Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]([CH2:15]P(OC)(OC)=O)=[O:14].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][C:31]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([CH:35]=O)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(OC(N1CCNC(CC2C=CC(F)=CC=2F)(C=O)C1)=O)(C)(C)C>C(Cl)Cl.CCOC(C)=O.O.C1COCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][C:31]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([CH:35]=[CH:15][C:13]([O:12][CH3:11])=[O:14])[CH2:30]1)=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNC(C=O)(Cc2ccccc2)C1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: CC(C)(C)OC(=O)N1CCNC(C=O)(Cc2ccc(F)cc2F)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C=CC1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a THF (1 mL) solution of NaHMDS at 0° C. was added trimethyl phosphonoacetate (0.18 mL, 1.1 mmol), dropwise. After stirring for 1 hour, a THF (1 mL) solution of crude 3-benzyl-3-formyl-piperazine-1-carboxylic acid tert-butyl ester (0.34 mg, 0.92 mmol), prepared analogous to the compound of Example 198, Step A, was added and the reaction was allowed to warm to room temperature. After stirring for 16 hours, the product was isolated by extraction from water with EtOAc (2×) and methylene chloride (2×). The combined extracts were washed with brine, dried (MgSO4) and concentrated. The product was then purified by silica gel chromatography using methylene chloride, then 5% MeOH in methylene chloride as eluents to afford a 7:3 E:Z mixture of olefins of the compound of Example 201, Step A (0.38 g, 81%), where the Z isomer had lactamized: +APcI MS (M+1, ester)+ 361, (M-tBu+1, ester)+ 305, (M-tBu+1, lactam)+ 273, (M-BOC+1, ester)+ 261, (M-BOC+1, lactam)+ 229; 1H NMR (400 MHz, CDCl3) δ: 7.30-7.05 (arom, series of m, 5H), 6.91 (lactam olefin, d, 0.3H), 6.75 (ester olefin, d, 0.7H), 6.09 (lactam olefin, d, 0.3H), 5.88 (ester olefin, d, 0.7H), 3.71 (ester Me, s, 2.1H), 1.47 (BOC, s, 9H),
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[C:4]([C:17]2[CH:18]=[N:19][C:20](S(CCC)(=O)=O)=[N:21][CH:22]=2)[CH:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:20]1[N:21]=[CH:22][C:17]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=2[O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:18][N:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CCCS(=O)(=O)c1ncc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cn1
Product: O=C(O)COc1ccc(Cl)cc1-c1cnc(NCc2ccccc2)nc1

Procedure:
The title compound was prepared from the product of example 20 step (iv) and benzylamine by the method of example 20 step (v).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10]1.Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[CH2:35][C:36]([OH:38])=[O:37]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:12][C:13]([CH2:20][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH2:35][C:36]([OH:38])=[O:37])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)CC1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ccccc2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(=O)O)NC(c2ccccc2)=NC1c1ccc(F)cc1Br
Yield: 49 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate (0.76 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.28 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.42 g, 49%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[C:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]
Reactant: O=C(Nc1ccccc1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)c1cn(-c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.3 %

Procedure:
A solution of 15.0 g of 1,2-dihydro-4-hydroxy-1-phenyl-N-phenyl-3-quinolinecarboxamide in 250 ml of toluene was treated with 60.0 g of activated manganese dioxide and stirred at room temperature for four hours. The slurry was filtered and evaporated. The residue was purified first by flash chromatography (silica gel: dichloromethane as eluent), and then by high pressure liquid chromatography (silica gel: dichloromethane). Recrystallization of the residue from dichloromethane yielded 6.75 g (45%) of 1,4-dihydro-4-oxo-1-phenyl-N-phenyl-3-quinolinecarboxamide, m.p. 203°-205° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1.[F:30][C:31]([F:37])([F:36])[CH:32]=[CH:33][C:34]#[N:35]>>[C:34]([CH2:33][CH:32]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:28])([F:27])[F:29])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1)[C:31]([F:37])([F:36])[F:30])#[N:35]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cn[nH]c4)cnn23)c1
Reactant: N#CC=CC(F)(F)F
Product: N#CCC(n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1)C(F)(F)F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 89, Step 2 starting from N-{3-[7-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 4,4,4-trifluorobut-2-enenitrile. LCMS (M+H)+: m/z=523.1.
Reaction SMILES: N#N.Cl.[F:4][C:5]1([F:10])[CH2:9][CH2:8][NH:7][CH2:6]1.Br[CH2:12][CH2:13][CH2:14][C:15]#[N:16].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:4][C:5]1([F:10])[CH2:9][CH2:8][N:7]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:6]1
Reactant: FC1(F)CCNC1
Reactant: N#CCCCBr
Agent: Cl
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: NCCCCN1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 3,3-difluoropyrrolidine hydrochloride (250 mg, 1.69 mmol) and 4-bromobutyronitrile (0.17 mL, 1.69 mmol) in dry CH3CN (9 mL) was added K2CO3 (1.28 g, 9.29 mmol) at rt followed by KI (28 mg, 0.17 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was filtered and the filtrate partitioned between water and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (8 mL) and treated with LiALH4 (75 mg, 1.92 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Sat. aq. Rochelle's salt solution and EA were then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 4-(3,3-difluoropyrrolidin-1-yl)butan-1-amine as a colorless oil. GC-MS-conditions 01: tR=1.56 min; [M+H]+=179.10.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[S:11][C:10]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1.[CH3:19][NH:20][NH2:21]>O>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][C:7]1[S:11][C:10]([C:12]2[CH2:13][CH2:14][C:15](=[O:17])[N:20]([CH3:19])[N:21]=2)=[CH:9][CH:8]=1
Reactant: CNN
Reactant: O=C(O)CCC(=O)c1ccc(Cc2ncc[nH]2)s1
Solvent: O
Product: CN1N=C(c2ccc(Cc3ncc[nH]3)s2)CCC1=O
Temperature: 90 °C

Procedure:
A mixture of 8.7 g of 4-[5-(1-imidazolylmethyl)-thien-2-yl]-4-oxobutyric acid, 2.9 ml methylhydrazine and 100 ml water was heated at 90° C. for 2 hours. After cooling, the precipitated solid was filtered off, dissolved in chloroform, the chloroform phase washed with dilute caustic soda solution and with water, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (Silica gel//chloroform) and finally recrystallized from ethanol.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([NH2:21])[CH2:17][CH:18]([CH3:20])[CH3:19]>>[CH2:16]([NH:21][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: CC(C)CCN
Product: CC(C)CCNC(=O)c1cccc(-c2ccccc2)c1

Procedure:
Using Preparation Method 1, 3-phenylbenzoic acid was reacted with isoamylamine. The resulting reaction mixture was purified using SiO2 with CH2Cl2 100%. An off-white crystalline solid was obtained (61%). NMR 1H (ppm, CDCl3): 7.96 (s, 1H), 7.69 (d, J3=8.3 Hz, 2H), 7.59 (d, J3=7.2 Hz, 2H), 7.50-7.33 (m, 4H), 6.10 (br. s., 1H), 3.52-3.45 (m, 2H), 1.76-1.64 (m, 1H), 1.52 (quart., 2H), 0.95 (d, J3=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:19][CH:17]([CH2:18]2)[C:16](=[O:20])[N:15]([CH2:21][CH2:22][CH3:23])[C:14]3=[O:24])=[CH:9][CH:8]=1.O>C(Cl)Cl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]23[CH2:18][CH:17]([CH2:19]2)[C:16](=[O:20])[N:15]([CH2:21][CH2:22][CH3:23])[C:14]3=[O:24])=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCN1C(=O)C2CC(c3ccc(NS(C)(=O)=O)cc3)(C2)C1=O
Reaction time: 5 h

Procedure:
A solution of 0.31 ml of methanesulphonic acid chloride in 3 ml of methylene chloride is added at room temperature to a solution of 1.03 g of 1-(4-aminophenyl)-3-n-propyl-3azabicyclo[3.1.1]heptane-2,4-dione and 24 mg of 4-dimethylaminopyridine in 10 ml of pyridine. After stirring for 5 hours, 50 ml of water are added, and the mixture is left to stand overnight at 0°-5°. Extraction is carried out with methylene chloride, and the organic phase is washed in succession with water, cold 2N hydrochloric acid, water, semi-saturated bicarbonate solution and water. After drying over magnesium sulphate, the mixture is filtered and concentrated by evaporation, and the residue is recrystallised from methanol. The title compound is obtained in the form of white crystals having a melting point of 159°-160°. Rf (hexane/ethyl acetate 1:1)=0.15.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(#N)C>[C:6]1([CH:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:3][CH2:2][CH2:1][NH2:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: NCCN
Solvent: CC#N
Product: NCCNC(c1ccccc1)c1ccccc1

Procedure:
A mixture of 90.15 g of ethylenediamine, 50.7 g of benzhydryl chloride and 300 ml of acetonitrile is heated under reflux for 24 hours. It is partitioned between 400 ml of diethyl ether and 175 ml of 10% sodium hydroxide solution, the ether phase is separated off, dried over magnesium sulphate, evaporated to dryness and distilled under reduced pressure. N-diphenylmethylethylenediamine is obtained, b.p.0.13 =116°-124° C., m.p. 23°-24° C.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][O:16][C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C@@H:20]2[C@@H:19]([CH2:27][OH:28])[O:18]1>>[CH3:15][O:16][C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C@@H:20]2[C@@H:19]([CH2:27][O:28][C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=2[C:6]#[N:7])[O:18]1
Reactant: CO[C@@H]1O[C@H](CO)[C@H]2OC(C)(C)O[C@@H]12
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CO[C@@H]1O[C@H](COc2cccc([N+](=O)[O-])c2C#N)[C@H]2OC(C)(C)O[C@@H]12
Yield: 70 %

Procedure:
Prepared as in Example 111c from 2,6 dinitrobenzonitrile and ((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol in 70% yield as white solid. 1H NMR (400 MHz, CDCl3) δ 1.33 (s, 3H), 1.49 (s, 3H), 3.32 (s, 3H), 4.23 (d, J=2.0 Hz, 1H), 4.24 (s, 1H), 4.60 (br t, J=6.0 Hz, 1H), 4.67 (d, J=6.0 Hz, 1H), 4.86 (br d, J=6.0 Hz, 1H), 5.01 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.72 (t, J=8.4 Hz, 1H), 7.87 (dd, J=0.8, 8.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]([O:33][C@H:34]([CH3:52])[CH2:35][N:36]1[C:40]([CH3:41])=[C:39]([C:42](O)=[O:43])[C:38](=[O:45])[N:37]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]([O:33][C@H:34]([CH3:52])[CH2:35][N:36]1[C:40]([CH3:41])=[C:39]([C:42](=[O:43])[NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)[C:38](=[O:45])[N:37]1[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:32])=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C[C@@H](C)OC(=O)CNC(=O)OC(C)(C)C
Reactant: COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CNC(=O)OC(C)(C)C)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Yield: 75.8 %

Procedure:
To a solution of 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine (399 mg, 1.38 mmol), (R)-1-(2-(2-(tert-butoxycarbonylamino)acetoxy)propyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (500 mg, 1.15 mmol) in dry CH2Cl2 (5 mL) was added EDCI (264 mg, 1.38 mmol) and HOAT (32 mg, 0.23 mmol). The mixture reaction was refluxed for 3 h. The reaction mixture was then concentrated in vacuo and the residue was purified by a silica gel column chromatography (100% EtOAc) to give the title compound as a white solid (610 mg, 76%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([CH:18](C(OCC)=O)C(OCC)=O)[C:12]=2[N+:29]([O-:31])=[O:30])=[CH:6][CH:5]=1>Cl>[CH3:17][C:15]1[N:16]=[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][OH:1])=[CH:9][CH:8]=2)[C:12]([N+:29]([O-:31])=[O:30])=[C:13]([CH3:18])[N:14]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1nc(C)nc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]
Agent: Cl
Product: Cc1nc(C)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Yield: 71.2 %

Procedure:
A mixture of diethyl 2-(6-{[4-(2-hydroxyethyl)phenyl]amino}-2-methyl-5-nitro-4-pyrimidinyl)propanedioate (step 2, 2.0 g, 6.48 mmol) in 2N aqueous HCl (15 ml) was heated at reflux temperature for 5 h. After cooling, the reaction was quenched with saturated NaHCO3 aqueous solution (100 ml), and the whole was extracted with ethyl acetate (100 ml×3). The organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (gradient elution from 1:1 to 0:100) to afford 1.33 g (71%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=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>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1B(O)O
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1-c1cccnc1
Temperature: 110 °C

Procedure:
(3-Bromo-2-methylphenyl)boronic acid (3 g, 13.96 mmol) and 3-bromopyridine (2.69 ml, 27.92 mmol) in toluene (24 ml) were stirred under argon, then Na2CO3 (5.18 g, 48.86 mmol) and Pd(PPh3)4 (161 mg, 0.14 mmol) were added and the reaction was heated to 110° C. for 48 h. The solvent was evaporated and after addition of ethyl acetate the organic layer was filtered through Celite, then washed with water and dried with Na2SO4, evaporated to dryness and the product was obtained and used without further purification in step 22.2. Yield: 3.01 g, 87
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.Cl.C([O:13][C@@H:14]1[C@@H:55]([O:56]C(=O)C)[C@H:54]([O:60]C(=O)C)[C@@H:53]([CH2:64][O:65]C(=O)C)[O:52][C@H:15]1[O:16][C:17]1[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][C:35]4([CH2:43][CH2:42][N:41]([C:44](=[O:47])[CH2:45][NH2:46])[CH2:40][CH2:39]4)[CH2:34]3)=[CH:25][C:24]=2[CH3:48])=[C:20]([CH:49]([CH3:51])[CH3:50])[NH:19][N:18]=1)(=O)C.C(N(C(C)C)CC)(C)C>ClCCl>[C@@H:15]1([O:16][C:17]2[C:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][CH2:36][C:35]5([CH2:43][CH2:42][N:41]([C:44](=[O:47])[CH2:45][NH:46][C:6]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH2:40][CH2:39]5)[CH2:34]4)=[CH:25][C:24]=3[CH3:48])=[C:20]([CH:49]([CH3:51])[CH3:50])[NH:19][N:18]=2)[O:52][C@H:53]([CH2:64][OH:65])[C@@H:54]([OH:60])[C@H:55]([OH:56])[C@H:14]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)CN)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)CN=C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(/C=C/CCN2CCCC3(CCN(C(=O)CNC(=O)NCC(C)C)CC3)C2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
Add isobutyl isocyanate (77 mg, 0.78 mmol) to a solution of 4-(4-{(1E)-4-[9-(aminoacetyl)-2,9-diazaspiro[5.5]undec-2-yl]but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (350 mg, 0.39 mmol) and diisopropylethylamine (302 mg, 2.34 mmol) in dichloromethane (1.0 mL). After 30 min at room temperature, concentrate to dryness under the reduced pressure. Treat the residue with 2.0 M NH3/methanol (1.0 mL) for 3 hours at room temperature, remove the solvent under the reduced pressure. Purify the resulting residue by preparative HPLC method: high pH, 29% B for 4 min, 29-44% B for 5 min @ 85 mL/min using a 30×75 mm, 5 um C18XBridge ODB column, solvent A—H2O w NH4HCO3 @ pH 10, solvent B—acetonitrile to yield the title compound as solid (134 mg, 0.18 mmol). MS (m/z): 755.2 (M+1), 753.2 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][CH2:7][CH:6]([NH2:15])[CH2:5]2.C=O>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][CH2:7][CH:6]([N:15]([CH2:5][CH2:4][CH3:9])[CH2:11][CH2:2][CH3:3])[CH2:5]2
Reactant: NC1CNc2c(cc(Br)cc2[N+](=O)[O-])C1
Agent: C=O
Solvent: O=CO
Product: CCCN(CCC)C1CNc2c(cc(Br)cc2[N+](=O)[O-])C1
Temperature: 100 °C
Yield: 0.2 %

Procedure:
A mixture of 6-bromo-1,2,3,4-tetrahydro-8-nitro-3-quinolinamine (1.5 g, 5.5 mol), 37% aqueous formaldehyde (1.8 mL) and formic acid (10 mL) was heated at 100° C. for 1 hour. The solution was then evaporated, partitioned between ethyl acetate (200 mL) and 4 N sodium hydroxide solution (10 mL), and the ethyl acetate was evaporated to give a red oil. This was chromatographed on silica gel to give 1.58 g of 6-bromo-1,2,3,4-tetrahydro-8-nitro-N,N-dipropyl-3-quinolinamine. The product was crystallized from ethyl acetate:hexane; mp 88°-91° C. Anal. Calcd. for C11H14BrN3O2 : C, 44.01; H, 4.70; Br, 26.62; N, 14.00. Found: C, 44.04; H, 4.89; Br, 26.62; N, 13.97.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][N:15]([C:19](=[O:23])[CH2:20][C:21]#[N:22])[C:14]=3[CH:24]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:26](N)[CH2:27][NH2:28]>>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][N:15]([C:19](=[O:23])[CH2:20][C:21]4[NH:28][CH2:27][CH2:26][N:22]=4)[C:14]=3[CH:24]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCC(=O)N1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Reactant: NCCN
Agent: Cl
Product: O=C(CC1=NCCN1)N1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21

Procedure:
1-(6-Benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-(4,5-dihydro-1H-imidazol-2-yl)-ethanone was prepared by treatment of 3-(6-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-oxo-propionitrile with HCl followed by ethylene diamine using the procedure described in Example 2. mp: 114-116.1° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][N:3]=1.[H-].[Na+].[C:14]1(C)C=CC=CC=1.C(OC(=O)C)C.CC1C=CC(C(OC)=O)=CN=1>C(OCC)(=O)C.O.CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:8])[CH3:14])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(C)nc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
50 g of methyl 6-methylnicotinate was dissolved in 200 ml of ethyl acetate; 60% NaH 26.5 g, toluene 400 ml and DMF 34 ml were added to a three-necked bottle, 10% methyl 6-methylnicotinate ethyl acetate solution 20 ml was added, heated to 80° C., stirred for 0.5 h. To the reaction bottle, the residual methyl 6-methylnicotinate ethyl acetate solution was added dropwise slowly within about 1.5 h. After addition, the reaction was conducted at 80° C. for 8 h. The reaction stopped, cooled to room temperature. 300 ml of water was added to the reaction bottle, skimmed, the water layer was extracted with ethyl acetate three times, 200 ml per time. All ethyl acetate layers were combined, distillated at a reduced pressure to evaporate ethyl acetate, then 10% H2SO4 aqueous solution 400 ml was added, heated to 110° C., refluxed for 2 h. The reaction was then stopped, cooled to room temperature. Solid K2CO3 was used to adjust PH to 9, suction filtration was performed, the filter cake was washed with ethyl acetate. The filtrate was extracted with ethyl acetate four times, combined and rotary evaporated to dry, to obtain 35 g of 2-methyl-5-acetylpyridine, yield was about 65%.