acid (R)-1-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-ylmethyl]-2-methyl-propyl ester in the presence of 275 mg of tetrabutylammonium cyanide in acetonitrile are used to afford the title compound as a yellow oil. Rf=0.30 (EtOAc-heptane 1:1); Rt=5.38.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)(C)=O.[Br-].[C:10]([CH2:15][S+](C)C)([O:12][CH2:13][CH3:14])=[O:11].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][C:33]([C:35]2[CH:40]=[CH:39][C:38]3[O:41][CH2:42][O:43][C:37]=3[CH:36]=2)=[O:34])[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28].Cl>CS(C)=O>[CH2:42]1[O:41][C:38]2[CH:39]=[CH:40][C:35]([C:33]([CH:32]3[CH:31]([C:23]4[CH:22]=[C:21]([O:20][CH3:19])[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=4)[CH:15]3[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:34])=[CH:36][C:37]=2[O:43]1
Reactant: CCOC(=O)C[S+](C)C
Reactant: COc1cc(C=CC(=O)c2ccc3c(c2)OCO3)cc(OC)c1OC
Agent: C[S+](C)(C)=O
Agent: Cl
Agent: [Br-]
Solvent: CS(C)=O
Product: CCOC(=O)C1C(C(=O)c2ccc3c(c2)OCO3)C1c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a three-neck one-liter round-bottom flask, equipped with a magnetic stirrer, dropping funnel, nitrogen inlet and a septum was placed sodium hydride (8.2 g, 0.17 moles, 50% dispersion). The dispersion was washed with petroleum ether (2×100 ml) and dried under nitrogen. Trimethylsulfoxonium iodide (37.7 g, 0.17 moles) was added, followed by a dropwise addition of dry dimethylsulfoxide (45 ml) via a syringe over a 30-minute period. The suspension was stirred at room temperature for 1.5 hours, and then a solution of carbethoxymethyl dimethylsulfonium bromide (41.2 g, 0.18 moles) in dimethylsulfoxide (60 ml) was added over a 10-minute period, under continuous stirring. The milky white suspension was further stirred at room temperature for 1.5 hours. A suspension of 3,4,5-trimethoxy-3',4'-methylenedioxy chalcone XXIIa (55.9 g, 0.16 moles) [prepared according to the procedure described by S. Wattanasin and W. S. Murphy, Synthesis, 647 (1980)] in dimethylsulfoxide (185 ml) was added in a steady stream over a 5-minute period, and then the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into cold 0.1N HCl (700 ml), and the resulting gummy material was separated from the aqueous solution. The aqueous solution was extracted with ether (2×500 ml). The combined extract together with an additional amount of ether (500 ml) was employed to dissolve the gummy precipitate. The etheral solution was sequentially washed with aqueous NaHCO3 solution (500 ml, 5%) and water, dried (Na2SO4 and MgSO4) and concentrated to yield the α-isomer of the title compound (68.0 g) as a light-yellow glass. The 1H NMR spectral data of this material was identical to the α-isomer reported by W. S. Murphy and S. Wattanasin, J.C.S. Perkin I, 271 (1982).
Reaction SMILES: C([C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:13]=1[O:26][CH3:27])([CH2:9][CH2:10][CH3:11])[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+]>C(O)C.O>[CH3:27][O:26][C:13]1[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][CH:16]=[CH:17][C:12]=1[CH:3]([CH2:9][CH2:10][CH3:11])[C:4]([OH:6])=[O:5]
Reactant: CCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2Cl)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC(C(=O)O)c1cccc(Oc2ccccc2Cl)c1OC
Yield: 62.9 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]valerate (7 g) and potassium hydroxide (5 g) in ethanol (80 ml) and water (40 ml) was treated in a similar manner to that of Example 14-(7) to give oily 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]valeric acid (3.8 g).