Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:11])[O:8][C:9](=O)[C:2]=12.[C:12]1([NH2:19])[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>CN(C)C=O>[NH:18]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:19]=[C:9]1[C:2]1[N:1]=[CH:6][CH:5]=[CH:4][C:3]=1[C:7]([OH:8])=[O:11]
Reactant: Nc1ccccc1N
Reactant: O=C1OC(=O)c2ncccc21
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1-c1nc2ccccc2[nH]1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
A mixture of furo[3,4-b]pyridine-5,7-dione (2.0 g, 13.41 mmol) and benzene-1,2-diamine (1.45 g, 13.41 mmol) in 20 ml of N,N-dimethylformamide (DMF) was heated to 100° C. for 3 hours. The reaction mixture was evaporated to dryness, the obtained residue taken up in 15 mL of dichloromethane and stirred for 30 minutes at 5° C. Filtration with suction and drying gave 1.0 g of a red solid, which was used further without additional purification.
Reaction SMILES: N1C=CC=CC=1C[C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[C:25](O)(=O)[CH3:26]>[Pd]>[NH:10]1[CH2:9][CH2:8][CH2:24][CH2:23][CH:25]1[CH2:26][C:17]1[CH:16]=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:12]=1[C:11]([NH:10][C:9]1[CH:8]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:20]
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)Nc2ccccc2Cc2ccccn2)cc1
Agent: [Pd]
Product: COc1ccc(C(=O)Nc2ccccc2)c(CC2CCCCN2)c1

Procedure:
Reduction of 2'-(2-pyridylmethyl)-p-anisanilide (4.65 g., 0.0146 mole) according to the procedure of Walker, J. Org. Chem., 27, 2966 (1962), in 150 ml. of acetic acid with 2.35 g. of 10% palladium on carbon catalyst affords 2'-(2-piperidylmethyl-p-anisanilide, m.p. 108° -109° C. (corr.), from benzene-hexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][C:8]=1[CH3:16])[CH3:2].FC(F)(F)S(O[CH2:38][CH:39]([F:41])[F:40])(=O)=O>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][N:13]2[CH2:38][CH:39]([F:41])[F:40])=[CH:9][C:8]=1[CH3:16])[CH2:17][C:18]([N:20]([N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH3:21])=[O:19])[CH3:2]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2[nH]ncc2cc1C
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2c(cnn2CC(F)F)cc1C
Yield: 68.1 %

Procedure:
Using the compound (1.25 g, 2.97 mmol) of Example 257, step B and 2,2-difluoroethyl trifluoromethanesulfonate (859 mg, 4.01 mmol), and according to the method of Example 241, step C, the title compound (982 mg, yield 68%) was obtained as a colorless amorphous solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2c(Br)cncc2n1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.75 h
Yield: 39.1 %

Procedure:
To a solution of 1-benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-c]pyridine (0.96 g, 2.84 mmol) in anhydrous THF (10 mL), at −35° C., was added a solution of lithium diisopropylamide (2.0M in heptane/THF/ethyl benzene, 2.84 mL, 5.68 mmol) dropwise. The mixture was stirred at −35° C. for 45 min and then methyl iodide (1.06 mL, 17.04 mmol) was added dropwise. The resulting solution was allowed to reach room temperature and was stirred for 3 h. The reaction mixture was quenched by addition of an aqueous solution of 1N HCl (5 mL); the solution was diluted with water (15 mL) and extracted with EtOAc (2×75 mL). The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, DCM:cyclohexane, gradient 0:100 to 100:0). The residue was triturated in EtOAc (2 mL) and collected by filtration to give the title compound as a white solid (0.39 g, 39%). LCMS (Method A): RT=4.47 min, [M+H]+ 351 (79Br), 353 (81Br)
Reaction SMILES: [O:1]=[C:2](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:17][Si:18]([CH3:21])([CH3:20])Cl.N12CCCCC1C=NCCC2>C(OCC)C>[C:11]1([CH:10]=[CH:9][C:2]([O:1][Si:18]([CH3:21])([CH3:20])[CH3:17])=[CH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)CCC(=O)/C=C/c1ccccc1
Agent: C1=NCCCN2CCCCC12
Solvent: CCOCC
Product: COC(=O)CC=C(C=Cc1ccccc1)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3 g of the product of Step B , 45 ml of diethyl ether and 2.2 ml of trimethylchlorosilane were mixed together and after the mixture was cooled to 0° C., then 2.5 ml of 1,5-diaza-5-bicyclo-[5,4,0]-undecene (DBU) and 20 ml of diethyl ether were added. The mixture was stirred while allowing the temperature to rise to 20° to 21° C. for one hour. After filtration, the ether was evaporated off to obtain 4.2 g of the desired product which was used as is in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I-:9].[K+].II>N.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1
Reactant: [I-]
Reactant: Oc1ccc(Br)cc1
Agent: II
Agent: N
Agent: [K+]
Solvent: O
Product: Oc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a solution of 4-bromophenol (25 g, 144.5 mmol) in 25% aqueous ammonia solution (350 mL) was added a solution of potassium iodide (72 g, 433.5 mmol) and iodine (36.7 g, 144.5 mmol) in water (288 mL). The reaction mixture was stirred at ambient temperature for 2 h and quenched with 250 mL of water. The reaction was acidified by addition of concentrated HCl (350 mL) and extracted with dichloromethane. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 9:1 hexanes/ethyl acetate) providing 4-bromo-2-iodophenol (33 g, 77%) as a pink solid: 1H NMR (CDCl3, 300 MHz) δ 7.78-7.75 (m, 1H), 7.37-7.31 (m, 1H), 6.88 (d, J=8.7 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1(O)[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[Cr](Cl)(O)(=O)=[O:14].N1C=CC=CC=1>ClCCl.C(OCC)C>[CH2:1]([C:5]1=[CH:11][C:10](=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[Cr](=O)(O)Cl
Reactant: CCCCC1(O)C=CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC1=CC(=O)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of (Z)-1-butylcyclohept-2-enol (2 g, 11.9 mmol) dissolved in dichloromethane (60 mL) was pyridine chlorochromate on basic alumina (20 wt. %, 25.7 g, 23.8 mmol). The resulting reddish solution was stirred at room temperature for 2 h until determined to be complete by TLC. The mixture was diluted in 100 mL diethyl ether and stirred for 1 h after which it was poured over filter paper that was subsequently washed with the ether. The filtrate was partially concentrated (30 mL) and passed through a Florisil column with ether (100 mL). The resulting colorless solution was concentrated and purified by flash chromatography (5% Et2O/Pentane) to provide a colorless oil (920 mg, 47% yield). IR (film) 3477, 2933, 2864, 1662, 1458, 1421, 1375, 1344, 1322, 1267, 1201, 1124, 1103, 1048, 937, 875, 855 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.89 (s, 1H, COCH), 2.58-2.53 (m, 2H, COCH2), 2.41-2.38 (m, 2H, HC═CCH2), 2.18 (t, 2H, J=6.91 Hz, HC═CCH2(CH2)2CH3), 1.80-1.74 (m, 2H, COCH2CH2), 1.50-1.40 (m, 2H, HC═CCH2CH2), 1.38-1.25 (m, 2H, HC═C(CH2)2CH2CH3), 0.90 (t, 3H, J=7.18 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) δ 204.4, 162.4, 128.2, 42.1, 40.8, 32.5, 29.7, 25.1, 22.4, 21.2, 13.9; HRMS (EI+) exact mass calculated for [M]+ (C11H18O) requires m/z 166.1358, found m/z 166.1359.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:38]=CC=1)/[CH:6]=[C:7]1\[CH2:8][C@@H:9]2[C@H:13]([CH2:14]\1)[C@H:12](/[CH:15]=[CH:16]/[C@@H:17]([O:24]C1CCCCO1)[CH:18]([CH3:23])[CH2:19][C:20]#[C:21][CH3:22])[C@H:11]([O:31]C1CCCCO1)[CH2:10]2)=O.[CH3:41][C:42]([CH3:44])=[O:43].O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1.CCOCC>ClCCl>[C:42]([C:44]1[CH:38]=[C:5]([CH:4]=[CH:3][CH:1]=1)/[CH:6]=[C:7]1\[CH2:8][C@@H:9]2[C@H:13]([CH2:14]\1)[C@H:12](/[CH:15]=[CH:16]/[C@@H:17]([OH:24])[CH:18]([CH3:23])[CH2:19][C:20]#[C:21][CH3:22])[C@H:11]([OH:31])[CH2:10]2)(=[O:43])[CH3:41]
Reactant: CC#CCC(C)[C@@H](/C=C/[C@H]1[C@H]2C/C(=C/c3cccc(C=O)c3)C[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC#CCC(C)[C@H](O)/C=C/[C@H]1[C@H]2C/C(=C/c3cccc(C(C)=O)c3)C[C@H]2C[C@H]1O
Reaction time: 0.25 h

Procedure:
In order to convert the thus-obtained carbinol into the methyl ketone, the residue is dissolved in 50 ml of dichloromethane and this solution is added to 6 g of Collins reagent in 80 ml of dichloromethane. After 15 minutes, the mixture is combined with 300 ml of ether, filtered, and the filtrate washed in succession with water, 5% sodium bicarbonate solution, 10% strength sulfuric acid, and water, dried over magnesium sulfate, and evaporated under vacuum.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[C:17]([NH:21][OH:22])([CH3:20])([CH3:19])[CH3:18]>C(Cl)(Cl)Cl>[C:17]([N+:21]([O-:22])=[CH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)NO
Reactant: O=CCCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)[N+]([O-])=CCCc1ccccc1
Reaction time: 22 h
Yield: 45.1 %

Procedure:
To a mixture of 3-phenylpropionaldehyde (10.0 g, 74.5 mmol, 1.0 equiv) and benzene (150 ml) was added chloroform (25 ml) until a clear solution was obtained. To the clear solution was added N-tert-butylhydroxylamine (7.31 g, 82.0 mmol, 1.1 (equiv) and the resulting mixture was refluxed under nitrogen and Dean-Stark trap for 22 h. Upon cooling oil separated. Oil was separated and product purified by flash chromatography (hexanes: EtOAc=1:1) to give N-tert-butyl-C-(2-phenylethyl)nitrone (7.31 g, 45.1%) as a light color oil: 1H NMR (CD3OD) δ 7.30–7.27 (m, 2H, Ar—H), 7.23–7.19 (m, 3H, Ar—H), 6.80 (t, 1H, Ar—H), 2.77–2.62 (m, 4H, 2CH2), 1.46 (s, 9H, t-Bu).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[H-].[Na+].F[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=1[F:36]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]([C:26]4[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=4[F:36])[C:18](=[O:22])[CH:17]=3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4F)c(=O)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A suspension of 4-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one (127 mg, 0.424 mmol, prepared according to procedures described in Example 230 Step C substituting 2-chloro-5-ethylpyrimidine (Aldrich) for 2-chloro-5-cyclopropylpyrimidine), sodium hydride (60 wt % mineral oil, 21 mg, 0.51 mmol) and DMF (5 mL) was purged with Argon and then stirred at room temperature for 1 h. To the reaction was added 1,2-difluoro-4-(methylsulfonyl)benzene (90 mg, 0.47 mmol, Matrix Scientific) and then heated at 110° C. for 1 h. The resulting mixture was quenched with H2O and extracted with EtOAc. The organic layer was concentrated in vacuo to a yellow solid. The solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 91 mg of the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (s, 2 H), 7.83-7.91 (m, 2 H), 7.64 (dd, J=8.53, 6.78 Hz, 1 H), 7.13 (dd, J=7.53, 1.00 Hz, 1 H), 6.08 (dd, J=7.65, 2.64 Hz, 1 H), 6.03 (d, J=2.51 Hz, 1 H), 4.54-4.63 (m, 1 H), 4.16-4.27 (m, 2 H), 3.60-3.70 (m, 2 H), 3.12 (s, 3 H), 2.49 (q, J=7.53 Hz, 2 H), 1.97-2.15 (m, 2 H), 1.78-1.97 (m, 2 H), 1.21 (t, J=7.53 Hz, 3 H). MS (ESI) 473 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:7]([CH3:9])[N:8]=1.S(Cl)([Cl:35])=O>ClCCl>[Cl:35][CH2:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:7]([CH3:9])[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCO)nc1C
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCCl)nc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-(1-(3-(2-(2-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 23, 75 mg, 0.18 mmol) in dichloromethane (5 mL). Thionyl chloride (25 μL, 0.35 mmol) was added and the resulting solution was stirred for 3 h at room temperature. The solvents were carefully removed under reduced pressure to yield 50 mg (crude) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:29]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1ccccc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
400 mg (1.16 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 173 mg (1.27 mmol, 1.1 eq.) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 373 mg (72% of theory)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([OH:20])[CH:14]=2)[N:9]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([O:20][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[F:21])[N:9]=[C:8]([Cl:7])[C:17]([CH:18]=[O:19])=[CH:16]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1cc2cc(O)c(F)cc2nc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc2cc(OCc3ccccc3)c(F)cc2nc1Cl
Temperature: 0 °C
Yield: 81.9 %

Procedure:
Potassium carbonate (9.2 g, 66 mmol) is added to a solution of 2-chloro-7-fluoro-6-hydoxy-3-quinolinecarbaldehyde (obtained according to 1.c, 13 g, 58 mmol) in anhydrous N,N-dimethylformamide (120 ml) and the mixture, placed under an argon atmosphere, is cooled down to 0° C. Benzyl bromide (7.9 ml, 66 mmol) is added dropwise and the reaction medium is maintained under agitation at ambient temperature for 16 hours. The reaction medium is then poured into ice cold water (200 ml) and the resulting yellow solid is filtered, then taken up in ethanol (200 ml) and concentrated under reduced pressure. The residue is taken up in ethyl ether (200 ml) and the resulting yellow solid is filtered then dried under reduced pressure in order to produce 15 g (82%) of a yellow solid, m.p. 228° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:12][C:13]1[C:14]([NH:20][NH2:21])=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19].[Cl-].[NH4+].[NH:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]([CH2:37][C:38](O)=[O:39])=[N:29]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:12][C:13]1[C:14]([NH:20][NH:21][C:38](=[O:39])[CH2:37][C:30]2[C:31]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[NH:28][N:29]=2)=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccnc(NN)c1Oc1cc(Cl)cc(Br)c1
Reactant: O=C(O)Cc1n[nH]c2ncccc12
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccnc(NNC(=O)Cc2n[nH]c3ncccc23)c1Oc1cc(Cl)cc(Br)c1
Reaction time: 2 h

Procedure:
To a solution of 3-(3-bromo-5-chlorophenoxy)-2-hydrazino-4-methylpyridine trifluoroacetate (112 mg, 0.253 mmol), 1H-pyrazolo[3,4-b]pyridin-3-ylacetic acid compound with ammonium chloride (1:1), (67.6 mg, 0.253 mmol), HOAT (6.89 mg, 0.051 mmol) and TEA (106 μL, 0.759 mmol) in DMF (1 mL) was added EDC (58.2 mg, 0.304 mmol) and the resulting mixture was stirred for 2 hours. The mixture was then filtered and purified on a Luna column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:15])[C:11]=1[O:12][CH2:13][CH3:14])[C:8]([CH3:17])([CH3:16])[CH2:7][CH2:6][CH2:5]2.C([O:22]O)(C)(C)C>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:8]([CH3:16])([CH3:17])[CH2:7][CH2:6][C:5]2=[O:22])=[C:10]([Cl:15])[C:11]=1[O:12][CH2:13][CH3:14]
Reactant: CCOc1c(Br)cc2c(c1Cl)C(C)(C)CCC2
Reactant: CC(C)(C)OO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Product: CCOc1c(Br)cc2c(c1Cl)C(C)(C)CCC2=O
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-8-chloro-7-ethoxy-1,1-dimethyl-1,2,3,4 tetrahydronaphthalene (Compound A-118, 4.1 g, 12.93 mmol) in dichloromethane (20 mL) and tert-butyl hydroperoxide (20 mL) at room temperature was added a catalytic amount of chromium (VI) oxide. The reaction was stirred overnight. Quenched with the reaction with water followed by extraction with ether. The organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (silica gel, 2% ethyl acetate/hexane) yielded the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([O:25][CH3:26])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[NH2:23])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C>CCN(CC)CC>[C:1]([C:5]1[CH:6]=[C:7]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[C:8]([O:25][CH3:26])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[NH:23][C:38]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:39])=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(N)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)N4CCOCC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 96 h
Yield: 19.2 %

Procedure:
A mixture of 7-amino-1-methylindole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide (64 mg, 0.14 mmol), morpholinecarbonyl chloride (0.13 mL, 1.1 mmol), diisopropylethylamine (0.2 mL) and Et3N (0.5 mL) was stirred for 4 days. The reaction mixture was extracted and purified by reverse phase HPLC on a C18 column eluting with an acetonitrile-water gradient to provide 15 mg (19%) of the title compound.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:13]3[CH2:20][C@@H:10]2[CH:11]=[CH:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.[Pd]>[C:1]1([C@@H:7]([N:9]2[C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:13]3[CH2:20][C@@H:10]2[CH2:11][CH2:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C[C@@H](C2)N1[C@@H](C)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1[C@@H]2CC[C@@H](C2)N1[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
To a solution of ethyl (1R, 3R, 4S)-2-[(S)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (791 mg, 2.91 mmol) obtained in Example 3 (a) in ethyl acetate (15 ml) was added 10% Pd—C (53 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. After a filtration through Celite, the solvent was concentrated. The residue was purified by silica gel column chromatography (5% ethyl acetate/hexane), to give ethyl (1S, 3R, 4R)-2-[(S)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (601 mg, 76%).
Reaction SMILES: Cl[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH2:15]>>[CH:2]([O:15][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O
Reactant: ClC(c1ccccc1)c1ccccc1
Product: c1ccc(C(OC(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture of 37 g of chlorodiphenylmethane and 100 ml of water were refluxed under nitrogen for 16 hours. After cooling the water was decanted and 40 ml of ethanol was added to induce crystallization. The yellow solid was recrystallized 3 times from ethanol to give 21.9 g of dibenzhydryl ether, m.p. 108°-110°.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=2[CH3:20])C(=O)O1>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:8][C:6]1[C:19]2[C:11](=[C:12]([CH3:20])[CH:13]=[C:14]([C:15]([OH:17])=[O:16])[CH:18]=2)[N:10]=[CH:9][CH:5]=1
Reactant: Cc1cc(C(=O)O)ccc1NC=C1C(=O)OC(C)(C)OC1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(C(=O)O)cc2c(O)ccnc12
Temperature: 280 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A mixture of 4-{[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl]amino}-3-methylbenzoic acid (10.1 g) and diphenyl ether (101 mL) was heated under stirring in an oil bath at 280° C. for 2 hours. The reaction mixture was returned to room temperature, diluted with petroleum ether and the precipitate was collected by filtration to obtain 4-hydroxy-8-methylquinoline-6-carboxylic acid (6.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6]2.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:8]1[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2[nH]c(=O)c(C(F)(F)F)cc2c1
Product: COc1ccc2nc(Cl)c(C(F)(F)F)cc2c1
Yield: 94 %

Procedure:
A solution of 6-methoxy-3-(trifluoromethyl)quinolin-2(1H)-one (4.60 g, 18.9 mmol) in POCl3 (30 mL) was refluxed for 2.5 hours. The solvent was removed under reduced pressure and the residue was neutralized by 2M NaOH to pH 7. An EtOAc workup was followed by removal of volatiles under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc=15/1) to give the product (4.60 g, yield 94%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:29](=[O:31])[C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: CN
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Product: CNC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Yield: 85 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with methylamine to give the title compound as a white solid (170 mg, 85%); NMR Spectrum 1.65 (d, 3H), 2.68 (d, 3H), 5.16 (q, 1H), 5.80 (s, 2H), 7.00 (d, 1H), 7.36 (d, 1H), 7.51 (s, 1H), 7.79-7.71 (m, 3H), 8.12 (s, 1H), 8.39 (m, 1H), 8.52 (m, 2H), 9.05 (s, 1H), 10.68 (br s, 1H); Mass spectrum MH+ 460.