Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].C([O:8][C:9](=O)[C:10]([CH3:14])([CH3:13])[CH2:11][CH3:12])C>O1CCCC1.Cl>[CH3:13][C:10]([CH3:14])([CH2:11][CH3:12])[C:9](=[O:8])[CH2:4][C:3]#[N:5]
Reactant: CC#N
Reactant: CCOC(=O)C(C)(C)CC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)CC#N
Temperature: 60 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
A suspension of sodium hydride (60% dispersion in mineral oil, 3.18 g, 79.4 mmol) in tetrahydrofuran (60 mL) was heated at 60° C. for 1 hour. The reaction mixture was then cooled to room temperature, acetonitrile (4.2 mL, 79.4 mmol) and 2,2-dimethyl-butyric acid ethyl ester [(7.95 g, 61 mmol), J. Am. Chem. Soc., 1942, 64, 2964] in tetrahydrofuran (100 mL) were added and the mixture was stirred for 4 hours at 25° C. The mixture was then diluted with 1M hydrochloric acid (100 mL) and the aqueous layer was separated and extracted with ethyl acetate. The organic solution was then dried over magnesium sulfate, concentrated in vacuo and the residue was triturated with heptane to afford the title compound as a pale brown solid in 27% yield, 2.3 g.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[C@H:15]([CH2:16][CH2:17][OH:18])[O:14][CH2:13][CH2:12][C:11]=3[CH:19]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CS(OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1)(=O)=O>>[CH3:20][S:21]([O:18][CH2:17][CH2:16][C@H:15]1[C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[CH:19][C:11]=2[CH2:12][CH2:13][O:14]1)(=[O:23])=[O:22]
Reactant: OCC[C@@H]1OCCc2cc(N3CCSCC3)ccc21
Reactant: CS(=O)(=O)Cl
Agent: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Product: CS(=O)(=O)OCC[C@@H]1OCCc2cc(N3CCSCC3)ccc21

Procedure:
Prepared from 2-[(1S)-6-(4-thiomorpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethanol and methanesulfonyl chloride, as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:24]1[CH2:25][CH2:26][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23]1)=[O:15]
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 3-phenyl-pyrrolidine (31.6 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1539.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]2=[O:22])=[CH:11][C:10]=1[F:23])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[F:23][C:10]1[CH:11]=[C:12]([N:15]2[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]2=[O:22])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1O[C@@H](CO)CN1c1ccc(O)c(F)c1
Yield: 69.6 %

Procedure:
A solution of (R)-3-(4-benzyloxy-3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (6.34 g, prepared according to WO 2004/096221) in THF/MeOH (1:1; 200 mL) was hydrogenated over Pd/C 10% (1 g) overnight. The catalyst was filtered off, the filtrate evaporated under reduced pressure and the residue stirred in EA. The crystals were collected by filtration, affording 3.16 g (70% yield) of a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>[Cu].ClC1C=CC=CC=1Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[N:6]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:5]3=[O:19])=[CH:23][CH:22]=1
Reactant: Clc1ccc(I)cc1
Reactant: Nc1ccc2c(c1)C(=O)N(Cc1cccnc1)C2=O
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccc(Nc3ccc(Cl)cc3)cc2C(=O)N1Cc1cccnc1
Yield: 49.5 %

Procedure:
A mixture of 260 mg of 5-amino-2-(3-pyridylmethyl)-1H-isoindole-1,3-(2H)-dione, 296 mg of 1-chloro-4-iodobenzene, 131 mg of copper dust, 54 mg of 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane), 569 mg of potassium carbonate and 4 ml of 1,2-dichlorobenzene was refluxed under heating for 1 hour. After finishing the reaction, the insoluble material was filtered off, and the filtrate was concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with chloroform and methanol (20:1) to give 185 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH2:11][CH3:12])=[C:5]([CH3:13])[N:4]=1>CO.Cl.[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][NH2:10])=[CH:7][C:6]([CH2:11][CH3:12])=[C:5]([CH3:13])[N:4]=1
Reactant: CCc1cc(C#N)c(OC)nc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCc1cc(CN)c(OC)nc1C
Reaction time: 15 h
Yield: 89.1 %

Procedure:
A solution of 2-methoxy-3-cyano-5-ethyl-6-methylpyridine (344 mg, 1.95 mmol) in methanol (8 mL) and 4.9M methanolic HCl (5 mL) containing 5% palladium on carbon (100 mg) was hydrogenated at atmospheric pressure for 10-20 hours. The catalyst was filtered off and the solvent evaporated. This residue was made basic with sodium hydroxide and the product was extracted into methylene chloride, dried (Na2SO4), filtered and evaporated to give 313 mg (89% yield) of oily product.
Reaction SMILES: [CH3:1][C:2]12[CH:10]([CH:11]([CH3:23])[CH:12]=[CH:13][CH2:14][C:15]3([CH3:22])[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]3)[CH2:9][CH2:8][CH:7]1[CH:6]([OH:24])[CH2:5][CH2:4][CH2:3]2.C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1C1C=CC=C[NH+]=1.[Cr](Cl)([O-])(=O)=O.C(O)(C)C>C(Cl)Cl.O>[CH3:1][C:2]12[CH:10]([CH:11]([CH3:23])[CH:12]=[CH:13][CH2:14][C:15]3([CH3:22])[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]3)[CH2:9][CH2:8][CH:7]1[C:6](=[O:24])[CH2:5][CH2:4][CH2:3]2
Reactant: CC(C=CCC1(C)COC(C)(C)O1)C1CCC2C(O)CCCC12C
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: CC(C=CCC1(C)COC(C)(C)O1)C1CCC2C(=O)CCCC21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.145 g of [1R-(1R*,2E,S*),1β,3aα,7aβ]-octahydro-7a-methyl-1-[1-methyl-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-2-butenyl]-4H-inden-4-ol in 9 ml of dry methylene chloride was treated with 0.250 g of anhydrous sodium acetate and 0.500 g of 2,2'-bipyridinium chlorochromate and the mixture stirred at room temperature for two hours. After this time, an additional 0.250 g of 2,2'-bipyridinium chlorochromate was added and the stirring continued for two more hours. After this time, 0.5 ml of isopropyl alcohol was added and the mixture stirred for 15 minutes, then diluted with water, and extracted with 3×50 ml of ether. The combined organic phases were washed with water, dried and evaporated to dryness. The residue obtained was purified by chromatography on silica gel, eluting with hexane-ethyl acetate (3:1) to give 0.134 g (93%) of pure [1R-(1R*,2E,S*),1β,3 aα,7aβ]-octahydro-7a-methyl-1-[1-methyl-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-2-butenyl]-4H-inden-4-one, [α]D25 (c 0.2, ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:35][CH2:36][CH2:37][S:38]([OH:41])(=[O:40])=[O:39]>CN(C=O)C>[C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:35][CH2:36][CH2:37][S:38]([OH:41])(=[O:40])=[O:39])=[CH:27][CH:28]=2)=[O:30])[C@@H:14]([CH3:31])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: O=S(=O)(O)CCCCl
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCS(=O)(=O)O)cc2)c2ccccc21

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (207 mg, 0.481 mmol) was dissolved in DMF (5 mL) at room temperature. NaH (58 mg, 2.40 mmol) was added followed by 3-chloro-propane-1-sulfonic acid (sodium salt, 135 mg, 0.60 mmol) and the reaction was allowed to stir over night. The mixture was partitioned between methylene chloride and HCl (1.0N/water), then extracted three times with methylene chloride, dried over MgSO4, filtered and concentrated. The crude residue was purified by preparatory HPLC to afford the product.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:27](=[O:28])([O:17][CH2:16][C:3]1([Si:2]([CH3:19])([CH3:18])[CH3:1])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)C1(CO)c2ccccc2-c2ccccc21
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: C[Si](C)(C)C1(COC(=O)Nc2ccccc2)c2ccccc2-c2ccccc21
Temperature: 80 °C
Yield: 91.9 %

Procedure:
A mixture of 1.0 g of 9-trimethylsilyl-9-fluorenemethanol and 0.4 mL of phenyl isocyanate in 2.0 mL of dry benzene was heated in an oil bath at 80° C. for seven hours. The mixture was cooled to room temperature and triturated with 20 mL of Skelly F. The crystals deposited were removed by filtration, rinsed with Skelly F, and recrystallized from Skelly B to give 1.31 g (91.9%) of the urethane as white crystals, m.p. 137°-138° C.; IR(KBr): 3300 (NH), 1700 (C=O) cm-1 ; 1H NMR (CDCl3) 5 -0.12 (s, 9H, SiMe3), 5.07 (s, 2H, CH2), 6.21 (b, 1H, NH), 6.80-8.00 (m, 13H, aryl).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Br:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[Br:21][CH2:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:26]=[CH:27][CH:28]=1
Reactant: BrCc1cccc(CBr)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of di-isopropylamine (4.04 g) and butyl-lithium (25 ml, 160 M in hexane) in dry tetrahydrofuran (40.0 ml), stirred at -78° under dry nitrogen, was treated over 5 minutes with t-butyl acetate (4.64 g). To this solution was added, over 5 minutes, a solution of α,α'-dibromo-m-xylene (11.60 g) and dry hexamethyl phosphoramide (1.42 g) in dry tetrahydrofuran (8.0 ml). The resulting yellow solution was stirred at -78° for 1/2 hour, then allowed to warm to room temperature over 3 hours. Excess ice-water was added, and the mixture extracted with ether, and the extract washed with 1N hydrochloric acid (60 ml) then water. The dried extract was concentrated in vacuo, to give a yellow oil which was purified by column chromatography on silica, eluting with 1:1 ether:hexane, giving t-butyl 3-(3-bromomethylphenyl)propionate as a colourless oil. Using the method described in the last foregoing paragraph this was converted to the desired diethylester which was used in each of Examples 22 to 25.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH:7]([C:9]1[N:14]=[N:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:11][CH:10]=1)[CH3:8])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]1[N:14]2[C:9]([CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:13]2)=[C:7]([CH3:8])[N:6]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccccc3F)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccccc4F)n3n2)cc1
Yield: 37.1 %

Procedure:
Applying the Cyclization Procedure 1, using 2-fluoro-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 64) (100 mg, 0.27 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.20 mL, 2.14 mmol), to afford 7-(2-fluorophenyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (35 mg) as a yellow solid. MS m/z 350 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[CH3:19])(=O)C.[OH-].[K+]>O>[OH:4][C:5]1[C:6]([CH3:19])=[C:7]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:18])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1cccc(C(=O)c2ccccc2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(O)cccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
A mixture of 3-benzoyl-2-methylphenyl acetate prepared as in Step 1 (6.85 g, 26.9 mmole) and KOH (15.0 g, 267 mmole) in H2O (100 mL) was stirred at room temperature for 18 h. The aqueous mixture was then washed with ethyl ether (3×200 mL), cooled to 0° C. and acidified with con. HCl. The resulting solid was filtered, washed with H2O and dried in vacuo to give 0.99 g (17% yield) of the product as an off-white crystalline solid: EIHRMS m/z 212.0829 (M+, C14H12O2, Calc'd 212.0837).
Reaction SMILES: C([O:5][C:6]1[C:18]([F:19])=[CH:17][C:9]([C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])=[C:8]([F:20])[CH:7]=1)(C)(C)C.Cl>O1CCOCC1>[F:20][C:8]1[CH:7]=[C:6]([OH:5])[C:18]([F:19])=[CH:17][C:9]=1[C:10]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])=[O:11]
Reactant: CC(C)(C)Oc1cc(F)c(C(=O)NS(C)(=O)=O)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)NC(=O)c1cc(F)c(O)cc1F
Reaction time: 3 h
Yield: 97.3 %

Procedure:
4-tert-Butoxy-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 17, 1.76 g, 5.73 mmol) was added to hydrochloric acid solution in dioxane (4 M, 30 mL) at room temperature and stirred for 3 hours. The solvent was then evaporated and the resulting residue dissolved in DCM. The solvent was evaporated again to yield the title compound as a white solid (1.4 g, 100%), which was used in the next stage without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH2:18][CH:17]3[C:23]([O:25]CC2C=CC([N+]([O-])=O)=CC=2)=[O:24])(=[O:13])=[O:12])[CH2:8][CH2:7][N:6]1[C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=1)=[O:4].C1CCC=CC=1.C(O)C>[Pd].CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][N:9]([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH2:18][CH:17]3[C:23]([OH:25])=[O:24])(=[O:13])=[O:12])[CH2:8][CH2:7][N:6]1[C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:38][N:37]=1)=[O:4]
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccc3c(c2)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC3)CCN1c1ccc(C(F)(F)F)cn1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCC=C1
Solvent: CO
Product: COC(=O)[C@H]1CN(S(=O)(=O)c2ccc3c(c2)C(C(=O)O)CC3)CCN1c1ccc(C(F)(F)F)cn1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
4-[3-(4-Nitro-benzyloxycarbonyl)-indane-5-sulfonyl]-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methyl ester (87 mg, 0.14 mmol) obtained from step 4 was combined with 10% Pd/C (75 mg), cyclohexadiene (260 μL, 2.8 mmol) and 2.0 mL of ethanol within an 8 mL Teflon-capped vial. This mixture was stirred at 70° C. for 6 h and then passed through a Celite plug (with MeOH washings). The resulting filtrate was evaporated in vacuo, and the crude residue was purified using flash silica chromatography (0-10% MeOH/CH2Cl2) to yield (R)-4-(3-Carboxy-indane-5-sulfonyl)-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methyl ester. 1H NMR (400M Hz, CD3OD) δ 8.37 (m, 1H), 7.85 (s, 1H), 7.80 (d, 1H), 7.69 (d, 1H), 7.52 (d, 1H), 6.94 (d, 1H), 5.55 (m, 1H), 4.33-4.29 (m, 1H), 4.20-4.11 (m, 2H), 3.84-3.81 (m, 1H), 3.74 (s, 3H), 3.47-3.41 (m, 1H), 3.20-3.14 (m, 1H), 3.07-2.99 (m, 1H), 2.65-2.61 (m, 1H), 2.51-2.42 (m, 3H). ESMS (M+H): 514.0
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:18]=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:10]=3[N:11]=[C:12]([C:14]#[N:15])[N:13]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[N:11]=[C:12]([C:14]#[N:15])[N:13]=2)=[CH:4][C:3]=1[C:29]([F:30])([F:31])[F:32]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(F)c(C(F)(F)F)c4)nc(C#N)nc32)cc1
Solvent: CC(=O)N(C)C
Product: N#Cc1nc(-c2ccc(F)c(C(F)(F)F)c2)c2cc[nH]c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Tris(dimethylamino)sulfonium difluorotrimethylsilicate (239 mg) was added to a mixture of 4-[4-fluoro-3-(trifluoromethyl)phenyl]-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (200 mg) and DMAc (3 mL), and the mixture was stirred at 100° C. for 1 hour under microwave irradiation. After the reaction mixture was cooled to room temperature, the reaction mixture was purified by silica gel column chromatography (Hex:EtOAc=98:2 to 60:40), whereby 4-[4-fluoro-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (81 mg) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].C(Cl)Cl>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2cc[nH]c2cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)NCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5,6-dimethoxyindole (2.00 g, 11.29 mmol) in acetic acid (120 mL), sodium cyanoborohydride (2.13 g, 33.86 mmol) was added in portions (slightly exothermic). After stirring at rt for 1 h, DCM was added and the org. layer was washed with sat. NaHCO3-solution and brine. The org. layer was dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 5,6-dimethoxyindoline as a brown solid, which was stored in the freezer until it was used in step 4. LC-MS conditions B: tR=0.28 min, [M+H]+=180.23.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[N:30]=[CH:31][S:32][C:33]=1[CH3:34]>>[CH3:28][C:29]1[N:30]=[C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:24])[CH3:25])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:4][CH:3]=2)[S:32][C:33]=1[CH3:34]
Reactant: Cc1ncsc1C
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1nc(-c2ccc(C(C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)sc1C

Procedure:
The title compound was prepared from 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 4,5-dimethyl-thiazole following a procedure analogous to that described in Example 180. Mass spectrum (ESI+): m/z=465 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([O:25][CH2:26][C:27]([NH2:29])=[O:28])=[CH:14][CH:13]=2)(C)(C)C.[ClH:36]>C(OCC)(=O)C>[ClH:36].[NH2:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([O:25][CH2:26][C:27]([NH2:29])=[O:28])=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(OCC(N)=O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(OCC(N)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of tert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.24 g, 0.5 mmol) in ethyl acetate (5 mL) was added a solution of 4N hydrogen chloride in ethyl acetate (5 mL) and the obtained solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diethyl ether to give 2-[[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy]acetamide hydrochloride (0.19 g, 95.0%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[N:3]=1.[C:15]([CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:15]([CH:19]1[CH2:24][CH2:23][C:22]2([O:14][CH:11]([CH2:10][NH:9][C:4]3[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:12][O:13]2)[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: Cc1cc(C)nc(NCC(O)CO)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1cc(C)nc(NCC2COC3(CCC(C(C)(C)C)CC3)O2)n1
Yield: 90 %

Procedure:
3-(4,6-dimethylpyrimid-2-ylamino)-propane-1,2-diol (4.0 g, 20 mmol), 4-t-butyl cyclohexanone (3.08 g, 20 mmol) and p-toluenesulfonic acid (4.3 g, 22 mmol) in 50 ml benzene were refluxed on a water trap for 1 hour. The reaction mixture was washed twice with saturated aqueous sodium carbonate (50 ml), dried with magnesium sulphate and evaporated in vacuum. Kugelrohr- distillation of the resulting oil yielded 6.0 g of a colourless oil (b.p. 200° C./0.2 mbar) which was recrystallised from light petroleum to yield 5.0 g of colourless crystals (m.p. 121°-124° C.). GLC-MS analysis indicates an approximately 1:1 mixture of diastereoisomers (cis/trans).
Reaction SMILES: BrC1S[C:5]([C:7]([NH:9][CH:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:14][CH:13]=2)[CH3:11])=[O:8])=[CH:4][CH:3]=1.NC(C1N=NC(NC2C=CC(OC)=CC=2)=NC=1)C.[S:45]1C=CC(C(O)=O)=[CH:46]1>C(OCC)(=O)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:15]2[N:16]=[N:17][C:12]([CH:10]([NH:9][C:7]([C:5]3[CH:4]=[CH:3][S:45][CH:46]=3)=[O:8])[CH3:11])=[CH:13][N:14]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccsc1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccc(Br)s3)nn2)cc1
Agent: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccsc3)nn2)cc1
Reaction time: 3 h

Procedure:
In a similar manner as described for Intermediate 48, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 3-thiophenecarboxylic acid (57 mg, 0.45 mmol). Except, that after 3 hours, the crude reaction mixture was diluted with ethyl acetate and washed twice with dilute aqueous hydrochloric acid (0.2 N) followed by saturated sodium bicarbonate solution. The organic layer was separated, dried with magnesium sulfate, filtered, reduced and then purified by chromatography on silica gel eluting with 40% ethyl acetate, in petrol to afford N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-3-thiophenecarboxamide (95 mg) as a yellow solid. MS m/z 356 (M+1).