Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:23][CH3:24])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C(N(C(C)C)CC)(C)C.Br[CH2:39][C:40]([NH2:42])=[O:41]>C(Cl)Cl>[C:40]([CH2:39][N:20]1[CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[O:23][CH3:24])[N:9]=[CH:8][N:7]=[C:6]3[NH:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=2[F:28])[CH2:18][CH2:19]1)(=[O:41])[NH2:42]
Reactant: NC(=O)CBr
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(CC(N)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (Example 2, 70 mg, 0.17 mmol) was dissolved in DCM (10 ml), and diisopropylethylamine (45 μl, 0.26 mmol) was added. 2-Bromoacetamide (36 mg, 0.26 mmol) was added, and the solution stirred for 16 hours at ambient temperature. The solvent was evaporated, and the residue purified by chromatography, eluting with 0 to 3% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated, and the residue crystallised from acetonitrile to give the product as a white crystalline solid (48 mg, 60%); 1H NMR: 1.70-1.84 (m, 2H), 1.98-2.09 (m, 2H), 2.38 (m, 2H), 2.70-2.80 (m, 2H), 2.89 (s, 2H), 3.92 (s, 3H), 4.54 (m, 1H), 7.08 (br. s, 2H), 7.20 (s, 1H), 7.26 (ddd, 1H), 7.47 (ddd, 1H), 7.51 (ddd, 1H), 7.80 (s, 1H), 8.35 (s, 1H), 9.53 (s, 1H); Mass Spectrum: 460.5, 462.4.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[C:23]([C:25]#[N:26])[CH:24]=4)[NH:21][C:20]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:26][CH2:25][C:23]1[CH:24]=[C:16]([NH:15][C:13]([C:10]2([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:11][CH2:12]2)=[O:14])[CH:17]=[C:18]2[C:22]=1[NH:21][C:20]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:19]2
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(C#N)c2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(CN)c2[nH]1
Yield: 31.9 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-cyano-1H-indol-5-yl)cyclopropanecarboxamide (375 mg, 0.934 mmol) was dissolved in 35 mL of ethyl acetate. The solution was recirculated through a continuous flow hydrogenation reactor containing 10% palladium on carbon at 100° C. under 100 bar of hydrogen for 8 h. The crude product was then evaporated to dryness and purified on 12 g of silica gel utilizing a gradient of 0-100% ethyl acetate (containing 0.5% triethylamine) in hexanes to yield N-(7-(aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]-dioxol-5-yl)-cyclopropanecarboxamide (121 mg, 32%). ESI-MS m/z calc. 405.2, found 406.5 (M+1)+. Retention time of 1.48 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6]([CH3:9])([CH3:8])[CH2:5][NH:4][CH2:3]1.[CH2:11]([O:18][CH2:19][CH:20]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH2:11]([O:18][CH2:19][CH2:20][N:4]1[CH2:5][C:6]([CH3:9])([CH3:8])[O:7][C:2]([CH3:10])([CH3:1])[CH2:3]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCOCc1ccccc1
Reactant: CC1(C)CNCC(C)(C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CC1(C)CN(CCOCc2ccccc2)CC(C)(C)O1
Yield: 63.3 %

Procedure:
Dissolve 500 mg (2.79 mmol) of 2,2,6,6-tetramethyl-morpholine (500 mg, 2.79 mmol) in dichloroethane (10 mL). Add benzyloxy-acetaldehyde (470 μl, 3.35 mmol) and stir at room temperature for 20 min. Add sodium triacetoxyborohydride (770 mg, 3.63 mmol) and continue stirring at room temperature for 20 h. Pour the reaction mixture into 100 mL of 1N NaOH (100 mL) and extract with CH2Cl2 (2×100 mL). Wash the combined organic layers with brine (100 mL). Purify using silica gel chromatography, using a gradient of 0% to 10% (2N NH3 in MeOH)/CHCl3 as eluent, to give 490 mg (63%) of the desired product. MS (ES+) 278.3 (M+1)+.
Reaction SMILES: Cl[CH:2]([CH2:19][CH2:20][CH2:21]Cl)[CH2:3][NH:4][C:5](=[O:18])[C:6]1[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:9]=[CH:8][C:7]=1[O:16][CH3:17].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>O>[CH:23]1([N:26]2[CH2:21][CH2:20][CH2:19][CH:2]2[CH2:3][NH:4][C:5](=[O:18])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:9]=[CH:8][C:7]=2[O:16][CH3:17])[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)NCC(Cl)CCCCl
Solvent: O
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)NCC1CCCN1C1CC1
Temperature: 0 °C
Yield: 189.6 %

Procedure:
36.9 g (0.1 mole) of N-(2,5-dichloropentyl)-2-methoxy-5-sulphamoyl-benzamide and 57 g of cyclopropylamine are placed in 250 ml bottle. They are brought to reflux for 6 hours, left to stand for 1 night then brought back to reflux for 5 hours. The suspension obtained is poured into 300 ml of water and 50 g of ice. The white precipitate is washed with water and dried in an oven at 60° C. It melts at 163° C. and weighs 29.5 g (83.6%). It is dissolved in 2 liters of acetonitrile and filtered in the presence of carbon black. The filtrate is left to crystallise. The crystals obtained are filtered, washed with acetonitrile and dried at 40° C. 67 g (yield 74.9%) of N-(1-cyclopropyl-2-pyrrolidinylmethyl)-2-methoxy-5-sulphamoylbenzamide is collected, melting at 180° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[N:5]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16].O>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH3:18])[C:15]([NH:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[N:5]=1)=[O:16]
Reactant: Cc1nc(N)nc(C)c1Cl
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(NC(=O)N(C)C)nc(C)c1Cl
Reaction time: 1 h

Procedure:
Sodium hydride (6 g., 55%, 0.137 mole) is added to a mixture of 2-amino-4,6-dimethyl-5-chloropyrimidine (19.5 g., 0.125 mole) in 250 ml of toluene. The mixture, under a nitrogen atmosphere is heated to reflux and stirred for one hour. Another portion of sodium hydride (6 g., 55%, 0.137 mole) is added and after two hours of reflux, dimethyl carbamoyl chloride (13.9 g., 0.125 mole) is added. After one hours of reflux the reaction is cooled, water is added, the toluene is removed by vacuum concentration and the product is extracted into petroleum ether from which it is crystallized by evaporation. N,N-Dimethyl-N'-(4,6-dimethyl-5-chloro-2-pyrimidinyl)urea melting at 127°-129° C. is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:32]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH2:19][Br:32])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc(-c2ccc(OC)cc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc(-c2ccc(OC)cc2)nc1CBr
Yield: 100.3 %

Procedure:
To a boiling solution of 23.5 g 2-(4-methoxy-phenyl)-4-methyl-oxazole-5-carboxylic acid ethyl ester in 250 ml tetrachloro-methane were added portionwise a mixture of 5.92 g 2,2′-azobis(2-methylpropionitrile) and 19.3 g N-bromosuccinimide. The reaction mixture was refluxed for seven hours. The cooled reaction mixture was filtered over a celite pad and the solvent removed in vacuo to obtain 30.7 g of crude 4-bromomethyl-2-(4-methoxy-phenyl)-oxazole-5-carboxylic acid ethyl ester. The material was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:32])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:29][CH2:30]C)=[N:23][C:24](SC)=[N:25][CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:33][O-:34].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:32])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:34][CH3:33])=[N:25][CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CCOc1nc(SC)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Agent: [Na+]
Solvent: CO
Product: COc1ncc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2)c(OC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-4-ethoxy-2-methylsulfanyl-pyrimidine (250 mg, 0.513 mmol) in methanol (10 mL) was added sodium methoxide (4.1 mL, 0.5M solution in methanol, Aldrich). The mixture was stirred at room temperature overnight then concentrated under reduced pressure. The crude residue was taken in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrate under reduced pressure to give rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2,4-dimethoxy-pyrimidine (˜200 mg). It was then taken in ethanol (15 mL) and sodium ethoxide (58.1 mg, Fluka) was added. The reaction mixture was left in the fridge overnight then concentrated under reduced pressure. The crude residue was taken in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrate under reduced pressure. Purification of the crude residue by flash column chromatography (12 g of silica gel, eluting with 20-100% ethyl acetate in hexanes then with 3% methanol in ethyl acetate) gave rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2,4-diethoxy-pyrimidine as an off-white foam (132 mg, 62%). HR-MS (ES, m/z) calculated for C25H27N4O2Cl2 [(M+H)+] 485.1506, observed 485.1508.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:30]=[CH:29][C:10]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH2:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([CH2:12][O:11][C:10]2[CH:29]=[CH:30][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=2)[CH2:18][CH2:17]1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
Methanesulphonyl chloride (1.91 g) was added to a stirred solution of the product of part (iii) (5.15 g) in pyridine (50 ml) at 0°. The solution was stirred at room temperature for 18 hours and then evaporated. The residue was treated with aqueous sodium bicarbonate solution and the mixture was extracted several times with ethyl acetate. The combined extracts were washed with water, dried (Na2SO4) and evaporated. The residue was crystallised from ethyl acetate/hexane to give the title compound, (5.17 g), m.p. 150°-151°.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].[CH2:15]([OH:17])[CH3:16]>>[ClH:1].[CH2:2]([O:4][C:5]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:6]=1[C:7](=[NH:8])[O:17][CH2:15][CH3:16])[CH3:3]
Reactant: CCOc1cc(OC)ccc1C#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1OCC
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2-ethoxy-4-methoxy-benzonitrile (6.3 g, 35.55 mmol) in anhydrous ethanol (70 mL) cooled to −10° C. After 30 min, hydrogen chloride gas was stopped and the reaction mixture was stirred at room temperature in a closed reaction vessel for 4 d. The reaction vessel was cooled to 0° C. before the stopper was removed. Argon gas was passed through the solution to remove excess hydrogen chloride gas. The solvent was evaporated and the residue was triturated in diethyl ether (100 mL) to afford ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride (7.3 g, 79%). It was used without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]=O.N1CCCCC1.C(O)(=O)C>C(OCC)(=O)C.C(O)C>[CH3:15][O:14][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[CH:9]=[C:8]([O:10][CH3:11])[C:7]=1[O:12][CH3:13]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1ccccn1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1cc(C(=O)C=Cc2ccccn2)cc(OC)c1OC

Procedure:
Combine 3,4,5-trimethoxyacetophenone (5.25 g, 25 mmol), 2-pyridinecarboxaldehyde (2 .35 mL, 25 mmol), piperidine (4.93 mL, 50 mmol), acetic acid (2.8 6 mL, 50 mmol) and ethanol (25 mL). Heat at reflux for 6 hour s, passing the distillate through a column of 3 Å molecular sieves (25 g). Dilute with ethyl acetate (600 mL), wash wit h saturated sodium hydrogen carbonate, then water, then saturated sodium chloride. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (70% ethyl acetate/hexane). Recrystallize (methylene chloride/ethyl ether/hexane) to yield the title compound; mp 94°-5° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:8]([CH3:11])=[CH:9][N:10]=1)=[O:5])C.[OH-].[K+:21]>C(O)C>[K+:21].[CH3:11][C:8]1[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[C:6]([C:4]([O-:5])=[O:3])=[N:10][CH:9]=1
Reactant: CCOC(=O)c1ncc(C)n1COCC[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(C(=O)[O-])n1COCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid ethyl ester (as prepared in the previous step, 0.090 g, 0.32 mmol) in 2 mL of ethyl alcohol (EtOH) at RT was added 0.16 mL of 2N KOH. The mixture was stirred for 1 h and then concentrated and dried under vacuum to afford the title compound as a solid that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][S:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)s1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCc1ccc(Br)s1)c1cccc(Cl)c1

Procedure:
In analogy to example 4, step 1, 1-(5-bromo-2-thienyl)methanamine was reacted with 3-chlorobenzenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give N-(5-bromo-thiophen-2-ylmethyl)-3-chloro-benzenesulfonamide as a colorless solid. MS: 363.9 ([M−H]−)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.I.[OH-].[Na+]>C(O)(=O)C>[Cl:12][C:4]1[N:3]=[CH:2][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Clc1cc2ccccc2cn1
Yield: 24.5 %

Procedure:
A mixture of 1,3-dichloroisoquinoline (5.00 g, 25.2 mmol), red phosphorus, (1.72 g, 55.5 mmol), and hydriodic acid (10.5 mL, 58.1 mmol) in acetic acid (25 mL) was heated to reflux for 24 hours. The reaction mixture was cooled and poured onto ice, and the resulting solution brought to pH 7 by the addition of 10N aqueous sodium hydroxide. The solution was extracted with dichloromethane (2×50 mL), and the organic layers concentrated. The residue was purified by silica gel chromatography (elution with 10% EtOAc/hexanes) to provide 1.01 g (24%) of the title compound. MS (DCI/NH3) m/z 164 (M+H)+.
Reaction SMILES: FC(F)(F)C([O-])=O.[S:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH3+:14].Br[C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.CCN(C(C)C)C(C)C>C(O)CCC>[C:25]1([C:24]2[C:17]3[C:16]([NH:14][CH2:13][CH:9]4[CH2:10][CH2:11][CH2:12][S:8]4)=[N:21][CH:20]=[N:19][C:18]=3[O:22][C:23]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [NH3+]CC1CCCS1
Reactant: Brc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc(-c2oc3ncnc(NCC4CCCS4)c3c2-c2ccccc2)cc1
Yield: 75.7 %

Procedure:
A mixture of (tetrahydrothiophen-2-yl)methylammonium trifluoroacetate 223 (60 mg, 0.25 mmol) and 4-bromo-5,6-diphenylfuro[2,3-d]pyrimidine 69 (46 mg, 0.15 mmol) was stirred in n-butanol (2 mL) and DIPEA (0.25 mL) was added. The mixture was heated at reflux for 1 hour, cooled and the solvent was evaporated. The residue was purified by flash column chromatography to afford 230 (44 mg, 73%) as a yellow oil. 1H NMR (CDCl3): 8.32 (1H, s); 7.56-7.40 (7H, m); 7.23-7.15 (3H, m); 5.00 (1H, br t, J=4 Hz); 3.69-3.60 (1H, m); 3.55-3.35 (2H, m); 2.75-2.60 (2H, m); 1.95-1.75 (3H, m) and 1.60-1.48 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]1[CH2:24][O:23][CH:19]([CH2:20][CH2:21]Cl)[CH:18]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[O:17]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:16]1[CH2:24][O:23][CH:19]([CH2:20][CH2:21][N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:15][CH2:14]2)[CH:18]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[O:17]1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: COc1ccc(C2OCCOC2CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C2OCCOC2CCN2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Yield: 37.7 %

Procedure:
4-(tert-Butoxycarbonylaminomethyl)piperidine (10.0 g) as a starting compound, 4-ethylenedioxy-4-(4-methoxyphenyl)butyl chloride (12.0 g) and potassium carbonate (19.3 g) were reacted and treated in the same manner as in Preparation Example 181 to give 7.65 g of 1-(4-ethylenedioxy-4-(4-methoxyphenyl)butyl)-4-(tert-butoxycarbonylaminomethyl)piperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]=1[CH2:15][C:16](=[O:21])C(OC)=O)([O-:3])=[O:2].OO.[O-:24]S([O-])=O.[Na+].[Na+]>CC(O)=O>[N+:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([C:11]([F:12])([F:13])[F:14])[C:5]=1[CH2:15][C:16]([OH:21])=[O:24])([O-:3])=[O:2]
Reactant: COC(=O)C(=O)Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
To crude methyl 3-[2-nitro-4-iodo-6-(trifluoromethyl)phenyl]-2-oxo-propanoate prepared above (40.98 g) in AcOH (750 mL) was added aqueous 30% H2O2 solution (266 mL) followed by 70% HClO4 (41 mL). The resulting mixture was stirred at 50° C. (bath temperature) for 4.5 hours. The solution was cooled and solid Na2SO3 (100 g) was added. The solvent was then removed in vacuo. The resulting orange solid was suspended in EtOAc (500 mL) and washed with H2O (300 mL). The organic phase was then extracted with aqueous saturated NaHCO3:aqueous 2N NaOH (6:1, 600 mL) followed by aqueous saturated NaHCO3 (200 mL). The aqueous extracts were combined and cooled in an ice-water bath. The solution was then acidified with aqueous 35% HCl. The resulting solid was isolated by filtration and dried to give the title compound as a yellow solid (7.086 g). The organic phase was then re-extracted with aqueous saturated NaHCO3 (6×50 mL). The extracts were combined and cooled in an ice-water bath, and then acidified with aqueous 35% HCl. The resulting solid was isolated by filtration and dried to give the title compound as a yellow solid (6.896 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.[CH3:10][C:11]1[C:15]([C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:27][CH2:28][C:29]4[S:33][C:32]([CH3:34])=[N:31][C:30]=4[CH3:35])=[C:21]([NH2:26])[CH:22]=[N:23]3)=[CH:18][C:17]=2[O:36][CH3:37])=[C:14]([CH3:38])[O:13][N:12]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH3:10][C:11]1[C:15]([C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:27][CH2:28][C:29]4[S:33][C:32]([CH3:34])=[N:31][C:30]=4[CH3:35])=[C:21]([NH:26][C:7]([CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[O:9])[CH:22]=[N:23]3)=[CH:18][C:17]=2[O:36][CH3:37])=[C:14]([CH3:38])[O:13][N:12]=1
Reactant: COc1cc2c(NCc3sc(C)nc3C)c(N)cnc2cc1-c1c(C)noc1C
Reactant: O=C(O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(NCc3sc(C)nc3C)c(NC(=O)C3CCOCC3)cnc2cc1-c1c(C)noc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tetrahydro-2H-pyran-4-carboxylic acid (0.381 g, intermediate 69) in DCM (60 ml) were successively added triethylamine (0.41 ml) then HATU (1.115 g) and the resulting mixture was stirred for 20 min room temperature. 7-(3,5-dimethyl-4-isoxazolyl)-N4-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-6-(methyloxy)-3,4-quinolinediamine (0.6 g, intermediate 69) was added and the mixture stirred at ambient temperature overnight. The reaction mixture was poured into water and extracted with DCM. The organic phase was washed with a dilute sodium hydroxide solution and then with water. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude residue was purified by flash silica gel chromatography eluting DCM/methanol (99:1 then 95:5) to give the desired product as a beige sticky solid (0.71 g). The solid was triturated with hot diisopropylether to give N-[7-(3,5-dimethyl-4-isoxazolyl)-4-{[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)-3-quinolinyl]tetrahydro-2H-pyran-4-carboxamide (0.6 g) as cream coloured crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[C:7](=[CH:9]/[CH:10]([CH3:12])[CH3:11])/[CH3:8].NC1C=CSC=1/C(=C\C(C)C)/C>CC(C)CC(=O)C>[NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([CH2:9][CH:10]([CH3:12])[CH3:11])=[CH2:8]
Reactant: C/C(=C\C(C)C)c1sccc1N
Agent: C/C(=C/C(C)C)c1sccc1N
Solvent: CC(=O)CC(C)C
Product: C=C(CC(C)C)c1sccc1N
Yield: 96 %

Procedure:
3-aminothiophenebenzene sulfonate (2.1 g, 7.7 mmol, purity: 91.6%) was added to 4-methyl-2-pentanone (121.2 g) and reacted at 60 degree centigrade for 8 hours. The reaction mixture in a suspended state at the beginning became a solution state after 6 hours. As a result of the analysis by the HPLC internal standard method of the reaction solution, 1.3 g was produced as a mixture of three compounds including 3-amino-2-{(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-amino-2-{(Z)-(4-methyl-2-penten-2-yl)}thiophene and 3-amino-2-(4-methyl-1-penten-2-yl)thiophene was produced (yield: 96%).
Reaction SMILES: C(P(C1C=CC=CC=1)CCP(CC1C(OC)=CC=CC=1)C1C=CC=CC=1)C1C(OC)=CC=CC=1.CO.[C:37]([NH:40][C:41](=[CH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:42]([OH:44])=[O:43])(=[O:39])[CH3:38].[H][H]>C(O)(C)C>[C:37]([NH:40][C@H:41]([C:42]([OH:44])=[O:43])[CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)(=[O:39])[CH3:38]
Reactant: [H][H]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Agent: COc1ccccc1CP(CCP(Cc1ccccc1OC)c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.013 g. of [Rh(COD)Cl]2 (0.026 m moles) and 0.024 g. 1,2-bis(o-anisylphenylphosphino) ethane prepared in Example 1 (0.051 m moles) in 5 ml. of methanol was made with stirring for 15 minutes at 25° C. With careful exclusion of air, 0.5 ml. of this solution was added to a slurry of 1.00 g. of α-acetamidocinnamic acid in 25 ml. of 88% i-propanol at 50° C. and the resulting mass was subjected to 3.5 atm. (abs. pressure) of hydrogen. The hydrogenation reaction was completed in 0.7 hours. N-acetyl-L-phenylalanine can be isolated from the reaction mass by crystallization. Analysis of the reaction mixture showed that an optical purity of 92.8% of the L isomer was obtained.