Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH:7]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:44])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][NH2:43])=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:46]1(=[O:53])[O:52][C:50](=[O:51])[CH2:49][O:48][CH2:47]1>CN(C)C=O>[C:1]([O:5][C:6](=[O:45])[CH:7]([N:11]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](=[O:44])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][NH:43][C:50](=[O:51])[CH2:49][O:48][CH2:47][C:46]([OH:53])=[O:52])=[CH:28][CH:29]=1)[S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH:8]([CH3:9])[CH3:10])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1COCC(=O)O1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)NCCOCCOCCOCCN)cc2)C(C(=O)OC(C)(C)C)C(C)C)cc1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)NCCOCCOCCOCCNC(=O)COCC(=O)O)cc2)C(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the amine (Compound 13*; 60 mg, 0.092 mmol), N, N′-diisopropyl ethylamine (96 μl, 0.55 mmol), and diglycolic anhydride (66 mg, 0.55 mmol) in dimethylformamide (6 ml) was stirred at ambient temperature for 3 hours when monitoring by HPLC indicated complete reaction. The solvent was removed under reduced pressure and the residue dissolved in acetonitrile containing 0.1% TFA. After stirring for 5 minutes, the mixture was evaporated to dryness and the crude product purified by flash chromatography using CHCl3MeOH/H2O, 65:25:4. The product was obtained as white foam. Yield 70.50 mg (99.80%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:11]2[O:12][CH:13]([CH2:15][NH:16][C:17](=O)OC)[CH2:14][C:10]=2[CH:9]=1.Cl>O1CCCC1>[Cl:7][C:8]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:11]2[O:12][CH:13]([CH2:15][NH:16][CH3:17])[CH2:14][C:10]=2[CH:9]=1
Reactant: COC(=O)NCC1Cc2cc(Cl)c3ccccc3c2O1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNCC1Cc2cc(Cl)c3ccccc3c2O1
Temperature: 25 °C
Reaction time: 40 h
Yield: 23.3 %

Procedure:
To a suspension of lithium aluminum hydride (95 wt. %, 0.45 g, 11.25 mmol) in tetrahydrofuran (45 mL) was added (±)-methyl (5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methylcarbamate (1.16 g, 3.98 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 40 h. The reaction mixture was diluted with tetrahydrofuran (150 mL), quenched with saturated ammonium chloride (50 mL), and the organic layer was separated and washed with saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash chromatography (silica, methanol:dichloromethane 1:39) provided a light brown oil. The oil was re-dissolved in tetrahydrofuran (50 mL) and aqueous hydrogen chloride (1.0 N, 1 mL) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.23 g (20%) of (±)-1-(5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)-N-methylmethanamine as a white solid, hydrochloride salt. mp 224-226° C.; Anal. calcd. for C14H14ClNOHCl.0.1H2O: C, 58.80; H, 5.36; N, 4.90. Found: C, 58.65; H, 5.30; N, 4.84.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:19]=1.[Li]CCCC.CN([CH:28]=[O:29])C>C1COCC1>[CH:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([CH:28]=[O:29])=[CH:19][C:6]=3[N:7]=2)[CH2:11][CH2:12]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCN(c2nc3cc(Br)ccc3s2)CC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2nc3cc(C=O)ccc3s2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-2-(4-isopropylpiperazin-1-yl)benzothiazole (300 mg, 0.88 mmol) in dry THF was added n-BuLi dropwise over 10 min at −78° C. After 30 min, DMF was added dropwise at −78° C. The reaction mixture was then stirred for 1.5 h at −78° C., quenched with water and extracted with ethyl acetate to give a residue which was purified by column chromatography on silica gel (eluent: 1% dichloromethane in methanol). This afforded 240 mg (94%) of 2-(4-isopropylpiperazin-1-yl)benzothiazole-5-carbaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][S:17][CH2:18][C:19](Cl)=[O:20]>CC(C)=O>[CH3:16][S:17][CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: CSCC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: CC(C)=O
Product: CSCC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 42.9 %

Procedure:
20.3 g (0.1 mole) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred with 14.9 g (0.12 mole) of 2-methylmercaptoacetyl chloride and 400 ml of absolute acetone for 10 hours at room temperature. The product was filtered off under suction at 10° C., washed with cold acetone and dried at 70° C. under reduced pressure. 12.5 g (43%) of 6-[p-(2-methylmercaptoacetylamino)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 220°-222° C.
Reaction SMILES: [C:1](=[O:26])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:20](=[O:22])[CH3:21])[C:11]2[C:6]1=[C:7]([OH:25])[CH:8]=[C:9]([CH:23]=[O:24])[CH:10]=2)[NH2:2].[H-].[Na+].[C:29](Cl)(=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(Cl)(Cl)Cl>O1CCCC1.CC(C)=O>[C:29]([O:25][C:7]1[CH:8]=[C:9]([CH:23]=[O:24])[CH:10]=[C:11]2[C:6]=1[CH:5]([CH2:4][O:3][C:1](=[O:26])[NH2:2])[C:17]1([OH:19])[O:18][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[C:20](=[O:22])[CH3:21])(=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCC(=O)Cl
Reactant: CC(=O)N1C2CN3OC(O)(C(COC(N)=O)c4c(O)cc(C=O)cc43)C21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CCCCCCCC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(O)ON2CC2C1N2C(C)=O
Reaction time: 1 h

Procedure:
11-Acetyl-4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (25 mg) was dissolved in tetrahydrofuran (2.5 ml) and the solution was added to a suspension of sodium hydride (60% in oil, 3 mg) in tetrahydrofuran (0.5 ml). To this mixture was added a solution of octanoyl chloride (12 μl) in tetrahydrofuran (108 μl) in an ice-water bath and the mixture was stirred for 1 hour in an ice-water bath. After stirring for 36 hours at room temperature, an additional amount of octanoyl chloride (50 μl) was added and the mixture was stirred for 3 hours at room temperature. The reaction mixture was then directly subjected to a preparative thin layer chromatography. Development was carried out with a mixture of chloroform and acetone (1:1, v/v) to afford 11-acetyl-8-carbamoyloxymethyl-4-formyl-9-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6-yl octanoate (7 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].C([Sn](CCCC)(CCCC)[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1)CCC.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.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].[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:16][CH:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(I)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ncccn2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To 4-[2-(4-Iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (77.6 mg) in DMF (1 mL) was added 2-(tributylstannyl)pyrimidine (74.1 mg), tris(dibenzylideneacetone)-di-Palladium, triphenylarsine (27 mg) and copper (I) iodide (3.2 mg) and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then allowed to cool to room temperature and was concentrated in vacuo. To the residue was then added ethylacetate (4 mL) and an aqueous solution of potassium fluoride (30%) and the mixture was stirred rigorously for one hour. Then the solid was filtered off and the biphasic filtrate was separated. The organic layer was dried with sodium sulfate and concentrated in vacuo. The residue was then purified by column chromatography to yield the title compound (41 mg, 59%).
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][S:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:13]=1)(C)(C)C.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:13]=[C:9]([S:8][CH2:7][C:6]([OH:21])=[O:5])[S:10][CH:11]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)CSc1nc(-c2ccc(Cl)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CSc1nc(-c2ccc(Cl)cc2)cs1
Reaction time: 5 h

Procedure:
709 mg (2.07 mmol) of [4-(4-chloro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid tert-butyl ester in 5 ml of 90% aqueous TFA were allowed to stand at room temperature for 5 h. The mixture was evaporated. Yield: 665 mg.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13](=[O:18])[CH2:14]C([O-])=O)[CH2:10][C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Na+].O>CS(C)=O>[C:13]([CH:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:19])[CH2:10]1)(=[O:18])[CH3:14]
Reactant: O=C([O-])CC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)C1CC(=O)N(Cc2ccccc2)C1
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A mixture of 3-(1-benzyl-2-oxopyrrolidin-4-yl)-3-oxopropanoate (24.0 g, 0.083 mole) and sodium chloride (10.6 g, 0.181 mole) in dimethylsulfoxide (105 mL)/water (4.4 mL) was heated at 135° with stirring for 16 hours. On cooling the reaction mixture was poured onto ice water (900 mL) and extracted with dichloromethane (800 mL). The organic phase was washed with water (4×500 mL) and dried (MgSO4). The solvent was removed under reduced pressure to give 4-acetyl-1-benzyl-2-pyrrolidinone (15.0 g, 83%) as a brown oil.
Reaction SMILES: [C:1]1([C:7]2([O:20][C:21]3([CH:24]([OH:27])CO)[CH2:23][CH2:22]3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.O.CCOC(C)=O>[C:1]1([C:7]2([O:20][C:21]3([CH:24]=[O:27])[CH2:22][CH2:23]3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC(O)C1(OC2(c3ccccc3)c3ccccc3-c3ccccc32)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=CC1(OC2(c3ccccc3)c3ccccc3-c3ccccc32)CC1

Procedure:
A suspension of 2-[1-(9-Phenyl-9-fluorenoxy)cyclopropyl]-1,2-dihydroxyethane in THF:H2O is treated with NalO4 (1.1 eq). The resulting suspension is stirred at room temperature for 4h and then diluted with H2O and EtOAc. The EtOAc extract is washed consecutively with 10% aq sodium thiosulfate solution and then brine. The EtOAc layer is dried (Na2SO4) and concentrated in vacuo. The crude product is purified by filtration through a short pad of silica gel.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.Cl[C:23]([O:25][CH3:26])=[O:24]>N1C=CC=CC=1>[CH3:26][O:25][C:23]([O:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@:20]1([CH3:21])[C:14](=[CH:15][C:16](=[O:17])[CH2:18][CH2:19]1)[CH2:13][CH2:12]3)=[O:24]
Reactant: COC(=O)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Product: COC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 76 %

Procedure:
Testosterone is treated with methyl chloroformate in pyridine to give 17β-methoxycarbonyloxyandrost4-en-3-one in 76% yield after recrystallization from methanol. A solution of the 17β-methoxycarbonyloxyandrost4-en-3-one in toluene is pyrolyzed at 460° C., and the crude product is recrystallized from acetone at room temperature to give androsta-4,16-dien-3-one in 90% yield. The androsta-4,16-dien-3-one is reduced at −55° with lithium tris(1,2-dimethylpropyl)hydridoborate in tetrahydrofuran to give a mixture of androsta-4,16-dien-3β-ol and androsta-4,16-dien-3α-ol; and chromatography on silica gel using dichloromethane/ethyl acetate gives pure androsta-4,16-dien-3β-ol and pure androsta-4,16-dien-3α-ol, each in 48% yield. These may be recrystallized (androsta-4,16-dien-3β-ol from cyclohexane at room temperature and androsta-4,16-dien-3α-ol from petroleum ether at −30° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:16](Br)=[C:17]([Br:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:16]=[C:17]([Br:19])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)c(Br)n2CCOC2CCCCO2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOC2CCCCO2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
Add 4-{4,5-dibromo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-imidazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester (39.0 g; 0.073 mol; 1.0 equiv) to THF (600 mL) and cool to −78° C. under an argon atmosphere. Add n-BuLi solution (1.6 M in cyclohexane) (53.7 mL; 0.087 mol; 1.2 equiv) drop-wise in 1 h and allow to come to −30° C. in 2 h. Quench the reaction with saturated ammonium chloride solution and extract with EA. Evaporate the organic layer and purify the residue with silica gel chromatography to give the title compound (13.2 g; 39%).
Reaction SMILES: [Cl:1][CH:2]([C:7](=[O:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].C(Cl)Cl.P>[Ru].CO>[Cl:1][CH:2]([C@H:7]([OH:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCC(=O)C(Cl)C(=O)OC
Agent: [Ru]
Agent: P
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](O)C(Cl)C(=O)OC
Yield: 95 %

Procedure:
In a 100 ml Hastelloy-made autoclave having been purged with nitrogen were put 10 g (0.0607 mol) of the methyl 2-chloro-3-oxopentanoate prepared in (1) above, 0.2 ml of a methylene chloride solution of 26 mg (0.144 mmol) of a ruthenium-optically active phosphine complex Ru2Cl4 [(+)-Tol-BINAP]2NEt3, and 30 ml of methanol, and the mixture was allowed to react at 50° C. under a hydrogen pressure of 30 atm for 18 hours. Methanol was removed by evaporation to give 9.61 g (0.0577 mol; yield: 95.0%) of the title compound. Optical rotation [α]D25 =+6.35° (c=0.976, CHCl3)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([C:10]([C:12]1[CH:16]=[C:15]([Cl:17])[O:14][N:13]=1)=O)=[CH:6][N:7](C)C)[CH3:2].Cl.[C:20]([NH:24]N)([CH3:23])([CH3:22])[CH3:21].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][N:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=1[C:12]1[CH:16]=[C:15]([Cl:17])[O:14][N:13]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)on1
Reactant: CC(C)(C)NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1-c1cc(Cl)on1
Temperature: 90 °C
Yield: 20960.6 %

Procedure:
A solution of 2-(5-chloro-isoxazole-3-carbonyl)-3-dimethylamino-acrylic acid ethyl ester (294.8 mg, 1.08 mmol) in absolute ethanol (1.4 mL, 0.77M) was treated with tert-butylhydrazine hydrochloride (137.3 mg, 1.10 mmol) and sodium acetate (108.6 mg, 1.32 mmol). The resulting mixture was heated to 90° C. overnight. At this time, the reaction was cooled to 25° C. and was concentrated in vacuo. The reaction was partitioned between water (200 mL) and dichloromethane (2×50 mL). The combined organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Biotage chromatography (40S column 60% ethyl acetate/hexanes) followed by ISCO CombiFlash (4 g column 0-20% ethyl acetate/hexanes) afforded 1-tert-butyl-5-(5-chloro-isoxazol-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (67.4 g, 21%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH:32]=[CH:31][CH:30]=[N:29]1.CCN(C(C)C)C(C)C>O>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: c1cn[nH]c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(-n2cccn2)n1
Temperature: 120 °C
Yield: 81.9 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) (0.49 mg, 1.22 mmol), 1H-pyrazole (1.0 g, 14.7 mmol), and DIPEA (3 mL) was heated to 120° C. for 40 min, cooled to 20° C., and diluted with water (50 mL). The resulting precipitate was collected by filtration, washed with water, and dried. Chromatography on silica, eluting with CH2Cl2/EtOAc (4:1), gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl]-1H-benzimidazole (428 mg, 82%): mp (CH2Cl2/hexanes) 274-277° C.; 1H NMR (DMSO-d6) δ 8.79 (dd, J=2.8, 0.5 Hz, 1H), 8.14 (dd, J=8.3, 0.5 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.88 (t, J=52.8 Hz, 1H), 7.49 (t, J=8.2 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 6.70 (dd, J=2.8, 1.5 Hz, 1H), 4.01 (m, 2H), 4.00 (s, 3H), 3.93 (m, 2H), 3.80-3.75 (m, 4H); Anal. Calcd. for C19H18F2N8O2: C, 53.3; H, 4.2; N, 26.2. Found: C, 53.1; H, 4.1; N, 25.9%.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]([O:39][C:40]4[CH:45]=[CH:44][C:43](F)=C(Cl)C=4)=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34]([O:36][CH3:37])=[O:35])[C@@H:29]([CH3:38])[CH2:28][CH2:27]4)[CH:21]=[N:20]2)[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]([O:39][CH:40]4[CH2:43][CH2:44][CH2:45]4)=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34]([O:36][CH3:37])=[O:35])[C@@H:29]([CH3:38])[CH2:28][CH2:27]4)[CH:21]=[N:20]2)[CH2:16]1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)c(Oc3ccc(F)c(Cl)c3)c2CC[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N1c2ccc(-c3cnn(C4CNC4)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.5 %

Procedure:
Trifluoroacetic acid (1.0 mL, 6.49 mmol) was added to a solution of (S)-methyl 6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3-chloro-4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.132 g, 0.265 mmol) in dichloromethane (1.0 mL) and the reaction mixture stirred at rt for 2 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl (S)-6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.115 g, 88%) as an off-white solid. MS (ESI, pos. ion) m/z 396 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[NH2:37][CH2:38][CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=[O:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:37][CH2:38][CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=[O:41])=[O:25]
Reactant: CN(C)C(=O)CCN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCC(=O)N(C)C)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-amino-N,N-dimethyl-propionamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)c(F)c5)cc34)cn2)c1
Yield: 19.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (150 mg, 0.263 mmol) was deprotected in TFA/DCM (2/5 ml). This afforded 30 mg (19.6% yield) of the titled. 1H NMR (CD3OD, 400 MHz): δ 8.67-8.66 (d, 1H), 8.60 (s, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.78 (s, 1H), 7.58-7.54 (m, 2H), 7.47-7.43 (t, 1H), 7.39-7.33 (q, 1H), 7.12-7.10 (d, 1H), 7.05-7.00 (m, 2H), 5.43 (s, 2H), 3.55-3.52 (d, 2H), 3.28-3.16 (m, 3H), 2.21-2.03 (m, 4H). MS: m/z=470.4 (M+1), HPLC: 98.34% in method A.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:11].[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.[OH-].[Na+]>O1CCOCC1>[S:37]([O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:11])([C:34]1[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)N1CCCCC1CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCOC(=O)N1CCCCC1CCOS(=O)(=O)c1ccc(C)cc1

Procedure:
1,4-Dioxane solution of octadecyl 2-(2-hydroxyethyl)piperidinecarboxylate and p-toluenesulfonyl chloride is added to sodium hydroxide solution and the mixture is reacted at room temperature to obtain octadecyl 2-[2-(tosyloxy)ethyl]piperidinecarboxylate.