Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.I[CH2:32][CH2:33][CH3:34]>C1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:32][CH2:33][CH3:34])[CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)N(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CCCI
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCN1CCC(N(C(=O)Cc2ccccc2)c2ccc(Cl)cc2)CC1
Product: Cl

Procedure:
To a stirred solution of 4 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide and 3 parts of N,N-diethylethanamine in 200 parts of benzene are added portionwise 4 parts of 1-iodopropane and the whole is stirred and refluxed for 47 hours. Then the second portion of 4 parts of 1-iodopropane is added and stirring and refluxing is continued for another 20h.20. The reaction mixture is cooled and filtered. The filtrate is washed with water, dried and evaporated in vacuo. From the oily free base, the hydrochloride salt is prepared in the conventional manner in 1,1'-oxybisethane. The precipitated solid salt is filtered off and dried, yielding 3.5 parts of N-(4-chlorophenyl)-N-(1-propyl-4-piperidinyl)benzeneacetamide hydrochloride; mp. 233.5° C.
Reaction SMILES: [CH:1]1([C:4](=O)[CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[CH2:3][CH2:2]1.[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16].[Na].C[OH:22]>>[CH:1]1([CH2:4][C:5](=[O:22])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[CH:18]([N+:15]([O-:17])=[O:16])[CH3:19])[CH2:3][CH2:2]1
Reactant: O=C(C=Cc1cccc(Cl)c1)C1CC1
Reactant: CC[N+](=O)[O-]
Reactant: CO
Agent: [Na]
Product: CC(C(C(=O)CC1CC1)c1cccc(Cl)c1)[N+](=O)[O-]

Procedure:
The procedure of Example IX using 33 g of 1-cyclopropyl-3-(m-chlorophenyl)prop-2-en-1-one, 15 ml of nitroethane and 2 g of sodium in 150 ml of methanol, gives 33.5 g of 1-cyclopropyl-3-(m-chlorophenyl)-4-nitropentanone as an oily residue which is used in the crude state for the remainder of the operations.
Reaction SMILES: C=CCCCCCC.B1[CH:14]2[CH2:15][CH2:16][CH2:17][CH:10]1[CH2:11][CH2:12][CH2:13]2.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[CH2:29][CH3:30])[O:25][C:24]([C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:33]([O:47][CH3:48])[CH:32]=1)=[C:23]([OH:49])[C:22]2=[O:50]>O1CCCC1.[OH-].[Na+]>[CH2:29]([C:28]1[CH:27]=[C:26]2[C:21]([C:22](=[O:50])[C:23]([OH:49])=[C:24]([C:31]3[CH:32]=[C:33]([O:47][CH3:48])[C:34]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[C:35]([O:37][CH3:38])[CH:36]=3)[O:25]2)=[CH:20][C:19]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:10])[CH3:30]
Reactant: CCc1cc2oc(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)c(O)c(=O)c2cc1Br
Reactant: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C=CCCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1cc2c(=O)c(O)c(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)oc2cc1CC
Reaction time: 7 h

Procedure:
To a stirring solution of 1-octene (0.032 g, 0.3 mmol, 1.4 eq) in tetrahydrofuran (1 ml) under argon at 0° C. was added 9-BBN in tetrahydrofuran (0.5M, 0.6 ml, 0.3 mmol, 1.5 eq). The reaction was stirred for 7 hours then 6-bromo-7-ethyl-3-hydroxy-2-(4-benzyloxy-3,5-dimethoxy-phenyl)-chromen-4-one 57 (0.102 g, 0.2 mmol) in tetrahydrofuran (4 ml), 3M NaOH solution (0.2 ml) and dichloropalladium(dppf) (0.005 g, 0.006 mmol, 0.03 eq) were added and the reaction heated to reflux for 15 hours. The reaction was then quenched with water and diethyl ether and acidified (6 M HCl). The organic layer was collected and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give a red oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]=[CH:7][CH2:8][CH2:9][CH3:10])[CH3:3].[H][H]>C(O)C.[Pd]>[CH3:3][C:2]([CH2:4][C@H:5]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH2:1]
Reactant: CCCC=C[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C=C(C)C[C@@H](CCCCC)NC(=O)OC(C)(C)C
Yield: 89 %

Procedure:
A solution of (S)-2 -methyl-4 -(tert butoxycarbonylamino)-5 -nonene (2.0 g) in absolute ethanol (75 mL) was hydrogenated over a 5% palladium on carbon catalyst (1.0 g) at 20°-25° and an initial pressure of 34 psi in a Paar apparatus. After one equivalent of hydrogen had been taken up (1 hour), the mixture was filtered and then concentrated under reduced pressure to give 1.78 g of product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].OC1C2N=NNC=2C=CC=1.[C:17]([NH:24][C@@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.C(N(CC)CC)C>[C:17]([NH:24][C@@H:25]([C:30]([NH:2][CH2:3][C:4]([NH2:6])=[O:5])=[O:32])[CH2:26][CH:27]([CH3:28])[CH3:29])([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(N)=O
Reaction time: 48 h

Procedure:
1.55 g (0.014 mole) of glycinamide hydrochloride is dissolved in 50 ml of DMF by warming to 50°. The solution is cooled to 25° and 2 ml of triethylamine is added, followed by 1.89 g of hydroxybenztriazole, 3.5 g (0.014 mol) of BOC-D-leucine H2O and lastly, 2.9 g (0.014 mol) of dicyclohexylcarbodiimide. The mixture is stirred two days at 25° and then evaporated in vacuo to an oil. The oil is dissolved in 200 ml EtOAC, 50 ml CHCl3. The organic solution is washed with water, 20% citric acid solution, water, 10% Na2CO3 solution. The EtOAc solution is dried over MgSO4 and the solvent removed in vacuo to a glass, 3.7 g (93%).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([O:25][CH3:26])[CH:22]([NH2:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([O:25][CH3:26])[CH:22]([NH:24][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:23]
Reactant: COC(c1ccc(Cl)cc1Cl)C(C)N
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(c1ccc(Cl)cc1Cl)C(C)NC(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (195 mg, 1.0 mmol) in dichloromethane (2 ml) was added dropwise to a stirred solution of (234 mg, 1.0 mmol) 2-(2,4-dichloro-phenyl)-2-methoxy-1-methyl-ethylamine, which was prepared as described in example P2, and triethylamine (202 mg, 2.0 mmol) in dichloromethane (6 ml) at 0° C. The reaction mixture was stirred for 1 hr at ambient temperature then allowed to stand for 4 h. After removal of the solvent the residue was purified by flash chromatography over silica gel (eluant:hexane/ethyl acetate 1:1). 170 mg (43% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4-dichlorophenyl)-2-methoxy-1-methyl-ethyl]-amide was obtained in the form of a resin as a mixture of diastereomeres.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH2:16].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1Cl>CN(C)C1C=CN=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:18]1[C:19]2[C:20](=[CH:11][CH:2]=[CH:3][CH:4]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O
Reactant: Clc1ccccc1Cl
Agent: CN(C)c1ccncc1
Product: COc1cc2nccc(Oc3cccc4ccccc34)c2cc1OC
Temperature: 150 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 1-hydroxy-2-naphthonic acid (252 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 150° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (119 mg, yield 80%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:18]([CH3:19])=[CH:17][C:16](O)=[C:15]([C:21]#[N:22])[C:14]1=[O:23].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:3][C:16]1[CH:17]=[C:18]([CH3:19])[N:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[Cl:6])[C:14](=[O:23])[C:15]=1[C:21]#[N:22]
Reactant: Cc1cc(O)c(C#N)c(=O)n1-c1ccccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(C#N)c(=O)n1-c1ccccc1Cl
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Phosphorus oxychloride (2.59 mL) was slowly added to N,N-dimethylformamide (17.8 mL) under ice-cooling, and the mixture was stirred for 15 min. To the reaction mixture was added a solution of 1-(2-chlorophenyl)-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step D (2.90 g) in N,N-dimethylformamide (4.50 mL) under ice-cooling, and the reaction mixture was heated overnight at 80° C. The reaction mixture was cooled to room temperature, and poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (2.50 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[C:13]([O:17][C:18](=[O:35])[NH:19][C@@H:20]([C:29](=[O:34])N(OC)C)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])([CH3:16])([CH3:15])[CH3:14].OS([O-])(=O)=O.[Na+]>C1COCC1.O>[C:13]([O:17][C:18](=[O:35])[NH:19][C@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[C:29](=[O:34])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Reactant: Cc1ccccn1
Agent: O=S(=O)([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1F)C(=O)Cc1ccccn1
Temperature: 15 °C

Procedure:
To a solution of 2-picoline (0.54 mL, 5.5 mmol) in 20 mL of THF at −52° C. is slowly added a 1.5 M solution of n-butyllithium in hexanes (3.6 mL, 5.5 mmol). The reaction is then warmed to 15° C. and is then immediately re-cooled to −52° C. To the reaction is added a solution of [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (0.6 g, 1.8 mmol) in 4 mL of THF. The reaction is then is poured into 8 mL of a 2M solution of NaHSO4 in water. The solution is adjusted to pH7 by addition of pH7 buffer and the product is extracted into ether. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:21]3[C:20](=[O:22])[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:18](=[O:32])[N:17]([C:33]4[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=4[F:40])[C:16]=3[N:15]([CH3:41])[C:14](=[O:42])[C:13]=2[CH3:43])(=O)=O)=CC=1.N1C(C)=CC=CC=1C.[NH2:52][C:53]1[CH:54]=[C:55]([CH:60]=[CH:61][CH:62]=1)[C:56]([O:58][CH3:59])=[O:57].O>CC(N(C)C)=O>[F:40][C:34]1[CH:35]=[C:36]([I:39])[CH:37]=[CH:38][C:33]=1[N:17]1[C:16]2[N:15]([CH3:41])[C:14](=[O:42])[C:13]([CH3:43])=[C:12]([NH:52][C:53]3[CH:54]=[C:55]([CH:60]=[CH:61][CH:62]=3)[C:56]([O:58][CH3:59])=[O:57])[C:21]=2[C:20](=[O:22])[N:19]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:18]1=[O:32]
Reactant: COc1ccc(Cn2c(=O)c3c(OS(=O)(=O)c4ccc(C)cc4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Reactant: COC(=O)c1cccc(N)c1
Solvent: CC(=O)N(C)C
Solvent: Cc1cccc(C)n1
Solvent: O
Product: COC(=O)c1cccc(Nc2c(C)c(=O)n(C)c3c2c(=O)n(Cc2ccc(OC)cc2)c(=O)n3-c2ccc(I)cc2F)c1
Temperature: 130 °C
Yield: 49.7 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzene sulfonate (3a) (8.70 gm, 12.13 mmol) in DMA (10 ml) was added 2,6-lutidine (3.5 ml, 30.3 mmol) and methyl 3-aminobenzoate (5.5 g, 36.4 mmol). The reaction mixture was heated at 130° C. for 16 h. The reaction mixture was cooled to room temperature and water was added followed by extraction with Ethyl acetate. The organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo and the residual solid was purified by silica gel column chromatography, eluting with Hexane:Ethyl acetate, to yield the titled compound (3b) (4.2 g)
Reaction SMILES: [CH:1]1([N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=3)[C:7]2=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([O:35]C)=[O:34])[CH:27]=2)[CH:23]=[CH:24][CH:25]=1.ClC1C=CC(C2C=CC=C(COC3C=C4C(CCN(C5CCCC5)C4=O)=CC=3)C=2)=CC=1C(O)=O>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][O:16][C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[C:7](=[O:17])[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:15][CH2:14]4)[CH:21]=2)=[CH:27][C:28]=1[C:33]([OH:35])=[O:34]
Reactant: O=C1c2ccc(O)cc2CCN1C1CCCC1
Reactant: COC(=O)c1cc(-c2cccc(CBr)c2)ccc1Cl
Agent: O=C(O)c1cc(-c2cccc(COc3ccc4c(c3)C(=O)N(C3CCCC3)CC4)c2)ccc1Cl
Product: O=C(O)c1cc(-c2cccc(COc3ccc4c(c3)CCN(C3CCCC3)C4=O)c2)ccc1Cl
Yield: 68.1 %

Procedure:
2-Cyclopentyl-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (0.106 g, 0.5 mmol) and methyl 3′-(bromomethyl)-4-chlorobiphenyl-3-carboxylate (0.208 g, 0.6 mmol) were processed according to the general procedure described for 4-chloro-3′-((2-cyclopentyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl)biphenyl-3-carboxylic acid, to provide 4-chloro-3′-((2-cyclopentyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)methyl)biphenyl-3-carboxylic acid (0.162 g, 69% over 2 steps) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 1H), 7.87-7.75 (m, 3H), 7.65-7.57 (m, 2H), 7.49-7.41 (m, 2H), 6.95-6.90 (overlapping doublets and singlet, 2H), 5.20 (s, 2H), 4.97-4.93 (m, 1H), 3.34 (t, 2H, J=6.1 Hz), 2.84 (t, 2H, J=6.1 Hz), 1.69-1.46 (m, 8H). LC-MS (ESI) Calcd for C28H26ClNO4 [M+H]+: 476.16. Found: 476.00. HRMS (ESI) calcd for C28H26ClNO4 [M+H]+: 476.1623. Found: 476.1623.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:10]1C(=O)C2=CC=CC=C2C1=O)([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].O.NN>C(O)C>[NH2:10][C:3]([C:2]([F:1])([F:21])[F:22])([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(CCC(=O)O)(N1C(=O)c2ccccc2C1=O)C(F)(F)F
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)(CCC(=O)O)C(F)(F)F

Procedure:
A solution of 15.2 g of 1-trifluoromethylpent-4-ene-1-one in 150 ml of methanol is heated at 0° C. with 1.7 g of sodium borohydride. The reaction mixture is stirred for 2 hours at 25° C. then neutralized with HCl. The residue obtained after evaporation of the solvent is extracted several times with chloroform, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1-trifluoromethylbut-4-ene-1-ol. A solution of 10 mmole of 1-trifluoromethylbut-4-ene-1-ol, 10 ml of triphenylphosphine and 10 ml of diethyl azodicarboxylate in 25 ml of tetrahydrofuran is stirred under nitrogen at 25° C. for 16 hours after which the solvent is evaporated under reduced pressure. The resulting residue is treated with benzene. The insoluble material is discarded and the semi-solid obtained after concentration of the filtrate under reduced pressure is recrystallized from methylene chloride-pentane to afford N-(1-trifluoromethyl-3-butenyl)phthalimide. To a solution of 25 mmole of the phthalimide in 25 ml of dioxane is added a solution of 12 mmole of potassium permanganate and 50 mmole of sodium metaperiodate in water. Potassium carbonate is added to adjust the pH of the solution to 8 and the reaction mixture is stirred for 24 hours at 25° C. then acidified with sulfuric acid to a pH of 1 and extracted with ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is recrystallized from methylene chloride-pentane to give 4-trifluoromethyl-4-phthalimidopentanoic acid. A solution of 20 ml of 4-trifluoromethyl-4-phthalimidopentanoic acid and 20 mmole of hydrazine hydrate in 20 ml of ethanol is heated at reflux temperature for 12 hours. The solid which separates on cooling is filtered and washed with water. The filtrate is concentrated under reduced pressure to give a solid which is recrystallized from water/acetone to give 4-amino-4-trifluoromethylpentanoic acid.
Reaction SMILES: CO.[CH:3]([C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[N:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[N:9]=1)=O.C1(C)C=CC(S([CH2:31][N+:32]#[C-])(=O)=O)=CC=1.[C:35](=[O:38])([O-])[O-]>C(OCC)(=O)C>[CH3:17][O:16][C:10]1[CH:11]=[C:12]([O:14][CH3:15])[N:13]=[C:8]([O:7][C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[C:3]2[O:38][CH:35]=[CH:31][N:32]=2)[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(OC)nc(Oc2ccccc2C=O)n1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(Oc2ccccc2-c2ncco2)n1
Reaction time: 0.25 h

Procedure:
To 10 ml methanol, were added 0.52 g 2-(2-formylphenoxy)-4,6-dimethoxypyrimidine), 0.49 g p-toluenesulfonylmethylisocyanide and 0.69 g pottasium carbonate, and the mixture was subjected to reflux with stirring during 15 min. The solution reacted was added with ice, and solid substance precipitated was filtrated. The solid substance obtained was dissolved in ethyl acetate, and the resulting solution was then dried by using anhydrous magnesium sulfate. Then, the solvent used was removed by distillation under reduced pressure, affording the objective substance in an amount of 0.54 g.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2Cl.[CH3:13][N:14]([CH2:16][CH2:17][CH2:18][NH2:19])[CH3:15]>N1C=CC=CC=1.C(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:19][CH2:18][CH2:17][CH2:16][N:14]([CH3:15])[CH3:13]
Reactant: Clc1nccc2c(Br)cccc12
Reactant: CN(C)CCCN
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CN(C)CCCNc1nccc2c(Br)cccc12
Reaction time: 0.13 h
Yield: 25 %

Procedure:
To a microwave vial containing 5-bromo-1-chloroisoquinoline (Step 3, 0.300 g, 1.2 mmol), dissolved in pyridine (3 mL), was added Dimethylaminopropyl-amine (0.16 mL, 1.3 mmol). The mixture was placed into CEM Microwave for 8 minutes at 100° C., while supplying 80 Watts of power via power-max. The mixture was diluted with DCM and water, and extracted with DCM (3×10 mL). Then dried organics (over sodium sulfate) was filtered, and concentrated in-vacuo. It was then purified by Amino-Propyl Silica-gel chromatography in MeOH/DCM. This gave tan colored oil, which was titled product (0.085 g, 0.3 mmol). MS (ESI pos. ion) m/z: 309; 310 (M+H). Calc'd Exact Mass for C14H18N3Br: 308
Reaction SMILES: C1(C)C=CC([S:7](Cl)(=[O:9])=[O:8])=CC=1.[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CC[N:21](C(C)C)C(C)C>ClCCl>[OH:12][CH:13]1[CH2:18][CH2:17][N:16]([S:7]([NH2:21])(=[O:9])=[O:8])[CH2:15][CH2:14]1
Reactant: OC1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: NS(=O)(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-toluenesulfonyl chloride (39.28 mmol) in dichloromethane (160 mL) was added 4-hydroxypiperidine (40.07 mmol) dropwise, followed by 13.7 ml i-Pr2NEt. The mixture was stirred at room temperature for 3 h. Solvent was removed under vacuum and crude product was purified with flash column chromatography to yield 4-hydroxypiperidin sulfonamide (I).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
2-fluoro-4-iodophenylamine (1.50 g) was dissolved in dichloromethane (40 ml) and to the solution were added pyridine (1.02 ml) and methanesulfonylchloride (700 μl). The mixture was stirred at room temperature for 1 hour and 1.5 N aqueous hydrochloric acid was added thereto to quench the reaction. The resulting mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was column-chromatographed (ethyl acetate/hexane=1/1) to yield the compound 3-2 (1.89 g, 95%).
Reaction SMILES: Br[C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:21]([CH:23]1[CH2:25][CH2:24]1)#[CH:22]>CN(C=O)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:23]1([C:21]#[C:22][C:2]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=2)[CH2:25][CH2:24]1
Reactant: COC(=O)c1nc(SC)ncc1Br
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(SC)ncc1C#CC1CC1
Temperature: 80 °C
Yield: 86.2 %

Procedure:
Methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (639 mg, 2.43 mmole) was dissolved in DMF (6 mL) and triethylamine (1.37 mL) was added. To the solution was added ethynylcyclopropane (287 uL, 3.40 mmole), followed by copper (I) iodide (22.4 mg 0.115 mmole) and bis(triphenylphosphine)palladium dichloride (85.4 mg 0.115 mmole). The reaction was placed under nitrogen at heated at 80° C. for 3.25 hours. The reaction was diluted with ethyl acetate (75 mL) and the solution was washed with water (25 mL). The organic layer was washed again with water (2×25 mL), brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5-10% ethyl acetate in cyclohexanes to afford the title compound (520 mg, 86%). Taken on directly to the next step.
Reaction SMILES: [CH2:1]=[C:2]([CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)=[O:35]>CN(C)C1C=CN=CC=1>[CH2:25]([S:32]([CH2:1][CH:2]([CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: SCc1ccccc1
Reactant: CC(C)=O
Agent: CN(C)c1ccncc1
Product: O=C(CCC(CS(=O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Yield: 90 %

Procedure:
To a solution of dibenzyl 2-methylenepentanedioate (12.16 g, 37.5 mmol) in acetone (100 mL), was added benzylmercaptan (9.31 g, 75.0 mmol) and 4-dimethylaminopyridine (0.46 g, 3.75 mmol) with stirring. The reaction mixture was refluxed for 16 hours. The cooled solution was concentrated under reduced pressure and purified by column chromatography to yield 15.2 g (90%) of clear oil.