Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.C[O:7][C:8](=[O:24])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=2)[CH:10]=1.O[Li].O>O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([OH:24])=[O:7])=[CH:10][C:11]=1[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: COC(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
A mixture of THF (15 mL) and water (1 mL) containing 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid methyl ester (1.7 g, 5.4 mmol) and LiOH.H2O (0.68 g, 16.1 mmol) was stirred at room temperature for 12 hrs. The mixture was acidified and extracted with ethyl acetate. The organic layer was washed with brine and water and was dried. Filtration and concentration gave 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid as a white solid (1.4 g). MS (M+H)+: 301.6, tR=7.048 min (method 2)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:50])[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9]([C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10].I[CH2:52][CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCOCC1>[CH3:1][O:2][C:3](=[O:50])[CH2:4][N:5]([CH2:52][CH2:53][CH3:54])[CH2:6][CH2:7][NH:8][C:9]([C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CCC)CC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 66.9 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-methoxy-2-oxoethylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (28 mg, 0.041 mmol), 1-iodopropane (55.4 mg, 0.326 mmol) and potassium carbonate (11.27 mg, 0.082 mmol) in acetonitrile (2 mL) and dioxane (2.000 mL) was heated up for 8 hours. LCMS indicated the formation of desired product and consumption of starting material. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a white solid (20 mg, 67%). LCMS: m/e 729.47 (M+H)+, 2.96 min (method 1).
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH:4]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=O.[C:20]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(P(N(C)C)(N(C)C)=O)C>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:4]1[CH:3]([CH:1]=[CH:28][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH2:11][CH2:10][C:5]21[O:9][CH2:8][CH2:7][O:6]2
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(C=CC1CCC2(OCCO2)C1CCCCCCCO)c1ccccc1

Procedure:
A mixture of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [4.0 g; prepared as hereinbefore described in Example 1(iv)] and benzoylmethylenetriphenylphosphorane (5.6 g; prepared according to the method of F. Ramirez and S. Dershowitz, J. Org. Chem. 1957, 22, 41) in hexamethylphosphotriamide (35 ml.) was heated on a steam bath under dry nitrogen for 48 hours then poured into water (200 ml.). The mixture was extracted with diethyl ether and the ethereal solution was washed with water, dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether, allowed to stand at 0° C, then filtered to remove triphenylphosphine oxide. The filtrate was evaporated to give 6-(7-hydroxyheptyl)-7-(3-phenyl-3-oxoprop-1-enyl)-1,4-dioxaspiro[4,4]nonane (5.5 g.) (νmax 950 cm-1, 985 cm-1, 1615 cm-1, 1660 cm-1, 3380 cm-1).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:33][C:34](=[O:53])[NH:35]C(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)[C:13]([NH:15][C@H:16]([C@@H:20]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)[CH3:21])[C:17]([OH:19])=[O:18])=[O:14])=O)C1C=CC=CC=1.Br.C(OCC)(=O)C>C(O)(=O)C>[NH2:11][C@@H:12]([CH2:33][C:34](=[O:53])[NH2:35])[C:13]([NH:15][C@H:16]([C@@H:20]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)[CH3:21])[C:17]([OH:19])=[O:18])=[O:14]
Reactant: COc1ccc(C(NC(=O)C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](C(=O)O)[C@H](C)N[C@@H](Cc2c[nH]cn2)C(=O)O)c2ccc(OC)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@H](N[C@@H](Cc1c[nH]cn1)C(=O)O)[C@@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)O
Temperature: 0 °C
Yield: 59 %

Procedure:
A solution of (2R,3S)-2-[[(2S)-2-benzyloxycarbonylamino-3-[N-[bis(4-methoxyphenyl)methyl]carbamoyl]propionyl]amino]-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]butyric acid (635 mg) and 30% hydrogen bromide in acetic acid (5 ml) was stirred for 2 hours at room temperature and the mixture was poured into a mixture of ice-water (20 ml) and ethyl acetate (20 ml). The aqueous phase was separated and subjected to a column of Dowex 50W x 8 (H+, 20 ml). The column was washed with water and the elution was carried out with 2.8% aqueous ammonia. The object fractions were collected and evaporated in vacuo. The residue was dissolved in water (50 ml) and lyophilized to give (2R,3S)-2-[[(2S)-2-amino-3-carbamoylpropionyl]amino]-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]butyric acid (190 mg) as a white powder.
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)#N.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([Li])=[O:16]>>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)=[O:16]
Reactant: [Li]C(=O)c1ccco1
Reactant: Cc1ccnc(C#N)c1
Product: Cc1ccnc(C(=O)c2ccco2)c1

Procedure:
2-Cyano-4-methylpyridine is reacted in an inert atmosphere with an ethereal solution of freshly prepared 2-furoyl-lithium followed by acid hydrolysis to form 2-(2-furoyl)-4-methylpyridine which is then reacted with methyl iodide to form 2-(2-furoyl)-1,4-dimethylpyridinium iodide. Both furoyl compounds exhibit thermal and chemical analgesic properties.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][O:42][CH:43]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:39]4[CH:40]=[N:41][O:42][CH:43]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(-c3cnoc3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Yield: 22.5 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (100 mg, 0.191 mmol) in 1,4-dioxane (2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (55.8 mg, 0.286 mmol), potassium carbonate (79 mg, 0.573 mmol) and bis(triphenylphosphine)palladium(II) chloride (13.40 mg, 0.019 mmol). Water (0.5 mL) was then added and the mixture heated at 100° C. in a microwave for 15 min. The solvent was then removed in vacuo and the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase was re-extracted with ethyl acetate (2×20 mL). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-40% ethyl acetate in cyclohexane, to give the title compound (22 mg). LCMS (A) m/z: 512 [M+1]+, Rt 1.36 min (acidic).
Reaction SMILES: [N+:1]([C:4]1(C([O-])=O)[CH:13]=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5]1)([O-:3])=[O:2].[CH3:17][OH:18]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([CH2:17][OH:18])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2]
Reactant: CO
Reactant: COC(=O)C1=CC=CC(C(=O)[O-])([N+](=O)[O-])C1
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)cc([N+](=O)[O-])c1

Procedure:
To a solution of monomethyl 3-nitroisophthalate (396.0 g, 1.76 mol) in anhydrous THF (1000 ml) was added 2.0M BMS (borane methylsulfide complex) in THF (880 ml, 1.76 mol) dropwise over 1 hour. The resulting solution was heated to reflux for 12 hours, and MeOH (750 ml) was slowly added to quench the reaction. The solution was concentrated to give a yellow solid which was recrystalized from toluene (297.5 g, 80%). 1H NMR (CDCl3): 8.71-8.70 (m, 1H), 8.41-8.40 (m, 1H), 8.31-8.30 (m, 1H), 4.86 (s, 2H), 3.96 (s, 3H), 2.47 (s, 1H); MP=76.5°-77.5° C.; DCI-MS: [M+H]=212.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:19])=[C:7]([CH:18]=1)[O:8][CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].[C-:20]#[N:21].[Na+]>CN(C=O)C>[CH3:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][O:8][C:7]1[CH:18]=[C:3]([CH2:2][C:20]#[N:21])[CH:4]=[CH:5][C:6]=1[F:19]
Reactant: [C-]#N
Reactant: Cc1cccc(C)c1COc1cc(CCl)ccc1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cc(CC#N)ccc1F
Temperature: 100 °C

Procedure:
To a stirred solution of 2-((5-(chloromethyl)-2-fluorophenoxy)methyl)-1,3-dimethylbenzene (Step C, 4 g, 14.3 mmol), KI (0.33 g) in DMF (30 ml) was added NaCN (1.02 g, 20.8 mmol). The reaction mixture was heated at 100° C. for 4 hours, concentrated, diluted with EtOAc and washed with water (2×), dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hexane:methylene chloride, 1:1) to give the title compound.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]C)=O)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:19][NH2:20]>CCO>[CH3:19][NH:20][C:15]([CH:12]1[CH2:13][CH2:14][CH:10]([C:8]2[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=2)[CH2:11]1)=[O:17]
Reactant: CN
Reactant: COC(=O)C1CCC(c2csc(NC(=N)N)n2)C1
Solvent: CCO
Product: CNC(=O)C1CCC(c2csc(NC(=N)N)n2)C1
Reaction time: 60 h

Procedure:
Methyl 3-(2-guanidinothiazol-4-yl)cyclopentane carboxylate (0.40 g.) and a solution of methylamine in EtOH (33% w/v; 15 ml.) was allowed to stand at ambient temperature for 60 hours. The solvent was removed by evaporation in vacuo and the residue was purified by medium pressure chromatography on silica gel using CHCl3 /MeOH/aqueous ammonia (s.g. 0.88) 8:2:0.3 v/v/v as eluant to give N-methyl-3-(2-guanidinothiazol-4-yl)cyclopentane carboxamide (0.27 g.), m.p. 216°-218°.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:20])[O:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH:9]1[CH2:10][O:11][C:12](=[O:20])[CH:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCC1COC(=O)C1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1COC(=O)C1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 151.9 %

Procedure:
(5-Oxo-4-phenyl-tetrahydrofuran-3-ylmethyl)carbamic acid tert-butyl ester (Description 4; 2.16 g, 7.4 mmol) was dissolved in dichloromethane (10 ml), cooled to 0° C., trifluoroacetic acid (1 ml) was added and the reaction was left to stand for 20 minutes to warm to room temperature. TLC showed the reaction to be incomplete so extra trifluoroacetic acid (1 ml) was added and the reaction was left for a further 30 minutes. The solvent was removed in vacuo and the residue was dispersed between ethyl acetate and saturate potassium carbonate solution. The aqueous layer was extracted with ethyl acetate (2×30 ml), the combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to dryness. Purification was carried out by flash column chromatography on silica gel eluting in increasing concentrations of methanol in dichloromethane and 0.2% ammonia (1-10%) to afford the title compound (2.15 g).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][C:4]([N:6]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C@@H:7]1[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]1)=[O:5].[CH:27]1[C:32]([CH:33]=O)=[CH:31][C:30]2[O:35][CH2:36][O:37][C:29]=2[CH:28]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCCC1>[O:37]1[C:29]2[CH:28]=[CH:27][C:32]([CH2:33][N:10]3[CH2:11][C@@H:7]([N:6]([C:4](=[O:5])[CH2:3][C:2]([CH3:26])([CH3:25])[CH3:1])[CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[CH2:8][C@H:9]3[C:12]([O:14][CH3:15])=[O:13])=[CH:31][C:30]=2[O:35][CH2:36]1
Reactant: COC(=O)[C@@H]1C[C@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1C[C@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1Cc1ccc2c(c1)OCO2
Reaction time: 0.75 h

Procedure:
A solution of methyl(2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]tetrahydro-1H-2-pyrrolecarboxylate (19b) (138 mg, 0.38 mmol), piperonal (58 mg, 0.39 mmol) and glacial acetic acid (225 μL, 3.93 mmol) in tetrahydrofuran (2.8 mL) was stirred for 30 min at room temperature. 95% Sodium cyanoborohydride (125 mg, 1.88 mmol) was added in small portions and stirring was continued for 45 min at the same temperature. After dilution with ethyl acetate (5 mL), the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution (2×5 mL) and brine (5 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 100% dichloromethane and dichloromethane-ethylacetate (4:1, v/v) to give the title pyrrole (20):
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:8]=2[CH:21]=1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:37])[CH3:36])[C:28](O)=O)#[N:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:23]([C:25]1[CH:26]=[C:27]([C:28]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:9][C:8]=4[CH:21]=3)[N:22]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:36])[CH3:37])#[N:24]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(C(=N)NO)cc2C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)no2)cc1C#N
Temperature: 120 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
A solution of 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 75) (0.84 g, 2.73 mmol), 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (0.617 g, 3.01 mmol), EDC (0.786 g, 4.10 mmol) and HOBT (0.502 g, 3.28 mmol) in DMF (10 ml) was stirred at RT overnight. Additional EDC (0.4 g) was added and the reaction stirred for 3 hours. Then additional 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (0.3 g) was added, the reaction heated at 120° C. for 1 hour and left standing overnight. The reaction mixture was partitioned between EtOAc/water, and the organic layer collected, dried (MgSO4) and evaporated. The resulting crude was purified by flash chromatography eluting with EtOAc/iso-hexane 20-30%. Analysis of the puried fractions by LCMS showed some 3-cyano-4-[(1-methylethyl)oxy]benzoic acid present so sodium bicarbonate and EtOAc was added. The EtOAc layer was separated, dried (MgSO4) and evaporated to give the title compound (410 mg) as a white solid. MS (ES): C26H28N4O5 requires 476; found 421 [M+H−56]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:33]([NH:35][C:36]2[CH:37]=[C:38]([S:54]([OH:57])(=[O:56])=[O:55])[CH:39]=[C:40]3[C:45]=2[C:44]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:43][C:42]([S:50]([OH:53])(=[O:52])=[O:51])=[CH:41]3)=[O:34])[CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([S:29]([OH:32])(=[O:31])=[O:30])[CH:14]=[C:15]3[C:20]=2[C:19]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:18][C:17]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:16]3)=[O:9])[CH:7]=1.[F:58][C:59]([F:70])([F:69])[C:60]1[CH:61]=[C:62]([N:66]=[C:67]=[O:68])[CH:63]=[CH:64][CH:65]=1>O>[F:58][C:59]([F:69])([F:70])[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([NH:66][C:67](=[O:68])[NH:1][C:2]2[CH:3]=[C:4]([C:33]([NH:35][C:36]3[CH:37]=[C:38]([S:54]([OH:57])(=[O:56])=[O:55])[CH:39]=[C:40]4[C:45]=3[C:44]([S:46]([OH:49])(=[O:47])=[O:48])=[CH:43][C:42]([S:50]([OH:53])(=[O:52])=[O:51])=[CH:41]4)=[O:34])[CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:12]=[C:13]([S:29]([OH:32])(=[O:30])=[O:31])[CH:14]=[C:15]4[C:20]=3[C:19]([S:21]([OH:24])(=[O:22])=[O:23])=[CH:18][C:17]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:16]4)=[O:9])[CH:7]=2)[CH:61]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c1
Solvent: O
Product: O=C(Nc1cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c1)Nc1cccc(C(F)(F)F)c1
Temperature: 95 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 4.0 g of 8,8'-[(5-amino-1,3-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfonic acid, hexasodium salt in 50 ml of water is added 4.0 ml of 3-trifluoromethylphenyl isocyanate. Stirring is continued for 6 hours at room temperature then the resulting mixture is heated to 95° C, is filtered through diatomaceous earth and washed with 50 ml of hot water. The hot filtrate is salted with 55 g of sodium acetate trihydrate and after standing for 40 hours is diluted with 700 ml of anhydrous ethanol. The precipitate is filtered and washed with absolute ethanol and ether. The product is then boiled and triturated with 100 ml of absolute ethanol, cooled to room temperature and is filtered and washed with absolute ethanol followed by ether to give 8,8'-{{5-[3-(α,α,α-trifluoro-m-tolyl)ureido]-1,3-phenylene}bis(carbonylimino)}di-1,3,6-naphthalenetrisulfonic acid, hexasodium salt.
Reaction SMILES: [CH:1]#[C:2][CH2:3][NH:4][C:5]([NH2:7])=[O:6].[F:8][C:9]1[C:10](I)=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])/[C:12]/2=[CH:19]\[C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:8][C:9]1[C:10]([C:1]#[C:2][CH2:3][NH:4][C:5]([NH2:7])=[O:6])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])/[C:12]/2=[CH:19]\[C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCNC(N)=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCNC(N)=O)c21

Procedure:
Using Method C above, 2-propynylurea (50 mg, 0.51 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-[3-[5-fluoro-2,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]urea. (Yield 11 mg, 16%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11].[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>ClCCCl>[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:14]1[NH:13][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)CCCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCCCCl)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 26.7 g (0.200 mol) of aluminium chloride and 31 g (0.200 mol) of 5-chlorovaleryl chloride in 200 ml of 1,2-dichloroethane is added slowly to a solution of 13.4 g (0.200 mol) of pyrrole in 250 ml of 1,2-dichloroethane. The reaction medium is stirred for 2 h at room temperature and is poured onto ice-cold hydrochloric acid. After extraction with methylene chloride, a red-brown oil is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=2[C:4](=[O:13])[CH2:3]1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:14][C:2]1([CH3:1])[CH2:10][C:9]2[N:8]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([F:15])[CH:21]=3)[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=2[C:4](=[O:13])[CH2:3]1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cn(-c2cccc(F)c2)c2c1C(=O)CC(C)(C)C2
Yield: 20.2 %

Procedure:
6,6-Dimethyl-3-ethyl-4,5,6,7-tetrahydro-1H-indol-4-one (50 mg, 0.26 mmol), copper acetate (71 mg, 0.39 mmol), 3-fluorophenyl boronic acid (73 mg, 0.52 mmol) and triethylamine (73 μL, 0.52 mmol) and triethylamine (73 μL, 0.52 mmol) in DCM (1 mL) was stirred at room temperature for 48 h. The crude reaction mixture was poured onto a bond elut tube (Anachem 1225-6034 10 g/60 mL) and eluted using isohexane : EtOAc (100:0→5:1) to afford a yellow solid. The solid was triturated in ether to afford the title compound (15 mg, 20%) as a colourless solid. 1H NMR (360 MHz, CDCl3) δ 1.08 (6H,s), 1.22 (3H,t, J=7.4Hz), 2.36 (2H,s), 2.62 (2H,s), 2.81 (2H,q, J=7.4 Hz), 6.57 (1H,s), 7.02-7.11 (3H,m), 7.41-7.45 (1H,m). MS (ES+) 286 (M+1).
Reaction SMILES: [H][H].[C:3]1([C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[C:3]1([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C1=C(c2ccccc2)CCCC1
Reactant: [H][H]
Solvent: C1CCOC1
Product: c1ccc(C2CCCCC2)cc1
Reaction time: 0.08 h
Yield: 99 %

Procedure:
In Example 7, hydrogenation reaction was conducted under the same condition as Example 1 for THF diluted solution concentration of the substance to be reduced, its flow rate, and hydrogen 9 flow rate, using 1-phenylcyclohexene as the substance to be reduced. The reaction time was within five minutes. The analytical result of the reaction product by 1H-NMR showed almost complete hydrogenation of 1-phenylcyclohexene, and phenylcyclohexane was obtained at 99% yield (See FIG. 6.).