Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH3:17])[CH:12]=[N:11][C:10]=2[N:9]([CH3:18])[C:7]1=[O:8].C[N+]1([O-])CCOCC1.[OH2:33].S([O-])([O-])=O.[Na+].[Na+].CC(C)=O.[OH2:44]>>[CH3:1][C@@H:2]([CH2:19][CH2:20][CH:21]([OH:44])[C:22]([OH:33])([CH3:23])[CH3:24])[CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH3:17])[CH:12]=[N:11][C:10]=2[N:9]([CH3:18])[C:7]1=[O:8]
Reactant: CC(C)=CCC[C@@H](C)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: O
Agent: C[N+]1([O-])CCOCC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@H](CCCn1c(=O)c2c(ncn2C)n(C)c1=O)CCC(O)C(C)(C)O
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 1-(4-(R)-Methyl-8-methylnon-7-enyl)-3,7-dimethylxanthine (0.48 g, 1.44 mmol), 4-methylmorpholine-N-oxide (0.51 g, 4.38 mmol) and potassium osmate dihydrate (5 mg, 0.015 mmol) in acetone/water 1:2 (9 mL) was stirred for 16 hours. Water (10 mL) and sodium sulfite (1 g) were added and the reaction mixture stirred for 1 hour. The reaction mixture was extracted with dichloromethane (3×30 ml) using dried magnesium sulfate and the solvent evaporated to yield 0.51 g (97% yield) 1-(4-(R)-Methyl-7,8-dihydroxy-8-methylnonyl)-3,7-dimethylxanthine (inventive compound no. 2537R) as a colorless oil.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(OC2CCC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclobutanol (0.470 mL, 6 mmol) was dissolved in toluene (2 mL) and sodium hydride (60% in mineral oil, 0.240 g, 6 mmol) was added. The reaction was stirred at room temperature for 10 minutes then 2,6-dibromo-pyridine (0.710 g, 3 mmol) was added. The reaction was heated to 110° C. for 16 hours then cooled to room temperature, filtered through Celite, and purified on silica gel (0-5% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5]1(=[O:16])=[O:15].Cl.[Cl:18]CCNCCCl>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:7][Cl:18])[S:5]([NH:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:16])=[O:15]
Reactant: O=S1(=O)N(CCCl)CCN1c1ccccc1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=S(=O)(Nc1ccccc1)N(CCCl)CCCl
Temperature: 100 °C

Procedure:
66 g of the product obtained in Step 1 above are added to a suspension of 38.6 g of N,N-bis(2-chloroethyl)amine hydrochloride in 265 ml of xylene heated to 100° C. The reaction mixture is heated at 140° C. for 12 hours and, after cooling, filtered over a frit. The filtrate is concentrated and then purified by flash chromatography (eluant CH2Cl2/AcOEt: 95/5) to yield the expected product.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[CH2:3][NH2:4].[CH2:21]([O:23][C:24]1[C:28](OCC)=[N:27][S:26](=[O:32])[N:25]=1)[CH3:22]>C(O)C>[OH:1][CH:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[CH2:3][NH:4][C:28]1[C:24]([O:23][CH2:21][CH3:22])=[N:25][S:26](=[O:32])[N:27]=1
Reactant: NCC(O)COCc1cccc(CN2CCCCC2)c1
Reactant: CCOC1=NS(=O)N=C1OCC
Solvent: CCO
Product: CCOC1=NS(=O)N=C1NCC(O)COCc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2.78 g (0.01 mol) of 2-hydroxy-3-[3-(1-piperidylmethyl)benzyloxy]propylamine in 10 ml of ethanol is added dropwise over a period of 30 minutes to a solution of 1.90 g (0.01 mol) of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide in 10 ml of ethanol and the mixture is stirred at room temperature for 4 hours. The title compound obtained after concentration of the reaction solution by evaporation is reacted without further purification.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]#[C:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12])=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([CH3:14])[CH:2]=[CH:3][C:4]([C:7]23[CH2:12][CH:11]2[CH2:10][C:9](=[O:13])[CH2:8]3)=[CH:5][CH:6]=1
Reactant: C=CCC(O)C#Cc1ccc(C)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C23CC(=O)CC2C3)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
PtCl2 (157 mg; 5 mol %) was added to a solution of 1-p-tolyl-hex-5-en-1-yn-3-ol (2.20 g; 11.8 mmol) in toluene (60 mL) and the resulting mixture was stirred at 80° C. for 24 h until the reaction was complete as shown by TLC. The toluene was concentrated at 45-50° C. using a rotary evaporator, and the residue was purified by flash chromatography (9:1→3:1 heptane/EtOAc) to give the desired product (880 mg; 40%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.68 (t, 1 H) 1.26-1.30 (m, 1 H) 1.92-1.97 (m, 1 H) 2.33 (s, 3 H) 2.39 (d, 1 H) 2.60-2.65 (d, 1H) 2.75-2.86 (m, 1 H) 2.88-2.93 (m, 1H) 7.07-7.14 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([C:29](O)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1>>[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([C:29]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CC(C)C[C@H]2CN1C(=O)c1ccccc1-c1ccccc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available biphenyl-2-carboxylic acid.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([NH2:15])[CH:2]=1.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[BH4-].[Na+].[OH-].[K+]>CO.C1(C)C=CC=CC=1>[CH:16]1([NH:15][C:3]2[CH:2]=[CH:1][C:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:10][CH:9]=3)=[CH:5][CH:4]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCCC1
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: c1cc(NC2CCCCC2)ccc1Cc1ccc(NC2CCCCC2)cc1
Temperature: 25 °C
Yield: 102.9 %

Procedure:
30 ml of toluene was added to 4.000 g (20.175 mmol) of 4,4-methylenedianiline, 15.839 g (161.396 mmol) of cyclohexanone, and 10.0 g of molecular sieves (4 Å). The mixture was reacted at 100° C. for 2 days. The mixture was cooled to room temperature, molecular sieves were filtered, and dried in a vacuum at 60° C. to prepare 4-(4-(cyclohexylideneamino)benzyl)-N-cyclohexylidenebenzeneamine. The obtained product was dissolved in 60 ml of methanol, 4.576 g (121.047 mmol) of sodium borohydride was added thereto, and the mixture was reacted at room temperature for 2 hours. Then, the mixture was neutralized with 80 ml of 1 N KOH. An aqueous layer was extracted twice with 60 ml of M.C, and dried with MgSO4. Then, the obtained product was recrystallized in hexane and ethylacetate. As a result, 3.765 g of white solid product (Compound 1) was obtained (Yield: 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23]OS(C)(=O)=O)[CH2:10][C:11]([N:13]([CH3:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Li+].[Li+].[Br-:35].[Li+].C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][Br:35])[CH2:10][C:11]([N:13]([CH3:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Reactant: [Br-]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C(=O)CC(CCBr)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Yield: 91.9 %

Procedure:
3,4-Dichloro-beta-(2-methanesulfonyloxyethyl)-N-methyl-N-(4-chlorophenyl)benzene propanamide (6.3 g) in THF (50 mL) was treated with lithium carbonate (2.0 g) and lithium bromide (2.34 g). The mixture was heated at reflux temperature for 2 hours. The cooled reaction mixture was diluted the CH2Cl2 (100 mL) and washed with H2O (2×100 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil, (5.6 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5](=[N:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[S:6][CH:7]=1.[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:33]([O:1][CH2:2][C:3]1[N:4]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:5](=[N:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=2)[S:6][CH:7]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(CO)csc1=Nc1ccc(OC(F)(F)F)cc1
Reactant: BrCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1c(COCc2ccccc2)csc1=Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (313 mg) obtained in the above (2) was dissolved in N,N-dimethylformamide (3 ml), and thereto was added sodium hydride (56 mg, 60% dispersion in oil) in an ice bath under nitrogen atmosphere, and the mixture was stirred for 30 minutes. To the reaction mixture was added benzyl bromide (179 mg), and the mixture was warmed to room temperature, and then stirred for one hour. The reaction mixture was poured into a 10% aqueous citric acid solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (5:1)] to give the title compound (137 mg) as oil.
Reaction SMILES: [S:1]1(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].[CH3:13]OS([O-])(=O)=O>O>[CH3:13][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1](=[O:10])[CH2:2]1
Reactant: COS(=O)(=O)[O-]
Reactant: O=S1C=Nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CS(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a 2-liter flask, 75.6 g (0.5 mol) of benzothiazolinone are dissolved in a solution containing 20 g of sodium hydroxide (0.5 mol) in approximately 800 cm3 of water. The solution is filtered. With magnetic stirring, 47.5 cm3 of methylsulfate (0.5 mol) are introduced dropwise with a dropping funnel. After the addition, the mixture is left stirring for 20 hours at room temperature. The medium is alkalinized with a slight excess of sodium hydroxide and left stirring for one hour. The precipitate obtained is drained and washed with water until the filtrate is neutral. The product is dried. It is recrystallized in propanol.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10].C(N(CC)CC)C.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>ClCCl>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][NH:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH3:34]
Reactant: NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a solution of N-(2-aminoethyl)-2-nitro-benzenesulfonamide acetic acid salt (15.15 g, 49.6 mmol) and triethylamine (15.16 g, 0.15 mol) in dichloromethane (100 mL) was added ethyl bromoacetate (16.7 g 0.100 mol) with stirring at room temperature. After additional stirring for 1 h, the reaction mixture was washed with brine (100 mL). The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and the residue was triturated in ethyl ether (100 mL) to afford the titled compound as a white solid (8.1 g, 49%). 1H-NMR (500 MHz; DMSO-d6) δ 8.02˜7.96 (m, 2H), 7.87˜7.84 (m, 2H), 4.05 (q, 2H), 3.23 (s, 2H), 2.95 (t, 2H), 2.57 (t, 2H) 1.16 (t, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[Cl:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[O:36][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:27])([F:26])[F:28])(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: O=S(=O)(Nc1nccnc1-c1ccc(COc2cccc(Cl)c2)cc1)c1ccccc1C(F)(F)F
Yield: 70 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 3-chlorophenol, the title compound was isolated as a yellow solid in 70% yield (98% purity by HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.I[CH2:20][CH2:21][CH2:22][CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:6]=[C:5]2[S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1
Reactant: CCCCI
Reactant: CN1CCC(Sc2c[nH]c3ccc(Br)cc23)CC1
Product: CCCCn1cc(SC2CCN(C)CC2)c2cc(Br)ccc21

Procedure:
Prepared as described in Example 56 by reaction of 5-bromo-3[(1-methylpiperidin-4-yl)thio]-1H-indole (prepared in Example 44) with iodobutane.
Reaction SMILES: [N+](C1C=CC(N)=CC=1)([O-])=O.[Cl:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][C:15]=2[N:16]=1.[N+]([O-])(O)=O>O1CCOCC1.S(=O)(=O)(O)O>[Cl:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)oc2c1
Agent: Nc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O=[N+]([O-])O
Product: Clc1nc2ccccc2o1
Yield: 44.4 %

Procedure:
A solution of 83 g of p-nitroaniline in 400 ml of dioxane is added at room temperature, with stirring, to 126 g of 2-chloro-6-nitrobenzoxazole obtained from 43.3 g of 2-chlorobenzoxazole with fuming nitric acid (d. 1.52) in sulphuric acid. The solution is heated to 40°C and stirred at this temperature for a further 19 hours. The solution is diluted with 200 ml of water; it is then cooled and the precipitate separated. The suction-filter residue is dried and dissolved in 500 ml of dimethylformamide. This solution is purified, and diluted with 200 ml of ethanol. The precipitating 6-nitro-2-(4'-nitroanilino)-benzoxazole has the melting point 305° to 310°C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][NH:5]/[C:6](/[NH:18][C:19]1[NH:23][N:22]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:20]=1)=[N:7]/[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>C1COCC1>[Cl:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:33](=[O:34])[N:23]2[N:22]=[C:21]([C:24]([F:25])([F:26])[F:27])[CH:20]=[C:19]2[NH:18]/[C:6]/1=[N:7]\[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1
Reactant: O=C(/N=C(/NCc1ccc(F)cc1Cl)Nc1cc(C(F)(F)F)n[nH]1)c1ccc(F)c(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(/N=c1\[nH]c2cc(C(F)(F)F)nn2c(=O)n1Cc1ccc(F)cc1Cl)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
To a solution of (Z)—N-(((2-chloro-4-fluorobenzyl)amino)((3-(trifluoromethyl)-1H-pyrazol-5-yl)amino)methylene)-3,4-difluorobenzamide (50 mg, 0.11 mmol) in THF (1 mL) was added 1,1′-carbonyldiimidazole (CDI) (26 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Purification by silica chromatography (EtOAc:hexanes) provided the title compound (14 mg, 27% yield). HPLC (Method A): 11.1 min.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd]Cl.C1(C)C=CC=CC=1.C(O)C.O>[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:48]([CH3:61])=[N:47]1
Reactant: COc1cccc(Cn2nc(C)c(B3OC(C)(C)C(C)(C)O3)c2C)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(Cn2nc(C)c(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)c2C)c1
Yield: 17.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (250 mg, 0.3 mmol) was coupled with 1-(3-methoxybenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 53) (131 mg, 0.4 mmol) in sodium carbonate (123 mg, 1 mmol), PdCl2 (dppf) (140 mg, 0.18 mmol), Toluene/ethanol/water (2/2/1 ml) to give 40 mg (14% yield) of titled compound. MS: m/z=747.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:30])=[C:21]([NH:23][C:24](=[O:29])C(F)(F)F)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=1C(Cl)=O.C(O)C(N)(CO)CO>CN(C=O)C.O.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:30])=[C:21]([NH:23][C:24](=[O:29])[C:35]4[C:34]([F:33])=[CH:42][CH:41]=[CH:40][C:39]=4[F:43])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F)C(F)(F)F
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: NC(CO)(CO)CO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
A solution of N-{5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorophenyl}-2,2,2-trifluoroacetamide (300 mg, 0.69 mmol) and 1M LiOH (4.13 ml, 4.13 mmol) in 10:1 THF:H2O (15 mL) was heated at 50° C. overnight. The reaction was washed with brine (25 mL) and the aqueous layer was extracted with EtOAc (25 mL). The organic layers were combined, filtered through a cotton plug, and solvent removed by rotary evaporation. After high vacuum removal of residual solvent, the crude mixture was dissolved in DCM (10 mL) and to this was added 2,6-difluorobenzoyl chloride (519 mg, 2.94 mmol). After stirring 3 h at ambient temperature, DMF (25 mL) was added to dissolve any suspended solids followed by the addition of excess polymer-bound trisamine resin. Upon overnight stirring, the amine resin was removed by vacuum filtration, rinsed with MeOH (50 mL), and filtrate concentrated under reduced pressure to afford the desired amide (162 mg, 49%) as an off-white solid. ESIMS (M+H)+=480.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][O:12][CH2:13]4.[S-]CC.[Na+]>CN(C)C=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][O:12][CH2:13]4
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CCOC3
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CCOC3

Procedure:
3-Methoxy-6-oxamorphinan (VIII) is demethylated using sodium thioethoxide in dimethylformamide by the general procedure of Example 2 to produce the title product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=2)[N:3]=1.[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:35]=[CH:36][C:37]([NH:38][C:2]3[N:7]=[C:6]4[N:8]([CH:11]5[CH2:16][CH2:15][CH2:14][CH2:13][O:12]5)[N:9]=[CH:10][C:5]4=[C:4]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=4)[N:3]=3)=[CH:39][CH:40]=2)[CH2:32][CH2:33]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3c2cnn3C2CCCCO2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)cc3)nc3c2cnn3C2CCCCO2)c1
Temperature: 200 °C

Procedure:
N-(3-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide (50 mg, 0.130 mmol), 4-morpholinoaniline (23.22 mg, 0.130 mmol) and Cs2CO3 (42.4 mg, 0.130 mmol) were dissolved in toluene (4.5 mL) in a sealable microwave compatible reaction tube, and then Pd2(dba)3 (2.386 mg, 2.61 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.01 mg, 5.21 μmol) were added. The reaction tube was sealed and the reaction heated under microwave irradiation (30 min, 200° C., 3 atm). After completion of the reaction, the solvent was removed by vacuum and product was purified by flash column chromatography. 1H NMR (400 MHz, CD3OD): δ 8.64 (s, 1H), 8.28 (s, 1H), 7.93 (d, 1H, J=8.0 Hz), 7.72 (m, 3H), 7.50 (m, 1H), 6.96 (m, 2H), 6.43 (m, 2H), 5.90 (d, 1H, J=8.4 Hz), 5.80 (dd, 1H, J=2.8 and 8.8 Hz), 4.09 (m, 1H), 3.83 (m, 4H), 3.75 (m, 1H), 3.09 (m, 4H), 3.05 (m, 1H), 2.66 (m, 1H), 2.12 (m, 1H), 1.96 (m, 1H), 1.83-1.73 (m, 2H); ESI-MS: [M+H]+.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=O)[C:4]([O:6]CC)=[O:5].[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26])([O-:21])=[O:20].[OH-].[Na+]>C(O)C>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:9]2[NH:26][C:25]([C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)=[N:2][C:3]=2[C:4]([OH:6])=[O:5])[CH:16]=[CH:15][CH:14]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(=NO)C(=O)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)O)c1

Procedure:
Ethyl 5-(3-methoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylate obtained by reacting and treating ethyl 2-hydroxyimino-3-(3-methoxyphenyl)-3-oxopropionate and 3-nitrobenzylamine in the same manner as in Starting Material Synthetic Example 1 is dissolved in ethyl alcohol and 1 M aqueous sodium hydroxide solution is added. The mixture is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(3-methoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylic acid.