Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O1CCCC1.[CH3:28][C:29]1[N:33]=[C:32]([NH:34][C:35]([C:37]2[C:42]([S:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]=O)=[CH:46][CH:45]=3)=[CH:41][CH:40]=[C:39]([S:54][C:55]3[N:59]([CH3:60])[CH:58]=[N:57][N:56]=3)[N:38]=2)=[O:36])[S:31][N:30]=1>O.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH2:52][CH2:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([S:43][C:42]2[C:37]([C:35]([NH:34][C:32]3[S:31][N:30]=[C:29]([CH3:28])[N:33]=3)=[O:36])=[N:38][C:39]([S:54][C:55]3[N:59]([CH3:60])[CH:58]=[N:57][N:56]=3)=[CH:40][CH:41]=2)=[CH:49][CH:48]=1
Reactant: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OCC=O)cc2)n1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OCCN(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.25 ml of 2 M dimethylamine/tetrahydrofuran solution and 0.21 mg of sodium triacetoxyborohydride were added to a tetrahydrofuran solution of 166 mg of N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]-3-{[4-(2-oxoethoxy)phenyl]thio}pyridine-2-carboxamide obtained in the step 1, and stirred at room temperature for 30 minutes. Chloroform and saturated saline water were added to it, and extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure, and the residue was purified through reversed-phase middle-pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water/acetonitrile/0.1% trifluoroacetic acid). The solvent of the resulting fraction was evaporated away under reduced pressure to obtain 190 mg of the entitled compound as its trifluoroacetate. The obtained salt was neutralized, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure, and the residue was purified through partitioning thin-layer chromatography (NH-PLC05 by Fuji Silicia Chemical, chloroform/methanol=95/5) to obtain 115 mg of the entitled compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(N(CC)CC)C.[CH3:21][C:22]1([CH3:33])[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:31])[C:25]=2[CH:24]([CH3:32])[CH2:23]1>C(OCC)(=O)C>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([NH:31][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[CH:24]([CH3:32])[CH2:23][C:22]2([CH3:33])[CH3:21])=[O:9]
Reactant: CC1CC(C)(C)c2cccc(N)c21
Reactant: Cc1occc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1occc1C(=O)Nc1cccc2c1C(C)CC2(C)C
Yield: 61.7 %

Procedure:
A mixture of 1.5 g (11.9 mmols) of 2-methyl-3-furan carboxylic acid with 3 ml of thionyl chloride was refluxed for 1 hour. The reaction solution was distilled under reduced pressure to remove excess thionyl chloride. The obtained residue was cooled and 20 ml of ethyl acetate, 2 g (19.8 mmols) of triethylamine, and 1.8 g (10.3 mmols) of 1,1,3-trimethylindane-4-amine were added thereto. The resultant mixture was stirred at room temperature for 2 hours. The reaction solution was sequentially washed with water and brine. The organic layer consequently separated was dried with magnesium sulfate and then concentrated under reduced pressure. The concentrated residue was purified by being recrystallized with ethyl acetate/n-hexane, to obtain 1.8 g of white crystals (Compound No. 17 shown in Table 6). The yield was 65%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][CH2:17][C:18]([NH:21]C(=O)OC(C)(C)C)([CH3:20])[CH3:19])=[C:14]([C:31]2[N:32]([CH3:37])[N:33]=[CH:34][C:35]=2[Br:36])[CH:13]=1.C(N(CC)C(C)C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:21][C:18]([CH3:20])([CH3:19])[CH2:17][O:16][C:15]1[CH:29]=[CH:30][C:12]([NH:11][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:13][C:14]=1[C:31]1[N:32]([CH3:37])[N:33]=[CH:34][C:35]=1[Br:36]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2ccc(F)cc2)ccc1OCC(C)(C)N
Reaction time: 8 h

Procedure:
4-Fluorobenzoyl chloride (6.63 μL, 0.056 mmol) was added to a solution of tert-butyl 1-(4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenoxy)-2-methylpropan-2-ylcarbamate (0.25 mL of a 0.2M solution in dichloromethane, 0.050 mmol) and N,N-diisopropylethylamine (13.1 μL, 0.075 mmol) in dichloromethane (0.5 mL) and the reaction vessel was agitated on a mechanical shaker overnight. TFA (0.25 mL) was added, and the reaction vessel was shaken for another 30 min. The solvent was evaporated in vacuo, and the crude product was purified by RP-HPLC and lyophilized to give the title compound as a TFA-salt (26 mg, 92%). LCMS m/z (%)=463.2 (M+H 81Br 43%), 461.2 (M+H 79Br 43%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (s, 3 H), 1.11 (s, 3 H), 3.60 (s, 3 H), 3.76 (d, J=9.60 Hz, 1 H), 3.92 (d, J=9.85 Hz, 1 H), 7.21 (d, J=9.09 Hz, 1 H), 7.27-7.36 (m, 2 H), 7.60 (s, 1 H), 7.62 (d, J=2.53 Hz, 1 H), 7.86 (s, 3H), 7.87 (dd, J=9.09, 2.53 Hz, 1 H), 7.93-8.00 (m, 2 H), 10.30 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=O)=[C:6]([O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]([O:17][CH3:18])=[C:4]([O:19][CH3:20])[CH:3]=1.[O-:21][C:22]#[N:23].[Na+].FC(F)(F)C(O)=O.O>ClCCl>[CH:13]1([O:12][C:6]2[C:5]([O:17][CH3:18])=[C:4]([O:19][CH3:20])[CH:3]=[C:2]3[C:7]=2[C:8]([OH:10])=[N:23][C:22]([OH:21])=[N:1]3)[CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1c(N)cc(OC)c(OC)c1OC1CCC1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1cc2nc(O)nc(O)c2c(OC2CCC2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Methyl 6-amino-2-cyclobutyloxy-3,4-dimethoxybenzoate (500 mg, 0.00177 mol) was added to a solution of sodium cyanate (462 mg, 0.00708 mol) and trifluoroacetic acid (0.55 ml, 0.00708 mol) in dichloromethane (15 ml) and the reaction stirred at room temperature for 1 hour. Water (25 ml) was then added and the mixture extracted with dichloromethane (3×25 ml). The combined organic extracts were washed again with water (40 ml), dried (MgSO4), filtered and evaporated under reduced pressure. The residue was suspended in a solution of sodium hydroxide (750 mg) in water (30 ml) and heated to 60° C. for 1 hour. On cooling, the mixture was acidified with concentrated hydrochloric acid, the resulting precipitate filtered and washed with water (20 ml) and diethyl ether (10 ml). Drying under air suction gave the subtitle compound as a solid (300 mg, 58%). 1H-NMR (DMSO-d6): δ=1.40 (1H, m), 1.67 (1H, m), 2.16 (4H, m), 3.68 (3H, s), 3.83 (3H, s), 4.58 (1H, m), 650 (1H, s).
Reaction SMILES: Cl[Si:2]([CH3:23])([CH3:22])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]1[CH3:21].CCN(CC)CC.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CCCCCC>[CH:31]1([NH:37][Si:2]([CH3:23])([CH3:22])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[CH3:21])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Reactant: NC1CCCCC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)NC1CCCCC1)CCC3
Reaction time: 24 h
Yield: 89.9 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-3-phenyl-s-indacen-1-yl) silane (9c)) (5.5340 g, 0.01633 moles) was stirred in hexane (100 mL) as NEt3 (2.9673 g, 0.02932 moles) and cyclohexylamine (1.6373 g, 0.01651 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (5.8969 g, 89.9 percent).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].O>N1C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:4][O:2][CH3:3])(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: CON
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CONS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 76 %

Procedure:
Methoxylamine hydrochloride(0.90 g (10.8 mmol) was suspended in pyridine (3.0 ml). To this, under cooling with ice and with stirring, 4-chloro-3-nitrobenzenesulfonylchloride (2.56 g (10.8 mmol)) was added and the mixture was stirred under cooling with ice for one hour and at room temperature for 3 hours. Water (50.0 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2.02 g (76%) of 4-chloro-N-methoxy-3-nitrobenzenesulfonamide as pale yellow-white crystals.
Reaction SMILES: C([N:3](CC)CC)C.N[C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([CH3:20])[CH:13]=2.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24].CO>ClCCl>[OH:19][C:18]1([NH:3][C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[C:17]2[C:12](=[CH:13][C:14]([CH3:20])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH2:9]1
Reactant: CCCC(=O)Cl
Reactant: CCN(CC)CC
Reactant: Cc1ccc2c(O)c(N)cnc2c1
Solvent: CO
Solvent: ClCCl
Product: CCCC(=O)NC1(O)CC=Nc2cc(C)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
Under a nitrogen atmosphere, triethylamine (0.71 mL, 5.1 mmol) was added to a suspension of 3-amino-7-methyl-4-quinolinol (800 mg, 4.6 mmol) in dichloromethane (30 mL). Butyryl chloride (0.53 mL, 5.1 mmol) was added. The reaction mixture was stirred at ambient temperature for about 2 hours. Analysis by thin layer chromatography (silica gel eluting with 9:1 dichloromethane:methanol) showed starting material. The reaction mixture was heated to reflux and then inadvertently allowed to go dry over the course of about 30 minutes. More solvent was added and the reaction mixture was heated at reflux for an additional hour at which time thin layer chromatography showed no starting material. The resulting precipitate was isolated by filtration and then rinsed with dichloromethane and water to provide 650 mg of N-(4-hydroxy-7-methylquinolin-4-yl)butyramide as a pale pink-tan solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:21])([CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].[CH2:22]([O:29][C:30](ON1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:23]1([CH2:22][O:29][C:30](=[O:31])[NH:1][CH2:2][C:3]([OH:21])([C:4]([F:7])([F:6])[F:5])[CH2:8][C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])([CH3:11])[CH3:10])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN)C(F)(F)F
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNC(=O)OCc1ccccc1)C(F)(F)F
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
Racemic 2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (which may be prepared according to WO03/082827, 894 mg, 2.89 mmol) was dissolved in dichloromethane (15 mL). N-(benzyloxycarbonyloxy)succinimide (1.08 g, 4.34 mmol) was added and the mixture was stirred for 5 min. Triethylamine (804 μL, 5.78 mmol) was added and stirring was continued for 3.5 hours after which time the reaction mixture was washed with saturated sodium bicarbonate solution and evaporated in vacuo. Purification of the residue by Flashmaster II using a 100 g silica cartridge and a solvent gradient of cyclohexane:EtOAc 100:0 to 0:100 over a period of 1 hour gave the racemic product as an oil (1.12 g). This oil was applied to a 2 inch×20 cm Chiralpak AD column eluted with heptane:IPA 97.5:2.5 with a flow rate of 75 mL/min to give Intermediate 7 (2R isomer, 443 mg) after ca. 42 min and Intermediate 8 (2S isomer, 441 mg) after ca. 60 min.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]=[CH:14][C:15]([OH:17])=[O:16])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)CC(=O)O
Reactant: O=CC1CCC2(CC1)OCCO2
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=CC1CCC2(CC1)OCCO2

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decane-8-carbaldehyde (3.1 g, 18.4 mmol, prepared as in STEP B above), malonic acid (3.8 g, 36.5 mmol), piperidine (0.182 mL, 1.8 mmol) in pyridine (20 mL) was stirred at 70° C. under an argon atmosphere. After 3 h the resulting solution was concentrated. The residue obtained was partitioned between ethyl acetate and water. The layers were separated, and the ethyl acetate layer was washed successively with water and brine. The ethyl acetate layer was dried over sodium sulfate and was filtered, concentrated, and dried in vacuo to yield 3-(1,4-dioxa-spiro[4.5]dec-8-yl)-acrylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].O.[CH2:24]([C@H:26]1[CH2:31][C@H:30]2[C@H:32]3[C@H:41]([CH2:42][CH2:43][C@:28]2([CH3:29])[C@H:27]1[O:45][C:46](=[O:49])[CH2:47]Br)[C@@H:40]1[C:35](=[CH:36][C:37](=[O:44])[CH2:38][CH2:39]1)[CH2:34][CH2:33]3)[CH3:25]>CC(C)=O>[CH2:24]([C@H:26]1[CH2:31][C@H:30]2[C@H:32]3[C@H:41]([CH2:42][CH2:43][C@:28]2([CH3:29])[C@H:27]1[O:45][C:46](=[O:49])[CH2:47][O:15][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C@@H:40]1[C:35](=[CH:36][C:37](=[O:44])[CH2:38][CH2:39]1)[CH2:34][CH2:33]3)[CH3:25]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Yield: 80.5 %

Procedure:
In 40 ml of acetone is dissolved 1.2 g of N-t-butoxycarbonylleucine, and 1.2 g of potassium t-butoxide and 8 ml of water are added, followed by addition of 1.1 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 12 hours. The solvent is then distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is subjected to column chromatography. After serial passage of diisopropyl ether-n-hexane mixtures (1:3, 400 ml and 5:2, 750 ml), elution is carried out with 1000 ml of a 4:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.2 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: [C:1]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[CH2:19](I)[CH3:20]>>[C:1]([N:8]([CH2:19][CH3:20])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1c(C)cccc1[N+](=O)[O-]
Reactant: CCI
Product: CCOC(=O)C(=O)N(CC)c1c(C)cccc1[N+](=O)[O-]

Procedure:
N-ethoxalyl-N-ethyl-2-nitro-6-methylaniline (oil) was prepared from N-ethoxalyl-2-nitro-6-methylaniline and ethyl iodide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](Cl)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15].C(C1C=CC(OC)=CC=1NC(C1SC=C(C(C)C)N=1)=O)(=O)C>>[C:11]([C:3]1[C:2]([NH:1][C:22]([C:19]2[S:20][CH:21]=[C:17]([CH:14]([CH3:16])[CH3:15])[N:18]=2)=[O:23])=[C:7]([F:8])[C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)(=[O:13])[CH3:12]
Reactant: CC(C)c1csc(C(=O)Cl)n1
Reactant: COc1ccc(C(C)=O)c(N)c1F
Agent: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1F
Yield: 84 %

Procedure:
N-(6-Acetyl-2-fluoro-3-methoxyphenyl)-4-isopropylthiazole-2-carboxamide 217c was synthesized from 1-(2-amino-3-fluoro-4-methoxyphenyl)ethanone and compound 214 as a beige solid in 84% yield, according to the procedure as described for compound 217a. MS (ESI, EI+): m/z=337 (MH+).
Reaction SMILES: COC(C1C(C2N=C(C3C=CC=CC=3)SC=2)C(C(OC)=O)=C(C)NC=1C)=O.[CH:28]([O:31][C:32]([C:34]1[CH:39]([C:40]2[N:41]=[C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[S:43][CH:44]=2)[C:38]([C:51]([O:53][CH:54](C)[CH3:55])=[O:52])=[C:37]([CH3:57])[NH:36][C:35]=1[CH3:58])=[O:33])(C)[CH3:29].C(OC(C1C(C2N=C(C3C=CC=CC=3)SC=2)C(C(OCCCC)=O)=C(C)NC=1C)=O)CCC>>[CH2:28]([O:31][C:32]([C:34]1[CH:39]([C:40]2[N:41]=[C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[S:43][CH:44]=2)[C:38]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:37]([CH3:57])[NH:36][C:35]=1[CH3:58])=[O:33])[CH3:29]
Reactant: CC1=C(C(=O)OC(C)C)C(c2csc(-c3ccccc3)n2)C(C(=O)OC(C)C)=C(C)N1
Agent: CCCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCCC)C1c1csc(-c2ccccc2)n1
Agent: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1csc(-c2ccccc2)n1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1csc(-c2ccccc2)n1

Procedure:
The following compounds were obtained in an analogous manner: (b) 2,6-dimethyl-4-(2'-phenylthiazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, (c) 2,6-dimethyl-4-(2'-phenylthiazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester and (d) 2,6-dimethyl-4-(2'-phenylthiazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid dibutyl ester.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[Cl:19][C:20]1[C:21]([CH3:27])=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C(O)(=O)C.[OH-].[Na+]>CN(C=O)C.O>[Cl:19][C:20]1[C:21]([CH3:27])=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Cc1c(N)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(Cl)c3C)c2cc1OC
Temperature: 100 °C
Yield: 80.7 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 3-chloro-2-methylaniline (25 μl, 0.21 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 4.5 h. After cooling the reaction mixture was diluted with water (15 ml) and made alkaline with 1 M NaOH. The precipitate was collected by filtration, rinsed with water and dried to give the title compound (51 mg, 79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:32]2[CH:33]=[N:34][CH:35]=[C:30]([F:29])[CH:31]=2)=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cncc(F)c1
Reactant: COc1cc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)ccc1Br
Product: COc1cc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)ccc1-c1cncc(F)c1

Procedure:
The title compound was prepared from rac-[2-(4-bromo-3-methoxy-phenyl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 5-fluoropyridine-3-boronic acid in analogy to Example 1b): MS (ISN): 503.0 (M−H)− and 429.01 ((M-tBuOH)−H)−.
Reaction SMILES: C([BH3-])#N.[Na+].[ClH:5].[O:6]([C:13]1([OH:24])[CH:23]=[CH:22][C:16]([C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19])=[CH:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.CCOCC>[ClH:5].[CH2:25]([NH:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]1[CH:15]=[CH:14][C:13]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([OH:24])[CH2:23][CH:22]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(CN)C1=CCC(O)(Oc2ccccc2)C=C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(CNCc1ccccc1)C1=CCC(O)(Oc2ccccc2)C=C1
Reaction time: 1 h

Procedure:
Sodium cyanoborohydride (10 mg, 0.17 mmol) was added to a solution of 83 (30 mg, 0.11 mmol) and benzaldehyde (12 μl, 0.12 mmol) in MeOH (2 ml). After 1 hour stirring, the reaction mixture was diluted with ether and washed with water. The aqueous was extracted with ether and then combined organic layers were washed with water, and brine, then dried over MgSO4. The crude product was purified via flash SiO2 (eluted with hexane/ethyl acetate (10:1)) to give the protected amine as a white solid. The protected amine was dissolved in 3 N HCl solution in ethylacetate (2 ml) and the reaction mixture was stirred at ambient temperature for 15 hours. The crude reaction mixture was concentrated in vacuo and dried under high vacuum pressure to give 84 as a white solid (25 mg, 61% yield). 1H-NMR (400 MHz, DMSO-d6) δ8.83 (brd s, 2 H), 7.52-7.32 (m, 10H), 7.15 (d, J=7.6 Hz, 1 H), 7.02-6.95 (m, 3 H), 4.09 (s, 2 H), 3.34 (s, 2 H), 1.35 (s, 6 H).
Reaction SMILES: [Br-:1].C[N+](C)(C)C1C=CC=CC=1.BrBr.[CH3:14][C:15]1[S:16][C:17]([C:21](=[O:23])[CH3:22])=[C:18]([CH3:20])[N:19]=1.Br>C(OCC)C.C(#N)C.C(O)(=O)C>[Br:1][CH2:22][C:21]([C:17]1[S:16][C:15]([CH3:14])=[N:19][C:18]=1[CH3:20])=[O:23]
Reactant: CC(=O)c1sc(C)nc1C
Reactant: [Br-]
Agent: Br
Agent: BrBr
Agent: C[N+](C)(C)c1ccccc1
Solvent: CCOCC
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1nc(C)c(C(=O)CBr)s1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
N,N,N-Trimethylanilinium bromide-bromine (1:1:1) (1.84 g, 4.9 mmol) was added to a solution of 1-(2,4-dimethyl-1,3-thiazol-5-yl)ethanone (800 mg, 5.15 mmol) in diethyl ether (9 mL) and acetonitrile (3 mL), and HBr in acetic acid (33% w/w, 4 mL). The mixture was stirred for 1 h. The reaction mixture was diluted with diethyl ether (25 mL) and washed with aqueous Na2S2O5 solution (5% w/v, 20 mL). The organic phase was separated off, and the aqueous phase was extracted with diethyl ether (25 mL). The organic phases were combined, then washed with saturated aqueous NaHCO3 solution (2×25 mL) and brine. The residue was dried over sodium sulfate, then filtered and concentrated under vacuum, to give the title compound (764 mg, 63%) as a light brown oil. δH (250 MHz, CDCl3) 4.22 (s, 2H), 2.69-2.76 (br s, 6H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C1COCC1.C(O)=O.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:23]=[C:24]([NH2:26])[CH:25]=1)=[O:19]>O>[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:23]=[C:24]([NH:26][CH:1]=[O:3])[CH:25]=1)=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Solvent: C1CCOC1
Solvent: O=CO
Solvent: O
Product: COC(=O)c1cc(NC=O)cc(-c2ccc(C)cc2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (11.0 g, 108 mmol) was added to THF (15 mL) followed by addition of formic acid (5.09 g, 133 mmol). The mixture was heated to 65° C. for 2.5 hours, then cooled to room temperature. 5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (5.0 g, 21 mmol) was added, and the reaction mixture was stirred for three hours at 70° C., then cooled to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 5-formylamino-4′-methyl-biphenyl-3-carboxylic acid methyl ester, which was used directly in the next step without further purification.