Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(I)cc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 682.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[C:4]=1[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(O)(=O)C.Br>[OH:2][C:3]1[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[C:4]=1[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1c(CC(=O)O)cc2ccoc2c1C(=O)c1ccccc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1cc2ccoc2c(C(=O)c2ccccc2)c1O
Reaction time: 1 h

Procedure:
6-Methoxy-7-benzoylbenzofuran-5-ylacetic acid (5.0 g) was heated at reflux in a mixture of acetic acid (50 ml) and 48% hydrobromic acid (50 ml). After the reaction was completed, approximately 1 hour, the cooled solution was added to 400 ml of water which was then extracted with ethyl acetate. The combined organic extracts were washed four times with water, dried with sodium sulfate and evaporated to give 6-hydroxy-7-benzoylbenzofuran-5-ylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[C:3]=1[F:22]
Reactant: COc1ccc2c(N)cc(=O)oc2c1OC1CCCC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COc1ccc2c(N)c(F)c(=O)oc2c1OC1CCCC1
Reaction time: 18 h

Procedure:
A mixture of 4-amino-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (100 mg, 0.36 mmol, Example 3, Step 1), Selectfluor (160 mg, 0.45 mmol), and acetonitrile (1.5 mL) were stirred vigorously for 18 h, concentrated, and then purified by silica gel chromatography (7:3→1:4; hexanes:ethyl acetate) to give 4-amino-8-(cyclopentyloxy)-3-fluoro-7-methoxy-2H-chromen-2-one: MS (ESI): 294.0.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19]Br)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])=[CH:14][CH:13]=1
Reactant: CCOP(OCC)OCC
Reactant: Clc1ccc(CCBr)cc1
Product: CCOP(=O)(CCc1ccc(Cl)cc1)OCC

Procedure:
Combine 24.9 g (0.15 mole) of triethyl phosphite and 32.9 g of 2-(4-chlorophenyl)ethyl bromide. Heat the mixture at reflux under a nitrogen atmosphere for 5-6 hours. Distill the reaction mixture at reduced pressure (0.2 mm Hg) and collect the fraction distilling at 110°-148° C. to obtain the title compound.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:11]3[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:31]1([NH:36][C:37]([NH2:39])=[NH:38])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:31]1([NH:36][C:37]2[N:39]3[N:13]=[C:14]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[C:15]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[N:12]=4)=[C:16]3[CH:17]=[CH:18][N:38]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)nccc12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3c(NC4CCCC4)nccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 140 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of 1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-one (160 mg, 0.41 mmol) in N,N-dimethylformamide (10 mL) was added N-cyclopentylguanidine hydrochloride (130 mg, 0.82 mmol). Freshly ground anhydrous potassium carbonate (56 mg, 0.41 mmol) was added and the reaction heated to 140° C. for 4 hours. Additional freshly ground anhydrous potassium carbonate (120 mg, 0.87 mmol) and N-cyclopentylguanidine hydrochloride (75 mg, 0.46 mmol) were added and the reaction heated for additional 3 hours. The reaction was allowed to cool and was stirred at room temperature for 16 hours. The mixture was quenched with water, extracted with ethyl acetate (2×), washed with brine, concentrated, and the residue purified by silica chromatography eluting with 5% acetone in dichloromethane to yield 140 mg (75%) of N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine. 1H NMR (CDCl3): δ 8.09 (d, 1H), 7.80 (d, 1H), 7.66 (dd, 2H), 7.54 (d, 1H), 7.19 (t, 2H), 6.42 (d, 1H), 6.30 (d, 1H), 5.14 (d, 1H), 4.57 (m, 1H), 4.34 (m, 1H), 2.22 (m, 2H), 2.09 (m, 2H), 1.52–1.89 (m, 12H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 42 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 144 mg (1 mmole) of n-octanoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 174 mg (Yield: 42%) of the title compound having the following structure as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>O1CCCC1>[C:33]([N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13]1)(=[O:35])[CH3:34]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.20 mmol) (from Example 25a supra) in tetrahydrofuran (3 mL) was added triethylamine (32 mg, 0.3 mmol) (Aldrich), followed by the addition of acetyl chloride (20 mg, 0.24 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give rac-3-(1-acetyl-piperidin-3-yl)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a white solid. (Yield 58 mg, 66%). Further purification by precipitation from dichloromethane-hexanes gave the product as a white solid. (Yield 45 mg).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[CH:12][C:13]([C:15]([NH2:17])=[O:16])=[CH:14][C:5]=3[C:4](=O)[O:3]1)[CH:8]=[CH:9][CH:10]=2.[NH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>C(O)C>[C:15]([C:13]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]2=[C:5]([CH:14]=1)[C:4](=[O:3])[N:19]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:2]3=[O:1])(=[O:16])[NH2:17]
Reactant: NCCCC(=O)O
Reactant: NC(=O)c1cc2c3c(cccc3c1)C(=O)OC2=O
Solvent: CCO
Product: NC(=O)c1cc2c3c(cccc3c1)C(=O)N(CCCC(=O)O)C2=O
Temperature: 150 °C

Procedure:
A mixture of 1,3-dioxo-1H,3H-benzo[de]isochromene-5-carboxamide (0.5 mmol), 4-Aminobutyric acid (1.5 mmol) and 4 mL ethanol was heated to 150° C. for 30 minutes in microwave reactor (Biotage, Initiator). The reaction mixture was cooled to room temperature and the cream color precipitate was collected by filtration and washed with ethanol. The final product was dried in vacuum for 24 hours to give desired compound.
Reaction SMILES: C([O:4][C:5]1[CH:36]=[CH:35][CH:34]=[CH:33][C:6]=1[C:7]([NH:9][C:10]1[CH:19]=[C:18]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28]C(=O)C)[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:8])(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>>[C:7]([NH:9][C:10]1[CH:19]=[C:18]([NH:20][C:21](=[O:32])[C:22]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[OH:28])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:6]1[C:5](=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:4]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2OC(C)=O)cc1NC(=O)c1ccccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(NC(=O)c2ccccc2O)cc1NC(=O)c1ccccc1O
Yield: 82 %

Procedure:
By the procedure similar to that described in Example 4, methyl 2,4-bis(2'-acetoxybenzamido)-benzoate was hydrolized with the aid of sodium carbonate to obtain crystals. Recrystallization of the crystals from a mixture of acetone, dioxane and water gave methyl 2,4-bis(salicylamido)-benzoate having a melting point between 259° - 260°C. (Yield: 82%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](SC)=[C:13]2[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]2=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:25][NH2:26]>C1COCC1.Cl[Hg]Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([NH:26][CH3:25])=[C:13]2[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]2=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN
Reactant: COc1ccc(NC(SC)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Product: CNC(Nc1ccc(OC)c(OC)c1)=C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
A mixture of 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (0.50 g, 1.4 mmol), methylamine (2 M in THF, 0.75 mL. 1.5 mmol), HgCl2 (0.38 g, 1.4 mmol) in THF (5 mL) was stirred at room temperature for 30 minutes. The mixture was extracted with DCM and water (3×) and dried with Na2SO4. Concentration in vacuo afforded 5-[(3,4-dimethoxy-phenylamino)-methylamino-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione as a yellow solid (0.48 g, 99% yield) and this compound was used without further purification. LCMS: m/z 335 (M−H)−.
Reaction SMILES: BrC1C=CC(OC2C=CC(C#N)=C(Cl)N=2)=CC=1C1OCCO1.[Br:23][C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[N:36]=[C:35](Cl)[CH:34]=[CH:33][C:30]=2[C:31]#[N:32])=[CH:26][C:25]=1[CH:40]1[O:44][CH2:43][CH2:42][O:41]1.BrC1C=CC(OC2C=CC(C#N)=[C:53]([N:59]([CH2:61][CH2:62][O:63]C)C)N=2)=CC=1C=O>C(#N)C>[Br:23][C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[N:36]=[C:35]([N:59]([CH2:61][CH2:62][OH:63])[CH3:53])[CH:34]=[CH:33][C:30]=2[C:31]#[N:32])=[CH:26][C:25]=1[CH:40]1[O:44][CH2:43][CH2:42][O:41]1
Reactant: N#Cc1ccc(Cl)nc1Oc1ccc(Br)c(C2OCCO2)c1
Reactant: COCCN(C)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Agent: N#Cc1ccc(Oc2ccc(Br)c(C3OCCO3)c2)nc1Cl
Solvent: CC#N
Product: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C3OCCO3)c2)n1
Temperature: 80 °C
Yield: 36 %

Procedure:
To a solution of compound mixture, 6-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile and 2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile, (4+5, 1 g, 2.6 mmol) in acetonitrile (anhydrous, 30 mL) was added 2-methylamino-ethanol (6, 2.1 mL, 26 mmol). The reaction was heated at 80° C. for 2 hours. After the reaction, all volatile components were evaporated under vacuum. Purification was accomplished by silica gel chromatography, eluting with 10%-80% EtOAc/Hexane gradient, affording the title compound 400 mg in 36% yield. 1H NMR 400 MHz (CDCl3) δ 7.62 (d, J=8.6 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.47 (d, J=3.1 Hz, 1H), 7.06 (dd, J=8.6 Hz, 3.1 Hz, 1H), 6.18 (d, J=8.6 Hz, 1H), 6.08 (s, 1H), 4.20-4.02 (m, 4H), 3.55 (t, J=3.2 Hz, 2H), 3.42 (t, J=3.2 Hz, 2H), 3.02 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19]1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH2:1]([NH:17][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=C1CCCO1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNC(=O)CCCO
Yield: 78.1 %

Procedure:
A mixture of 59.45 g of hexadecylamine, 10.60 g of gamma butyrolactone, 200 ml of toluene, and 20 mg of zinc chloride was refluxed under nitrogen for three days. Upon cooling, the reaction mixture formed a precipitate which was recrystallized twice from toluene to yield 31.5 g (78.12%) of N-hexadecyl-4-hydroxybutyramide, m.p. 89.5°-90°
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.[NH3:22].C(O)C>>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1
Reactant: N#CCCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CCO
Product: N#CCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylthio]butyronitrile (0.32 g.), saturated ethanol ammonia (20 ml.) and yellow mercuric oxide (0.5 g.) was stirred at room temperature for 20 hours and then filtered and the filtrate evaporated to dryness. The residue was recrystallised from a mixture of acetone and petroleum ether (b.p. 60°-80°) to give 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyronitrile (0.29 g.), m.p. 137°.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([CH2:13][C:14]([OH:16])=[O:15])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[C:19]([O:21][CH:22]1[CH:29]2[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:31][CH:23]1[CH2:24]3)[CH2:28]2)=[O:20].CCN(C(C)C)C(C)C>C(#N)C>[CH:29]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:31][CH:23]([CH2:24]3)[CH:22]1[O:21][C:19]([N:10]1[CH2:9][CH2:8][C:7]([CH2:13][C:14]([OH:16])=[O:15])([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:17])[CH2:12][CH2:11]1)=[O:20])[CH2:28]2
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: Cc1ccccc1C1(CC(=O)O)CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C1(CC(=O)O)CCN(C(=O)OC2C3CC4CC(C3)CC2C4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
A fraction of the above aqueous solution (contains ˜15 mg of 2-(4-o-tolylpiperidin-4-yl)acetic acid, 0.064 mmol) was mixed with 2-adamantyl chloroformate (15 mg, 1.1 equiv). i-Pr2NEt (100 μL, excess) was added. Acetonitrile was added to make the mixture homogeneous. After stirring for 1 h at rt, the mixture was acidified and purified by prep HPLC to afford 2-(1-(2-adamantyloxycarbonyl)-4-o-tolylpiperidin-4-yl)acetic acid (4.4 mg). LC-MS Method 1 tR=2.13 min, m/z=412, 1H NMR (CDCl3) [selected resonances] 7.14 (m, 4H), 4.82 (s, 1H), 3.72 (br s, 2H), 2.78 (s, 2H), 2.52 (s, 3H), 2.46 (dt, 2H), 2.0 (m, 5H), 1.06 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:11]([C:18]1[S:22][C:21]([CH2:23][NH2:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:21]1[S:22][C:18]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:19][CH:20]=1)=[O:6]
Reactant: NCc1ccc(Oc2ccccc2)s1
Reactant: Nc1ncccc1C(=O)O
Product: Nc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1

Procedure:
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (250 mg, 0.768 mmol) obtained from 2-aminonicotinic acid and C-(5-phenoxy-thiophen-2-yl)methylamine described in Preparation Example 24 according to an analogous method to Preparation Example A+-5, and N-iodosuccinimide (190 mg, 0.845 mmol) were dissolved in tetrahydrofuran (5 mL), and the solution was stirred for 16 hours at room temperature. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1), and title compound (45 mg, 0.10 mmol, 13%) was obtained as a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>CC(O)C.[Cu](I)I>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Temperature: 80 °C
Yield: 43.3 %

Procedure:
A mixture of 4-iodoaniline (0.654 g, 3 mmol), piperazine-1-carboxylic acid tert-butyl ester (0.67 g, 3.6 mmol), potassium phosphate (1.272 g, 6 mmol), ethylene glycol (0.33 ml) and copper iodide (0.03 g, 0.15 mmol) in 2-propanol (3 ml) was placed under argon in a sealed-tube and heated to 80° C. for 30 hours. After being cooled to room temperature, the medium was washed with water (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 70:30) to yield 43a (0.36 g, 1.3 mmol, 43%) as a yellow powder.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:9])/[CH2:4][CH2:5][CH2:6][O:7][CH3:8].Cl[C:11](=O)[C:12]([O:14][CH3:15])=[O:13]>>[CH3:8][O:7][CH2:6][CH2:5][CH2:4][C:3]1[N:9]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[O:1][N:2]=1
Reactant: COCCC/C(N)=N/O
Reactant: COC(=O)C(=O)Cl
Product: COCCCc1noc(C(=O)OC)n1

Procedure:
In analogy to the procedure described for example D27 (1Z)—N′-hydroxy-4-methoxybutanimidamide (1.29 g), CaH2 (452 mg) and methyl chloro(oxo)acetate (1.32 g) yield the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:16][S:17]([OH:20])(=O)=[O:18])[CH2:11][S:12]([OH:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].O=P(Cl)(Cl)Cl>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][S:12](=[O:15])(=[O:13])[O:14][S:17](=[O:20])(=[O:18])[CH2:16]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(CS(=O)(=O)O)CS(=O)(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C2CS(=O)(=O)OS(=O)(=O)C2)cc1

Procedure:
2-(4-Nitro-phenyl)-propane-1,3-disulfonic acid (as prepared in the previous step) is treated with POCl3 as described in Chem. Berichte., 91, 1512-15 (1958) and the title compound is isolated and used in the following step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([N+:14]([O-])=O)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]1[C:5]([C:17]([F:18])([F:19])[F:20])=[CH:6][C:7]([NH2:14])=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])[CH3:2]
Reactant: CCOc1c(C(F)(F)F)cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CCOc1c(C(F)(F)F)cc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
2-Ethoxy-5-nitro-1,3-bis(trifluoromethyl)benzene (2) (1.00 g, 3.30 mmol) was dissolved in MeOH (150 mL) and passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 30° C. under H2 (full H2 mode). The solvent was removed in vacuo and the residue was dissolved in EtOH (20 mL) and then treated with 10% Pd/C (182 mg, 171 μmol). Hydrogen gas was bubbled through the mixture, with stirring at RT for 2 h. The mixture was then filtered through Celite and concentrated in vacuo. The residue was purified by silica gel chromatography (15% EtOAc in isohexane) to afford 4-ethoxy-3,5-bis(trifluoromethyl)aniline (3) (460 mg, 56%) as a white solid: m/z 273 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.09 (2H, s), 5.76 (2H, s), 3.87 (2H, q), 1.29 (3H, t).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([N:17]2[C:22](=[O:23])[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[S:18]2(=[O:29])=[O:28])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([F:42])[C:33]=1[CH2:34]Br.C([O-])([O-])=O.[K+].[K+].COC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>CN(C=O)C>[F:31][C:32]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([F:42])[C:33]=1[CH2:34][N:21]1[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[S:18](=[O:29])(=[O:28])[N:17]([C:11]2[N:10]=[C:9]([CH2:8][NH:7][C:6](=[O:30])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:14]([O:15][CH3:16])=[CH:13][CH:12]=2)[C:22]1=[O:23]
Reactant: COc1cc(F)c(CBr)c(F)c1
Reactant: COc1ccc(N2C(=O)Nc3ccccc3S2(=O)=O)nc1CNC(=O)OC(C)(C)C
Agent: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(CNC(=O)OC(C)(C)C)n3)S(=O)(=O)c3ccccc32)c(F)c1
Yield: 64.6 %

Procedure:
The title compound (301 mg, 0.51 mmol) was prepared from tert-butyl[6-(1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl)-3-methoxypyridin-2-yl]methylcarbamate (IntA31) (343 mg, 0.79 mmol), 2,6-difluoro-4-methoxybenzyl bromide (225 mg, 0.95 mmol) and K2CO3 (164 mg, 1.19 mmol) in DMF (4 mL) at rt using the methods of (115).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([OH:13])=O)[CH:3]=1.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:11]([C:4]4[CH:3]=[C:2]([CH3:1])[O:6][C:5]=4[C:7]([F:8])([F:9])[F:10])=[O:13])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: Cc1cc(C(=O)O)c(C(F)(F)F)o1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: Cc1cc(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)c(C(F)(F)F)o1

Procedure:
Following the procedure of Example 9, making variations only as required to use 5-methyl-2-trifluoromethylfuran-3-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (53% yield). m.p. 128-130° C. 1H NMR (500 MHz, CDCl3) δ 8.08, 7.99, 7.01, 6.15, 3.89-3.94), 3.77-3.82, 3.52-3.60, 2.39, 1.52, 0.71-0.80, 0.45-0.49, 0.08-0.13. MS (ES+) m/z 452 (M+1).