Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:7][CH2:8][CH:9]1[CH:14]2[O:15][CH:11]([CH2:12][CH2:13]2)[CH:10]1[CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][C:21]([CH3:34])([CH3:33])[C:22](=[N:31]O)[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I([O-])(=O)(=O)=[O:36].[Na+].O1CCCC1>CO>[CH2:1]([S:7]([CH2:8][CH:9]1[CH:14]2[O:15][CH:11]([CH2:12][CH2:13]2)[CH:10]1[CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][C:21]([CH3:34])([CH3:33])[C:22](=[NH:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSCC1C2CCC(O2)C1CC=CCCC(C)(C)C(=NO)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCS(=O)CC1C2CCC(O2)C1CC=CCCC(C)(C)C(=N)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 634 mg (1.72 mmol) of [1α,2β(5Z),3β,4α]-7-[3-([hexylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-2,2-dimethyl-5-heptenimidic acid, phenylmethyl ester (prepared as described in Example 17) in 6.78 ml of methanol at 0° C. is added dropwise over 4 minutes 4.8 ml of 0.5M aqueous sodium periodate solution. Tetrahydrofuran (2 ml) is then added and the resulting reaction mixture is stirred at room temperature for 15 hours. A precipitate is removed by filtration and washed with ether (3×50 ml). The filtrate is washed with 60 ml of saturated aqueous NaHCO3 solution and dried over anhydrous magnesium sulfate. Concentration in vacuo affords an oily crude product. This is chromatographed on silica gel 60 using 0.5-1.0% CH3OH in CH2Cl2 as eluant. This gives [1α,2β(5Z),3β,4α]- 7-[3-[(hexylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-2,2-dimethyl-5-heptenimidic acid, phenylmethyl ester and [1α,2β(5Z),3β,4α]-7-[3-[(hexylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-2,2-dimethyl-5-heptenimidic acid, phenylmethyl ester.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:5]=1[C:6]([N:8]([CH2:10][CH2:11][OH:12])[CH3:9])=[O:7].O>CN(C=O)C>[F:18][C:14]1[C:15]([F:17])=[CH:16][C:4]2[O:12][CH2:11][CH2:10][N:8]([CH3:9])[C:6](=[O:7])[C:5]=2[CH:13]=1
Reactant: CN(CCO)C(=O)c1cc(F)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCOc2cc(F)c(F)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Sodium hydride (52 mg, 1.29 mmol) was added portionwise to a solution of 2,4,5-trifluoro-N-(2-hydroxyethyl)-N-methylbenzamide (300 mg, 1.29 mmol) in DMF (13 mL) and reaction was allowed to stir at RT for 2 hours. Water (30 mL) was added and the white solution was extracted with ethyl acetate (3×30 mL) and dried (MgSO4), filtered and evaporated to give the desired compound as a colourless oil (275 mg). The compound was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[OH-].[K+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23]C(CCl)=[CH:19][CH:18]=1>C(O)C>[OH:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(COC(=O)C2CCC(O)CC2)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl 4-hydroxycyclohexanoate (8.61 g, 50 mmole) in 50 ml ethanol was added a solution of potassium hydroxide 85% (3.63 g, 55 mmole) and the mixture was stirred for 6 hours at 70° C. The mixture was evaporated under reduced pressure, coevaporated two times with N,N-dimethylformamide and reduced to about 100 ml. 4-Methoxybenzyl chloride (9.4 g, 60 mmole) was added and the mixture was stirred for 18 hours at 60° C. The mixture was evaporated under reduced pressure and 250 ml ethyl acetate was added. The organic phase was washed five times with water, dried with sodiun sulfate and evaporated under reduced pressure. Yield: 13.2 g=100% (crude)
Reaction SMILES: BrBr.[OH-:3].[Na+].[CH3:5][C:6]1([CH3:22])[C@@H:8]([C:9](=[O:11])C)[C@@H:7]1[CH:12]=[C:13]([Cl:21])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>O.O1CCOCC1>[CH3:22][C:6]1([CH3:5])[C@@H:8]([C:9]([OH:11])=[O:3])[C@@H:7]1[CH:12]=[C:13]([Cl:21])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: CC(=O)[C@H]1[C@H](C=C(Cl)c2ccc(Cl)cc2)C1(C)C
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)[C@@H](C=C(Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)O
Reaction time: 3 h
Yield: 75 %

Procedure:
13.8 g of bromine were added dropwise to a solution of 11.5 g of sodium hydroxide in 60 ml of water at 5°-10° C., and a solution of 8.1 g (0.029 mol) of trans-3,3-dimethyl-2-(2-chloro-2-(4-chloro-phenyl)-vinyl)-1-acetylcyclopropane in 30 ml of dioxane was then added dropwise at 0°-5° C. The mixture was subsequently stirred for 3 hours, without cooling, pouredonto 250 ml of water and extracted twice with 50 ml of ether each time. The aqueous phase was freed from adhering ether in vacuo and then brought to pH 2 by adding aqueous hydrochloric acid. After crystallization, the product was filtered off and rinsed with water. 6.2 g (77% of theory) of trans-3,3-dimethyl-2-(2-chloro-2-(4-chlorophenyl)-vinyl)-cyclopropanecarboxylic acid were thus obtained in the form of pale yellow-colored crystals with a melting point of 103°-106° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH:18]([CH2:23][CH3:24])[C:19]([O:21][CH3:22])=[O:20]>>[C:15]([C:7]1[C:8]([C:11]([F:12])([F:14])[F:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH:18]([CH2:23][CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:2]([CH3:1])=[CH:10]2)#[N:16]
Reactant: CCC(Br)C(=O)OC
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CCC(C(=O)OC)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized in a manner similar to Example 1 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and methyl 2-bromobutanoate: MS (ESI): m/z 325 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:23])[N:7]([CH:14]([CH2:18][CH2:19][C:20](=[O:22])[NH2:21])[C:15]([OH:17])=[O:16])[C:8]2=[O:13])([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:23])[N:7]([CH:14]([CH2:18][CH2:19][C:20](=[O:22])[NH2:21])[C:15]([OH:17])=[O:16])[C:8]2=[O:13]
Reactant: [H][H]
Reactant: NC(=O)CCC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: NC(=O)CCC(C(=O)O)N1C(=O)c2cccc(N)c2C1=O

Procedure:
A mixture of 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid (5 mmol) and 10% Pd/C (250 mg) in dimethylformamide is hydrogenated under 60 psi of hydrogen in a Parr Type Shaker to afford 2-(4-amino-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[O-:2].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O+]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:30]([C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].NC1C=CC=CC=1>C(O)C>[S:1](=[O:3])(=[O:2])([OH:5])[O-:4].[CH2:30]([C:44]1[CH:45]=[CH:46][C:47]([N+:48]2[C:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:14]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:49][CH:50]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCCCc1ccc(N)cc1
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Agent: O=S(=O)([O-])O
Solvent: Nc1ccccc1
Solvent: CCO
Product: CCCCCCCCCCCCCCc1ccc(-[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)cc1
Temperature: 90 °C
Yield: 21 %

Procedure:
In a 500-ml round-bottom flask is placed 2.03 g (0.005 mole) of 2,4,6-triphenylpyrylium bisulfate. To this is added 150 ml of ethanol followed by 2.90 g (0.01 mole) of p-tetradecylaniline. This mixture is heated at 90° C. for about 8 hours and then allowed to cool. Upon cooling some of the starting aniline separates and is removed by filtration. The ethanol is then removed to give a yellow waxy substance which is rinsed with ether to remove any excess pyrylium. The resulting product is then dissolved in acetonitrile to remove any aniline still present. The acetonitrile is then stripped and the product is rinsed a final time with ether. The final product is a yellow crystal which turns a pale yellow color upon grinding. The yield is 0.71 g (0.00105 mole) of N-(p-tetradecylphenyl)-2,4,6-triphenylpyridinium bisulfate (yield 21 percent).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([CH3:29])=[N:11][N:12]([C:19]3[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]([CH3:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:31][C:32]2[CH:33]=[C:34]([CH3:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=2)[C:9]2[C:10]([CH3:29])=[N:11][N:12]([C:19]3[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C)nn1-c1cnc(OC)nc1OC
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1c(C(Nc2cc(C)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C)nn1-c1cnc(OC)nc1OC

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-1H-pyrazole-5-carboxylate (Step 52.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.74 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 553 [M+H]+ (LC-MS 2); Rf=0.55 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.99 min; [M+H]+=393.41.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1[O:23][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6](=[O:7])[NH:8][C:9]2=[O:10]
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(Oc2cc3c(cc2[N+](=O)[O-])C(=O)NC3=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 4-chloro-5-nitrophthalimide (1.05 g, 4.4 mmol), methyl 2-(3-chloro-4-hydroxyphenyl)acetate (821 mg, 4.4 mmol) and potassium carbonate (1.34 g, 9.7 mmol) in 10 mL of DMSO was allowed to stir at 25° C. for 22 h. Upon completion, the mixture was added to 50 mL of water. The resulting mixture was extracted with ethyl acetate (2×30 ml,). The combined extracts were washed with water (2×30 mL) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on a silica gel column using 20% EtOAc/hexane as the eluent to give methyl 2-(3-chloro-4-(6-nitro-1,3-dioxoisoindolin-5-yloxy)phenyl)acetate (30.1). MS ESI (pos.) m/e calcd for (M+H)+ 391.0. found 391.0.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:17][CH:16]=2)[CH2:6][CH:5]1[CH3:40])(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][OH:22])=[CH:19][CH:20]=2)[CH2:6][CH:5]1[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2C(Nc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)CC1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)N1c2ccccc2C(Nc2ccc(CO)cc2)CC1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[Step 3] 615 mg of 1-acetyl-4-[(4-tert-butyldiphenylsilyloxymethylphenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 2 mL of tetrahydrofuran, and 2.8 mL of tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) was added to the solution. The mixture was stirred for 3 hours at room temperature. After completion of the reaction, the reaction liquid was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate solution and saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (developing solvent: ether only), and thus 264 mg)(79° of 1-acetyl-4-[(4-hydroxymethylphenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was obtained as a yellow oily substance (cis:trans=3:1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:16]([OH:18])=[O:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1>>[CH:19]1([C:2]2[CH:3]=[CH:4][C:5]([C:16]([OH:18])=[O:17])=[N:6][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:21][CH2:20]1
Reactant: OB(O)C1CC1
Reactant: O=C(O)c1ccc(Br)c(OCc2ccccn2)n1
Product: O=C(O)c1ccc(C2CC2)c(OCc2ccccn2)n1

Procedure:
The title compound was synthesized in analogy to Example 42 a, using 5-bromo-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid and cyclopropylboronic acid (CAN 411235-57-9) as starting materials, LC-MS (UV peak area/ESI) 100%, 271.1081 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=3)=[N:12]2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]=[C:43]=[S:44])([CH3:35])[CH3:34]>ClCCl>[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43]([NH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:14]=[CH:15][N:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]([F:2])([F:24])[F:25])=[CH:10][CH:9]=3)[N:12]=2)=[CH:17][CH:18]=1)=[S:44])([CH3:35])[CH3:34]
Reactant: NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1ccccc1N=C=S
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1NC(=S)NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
In a 100 mL flask, to a solution of (4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl) methanamine hydrochloride (0.200 g, 0.598 mmol) in dichloromethane (5 mL) was added triethylamine (0.0720 g, 0.718 mmol) and 1-isopropyl-2-isothiocyanatobenzene (0.106 g, 0.598 mmol) in dichloromethane (5 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue purified by flash column chromatography eluting with 10-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent to give the title compound as a white solid (0.145 g, 48%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[N:10]1([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: CCO
Product: c1ccc(CN2CCCC2)nc1
Temperature: 90 °C
Yield: 94 %

Procedure:
With stirring and external cooling with ice, a solution of 2-(chloromethyl)pyridine hydrochloride (100 g, 0.61 mol) in 95% ethanol (600 ml) is added dropwise to pyrrolidine (500 ml, 426 g, 5.99 mol) and the resulting mixture is heated to 90° C. for 1 hour. After cooling, the mixture is suction filtered, the filter residue is thoroughly washed with ether, the filtrate is concentrated in vacuo and the residue is made strongly alkaline with 40% potassium hydroxide solution. It is extracted exhaustively with ether, the extracts obtained are freed from solvent and the remaining residue is distilled in vacuo. The desired compound (93.0 g) is obtained. Boiling point 19 mm Hg 118°-121° C.
Reaction SMILES: [OH-].[K+].O.NN.[CH3:6][CH:7]([CH3:15])[C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=O>C(O)COCCO.O>[CH2:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH:7]([CH3:15])[CH3:6]
Reactant: CC(C)C(=O)c1cccs1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CC(C)Cc1cccs1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
To a mixture of potassium hydroxide (2.24 g, 40 mmol) and hydrazine monohydrate (3.0 g, 60 mmol) in diethylene glycol (25 ml) was added 2-methyl-1-thiophen-2-yl-propan-1-one (1.54 g, 10 mmol). The combined mixture was heated at 180° C. for 1 h and then at 210° C. for a further 2 h. The mixture was cooled to rt and diluted with water (100 ml) and extracted with diethyl ether (3×). The combined organic extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield a yellow oil: 0.9 g (61%) GC-MS: M=140.0.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[N:38][C:39]([O:42][CH2:43][CH3:44])=[N:40][CH:41]=1>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:37]=[N:38][C:39]([O:42][CH2:43][CH3:44])=[N:40][CH:41]=2)[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOc1ncc(Br)cn1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Product: CCOc1ncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cn1
Yield: 62 %

Procedure:
The title compound was synthesized as described for Intermediate example I-28 in 62% yield starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)chroman-3-amine and 5-bromo-2-ethoxypyrimidine. The reaction mixture was irradiated in a microwave at 140° C. for 20 min; MS (ESI) m/z 452[M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br)=[CH:4][CH:3]=1.[CH3:17][C@H:18]1[O:23][C@@H:22]([CH3:24])[CH2:21][NH:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:20]2[CH2:19][C@H:18]([CH3:17])[O:23][C@H:22]([CH3:24])[CH2:21]2)=[CH:4][CH:3]=1
Reactant: BrCCCCCCCOc1ccc(Br)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(CCCCCCCOc2ccc(Br)cc2)C[C@H](C)O1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 1-bromo-4-(7-bromoheptyloxy)benzene (4.405 g), cis-2,6-dimethylmorpholine (1.55 ml) and potassium carbonate (2.09 g) in N,N-dimethylformamide (22 ml) was stirred for 1 hour at 70° C. To the reaction mixture was added cis-2,6-dimethylmorpholine (7.75 ml) and stirred for 1 hour at 70° C. Ethyl acetate (100 ml) was added, and the mixture washed with water (50 ml×2) and brine. The separated organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a crude pale yellow oil (5.30 g). The crude oil was purified by silica gel chromatography (20:1-1:2 hexane-ethyl acetate) to give 4-[7-(4-bromophenoxy)heptyl]-cis-2,6-dimethylmorpholine (4.43 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CSc1cccc(OC)c1)c1ccc(OC)cc1
Agent: Cl
Product: COc1ccc(C(CSc2cccc(OC)c2)C(=O)O)cc1

Procedure:
A process for preparing a compound of formula (6): ##STR120## characterized in that a compound of formula (1): ##STR121## is reacted with oxalic acid diethyl ester and sodium hydride to produce a compound of formula (2): ##STR122## the resulting compound of formula (2) is reacted with 3-methoxybenzenethiol represented by the formula: ##STR123## to produce a compound of formula (3): ##STR124## the resulting compound of formula (3) is reacted with hydrochloric acid to produce a compound of formula (4): ##STR125## the compound of formula formula (4) is then cyclized to produce a compound of formula (5): ##STR126## and the compound of formula (5) is reacted with methyl iodide in the presence of lithium diisopropylamide to produce the compound of formula (6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]#[N:29].[CH3:30][C:31]([CH3:33])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([C:20]3[CH2:21][CH2:22][N:23]([CH:31]([CH3:33])[CH3:30])[CH2:24][CH:25]=3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]#[N:29]
Reactant: CC(C)=O
Reactant: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1C1=CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1C1=CCN(C(C)C)CC1
Temperature: 55 °C
Reaction time: 6 h
Yield: 54.5 %

Procedure:
To a solution of 4-(2-fluoro-4-methylphenylamino)-7-methoxy-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline-3-carbonitrile (Method 88, 200 mg, 0.51 mmol) in dichloroethane (5 mL), acetone (0.566 mL, 7.70 mmol), and acetic acid (0.147 mL, 2.57 mmol) was added sodium triacetoxyborohydride (544 mg, 2.57 mmol) and the reaction stirred at 55° C. for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue purified with silica chromatography (MeOH/EtOAc (1:1)) to give 120 mg (50%) product. m/z 432.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([CH3:37])[CH:28]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([CH3:37])[CH:28]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.6 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.15 g) in dichloromethane (3 ml) was added TFA (3 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a light brown solid (0.064 g, 25%). MS (ISP) 490.1 [(M+H)+]; mp 242° C.