Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[C:24](=O)[C:25]([N:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])=O)(C)(C)C.[F-].[Cs+].C[Si]([N:43]=[C:44]=[N:45][Si](C)(C)C)(C)C.Cl.C(=O)(O)[O-]>C(#N)C>[NH2:43][C:44]1[N:45]=[C:24]([C:25]([N:27]2[CH2:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:35]2)=[O:26])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([CH:15]([CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=2)[N:8]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CCCC(C(=O)OCC)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CC#N
Product: CCCC(C(=O)OCC)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.4 g of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]pentanoate are dissolved in 50 ml of acetonitrile under argon. 431 mg of caesium fluoride and 769 μl of bis(trimethylsilyl)carbodiimide are added to the solution. The mixture is stirred at room temperature for 15 min, and 6 ml of hydrochloric acid (1N) are then added, and the mixture is neutralised using bicarbonate. The aqueous phase is washed three times with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo. Yield: 1.1 g (92%) of ethyl 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]pentanoate (oil); LC-MS retention time: 1.84 min (“nonpolar” gradient).
Reaction SMILES: [C:1]1(B2OC(C)(C)C(C)(C)O2)[CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:15][C:16]1[CH:21]=[C:20]([C:1]2[CH2:5][CH2:4][CH2:3][CH:2]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1cc(I)ccn1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
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: O
Solvent: C1COCCO1
Product: Clc1cc(C2=CCCC2)ccn1
Temperature: 90 °C
Yield: 85.8 %

Procedure:
To a solution of 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (681 mg, 3.51 mmol) and 2-chloro-4-iodopyridine (700 mg, 2.92 mmol) in 1,4-dioxane (12 mL) was added 2.0 M aqueous Na2CO3 (4.39 mL, 8.77 mmol) and tetrakis(triphenylphosphine)palladium(0) (67.6 mg, 0.059 mmol). The reaction mixture was heated at 90° C. for 3.5 h then cooled to room temperature, diluted with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (0% to 10% EtOAc/hexanes) to afford 450 mg (86%) of 2-chloro-4-cyclopent-1-enyl-pyridine as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)=[C:6]([N+:22]([O-])=O)[CH:5]=[N:4]1)[CH3:2].[C:25]([O:29][C:30]([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:36]1[S:37][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:34]([C:46](=[O:47])[NH:22][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[N:8]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)[N:35]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CCn1ncc([N+](=O)[O-])c1N1CCC[C@H](NC(=O)C(F)(F)F)CC1
Product: CCn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@H](NC(=O)C(F)(F)F)CC1
Yield: 66 %

Procedure:
Following the procedure for Example 517 starting with (S)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave (S)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (151 mg, 66%). 1H-NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.75 (s, 1H), 7.95 (s, 1H), 7.45-7.34 (m, 1H), 7.12-7.02 (m, 2H), 6.37 (d, J=8 Hz, 1H), 4.23-4.16 (m, 1H), 4.05 (q, J=7 Hz, 2H), 3.43-3.31 (m, 2H), 3.25-3.15 (m, 2H), 2.22-2.05 (m, 2H), 2.03-1.89 (m, 2H), 1.89-1.72 (m, 2H), 1.55 (s, 9H), 1.46 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[CH2:14]([O:16][CH:17]([O:22][CH2:23][CH3:24])[CH2:18][N:19]=[C:20]=[S:21])[CH3:15]>C(O)C>[CH2:23]([O:22][CH:17]([O:16][CH2:14][CH3:15])[CH2:18][NH:19][C:20]([NH:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2)=[S:21])[CH3:24]
Reactant: CCOC(CN=C=S)OCC
Reactant: Cc1ccc2c(N)c(F)ccc2n1
Solvent: CCO
Product: CCOC(CNC(=S)Nc1c(F)ccc2nc(C)ccc12)OCC

Procedure:
To 17.85 g (0.1013 mole) of 5-amino-6-fluoro-2-methylquinoline was added 19.5 g (0.1114 mole) of 2,2-diethoxyethylisothiocyanate and the mixture was heated at 80°-90° C. for 1.5 hours. The residue was slurried in ethanol, separated by filtration, washed with ethanol and then recrystallized from ethanol to provide N-(2,2-diethoxyethyl)-N'-(6-fluoro-2-methylquinolin-5-yl)thiourea, m.p. 189°-191° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O)[O:22][CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([N:34](CC)[CH2:35]C)C.[Cl-]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([O:22][CH3:23])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:34]([CH3:35])[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: COC(COCCCCCCCCCCCCC1CCCCC1)COCCOCCO
Agent: [Cl-]
Solvent: ClCCl
Product: COC(COCCCCCCCCCCCCC1CCCCC1)COCCOCCN(C)C
Reaction time: 1 h
Yield: 110.7 %

Procedure:
5.95 g (13.4 millimole) of 1-O-(12-cyclohexyldodecyl)-3-O-[2-(2-hydroxyethoxy)ethyl]-2-O-methylglycerol was dissolved in 30 ml of dichloromethane, to which 1.76 g (17.4 millimole) of triethylamine was added, and then 1.84 g (16.1 millimole) of methaneslfonyl chloride was added dropwise over a period of 30 minutes under ice cooling. The reaction mixture was stirred at the same temperature for 1 hour, washed with water, and dried over anhydrous magnesium sulfate. Dichloromethane was distilled off to give 7.0 g of colorless oil. 2.0 g of this product was dissolved in 10 ml of 20% dimethylamine in toluene, and stirred at room temperature overnight and then at 30° C. for 4 hours, and then concentrated under reduced pressure. To the residue were added 30 ml of dichloromethane and 10 ml of saturated aqueous solution of sodium hydrogencarbonate, and the mixture was shaken thoroughly. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel (50 g) column chromatography, and eluted with chloroform-methanol (6:1), to give the above-captioned compound as colorless oil. Yield: 1.5 g (83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([C:23]([NH2:25])=[O:24])[O:20][C:19]2=[O:26])[CH:5]=[C:6]([F:17])[C:7]=1[C:8]1([CH3:16])[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]1.[CH3:27]N>CO>[CH3:27][NH:25][C:23]([C@@H:21]1[O:20][C:19](=[O:26])[N:18]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([C:8]3([CH3:16])[CH2:9][N:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11]3)=[C:6]([F:17])[CH:5]=2)[CH2:22]1)=[O:24]
Reactant: CN
Reactant: COC(=O)N1CC(C)(c2c(F)cc(N3C[C@H](C(N)=O)OC3=O)cc2F)C1
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c(C3(C)CN(C(=O)OC)C3)c(F)c2)C(=O)O1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
A suspension of methyl (5R)-3-[3,5-difluoro-4-(1-methoxycarbonyl-3-methylazetidin-3-yl]-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 57, Step 4, 500 mg, 1.30 mmol) in MeOH (10 mL) is heated at 50° C. to achieve full dissolution, then cooled to 0° C. and treated with methylamine (15 mL, 2.0 M in MeOH). The reaction mixture is stirred for 20 min at 0° C. and then concentrated under reduced pressure. Trituration (Et2O) affords the title compound as a white solid in 90% yield; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, 1H), 7.35 (d, 2H), 5.09 (dd, 1H), 4.26 (m, 2H), 4.25 (t, 1H), 4.02 (dd, 1H), 3.86 (d, 2H), 3.56 (s, 3H), 2.66 (d, 3H), 1.56 (s, 3H); hMS (ESI) calcd for C17H19F2N3O5+H1 384.1371, found 384.1360; [α]25D=−35 (c 0.90, DMSO).
Reaction SMILES: C(OC([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.CS(C)=O.[NH2:28][C:29]1[CH:38]=[C:37](F)[C:36]([O:40][CH3:41])=[C:35]2[C:30]=1[C:31](=[O:49])[C:32]([C:46]([OH:48])=[O:47])=[CH:33][N:34]2[C@@H:42]1[CH2:44][C@@H:43]1[F:45]>C(Cl)(Cl)Cl>[NH2:28][C:29]1[CH:38]=[C:37]([N:14]2[CH2:15][CH2:16][C@@H:12]([C:9]3([NH2:8])[CH2:10][CH2:11]3)[CH2:13]2)[C:36]([O:40][CH3:41])=[C:35]2[C:30]=1[C:31](=[O:49])[C:32]([C:46]([OH:48])=[O:47])=[CH:33][N:34]2[C@@H:42]1[CH2:44][C@@H:43]1[F:45]
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Reactant: COc1c(F)cc(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(N2CC[C@@H](C3(N)CC3)C2)cc(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 90 °C
Reaction time: 168 h
Yield: 5.1 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyrrolidine (788 mg, 3.48 mmol) and triethylamine (2 ml) to dried dimethyl sulfoxide (1 ml, 5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (621 mg, 2.00 mol) was added thereto and stirred at 90° C. for 168 hours while sealing in a sealed tube under a nitrogen atmosphere. After letting the reaction solution cool and then concentrating the reaction solution under a reduced pressure, the residue obtained was dissolved in chloroform (200 ml) and washed with a 10% aqueous citric acid solution (100 ml). The organic layer was then dried over anhydrous sodium sulfate, and after filtering, the filtrate was concentrated under a reduced pressure. After adding dropwise concentrated hydrochloric acid (10 ml) to the obtained residue while cooling with ice, it was stirred at the same temperature for 30 minutes. 1 mol/l Hydrochloric acid (20 ml) was then added to the reaction solution, and after washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.8 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. The organic layers were then combined and dried over anhydrous sodium sulfate, and then the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by recrystallization from a mixed solvent of ethanol and diethyl ether, and then dried under a reduced pressure. 74 mg (9%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:22]1([S:25]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][CH:32]=[CH:31]3)(=[O:27])=[O:26])[CH2:24][CH2:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([S:25]([CH:22]5[CH2:24][CH2:23]5)(=[O:27])=[O:26])=[CH:36][CH:35]=4)[CH:31]=[CH:32]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=S(=O)(c1ccc2[nH]ccc2c1)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(=O)(=O)C5CC5)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 5-(Cyclopropylsulfonyl)-1H-indole (intermediate 24).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[N:17][N:16]=[CH:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:15]=[N:16][N:17]=[C:18]2[C:19](=[O:21])[CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC(n3cnnc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1nncn1C1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 1-benzyl-4-(4H-1,2,4-triazol-4-yl)piperidine (200 mg) in acetic anhydride (20 ml) was refluxed for 18 hours. The reaction mixture was concentrated under reduced pressure to a thick oil. Flash chromatography eluting with dischloromethane then 5% methanol in dichloromethane gave 1-[4-(1-benzylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl]ethanone as a colourless oil (60 mg).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:18]([OH:24])[CH2:19][CH2:20][CH2:21][C:22]#[CH:23]>O>[S:7]([O:24][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: C#CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h

Procedure:
In this preparation 1.0 mole of p-toluenesulfonyl chloride is dissolved in 700 ml. of pyridine at 0° C, under nitrogen, and then 0.5 mole of hex-5-yn-1-ol is added dropwise. The mixture is stirred for 2 hours and then 10 ml. of water is added slowly, keeping the temperature below 10° C. The pyridine is then removed by evaporation under vacuum and the residue poured into 1 liter of ethyl acetate, then washed twice with excess 2N aqueous hydrochloric acid, and then with water. The organic layer is separated and dried over anhydrous magnesium sulfate, filtered, and the filtrate then evaporated to dryness, under vacuum, affording hex-5-yn-1-ol tosylate.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[C:31]([CH3:36])([CH3:35])[C:32]([NH2:34])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([C:31]([CH3:36])([CH3:35])[C:32]([NH2:34])=[O:33])[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCNCC3)ccc1OCC2
Reactant: CC(C)(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C(N)=O)CC3)ccc1OCC2
Temperature: 120 °C
Yield: 88.7 %

Procedure:
A mixture of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-(piperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 2 (0.244 g, 0.594 mmol), 2-bromo-2-methylpropionamide (0.494 g, 2.976 mmol) and Cs2CO3 (0.774 g, 2.376 mmol) in CH3CN (15 mL) was heated at 120° C. for 2 h using microwave irradiation. The crude mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% 2M NH3/MeOH in DCM) to give 0.261 g (89% yield) of 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}isobutyramide as a colorless foam. A portion of the resulting residue (28 mg) was further purified by column chromatography (C18, gradient 15-55% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH affording the title compound (13 mg). LCMS: RT 2.92 min [M+H]+ 496.1.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:4][O:3]1>C(O)(=O)C>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1
Reactant: COc1ccc(OCCCCC2COC(C)(C)O2)cc1
Solvent: CC(=O)O
Product: COc1ccc(OCCCCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.08 g of 4-methoxyphenyl 4-(2,2-dimethyldioxolan-4-yl)butyl ether from Example 1b were dissolved in 165 ml of 80% acetic acid and stirred at room temperature for 4 h. The acetic acid was separated off in vacuo, and the mixture was then coevaporated with toluene/methanol twice. This resulted in a crystalline product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:19]3[CH:20]=[C:21]([C:25](=[NH:28])[NH:26][OH:27])[CH:22]=[CH:23][CH:24]=3)[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:36](OCC)(OCC)OCC>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:15][N:16]([C@@H:18]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:19]3[CH:20]=[C:21]([C:25]4[N:28]=[CH:36][O:27][N:26]=4)[CH:22]=[CH:23][CH:24]=3)[CH2:17]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C(=N)NO)c2)C1
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1C
Product: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(-c3ncon3)c2)C1
Temperature: 127.5 °C
Reaction time: 4 h

Procedure:
A mixture of 70 mg (0.125 mmol) of 3-[(S)-{3-[(1S)-1-(3-bromo-5-fluoro phenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]-N-hydroxybenzenecarboximidamide, 1.5 mL of triethyl orthoformate, and 2 mL of xylene was stirred for 4 h at 125-130° C. Then it was concentrated, and the residue was purified by silica gel chromatography with hexanes/acetone to afford the title compound as a white solid; Mass Spectrum: m/e=572 (M+1, 35Cl), 574 (M+1, 37Cl).
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[Br:8][C:9]1[CH:10]=[C:11]([CH3:17])[C:12]([NH:15][NH2:16])=[N:13][CH:14]=1>C1COCC1.O1CCOCC1.C(O)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH3:17])[C:12]2[N:13]([C:1]([CH3:2])=[N:16][N:15]=2)[CH:14]=1
Reactant: Cc1cc(Br)cnc1NN
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Br)cn2c(C)nnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
A solution of acetic anhydride (12.22 mL, 129 mmol) in THF (10 mL) was added over a 10 min period to a suspension of 5-bromo-2-hydrazinyl-3-methylpyridine (25 g, 118 mmol) (Step 130.5) in dioxane (125 mL) and acetic acid (25 mL), at rt. The reaction mixture was stirred for 10 min at rt, heated to 100° C., stirred for 7 h at this temperature, and concentrated. The solid residue was purified by trituration with TBME to provide the title compound (25.7 g) as a colorless solid. tR: 0.39 min (LC-MS 2); ESI-MS: 225.9 [M+H]+ (LC-MS 2).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:42]=[C:43]1[CH2:47][CH2:46][CH2:45][N:44]1[CH2:48][CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH2:68])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:58][CH:57]=1>CN(C=O)C>[O:42]=[C:43]1[CH2:47][CH2:46][CH2:45][N:44]1[CH2:48][CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH:68][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:55][C:56]1[CH:57]=[CH:58][C:59]([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)=[CH:60][CH:61]=1
Reactant: O=C(O)c1c[nH]nn1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCCN1CCCC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20.2 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-(2-oxo-pyrrolidin-1-yl)-ethyl ester (52.6 mg, 124 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (13 mg; purity 95%). MS m/z [M+H]+ calc'd for C28H33N5O5, 520.25. found 520.4.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8]([O:12][C:13]([NH:15][CH:16]=[CH:17][CH:18]=[CH2:19])=[O:14])([CH3:11])([CH3:10])[CH3:9]>O1CCCC1>[C:8]([O:12][C:13]([NH:15][CH:16]1[CH:17]=[CH:18][CH2:19][CH:3]2[CH:2]1[C:1](=[O:7])[NH:5][C:4]2=[O:6])=[O:14])([CH3:10])([CH3:11])[CH3:9]
Reactant: C=CC=CNC(=O)OC(C)(C)C
Reactant: O=C1C=CC(=O)N1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C=CCC2C(=O)NC(=O)C12
Reaction time: 8 h

Procedure:
48.0 g (0.5 mol) of maleimide are initially introduced into the reaction vessel as a solution in 200 ml of absolute tetrahydrofuran, and 120 g (0.5 mol) of approximately 70% strength 1-(tert.-butyloxycarbonylamino)-1,3-butadiene are added dropwise as a solution in 500 ml of absolute tetrahydrofuran, the temperature being kept at 20° to 30° C. The mixture is subsequently stirred overnight at room temperature. It is then concentrated and the residue is recrystallised from ethyl acetate. 57 g of product having a melting point of 177° to 182° C. are obtained. A further 13 g of melting point 158° to 160° C. are obtained from the mother liquor.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C(OCC)C>[N+:10]([C:9]1[C:5]([CH2:3][OH:2])=[N:6][N:7]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1nn(C2CCCCO2)cc1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cn(C2CCCCO2)nc1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
A stirred solution of 4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester [500 mg, Reference Example 54(a)] in tetrahydrofuran (20 ml) under nitrogen at −78° C. was treated dropwise with a solution of diisobutylaluminium hydride in tetrahydrofuran (8.82 ml, 1M). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was taken up in diethyl ether (100 ml) and quenched with water (150 ml). The resulting suspension was filtered through celite and the organic layer was collected from the filtrate, then dried over magnesium sulfate and then evaporated to yield [4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-methanol (349 mg) as a peach oil. LC-MS (Method H): RT=2.08 minutes, 250.29 (M+H+ Na)+.