Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCOCC1.C([Si]([O:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[C:17]([O:30][CH3:31])[CH:16]=1)(C)C)(C)(C)C.Cl[C:33]1[N:38]=[N:37][C:36]([N:39]([CH3:50])[CH:40]2[CH2:45][C:44]([CH3:47])([CH3:46])[NH:43][C:42]([CH3:49])([CH3:48])[CH2:41]2)=[CH:35][CH:34]=1.C(=O)(O)[O-].[Na+]>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.O>[CH3:31][O:30][C:17]1[CH:16]=[C:15]([OH:14])[CH:20]=[CH:19][C:18]=1[C:33]1[N:38]=[N:37][C:36]([N:39]([CH3:50])[CH:40]2[CH2:45][C:44]([CH3:46])([CH3:47])[NH:43][C:42]([CH3:49])([CH3:48])[CH2:41]2)=[CH:35][CH:34]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
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: COc1cc(O)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 72 °C
Yield: 53 %

Procedure:
A 20 L jacketed reactor fitted with a reflux condenser, N2 inlet, thermocouple and overhead stirrer was charged with 2.7 L of dioxane followed by tert-butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (290 g, 557 mmol), 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 113 g, 398 mmol), and sodium bicarbonate (100 g, 1194 mmol). 700 mL of water was added, followed by addition of Pd(PPh3)4 (27.6 g, 23.88 mmol). The reaction mixture was heated at 72° C. overnight. After cooling to RT, the layers were separated. The organic layer was concentrated, and the reside was purified by silica gel chromatography using 5% MeOH (containing 1% TEA) in DCM to provide the desired product, 3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (83 g, 211 mmol, 53% yield). MS=371.4.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2)#N.[OH-].[Na+].Cl>CO.O>[C:4]([C:17]1[CH:22]=[CH:21][C:1]([C:3]2[C:4]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:5][C:6]3[C:11]([N:12]=2)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=3)=[CH:19][CH:18]=1)#[N:5]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(C#N)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
A solution of methyl 3-cyano-2-phenylquinoxaline-6-carboxylate (50 mg, 0.17 mmol, 1.00 equiv) and NaOH (16 mg, 0.40 mmol, 3.00 equiv) in MeOH/H2O (5/5 mL) in a 50-mL round-bottom flask was allowed to react, with stirring, for 1 hr at room temperature, followed by a further 1 hr at 50° C. in an oil bath. The reaction progress was monitored by TLC (ethyl acetate:petroleum ether (1:2)). The pH value of the solution was adjusted to 4 with 1N HCl, and the resulting mixture was concentrated under vacuum. The solids were collected by filtration and dried in an oven under reduced pressure, giving 30 mg (46%) of 3-(4-cyanophenyl)-2-phenylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][C:24](O)=[O:25])=[C:9]2[CH3:27])=[CH:4][CH:3]=1.[NH2:28][C@@H:29]([CH2:33][OH:34])[C:30]([OH:32])=[O:31]>>[OH:34][CH2:33][C@H:29]([NH:28][C:24](=[O:25])[CH2:23][C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]=1[CH3:27])[C:30]([OH:32])=[O:31]
Reactant: N[C@@H](CO)C(=O)O
Reactant: Cc1c(CC(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Product: Cc1c(CC(=O)N[C@@H](CO)C(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Yield: 90 %

Procedure:
Obtained from 6g and (S)-2-amino-3-hydroxypropionic acid similarly to example 28-II, yield 90%, m.p. 120° C. 1H NMR (400 MHz, CDCl3) δ: 7.70 (d, 2H), 7.31 (m, 4H), 7.22 (m, 2H), 6.73 (s broad, 1H), 6.50 (s, 1H), 4.70 (m, 1H), 4.20 (m, 2H), 3.54 (s, 2H), 3.01 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11](Cl)[CH3:12].[SH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:21].[Na]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:21])[CH3:12]
Reactant: [O-][n+]1ccccc1S
Reactant: CC(Cl)c1ccc2ccccc2c1
Agent: [Na]
Product: CC(Sc1cccc[n+]1[O-])c1ccc2ccccc2c1

Procedure:
The intermediate 2-(1-[2-naphthyl]ethylthio)-pyridine N-oxide is prepared from 1-(2-naphthyl)ethyl chloride and 2mercapto pyridine N-oxide, sodium salt by the procedure described in Example 2. Melting point 112° - 115°C. Structure confirmed by IR and NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:16])OC(C)(C)C.[F:17][C:18]([F:27])([F:26])[C:19](=O)C(OCC)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:8][C:5]1[CH:4]=[C:3]2[C:2]([N:1]=[C:19]([C:18]([F:27])([F:26])[F:17])[C:10]([OH:16])=[N:9]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1nc2cc(F)ccc2nc1C(F)(F)F
Temperature: 63 °C
Yield: 83 %

Procedure:
tert-Butyl 2-amino-5-fluorophenylcarbamate (30.5 g), toluene (300 mL), triethylamine (34.1 g) and ethyl 3,3,3-trifluoro-2-oxopropanoate (69.5 g) were charged into a reactor and warmed to 63° C. for 14 h, then cooled to ambient temperature. A 5% aq. NaOH solution (390 mL) was added, stirred, settled, and then the lower layer was separated. The organic layer extracted with another charge of 5% aq. NaOH solution (130 mL). To the combined aq. NaOH layers was charged 2-methyl-THF (390 mL) and concentrated HCl (77.9 g), keeping the temperature below 25° C. The layers were mixed, settled and separated. The acidic aq. layer was separated, and the organic layer was extracted with water (260 mL). The layers were separated and the organic layer was filtered to remove insoluble material. The product was isolated by switching the solvent to toluene by distillation (a total of 1.1 L toluene used). The final slurry was briefly warmed to 80° C. and then cooled −10° C. and filtered. The cake was washed with toluene (128 mL), then dried under vacuum at 60° C. To the crude solid was added ethanol (350 mL) and warmed to reflux to dissolve the solids. The solution was cooled to room temperature and concentrated to approximately 270 mL total volume by distillation. Water (250 g) was then added over 30 min. The slurry was filtered and washed with cold (1:1) ethanol: water (2×60 mL). The solid was dried under vacuum at 60° C. (26.1 g, 83% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH2:7]1.O.NN>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:10][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(Oc2ccc(F)c(F)c2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCN1CCC(Oc2ccc(F)c(F)c2)CC1

Procedure:
To the product of Example 3, Step (c) in EtOH (30 ml) was added hydrazine monohydrate (0.562 ml). The reaction was refluxed for 4 hrs and the solvent evaporated. Dichlorornethane (40 ml) was added and the solid by-product filtered. The organic residue was evaporated and the product purified by reverse phase HPLC {with a gradient eluent system [25% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)]} to give the sub-title compound as a solid (0.622 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:2]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1[NH2:22].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:22][C:21]1[C:16]([NH:15][C:10]([C:7]2([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:17][CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:20]=1
Reactant: O=C(O)C1(c2cccnc2)CC1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cccnc2)CC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
1-(Pyridin-3-yl)cyclopropanecarboxylic acid (30.7 mg, 0.188 mmol), (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (75 mg, 0.19 mmol), and N-methylmorpholine (83 μL, 0.76 mmol) were combined and dissolved in N,N-dimethylformamide (1.0 mL). Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) (122 mg, 0.207 mmol) was added and the reaction mixture was stirred at 50° C. for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. A saturated aqueous solution of sodium bicarbonate was added. The organics were collected and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-10% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyridin-3-yl)cyclopropanecarboxamide (69 mg, 84%). MS (AP+) (M+H) 435.2; LCMS retention time 1.51 min (Method L).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[N:24]1C(=O)C(=CC2C=CC=CC=2)S[C:25]1=[S:37])(=O)C.[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1>CO>[C@@H:6]1([NH:24][C:25]([NH:45][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([O:39][CH3:38])=[CH:41][CH:42]=2)=[S:37])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: COc1ccc(CN)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](N2C(=O)C(=Cc3ccccc3)SC2=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Product: COc1ccc(CNC(=S)N[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
N-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-5-benzylidenerhodanine(1.102 g., 0.002 mole) was added to a solution of p-methoxybenzylamine(3.5 g., 0.024 mole) in 50 ml. of methanol in a pressure bottle. The reaction mixture was stirred for 19 hours at room temperature in the pressure bottle with the stopper well closed. The mixture was filtered and the filtrate was evaporated to a sticky syrup in vacuo. The residual syrup was dissolved in the minimum amount of acetone, and anhydrous ether was added to the solution to give a sticky yellow solid. The supernatent was decanted, and the residual sticky solid was dissolved in the minimum amount of actone. Ethyl acetate was added to the solution to give a precipitate. The solid was filtered, partially dissolved in ethyl acetate, and then chromatographed on a column of silica gel (1×20 cm) using ethyl acetate as the first solvent, and acetone as the second solvent. Fifty ml. of ethyl acetate effluent was collected in the first Erlenmeyer flask, and 75 ml. of actone effluent was collected in the second Erlenmeyer flask. The volume of the acetone effluent was reduced to ca. 25 ml. and was set aside at 5° for 24 hours. The straw crystals were filtered, washed with ethyl acetate, and dried in vacuo at room temperature, yielding 0.525 g. (73.2%); m.p. 83°-85°(dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([S:15]C(Cl)(Cl)Cl)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(SC(Cl)(Cl)Cl)cc1
Solvent: CO
Product: O=C(c1ccc(S)cc1)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 98 %

Procedure:
16.5 g said 4′-chloro-4(trichloromethyl sulfenyl)benzophenone is added in a 100 ml three-neck flask, and then 30 g methanol is added. Under nitrogen protection, the solution is heated with stirring to reflux. After reacting for 3 hours, it is analyzed to find that 4′-chloro-4(trichloromethyl sulfenyl)benzophenone is completely consumed. Distilling to remove the methanol and all low-boiling-point substances, the residue has a mass of 11.0 g, and the yield is 98%. Said residue is recrystallized in a mixed solvent consisting of dichloroethane and petroleum ether in a weight ratio 1:3 to obtain 9.5 g white flake crystal with a purity of 99.0%, and the melting point is 157-161° C. 1H-NMR data (solvent CDCl3): δ3.656 ppm, s, 1H, δ7.320, 7.348 ppm, d, 2H, δ7.443, 7.471 ppm, d, 2H; δ7.644, 7.672 ppm, d, 2H, δ7.698, 7.726 ppm, d, 2H.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:19][CH:20]([CH:28]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([CH:28]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:19][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([O:10][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:12])[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCC(NC(=O)OC(C)(C)C)C(CCCCCCO)CN(CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCC(NC(=O)OC(C)(C)C)C(CCCCCCOS(C)(=O)=O)CN(CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (1.25 ml, 16.21 mmol) was added to a stirred solution of B6 (9.67 g, 13.5 mmol) in dry dichloromethane (100 ml) containing triethylamine (2.82 ml, 20.26 mmol) at 0° C. The flask was stirred at 0° C. for 1 hr, then overnight at room temperature. The solvent was removed and the residue chromatographed (silica—50% ethyl acetate in hexane) to yield the title compound (8.5 g, 79%. C38H74N4O11S requires 794. Found DCl: M+ +1, 795.6. δH(CDCl3) 3.45(2H, t, CH2O), 2.9-3.3 (12H, m, CH2N), 2.99 (3H, s, MeS), 1.95 (1 H, brm, CH2CH(CH2)2), 1.2-1.8 (50H, m, CH2).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:18]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:18])[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCCCOC(=O)c1ccc2c(N)ncnn12
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1cc(Br)c2c(N)ncnn12
Reaction time: 96 h
Yield: 154.3 %

Procedure:
To a solution of butyl 4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (225.0 mg, 0.96 mmol) in DMF (7.5 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (137.3 mg, 0.48 mmol) in two portions. The solution was stirred for 4 days and then quenched by addition of saturated aqueous sodium sulfate solution (20 mL) and water (20 mL). The solid was filtered, washed with water and air-dried. The crude material was purified by HPLC using a gradient of 30-80% of MeCN in water to afford 232.0 mg (77%) of the title compound as an off-white solid. 1H-NMR (DMSO-d6) δ 8.42 (bs, 1 H), 8.03 (s, 1 H), 7.35 (s, 1 H), 7.03 (bs, 1 H), 4.23 (t, J=6.4 Hz, 2 H), 1.69-1.62 (m, 2 H), 1.46-1.36 (m, 2 H), 0.92 (t, J=7.3, 3H); MS [M+H]+=313.0; LCMS RT=2.83 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: Nc1ccc(F)cc1Nc1cccnc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
A mixture of 4-fluoro-N2-pyridin-3-ylbenzene-1,2-diamine (1.03 g, 5.07 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.05 g, 5.58 mmol), HOAt (759 mg, 5.58 mmol), 4-methylmorpholine (1.23 mL, 11.15 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.07 g, 5.58 mmol) in DCM (30 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM and a saturated solution of NaHCO3. A precipitate was present in the organic fraction which was filtered off to afford the title compound as a pale yellow solid (503 mg). The filtrate was dried (MgSO4) and concentrated in vacuo and the resulting residue was triturated with DCM to afford a second batch of the title compound as a yellow solid (765 mg; 67% yield for the combined batches). LCMS (Method C): RT 2.06 min [M+H]+ 375.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:7]2.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]1[NH:26][C:34](=[O:35])[NH:28][N:27]=1)=[CH:7]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3cccc(Cl)c23)C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(Cl)c23)C1
Yield: 24.1 %

Procedure:
To (S)-tert-butyl 3-((8-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (130 mg, 1.61 mmol) in dioxane (10 mL) was added CDI (78 mg, 0.48 mmol). The resulting mixture was heated to reflux for 2 hours and was then cooled and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (50 mg, 35%). ESI-MS m/z [M+H-Boc]+ 332.2.
Reaction SMILES: [Li].[CH3:2][Si:3](Cl)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.II.[F:19][C:20](F)=[CH2:21]>O1CCCC1>[F:19][C:20]([Si:3]([CH3:2])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:21]
Reactant: C=C(F)F
Reactant: C[Si](Cl)(c1ccccc1)c1ccccc1
Agent: II
Agent: [Li]
Solvent: C1CCOC1
Product: C=C(F)[Si](C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of lithium wire (2.08 g, 300 mmol) in dry tetrahydrofuran (150 ml) was added methyldiphenylsilyl chloride (15.8 ml, 75 mmol) and a catalytic amount of iodine. The reaction mixture was sonicated for 40 min and then stirred overnight at room temperature. The reaction mixture was cooled to −78° C. and 1,1-difluoroethylene (approx. 225 mmol) was passed through the mixture for 30 min. The mixture was stirred at −78° C. for 2 h and then warmed to room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[CH3:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH2:34])=[NH:33])[CH:27]=[CH:28][C:29]=1[CH3:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:33]=[C:32]([NH:31][C:26]4[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=4)[N:34]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: Cc1ccc(NC(=N)N)cc1C
Solvent: O=[N+]([O-])O
Product: Cc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1C

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3,4-dimethyl-phenyl)-guanidine nitrate were converted to I-29 (59%): HRMS Calcd. for C20H17ClN40: 365.1169, Found 365.1143.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:32]1([CH2:38][CH2:39][S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[OH:46][C:45]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[O:16][C:42](=[O:43])[C:41]=1[S:40][CH2:39][CH2:38][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(Oc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-phenoxyacetophenone (1.07 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 127°-128° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77 (t, 2 H), 2.99 (t, 2 H), 6.72 (s, 1 H), 7.18 (m, 10H), 7.46 (t, 2 H), 7.82 (d, 2 H).
Reaction SMILES: C([O:8][CH2:9][C@:10]12[S:18](=[O:20])(=[O:19])[N:17]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=3)[CH2:16][C@H:15]1[C@@H:14]1[CH2:33][C@H:11]2[CH:12]=[CH:13]1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CO.[Pd]>[OH:8][CH2:9][C@:10]12[S:18](=[O:20])(=[O:19])[N:17]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:31])([F:32])[F:30])[CH:22]=3)[CH2:16][C@H:15]1[C@@H:14]1[CH2:33][C@H:11]2[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: N#Cc1ccc(N2C[C@H]3[C@H]4C=C[C@H](C4)[C@@]3(COCc3ccccc3)S2(=O)=O)cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2C[C@H]3[C@H]4CC[C@H](C4)[C@@]3(CO)S2(=O)=O)cc1C(F)(F)F
Yield: 82.3 %

Procedure:
A solution-suspension of Example 30 (50 mg, 0.11 mmol) and Degussa-type Pd/C (10 mg; 20 wt %) in 4 mL EtOAc/MeOH (2:1) was stirred under 1 atmosphere of hydrogen at ambient temp for 5 hrs. The reaction vessel was then purged with N2 to give a black suspension that was then filtered. The resulting colorless filtrate was concentrated in vacuo to give 35 mg of a mixture of starting material and product in a 2:1 ratio. The mixture was dissolved in CH2Cl2, loaded onto a preparative TLC plate, and eluted with 30% acetone/heptane to afford 15 mg Example 32 (36% yield) as a colorless film. HPLC: 98% at 3.015 min (retention time) (YMC ODS-A column 4.6×50 mm eluting with 10-90% aqueous MeOH over 4 min containing 0.1% H3PO4, 4 mL/min, monitoring at 220 nm); and MS (ES): m/z 445.11 [M−H+ OAc]−.
Reaction SMILES: [OH-].[K+:2].C(=O)([O-])[O-].[S:7](=[O:9])=[O:8].[S:10](=[O:13])([OH:12])[O-:11].[K+]>>[S:10]([S:7]([O-:9])=[O:8])([O-:12])(=[O:11])=[O:13].[K+:2].[K+:2]
Reactant: O=S([O-])O
Reactant: O=S=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Product: O=S([O-])S(=O)(=O)[O-]

Procedure:
In U.S. Pat. No. 3,369,866, potassium hydroxide or carbonate and sulfur dioxide are reacted in potassium bisulfite solution at a pH of 4 to 7.5, and a temperature of 50° to 80° C. The solution is transferred to a second vessel where its pH is reduced to 5.5 by the addition of more sulfur dioxide in order to prevent precipitation of potassium sulfite, and the solution is cooled to 15° to 25° C. to obtain a crop of potassium metabisulfite crystals. The main concerns are to avoid product oxidation and the inclusion of sulfite in the product. No mention is made of crystal size.