Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([CH:14]1[CH2:18][NH:17][C:16]([C:19]2[S:23][C:22]([N:24]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:25]3=[O:37])=[CH:21][C:20]=2[CH3:38])=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH2:7]([C:14]1[N:15]=[C:16]([C:19]2[S:23][C:22]([N:24]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[C:25]3=[O:37])=[CH:21][C:20]=2[CH3:38])[NH:17][CH:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C1=NC(Cc2ccccc2)CN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1-c1nc(Cc2ccccc2)c[nH]1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 9 %

Procedure:
To a stirred solution of oxalyl chloride (0.05 mL, 0.62 mmol) in dichloromethane (1 mL) at −78° C. under nitrogen atmosphere was added dropwise N,N-dimethylsulfoxide (0.06 mL, 0.83 mmol). After 10 minutes, 1-(5-(4-benzyl-4,5-dihydro-1H-imidazol-2-yl)-4-methylthiophen-2-yl)-3-(4-fluorobenzyl)imidazolidin-2-one (0.06 g, 0.14 mmol) in dichloromethane (0.5 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 40 minutes, then triethylamine (0.23 mL, 1.66 mmol) was added, and the cooling bath was removed. After stirred for 1 h, the reaction mixture was partitioned between water (25 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (50 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by ion exchange chromatography eluted sequentially with methanol, 2.0 M ammonia in methanol solution, and further purified by preparative thin layer chromatography eluted with dichloromethane/methanol/triethylamine (95/5/0.5) to afford the title compound as a light yellow solid in 9% yield (0.01 g): 1H NMR (300 MHz, CDCl3) δ 7.34-7.21 (m, 8H), 7.06-6.99 (m, 2H), 6.72 (s, 1H), 6.13 (s, 1H), 4.41 (s, 2H), 3.98 (s, 2H), 3.81-3.73 (m, 2H), 3.44-3.37 (m, 2H), 2.42 (s, 3H): MS (ES+) m/z 447.2 (M+1).
Reaction SMILES: [Br-:1].[CH3:2][N:3]([CH3:39])[C:4]1[CH:5]=[CH:6][C:7]2[C:16]([CH:17]=1)=[O+:15][C:14]1[C:9](=[CH:10][CH:11]=[C:12]([N:18]([CH3:20])[CH3:19])[CH:13]=1)[C:8]=2[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([NH2:30])[C:22]=1[C:31]([O:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])=[O:32]>C(O)C.ClCCl.[Pd]>[Br-:1].[CH3:20][N:18]([CH3:19])[C:12]1[CH:11]=[CH:10][C:9]2[C:14]([CH:13]=1)=[O+:15][C:16]1[C:7](=[CH:6][CH:5]=[C:4]([N:3]([CH3:2])[CH3:39])[CH:17]=1)[C:8]=2[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:30])[C:22]=1[C:31]([O:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])=[O:32]
Reactant: CC(=O)OCOC(=O)c1c(-c2c3ccc(N(C)C)cc3[o+]c3cc(N(C)C)ccc23)ccc([N+](=O)[O-])c1N
Agent: [Pd]
Agent: [Br-]
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)OCOC(=O)c1c(-c2c3ccc(N(C)C)cc3[o+]c3cc(N(C)C)ccc23)ccc(N)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
The aforementioned 3,6-bis(dimethylamino)-9-(2-acetoxymethoxycarbonyl-3-amino-4-nitrophenyl)xanthylium bromide (443 mg) was dissolved in a mixed solvent of ethanol (100 ml) and dichloromethane (100 ml), and the solution was added with 0.25 g of 10% Pd/C catalyst. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain 3,6-bis(dimethylamino)-9-(2-acetoxymethoxycarbonyl-3,4-diaminophenyl)xanthylium bromide (214 mg, 50.9%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)=[CH:8][CH:9]=2)[CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[OH:19][C:15]1[CH:14]=[C:13]([C:7]2[CH:6]=[C:5]3[C:10]([CH:11]=[CH:12][C:3]([OH:2])=[CH:4]3)=[CH:9][CH:8]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(-c2ccc3ccc(OC)cc3c2)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1cccc(-c2ccc3ccc(O)cc3c2)c1

Procedure:
The title compound was prepared by reacting 2-methoxy-7-(3-methoxyphenyl)naphthalene (0.52 g, 1.97 mmol) with pyridinium HCl (8 g) at 190° C. according to Method B to yield 0.13 g (28%) of a white solid: mp 163-165° C.; 1H NMR (DMSO-d6): δ 6.78-6.80 (1H, m), 7.08 (1H, dd, J=2.56 Hz, J=8.54 Hz), 7.13-7.14 (1H, m), 7.17-7.20 (2H, m), 7.27-7.30 (1H, m), 7.51 (1H, dd, J=2.14 Hz, J=8.54 Hz), 7.70 (1H, d, J=8.97 Hz), 7.83 (1H, d, J=8.54 Hz), 7.90 (1H, d, J=1.28 Hz), 9.55 (1H, s), 9.78 (1H, s); MS (ESI) m/z235 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][NH:10][C:11](=[O:12])[C:3]=12.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:3]=12
Reactant: COC(=O)CBr
Reactant: Cc1cc(C)c2c(=O)[nH]sc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)COc1nsc2nc(C)cc(C)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 7.2 %

Procedure:
A mixture of pyridinothiazolone 4 (500 mg, 2.77 mmol), methyl 2-bromoacetate (900 mg, 5.88 mmol), Cs2CO3 (700 mg, 3.07 mmol) and DIEA (1.5 mL, 8.61 mmol) in anhydrous CH2Cl2 (20 mL) was stirred at room temperature for 5 h, and then concentrated under reduced pressure. In addition to the main N-alkylation product 7 (55%), the title compound (50 mg, 7% yield) was obtained after purification by flash chromatography on a silica gel column (EtOAc/hexane (1:4)). C11H12N2O3S; white solid; mp 89-91° C.; IR vmax (neat) 3053, 2958, 2929, 2851, 1767, 1592, 1562, 1504, 1445, 1398, 1334, 1228, 1128, 1039, 961 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.91 (1H, s), 5.05 (2H, s), 3.78 (3H, s), 2.89 (3H, s), 2.61 (3H, s); 13C NMR (100 MHz, CDCl3) δ 172.3, 168.4, 160.7, 160.2, 145.6, 121.4, 115.7, 64.2, 52.3, 24.6, 19.1; ESI-HRMS calcd for C11H13N2O3S: 253.0647. found: m/z 253.0647 [M+H]+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][CH2:6][CH2:7][N:8]=[C:9]=[O:10]>CC#N>[Cl:5][CH2:6][CH2:7][NH:8][C:9]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:10]
Reactant: CC(C)N
Reactant: O=C=NCCCl
Solvent: CC#N
Product: CC(C)NC(=O)NCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
A solution of isopropylamine (3.00 g, 50.8 mmol) in MeCN (30 mL) was treated with 2-chloroethylisocyanate (6.00 g, 56.9 mmol), stirred at RT for 1 h and the resulting solid collected via filtration to afford 1-(2-chloroethyl)-3-isopropylurea (6.12 g, 73%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 5.96 (t, J=5.9 Hz, 1 H), 5.87 (d, J=7.7 Hz, 1 H), 3.62 (m, 1 H), 3.53 (t, J=6.3 Hz, 2 H), 3.25 (m, 2 H), 0.99 (d, J=6.5 Hz, 6 H); MS (ESI) m/z: 165.1 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([CH2:19]/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])[C:11](=[O:18])[C:12]([CH:15]([CH3:17])[CH3:16])([CH3:14])[N:13]=2)=[N:7][CH:8]=1)[CH3:2].O1CCCC1.O.[OH-].[Na+]>O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([CH2:19]/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])[C:11](=[O:18])[C:12]([CH:15]([CH3:17])[CH3:16])([CH3:14])[N:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/CN1C(=O)C(C)(C(C)C)N=C1c1ccc(CC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(C2=NC(C)(C(C)C)C(=O)N2C/C=C/C(=O)O)nc1
Reaction time: 16.5 h

Procedure:
A stirred solution of ethyl 2-(5-ethyl-2-pyridyl)-4-isopropyl-4-methyl-5-oxo-2-imidazoline-1-crotonate, (E)- (1.16 g, 3.25 mmol) in 1:1 tetrahydrofuran/water is treated with sodium hydroxide (0.45 g, 11.3 mmol) at once. The resulting mixture is stirred at reflux for 1.5 hours, then at room temperature for 16.5 hours. After this period, the reaction mixture is diluted with water, and washed with ether. The aqueous layer is acidified with 1N hydrochloric acid (15 mL), and extracted with ether. The organic extract is dried over sodium sulfate, decolorized with charcoal and vacuum filtered through diatomaceous earth. The filtrate is concentrated in vacuo to give the title product as a yellow solid, mp 53°-58° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([OH:14])=[O:13].B(Br)(Br)Br.Cl[CH2:20]Cl>>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([O:14][CH3:20])=[O:13]
Reactant: ClCCl
Reactant: COc1cc(F)c(CC(=O)O)c(F)c1
Agent: BrB(Br)Br
Product: COC(=O)Cc1c(F)cc(O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (2,6-difluoro-4-methoxyphenyl)acetic acid (1.50 g, 7.42 mmol) in 20 ml anhydrous dichloromethane at 0° C. was added a solution of boron tribromide (4.29 ml, 44.5 mmol) in 10 ml anhydrous dichloromethane. The cooling bath was removed and the mixture allowed to warm to RT for 2 hours. The reaction was diluted with 20 ml anhydrous methanol, and stirred for 30 minutes. The mixture was concentrated under reduced pressure, and the residue purified by column chromatography on silica gel, (Biotage column, 50 g) using a gradient eluent of 0-30% ethyl acetate in hexanes (700 ml) to afford the title compound. 1H NMR (CDCl3): δ 6.30 (d, J=8.3 Hz, 2H), 6.12 (br, 1H), 3.76 (s, 3H), 3.63 (s, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:5]=1[CH:14]([CH3:17])[C:15]#[N:16].[CH3:18]N(C=O)C>>[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:5]=1[C:14]([CH3:18])([CH3:17])[C:15]#[N:16]
Reactant: CC(C#N)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C#N)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH 80% (0.0918 mole) was added portionwise at 0° C. under N2 flow to a solution of intermediate (1) (0.0612 mole) in DMF (100 ml). The mixture was stirred at 0° C. under N2 flow for 1 hour. CH3l (0.0918 mole) was added dropwise at 0° C. The mixture was stirred at 50° C. for 12 hours, then poured out on ice and extracted with EtOAc. The organic layer was separated, washed with H2O, dried, filtered and the solvent was evaporated, yielding 17.1 g of 2,6-dichloro-α,α-dimethyl-4-nitrobenzeneacetonitrile (intermediate 2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[C:16]([NH:23][CH2:24][CH2:25]Br)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:25][CH2:24][NH:23][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1H-Indole-6-carboxylic acid methyl ester (0.503 g, 2.87 mmol) and DMF (9.0 mL) under argon was cooled to 0° C. for 10 min. Sodium hydride (˜48%, 0.190 g, 3.80 mmol) was added and reaction warmed to room temperature for 30 min. 2-(Boc-amino)ethyl bromide (0.787 g, 3.52 mmol) was added and the reaction stirred for 17 hr. The reaction was quenched with H2O and extracted with ethyl acetate (3×). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0-50% EtOAc:Hexane). ESI-MS m/z 319 (MH)+.
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:6]=[C:5]([C:12]([OH:14])=[O:13])[C:4]=1[Cl:15].S(Cl)(Cl)=O.[OH-].[Na+].Cl.[CH3:23]O>>[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:6]=[C:5]([C:12]([O:14][CH3:23])=[O:13])[C:4]=1[Cl:15]
Reactant: CO
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 60 °C
Yield: 80 %

Procedure:
A 1-L flask equipped with a nitrogen bubbler connected to a trap and caustic-containing scrubber, an addition funnel, reflux condenser and thermocouple, was charged with 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid monohydrate (144 g, 0.62 mol) and methanol (500 mL). Thionyl chloride (185 g, 115 mL, 1.58 mol) was added over about 30 minutes with cooling, and then the reaction mixture was heated at 60° C. for 12 h. The resulting mixture was concentrated at 40-45° C./6 kPa to remove excess methanol (about 300 mL), and the reaction mixture was diluted with water (580 mL). Phenolphthalein (5 mg) was added, and 50% aqueous NaOH (80 g, 1.0 mol) was added dropwise with cooling at 10-25° C. to bring the pH to about 9 as indicated by appearance of pink color. Then just enough 1 N aqueous hydrochloric acid was added to extinguish the pink color. The resulting slurry was cooled to 5° C. and filtered. The filtered wet cake was washed with water and dried to constant weight at 50° C./6 kPa to give 123 g (80% yield) of the title compound with 98% purity by HPLC analysis as a solid melting at 147-148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:17]1([C:23](Cl)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([NH:1][C:23](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(Cl)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4-chlorobenzonitrile (7.25 g, 47.5 mmol ), in anh. pyridine (38 mL, 475 mmol) and DCM (300 mL) cooled in an ice-H2O bath under Ar was added PhCOCl (5.8 mL, 50 mmol) dropwise. The reaction was allowed to slowly warm to rt within the cooling bath and then was stirred at rt overnight. The reaction mixture was washed (H2O, 2 M aq HCl (2×), H2O, brine), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a white solid; MS (ES+): m/z 257.1 (100) [MH+]; HPLC: tR=3.27 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.C1C(=O)N([Br:32])C(=O)C1>>[Br:32][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[NH:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)cc2)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 15 using N-(3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide (Example 19) and NBS (reaction time 30 min at room temperature). The crude product was purified by column chromatography on silica gel using ethyl acetate as eluent giving the final product in 78% yield, m.p. 208° C. (dec). The product was recrystallized using hexane/ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5].[C:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[C:27]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:1][C:2]2[CH:18]=[CH:17][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:15][C:3]=2[C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)=[O:5])=[O:36])=[CH:38][CH:39]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NC(=O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2N)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 84.4 %

Procedure:
Using the procedure described in Example 68, Part A, 2-amino-5-(tert-butyldimethylsilyloxy)-N-(4-methoxyphenyl)benzamide (460 mg, 1.23 mmol) was reacted with 4-tert-butylbenzoyl chloride (0.243 mL, 1.24 mmol) in N,N-dimethylformamide (10 mL). After quenching the reaction with saturated aqueous sodium carbonate, the resulting precipitate was filtered and washed with 2:1 diethyl ether/hexane. The solid was vacuum dried at 85° C./0.1 mm for 14 h to give 553 mg (84%) of the title compound as a white solid; mp 207° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=2[O:20][CH3:21])[CH2:8][C:7](=[O:22])[NH:6]1)=[O:4].[H-].[Na+].[CH3:25]I.Cl>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]2[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[CH:14][C:15]=2[O:16][CH3:17])[CH2:8][C:7](=[O:22])[N:6]1[CH3:25])=[O:4]
Reactant: COC(=O)C1NC(=O)CC1c1c(OC)cc(OC)cc1OC
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1C(c2c(OC)cc(OC)cc2OC)CC(=O)N1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
(+)-Methyl-5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2-carboxylate (1.7 g, 0.0055 mol) was dissolved in N,N-dimethylformamide (15 mL) and the solution cooled to 0° C. Sodium hydride (0.134 g, 0.0056 mmol) was added in portions over a period of 10 minutes and stirred for another 20 minutes at 0° C. Methyl iodide (0.514 mL, 0.0082 mol) was added dropwise and the reaction allowed to warm to room temperature in 1 hour. The reaction mixture was poured slowly over a mixture of crushed ice (20 g) and 1:1 hydrochloric acid solution (5 mL). The mixture was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield an oil. The oil was triturated with petroleum ether and the resulting solid was filtered.
Reaction SMILES: C(O)=O.[C:4]1([CH:10]2[O:15]C(=O)CC(=O)[O:11]2)C=CC=CC=1.[CH:18](=O)[C:19]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:21]([O:22][CH3:23])[CH:20]=1>C(N(CC)CC)C>[CH3:23][O:22][C:21]1[CH:20]=[C:19]([CH2:18][CH2:4][C:10]([OH:15])=[O:11])[CH:28]=[CH:27][C:24]=1[O:25][CH3:26]
Reactant: O=C1CC(=O)OC(c2ccccc2)O1
Reactant: COc1ccc(C=O)cc1OC
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
25 ml of the mixture of formic acid and triethylamine prepared as described in Example 1 were added to a mixture of 4.8 g (0.025 mol) of 2-phenyl-1,3-dioxane-4,6-dione (m.p.: 148° C.) and 4.15 g (0.025 mol) of veratraldehyde. The reaction was carried out according to Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH:7]=[N:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([O-:3])=[O:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH3:50][C:49]1([CH3:51])[CH:48]([OH:52])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:11]=2)[NH:8][CH:7]1[C:6]1[CH:19]=[CH:20][CH:21]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CC(C)C=O
Reactant: O=[N+]([O-])c1cccc(C=Nc2ccc(C(F)(F)F)cc2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(O)c2cc(C(F)(F)F)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.9 %

Procedure:
To a mixture of (3-nitro-benzylidene)-(4-trifluoromethyl-phenyl)-amine (5.88 g, 20 mmol) and ytterbium(III) triflate hydrate (1.24 g, 2 mmol) in dry tetrahydrofuran (50 mL) at 25° C. was added isobutyraldehyde (2 mL, 22 mmol) and water (0.36 mL, 20 mmol) dropwise. The reaction mixture was stirred at 25° C. for 72 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-ol (7.1 g, 96%) as a light yellow oil: LC/MS m/e calcd for C18H17F3N2O3 (M+H)+: 367.34, observed: 349.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]CC)=[O:27])[CH:20]=2)[NH:15]1)=[O:6].O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=2)[NH:15]1)=[O:6]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NC(=O)c1cccc(F)c1)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(c2ccccc2NC(=O)c2cccc(F)c2)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 2-(2-(3-fluorobenzamido)phenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous Sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-[2-(3-fluoro-benzoylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid. LC/MS m/e obsd. (ESI−) [(M−H)−] 417.30.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:8]=2[CH2:7][N:6]2[CH2:17][CH2:18][CH2:19][CH:5]2[CH2:4]1>CO>[ClH:1].[NH2:14][C:12]1[CH:11]=[CH:10][C:9]2[N:3]([CH3:2])[CH2:4][CH:5]3[CH2:19][CH2:18][CH2:17][N:6]3[CH2:7][C:8]=2[CH:13]=1
Reactant: CN1CC2CCCN2Cc2cc([N+](=O)[O-])ccc21
Agent: Cl
Solvent: CO
Product: CN1CC2CCCN2Cc2cc(N)ccc21
Reaction time: 1 h

Procedure:
To 10-methyl-7-nitro-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazapine hydrochloride (2.6 g, 9.16 mmol) in methanol (100 ml) was added a catalytic amount of 10% Pd--C. The mixture was hydrogenated at 50 psi for 1 h, filtered, and concentrated to an oil which was used immediately in the next reaction.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:22][CH3:23])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]O)[CH3:14]>>[C:1]([O:12][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:15]([CH2:22][CH3:23])[CH2:13][CH3:14])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCN(CC)CCOCCO
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OCCOCCN(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-(2-(diethylamino)ethoxy)ethanol as starting materials to give the aimed compound.
Reaction SMILES: C(Cl)CCl.[CH3:5][NH:6][CH3:7].[Cl:8][C:9]1[N:14]=[C:13]([C:15](O)=[O:16])[C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][CH:10]=1.[Cl-].[NH4+]>ClCCl>[Cl:8][C:9]1[N:14]=[C:13]([C:15]([N:6]([CH3:7])[CH3:5])=[O:16])[C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][CH:10]=1
Reactant: O=C(O)c1nc(Cl)ccc1C(F)(F)F
Reactant: CNC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)C(=O)c1nc(Cl)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
EDC (650 mg, 3.39 mmol) and dimethylamine (2.0 M solution in THF, 2.30 mL, 4.60 mmol) were added at room temperature to a solution of 6-chloro-3-(trifluoromethyl)pyridine-2-carboxylic acid (516 mg, 2.29 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 4 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=100/0-70/30 (gradient)] to obtain the title compound (246 mg, yield: 43%).