Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1>CN(C)C(=O)C>[F:23][C:22]([F:25])([F:24])[C:18]1[CH:17]=[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Nc1ccc(O)cc1
Reactant: Fc1ccnc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Temperature: 20 °C
Yield: 79.5 %

Procedure:
A cold (−5° C.), de-gassed solution of 4-aminophenol (41.6 g, 0.38 mol) in N,N-dimethylacetamide (250 mL) was treated with potassium tert-butoxide and stirred while warming to 20° C. A solution containing 4-fluoro-2-trifluoromethylpyridine (60 g, 0.36 mol) in dimethylacetamide (150 mL) was slowly added and the mixture was stirred at 25° C. for 18 h. The reaction mixture was then concentrated in vacuo and the residue was added to vigorously stirred water (1 L). The precipitated solids were collected by suction filtration and washed with isopropanol/ether (1:1) followed by ether and hexane. The yellow tan solids were dried to afford 72.8 g (79%) of product. 1H NMR (DMSO-d6) δ 5.20 (s, 2H, —NH2), 6.62 (m, 2H), 6.86 (m, 2H), 7.04 (dd, 1H, J=5.6, 2.4 Hz), 7.24 (d, 1H, J=2.4 Hz), 8.54 (d, 1H, 5.7 Hz). MS ES 255 (M+H)+, calcd 255, RT=1.66 min.
Reaction SMILES: OS(C(F)(F)F)(=O)=O.[C:9](=[NH:32])([O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[CH:16][CH:15]=1)[NH2:10].[CH:33]([CH:35]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36](OCC)=O)=[O:34].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][O:11][C:9]3[NH:10][CH:36]=[C:35]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:33](=[O:34])[N:32]=3)=[CH:19][CH:18]=2)=[CH:22][C:23]=1[C:28]([F:31])([F:30])[F:29]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)C(C=O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1ccccc1
Temperature: 160 °C
Yield: 39.8 %

Procedure:
The mixture of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate triflate (120 mg, 0.236 mmol), ethyl 2-formyl-3-phenylpropanoate (122 mg, 0.591 mmol) and K2CO3 (98 mg, 0.709 mmol) in DMA (5 mL) was heated with a microwave reactor at 160° C. for 1 hour. Purification via MDAP then afforded the title compound as an off-white solid (47 mg, 39.7% yield). LCMS: rt=4.08 min, [M+H+]=501.2
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6](Cl)=[O:7])#[N:2].[CH3:15][N:16]([CH3:24])[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([C:18](=[CH:17][N:16]([CH3:24])[CH3:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:7])#[N:2]
Reactant: CCOC(=O)C=CN(C)C
Reactant: N#Cc1c(F)c(F)cc(C(=O)Cl)c1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)c(C#N)c1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 55 g of 3-cyano-2,4,5-trifluoro-benzoyl chloride in 50 ml of toluene is added dropwise to a solution of 36,5 g of ethyl 3-dimethylamino-acrylate and 26,5 g of triethylamine in 140 ml of toluene at a temperature between 50 and 55° C. After stirring at 50° C. for 2 hours the reaction mixture is concentrated in vacuo. The crude product is used for the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[OH-].[Na+]>FC(F)(F)C(O)=O.CCOCC.[Pt]=O>[NH:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=[Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)C1CC2CCCCC2N1

Procedure:
Dissolve 27.0 g of ethyl indole-2-carboxylate in 250 ml of trifluoroacetic acid. Add 2.05 g of platinum oxide, hydrogenate the mixture at 50 lb/in2 at room temperature. Filter the mixture and concentrate the filtrate in vacuo to give a residue. Suspend the residue in ether and treat with cold dilute sodium hydroxide solution. Dry the organic layer over magnesium sulfate and concentrate it to give ethyl octahydroindole-2-carboxylate, a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18]Br)[CH3:15].[OH-].[K+]>CS(C)=O.O>[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH3:15]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(COc1ccc(-c2ccccc2)cc1)OCC
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A mixture of 4-phenylphenol (5 g, 29.4 mmol), bromoacetaldehyde diethyl acetal (4.56 mL, 29.4 mmol) and KOH (1.94 g, 29.4 mmol) in DMSO (15 mL) was stirred at reflux for 6 h. The reaction mixture was allowed to cool down to room temperature and poured over ice containing 0.60 g of KOH and diluted to 100 mL with water. The solution was extracted with Et2O (20 mL×3); the combined extracts were washed with 1N NaOH solution, water and brine, dried, and concentrated under reduced pressure to yield 7.97 g (94%) of a yellow oil that was used without further purification: 1H NMR (400 MHz, CDCl3) δ 7.56-7.50 (m, 4H), 7.41 (t, 2H), 7.30 (t, 1H), 7.00 (dt, 2H), 4.86 (t, 1H), 4.05 (d, 2H), 3.82-3.74 (m, 2H), 3.69-3.62 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14]CC)=[O:13])=[C:7]2[N:17]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][CH3:32])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH3:18].[OH-].[Na+].CO>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[C:7]2[N:17]([S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]#[C:31][CH3:32])=[CH:26][CH:27]=1)(=[O:20])=[O:21])[CH3:18]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(C(=O)OCC)cnc3c(Br)cccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(C(=O)O)cnc3c(Br)cccc23)cc1
Yield: 79.7 %

Procedure:
Ethyl 8-bromo-4-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-3-quinolinecarboxylate (0.52 g, 1.0 mmol), the product of Example 97, was treated with 1 N aqueous sodium hydroxide (1.1 mL) in 1:1 methanol:water (6 mL) to give 0.390 g of 8-bromo-4-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-3-quinolinecarboxylic acid as an off-white powder. Electrospray Mass Spec 489 and 490.9 (M+H)+
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[C:13]([OH:15])=[O:14].[OH-].[K+].O>CC(C)=O>[CH3:1][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:3])[C:9]([C:13]([OH:15])=[O:14])=[CH:10]1
Reactant: Cc1cccc2c(C(=O)O)c[nH]c12
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc2c(C(=O)O)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
Methyl iodide (30 g) was added to a stirred mixture of 7-methylindole-3-carboxylic acid (4.3 g) and powdered potassium hydroxide (20 g) in anhydrous acetone at 0° C. The resulting suspension was then stirred at room temperature overnight, then poured into water (500 ml), washed with dichloromethane (3×100 ml) and the aqueous phase acidified to pH 2 with hydrochloric acid. The product was isolated by filtration and dried under vacuum to afford white crystals (4.5 g); m.p. 243° C.; 6 H (360MHz, DMSO-d6) 2.72 (3 H, s, CH3), 4.09 (3 H, s, NCH3), 6.92 (1 H, d, J=6 Hz, H-6), 7.02 (1 H, t, J=6 Hz, H-5), 7.87 (1 H, d, J=6, H-4), 7.92 (1 H, s, H-2); m/z 189 (M+ , 100%), 172 (40), 144 (30), 91 (55).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CCCCCC.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>S(=O)(=O)(O)O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: Oc1ccc(I)cc1
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: Ic1ccc(OC2CCCCO2)cc1
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
4-Iodophenol 10.0 g (45.5 mmol) was dissolved in 20 mL 3,4-dihydro-2H-pyran, then one drop of concentrated sulfuric acid was added, the reaction mixture was stirred for 30 min, then the mixture was poured into 1000 mL of n-hexane, filtered, washed with 300 mL (100 mL×3) hexane, and dried in vacuum to afford the desired product as a white solid (9.1 g, 65.9%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([S:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccccc1S
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1Sc1ccc(C=O)c(Cl)c1Cl
Temperature: 50 °C
Yield: 84.5 %

Procedure:
2,3-Dichloro-4-trifluoromethanesufonyloxy-benzaldehyde (2.50 g) was dissolved in 6 mL acetonitile. 2-Methoxybenzenethiol (2.55 g of 70% pure material, 50% excess) was added. With cooling 2.50 g diisopropylethylamine was added slowly. The solution was removed from the ice bath, whereon a solid formed. The solution was warmed in a 50° C. waterbath for 5 minutes. More acetonitrile (5 mL) was added and the mixture was cooled in ice, and then filtered to get 2.047 g of product, m.p. 137-139° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][C@H:23]1[C@H:27]([CH3:28])[CH2:26][NH:25][CH2:24]1>C1(C)C(C)=CC=CC=1>[NH2:22][C@H:23]1[C@H:27]([CH3:28])[CH2:26][N:25]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([F:17])[C:10]=2[F:16])[CH2:24]1
Reactant: C[C@@H]1CNC[C@H]1N
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: Cc1ccccc1C
Product: C[C@@H]1CN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1N

Procedure:
In the same manner as described in Example 5, a mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, trans-3-amino4-methylpyrrolidine, and xylene was refluxed for 3 hours to give 7-(trans-3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline3-carboxylic acid, m.p. 255°-256° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:20]2[CH2:25][C@@H:24]([C:26](=[O:31])N(OC)C)[CH2:23][N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:43][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[C:26]([C@@H:24]1[CH2:25][C@H:20]([N:19]([C:17]([C:8]2[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[N:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][CH:7]=2)=[O:18])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:21][N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:23]1)(=[O:31])[CH3:43]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N(C)OC)CN(C(=O)OC(C)(C)C)C1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(C)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (75 mg) was dissolved in tetrahydrofuran (10 ml), 1 M methylmagnesium bromide in THF solution (1.3 ml) was added at 0° C., and the mixture was stirred at room temperature for 10 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-1:1) was concentrated under reduced pressure to give the object compound (38 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[N:16]O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na]>C(O)CCCC>[CH2:1]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([NH2:16])[CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ON=C1CC2CCC(C1)N2Cc1ccccc1
Agent: [Na]
Solvent: CCCCCO
Product: NC1CC2CCC(C1)N2Cc1ccccc1

Procedure:
2,5-dimethoxytetrahydrofuran (95) is combined with acetone dicarboxylic acid (96) and benzyl amine HCl salt (97) in sodium acetate to give 8-benzyl-8-azabicyclo[3.2.1]octan-3-one 98. The ketone 98 in ethanol is added to hydroxylamine hydrochloride and pyridine, and heated under reflux conditions to afford 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime 99. The oxime 99 in 1-pentanol is combined with sodium metal and heated under reflux to produce 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine 100. The amine 100 in CH2Cl2 (13 mL) is treated with 1M Na2CO3 and isobutyryl chloride to yield amide 101. The amide 101 is dissolved in CHCl3 and pyridine followed by the addition of POCl3. To this was then added diisopropylethylamine and appropriately deuterated acetylhydrazine 110 to produce triazol 102. The triazole 102 in EtOH was treated with Pd(OH)2/C (140 mg) under an H2 atmosphere to yield amine 103. Amine 103 was combined with appropriately deuterated aldehyde 111 in CH2Cl2 (5 mL), Na2SO4 and NaCNBD3 to afford 107. A solution of 107 in HCl/MeOH was heated to reflux to afford the free amine 108. The amine 108 in CH2Cl2 was combined with saturated Na2CO3 and H2O followed by appropriately deuterated cyclohexanecarbonyl chloride 109 to produce a compound of Formula II.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35]>CC(C)=O>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[CH2:27][O:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1O
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1F
Temperature: 50 °C

Procedure:
To a stirred solution of methyl 2-hydroxy-5-(4-morpholinylcarbonyl)benzoate (may be prepared as described in Description 108, 270 mg, 1.02 mmol) in acetone (3 ml) was added cesium carbonate (663 mg, 2.04 mmol) and 1-(bromomethyl)-2,4-difluorobenzene (0.17 ml, 1.32 mmol). The mixture was heated at 50° C. for 2 hours, cooled and the solvent removed in vacuo. The residue was partitioned between water (5 ml) and ethyl acetate (10 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give a residue. Purification by column chromatography (silicon, 4:1 ethyl acetate/cyclohexane) yielded the title compound as a yellow gum. 100 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2F)=O)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH3:20][NH:21][NH2:22]>C(O)C>[CH3:20][N:21]1[C:11]2[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=2)=[N:22]1
Reactant: Nc1ccc(C(=O)c2ccccc2F)cc1[N+](=O)[O-]
Reactant: CNN
Solvent: CCO
Product: Cn1nc(-c2ccc(N)c([N+](=O)[O-])c2)c2ccccc21
Reaction time: 40 h
Yield: 51.3 %

Procedure:
A mixture of 10.4 parts of (4-amino-3-nitrophenyl) (2-fluorophenyl)methanone, 14.03 parts of methylhydrazine and 79 parts of ethanol was stirred for 40 hours at reflux temperature. After cooling, the precipitated product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 5.5 parts (51.3%) of 4-(1-methyl-1H-indazol-3-yl)-2-nitrobenzenamine; mp. 230.6° C. (interm. 7). In a similar manner there was also prepared: 4-(1H-indazol-3-yl)-2-nitrobenzenamine (interm. 8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:22])[CH2:11][C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[O:13])=[CH:4][CH:3]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:22])[CH:11]([CH3:23])[C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[O:13])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(C(=O)CC(=O)CCc2ccc(F)cc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CC(C(=O)CCc1ccc(F)cc1)C(=O)c1cccc(C#N)c1
Temperature: 60 °C
Yield: 60.1 %

Procedure:
A mixture of 3-[5-(4-fluorophenyl)-3-oxo-pentanoyl]-benzonitrile (Example 6 Step 1) (1.0 g, 3.39 mmol), K2CO3 (469 mg, 3.39 mmol), MeI (264 μL, 4.23 mmol) and acetone (25 mL) was heated at 60° C. for 36 hours and then concentrated under reduced pressure. The residue was partitioned between H2O (20 mL) and Et2O (80 mL) and acidified to pH=3 using 2 M HCl solution. The organics were separated and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 30% EtOAc/iso-hexanes to yield the alkylated product (0.63 g, 60%). 1H NMR (CDCl3, 360 MHz) δ 8.14 (1H, s), 8.04 (1H, d, J=8.0 Hz), 7.83 (1H, d, J=7.7 Hz), 7.57 (1H, J=7.8 Hz), 7.08-7.00 (2H, m), 6.87 (2H, t, J=8.6 Hz), 4.38 (1H, q, J=7.0 Hz), 2.85-2.70 (4H, m), 1.43 (3H, d, J=7.0 Hz). MS (ES−) C19H16FNO2 requires: 309, found: 308 (M+H+, 100%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:32]=[CH:31][C:13]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH:26]([CH3:28])[CH3:27])[C:24]([CH3:29])=[N:23][CH:22]=4)[C:18]([F:30])=[CH:17][N:16]=3)=[CH:12][C:11]=2[CH3:33])[CH2:6][CH2:5]1)(=O)C.O.Cl>C(O)(C)C>[N:7]1([C:10]2[CH:32]=[CH:31][C:13]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH:26]([CH3:28])[CH3:27])[C:24]([CH3:29])=[N:23][CH:22]=4)[C:18]([F:30])=[CH:17][N:16]=3)=[CH:12][C:11]=2[CH3:33])[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(-c4cnc(C)n4C(C)C)n3)cc2C)CC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(Nc2ncc(F)c(-c3cnc(C)n3C(C)C)n2)ccc1N1CCNCC1

Procedure:
2-{4-[4-(Acetyl)piperazin-1-yl]3-methylanilino}-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)-5-fluoropyrimidine (Example 116; 1.89 g, 4.19 mmol) was stirred and heated in isopropanol (20 ml), H2O (5 ml) and 33% hydrochloric acid (4 ml) at 90° C. for 10 hours. The solvent was evaporated under reduced pressure to give a residue which was partitioned between water and DCM, basified with sat. sodium hydrogen carbonate and the aqueous layer was extracted with DCM twice. The organics were combined, washed with brine, dried and evaporation of solvent to give the title compound as a crisp foam which was dried in vac oven overnight at 50° C. (1.53 g, 89%) NMR (400 MHz) 1.39 (d, 6H), 2.23 (s, 3H), 2.51 (s, 3H, under DMSO signal), 2.72 (m, 4H), 2.85 (m, 4H), 3.29 (s, 1H under H2O signal), 5.42 (septet, 1H), 6.95 (d, 1H), 7.30 (d, 1H), 7.35 (d, 1H), 7.40 (dd, 1H), 8.48 (d, 1H), 9.24 (s, 1H); 19F NMR (400 MHz) −149.59 (t, 1F); m/z 410.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[C:34](O)=[O:35].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[C:34]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:35]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)c1cc2ccccc2o1
Yield: 98.4 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (2.2 mL), benzofuran-2-carboxylic acid (3.1 g), WSC.HCl (3.6 g), and methylene chloride (100 mL), to give the captioned compound (5.6 g, 98%) as an oily product.
Reaction SMILES: O[C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6].C(NCC)C.C([OH:22])C>>[CH3:13][C:2]1([CH3:14])[C:3](=[O:22])[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[O:6]1
Reactant: CC(C)(O)C#CC(=O)c1ccncc1
Reactant: CCO
Solvent: CCNCC
Product: CC1(C)OC(c2ccncc2)=CC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 4-hydroxy-4-methyl-1-(pyridin-4-yl) pent-2-yn-1-one (1.8 g, 9.50 mmol) in ethanol (18 mL) was added diethyl amine (1.04 g, 14.0 mmol) in EtOH (1 mL) dropwise at RT and the reaction mixture was stirred for additional 1 h. The reaction mixture was concentrated, diluted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford crude 2,2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (1.3 g) as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]2([CH3:35])[CH3:34]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:31]4[CH:22]=[CH:23][C:24]5[C:25]([CH3:35])([CH3:34])[CH2:26][CH2:27][C:28]([CH3:33])([CH3:32])[C:29]=5[CH:30]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Product: CC1(C)CCC(C)(C)c2cc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)ccc21

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (140.0 mg, 0.5239 mmol) in a manner analogous to Step 2d and was isolated as a yellow foam (0.049 g, 30%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (dd, J=6.7, 1.1 Hz, 1H), 8.29-8.25 (m, 2H), 8.10-8.05 (m, 2H), 7.65 (dd, J=7.5, 1.2 Hz, 1H), 7.57 (d, J=2.3 Hz, 1H), 7.36-7.27 (m, 2H), 7.00 (dd, J=7.2, 7.2 Hz, 1H), 6.76 (s, 1H), 3.10 (s, 3H), 1.74-1.66 (m, 4H), 1.33 (s, 6H), 1.28 (s, 6H). MS=475 (MH)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([CH:16]=1)[NH2:15].[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([NH:15][C:18](=[O:20])[CH3:19])[CH:16]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C)c(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of triethylamine (2.9 g, 14.4 mmol) and 5-methoxy-2-methylaniline (1.0 g, 7.2 mmol) in DCM (30 mL) at 0° C., was added acetyl chloride (0.57 g, 7.2 mmol) dropwise. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution, and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to give N-(5-methoxy-2-methylphenyl)acetamide as needle-shaped crystals. The crude product was used in the next step without further purification.