Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[CH2:32]([N:39]1[C:43]([CH:44]=O)=[CH:42][N:41]=[CH:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:32]([N:39]1[C:43]([CH2:44][NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=2[C:12]2[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:42][N:41]=[CH:40]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=Cc1cncn1Cc1ccccc1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCc4cncn4Cc4ccccc4)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-(4-(6-(2-amino-4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)-acetamide (0.20 g, 0.45 mmol, prepared as described in WO04014871) and 1-benzyl-1H-imidazole-5-carbaldehyde (0.21 g, 1.1 mmol, Combi-Blocks) in 1,2-dichloroethane (4 mL) was stirred for 24 h at 25° C. Sodium triacetoxy-borohydride (0.24 g, 1.1 mmol) was added and the mixture was stirred for 4 d at 25° C. Additional amounts of 1-benzyl-1H-imidazole-5-carbaldehyde (0.21 g, 1.1 mmol, Combi-Blocks) and sodium triacetoxyborohydride (0.24 g, 1.1 mmol) were added, and the mixture was stirred for 24 h at 25° C. The mixture was partitioned between H2O and EtOAc, the organic phase was separated, washed with H2O and brine, dried over Na2SO4, and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [gradient: 0.5-2.2% MeOH (2 M in NH3)/CH2Cl2] to give the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 616 (M+1). Mp: 264.0-264.1° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15]I.CCCCCCC>C(#N)C>[Cl:12][CH2:13][CH2:14][CH2:15][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: ClCCCI
Reactant: O=C1COc2ccccc2N1
Solvent: CC#N
Solvent: CCCCCCC
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2H-1,4 benzoxazine-3(4H)one (1.0 g, 6.70 mmol) and Cs2CO3-(3.28 g, 10.1 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.58 g, 7.38 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacou to give 1.65 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the pure title compound as a colorless oil. Yield 1.36 g, 89.2%. Rf=0.24 [Heptane:EtOAC(4:1)], 1H NMR (CDCl3): δ 2.16 (m, 2H), 3.62 (t, 2H), 4.10 (t, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.05 (m, 2H), 13C NMR (CDCl3): δ 30.16, 39.04, 42.45, 67.72, 114.80, 117.38, 123.07, 124.14, 128.49, 145.47, 164.58.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][S:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[CH:11][CH:10]=1.C(Cl)Cl.[C:26]([S:34][CH2:35][C@@H:36]([CH3:49])[C:37](OC1C=CC([N+]([O-])=O)=CC=1)=[O:38])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:26]([S:34][CH2:35][C@@H:36]([CH3:49])[C:37]([NH:17][C@@H:16]([CH2:15][S:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([CH3:8])=[CH:22][CH:21]=1)[C:18]([OH:20])=[O:19])=[O:38])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(CSC[C@H](N)C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(CSC[C@H](NC(=O)[C@H](C)CSC(=O)c2ccccc2)C(=O)O)cc1
Yield: 68.9 %

Procedure:
Triethylamine (0.464 ml) is added to a solution of S-(4-methylbenzyl)-L-cysteine (reference compound No. 2-1, 500 mg) in a mixed solvent of methylene chloride (20 ml)/dimethylformamide (5 ml) under ice-cooling, and the mixture is stirred. 4-Nitrophenyl (2S)-3-benzoylthio-2-methylpropionate (reference compound No. 1-1, 919 mg) is added to the system of reaction, and the system is stirred overnight. The system of reaction is further stirred overnight at 40° to 50° C. After the reaction is completed, the mixture is concentrated under reduced pressure, a 10%, aqueous citric acid solution is added to the residue, and the whole is extracted with ethyl acetate. The organic layer is washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 660 mg (68.9%) of the titled compound. (Compound No. 1-1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][C:40](O)=[O:41])[C:34](=[O:43])[C:33]2=[O:44].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:40](=[O:41])[CH2:39][N:35]1[C:36]2[C:32](=[CH:31][C:30]([O:29][CH3:28])=[CH:38][CH:37]=2)[C:33](=[O:44])[C:34]1=[O:43]
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.2 g, 0.476 mmol), 2-(5-methoxy-2,3-dioxoindolin-1-yl)acetic acid (0.112 g, 0.476 mmol), DMAP (0.029 g, 0.238 mmol) and EDC (0.274 g, 1.428 mmol) in DCM (10 ml) was stirred at room temperature overnight. The reaction was washed with 1N HCl, aqueous 5% NaHCO3 and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel (ethyl acetate:DCM=7:3) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-methoxy-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.18635 g, 0.292 mmol, 61% yield). MS/ESI+ 637.19 [MH]+; [αD]=+60.39 c=0.155 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.41 (s, 2H), 7.22 (dd, 1H), 7.19-7.21 (m, 1H), 7.18 (d, 1H), 7.06 (d, 1H), 6.89-6.98 (m, 2H), 7.07 (t, 1H), 6.03 (dd, 1H), 4.62 (d, 1H), 4.54 (d, 1H), 3.89 (d, 2H), 3.81 (s, 3H), 3.40 (dd, 1H), 3.21 (dd, 1H), 1.09-1.37 (m, 1H), 0.51-0.67 (m, 2H), 0.28-0.47 (m, 2H)
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH2:44][C:45]6[CH:50]=[CH:49][C:48]([B:51]7[O:55]C(C)(C)C(C)(C)[O:52]7)=[CH:47][CH:46]=6)[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1>C1COCC1.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH2:44][C:45]6[CH:46]=[CH:47][C:48]([B:51]([OH:55])[OH:52])=[CH:49][CH:50]=6)[S:40]([CH3:43])(=[O:41])=[O:42])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34](=[O:35])[NH:36][CH3:37])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3ccc(B(O)O)cc3)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12

Procedure:
A solution of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)benzofuran-3-carboxamide (0.12 g, 0.15 mmol) and NaIO4 (0.16 g, 0.74 mmol) in THF/H2O (12 mL/4 mL) was stirred at room temperature for 24 hours. The mixture was filtered and extracted by EtOAc. The combined organic phases was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-HPLC to provide Compound 205. 1H-NMR (Methanol-d4, 400 MHz) δ 8.00 (s, 2H), 7.77˜7.79 (m, 2H), 7.53˜7.66 (m, 1H), 7.51˜7.52 (m, 1H), 7.22˜7.44 (m, 6H), 7.11˜7.14 (m, 1H), 6.99˜7.01 (m, 1H), 6.91˜6.93 (m, 1H), 6.82˜6.86 (m, 1H), 6.14 (s, 2H), 4.84˜4.86 (m, 1H), 4.50˜4.58 (m, 1H), 3.17˜3.20 (m, 3H), 2.93 (s, 3H). MS (M+H)+: 735.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[C:8]([O:12][C:13]([NH:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]1[CH2:24][N:23]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:22]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CN(C=O)C>C(#N)C>[C:8]([O:12][C:13]([NH:15][N:16]1[C:20]([C:6]#[N:5])=[CH:19][CH:18]=[C:17]1[CH:21]1[CH2:22][N:23]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:24]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nn1cccc1C1CN(C(=O)OCc2ccccc2)C1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nn1c(C#N)ccc1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
A solution of chlorosulfonylisocyanate (541 μL, 6.22 mmol) in acetonitrile (5 mL) was added dropwise to a cooled (0° C.) solution of benzyl 3-{1-[(tert-butoxycarbonyl)amino]-1H-pyrrol-2-yl}azetidine-1-carboxylate (2.10 g, 5.65 mmol) in acetonitrile (15 mL). The mixture was stirred at 0° C. for 30 min and was warmed to rt. After 1 h, the mixture was recooled (0° C.) and DMF was added dropwise. The reaction was allowed to warm to rt. After 30 min, the mixture was poured onto crushed ice (100 g) and was allowed to warm to rt. The aqueous mixture was extracted with EtOAc (3×75 mL) and the combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to obtain 800 mg (36%) of the desired product, which was used without further characterization.
Reaction SMILES: [C:1]1([NH:7][NH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC>[CH3:9][NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CNNc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNNc1ccccc1
Yield: 76.3 %

Procedure:
A solution of N'-phenylformohydrazide (20.59 g) in dry tetrahydrofuran (750 ml) was added dropwise under nitrogen to a stirred suspension of lithium aluminium hydride (10 g) in dry tetrahydrofuran (200 ml), then the mixture was stirred and heated under reflux for 4 hours. The mixture was quenched by the slow dropwise addition of water (10 ml), followed by 5M aqueous sodium hydroxide solution (10 ml), then water (20 ml), then it was filtered, dried (MgSO4) and the solvent removed in vacuo to yield an oil. The oil was dissolved in ether, redried (MgSO4) and the solvent removed in vacuo to yield 1-methyl-2-phenylhydrazine (14.1 g) as a yellow oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=O)=O.[C:30]([Sn](CCCC)(CCCC)CCCC)#[C:31][CH2:32][CH2:33][CH3:34].[Cl-].[Li+]>O1CCOCC1.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>[CH2:21]([O:20][C:18]([NH:17][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[C:30]#[C:31][CH2:32][CH2:33][CH3:34])[C:13]([O:15][CH3:16])=[O:14])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCC#C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(=O)OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCCC#Cc1ccc(C(=O)OC)cc1NC(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 65.4 %

Procedure:
A mixture of 2-benzyloxycarbonylamino-4-methoxycarbonylphenyl trifluoromethanesulfonate (1.01 g), 1-pentynyl(tributyl)stannane (1.02 g), lithium chloride (0.29 g) and tetrakis(triphenylphosphine)palladium (80 mg) in dioxane (24 ml) was heated at 100° C. for 2 hours. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (4:1) to give methyl 3-benzyloxycarbonylamino-4-(1-pentynyl)benzoate (536 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:11]=1)=[O:5].N1C=CC=CC=1.[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])=[O:41]>ClCCl.C(OCC)(=O)C>[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40](=[O:41])[C:42]1[CH:50]=[CH:49][CH:48]=[C:44]([C:45]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[NH:8][N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:11]=2)=[O:46])[CH:43]=1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2nc(-c3cccc(C(F)(F)F)c3)n[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
To a solution of 2-amino-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3-yl)benzamide (50 mg, 0.12 mmol, 1.00 equiv) in dichloromethane (3 mL) was added pyridine (73 mg, 0.92 mmol, 8.00 equiv) followed by the dropwise addition of a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride (54 mg, 0.17 mmol, 1.50 equiv) in dichloromethane (2 mL) and the resulting solution was stirred for 30 min at room temperature. The mixture was diluted with 50 mL of ethyl acetate, washed with 2×20 mL of NH4Cl and 2×20 mL of brine, dried over anhydrous sodium sulfate and then concentrated under vacuum. The crude product (50 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 12 mg (10%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.34(m, 3H), 8.17(t, J=7.8 Hz, 2H), 7.73(m, 5H), 7.42 (m, 1H), 3.98(s, 2H), 3.55(m, 3H), 3.40(m, 5H), 3.29(m, 1H), 3.09(m, 3H), 1.86(d, J=4.8 Hz, 4H), 1.71(t, J=5.1 Hz, 2H). MS (ES, m/z): 705 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[N:7]([CH3:11])[CH2:8][CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][N:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:12])[N:7]([CH2:8][CH2:9][N:23]1[CH2:24][CH2:25][N:20]([C:15]2[C:14]([Cl:13])=[N:19][CH:18]=[CH:17][N:16]=2)[CH2:21][CH2:22]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1nccnc1N1CCNCC1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add methyl-(2-oxo-ethyl)-carbamic acid t-butyl ester (27.69 mmoles; 4.80 g) and 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazine (25.17 mmoles; 5.00 g) to 1,2 dichloroethane (50.0 mL) on ice. Add sodium triacetoxyborohydride (32.7 mmoles; 6.93 g) in 3 portions. Stir the reaction mixture at room temperature overnight. Quench the reaction with water, separate the organic layer and concentrate. Wash in hexanes and filter to provide [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-carbamic acid t-butyl ester as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[Cl:28][CH2:29][C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:31].CCOCC>C(OCC)(=O)C>[Cl-:28].[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][CH:8]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:16][CH2:15][N+:14]([CH2:29][C:30](=[O:31])[C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)([CH2:19][CH2:18]3)[CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(CCl)c1cccs1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(NCc1ccc(F)cc1)c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(NCc1ccc(F)cc1)c1ccccc1)C2)c1cccs1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
(R)-Quinuclidin-3-yl 2-(4-fluorobenzylamino)-2-phenylacetate (C78) (85 mg, 0.23 mmol) is dissolved in ethyl acetate (2.31 mL) and 2-chloro-1-(thiophen-2-yl)ethanone (40.8 mg, 0.25 mmol) is added. The solution is stirred at RT overnight. The suspension is evaporated and the white residue is first purified by flash chromatography (DCM/MeOH=9/1 to 8/2) and then by trituration with Et2O to afford the title compound as an off-white powder (83 mg, 68% yield, chloride salt, mixture of diastereoisomers).
Reaction SMILES: CO[C:3]1[C:15]2[C:14]3[CH:13]=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=3[N:8]([CH3:20])[C:7]=2[C:6]([C:21]#[N:22])=[CH:5][N:4]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:3]1[C:15]2[C:14]3[CH:13]=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=3[N:8]([CH3:20])[C:7]=2[C:6]([C:21]#[N:22])=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ncc(C#N)c2c1c1ccc(C(F)(F)F)cc1n2C
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c2cc(C(F)(F)F)ccc2c2c(Cl)ncc(C#N)c21

Procedure:
A solution of the product from Step 1 in POCl3 (0.057 M) was set up on the Smith Creator microwave reactor for 10 min at 175° C. The resulting solution was poured onto cold saturated NaHCO3 solution and the suspension was stirred until all the reagent was consumed and the final pH was 7-8. The suspension was then filtered to give the title compound as an off-white solid.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:33])[C@@H:8]([O:30][CH2:31][CH3:32])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)C>O.O1CCCC1>[CH2:31]([O:30][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)[C:7]([OH:33])=[O:6])[CH3:32]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 20 °C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
Lithium hydroxide hydrate (0.229 g; 5.45 mmole) dissolved in water (6 ml) was slowly added to a mixture of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl} ethoxy)phenyl]-propanoic acid ethyl ester (2.29 g; 5.24 mmole) in tetrahydrofuran (50 ml) and water (10 ml) at 5° C. The reaction mixture was stirred at 5° C. for 2.5 hours, at 20° C. for 3 hours, at 0° C. for 15 hours and at 20° C. for 3,5 hours. More lithium hydroxide hydrate (44 mg, 1.05 mmole) dissolved in water (1 ml) was added at 10° C. After another 21.5 hours of stirring at 10° C., more lithium hydroxide hydrate (44 mg; 1.05 mmole) dissolved in water (1 ml) was added. The reaction mixture was stirred at 25° C. for 3 hours and then kept at 2° C. for 67 hours. Tetrahydrofuran was evaporated in vacuo and then water and ethyl acetate were added. Insoluble material was filtered off and the phases of the filtrate were separated. The water phase was washed twice with ethyl acetate, acidified with hydrochloric acid (2 M; 3.2 ml) and extracted with ethyl acetate (30 ml). The organic phase was washed twice with water, dried (magnesium sulfate), filtered and the solvent was evaporated in vacuo to give 1.9 g (yield 72% in 2 steps) of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic acid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[N:8][O:7][N:6]=1)N.[ClH:15].[Cl-].[Na+].N([O-])=O.[Na+]>C(OCC)(=O)C.O>[OH:1][N:2]=[C:3]([Cl:15])[C:5]1[C:9]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[N:8][O:7][N:6]=1
Reactant: COCCNc1nonc1C(N)=NO
Reactant: Cl
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COCCNc1nonc1C(Cl)=NO
Temperature: 5.5 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
At room temperature N′-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidamide (50.0 g, 0.226 mol) was dissolved in 6.0 M hydrochloric acid aqueous solution (250 mL, 1.5 mol). Sodium chloride (39.5 g, 0.676 mol) was added followed by water (250 mL) and ethyl acetate (250 mL). At 3-5° C. a previously prepared aqueous solution (100 mL) of sodium nitrite (15.0 g, 0.217 mol) was added slowly over 1 hr. The reaction was stirred at 3-8° C. for 2 hours and then room temperature over the weekend. LCMS indicated reaction completed. The reaction solution was extracted with ethyl acetate (2×200 mL). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (49.9 g, 126%) as a crude white solid. LCMS for C6H10C1N4O3 (M+H)+: m/z=221.0. 1H NMR (400 MHz, DMSO-d6): δ 13.43 (s, 1H), 5.85 (t, J=5.6 Hz, 1H), 3.50 (t, J=5.6 Hz, 2H), 3.37 (dd, J=10.8, 5.6 Hz, 2H), 3.25 (s, 3H).