Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[S:8])[O:5][C:6]=1[CH3:7].C(N1C(=O)C2=CC=C[CH:21]=[C:14]2[C:13]1=[S:22])CC>>[CH3:1][C:2]1[N:3]=[C:4]([S:8][S:22][CH2:13][CH2:14][CH3:21])[O:5][C:6]=1[CH3:7]
Reactant: CCCN1C(=O)c2ccccc2C1=S
Reactant: Cc1[nH]c(=S)oc1C
Product: CCCSSc1nc(C)c(C)o1

Procedure:
Starting from 4,5-dimethyl-2-thiono-4-oxazoline and N-propylthiophthalimide there is obtained (4,5-dimethyl-2-oxazolyl)propyl-disulphide.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([Cl:1])=[CH:3][C:4]3[CH2:8][CH2:7][O:6][C:5]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a solution of 5-(5-chloro-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (151) (15 mg, 0.06 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (11 μl, 0.088 mmol) followed by addition of DIEA (52 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (120 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(5-chloro(2,3-dihydrobenzo[3,4-b]furan-6-yl))(2-pyridyl)]carboxamide (152) (14 mg, yield: 60.1%, purity>90%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[CH3:17][N:18]([CH3:31])[C:19]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][N:14]([CH:22]2[CH2:21][CH2:20][C:19]([N:18]([CH3:31])[CH3:17])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:24][CH2:23]2)[CH2:15][CH2:16]1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCCCC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(N2CCC(c3c[nH]c4ccc(Cl)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (218 mg, 1 mmole) and 4-dimethylamino-4-phenylcyclohexane (217 mg, 1 mmole) were dissolved in dry 1,2-dichloroethane (20 ml). Glacial acetic acid (1 mmole) and sodium triacetoxy boron hydride (300 mg, 1.4 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluted with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds, which were separated by chromatography with methanol. The non-polar diastereoisomer was obtained as a colourless oil in a yield of 210 mg (48%), and the polar diastereoisomer was obtained as a colourless oil in a yield of 80 mg (18%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1([CH2:31][C@H:32]([C:34]2[CH:43]=[CH:42][C:37]3[C:38](=[O:41])[O:39][CH2:40][C:36]=3[C:35]=2[CH3:44])[OH:33])[CH2:16][CH2:15][N:14]([CH2:17][C@H:18]([C:20]2[CH:29]=[CH:28][C:23]3[C:24](=[O:27])[O:25][CH2:26][C:22]=3[C:21]=2[CH3:30])[OH:19])[CH2:13][CH2:12]1>C(Cl)Cl>[OH:19][C@@H:18]([C:20]1[CH:29]=[CH:28][C:23]2[C:24](=[O:27])[O:25][CH2:26][C:22]=2[C:21]=1[CH3:30])[CH2:17][N:14]1[CH2:13][CH2:12][N:11]([CH2:31][C:32]([C:34]2[CH:43]=[CH:42][C:37]3[C:38](=[O:41])[O:39][CH2:40][C:36]=3[C:35]=2[CH3:44])=[O:33])[CH2:16][CH2:15]1
Reactant: Cc1c([C@H](O)CN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c(C(=O)CN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (71 uL, 0.82 mmol) in DCM (30 mL) was dropped DMSO (120 uL, 1.6 mmol) at −78° C. After stirring the mixture for 10 minutes, a DCM solution of 5,5′-{piperazine-1,4-diylbis[(1S)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1(3H)-one) (380 mg, 0.82 mmol) was added into the reaction. The reaction was stir for another 20 minutes before TEA (570 uL, 4.1 mmol) was added to the reaction mixture. The reaction was then allowed to warm up to RT slowly. TLC analysis showed two new spots right above the SM. LC analysis suggested formation of the mono-ketone as well as the di-ketone. The reaction was diluted with DCM, washed with water, dried over sodium sulfate, and purified by flash chromatography. The title product was collected after removal of solvent.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][SiH3])=[CH:9][CH:8]=1)=[CH2:2].C1(=O)OC(=O)C=C1.[OH-].[Na+]>O>[CH:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[CH:11][CH:12]=1)=[CH2:2]
Reactant: C=COCCOc1ccc(CO[SiH3])cc1
Agent: O=C1C=CC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=COCCOc1ccc(CO)cc1
Temperature: 75 °C

Procedure:
Aqueous Dissolution of 2-(4-SilyloxymethylPhenoxy)-Ethyl Vinyl Ether/Maleic Anhydride Copolymer--A slurry was made with 20 g of 2-(4-silyloxymethyl-phenoxy)ethyl vinyl ether/maleic anhydride copolymer in 498 g of distilled water. To this was added 108 g of a 20% aqueous NaOH solution. The slurry was heated to 75° C. for 48 hours. The reaction was then cooled to room temperature to give a 3.37% concentrated solution of 2-(4-hydroxymethyl-phenoxy)-ethyl vinyl ether/maleic diacid at pH 12.7.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=[C:11]([Cl:12])[C:4]=2[N:3]=1.[Cl:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:21]([NH2:22])=[C:20]([O:26][CH3:27])[CH:19]=1.C(=O)([O-])O.[Na+]>>[Cl:12][C:11]1[C:4]2[N:3]=[C:2]([NH:22][C:21]3[C:23]([CH3:25])=[CH:24][C:18]([Cl:17])=[CH:19][C:20]=3[O:26][CH3:27])[N:6]([CH3:7])[C:5]=2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(Cl)c2nc(Cl)n(C)c12
Reactant: COc1cc(Cl)cc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 130 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
A mixture of methyl 2,4-dichloro-1-methyl-1H-benzimidazole-7-carboxylate (100 mg, 0.39 mmol) and 4-chloro-2-methoxy-6-methylaniline (200 mg, 1.17 mmol) was stirred at 130° C. overnight. After cooling, the reaction mixture was neutralized by aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on a silica gel column to give 68 mg (0.17 mmol, 44%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](Cl)=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[N:17]2)=[CH:12][CH:11]=1>ClCCl>[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[N:17]2)=[CH:12][CH:11]=1
Reactant: NCC1CCCCC1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
Under a nitrogen atmosphere, cyclohexylmethylamine (40.9 mL, 315 mmol) was added dropwise to a solution of 7-bromo-4-chloro-3-nitroquinoline (30.0 g, 105 mmol) in dichloromethane (524 mL). The reaction was stirred for 18 hours at ambient temperature and then concentrated under reduced pressure. Water (200 mL) was added to the residue, and the mixture was stirred for three hours. Acetonitrile was added; a precipitate formed. The solid was isolated by filtration, dried under a flow of air for two hours, and recrystallized from acetonitrile to provide 24.0 g of (7-bromo-3-nitroquinolin-4-yl)cyclohexylmethylamine as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[C:23](O)=[O:24])([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:33][C:30]([C:27]1[CH:26]=[C:22]([C:23]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)=[O:24])[CH:21]=[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:28]=1[OH:29])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
2.07 g (10 mmoles) of 1-(4-nitrophenyl)piperazine, 2.5 g (10 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide are introduced into a 100 ml flask containing 25 ml of DMF. The reaction medium is agitated for 15 hours at ambient temperature, the precipitate which appears is filtered out and rinsed with ethyl acetate. After concentration of the filtrate under reduced pressure, the residue is diluted in 20 ml of ethyl acetate and a new insoluble is eliminated by filtration. The solvent is evaporated off under vacuum and the residue is precipitated from diethyl ether. The solid is filtered, rinsed with 2×20 ml of ethyl acetate in order to obtain a yellow powder with a yield of 89%. Melting point: 159.5-160.5° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([OH:7])=O)[CH3:3].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN(C=O)C.[NH2:35][CH:36]1[CH2:42][C:41]([CH3:44])([CH3:43])[C:40]2[CH:45]=[CH:46][C:47]([N+:49]([O-:51])=[O:50])=[CH:48][C:39]=2[NH:38][C:37]1=[O:52]>CCOCC>[CH3:1][N:2]([CH3:3])[CH2:4][C:5]([NH:35][CH:36]1[CH2:42][C:41]([CH3:44])([CH3:43])[C:40]2[CH:45]=[CH:46][C:47]([N+:49]([O-:51])=[O:50])=[CH:48][C:39]=2[NH:38][C:37]1=[O:52])=[O:7]
Reactant: CC1(C)CC(N)C(=O)Nc2cc([N+](=O)[O-])ccc21
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)CC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethylamino-acetic acid (0.124 g, 1.20 mmol), EDCl (0.461 g, 2.41 mmol), HOBT (0.276 g, 2.05 mmol) and DMF (1.00 mL, 12.9 mmol) were stirred at rt for 30 minutes, followed by the addition of TEA (0.235 mL, 1.68 mmol) and 3-Amino-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (0.300 g, 1.20 mmol). The reaction mixture was stirred at rt for 3 h, diluted with ether and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Title compound was isolated as a white solid (80 mg, 20%).
Reaction SMILES: Cl.CN([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]1=[O:18])C.Cl.[C-:20]#[N:21].[K+]>O>[C:20]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]1=[O:18])#[N:21]
Reactant: COc1ccc2c(c1)CCC(CN(C)C)C2=O
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc2c(c1)CCC(CC#N)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: 13.5 g of 2-dimethylaminomethyl-6-methoxy-1-tetralone hydrochloride (C. A. 41, 6253 g) are dissolved in 200 ml of water and 4 ml of concentrated hydrochloric acid are added, followed by the concentrated aqueous solution of 6.5 g of potassium cyanide, introduced below the surface of the liquid. The mixture is refluxed for one hour, stirred at room temperature overnight and filtered, to yield the 2-cyanomethyl-6-methoxy-1-tetralone melting at 90°-93°. Similarly prepared are the following nitriles: 2-cyanomethyl-1-tetralone, b.p. 125°-30°/0.005 mm Hg; 2-cyanomethyl-6,7-dimethoxy-1-tetralone, m.p. 116°-118°; 2-cyanomethyl-7-methoxy-1-tetralone, m.p. 80°-84°: 2-cyanomethyl-5-methoxy-1-tetralone, m.p. 91°-94°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([C@@H:30]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[NH:31]1)[CH3:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[C@H:30]([CH2:28][CH3:29])[CH2:34][CH2:33][S:32]3(=[O:36])=[O:35])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: CC[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)c(S(C)(=O)=O)c1
Yield: 8.5 %

Procedure:
To a mixture of (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110, (R)-3-ethylisothiazolidine 1,1-dioxide (150 mg) described in Preparation Example 3, potassium carbonate (276 mg), potassium iodide (332 mg) and copper(I) iodide (95 mg) were added toluene (3 mL) and N,N′-dimethylethylenediamine (110 μL), and the mixture was stirred with heating under reflux for 15 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (44 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[H-].[Na+].[C:14]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24](SC)[S:25][CH3:26])(=[O:22])=[O:21].O>CN(C)C=O>[C:14]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:23][C:24](=[N:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1)[S:25][CH3:26])(=[O:21])=[O:22]
Reactant: CSC(=NS(=O)(=O)c1ccccc1-c1ccccc1)SC
Reactant: COc1nc(N)nc(OC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(N=C(NS(=O)(=O)c2ccccc2-c2ccccc2)SC)nc(OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
15.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine were suspended in 300 ml of dimethylformamide, and 4 g of sodium hydride (oily, 60%) were added to the suspension. The mixture was stirred at room temperature for 1 hour. Furthermore, 33.7 g of dimethyl N-(2-biphenylylsulfonyl)carbonimidodithioate were added, and the mixture was stirred at room temperature for a day and night. The reaction mixture was poured into 2 liters of water and filtered. The filtrate was made weakly acidic to precipitate white crystals. The crystals were collected by filtration and recrystallized from ethanol to give 36.2 g of 1-(2-biphenylylsulfonyl) 3-(4,6-dimethoxy-1,3,5-triazin-2-yl) 2-methylisothiourea (compound No. II-1), the same compound as obtained in Example 5. The melting point of the product was 135° to 137° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:17])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)cc(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: BrCc1cc(Br)cc(Br)c1
Temperature: 80 °C

Procedure:
Step H1. A mixture of 3,5-dibromo-toluene (4.25 g, 17 mmol), NBS (3 g, 17 mmol), and AIBN (150 mg) in carbon tetrachloride (50 mL) was heated at 80° C. for 3 hours. The resulting mixture was run through a silicon gel column with dichloromethane as the eluant. The fraction was collected and solvent was removed by rotovap, crude 1,3-dibromo-5-(bromomethyl)benzene was obtained as a white residue.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([O-:15])=[O:14])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].[NH2+]1CCOCC1.Cl>O.CO>[OH:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1cc(C=CC(=O)Nc2ccccc2C(=O)[O-])ccc1O
Agent: C1COCC[NH2+]1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc(C=CC(=O)Nc2ccccc2C(=O)O)ccc1O
Yield: 82.5 %

Procedure:
A 10 g quantity of morpholinium N-(4-hydroxy-3-methoxycinnamoyl)anthranilate is dissolved in a mixture of 80 ml of water and 60 ml of methyl alcohol with heating, and the resultant solution is added dropwise to 85 ml of diluted hydrochloric acid (5 ml of conc. hydrochloric acid and 80 ml of water) with stirring. The precipitated crystals which form are collected by filtration, washed with water and then dried at 90°-100° C. under reduced pressure for 3 hours to yield N-(4-hydroxy-3-methoxycinnamoyl)anthranilic acid (82.5% yield). The compound is confirmed as identical to that obtained in Example II.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:13]O)=[CH:5][C:4]=1[C:18]1[NH:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:19]=1.CCN(S(F)(F)[F:41])CC>C(Cl)Cl>[F:41][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]([NH:10][CH2:9][C:6]1[CH:7]=[N:8][C:3]([CH:2]([F:1])[F:34])=[C:4]([C:18]2[NH:22][C:21](=[O:23])[N:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:19]=2)[CH:5]=1)=[O:17]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(CO)C(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: ClCCl
Product: CC(C)(CF)C(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 8.5 %

Procedure:
The title compound was prepared by following the procedure as described in step-2 of Example-134 by using N-((6-(difluoromethyl)-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)-3-hydroxy-2,2-dimethylpropanamide (0.060 g, 0.12 mmol), DAST (0.060 g, 0.37 mmol), DCM (10 mL) to afford 0.005 g the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.80 (br s, 6H), 4.22 (br s, 1H), 4.38-4.42 (m, 3H), 7.41-7.66 (m, 3H), 7.95 (br s, 1H), 8.08-8.11 (m, 2H), 8.61 (s, 1H); MS (m/z): 488.23 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[C:23]([F:29])[C:24]=1[C:25]([F:28])([F:27])[F:26].C(Cl)Cl>CO.Cl[Pd]Cl.O>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:22]=[C:23]([F:29])[C:24]=1[C:25]([F:26])([F:27])[F:28]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CC1(C)OB(c2cc(F)c(C(F)(F)F)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2cc(F)c(C(F)(F)F)c(F)c2)c1
Temperature: 100 °C
Yield: 53.3 %

Procedure:
Methyl 2-chloroisonicotinate (1,838 g, 10.71 mmol), potassium carbonate (0.888 g, 6.43 mmol) and PdCl2 (dppf) (0.233 g, 0.32 mmol) were added to a microwave vial. 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.3 g, 10.71 mmol) dissolved in MeOH (15 mL) was added and the reaction heated in a single node microwave reactor at 100° C. for a total of 40 min. DCM (100 mL) and water (100 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (100 mL). The combined organic phases were washed with brine (200 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient from 5% EtOAc in heptane over 3 CV followed by 5% to 30% of EtOAc in heptane over 9 CV was used as mobile phase. The product was collected using the wavelength 250 nm. Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)isonicotinate (1.810 g, 53%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 3.99 (s, 3H), 7.74 (d, 2H), 7.86-7.89 (m, 1H), 8.27 (s, 1H), 8.86 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2([CH2:18][NH2:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[C:29](Cl)=[O:30].C(N(CC)CC)C>O1CCOCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2([CH2:18][NH:19][C:29]([C:21]3[O:20][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH:22]=3)=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C2(CN)CCCC2)cc(OC)c1OC
Reactant: O=C(Cl)c1cc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cc(C2(CNC(=O)c3cc4ccccc4o3)CCCC2)cc(OC)c1OC
Reaction time: 15 h
Yield: 11.7 %

Procedure:
C-[1-(3,4,5-Trimethoxy-phenyl)-cyclopentyl]-methylamine (53.1 mg, 0.200 mmol) and benzofuran-2-carbonyl chloride (36.1 mg, 0.200 mmol) were dissolved in 2 mL of 1,4-dioxane containing triethylamine (84 μL, 0.60 mmol). The reaction mixture was stirred for 15 hours, evaporated to dryness, and purified by reverse phase preparative liquid chromatography to yield the pure product (9.59 mg, 0.0234 mmol, 11.7%). ESI-MS m/z calc. 409.2, found 410.4 (M+1)+. Retention time of 3.29 minutes.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:16][NH:17][O:18][CH3:19].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:19][O:18][N:17]([CH3:16])[C:4]([C:3]1[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=1)=[O:5]
Reactant: CNOC
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-6-trifluoromethylnicotinic acid (500 mg, 2.44 mmol) and N,O-dimethylhydroxylamine hydrochloride (285 mg, 2.92 mmol) in dichloromethane (10 mL) were added N-methylmorpholine (0.32 mL, 2.92 mmol) and N-(3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (EDC, 560 mg, 2.92 mmol). The mixture was stirred at room temperature for 2 hours and washed with 1 N HCl and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-2-methyl-6-trifluoromethyl-3-pyridinecarboxamide quantitatively as oil. The crude product was used directly in the following reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:30]=[C:29]([OH:31])[C:11]2[C:12](=[O:28])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[C:17]=3[CH2:25][CH:26]=[CH2:27])[O:15][C:10]=2[CH:9]=1)=[O:5])[CH3:2].[H][H]>CN(C)C=O.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:30]=[C:29]([OH:31])[C:11]2[C:12](=[O:28])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[C:17]=3[CH2:25][CH2:26][CH3:27])[O:15][C:10]=2[CH:9]=1)=[O:5])[CH3:2]
Reactant: C=CCc1c(-c2cc(=O)c3c(O)cc(OCC(=O)OCC)cc3o2)ccc(OC)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCCc1c(-c2cc(=O)c3c(O)cc(OCC(=O)OCC)cc3o2)ccc(OC)c1O

Procedure:
21.3 g of 7-ethoxycarbonylmethoxy-5-hydroxy-2-(2-allyl-3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one are dissolved in 300 ml of dimethylformamide. The solution is poured into 2 g of 10% palladium on carbon. The whole is hydrogenated at 50° C. under a pressure of 63×104Pa until the theoretical amount of hydrogen has been absorbed. The mixture is then filtered over Millipore and the solvent is removed by distillation under reduced pressure. The crude residue (21 g) may be used as it is. An analytical sample, obtained by recrystallisation from isopropanol, melts at 138° C.