Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[CH:8][C:4]3[O:5][C:6](=[O:7])[C:2]([CH3:17])([CH3:1])[C:3]=32)=[CH:11][CH:12]=1
Reactant: Cc1ccc2ccc3c(c2c1)C(C)(C)C(=O)O3
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(=O)Oc2ccc3ccc(CBr)cc3c21

Procedure:
A mixture of 1,1,8-trimethyl-2(1H)-naphtho[2,1-b]furanone (1.13 g), N-bromosuccinimide (0.98 g), benzoyl peroxide (0.05 g) and carbon tetrachloride (30 ml) was heated under reflux for 1.5 h and filtered, and the filtrate was evaporated to dryness under reduced pressure, to give 8-bromomethyl-1,1-dimethyl-2[1H]-naphtho[2,1-b]furanone, which was used without further purification.
Reaction SMILES: [CH2:1]([S:7][C:8]1[S:18][C:11]2=[N:12][C:13](I)=[CH:14][C:15](=[O:16])[N:10]2[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cu](C#N)[C:20]#[N:21].[C-]#N.[Na+].C(Cl)(Cl)Cl>CN(C)C=O.O>[C:20]([C:13]1[N:12]=[C:11]2[S:18][C:8]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:9][N:10]2[C:15](=[O:16])[CH:14]=1)#[N:21]
Reactant: N#C[Cu]C#N
Reactant: CCCCCCSc1nn2c(=O)cc(I)nc2s1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCSc1nn2c(=O)cc(C#N)nc2s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
In 100 ml of dimethylformamide, 6 g of 2-hexylthio-7-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved. To this solution, 1.77 g of copper cyanide and 0.97 g of sodium cyanide were added and the solution was stirred at 100° C. for 1 hour. After the reaction mixture was cooled to room temperature, it was wxtracted with chloroform and water. The organic layer was washed with water and dried over anhydrous sodium sulfate. Florisil® was added to the organic layer and it was shaken. The solvent was distilled off, and 2.3 g of 7-cyano-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7]CC)=O)[CH2:3][CH2:2]1.[F:12][C:13]1[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:18]=1[CH3:19].[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>>[F:12][C:13]1[CH:14]=[C:15]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)=[O:7])[CH2:10][CH2:11]2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccc(Br)cc1F
Reactant: C1CSCCN1
Reactant: CCOC(=O)C1CCNCC1
Product: Cc1ccc(N2CCC(C(=O)N3CCSCC3)CC2)cc1F

Procedure:
The title compound was prepared from commercially available ethyl isonipecotate, 3-fluoro-4-methylbromobenzene as the aryl halide, and thiomorpholine as the secondary amine utilizing general procedures A and B described above. 1H NMR (300 MHz, CDCl3) 1H NMR (CDCl3) δ 7.02 (dd, J=7.2, 9.2 Hz, 1H), 6.63-6.55 (m, 2H), 3.90 (m, 2H), 3.80 (m, 2H), 3.70 (m, 1H), 3.65 (m, 1H), 2.75-2.51 (m, 7H), 2.17 (d, J=1.6 Hz, 3H), 2.01 (dd, J=3.3, 13.4 Hz, 1H), 1.91 (dd, J=4.0, 11.4 Hz, 1H), 1.80 (m, 1H), 1.76 (m, 1H). ESI MS: 323.3 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][S:17][C:3]1=2.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C)C=O.O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][S:17][C:3]1=2
Reactant: NC(=O)c1ccc2nc3c(c(=O)n2c1)SCC3
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2nc3c(c(=O)n2c1)SCC3
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide (1.7 g., 0.007 mol), p-toluene-sulfonyl chloride (2.0 g., 0.01 mol) and pyridine (1.7 ml, 0.021 mol) in dimethylformamide (30 ml) is heated at 100° C. under nitrogen for 40 minutes. The reaction mixture is cooled and diluted with water (15 ml). The resulting aqueous solution is stirred for one hour. The precipitate is filtered off, washed with water and sucked dry. Recrystallization from methanol gives the product (1.1 g.), mp 261°-263° C.
Reaction SMILES: [O-2:1].[Ca+2:2].[S-2:3].[Ca+2].[S:5]([O-:8])([O-:7])=[O:6].[NH4+:9].[NH4+]>O>[S:5]([O-:1])([O-:8])(=[O:7])=[O:6].[Ca+2:2].[S:5]([O-:8])([O-:7])=[O:6].[Ca+2:2].[NH4+:9]=[S:3]
Reactant: [NH4+]
Reactant: [S-2]
Reactant: [O-2]
Agent: O=S([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=S(=O)([O-])[O-]

Procedure:
reacting said waste water with a mixture of calcium oxide and calcium sulfide and with recycled ammonium sulfite from step (f), the molar ratio CaS/CaO being at least 0.5:1 and the amounts of the reactants being sufficient to form simultaneously insoluble calcium sulfate, insoluble calcium sulfite, and ammonium sulfide dissolved in the aqueous phase and then separating the resulting mixture of insoluble calcium sulfate and calcium sulfite from the aqueous phase,
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([NH2:10])=[O:9].[C:11]1([CH3:21])[CH:16]=CC(S(O)(=O)=O)=[CH:13][CH:12]=1.CN(C=O)C.C(=O)CC(C)C>C1(C)C=CC=CC=1>[CH2:12]([C:13]1[NH:10][C:8](=[O:9])[C:3]2[C:4]([CH3:7])=[N:5][S:6][C:2]=2[N:1]=1)[CH:11]([CH3:21])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1nsc(N)c1C(N)=O
Agent: CC(C)CC=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nsc2nc(CC(C)C)[nH]c(=O)c12
Temperature: 130 °C
Reaction time: 7 h
Yield: 89 %

Procedure:
To a 2 L flask equipped with Dean Stark was charged 5-amino-3-methylisothiazole-4-carboxamide (method 63) (1 equiv), p-toluene sulphonic acid (0.049 equiv), DMF (9.75 volumes). The reaction was stirred until a solution was obtained and isovaleraldehyde (1.10 equiv) and toluene (4.9 volumes) were added. The resulting mixture was heated to 130° C. and held at reflux for 1 hour removing water via a Dean Stark apparatus. Once the reaction was complete toluene was removed under vacuum distillation. Sodium bisullfite (2.50 equiv) was charged and the mixture was held at 115° C. for 7 hours, then cooled to room temperature overnight. The solid was removed by filtration through harborlite and washed with DMF (1 volume). Analysis showed conversion to product and the reaction was heated to 50° C., water (15 volumes) was added and the resulting precipitate was cooled to room temperature and held for 1 h. The product was isolated by filtration and washed with water (2×0.5 volumes), dried to give a pale brown solid (typical yield 89%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[C:11]([CH3:12])=[C:10]([NH:13][CH2:14][CH2:15][CH2:16]O)[C:9]([N+:18]([O-:20])=[O:19])=[C:8]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]=1>ClCCl>[ClH:3].[Cl:3][CH2:16][CH2:15][CH2:14][NH:13][C:10]1[C:9]([N+:18]([O-:20])=[O:19])=[C:8]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]=[C:6]([CH3:5])[C:11]=1[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCO)c1C
Solvent: ClCCl
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCl)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 187 %

Procedure:
Thionyl chloride (2.86 mL, 39.2 mmol) was added to a chilled (0° C.) solution of 3-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]propan-1-ol (11.3 g, 35.6 mmol) in dichloromethane (170 mL). The reaction mixture was stirred at ambient temperature for 0.5 hr and then heated at reflux for 0.5 hr. The reaction mixture was allowed to cool to ambient temperature. A precipitate was isolated by filtration and then dried under vacuum to provide 13.64 g of N-(3-chloropropyl)-2,3-dimethyl-5-nitro-6-phenoxypyridin-4-amine hydrochloride.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([NH2:11])[C:6](=[CH:9][CH:10]=1)[O:7][CH3:8].[N:14]([O-])=O.[Na+].O.O.Cl[Sn]Cl>>[CH3:8][O:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:4][C:5]=1[NH:11][NH2:14]
Reactant: O=N[O-]
Reactant: COc1ccc(C(F)(F)F)cc1N
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1NN
Yield: 74 %

Procedure:
The title compound was prepared by the general procedure described above for Preparations 2a-i using 4-trifluromethyl-o-anisidine (V, R1=R2=H, R3=CF3), (22.7 g), NaNO2 (9.02 g), and SnCl2.2H2O (60 g). Workup gave 18.1 g (74%) of (2-methoxy-5-trifluoromethylphenyl)hydrazine which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ7.23 (d, J=2.0 Hz, 1 H), 7.05 (dd, J=8.2, 2.0 Hz, 1 H), 6.81 (d, J=8.3 Hz, 1 H), 3.89 (s, 3 H).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][C:43](O)=[O:44])=[CH:34]1>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:43](=[O:44])[CH2:42][C:35]4[C:36]5[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:33]([CH3:32])[CH:34]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Agent: Cl
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)Cc3cn(C)c4ccccc34)C[C@H]21
Yield: 58 %

Procedure:
By working in accordance with Use Example 4, starting from 0.75 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2methoxyphenyl)-perhydroisoindol-4-ol hydrochloride and 0.32 g of (1-methyl-3-indolyl)-acetic acid, 0.56 g of (3aS, 4S, 7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(1methyl-3-indolyl)-acetyl]-perhydroisoindol-4-ol is obtained in the form of a beige foam.
Reaction SMILES: C(N(C(S)=S)[CH2:7][C:8](F)(F)F)C(F)(F)F.[C:15]([O:18][C:19](=[O:21])[CH3:20])(=[O:17])[CH3:16].[CH2:22]1[CH2:26]O[CH2:24][CH2:23]1>>[C:19]1(=[O:21])[O:18][C:15](=[O:17])[CH2:16][CH2:8][CH2:7][CH2:24][CH2:23][CH2:22][CH2:26][CH2:20]1
Reactant: CC(=O)OC(C)=O
Reactant: C1CCOC1
Reactant: FC(F)(F)CN(CC(F)(F)F)C(=S)S
Product: O=C1CCCCCCCCC(=O)O1

Procedure:
BTCA was reacted with two equivalents of methoxy PEG amine in refluxing THF for 5 hours to yield dimethoxy-PEG tetracarboxybenzoate, with two remaining carboxylic groups. The PEG-dimer was reacted with acetic anhydride and then with sebacic anhydride to form the tetra-armed diblock PEG2 -benzene-PSA2.
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5]([C:8](OC)=O)=[CH:6]O.S(O)(O)(=O)=O.[CH3:19][S:20][C:21](=[NH:23])[NH2:22]>CO.C(OCC)(=O)C>[CH3:19][S:20][C:21]1[N:23]=[CH:8][C:5]([C:4]([O:3][CH3:2])=[O:12])=[CH:6][N:22]=1
Reactant: CSC(=N)N
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cnc(SC)nc1
Yield: 76 %

Procedure:
A solution of the sodium salt of 3,3-dimethoxy-2-methoxycarbonylpropen-1-ol (5.0 g, 25 mmol), 2-methyl-2-thiopseudourea sulfate (3.5 g, 25 mmol) in anhydrous methanol (25 mL) was refluxed for 3 hours under anhydrous conditions. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was filtered and the residue was washed with ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel) using 25% ethyl acetate in hexane to afford the desired product (3.5 g, 75%) as a white powder. 1H-NMR (d6-DMSO, 400 MHz) δ 9.0 (s, 2H), 3.92 (s, 3H), 2.58 (s, 3H); ES-HRMS m/z 185.041 (M+H C7H8N2O2S requires 185.0379).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:10](=[O:11])[N:9]([C:12]3[S:13][C:14]([C:18]([O:20]CC)=[O:19])=[C:15]([CH3:17])[N:16]=3)[CH:8]=[N:7]2)[CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCCC1.O>[CH:1]1([CH2:4][CH2:5][N:6]2[C:10](=[O:11])[N:9]([C:12]3[S:13][C:14]([C:18]([OH:20])=[O:19])=[C:15]([CH3:17])[N:16]=3)[CH:8]=[N:7]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1sc(-n2cnn(CCC3CC3)c2=O)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-n2cnn(CCC3CC3)c2=O)sc1C(=O)O
Yield: 55 %

Procedure:
To a solution of ethyl 2-(1-(2-cyclopropylethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate (0.20 g, 2.78 mmol) in tetrahydrofuran (10 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.15 g, 3.11 mmol) at ambient temperature. The resulting reaction mixture was heated to reflux for 20 hours. The solvent was removed in vacuo and the residue was neutralized to pH 4-5 with 10% hydrochloric acid. The resulting precipitate was collected by filtration and dried to afford 2-(1-(2-cyclopropylethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid in 55% yield (0.10 g): MS (ES−) m/z 293.1 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(Cl)Cl.[C:13]1([CH2:21][NH2:22])[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[BH4-].[Na+]>C(O)(C)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:21][NH:22][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NCc1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: Fc1ccc(CNCc2ccc(CNCc3ccc(F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
To a solution of 4-fluorobenzaldehyde (2.482 g, 20.00 mmol) in a mixed solvent (20 mL of methylene chloride nd 10 mL of i-propanol) at rt, was added 1,4-phenylenedimethanamine (1.362 g, 10 mmol, Aldrich). The reaction mixture was stirred at rt for 5 h. To this mixture, sodium borohydride (0.567 g, 15.0 mmol, 1.5 eq) was added, and it was stirred at rt overnight. The reaction mixture was quenched by adding 10 mL of MeOH and 10 mL of aq. NaHCO3. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were dried, concentrated and purified by ISCO system, eluting with CH2Cl2/EtOAc to give the title compound (2.45 g, 66%) as a viscous material, MS (ESI): 353.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]1[CH3:26].[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH:21]([CH3:26])[CH2:22][CH2:23][CH:24]1[OH:25]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2C(=O)CCC2C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2C(C)CCC2O)c1
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask was charged with 66.56C (mixture of diastereomers) (0.59 g, 1.7 mmol) and 1:1 THF/MeOH (15 mL). To the solution was added sodium borohydride (0.063 g, 1.7 mmol) in one portion at room temperature. The mixture was stirred for 1 hour, quenched with 1 N HCl, and extracted with ether. The combined organic layers were dried (MgSO4) and concentrated to afford 66.56D (mixture of diastereomers) as a colorless oil. The product thus obtained was used without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]4([C:28]([OH:30])=O)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:39][NH:40][CH3:41]>>[CH3:39][N:40]([CH3:41])[C:28]([C:25]1([C:22]2[N:23]=[N:24][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:37])[CH3:38])([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)=[CH:20][CH:21]=2)[CH2:27][CH2:26]1)=[O:30]
Reactant: CNC
Reactant: C[C@@H](c1ccc(-c2ccc(C3(C(=O)O)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C(=O)N(C)C)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 21 %

Procedure:
The title compound was prepared from 1-[6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-pyridazin-3-yl]-cyclopropanecarboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 21% of theory; LC (method 1): tR=1.79 min; Mass spectrum (ESI+): m/z=543 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:8])[C:3]([O:5][CH3:6])=[O:4].CCN(CC)CC.[C:24](Cl)([CH3:26])=[O:25]>C(Cl)Cl>[C:24]([NH:1][CH:2]([C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)=[O:8])[C:3]([O:5][CH3:6])=[O:4])(=[O:25])[CH3:26]
Reactant: CC(=O)Cl
Reactant: COC(=O)C(N)C(=O)c1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(NC(C)=O)C(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60.5 %

Procedure:
To a solution of methyl 2-amino-3-(4-methoxyphenyl)-3-oxopropanoate (35.5 g, 137 mmol) and Et3N (57.2 mL, 411 mmol) in DCM (120 mL) at 0° C. was added AcCl (12.9 g, 164 mmol) dropwise. The reaction mixture was stirred at 0° C. for 40 min and then quenched with water (500 mL). The resulting mixture was extracted with DCM (300 mL×2) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was washed with petroleum ether/EtOAc (300 mL, 100:1) to methyl 2-acetamido-3-(4-methoxyphenyl)-3-oxopropanoate (22.0 g, 61% yield) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[ClH:30].[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Cl:30][C:6]1[CH:5]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[NH:23])[NH:31][OH:32])=[CH:18][N:17]=2)=[O:14])[CH:3]=[CH:2][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cl
Reactant: NO
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccc(C#N)cn2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccc(C(=N)NO)cn2)cc1Cl
Temperature: 70 °C
Yield: 34.2 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-cyano-pyridin-2-yl)-3-cyclopentyl-propionamide (74 mg, 0.17 mmol) in ethanol (1 mL) and water (0.5 mL) was treated with hydroxylamine hydrochloride (14 mg, 0.21 mmol) and sodium carbonate (9 mg, 0.08 mmol). This solution was then heated at 70° C. for 1.5 h, after which time, the product precipitated out of solution. The resulting solid was collected by filtration, washed with water, and dried under vacuum to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxycarbamimidoyl)-pyridin-2-yl]-propionamide (27 mg, 34%) as a white solid: (ES)+-HRMS m/e calcd for C21H25ClN4O4S (M+H)+ 465.1358, found 465.1362.
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH:16]([CH:26]3[CH2:28][CH2:27]3)[O:15][C:14]2=[O:29])=[O:12])=CC=1)([O-])=O.Cl.Cl.FC1C=CC=CC=1[C@H]1CC[C@H](N2CCC(N)C2)CC1>>[CH:26]1([CH:16]2[O:15][C:14](=[O:29])[N:13]([C:11]([OH:12])=[O:10])[CH:17]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:27][CH2:28]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1C(=O)OC(C2CC2)C1c1ccc(F)c(F)c1
Agent: Cl
Agent: NC1CCN([C@H]2CC[C@H](c3ccccc3F)CC2)C1
Product: O=C(O)N1C(=O)OC(C2CC2)C1c1ccc(F)c(F)c1

Procedure:
The title compound was prepared from the reaction of the product of Step C above and trans-1-[4-(2-fluoro-phenyl)-cyclohexyl]-pyrrolidin-3-ylamine dihydrochloride
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])=[CH:35][C:34]=4[CH2:46][OH:47])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=O)(C)(C)C.[OH-].[Na+].[ClH:50]>CCO.C1COCC1>[ClH:50].[ClH:50].[NH2:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:33]4[N:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:35][C:34]=4[CH2:46][OH:47])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11]
Reactant: CCOC(=O)CCc1cnc(N2CCN(c3ncc(-c4cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c4)cn3)CC2)c(CO)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(Cc1cccc(-c2cnc(N3CCN(c4ncc(CCC(=O)O)cc4CO)CC3)nc2)c1)C(=O)CN
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 3-[6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-(hydroxymethyl)pyridin-3-yl]propanoate (222 mg) was dissolved in EtOH (1 ml) and THF (2 ml), and a 1 M aqueous NaOH solution (1 ml) was added thereto, followed by stirring at room temperature for 5 hours. To the reaction mixture was added 1 M hydrochloric acid (1 ml), and the solvent was evaporated under reduced pressure. To the obtained residue was added water, followed by extraction with CHCl3. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The product was dissolved in dioxane (2 ml), and 4 M hydrogen chloride/dioxane (0.8 ml) was added thereto. After stirring at room temperature overnight, the precipitated solid was collected by filtration to obtain 3-[6-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-5-(hydroxymethyl)pyridin-3-yl]propionic acid dihydrochloride (203 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH2:26]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH3:27]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:14])[N:28]([CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH2:26][CH3:27])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: CCNCCN(C)C
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Product: CCN(CCN(C)C)C(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with N′-ethyl-N,N-dimethyl-ethane-1,2-diamine gives “A91”; method 1: HPLC/MS: 1.08 min, [M+H]=433;
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:27]3[CH:26]=[C:25]([Cl:28])[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:9]1)=O)(C)(C)C.Cl>C(OCC)C.C(OCC)(=O)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[C:27]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N2c3ccccc3Sc3ccc(Cl)cc32)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Clc1ccc2c(c1)N(C1CCCNC1)c1ccccc1S2
Temperature: 0 °C
Reaction time: 8 h
Yield: 127.8 %

Procedure:
3-(2-Chlorophenothiazin-10-yl)piperidine-1-carboxylic acid tert-butyl ester (4.1 g, 9.83 mmol) was dissolved in diethyl ether (200 mL), and the solution cooled to 0° C. A solution of HCl in ethyl acetate (˜4 M, 30 mL) was slowly added. The mixture was allowed to warn to room temperature and stirred for 8 h. The solvent was removed under vacuum. The residue treated with HCl in ethyl acetate (˜4 M, 75 mL) and stirred overnight. The solvent was removed under vacuum to provide 2-chloro-10-piperidin-3-yl-10H-phenothiazine (3.98 g, 100%) as an off-white solid.