Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][CH:17](O)[CH:18]=[CH2:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:12]([C:9]([CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:16]/[CH:17]=[CH:18]/[CH3:19])[CH:10]=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC(C=O)CSc1ccccc1
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C/C=C/CC(C=O)(CCCC)CSc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Phenylthiomethyl)hexanal (2.67 g, 12 mmol), 3-buten-2-ol (5 mL, 58 mmol), and p-toluenesulfonic acid (0.05 g, 0.26 mmol) are added to 25 ml of xylenes. The reaction mixture is heated to reflux using a Dean-Stark trap to collect water. After 3 hours, the mixture is cooled to room temperature and diluted with ethyl acetate, which is washed saturated NaHCO3 solution, brine, and dried with MgSO4. After removing solvents, the crude product is purified by chromatography. The product is obtained in 78.6% as a colorless oil.
Reaction SMILES: [Si](OC1C=C(C=CC=1)C(NNC(=O)[C@H](NC1C=CC(C#N)=C(Cl)C=1C)[C@H](O[Si](C(C)(C)C)(C)C)C)=O)(C(C)(C)C)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[Si:64]([O:71][C@@H:72]([CH3:104])[C@@H:73]([NH:93][C:94]1[CH:101]=[CH:100][C:97]([C:98]#[N:99])=[C:96]([Cl:102])[C:95]=1[CH3:103])[C:74]1[O:75][C:76]([C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([O:85][Si:86]([C:89]([CH3:92])([CH3:91])[CH3:90])([CH3:88])[CH3:87])[CH:80]=2)=[N:77][N:78]=1)([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65]>>[Si:64]([O:71][C@H:72]([CH3:104])[C@@H:73]([NH:93][C:94]1[CH:101]=[CH:100][C:97]([C:98]#[N:99])=[C:96]([Cl:102])[C:95]=1[CH3:103])[C:74]1[O:75][C:76]([C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([O:85][Si:86]([C:89]([CH3:90])([CH3:91])[CH3:92])([CH3:87])[CH3:88])[CH:80]=2)=[N:77][N:78]=1)([C:67]([CH3:68])([CH3:69])[CH3:70])([CH3:65])[CH3:66]
Reactant: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
3-(tert-butyldimethylsilyloxy)-N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)benzohydrazide (intermediate 9b) (362 mg, 0.57 mmol) was cyclized with PS-PPh3 (3.0 mmol/g, 389 mg, 1.2 mmol), I2 (289 mg, 1.1 mmol), and TEA (0.65 mL, 4.7 mmol) as described for the preparation of intermediate 7c. After column chromatography (20% EtOAc/hexanes) the title compound was isolated as a white solid (229 mg, 65%). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.56 (m, 1H), 7.44 (m, 1H), 7.33 (m, 2H), 6.98 (m, 1H), 6.62 (d, J=8.8 Hz, 1H), 5.13 (ad, J=9 Hz, 1H), 4.83 (m, 1H), 4.44 (m, 1H), 2.32 (s, 3H), 1.30 (d, J=6.4 Hz, 3H), 0.99 (s, 9H), 0.93 (s, 9H), 0.21 (s, 6H), 0.13 (s, 3H), 0.11 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:5][C:6]([C:9]2[C:10]([CH2:34][CH3:35])=[CH:11][C:12]([CH2:32][CH3:33])=[C:13]([CH:31]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=O)=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:7][N:8]=1)[CH3:2].C(N(CC)CC)C.O(C(C(F)(F)F)=O)C(C(F)(F)F)=O>ClCCl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[NH:5][C:6]([C:9]2[C:10]([CH2:34][CH3:35])=[CH:11][C:12]([CH2:32][CH3:33])=[C:13]([CH:31]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]#[N:28])=[CH:29][CH:30]=3)[CH2:18][CH2:17]2)=[O:15])=[N:7][N:8]=1)[CH3:2]
Reactant: CCOc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C(N)=O)cc4)CC3)c(CC)cc2CC)[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(CC)cc2CC)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a round-bottom flask was added a solution of 4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzamide (compound 204.9, 100 mg, 0.170 mmol, 1.00 equiv) in dichloromethane (10 mL). Triethylamine (170 mg, 1.68 mmol, 8.00 equiv) was added to the reaction at room temperature, followed by dropwise addition of a solution of (CF3CO)2O (160 mg, 0.760 mmol, 4.50 equiv) in dichloromethane (0.5 mL) at 0 to 5° C. The resulting solution was stirred at room temperature for another 2 hours. The mixture was diluted with 60 mL of ethyl acetate, then washed with 3×20 mL of brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by prep-HPLC (SunFire Prep C18, 19*150 mm 5 um, water with 0.05% TFA and CH3CN (53.0% CH3CN up to 65.0% in 8 min, up to 100.0% in 2 min, down to 53.0% in 1 min). The fractions containing pure compound were combined and lyophilized to yield 50 mg (50%) of the title compound as a white solid. m/z (ES+) 458 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.63 (d, 2H), 7.45-7.30 (m, 4H), 4.89-4.80 (m, 1H, overlapped), 4.36 (q, 2H), 3.60-3.57 (m, 1H), 3.29-3.23 (m, 1H), 3.19-2.85 (m, 4H), 2.74-2.56 (m, 2H), 2.00-1.82 (m, 1H), 1.77-1.66 (m, 3H), 1.40 (t, 3H), 1.30-1.21 (m, 3H), 1.11 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([Cl:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][NH:30][CH3:31])=[CH:27][CH:26]=1>CCOCC>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][N:30]([CH3:31])[C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[C:3]([F:22])=[CH:4][C:5]=4[Cl:21])[C:9](=[O:20])[N:10]3[CH3:19])=[CH:15][N:14]=2)=[CH:27][CH:26]=1
Reactant: Cn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: CNCc1ccc(OC)cc1
Solvent: CCOCC
Product: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2Cl)c(=O)n3C)cc1
Temperature: 180 °C
Yield: 89 %

Procedure:
A mixture of 3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (2.5 g, 7.4 mmol) and 4-methoxy-N-methylbenzylamine (4 mL) was heated to 180° C. under N2 for 3 h. After cooling, the reaction mixture was diluted with Et2O. The precipitate was filtered, washed with water, and dried to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 89% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (s, 1H), 7.77 (s, 1H) 7.22 (m, 2H), 7.17 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 5.86 (d, J=9.6 Hz, 1H), 6.30 (s, 1H), 5.32 (s, 2H) 4.87 (s, 1H), 3.72 (s, 3H), 3.52 (s, 3H), 3.09 (s, 3H); MS (ESI) m/z: 453.2[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24](=[O:32])[CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[NH2:33][CH2:34][CH2:35][OH:36]>C(#N)C>[Cl:1][C:2]1[C:3]([NH:23][C:24](=[O:32])[CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:33][CH2:34][CH2:35][OH:36])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: NCCO
Reactant: CS(=O)(=O)O[C@@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Solvent: CC#N
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCCC(NCCO)C3)ccc12
Temperature: 80 °C

Procedure:
N-[6-Chloro-2-[(3R)-3-[(methylsulfonyl)oxy]-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 80(a)) (0.2 g), 2-amino-ethanol (0.075 ml) and acetonitrile (3 ml) were loaded into a 10 ml microwave reaction vial, capped and heated at 80° C. for 90 minutes within a single mode microwave. The solvent was removed under vacuum and the residue was purified by chromatography (SiO2, 7M ammonia in methanol:dichloromethane 1:99 as eluant) to give the title compound as a solid (0.018 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[NH2:33][C:34]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[CH:52][C:35]=1[C:36]([NH:38][C:39]1[CH:43]=[CH:42][N:41]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[C:46]([CH3:51])[CH:45]=2)[N:40]=1)=[O:37]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:51][C:46]1[CH:45]=[C:44]([N:41]2[CH:42]=[CH:43][C:39]([NH:38][C:36]([C:35]3[CH:52]=[C:53]([N:56]4[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]4)[CH:54]=[CH:55][C:34]=3[NH:33][C:14]([C:13]3[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])=[O:37])=[N:40]2)[CH:49]=[CH:48][C:47]=1[CH3:50]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3N)n2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)n2)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (167 mg, 0.56 mmol, 1.10 equiv) in dichloromethane (10 mL), EDC.HCl (148 mg, 0.77 mmol, 1.50 equiv), 4-dimethylaminopyridine (95 mg, 0.77 mmol, 1.50 equiv), and 2-amino-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)-5-(piperidin-1-yl)benzamide (200 mg, 0.51 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1) to yield 150 mg (44%) of product as a green solid.
Reaction SMILES: [Br-].[O:2]=[C:3]1[CH:7]([P+:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4]1>O>[O:2]=[C:3]1[C:7](=[P:8]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][O:4]1
Reactant: O=C1OCCC1[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: O=C1OCCC1=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
2-Oxotetrahydrofuran-3-yltriphenylphosphonium bromide (1.717 g) was dissolved in water (20 mls) and the solution filtered through kieselguhr. The pH was adjusted to 7.5 with 5M sodium hydroxide. The greyish precipitate was filtered off, washed with 50% ether/acetone and dried, to give the title compound as an off white solid, (0.77 g, 55%), (Found; M+, 346.1124. C22H19O2P requires M, 346.1123); νmax (CH2Cl2) 1645, 1480(w), 1430(w), 1365(w) and 1315(w)cm-1 ; δH (CDCl3) 2.62 (2H, t, 7Hz), 4.27 (2H, t, J 7Hz) and 7.3-7.9 (15H, m).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35]C(=O)OCC2C=CC=CC=2)[CH2:31][CH2:30]1.O>CS(C)=O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: NC1CCN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)CC1
Temperature: 100 °C

Procedure:
A mixture of 56.3 mg (0.150 mmol) of 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 211 mg, 0.90 mmol) of benzyl piperidin-4-ylcarbamate in 1.0 ml of dimethyl sulfoxide was heated at 100° C. for 24 hours. The mixture was mixed with water and extracted with ethyl acetate. The organic extracts were washed with water, 1% aqueous citric acid, water, brine, dried over MgSO4 and concentrated. The residue was heated in a mixture of 4 M of hydrogen chloride in 6 ml of dioxane and 2 ml of conc. hydrochloric acid at 60° C. for 18 hours. The mixture was concentrated in high vacuum and triturated with ethyl ether. The solid material was filtered out and washed with ethyl ether to give 144. Yield 13.7 mg (19%) over two steps. ESI MS m/z 372.1 (M+1). 1H NMR (400 MHz, DMSO): 14.17 (s, 1H), 9.41 (s, 1H), 9.29 (s, 1H), 8.99 (s, 1H), 8.93 (d, J=7.9 Hz, 1H), 8.87 (d, J=5.0 Hz, 1H), 8.14 (s, 3H), 8.07-7.99 (m, 1H), 7.76-7.69 (m, 1H), 7.51 (d, J=7.4 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 4.52 (d, J=13.3 Hz, 3H), 3.40 (s, 2H), 3.12 (t, J=11.9 Hz, 2H), 2.08 (d, J=10.1 Hz, 2H), 1.66 (dt, J=12.0, 8.5 Hz, 2H)
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])C.C(OCC)(=O)C>O>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:1])[C:3]([O:20][CH3:18])=[O:4]
Reactant: CC(C)(CO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C(C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-methyl-2-phenyl-propanol (Intermediate 3) (0.5 kg) and pyridine (268 ml) were charged to a reactor and chilled to 0° C. Acetic anhydride (680 gms) was slowly added through a dropper at 10-20° C. The mixture was stirred for 2 hours at 10-20° C. Ethyl acetate (1.5 ltr) was added and chilled water (2 ltrs) was slowly added through a dropper at 10-20° C. The mixture was stirred for ½ hr. The ethyl acetate layer was separated and 10% chilled dilute HCl was added. The ethyl acetate layer was then washed with sodium bicarbonate until a pH of 7 was obtained. The ethyl acetate layer was dried with sodium sulphate and concentrated under vacuum The resulting oil was distilled under vacuum (15 mm of Hg). at 80-100° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>O1CCCC1>[CH:3]1([NH:9][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(NC2CCCCC2)nc1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.99 g, 49.8 mmol) was washed 3× with hexanes then a solution of cyclohexylamine (3.8 mL, 33.2 mmol) dissolved in tetrahydrofuran (50 mL) was added. After stirring for 30 minutes at 22° C., 2-chloro-5-nitropyridine (5.00 g, 31.5 mmol) was added and the reaction mixture was heated to reflux for 3 hours. The solution was cooled to ambient temperature, quenched with saturated aqueous NH4Cl and concentrated in vacuo. The residue was redissolved in ethyl acetate then washed 2× with saturated NaHCO3, saturated NaCl, dried over anhydrous Na2SO4 and concentrated in vacuo. The product was recovered as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:21]=1[CH:9]1[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11](=[O:13])[CH2:12][CH:8]1[CH2:7]2.[C:22]1(C)[CH:27]=CC=C[CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:21]=1[CH:9]1[N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C:11](=[O:13])[CH2:12][CH:8]1[CH2:7]2)[CH:22]=[CH2:23]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2Cc3cccc(Br)c3C21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1cccc2c1C1C(CC(=O)N1C(=O)OC(C)(C)C)C2

Procedure:
A solution tert-butyl 8-bromo-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (Example F10, 700 mg), Pd(PPh3)4 (280 mg, 0.12 equiv.), allyltributylstannate (1.65 g, 2.5 equiv.) in toluene (17 mL) was degassed and stirred at reflux over night. The solvent was removed under vacuum. The residue was taken up in acetonitrile (40 mL) and washed twice with n-hexane. The acetonitrile was removed in vacuo and the residue was purified by flash chromatography eluting with ethyl acetate and cyclohexane (1 to 25%) to give 350 mg of the desired products (mixture of allyl and isomer) F14: LCMS (method E), RT: 1.06 min, [ES+[377, M+CH3CN+Na].
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].[CH2:12]([O:19][N:20]1[C:26](=[O:27])[N:25]2[CH2:28][C@H:21]1[CH2:22][CH2:23][C@H:24]2[C:29](Cl)=[N:30][OH:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.CCOC(C)=O>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:1][C:2]1[O:31][N:30]=[C:29]([C@@H:24]2[CH2:23][CH2:22][C@@H:21]3[CH2:28][N:25]2[C:26](=[O:27])[N:20]3[O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=C1N2C[C@@H](CC[C@H]2C(Cl)=NO)N1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
tert-Butyl prop-2-yn-1-ylcarbamate (0.37 g, 2.4 mmol) was added to the solution of (2S,5R)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbimidoyl chloride (˜2.0 mmol) in dry DCM (20 mL), followed by the addition of TEA (0.31 mL, 2.2 mmol) in dry DCM (2.0 mL) over a period of 30 minutes. The reaction mixture was stirred at rt overnight, then the mixture was diluted with EtOAc, washed with water and saturated sodium chloride. The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (1:2 petroleum ether/EtOAc) to afford tert-butyl((3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)isoxazol-5-yl)methyl)carbamate (180 mg, 21% for two steps) as a white solid. ESI-MS (EI+, m/z): 429.1 [M+H]+. 1H NMR (500 MHz, CDCl3): δ 7.45-7.35 (m, 5H), 6.24 (s, 1H), 5.09 (d, J=11.5 Hz, 1H), 4.93 (d, J=11.5 Hz, 1H), 4.58 (d, J=7.5 Hz, 1H), 4.43 (m, 2H), 3.32 (s, 1H), 2.86-2.84 (m, 1H), 2.68 (d, J=11.5 Hz, 1H), 2.34-2.30 (m, 1H), 2.23-2.18 (m, 1H), 2.10-2.04 (m, 1H), 1.82-1.78 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:17][C:18]([OH:20])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.Cl.[CH3:40][C@H:41]1[NH:47][CH2:46][CH2:45][CH2:44][NH:43][C:42]1=[O:48]>ClCCl.CN(C=O)C>[C:8]([O:12][C:13]([NH:15][C@H:16]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:17][C:18]([N:47]1[CH2:46][CH2:45][CH2:44][NH:43][C:42](=[O:48])[C@H:41]1[CH3:40])=[O:20])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: C[C@H]1NCCCNC1=O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@@H]1C(=O)NCCCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 28 h

Procedure:
To a solution of N-methylmorpholine (0.38 μL) and (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (1.0 g) in 20 mL of dichloromethane at −20° C. was added isobutyl chloroformate (0.39 mL). The resultant mixture was stirred for 1 h. (3R)-hexahydro-3-methyl-2H-1,4-diazepin-2-one hydrochloride (500 mg) and N-methylmorpholine (0.40 mL) in dichloromethane (5 mL) and DMF (8 mL) were added. The mixture was stirred for 28 h, initially at −20° C. and then with slow warming to ambient temperature. The reaction was quenched by the addition of saturated ammonium chloride solution and extracted sequentially with dichloromethane and ethyl acetate. The combined organic layer was washed sequentially with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography (silica gel, 3 to 7% 10:1 methanol/concentrated ammonium hydroxide in dichloromethane) to afford the coupled product. This was further purified by dissolving the product in a mixture of ethanol (7.5 mL) and hexane (16 mL) at 50° C. The solution was allowed to cool to ambient temperature overnight, and then placed in the refrigerator for 3 h. The solid was collected and washed with cold 5% ethanol/hexane to give the title compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[C:16]2[O:15][CH2:14][CH2:13][C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1>CO>[CH3:1][O:2][CH2:5][C:6]1[C:16]2[O:15][CH2:14][CH2:13][C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C1=Cc2cccc(CCl)c2OCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cccc2c1OCCC(C(=O)OC)=C2
Reaction time: 2 h

Procedure:
28% Sodium methoxide in methanol (1.2ml) was added to a solution of methyl 2,3-dihydro-9-chloromethyl-1-benzoxepin-4-carboxylate (0.8 g) in methanol (8 ml) under ice-cooling and the mixture was stirred at the same temperature for 2 hours. The solvent was removed by concentration and to the residue was added a mixture of ethyl acetate and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give methyl 2,3-dihydro-9-methoxymethyl-1-benzoxepin-4-carboxylate (0.48 g).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](F)[C:12]([F:16])=[CH:11][C:3]=1[C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([OH:29])[CH:21]=[N:22][C:23]=1[O:24][CH:25]1[CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:17][C:18]1[CH:19]=[C:20]([O:29][C:13]2[C:12]([F:16])=[CH:11][C:3]([C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5])=[C:2]([F:1])[CH:14]=2)[CH:21]=[N:22][C:23]=1[O:24][CH:25]1[CH2:28][CH2:27][CH2:26]1
Reactant: Oc1cnc(OC2CCC2)c(Cl)c1
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(Oc2cnc(OC3CCC3)c(Cl)c2)cc1F
Temperature: 90 °C
Yield: 11.8 %

Procedure:
2,4,5-trifluoro-N-(methylsulfonyl)benzamide (Preparation 27, 0.317 g, 1.25 mmol), 5-chloro-6-cyclobutoxypyridin-3-ol (Preparation 19, 0.250 g, 1.25 mmol) and potassium carbonate (0.346 g, 2.50 mmol) were suspended in DMSO (16 mL) and heated at 90° C. for 48 hours. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×20 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 20% EtOAc (with 0.5% AcOH) in heptane to afford the title compound as a white solid (64 mg, 12%):
Reaction SMILES: ClC1C=CC([C@@H](C2C=CN(C)N=2)N)=CC=1F.[F:17][C:18]1[CH:19]=[C:20]([C@@H:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[NH2:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[CH:34]1([CH2:37][NH:38][C:39]2[N:48]=[CH:47][C:46]3[C:41](=[CH:42][C:43]([C:50](O)=[O:51])=[CH:44][C:45]=3[F:49])[N:40]=2)[CH2:36][CH2:35]1>>[F:17][C:18]1[CH:19]=[C:20]([C@H:26]([NH:27][C:50]([C:43]2[CH:42]=[C:41]3[C:46]([CH:47]=[N:48][C:39]([NH:38][CH2:37][CH:34]4[CH2:35][CH2:36]4)=[N:40]3)=[C:45]([F:49])[CH:44]=2)=[O:51])[C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Reactant: O=C(O)c1cc(F)c2cnc(NCC3CC3)nc2c1
Agent: Cn1ccc([C@@H](N)c2ccc(Cl)c(F)c2)n1
Product: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(NCC4CC4)nc3c2)c2cnn(C)c2)cc1F

Procedure:
2-(Cyclopropylmethyl-amino)-5-fluoro-quinazoline-7-carboxylic acid [(S)-(3-fluoro-4-methoxy-phenyl)-(1-methyl-1H-pyrazol-4-yl)-methyl]-amide (I-60) was prepared analogously except 32b was replaced with 40f and 84b was replaced with 87c.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13](O)=[O:14])=[C:10]([F:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(Cl)(=O)C([Cl:20])=O.CN(C)C=O>ClCCl>[F:1][C:2]1[C:11]([CH2:12][C:13]([Cl:20])=[O:14])=[C:10]([F:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1c(F)cc2ncccc2c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1c(F)cc2ncccc2c1F
Temperature: 0 °C

Procedure:
(5,7-Difluoro-quinolin-6-yl)-acetic acid (1 g, 4.48 mmol) was added to an oven-dried round-bottom flask and suspended in dichloromethane (18 ml) The suspension was maintained under nitrogen atmosphere and cooled to 0° C. Next, the oxalyl chloride (470 uL, 5.38 mmol) was added slowly, followed by a catalytic amount of dimethylformamide. The solution was allowed to warm to room temperature over 2 hours. The solution was then concentrated in vacuo and dried via azeotropic distillation with toluene to afford the title compound. ES-MS m/z: 238 (M+H+) of methyl ester.