Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH:8]([PH:20](=[O:22])[OH:21])[NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](=[CH2:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=1>>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH:31]([CH2:37][P:20]([OH:21])([CH:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:22])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:29]=1
Reactant: O=C(NC(Cc1ccccc1)[PH](=O)O)OCc1ccccc1
Reactant: C=C(Cc1ccc(Br)cc1)C(=O)OCC
Product: CCOC(=O)C(Cc1ccc(Br)cc1)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 84.1 %

Procedure:
The process is performed according to the operating conditions described in 1.6., starting with 2 g (6.27 mmol) of [2-phenyl-1-[(phenylmethoxy)carbonyl]aminoethyl]phosphinic acid synthesized in 1.4. and 2 g (7.44 mol) of ethyl 4-bromo-α-methylenebenzenepropanoate. 3.1 g of product are recovered (yield=84.1%)
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:43]([O:45][CH3:46])=[O:44])=[N:23][C:24]=2[NH:28][CH2:29][CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:43]([O:45][CH3:46])=[O:44])=[N:23][C:24]=2[NH:28][CH2:29][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Yield: 93.6 %

Procedure:
A solution of methyl 9-{(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-[(acetyloxy)methyl]-tetrahydro-2-furanyl}-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 15) (2.0 g, 3.17 mmol), sodium carbonate (35 mg) and dry methanol (40 ml) was stirred at room temperature for 3.5 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient elution with dichloromethane:methanol (94:6, by volume) then dichloromethane:methanol (92:8, by volume) to afford the title compound as a white powder (1.5 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)(=[O:3])[CH3:2].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>N1C=CC=CC=1>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)NCCc1cccc(N)c1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cccc(CCNC(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
In pyridine (5 ml) was dissolved 1.7 g of N-acetyl-N-(3-aminophenethyl)amine (Preparation Example 29), followed by dropwise addition of ethyl chloroformate (1.4 ml) under ice-cooling. After stirring at room temperature for 1 hour, the mixture was ice-cooled again. Water was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give the title compound (2.358 g, 97%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:27]=[C:26]([OH:28])[C:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1.N1C=CC=CC=1.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>CN(C)C=O>[CH:35]1([C:38]([O:28][C:26]2[C:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=[C:17]([CH2:16][NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=4)[CH:27]=2)=[O:39])[CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CC1
Reactant: CC1(C)Oc2cc(CN/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc(O)c2O1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1(C)Oc2cc(CN/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc(OC(=O)C3CC3)c2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4Z)-6-bromo-4-({[(7-hydroxy-2,2-dimethyl-1,3-benzodioxol-5-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (30 mg, 67 μmol) in dimethylformamide (0.5 mL) is added pyridine (12 μL, 0.17 mmol) and cyclopropanecarbonyl chloride (10 μL). The reaction mixture is shaken overnight at room temperature and then purified by reverse-phase high performance liquid chromatography to give 6-({[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)-2,2-dimethyl-1,3-benzodioxol-4-yl cyclopropanecarboxylate.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)(=[O:11])[CH3:10].[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>C1COCC1>[CH3:25][Si:26]([CH3:28])([CH3:27])[O:11][C:9]([CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)=[CH2:10]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(O[Si](C)(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of LDA in THF (70 mL) under nitrogen atmosphere, cooled to −78° C. via dry ice/acetone bath, was added tert-butyl 4-acetylpiperidine-1-carboxylate (5 g, 22 mmol) in THF (30 mL) dropwise over 30 min. The resulting mixture was stirred for an additional 30 min and then TMSCl (2.81 mL) was added via syringe dropwise over 10 min and the resulting solution stirred for 1 h at −78° C. Quench with saturated sodium bicarbonate (300 mL) and extracted with ether (2×200 mL). Combined the organics, wash with brine, dry over sodium sulfate, filter, and concentrate under vacuum. The compound obtained (6.0 g, 92%) was used for the next reaction without further purification.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:30][CH:31]([C:33]1[C:34](=[O:50])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=2)=[N:37][N:38]=1)[CH3:32].[C:51]([C:54]([CH3:67])([CH2:58][CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55](O)=[O:56])(=[O:53])[CH3:52]>>[C:51]([C:54]([CH3:67])([CH2:58][CH2:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]([NH:30][CH:31]([C:33]1[C:34](=[O:50])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=2)=[N:37][N:38]=1)[CH3:32])=[O:56])(=[O:53])[CH3:52]
Reactant: CC(=O)C(C)(CCCc1ccccc1)C(=O)O
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(C)(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)cc1OC

Procedure:
The amount of 2-acetyl-2-methyl-5-phenylpentanoic acid in 20 ml dichloromethane from Example 38A is reacted analogously to Example 39A with 300 mg (2.20 mmol) of 1-hydroxy-1H-benzotriazole, 670 mg (6.60 mmol) of 4-methylmorpholine, 420 mg (2.20 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 620 mg (2.14 mmol) of 6-(1-aminoethyl)-3-(3,4-dimethoxybenzyl)-1,2,4-triazin-5(4H)-one to give 2-acetyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-2-methyl-5-phenyl-pentanamide.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:42]=[N:41][C:40]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[N:42]=[N:41][C:40]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CC(C)(O)c1ccc(Cl)nn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(C(C)(C)O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
A solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (50 mg, 0.104 mmol), 2-(6-chloropyridazin-3-yl)-propan-2-ol (20 mg, 0.151 mmol), Pd(PPh3)2Cl2 (30 mg, 0.046 mmol), 2 M aq Cs2CO3 (0.4 mL) in dioxane (5 mL) was heated at reflux for 2 h. The reaction mixture was concentrated, and the residue was treated with water (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layer was washed with satd aq NaCl solution, dried with anhydrous Na2SO4, and concentrated to give an oil, which was purified by preparative TLC and HPLC to give the product. LC-MS Method 2 tR=1.031 min, m/z=490.3; 1H NMR (CD3OD): δ0.89 (s, 1H), 0.96 (s, 3H), 1.28 (m, 6H), 1.57 (d, 3H), 1.66 (m, 6H), 2.15 (s, 2H), 2.28 (m, 1H), 2.56 (m, 2H), 3.08 (m, 1H), 5.62 (m, 1H), 7.13 (d, 2H), 7.38 (m, 5H), 7.82 (m, 2H), 8.05 (m, 2H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:15]=[C:16]([C:31]#[N:32])[C:17]2[CH:18]=[CH:19][CH:20]=[N:21][C:22]=2[C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[F:30][C:26]1[CH:25]=[C:24]([C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]([C:31]#[N:32])=[CH:15][C:14]=2[CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(N)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1

Procedure:
A mixture of 6-bromo-9H-purine (0.0246 g, 0.124 mmol), 7-(1-aminoethyl)-8-(3-fluorophenyl)quinoline-5-carbonitrile (0.018 g, 0.062 mmol), and N,N-diisopropylethylamine (0.0216 mL, 0.124 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C23H17FN7 (M+H)+: m/z =410.2; Found: 410.1.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].[Cl:11][CH2:12][CH2:13][C:14]#[N:15]>C(Cl)Cl.CC(C)=O>[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].[S:1]([NH:5][C:14](=[NH:15])[CH2:13][CH2:12][Cl:11])(=[O:3])(=[O:2])[NH2:4]
Reactant: NS(N)(=O)=O
Reactant: N#CCCCl
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: ClCCl
Product: N=C(CCCl)NS(N)(=O)=O
Temperature: 57.5 °C
Yield: 47.2 %

Procedure:
Sulfamide (9.6 g, 0.1 mole) was added to a solution of methanesulfonic acid anhydrous (48.0 g, 0.5 mole) in 3-chloropropionitrile (51.3 g, 0.6 mole). The suspension was heated at 55-60° C., for 18 hours. At the end of the reacting period, the mixture was diluted with methylene chloride (150 ml), and filtered. The solid, thus obtained, was suspended in acetone (50 ml), and the suspension filtered and the product dried, to yield 13.3 g of product.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:8]([C:7]1[C:2]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Oc1ccccc1
Product: O=[N+]([O-])c1cccnc1Oc1ccccc1

Procedure:
In step (3) of Reaction Scheme IV a 2-chloro-3-nitropyridine of Formula XXIV is reacted with phenol to provide a 3-nitro-2-phenoxypyridine of Formula XXV. Phenol is reacted with sodium hydride in a suitable solvent such as diglyme or tetrahydrofuran to form the phenoxide. The phenoxide is then reacted at ambient temperature, or optionally at an elevated temperature, with a compound of Formula XXIV.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][CH3:22])[C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:8][C:7]([OH:19])=[CH:6][CH:5]=2.[CH2:23]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[C:27]([CH3:29])([O:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:20][CH2:21][CH3:22])[C:2]([CH3:1])=[C:10]2[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:28])[CH3:24]
Reactant: CCCn1c(C)c(CCc2ccccc2)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(C)c(CCc2ccccc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 2-methyl-3-(2-phenyl-ethyl)-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][C@H:19]([CH3:21])[N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:17]([CH3:29])[CH2:16]2)=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5]C)=[O:4].O.[OH-].[Li+]>O.O1CCOCC1>[CH3:28][C:25]([O:24][C:22]([N:18]1[C@@H:17]([CH3:29])[CH2:16][N:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:2]([CH3:1])([CH3:7])[C:3]([OH:5])=[O:4])=[CH:9][CH:10]=2)[CH2:20][C@H:19]1[CH3:21])=[O:23])([CH3:26])[CH3:27]
Reactant: COC(=O)C(C)(C)c1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(C(C)(C)C(=O)O)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.7 %

Procedure:
A mixture of D47 (395 mg, 0.978 mmol) and lithium hydroxide monohydrate (82 mg, 1.95 mmol) in water (5 ml) and 1,4-dioxane (10 ml) was stirred at room temperature for 3 days. The solvents were removed in vacuo and the residue dissolved in water. The solution was washed with ether, acidified to pH4 with 1M HCl then extracted with DCM (×2). The combined organics were dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow foam (316 mg). δH (CDCl3, 250 MHz) 7.35 (4H, m), 4.11 (2H, br), 3.71 (2H, br), 2.67 (2H, br), 2.17 (2H, br), 1.61 (6H, s), 1.46 (9H, s), 1.33 (6H, br d). MS (ES): MH+ 391, (M−H+) 389.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)(=[O:9])[CH3:8]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:1]1([C:13]2[CH2:14][CH2:15][N:10]([C:7](=[O:9])[CH3:8])[CH2:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)N1CC=C(N2CCOCC2)CC1
Yield: 100.1 %

Procedure:
According to Scheme 1, step 1: a mixture of morpholine (67.85 g, 0.779 mol), 1-acetyl-4-piperidone (99.95 g, 0.708 mol) and para-toluenesulfonic acid (0.366 g, 2.1 mmol) in toluene (300 ml) was heated in a Dean-Stark trap apparatus for 16 h at reflux. Solvents were evaporated in vacuo to give 149 g of 1-(4-Morpholin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (1) which was used in the next step without any further purification.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=1)=[O:16])C1C=CC=CC=1>CO.[Pd]>[CH3:27][N:25]([CH3:26])[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][NH:17][C:15](=[O:16])[NH:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][OH:8])=[O:28])=[CH:24][CH:23]=1
Reactant: CN(C)c1ccc(CNC(=O)NCCCC(=O)NOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc(CNC(=O)NCCCC(=O)NO)cc1
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of the N-benzyloxy-4-[3-(4-dimethylamino-benzyl)-ureido]-butyramide (287 mg, 0.747 mmol) in methanol (15 mL) was added 10% palladium on carbon (30 mg) and the resulting reaction was allowed to stir under a hydrogen atmosphere for 18 hr, after which time the reaction mixture was filtered and concentrated in vacuo to provide provide compound 2, which was used without further purification. (203 mg, 92% yield). 1H NMR (300 MHz, DMSO-d6) δ (ppm) 10.38 (s, 1H), 8.69 (s, 1H), 7.06 (d, J=9.0 Hz, 2H), 6.67(d, J=9.0 Hz, 2H), 6.10 (t, J=5.4 Hz, 1H), 5.87 (t, J=5.4 Hz, 1H), 4.06 (d, J=5.7 Hz, 2H), 2.97 (dt, J=6.6, 6.3 Hz, 2H), 2.85 (s, 6H), 1.94 (t, J=7.2 Hz, 2H), 1.57 (m, 2H). 13C NMR (75 MHz, DMSO-d6) δ (ppm) 168.8, 157.9, 149.4, 128.2, 127.9, 112.3, 42.4, 40.2, 38.8, 29.8, 26.3.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[C:41]([F:52])([F:51])[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3C(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-(trifluoromethyl)phenyl)boronic acid gave 270. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.88 (t, J=8.7 Hz, 1H), 7.83 (s, 1H), 7.77 (dd, J=6.5, 1.5 Hz, 2H), 7.72-7.62 (m, 1H), 7.46 (s, 2H), 4.87 (dd, J=8.5, 3.4 Hz, 1H), 4.82-4.60 (m, 1H), 3.97-3.83 (m, 2H), 3.71 (s, 3H), 3.17 (ddt, J=23.0, 9.2, 2.5 Hz, 1H), 2.15-2.04 (m, 1H), 1.86-1.54 (m, 4H). LCMS (ES+) m/z 499 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:9]([OH:13])(=[O:12])[CH:10]=O.S(=O)(=O)(O)O.[OH-].[K+]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:10]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: O=CC(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
Fluorobenzene (13.6 g, 0.142 mol) and glyoxylic acid monohydrate (2.35 g, 0.0255 mol) were dissolved in warm acetic acid (30.0 mL). The mixture was cooled in an ice/water bath and concentrated sulfuric acid (20.0 mL) was added dropwise over 0.5 h. The resulting thick red suspension was stirred at 80° C. for 12 h and then cooled to room temperature. Water (300 mL) was added and the pH was adjusted to 3 with potassium hydroxide pellets and 10% KOH solution. The aqueous solution was extracted with ethyl acetate (3×100 mL) and the combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (5.18 g, 82%) as a red solid, which was used in the subsequent step without further purification: 1H NMR (400 MHz, CD3OD) δ 9.45 (br s, 1H), 7.31–7.25 (m, 4H), 7.06–7.0 (m, 4H), 5.01 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])[CH:8]=2)[N:3]=1.[C:27]1([Mg]Cl)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1COCC1>>[NH:21]=[C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]1[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:18]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[CH:10]2
Reactant: Cc1cccc(C#N)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(C(=N)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 60 °C

Procedure:
To a sealed vessel containing 2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylbenzonitrile (0.10 g, 0.290 mmol, prepared as in Example 14, Step 1) was added phenylmagnesium chloride, 2.0M solution in THF (0.58 mL, 1.161 mmol). The mixture was sonicated until all solids were in solution and then warmed vessel to 60° C. for 15 h. The reaction mixture was cooled to RT and divided into two portions. The imine solution was concentrated in vacuo. The residue was taken up in 2.5 mL MeOH and purified by HPLC (10-100% MeCN/H2O with 0.1% TFA modifier) to afford 6-(2-(imino(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:13]([CH3:24])=[N:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:16]=1[CH3:17])=O)C>O1CCCC1>[CH3:24][C:13]1[C:12]([CH2:10][OH:9])=[C:16]([CH3:17])[N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:14]=1
Reactant: CCOC(=O)c1c(C)nn(-c2ccccn2)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccn2)c(C)c1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
Suspend lithium aluminum hydride (0.359 g, 9.46 mmol) in tetrahydrofuran (25 mL) at −10° C. and add 3,5-dimethyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid ethyl ester (1.160 g, 4.73 mmol) dropwise in tetrahydrofuran (5 mL). Allow the mixture to warm to 25° C. and stir for 4 hr. Cool the mixture to 0° C. then quench carefully with saturated sodium sulfate solution (1 mL). Allow the mixture to stir at room temperature for 2 hr. then filter off the precipitate, dry the solution and concentrate to give (3,5-dimethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-methanol as a yellow solid (0.821 g, 86%). 1H-NMR (400 MHz, DMSO) 8.408 (m, 1H); 7.889 (m, 1H); 7.738 (m, 1H); 7.256 (m, 1H); 4.269 (s, 2H); 2.459 (s, 3H); 2.181 (s, 3H)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1.[C:8](Cl)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>N1C=CC=CC=1>[C:8]([O:1][C@@H:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1C[C@H](O)CO1
Solvent: c1ccncc1
Product: O=C1C[C@H](OC(=O)c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To the solution of (S)-β-Hydroxy-γ-butyrolactone (1.0 g, 9.8 mmol) in 25 mL pyridine was added dropwise BzCl (1.4 mL, 12.2 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was concentrated and coevaporated with toluene two times in vacuo. The residue was partitioned between H2O (15 mL) and EtOAc (40 mL). The organic layer was washed with water and brine, and concentrated in vacuo. The residue was purified by chromatography on a silica gel column (n-hexane/EtOAc=8:1) to afford 101 (1.78 g, 8.6 mmol) as a white solid, in 89% yield, which was characterized as follows: