Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Na].[H-].[Na+].C1[CH2:15][O:14]CC1.CN(C=[O:20])C>C1COCC1.O>[N:5]1[CH:6]=[CH:7][CH:2]=[C:3]([C:15]([OH:14])=[O:20])[CH:4]=1
Reactant: C1CCOC1
Reactant: Sc1ccncc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.2 g of 90% pyridinium bromide perbromide was added in one portion to a solution of 5 g of 3-pyridinecarboxylic acid, 5-cyano-1,4-dihydro-2,6-dimethyl-4-[2-(trifluoromethyl)phenyl]-, ethyl ester and 1.2 ml pyridine in 150 ml of dry ethanol-free CHCl3 at -10° C. The mixture was stirred for 45 minutes at 0° C. and the bromide (6 g) was obtained by flash chromatography over silica gel (10% EtAc/CH2Cl2). This was dissolved in 30 ml of THF and added dropwise to a suspension of 4-mercaptopyridine, sodium salt (prepared from 1.5 g of 4-mercapto pyridine and 0.5 g of 60% NaH in THF/DMF (1:1, 40 ml) at 0° C. and the mixture was warmed to room temperature. After stirring for one hour, the reaction mixture was diluted with water and extracted with CH2Cl2. The organic extracts were washed with water, dried, and evaporated. The residue was crystallized from EtAc to give 5.1 g of 3-pyridinecarboxylic acid, 5-cyano-1,4-dihydro-6-methyl-2[4-pyridinylthiomethyl]-4-[(2-trifluoromethyl)phenyl]-, ethyl ester, mp 222°-224° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16].C(N(CC)CC)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C(C)=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6]1=[O:16]
Reactant: COCCn1cc(-c2ccccc2)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: COCCn1cc(-c2ccccc2)n(C(=O)c2ccccc2)c1=O

Procedure:
Approximately 4.36 g. of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one, 3 g. of triethylamine and 3 g. of benzoyl chloride are refluxed together for three hours in chloroform. The solution is cooled, washed with water, dried and the solvent removed to give an oil which is the O-benzoyl ester. The ester is refluxed for three hours in 20 ml. of xylene. The xylene is removed at reduced pressure. Recrystallization from ether gives the title compound as a pale yellow solid; m.p. 112°-117° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: O
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1Br
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a stirred, ice-cold solution of 4-bromo-3-methyl-benzenesulfonyl chloride (11 g, 40.8 mmol) and N′N-diisopropylethylamine (8.5 ml, 49 mmol, 1.2 equiv.) in dichloromethane was added dropwise tert. butylamine (5.2 ml, 49 mmol, 1.2 equiv.). After two hours at room temp., the reaction mixture was diluted with water and extracted with dichloromethane. The organic extracts were concentrated under reduced pressure, the residue stirred with n-heptane and filtered to obtain 11.2 g of the desired compound as a yellow solid. MS (ES): m/e 304.2 (M−H)
Reaction SMILES: [C:1]1([CH3:34])[CH:6]=[CH:5][C:4]([C:7]2[C:20]3[C:11](=[CH:12][C:13]4[C:18]([CH:19]=3)=[C:17]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:16]=[CH:15][CH:14]=4)[C:10]([CH3:33])([CH3:32])[CH2:9][CH:8]=2)=[CH:3][CH:2]=1.CO.[Li+].[OH-].Cl>C1COCC1.CCOCC>[C:1]1([CH3:34])[CH:2]=[CH:3][C:4]([C:7]2[C:20]3[C:11](=[CH:12][C:13]4[C:18]([CH:19]=3)=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:16]=[CH:15][CH:14]=4)[C:10]([CH3:32])([CH3:33])[CH2:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2cccc3cc4c(cc23)C(c2ccc(C)cc2)=CCC4(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(C2=CCC(C)(C)c3cc4cccc(-c5ccc(C(=O)O)cc5)c4cc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a degassed solution of ethyl 4-[1(tol-4-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoate (Compound 1, 35 mg, 0.08 mmol), in THF (1.5 mL) and MeOH (1.5 mL) was added LiOH (1M solution in water, 0.3 mL, 0.3 mmol). The mixture was stirred at ambient temperature for 16 hours, diluted with ether (60 mL). The mixture was acidified with 10% HCl to pH 4, the product was isolated as an ether insoluble white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[OH:18].C(N(CC)CC)C>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(F)c(O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)c(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl chloride (4.22 g, 30 mmol) was added dropwise with a syringe to a solution of 2-fluoro-5-methylphenol (3.784 g, 30 mmol) and triethylamine (5 mL) in dichloromethane (50 mL), The mixture was stirred for 18 h at room temperature and concentrated under reduced pressure. Diethyl ether (200 mL) and water (100 mL) were added, the organic layer was separated and extracted with 2N NaOH (2×30 mL) and brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure to give a white solid. Yield: 6.601 g (96%). 1H-NMR (400 MHz, CDCl3) δ=2.36 (s, 3H, —CH3), 7.01-7.12 (m, 3H), 7.49-7.55 (m, 2H), 7.63-7.68 (m, 1H), 8.19-8.23 (m, 2H). LRMS (FAB+): 231.1 (100, [M+H]+).
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:15][N:16]2COCC[Si](C)(C)C)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(N)CN>>[CH3:1][N:2]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:15][NH:16]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1
Reactant: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1
Temperature: 70 °C
Yield: 70.5 %

Procedure:
To N-methyl-N-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine (237 mg, 0.5 mmol) was added 1M TBAF in THF (10.1 mL, 10.1 mmol), followed by ethylenediamine (0.34 mL, 5.04 mmol, 10 equiv). The resulting mixture was heated to 70° C. for 5 h. The reaction was then quenched with saturated NaHCO3 (10 mL) and extracted 3×35 mL EtOAc. The pooled EtOAc phase was washed 5×20 mL H2O, then brine (20 mL), dried with Na2SO4, decanted and concentrated under reduced pressure to a foam. The crude material was purified by silica gel chromatography (9:1 dichloromethane/ethyl acetate) to give N-methyl-N-(3-styryl-1H-indazol-6-yl)-benzene-1,3-diamine as a foam (120 mg, 70% yield). Rf sm 0.73, Rf p 0.27 (dichloromethane:ethylacetate 7:3); 13C NMR (75 MHz, CDCl3) δ 150.3, 148.8, 147.5, 147.5, 143.9, 143.4, 137.5, 131.1, 130.3, 129.3, 128.9, 128.2, 127.9, 126.7, 121.0, 120.5, 117.0, 116.0, 112.6, 109.8, 109.0, 98.3, 40.7; LCMS (ESI) [M+H]/z Calc'd 341, Found 341. Anal. Calc'd: C, 77.62; H, 5.92; N, 16.46. Found: C, 76.16; H, 5.88; N, 15.95.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33].O>CO>[OH:33][CH2:32][CH2:31][CH2:30][NH:29][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[N:6][CH:5]=1)=[O:28]
Reactant: NCCCO
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Solvent: O
Solvent: CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCCO)cn2)CC1
Reaction time: 2 h
Yield: 78 %

Procedure:
6-[1-[3-(Isopropylamino)-2-pyridyl]piperazine-4-yl-carbonyl]nicotinic acid methyl ester (2.5 g) was dissolved in methanol (40 ml) and with the addition of 3-amino-1-propanol (0.95 g), the mixture was heated to reflux for 12 hours and cooled. The excess of water was added slowly at 25° C. for precipitation, the mixture was stirred for 2 hours and filtered. The filtered solid was recrystallized with isopropanol and ether, filtered and dried to give a desired compound of 2.17 g (yield: 78%).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10](=[N:12][OH:13])[CH3:11])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[CH2:19]([C:27]1[CH:36]=[CH:35][C:30]([C:31](OC)=O)=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>O1CCCC1>[CH2:1]([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:31]([C:30]3[CH:35]=[CH:36][C:27]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCc1ccc(C(=O)OC)cc1
Reactant: CCCCc1ccc(C(C)=NO)s1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(-c2cc(-c3ccc(CCCC)s3)no2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The 1-(5-butylthiophen-2-yl)-ethanone oxime obtained in step 2 is dissolved in tetrahydrofuran under an inert gas atmosphere and doubly deprotonated with 2 equivalents of n-butyllithium at 0° C. The solution is admixed with a solution of 0.5 equivalents of methyl 4-octylbenzoate in tetrahydrofuran, and the mixture is stirred for 30 min at 0° C., then admixed with 3 M HCl and refluxed for 1 h. Customary work-up followed by purification by column chromatography over silica gel 60 (eluent: dichloromethane/heptane 1:1) and recrystallizsation affords 3-(5-butylthiophen-2-yl)-5-(4-octylphenyl)-isoxazole; X 63 SC 82 SA 88 N 89 I.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH:11]1[CH:16]=[CH:15][C:14]([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.[C:30]1(C)C=CC=CC=1>>[Br-:1].[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:30][P+:17]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:15]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:10])=[O:9]
Reactant: Cc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCCCCCBr
Product: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C

Procedure:
A solution of 7-bromoheptanoic acid (5.000 g, 23.913 mmol) and PPh3 (6.899 g, 26.304 mmol) in 50 mL of toluene was refluxed for 63 h. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was tritiated with ether three times and dried in vacuum to give the title compound as a white foam solid (9.240 g, 82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:29]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:29])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (147 mg, 0.44 mmol) in toluene (5 mL) with N,N-dimethylformamide (2 drops) at 25° C. was treated with oxalyl chloride (0.05 mL, 0.53 mmol). The reaction was stirred at 25° C. for 30 min. At this time, the reaction was cooled to −60° C. and treated with ammonium hydroxide (0.50 mL, 3.8 mmol). The resulting suspension was allowed to warm to 25° C. and stirred at 25° C. for 1 h. At this time, the reaction was quenched by the addition of a 2N aqueous hydrochloric acid solution (1 mL) and then extracted with diethyl ether (3×25 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 65/35 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (130 mg, 89%) as a white foam: EI-HRMS m/e calcd for C5H20ClNO3S (M+) 329.0852, found 329.0852.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][N:29]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)[CH:30]=2)O1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=1>>[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:2]2[CH:3]=[C:4]3[C:10]([C:26]4[CH:27]=[N:28][N:29]([CH:31]5[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:35][CH2:36]5)[CH:30]=4)=[N:9][N:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13]4)[C:5]3=[CH:6][N:7]=2)[CH:46]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Brc1cc2c(I)nn(C3CCCCO3)c2cn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)cn2)CC1
Yield: 75 %

Procedure:
Following the Suzuki coupling procedure of Example 159, 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate were reacted and the product was consequently reacted by the Suzuki coupling procedure of Example 10 with 3-pyridineboronic acid pinacol ester. The product mixture was purified via silica gel chromatography using a gradient of methanol in DCM to afford 230 mg (75%) of tert-Butyl 4-(4-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate over two steps. ESI MS m/z 530.2 (M+1).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31])(=O)=O.C(N(CC)CC)C>CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[C:30]([O:32][CH3:33])=[O:31])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
Diphenylphosphine (0.72 mL, 4.14 mmol, 1 eq) was added to a stirred solution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.373 g, 4.11 mmol, 1 eq), triethylamine (0.64 mL, 4.59 mmol, 1.1 eq) and palladium acetate (0.005 g, 0.02 mmol, 0.005 eq) in degassed DMSO (10 mL) instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and an aliquot taken for NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@H:13]([OH:17])[CH2:14][NH:15][CH3:16])[CH2:8][CH2:7]1.[O:22]=[C:23]1[NH:27][C:26]([C:28]([F:31])([F:30])[F:29])=[C:25]([C:32]([OH:34])=O)[S:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C@H:13]([OH:17])[CH2:14][N:15]([CH3:16])[C:32]([C:25]2[S:24][C:23](=[O:22])[NH:27][C:26]=2[C:28]([F:29])([F:30])[F:31])=[O:34])[CH2:10][CH2:11]1
Reactant: O=C(O)c1sc(=O)[nH]c1C(F)(F)F
Reactant: CNC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: CN(C[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)C(=O)c1sc(=O)[nH]c1C(F)(F)F
Yield: 35.7 %

Procedure:
Prepared as Example 1 using (2R)-1-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-3-(methylamino)propan-2-ol (150mg, 0.45 mmol) and 2-oxo-4-(trifluoromethyl)-2,3-dihydro-1,3-thiazole-5-carboxylic acid (0.096 g) to yield the title compound as a colourless solid (0.085 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Br.[CH3:12][N:13]([CH2:15][C:16]1[C:17]([S:23][CH3:24])=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:13]([CH3:12])[CH3:14])[C:17]=2[S:23][CH3:24])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CSc1c(O)cccc1CN(C)C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Yield: 57.6 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.974 g, 6.26 mmol), 3-dimethylaminomethyl-2-methylsulfanyl-phenol hydrobromide (1.74 g, 6.26 mmol) and cesium carbonate (4.08 g, 12.5 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 17 h. The reaction was complete by LC/MS analysis. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10%-sodium carbonate solution (2×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-dimethylaminomethyl-2-methylsulfanyl-phenoxy)-benzonitrile (1.2 g, 58%) as a yellow oil. Fumaric acid (92 mg, 0.3 mmol) in methanol (5 mL) was added to 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (91 mg, 0.26 mmol). The solvent was removed in vacuo and diethyl ether (20 mL) was added with stirring. After 17 h, 4-chloro-2-(3-dimethylaminomethyl-2-methysulfanyl-phenoxy)-benzonitrile fumarate (63.2 mg, 47%) was filtered off as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[C:13]1(OB(O)O)[CH:18]=[CH:17]C=[CH:15][CH:14]=1.[C:23](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:6]1[CH:8]=[C:2]([CH3:23])[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]=1[C:9]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1N
Reactant: OB(O)Oc1ccccc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1cc(N)c(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
1.87 g (0.01 mole) of 5-chloro-2-methyl-4-nitroaniline and 0.013 mole of phenylboric acid were dissolved in 70 mL of 1,2-dimethoxyethane under argon. Then, 0.5 g (0.0005 mole) of tetrakis(triphenylphosphine)palladium and 13 mL of 2 N potassium carbonate solution were added, and the reaction mixture was heated to 80° C. At the end of the reaction, the reaction mixture was poured into 100 mL of ethyl acetate. The organic phase was extracted with dilute sodium hydroxide solution and then dried over magnesium sulfate. The solvent was distilled off from a rotary evaporator, and the residue was purified [by column chromatography] on silica gel using hexane/ethyl acetate (8:1) [as the eluent].
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[C:3]=1C(O)=O.[OH-:24].[Na+].C1C[O:29]CC1>O>[C:1]([C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1)([OH:29])=[O:24]
Reactant: [OH-]
Reactant: COc1ccc(-c2nc3c(C)c(C(=O)O)c(OC)cc3s2)cc1
Reactant: C1CCOC1
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2nc3c(C(=O)O)cc(OC)cc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
To a solution of 4-methylcarboxy-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (0.37 g, 1.12 mmol) in THF (6 mL) and water (3 mL) was added 1N sodium hydroxide (2.24 mL, 2.24 mmol) and the solution was stirred at room temperature for 24 h. THF was then evaporated. 1 N HCl was added to PH 1. The solid was collected by filtration and washed with water to give 4-carboxy-6-methoxy-2-(4-methoxy-phenyl)benzothiazole (0.29 g, 82% yield) as a white solid. Mass spec: MH+=316.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][CH:6]=1)C.CO.O.O[Li].O>C1COCC1>[C:12]1([NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:18])=[O:3])=[CH:6][N:7]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(Nc2ccccc2)nc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Nc2ccccc2)nc1
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of 6-chloronicotinic acid ethyl ester (0.2 g, 0.00108 mole) and aniline (0.119 g, 0.00129 mole) in ethoxyethanol (10 mL) was heated to reflux for overnight. The mixture was then concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (5% ethyl acetate in hexane) to afford 0.23 g (88%) of 6-phenylamino-nicotinic acid ethyl ester. To a stirred solution 6-phenylamino-nicotinic acid ethyl ester (0.23 g, 0.00095 mol) in a mixture of THF (4 mL), methanol (4 mL) and H2O (2 mL) was added LiOH.H2O (0.159 g, 0.0038 mol) at ambient temperature and the resulting mixture was stirred overnight. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous citric acid solution. The resulting precipitate was isolated by filtration and dried to afford 0.174 g (85%) of 6-Phenylamino-nicotinic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].FC(F)(F)S(O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]2[O:16][CH:1]3[C:10]4[C:5]([CH:4]=[CH:3][N:2]3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]2=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc2cnccc2c1
Reactant: O=Cc1cccc(Br)c1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1cccc(C2OC3c4ccccc4C=CN3c3ccccc32)c1
Yield: 62 %

Procedure:
Following the general procedure, treatment of isoquinoline (0.064 g, 59 μL, 0.50 mmol) and 3-bromobenzaldehyde (0.139 g, 884, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=93/07) of the crude reaction mixture afforded 6-(3-bromophenyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline as inseparable mixture of diastereomers as a yellow solid (0.121 g, 62% yield, dr determined by 1H NMR analysis of crude reaction mixture is 3:2).