Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[C:9](NC(=O)OCC)[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)=[C:20]([O:34][CH3:35])[CH:19]=3)[C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)CCC.C([N:57](CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:35][O:34][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[O:24][CH2:25][C:26]1[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[CH2:17][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[CH:3]=[C:4]2[N:10]=[C:9]1[NH2:57]
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5ccccn5)cnc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12.7 %

Procedure:
To a stirred solution of ethyl (6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.250 g, 0.42 mmol), 2-(tributylstannyl)pyridine (0.235 g, 0.63 mmol), copper(I) iodide (0.040 g, 0.21 mmol) and triethylamine (0.130 g, 1.26 mmol) in N,N-dimethylformamide (5 mL) was added bis(triphenylphosphine)palladium(II) dichloride (0.018 g, 0.042 mmol). The mixture was irradiated in a microwave reactor at 140° C. After 1.5 h, the mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated. The residue was purified by prep-HPLC to afford 0.025 g (13%) of the product as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J=4.0 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.5 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.84-7.76 (m, 1H), 7.74-7.72 (m, 1H), 7.32-7.29 (m, 1H), 7.12 (d, J=6.0 Hz, 1H), 7.00-6.77 (m, 3H), 6.82 (d, J=8.5 Hz, 1H), 6.83-6.74 (m, 1H), 5.24 (s, 2H), 4.96 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H) ppm; (M+1)=469.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([NH2:8])=[S:7].C([O:11][CH:12](OCC)[CH2:13][C:14](OCC)=O)C.C[O-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12](=[O:11])[NH:8][C:6]1=[S:7]
Reactant: CCOC(=O)CC(OCC)OCC
Reactant: COCCNC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCn1ccc(=O)[nH]c1=S
Temperature: 60 °C
Yield: 44.8 %

Procedure:
To a stirring solution of 1-(2-methoxyethyl)thiourea (21.38 g, 159.3 mmol) and ethyl 3,3-diethoxypropanoate (46.5 mL, 239.0 mmol) in MeOH (300 mL) was added a freshly prepared solution of 0.96N sodium methoxide in MeOH (250 mL, 239.0 mmol) dropwise over 30 minutes at room temperature under argon. The reaction mixture was heated to 60° C. for 45 minutes and cooled to room temperature. Solvent was removed under reduced pressure and toluene (250 mL) was added to the residue. The mixture was stirred at reflux for an additional 3 hours and then cooled to room temperature. Water (200 mL) was added and the layers were separated. The aqueous layer was washed with CH2Cl2 (50 mL), neutralized with 2N aqueous HCl and extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from i-PrOH (200 mL) to give the title compound (13.3 g, 45%) as a light yellow crystalline solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[CH:19][C:18]=3[C:28]([F:31])([F:30])[F:29])(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[CH:19][C:18]=3[C:28]([F:29])([F:31])[F:30])(=[O:15])=[O:16])[CH2:11][N:10]2[C:32](=[O:34])[CH3:33])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(-n4cccn4)cc3C(F)(F)F)CN2)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C[C@H](S(=O)(=O)c2ccc(-n3cccn3)cc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(4-pyrazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide from experiment D9 was acylated with acetic anhydride in analogy to experiment L29 to give (2S,4R)-1-acetyl-4-(4-pyrazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless solid. MS: 496.3 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=O.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>ClCCl>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([Cl:14])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CC2C=CC1C2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-norbornene-2-carboxylic acid (Aldrich, mixture of endo and exo, 1.25 g, 9.05 mmol) in dichloromethane (50 mL) was treated with oxalyl chloride (0.99 mL, 11.31 mmol) and a catalytic amount of N,N-dimethylformamide (100 μL). The reaction mixture was stirred at ambient temperature for 2 hours and then solvent and excess oxalyl chloride were removed under reduced pressure to yield the title compound which was used without further purification.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:4][CH2:3][CH2:2]1.CN(C)C=O.[H-].[Na+].CS(O[CH:38]1[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C:40](=[O:51])[CH2:39]1)(=O)=O>O>[CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:20]=[N:19][N:18]([CH:38]4[CH2:43][CH2:42][NH:41][C:40](=[O:51])[CH2:39]4)[CH:17]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1c2ccc(-c3cnn(C4CCNC(=O)C4)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
An 8-mL resealable tube was charged with (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.050 g, 0.15 mmol) and N,N-dimethylformamide (2 mL). Sodium hydride (60% dispersion in mineral oil, 0.012 g, 0.50 mmol) was added, and the resulting mixture stirred for 15 min at room temperature. tert-Butyl 4-(methylsulfonyloxy)-2-oxopiperidine-1-carboxylate (0.141 g, 0.48 mmol) was added, and the resulting mixture stirred overnight at 50° C. The reaction mixture was cooled to room temperature and water (10 mL) was added. The aqueous phase was separated and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, Xbridge RPC18, 19×150 mm, 5 um; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (13% to 60% acetonitrile in 8 min; flow rate: 20 mL/min); Detector, UV254&220. This afforded (2S)-methyl 5-cyclobutoxy-2-methyl-6-(1-(2-oxopiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.0091 mg, 14%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.17-1.20 (m, 3H), 1.29-1.40 (m, 1H), 1.40-1.51 (m, 1H), 1.58-1.68 (m, 1H), 2.03-2.19 (m, 4H) m 2.22-2.35 (m, 3H), 2.41-2.49 (m, 1H), 2.92-2.99 (m, 1H), 3.32-3.48 (m, 2H), 3.78 (s, 3H), 4.12-4.22 (m, 1H), 4.50-4.60 (m, 1H), 4.78-4.88 (m, 1H), 7.25-7.33 (m, 2H), 7.87 (s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 439 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Br[CH2:21][CH3:22]>CN(C)C(=O)C>[CH2:21]([N:12]1[C:13](=[O:16])[CH:14]=[CH:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[C:11]1=[O:17])[CH3:22]
Reactant: CCBr
Reactant: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)ccn(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A mixture of 3 parts of 1-(4-nitrophenyl)-2,4(1H,3H)-pyrimidinedione, 1,4 parts of potassium hydroxide and 67.5 parts of N,N-dimethylacetamide was stirred for 1 hour at room temperature under nitrogen atmosphere. 1.52 Parts of bromoethane were added and stirring was continued overnight at room temperature. The reaction mixture was poured into 100 parts of ice water. The product was filtered off and stirred in methanol. The product was filtered off and dried in vacuo at 60° C., yielding 2.4 parts (65.6%) of 3-ethyl-1-(4-nitro-phenyl)-2,4(1H,3H)-pyrimidinedione; mp. 182.5° C. (int. 24).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][NH:9][CH2:10][CH2:11][NH:12][CH3:13]>C1(C)C=CC=CC=1>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([CH3:13])[CH:6]1[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: CNCCNC
Reactant: O=Cc1ccsc1
Solvent: Cc1ccccc1
Product: CN1CCN(C)C1c1ccsc1
Reaction time: 16 h

Procedure:
3-Thiophenecarbaldehyde (22.43 g) was dissolved in toluene (200 ml) and N,N'-dimethylethylenediamine (22.3 ml) was added. The mixture was stirred for 16 hours with removing azeotropic water under reflux by Dean-stark trap. The reaction mixture was concentrated under reduced pressure and the residue was distilled under reduced pressure to give 1,3-dimethyl-2-(3-thienyl)imidazolidine (5.88 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.[C:33]([NH:40][CH2:41][C:42](O)=[O:43])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[C:36]([O:35][C:33]([NH:40][CH2:41][C:42]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])=[C:20]([O:26][CH3:27])[CH:21]=1)=[O:43])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(OC(=O)CNC(=O)OC(C)(C)C)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 30.2 mg, 0.070 mmol) and Boc-glycine (15.1 mg, 0.086 mmol) were dissolved in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (31.4 μL, 0.18 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (35.4 mg, 0.093 mmol) were added thereto, and then the mixture was stirred at room temperature overnight. Ethyl acetate (10 mL) was added to the reaction mixture, then the mixture was washed with water (10 mL) and saturated brine (10 mL) successively. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (35.3 mg) as a colorless amorphous product. (Yield 86%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:32])[CH:21]=[CH:22][C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:32][C:14](=[O:16])/[CH:13]=[CH:12]/[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][N:25]1[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Cl
Reactant: CC1CCN(Cc2ccc(N)cc2Cl)CC1
Product: CC1CCN(Cc2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
Prepared analogously to Example 143 starting from (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 3-chloro-4-(4-methyl-piperidin-1-ylmethyl)-phenylamine (Z36b). The crude product was purified by column chromatography (Alox, neutral, act. II-III, petroleum ether/EtOAc 3:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH:12]2[CH2:15][N:14](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:13]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.ClC(OC(Cl)C)=O.C(OCC)C>ClCCCl>[ClH:1].[Cl:1][C:2]1[C:3]([O:11][CH:12]2[CH2:13][NH:14][CH2:15]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1OC1CN(C(c3ccccc3)c3ccccc3)C1)CCC2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCOCC
Product: Cl
Product: Clc1ccc2c(c1OC1CNC1)CCC2
Temperature: 120 °C
Yield: 111.5 %

Procedure:
4.22 g of 3-[(5-chloro-2,3-dihydro-1H-inden-4-yl)oxy]-1-((diphenylmethyl))-azetidine were dissolved in 71 ml of 1,2-dichloroethane. 1.58 g of 1-chloroethyl chloroformate was added. The mixture was refluxed in an oil bath at 120° C. for 2.5 hours. After evaporation in vacuo the residue was refluxed in 71 ml of anhydrous methanol for 2 hours. Evaporation in vacuo gave a semi solid that was stirred with diethyl ether and filtered. The solid was recrystallized from ethanol/diethyl ether, yielding 1.57 g of 3-[(5-chloro-2,3-dihydro-1H-inden-4-yl)oxy]-azetidine hydrochloride, mp. 188° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f8) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([S:17][CH3:18])[C:14]([F:19])=[CH:13][N:12]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C([O-])([O-])=O.[K+].[K+]>ClCCl.ClC1C=CC=C(C(OO)=O)C=1>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([S:17]([CH3:18])=[O:38])[C:14]([F:19])=[CH:13][N:12]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: CSc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(F)cnc32)cc1
Reaction time: 2 h
Yield: 96 %

Procedure:
5-fluoro-3-(5-fluoro-4-methylsulfanyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 24a, (2.30 g, 5.32 mmol) was dissolved in dichloromethane (107 mL) and treated portionwise with 3-chloroperbenzoic acid (1.19 g, 5.30 mmol), keeping the temperature below 20° C. After stirring for 2 hours, another portion of 3-chloroperbenzoic acid (0.18 g, 0.80 mmol) was added, and stirring was continued for another hour. A third portion of 3-chloroperbenzoic acid (0.07 g, 0.05 mmol) was added and stirring was continued for 30 minutes. The reaction mixture was treated with an aqueous 15% K2CO3 solution (30 mL) and the layers were separated. The organic layer was washed with 15% K2CO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 2.3 g (96%) of the desired product as a yellow solid, which was used without further purification: 1H NMR (300 MHz, DMSO-d6) δ 9.12 (d, J=1.5 Hz, 1H), 8.70 (s, 1H), 8.67 (dd, J=9.1, 2.8 Hz, 1H), 8.53 (d, J=1.5 Hz, 1H), 8.11 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 3.05 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:16].C(O)(=O)C>>[N+:13]([C:11]1[CH:10]=[CH:9][C:8]([OH:16])=[C:7]([N:6]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:12]=1)([O-:15])=[O:14]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: c1ccoc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)c(-n2cccc2)c1
Temperature: 100 °C
Yield: 68 %

Procedure:
Furan, tetrahydro-2,5-dimethoxy- (4.72 g, 0.0357 mol) was added dropwise to 2-Amino-4-Nitrophenol (5.00 g, 0.0324 mol) in Acetic acid (200 mL, 3 mol) and the reaction mixture was heated to 100° C. for 3 h The reaction mixture was concentrated, taken up in EtOAc, washed with sat'd NaHCO3 and brine, was dried over MgSO4, filtered, and concentrated under reduced pressure. Product was obtained as a pale yellow oil (4.51 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=[CH2:24])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].C(Cl)(Cl)Cl.C(OCC)(=O)C>O1CCOCC1.[Pt](=O)=O>[Cl:1][C:2]1[CH:22]=[C:21]([CH2:23][CH3:24])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: C=Cc1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Agent: O=[Pt]=O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Yield: 92.5 %

Procedure:
To a solution of methyl 3-(2-chloro-4-vinylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (230 mg, 0.67 mmol) in 1,4-dioxane (4.6 ml) was added platinum dioxide (23 mg) and the mixture was subjected to catalytic reduction at normal temperature. Six hours later, the reaction mixture was filtered through Celite and the filtrate was concentrated to give black crystals. The obtained crystals were subjected to flash silica gel chromatography (silica gel 40 ml, eluent: chloroform/ethyl acetate=5/1-4/1) and crystallized from diisopropyl ether to give the object compound (213 mg) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:6][C:7](Cl)=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[NH:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:35]1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[C:43]([O:42][C:41]([NH:40][C@@H:36]1[CH2:37][CH2:38][CH2:39][N:34]([C:7]2[N:6]=[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[C:4]([C:1](=[O:3])[NH2:2])=[CH:9][CH:8]=2)[CH2:35]1)=[O:47])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)n2)C1
Temperature: 100 °C
Yield: 87.2 %

Procedure:
A mixture of benzyl 4-(4-(3-carbamoyl-6-chloropyridin-2-ylamino)phenyl)piperazine-1-carboxylate (4 g, 8.58 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (2.58 g, 12.88 mmol), and DIEA (3.00 mL, 17.17 mmol) in N-methyl-2-pyrrolidinone (6 mL) was placed in two capped scintillation vials and heated at 100° C. overnight. The reaction mixtures were quenched with water and filtered. The solid was purified by MPLC chromatography (ISCO, 6% NH4OH/MeOH/CH2Cl2, two 40 g stacked silica gel columns) to give 4.71 g of ((R)-benzyl 4-(4-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-carbamoylpyridin-2-ylamino)phenyl)piperazine-1-carboxylate).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[NH:32][N:31]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=5)[CH:29]=4)=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]1=[O:13].Br[C:41]1(CCOCC)C(=O)NC(=O)NC1=O>>[CH2:1]([O:2][CH2:3][CH2:4][C:5]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[NH:32][N:31]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=5)[CH:29]=4)=[CH:26][CH:27]=3)=[CH:17][CH:16]=2)[C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9][C:10]1=[O:11])[CH3:41]
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: COCCC1(Oc2ccc(Oc3ccc(-c4cc(-c5cccc(F)c5)n[nH]4)cc3)cc2)C(=O)NC(=O)NC1=O
Product: CCOCCC1(Oc2ccc(Oc3ccc(-c4cc(-c5cccc(F)c5)n[nH]4)cc3)cc2)C(=O)NC(=O)NC1=O

Procedure:
By the same procedure as Example 1, Part C, 4-{4-[1-(3-fluorophenyl)-1H-pyrazol-3-yl]-phenoxy}phenol (from Example 71, Part C) and 5-bromo-5-(2-ethoxyethyl)-pyrimidine-2,4,6-trione (from Preparation 3B) were converted to the title compound. MS m/z: ESI+ 545.1 (M+H)+, ESI− 543.3 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[C:4]([CH3:14])[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].CO.CCOC(C)=O>C(N(CC)CC)C.[Cu]I>[CH3:14][C:4]1[CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:13]=[CH:12][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Br)ccc1Cn1ccnc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(C#C[Si](C)(C)C)ccc1Cn1ccnc1
Temperature: 70 °C
Yield: 82 %

Procedure:
Using General Procedure D; 1-(4-bromo-2-methyl-benzyl)-1H-5 imidazole (Intermediate 139, 160.0 mg, 0.64 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (12.0 mg, 0.07 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 0.71 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(1I) (45.0 mg, 0.07 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (140.0 mg, 82%) was isolated by chromatography (5% MeOH-EtOAc) as an orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)([C:14]([O:16]C)=O)[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOC(C)=O>[O:16]=[C:14]1[C@:12]2([CH:11]=[CH:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13]2)[CH2:18][CH2:19][O:20]1
Reactant: COC(=O)[C@@]1(CCO[Si](C)(C)C(C)(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@]2(CCOC2=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Step D (1149 g, 2.875 mol) and THF (5.75 L) was added TBAF (1M in THF, 2.875 L) over ˜1 h. The reaction was stirred for 1 h at rt, and diluted with EtOAc. The organic layer was washed with brine, diluted with heptanes and the organic layer was further washed with water and brine. The organic layer was evaporated, the crystallized product was filtered, and washed with heptanes to provide the product of Step E as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) d=5.86-5.98 (m, 3H), 5.67 (d, J=5.4 Hz, 3H), 5.03-5.20 (m, 2H), 4.76-4.87 (m, 3H), 4.28 (t, J=7.0 Hz, 5H), 2.08-2.31 (m, 8H), 1.99 (d, J=2.4 Hz, 3H), 1.34 (s, 25H).