Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]([CH3:19])[CH2:7]2)[N:5]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:4](=[O:37])[N:3]=1.[CH3:38][O:39][CH:40]([O:43][CH3:44])[CH2:41]N>CCOC(C)=O>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]2([N:5]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=3)[C:4](=[O:37])[N:3]=[C:2]2[NH:1][CH2:41][CH:40]([O:43][CH3:44])[O:39][CH3:38])[CH2:7][CH:8]1[CH3:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1CC2(CCN1Cc1ccccc1)C(N)=NC(=O)N2c1cc(F)ccc1-c1ccc(S(C)(=O)=O)cc1
Reactant: COC(CN)OC
Solvent: CCOC(C)=O
Product: COC(CNC1=NC(=O)N(c2cc(F)ccc2-c2ccc(S(C)(=O)=O)cc2)C12CCN(Cc1ccccc1)C(C)C2)OC
Temperature: 85 °C
Reaction time: 18 h

Procedure:
A solution of 4-amino-8-benzyl-1-[4-fluoro-4′-(methylsulfonyl)biphenyl-2-yl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one (50 mg, 0.10 mmol) in 2,2-dimethoxyethylamine (2.0 ml) was sealed and allowed to stir at 85° C. for 18 h. The temperature was increased to 110° C., and the reaction was allowed to stir for an additional 16 h. The reaction was diluted with EtOAc and washed with brine. The organic portion was dried over sodium sulfate, filtered, and concentrated in vacuo to yield 8-benzyl-4-[(2,2-dimethoxyethyl)amino]-1-[4-fluoro-4′-(methylsulfonyl)biphenyl-2-yl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one. LCMS (M+H) 609.0.
Reaction SMILES: C([O:8][C@H:9]([CH3:26])[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1>[C].[Pd].CO>[OH:8][C@H:9]([CH3:26])[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:11]
Reactant: C[C@@H](OCc1ccccc1)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](O)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
At room temperature, to a methanol solution (200 ml) of tert-butyl 4-{[(2R)-2-(benzyloxy)propanoyl]amino}piperidine-1-carboxylate (6.90 g) was added 10% palladium carbon (2.03 g), followed by stirring overnight under a hydrogen atmosphere. The reaction solution was filtered through Celite, and then concentrated under reduced pressure to afford tert-butyl 4-{[(2R)-2-hydroxypropanoyl]amino}piperidine-1-carboxylate (5.19 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (3.0 g) and imidazole (2.03 g) in N,N-dimethylformamide (30 mL) was added tert-butylchlorodiphenylsilane (4.66 mL), and the mixture was stirred at room temperature for 7 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 1-bromo-4-[2-(tert-butyldiphenylsilyloxy)ethyl]benzene (6.27 g). The title compound was prepared in a similar manner to that described in Step 2 of Reference Example 46 using this material instead of 1-bromo-2-fluoro-4-methoxybenzene.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19]Br.CCOC(C)=O>C1COCC1>[Br:16][CH2:17][CH2:18][CH2:19][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: BrCCCn1c2ccccc2c2ccccc21
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 115.9 %

Procedure:
A 250-mL round-bottomed flask was charged with a solution of 9H-carbazole (5 g, 29.94 mmol, 1.00 equiv) in THF (200 mL). To this was added NaH (1.8 g, 75.00 mmol, 1.50 equiv) in small portions at and allowed to stir for 30 minutes. To the mixture was added 1,3-dibromopropane (18 g, 89.55 mmol, 3.00 equiv) at −10° C. and warmed up to 30° C. in an oil bath for 30 minutes. The reaction progress was monitored by TLC (EtOAc:PE=1:5). Upon completion, the reaction was then quenched by the addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). Combined organic layers were washed with brine (3×50 mL), dried over anhydrous sodium sulfate. Solids were filtered off and the mixture was concentrated on a rotary evaporator affording 9-(3-bromopropyl)-9H-carbazole as yellow solid (10 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=3[N:14]=2)=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[O-:24]S([O-])(=S)=O.[Na+].[Na+].C(O)(=O)C>C(O)C.OO.O>[CH3:10][C:6]1[CH:5]=[N:4][C:3]([CH2:11][S+:12]([O-:24])[C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=3[N:14]=2)=[C:2]([CH3:1])[C:7]=1[O:8][CH3:9]
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
0.35 g of 2-[[(3,5-dimethyl-4-methoxy-2-pyridinyl)methyl]thio]-5-methoxy-1H-benzimidazole was suspended in 5 ml of ethanol at room temperature. 0.035 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.099 g H2O2 (35% aqueous solution), and further diluted with 2 ml of water. The oxidant/catalyst solution was added to the reactant suspension dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 6 hours while stirring. 2 ml of 10% Na2S2O3 aqueous solution was then, added, and the resulting mixture was subjected to a reduced pressure to remove ethanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Omeprazole with a yield of about 69% (LC purity>80%).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:16][C:17]([O:19][CH:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:18])=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:43])[CH3:42].CO>C(Cl)Cl>[C:41]([NH:15][C:12]1[CH:11]=[C:10]([NH:16][C:17]([O:19][CH:20]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[O:18])[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][CH:33]=2)=[CH:14][CH:13]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Reaction time: 16 h
Yield: 76.6 %

Procedure:
A solution of N1-(4-chlorobenzoyl)-N2-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl]-1,2,4-benzenetriamine (40 mg, 0.08 mmol) in 5 mL of CH2Cl2 was treated with pyridine (1 mL) and acetyl chloride (0.006 mL, 0.09 mmol). After 16 h, the mixture was treated with MeOH (1 mL) and then concentrated. The residue was partitioned between EtOAc and NaOH (aq). The organic layer was dried (MgSO4), concentrated, and purified by chromatography (17:3 CH2Cl2:MeOR), affording 32 mg (76%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[C:9]([C:20]#[N:21])[CH:8]=2)=[N:3][CH:2]=1.O.S(=O)(=O)(O)[OH:24].N>C(O)(C(F)(F)F)=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[C:9]([C:20]([NH2:21])=[O:24])[CH:8]=2)=[N:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccncn2)cc1C#N
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccncn2)cc1C(N)=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
To a solution of 5-(pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carbonitrile (85 mg, 0.28 mmol) in TFA (1.0 mL) were sequentially added water (0.15 mL) and 98% sulfuric acid (0.30 mL) under efficient stirring. The mixture was allowed to stir for 5 h at 70° C. and then was diluted by drop wise addition of water (1 mL). The reaction mixture was made basic (pH 10-12) by adding 30% aqueous ammonia (3 mL) under stirring. The precipitated solid was collected by filtration, washed with water and finally dried in a vacuum oven at 50° C. affording the title compound (72 mg, 83%).
Reaction SMILES: [Si]([O:8][CH:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:10]([NH:12][C:13]1[S:14][C:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)=[N:16][N:17]=1)=O)(C(C)(C)C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.CCOCC>[CH:24]1[C:25]2[C:20](=[CH:19][C:18]([C:15]3[S:14][C:13]([NH:12][CH2:10][CH:9]([OH:8])[CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[N:17][N:16]=3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)[Si](C)(C)OC(Cc1ccccc1)C(=O)Nc1nnc(-c2ccc3cnccc3c2)s1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(CNc1nnc(-c2ccc3cnccc3c2)s1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.5 %

Procedure:
(±)-2-(tert-Butyldimethylsilyloxy)-N-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-3-phenylpropanamide (0.44 g, 0.9 mmol) was taken up in 9 mL of THF and chilled to 0° C. Lithium aluminum hydride (4 mL, 1.0 M in THF) was added. After 1 hour, the mixture was poured into 50 mL of ½ saturated aqueous Rochelle's salt and diluted with 25 mL of ether. The mixture was stirred for 1 hour. The mixture was partitioned in a separatory funnel, and the aqueous portion was extracted twice with 50 mL of EtOAc. The combined organic extracts were washed with 50 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by purification by flash chromatography on silica gel (eluting with a gradient of 2% to 10% MeOH in DCM) afforded (±)-1-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-ylamino)-3-phenylpropan-2-ol (0.005 g, 2%) as a yellow oil. LCMS (M+H) 363 calc. for C20H19N4OS 363.1. 1H NMR (400 MHz, CD3OD): ppm 9.27 (s, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.24 (s, 1H), 8.20 (d, J=1.5 Hz, 2H), 7.90 (d, J=5.8 Hz, 1H) 7.33-7.29 (m, 5H), 7.26-7.22 (m, 1H), 4.14-4.10 (m, 1H), 3.60 (dd, J=3.9 Hz, 13.5 Hz, 1H), 3.40 (dd, J=7.5 Hz, 13.5 Hz, 1H), 2.91 (dd, J=5.4 Hz, 13.7 Hz, 1H), 2.82 (dd, J=7.6 Hz, 13.7 Hz, 1H). 1H not detected.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]#[CH:13])=[CH:6][C:5]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)[OH:15])([O-])=O.O.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]#[CH:13])=[CH:6][C:5]=1[C:14]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]2[CH2:23][CH2:24]2)=[CH:20][CH:21]=1)=[O:15]
Reactant: C#CCOc1ccc([N+](=O)[O-])c(C(O)c2ccc(C3CC3)cc2)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: C#CCOc1ccc(N)c(C(=O)c2ccc(C3CC3)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2.2 g (6.85 mmol) of (2-nitro-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanol (step C above) in 40 ml glacial acetic acid is heated to 50° C. and treated with 3.06 g (8 equiv.) of iron powder. After 5 h stirring at that temperature the reaction is complete. The green-grey suspension is cooled to rt, diluted by the addition of 500 ml water and 200 ml ethyl acetate and filtered through a pad of Celite. The layers are separated and the organic phase washed with water and sat. bicarbonate solution. The yellow and sticky crude product is purified by chromatography (dichloromethane/MeOH) to yield a viscous yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[N:10]([CH3:11])[C:6]=2[C:5]([C:13]([O:15]C)=[O:14])=[CH:4][N:3]=1>Cl>[ClH:1].[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[N:10]([CH3:11])[C:6]=2[C:5]([C:13]([OH:15])=[O:14])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)c2cc(C)n(C)c12
Agent: Cl
Product: Cc1cc2c(Cl)ncc(C(=O)O)c2n1C
Yield: 193.5 %

Procedure:
A solution of methyl 4-chloro-1,2-dimethyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (1.027 g) in 5N hydrochloric acid was heated under microwave conditions at 120° C. for one and a half hours, then evaporated to dryness to afford the title compound as a white solid 1.087 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:24][C:11]3=[N:12][C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:14]([C:16]([CH3:18])=[CH2:17])[CH:15]=[C:10]3[C:9]=2[C:25]([NH:27][CH3:28])=[O:26])=[CH:4][CH:3]=1.I[CH2:30][C@@H:31]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:32]=[CH2:33].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:35]([O:34][C@@H:31]([CH:32]=[CH2:33])[CH2:30][N:19]([C:13]1[N:12]=[C:11]2[O:24][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]([C:25]([NH:27][CH3:28])=[O:26])[C:10]2=[CH:15][C:14]=1[C:16]([CH3:18])=[CH2:17])[S:20]([CH3:23])(=[O:21])=[O:22])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C=C(C)c1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1NS(C)(=O)=O
Reactant: C=C[C@@H](CI)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C=C[C@@H](CN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1C(=C)C)S(C)(=O)=O)OCc1ccccc1
Yield: 57.4 %

Procedure:
2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)-5-(prop-1-en-2-yl)furo[2,3-b]pyridine-3-carboxamide (87 mg, 0.216 mmol), (S)-((1-iodobut-3-en-2-yloxy)methyl)benzene (62.1 mg, 0.216 mmol) and cesium carbonate (70.3 mg, 0.216 mmol) are heated under microwave irradiation for 30 min at 120° C. HPLC affords (S)-6-(N-(2-(benzyloxy)but-3-enyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(prop-1-en-2-yl)furo[2,3-b]pyridine-3-carboxamide (70 mg, 0.124 mmol, 57.6% yield)
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.F[B-](F)(F)F.[O:24]=[N+:25]=[O:26].O>C(#N)C>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([N+:25]([O-:26])=[O:24])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(c2ccccn2)c2cc([N+](=O)[O-])ccc2O1
Yield: 15.7 %

Procedure:
1.32 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 20 ml of acetonitrile and 0.73 g of nitronium tetrafluoroborate was added at room temperature. After 1 hour the mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with sodium chloride solution, dried over sodium sulphate and evaporated to give an oil. This oil was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. 245 mg of 3,4-dihydro-2,2-dimethyl-6 -nitro-4-(2-pyridyl)-2H-1-benzopyran were obtained in the form of an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a −78° C. solution of 2M oxalyl chloride (31.8 mL, 63.5 mmol) in 200 mL DCM was added DMSO (9.01 mL, 127 mmol), followed by the slow addition by addition funnel of a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (10.0 g, 57.7 mmol) in 200 mL DCM. The cloudy reaction mixture was stirred at −78° C. for 15 minutes, then a solution triethylamine (32.2 mL, 231 mmol) in 40 mL DCM was added slowly by addition funnel. The reaction mixture was stirred another 15 minutes, the bath was removed, and the reaction was allowed to warm to ambient temperature and stirred for 15 hours. Water and brine were added, and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered and concentrated. The crude was purified on silica gel (3-20% ethyl acetate in hexanes gradient) to give the desired product (9.0 g, 91.1% yield) as a white solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:57][CH3:58])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([O:51][Si](C)(C)C)[CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:40]([CH3:56])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:59])=[CH:25][N:24]=1>O1CCCC1>[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([OH:51])[CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:40]([CH3:56])[CH:39]=3)[CH2:57][CH3:58])=[CH:31][C:30]=2[CH3:59])=[CH:25][N:24]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)nc2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)nc2)c(C)c1
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.0466 mL, 0.0466 mmol) was added to a solution of [5-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-2-yl]-acetic acid methyl ester (Example 95-(1); 18.1 mg, 0.031 mmol) in tetrahydrofuran (0.050 mL), and the mixture was stirred for 30 minutes. The reaction mixture was purified by silica gel chromatography (25% ethyl acetate/hexane) to give the title compound (7.6 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH3:34])=[C:17]([NH:20][C:21](=[O:31])[CH2:22]P(OCC)(OCC)=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:52][N:53]1[CH2:57][CH2:56][CH2:55][C@@H:54]1[CH:58]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH3:34])=[C:17]([NH:20][C:21](=[O:31])/[CH:22]=[CH:58]/[C@H:54]4[CH2:55][CH2:56][CH2:57][N:53]4[CH3:52])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCC[C@@H]1C=O
Reactant: CCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/[C@H]1CCCN1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 7b (300 mg, 0.59 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath. Under argon, a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (1.2 mL, 1.18 mmol) was added dropwise. After the mixture was stirred for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (133 mg, 1.18 mmol) was added, and the mixture was stirred for another 1 hour, then warm up to room temperature and stirred for 12 hours. The reaction mixture was concentrated, added with 10 mL of water, extracted with dichloromethane (25 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2R)-1-methylpyrrodin-2-yl]prop-2-enamide 9 (130 mg, yield 47.3%) as a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:3]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O:55][C:56](=O)[C@H:57]([O:59][C:60]1[CH:65]=[C:64](Cl)[N:63]=[C:62]([S:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=2[F:76])[N:61]=1)[CH3:58])C>O1CCOCC1.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]>[F:76][C:70]1[C:71]([F:75])=[CH:72][CH:73]=[CH:74][C:69]=1[CH2:68][S:67][C:62]1[N:63]=[C:64]([NH:12][S:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]2)(=[O:10])=[O:11])[CH:65]=[C:60]([O:59][C@H:57]([CH3:58])[CH2:56][OH:55])[N:61]=1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: C[C@@H]1CN(S(N)(=O)=O)C[C@H](C)N1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1CN(S(=O)(=O)Nc2cc(O[C@H](C)CO)nc(SCc3cccc(F)c3F)n2)C[C@H](C)N1
Temperature: 100 °C

Procedure:
To a solution of (2R,6S)-2,6-dimethylpiperazine (1 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 72 h The reaction mixture was partitioned between EtOAc (150 ml) and H2O (150 ml) and the aqueous re-extracted with EtOAc (2×150 ml). Organics were collected dried and reduced in vacuo to yield (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide as a white solid (0.29 g). A mixture of (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide (0.29 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.628 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 5 step i), 0.5 g) in dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.940 g