Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:6](O)[CH2:7][CH2:8][OH:9].P(=O)(O)(O)O.C(=O)CCC.O>O>[CH2:2]([CH:1]1[O:9][CH2:8][CH2:7][CH2:6][O:5]1)[CH2:3][CH3:4]
Reactant: CCCC=O
Reactant: OCCCO
Agent: O=P(O)(O)O
Solvent: O
Product: CCCC1OCCCO1

Procedure:
Examples 5-7 are carried out using the apparatus described above. Prior to each example, the column is heated to 100° C. with boiling water as described above. Butyraldehyde is fed through the bottom feed plate and a mixture of 1,3-propanediol and 500 ppmw phosphoric acid is fed through the upper feed plate at rates described in Table I. A butyraldehyde/water azeotrope is condensed overhead at 73° C. The basepot reaches a maximum temperature of 165° C. Material is removed from the basepot throughout the run. The material separates into two phases, each of which is analyzed by gas chromatography. The results are listed in Table II.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Br:9])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:16]([O:20][C:21](=[O:25])[CH2:22][CH2:23][OH:24])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.[Cl-].[Na+].O>[C:16]([O:20][C:21](=[O:25])[CH2:22][CH2:23][O:24][C:6]1[C:5]([Br:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)CCO
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CCOc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2,4-Dichloro-5-bromopyrimidine (7.98 g, 35 mmol) is dissolved in DMF (35 ml) and Cs2CO3 (11.4 g, 35 mmol) and 3-hydroxy-propionic acid tert-butyl-ester (5.12 g, 35 mmol) are added. The reaction mixture is stirred for 5 h at rt. The reaction mixture is diluted with brine and the extracted with ethyl acetate (3×). The organic layers are washed with brine, dried over sodiumsulfat and evaporated to dryness. The crude product is used for the following reaction without any further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=3[O:38][CH3:39])[CH2:7][CH2:6]2)=[N:9]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2noc3ccccc23)CC1
Temperature: 75 °C
Yield: 94.7 %

Procedure:
A mixture of 3-(4piperidinyl)-1,2-benzisoxazole hydrochloride (4.3 g, 18 mmol), K2CO3 (5.5 g, 40 mmol), and 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.5 g, 18 mmol), and dimethylformamide (60 ml) was stirred and heated at 75° C. for 16 hours. The reaction was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent concentrated to afford 7.2 g of a beige solid. Recrystallization (twice) from ethyl alcohol yielded 3.3 g (43%) of 1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy-3-methoxyphenyl]ethanone, m.p.=99°-101° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[CH2:29]([O:36][C:37]1[C:45]([O:46][CH3:47])=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][C:38]=1[Cl:48])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:29]([O:36][C:37]1[C:45]([O:46][CH3:47])=[CH:44][C:40]([C:41]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:42])=[CH:39][C:38]=1[Cl:48])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1cc(C(=O)Cl)cc(Cl)c1OCc1ccccc1
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CSc3ccccc32)cc(Cl)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (347 mg) and 37% formalin (0.23 mL) in the same manner as in Example 1 was dissolved in dichloromethane (3 mL), and diisopropylethylamine (0.63 mL) and 4-benzyloxy-3-chloro-5-methoxybenzoyl chloride (578 mg) were added to the solution, and then the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (498 mg) as a pale yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.COC1C(O[C@@H]2CCC[C@H](NC(=O)CC)C2)=CC=C2C=1C=NN2.Cl.O1CCOCC1>C(O)(C)C>[CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(O[C@@H]2CCC[C@H](N(c3ccccc3)c3ccccc3)C2)ccc2c1cnn2C1CCCCO1
Agent: CCC(=O)N[C@H]1CCC[C@@H](Oc2ccc3[nH]ncc3c2OC)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1c(O[C@@H]2CCC[C@H](N(c3ccccc3)c3ccccc3)C2)ccc2[nH]ncc12
Yield: 76.1 %

Procedure:
Under nitrogen, the N-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N,N-diphenylamine (82 mg, 0.172 mmol) obtained in Example 731, (a) was dissolved in isopropyl alcohol (4 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (4 ml), and the resulting mixture was stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure and a saturated aqueous sodium hydrogencarbonate solution was added to the residue, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and then a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to obtain N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N,N-diphenylamine (52 mg, yield 76.8%) as a whitely yellow amorphous substance.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]([O:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[CH2:18]([N:10]1[C:9]2[C:8]([O:25][CH2:26][CH3:27])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOc1ccc(C(=O)OC)c2c3ccccc3n(Cc3ccccc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(C(=O)O)c2c3ccccc3n(Cc3ccccc3)c12
Yield: 85.6 %

Procedure:
To a solution of methyl-9-benzyl-1-ethoxy-9H-4-carbazolecarboxylate (728 mg, 2.027 mmoles), in methanol (10 ml), aqueous sodium hydroxide (81 mg, 2.027 mmoles) was added and the reaction mixture was refluxed for 1 hr. Methanol was evaporated under reduced pressure, the reaction mixture was acidified with 1N HCl and filtered to yield 599 mg of title compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:29]([O:31]CC(C)C)=O)[CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[C:11]([C:36](=[O:49])[NH:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[N:15]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]1)[C:29](=[O:31])[N:37]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1)[C:36]2=[O:49])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)ccc2N(C(=O)OCC(C)C)C2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCN(C(=O)OC(C)(C)C)CC3)c2=O)cc1OC
Yield: 296.5 %

Procedure:
A mixture of 2.5 g of 1,1-dimethylethyl 4-[{4-(benzyloxy)-2-[(3,4-dimethoxybenzyl)carbamoyl]phenyl}(isobutoxycarbonyl)amino]piperidine-1-carboxylate obtained in stage 1.4 and 7.4 g of NaOH in 18.5 ml of DCE is irradiated under a microwave field at 110° C. for 30 min. The same reaction is repeated with 2 other lots of 2.5 g of 1,1-dimethylethyl 4-[{4-(benzyloxy)-2-[(3,4-dimethoxybenzyl)carbamoyl]phenyl}-(isobutoxycarbonyl)amino]piperidine-1-carboxylate. The 3 reaction media are combined. The combined product is taken up in DCM, washed with water, dried over Na2SO4 and filtered, and the solvent is evaporated under reduced pressure to give 6.6 g of expected product.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][NH:7][C:8](=[O:40])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]=[N+:37]=[N-:38])[CH:30]=2)[CH:10]=1.[CH2:46]([OH:50])[CH2:47][C:48]#[CH:49]>CS(C)=O.N.O.[Cu]I>[OH:50][CH2:46][CH2:47][C:48]1[N:38]=[N:37][N:36]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:41]=[CH:42][CH:43]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:4]=2)=[O:40])=[O:39])[CH:49]=1
Reactant: [N-]=[N+]=NCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: C#CCCO
Agent: [Cu]I
Agent: N
Solvent: CS(C)=O
Solvent: O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(Cn3cc(CCO)nn3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(azidomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (55 mg, 0.09 mmol, 1.00 equiv, 95%) in DMSO (3 mL), but-3-yn-1-ol (19 mg, 0.27 mmol, 3.00 equiv), and copper(I) iodide (0.84 mg, 0.05 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 10 mL of 10% NH3.H2O. The resulting solution was extracted with 5×30 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (60 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 10 mg (14%) of a yellow to green solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.48 (s, 1H), 9.55-9.58 (t, J=6 Hz, 1H), 8.93 (s, 1H), 8.36 (s, 2H), 7.96 (s, 1H), 7.85-7.96 (s, 1H), 7.71-7.77 (m, 3H) 7.64 (s, 1H), 7.55-7.60 (m, 5H), 7.44 (s, 1H), 5.67 (s, 2H), 4.63 (t, 2H), 3.58-3.61 (t, 2H), 3.40 (s, 4H), 2.75-2.77 (t, J=9 Hz, 2H), 1.61-1.78 (d, 6H). MS (ES, m/z): 684 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][CH2:17][N:10]1[CH2:9][CH2:8][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)([OH:13])[CH2:12][CH2:11]1
Reactant: OCCCBr
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Product: Cc1ccc(CC2(O)CCN(CCCO)CC2)cc1

Procedure:
The title compound, MS: m/e=263.3 (M+) was prepared from 4-(4-methyl-benzyl)-piperidin-4-ol and 3-bromo-1-propanol.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:10])[CH2:8][NH2:9])=[CH:3][CH:2]=1.CS[C:13](SC)=[CH:14][N+:15]([O-:17])=[O:16]>C(O)C.C1(C)C(C)=CC=CC=1>[N+:15]([CH:14]=[C:13]1[NH:9][CH2:8][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[O:10]1)([O-:17])=[O:16]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCC(O)c1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])C=C1NCC(c2ccccc2)O1
Yield: 56.5 %

Procedure:
In a mixture of 60 ml of ethanol and 200 ml of xylene was dissolved 40 g of DL-β-hydroxyphenethylamine, and the resulting solution was added dropwise to a solution of 57.8 g of 1,1-bis(methylthio)-2-nitroethene in 600 ml of xylene under reflux over a period of 1.5 hours to effect reaction. During the reaction, the low-boiling fractions were gradually removed by distillation and the reaction temperature was maintained at 130° C. to 140° C. After completion of the reaction, crystals were deposited with stirring under ice-cooling. The crystals deposited were collected by filtration, dried, and then mixed with 200 ml of a 5% (by weight) aqueous sodium hydroxide solution. After a slight amount of insolubles were removed by filtration, the filtrate was adjusted to pH 6 with a 10% (by weight) aqueous acetic acid solution, and the crystals deposited were collected by filtration and dried to obtain 34 g of 2-nitromethylene-5-phenyloxazolidine having a melting point of 139°-141° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10](=[O:12])[CH3:11].C[O:14][C:15]1C=CC=C[C:16]=1C1CC(=O)CC(=O)C1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15](=[O:14])[CH2:11][C:10](=[O:12])[CH2:9]1
Reactant: CC(=O)C=Cc1ccccc1Br
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Product: O=C1CC(=O)CC(c2ccccc2Br)C1

Procedure:
The title compound was prepared from 4-(2-bromo-phenyl)-but-3-en-2-one (1.2 g, 4.44 mmol), stage 1, following the procedure describing the synthesis of 5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (example 1/a stage 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[NH:12])SC)[CH:5]=[C:4]([Cl:13])[C:3]=1[CH3:14].[NH2:15][NH2:16].O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH2:12])=[N:15][NH2:16])[CH:5]=[C:4]([Cl:13])[C:3]=1[CH3:14]
Reactant: CSC(=N)Nc1cc(Cl)c(C)c(Cl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1c(Cl)cc(NC(N)=NN)cc1Cl

Procedure:
To 7.18 g of 1-(2,6-dichloro-4-tolyl)-2-methylisothiourea.HJ (C), suspended in 26 ml of ethanol, 1.3 ml of hydrazine.hydrate is added after which the mixture is refluxed for 20 hours. The precipitate formed is filtered off and the filtrate evaporated to dryness. Yield: 6.35 g. Melting point HJ salt: 203°-205°C; melting point HCl salt: 149°-150°C.
Reaction SMILES: C([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:18][N:19]=3)=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)C.Cl.C([O-])(O)=O.[Na+]>O1CCCC1>[F:29][C:26]([F:27])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([C:17]2[O:16][C:15]([NH:14][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[CH2:13][C:4](=[O:3])[CH2:5][CH2:6]4)=[N:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Temperature: 40 °C

Procedure:
A solution of the product of Example 1H (150 mg, 0.375 mmol) in tetrahydrofuran (2.3 mL) was treated with 2N HCl (0.76 mL, 1.52 mmol), and the mixture was heated at 40° C. for 1 hour. After cooling to room temperature, the solution was brought to pH 8 with saturated NaHCO3 solution, and extracted with ethyl acetate. The organic extracts were washed with H2O, dried over Na2SO4, filtered and evaporated in vacuo to the title compound as a brown residue (140 mg, 100%). 1H NMR (DMSO-d6) δ 9.56 (s, 1H), 7.78 (m, 4H), 7.67 (d, 1H, J=7.8 Hz), 7.62 (s, 1H), 7.22 (t, 1H, J=7.8 Hz), 7.06 (d, 1H, J=7.4 Hz), 3.58 (s, 2H), 3.36 (m, 2H), 3.06 (t, 2H, J=6.8 Hz); MS (ESI+) m/z 373 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:34][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18]([C:22]5[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:33])[N:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=5)=[N:19][NH:20][CH:21]=4)=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:32][N:30]([CH3:31])[C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C:18]2[C:17]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:34][C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:1][N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[CH:8][CH:7]=5)=[CH:10][C:11]=34)=[CH:21][NH:20][N:19]=2)=[CH:23][CH:24]=1)=[O:33]
Reactant: CN(C)C(=O)Nc1ccc(-c2n[nH]cc2-c2ccnc3[nH]c(-c4ccc(C=O)cc4)cc23)cc1
Reactant: C1CCNC1
Product: CN(C)C(=O)Nc1ccc(-c2n[nH]cc2-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)cc1

Procedure:
Following the procedure described for Intermediate 101 using N′-(4-{4-[2-(4-formylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea and pyrrolidine provided the title compound. ESMS [M+H]+: 506.4
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].O[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(CO)cc2Cl)cc1C
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An oven-dried 1 L round-bottomed flask was charged with compound 10.5 (33.5 g, 91.3 mmol), 4-hydroxybenzotrifluoride (16.3 g, 101 mmol), triphenylphosphine (28.7 g, 109 mmol) and THF (335 mL). Next, diethyl azodicarboxylate (17.0 mL, 110 mmol) was added dropwise at 0° C., and the reaction was stirred at room temperature for 30 min. The reaction mixture was concentrated and purified by flash chromatography (SiO2 gel 60 N, eluted with 10% AcOEt/hexanes-15% AcOEt/hexane-20% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to a slightly yellow oil (43.4 g). 1H NMR (400 MHz) (CDCl3) δ 7.54 (2H, d, J=8.8 Hz); 7.42 (1H, d, J=1.6 Hz); 7.34-7.30 (2H, m); 7.09 (1H, dd, J=1.8, 8.2 Hz); 6.99 (2H, d, J=8.8 Hz); 6.76-6.72 (2H, m); 5.00 (2H, s); 4.68 (2H, s); 4.28 (2H, q, J=7.1 Hz); 2.29 (3H, s); 1.31 (3H, t, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([N+:24]([O-])=O)[N:8]([C@@H:27]3[CH2:31][CH2:30][N:29]([C:32](=[O:41])/[CH:33]=[CH:34]/[CH2:35][N:36]([CH:38]4[CH2:40][CH2:39]4)[CH3:37])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+].[Cl-].C(#N)C>C1COCC1.CO.O.O.[Fe]>[CH:38]1([N:36]([CH3:37])[CH2:35]/[CH:34]=[CH:33]/[C:32]([N:29]2[CH2:30][CH2:31][C@@H:27]([N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:15][CH:16]=4)=[C:9]3[NH2:24])[CH2:28]2)=[O:41])[CH2:40][CH2:39]1
Reactant: CN(C/C=C/C(=O)N1CC[C@@H](n2c([N+](=O)[O-])c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1)C1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2c(N)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1)C1CC1
Temperature: 50 °C
Yield: 5.6 %

Procedure:
To a stirred solution of (R,E)-1-(3-(4-amino-6-nitro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-4-(cyclopropyl(methyl)amino)but-2-en-1-one (160) (227 mg, 0.41 mmol) in THF/MeOH/H2O (4 mL/2 mL/1 mL) was added iron powder (92 mg, 1.64 mmol) and NH4Cl (89 mg, 1.64 mmol). The resulting mixture was heated at 50° C. for 1 hrs under N2, and then filtered through a pad of Celite. The filtrate was directly loaded and purified by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water (0.1% HCOOH)) to give (R,E)-4-(cyclopropyl(methyl)amino)-1-(3-(4,6-diamino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)but-2-en-1-one (162) (12 mg, 6% yield) as a white solid. LC-MS (ESI): m/z (M+1) 524.1. 1H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 7.91 (d, J=6.4 Hz, 1H), 7.40 (t, J=7.8 Hz, 2H), 7.32 (d, J=5.6 Hz, 2H), 7.14 (t, J=7.2 Hz, 1H), 7.07 (t, J=6.9 Hz, 3H), 6.74-6.57 (m, 1H), 6.38 (dd, J=31.6, 15.5 Hz, 1H), 5.51 (s, 2H), 5.25 (d, J=11.5 Hz, 2H), 5.17-4.96 (m, 1H), 4.35-3.45 (m, 4H), 3.29-3.20 (m, 3H), 3.09-2.94 (m, 1H), 2.22 (d, J=15.3 Hz, 3H), 1.76-1.61 (m, 1H), 0.47-0.34 (m, 2H), 0.34-0.22 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([NH:8][C:9]([NH2:11])=S)[CH:7]=1.O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([NH:8][C:9]#[N:11])[CH:7]=1
Reactant: NC(=S)Nc1cc(Cl)ccc1N1CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CNc1cc(Cl)ccc1N1CCOCC1

Procedure:
A mixture of 1-(5-chloro-2-morpholinophenyl) thiourea (5.97 g) suspended in water (40 ml), lead acetate trihydrate (8.75 g) in water (40 ml) and potassium hydroxide (12.6 g) in water (35 ml) was heated under reflux for 15 minutes to give N-(5-chloro-2-morpholinophenyl)cyanamide as a white solid (m.p. 305°-308° C.).
Reaction SMILES: C(Cl)CCl.[N:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:12]=2)[NH:7][CH:6]=1.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH2:29][NH:30][CH3:31].C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[N:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]([N:30]([CH3:31])[CH2:29][C:21]3[N:20]([CH3:19])[C:28]4[C:23]([CH:22]=3)=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:18])[CH:12]=2)[NH:7][CH:6]=1
Reactant: O=C(O)/C=C/c1cnc2[nH]cnc2c1
Reactant: CNCc1cc2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2[nH]cnc2c1

Procedure:
EDC (230 mg, 1.2 mmole) was added to a solution (E)-3-(3H-imidazo[4,5-b]pyridin-6-yl)acrylic acid (189 mg, 1.0 mmole), 1-methyl-2-(methylaminomethyl)-1H-indole (209 mg, 1.2 mmole), HOBt.H2O (162 mg, 1.2 mmole), and Et3N (0.28 mL, 2.0 mmole) in dry DMF (5 mL) at RT. After 18 hr the mixture was diluted with H2O. The title compound (193 mg, 56%) was collected as a white solid by filtration, washed with H2O, and dried in vacuo: 1H NMR (400 MHz, d6-DMSO) δ 8.72 (s, 1H), 830 (s, 2H), 7.68 (d, J=15.4 Hz, 1H), 7.45 (m, 3H), 7.13 (m, 1H), 7.01 (m, 1H), 6.43 (s, 1H), 4.87 (s, 2H), 3.70 (s, 3H), 3.15 (s, 3H); for minor rotomer δ 8.68 (s, 1H), 8.47 (s, 2H), 6.19 (s, 1H), 5.10 (s, 2H), 3.74 (s, 3H), 3.01 (s, 3H); MS (ES) m/e 346 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[CH:4][CH:3]=1
Reactant: O=CNc1ccc(Br)cc1
Agent: Cl
Agent: FB(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNc1ccc(Br)cc1
Reaction time: 1 h

Procedure:
To a solution of N-(4-Bromo-phenyl)-formamide D32a (8.2 g, 41 mmol) in dry THF (100 mL) was added BF3.Et2O (8.2 mL, 61 mmol). The mixture was heated to reflux and BH3. THF (103 mL, 103 mmol) added dropwise, the mixture was heated for a further 2 hours. After cooling to room temperature concentrated HCl (100 mL) was added and the mixture stirred for one hour. The pH of the mixture was adjusted to pH 13 using concentrated NaOH. Extraction with ether, drying over MgSO4 and evaporating to dryness gave the subtitled compound as light brown oil (7.58 g). MH+ 186/188. 1H NMR δ (CDCl3) 2.81 (3H, s), 3.63-3.78 (1H, br.s), 6.43-6.52 (2H, d), 7.22-7.30 (2H, d).