Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[N:13][C:12]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]2=3)[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH3-])(=O)C.[Na+].CO>ClCCl>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:15](=[O:16])[CH:14]=[N:13][C:12]5[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]4=5)[CH2:6][CH2:7]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2n1
Yield: 64.4 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (Intermediate 202, 75 mg) was reacted with 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (48 mg) and sodium acetoxyborohydride (0.11) as described for Example 107. Chromatography on silica gel with 0-2% methanol in dichloromethane to give 72 mg of the product.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[O:30][N:29]=[C:28]([C:31]([OH:33])=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:66])[C:58]2[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=2[Cl:65])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[Cl:65][C:59]1[CH:60]=[CH:61][C:62]([Cl:64])=[CH:63][C:58]=1[C:57]([N:54]1[CH2:53][CH2:52][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:31]([C:28]2[CH:27]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:30][N:29]=2)=[O:33])[CH2:56][CH2:55]1)=[O:66]
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1)c1cc(-c2ccccc2)on1
Temperature: 10 °C
Reaction time: 8 h
Yield: 53.39 %

Procedure:
HOBt (24 mg, 0.18 mmol) and DIPEA (74 mg, 0.57 mmol) were added to a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid (27 mg, 0.14 mmol) in DMF (1.0 mL). The mixture was then cooled to 10° C. and EDCI.HCl (34 mg, 0.18 mmol) followed by 2-amino-1-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-ethanone hydrochloride (50 mg, 0.15 mmol) were added. The reaction mixture was then stirred at room temperature overnight. Water was added, and the resulting precipitate was isolated by filtration under reduced pressure and dried in vacuo to afford 5-phenyl-isoxazole-3-carboxylic acid {2-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a solid 53.39% yield. LC-MS purity: 92.758%. 1H-NMR (DMSO): δ 8.78 (t, 1H), 8.0 (m, 2H), 7.6 (m, 6H), 7.47 (s, 1H), 4.2 (m, 2H), 3.8 (m, 1H), 3.7 (m, 2H), 3.56 (m, 2H), 3.2 (m, 3H).
Reaction SMILES: Br[C:2]1[C:13](=[O:14])[N:12]([CH:15]([CH3:17])[CH3:16])[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29].C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:13](=[O:14])[N:12]([CH:15]([CH3:17])[CH3:16])[C:5]3[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=3[CH:3]=2)=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29]
Reactant: CSc1ncc2cc(Br)c(=O)n(C(C)C)c2n1
Reactant: O=[N+]([O-])c1cc(B(O)O)ccc1F
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: COCCOC
Product: CSc1ncc2cc(-c3ccc(F)c([N+](=O)[O-])c3)c(=O)n(C(C)C)c2n1
Temperature: 80 °C
Yield: 109.5 %

Procedure:
To a degassed solution of 6-bromo-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)one (0.78 g, 2 mmol; J. Med. Chem., 48, 2371, 2005) in DME (10 ml) was added Pd(PPh3)4 (0.1 g, 5% mol), 4-fluoro-3-nitrophenylboronic acid (0.5 g, 3 mmol) and 2M Na2CO3 solution (3 ml, 6 mmol) and the mixture was heated to 80° C. for 16 h. The mixture was poured into water (40 mL), and product was extracted with EtOAc (3×25 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo afforded crude product. Purification by silica gel chromatography provided 6-(4-fluoro-3-nitrophenyl)-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as off-white solid (0.82 g, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 8.52 (dd, J=7.2 Hz, 2.4 Hz, 1H), 8.28 (s, 1H), 8.15-8.12 (m, 1H), 7.70 (dd, J=11.6 Hz, 8.8 Hz, 1H), 5.81-5.78 (m, 1H), 2.63 (s, 3H), 1.60 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 375.0 (M+H+).
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH4+:9].N>>[NH2:9][C@H:2]([C:1]([O-:8])=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[NH4+:9].[NH4+:9]
Reactant: O=C([O-])/C=C\C(=O)O
Agent: N
Agent: [NH4+]
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]

Procedure:
subjecting monoammonium maleate in an aqueous solution in the presence of ammonia to an isomerization reaction and an enzyme reaction caused by aspartase to produce ammonium L-aspartate in a reaction solution;
Reaction SMILES: COC(=O)[NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:6]=1[C:14]#[C:15][CH2:16][CH2:17][CH2:18]Cl.C(OC1C=CC2[N:29]3CC[CH2:35][C:28]3=[CH:27]C=2C=1)C.[OH-].[K+]>C(#N)C.[Pd](Cl)Cl>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]2[N:4]3[CH2:18][CH2:17][CH2:16][C:15]3=[C:14]([CH2:27][C@@H:28]([NH2:29])[CH3:35])[C:6]=2[CH:7]=1)[CH3:13]
Reactant: CCOc1ccc(NC(=O)OC)c(C#CCCCCl)c1
Reactant: CCOc1ccc2c(c1)cc1n2CCC1
Agent: Cl[Pd]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCOc1ccc2c(c1)c(C[C@H](C)N)c1n2CCC1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 53.8 %

Procedure:
Iodoethane (15.8 mL, 220.64 mmol) and potassium carbonate (28.4 g, 220.05 mmol) were added to [2-(5-Chloro-pent-1-ynyl)-4-hydroxy-phenyl]-carbamic acid methyl ester (39 g, 145.68 mmol) in N,N-dimethylformamide (300 mL). The mixture was stirred 3 h at room temperature. The mixture was poured into 1M pH7 phosphate buffer and the organic phase extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated to dryness. The oily residue was purified by column chromatography on silica gel (6:1 to 5:1 hexane/ethyl acetate eluant) to afford the product as an oil (29 g, 67% over two steps) which solidified upon standing in the refrigerator. m.p. 55-56° C. 6-Ethoxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]indene [2-(5-Chloro-pent-1-ynyl)-4-ethoxy-phenyl]-carbamic acid methyl ester (28.5 g, 96.36 mmol) was dissolved in acetonitrile (600 mL). Palladium (II) chloride (0.9 g, 5.08 mmol) was added and the mixture was heated 2 h at 70° C. The dark mixture was cooled to room temperature and filtered through a small pad of celite, while washing the pad with acetonitrile. The solvent was evaporated to dryness and the brown residue (30 g) taken up in tert-butanol (600 mL). Powdered potassium hydroxide (22 g, 392.09 mmol) was added and the mixture stirred 40 min in an oil-bath at 105° C. The mixture was cooled, poured onto ice and extracted twice with ethyl acetate. The combined organic phases were washed with water, brine, dried over sodium sulfate and evaporated. The brown residue was purified by column chromatography on silica gel (5:1 hexane/ethyl acetate) to afford the product as an off-white solid (13.4 g, 69%). m.p.101-102° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@H:14]([C:23]([N:25]([CH2:35][C:36]1[C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[S:39][CH:40]=1)[C@@H:26]([CH3:34])[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:24])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[S:39]1[CH:40]=[C:36]([CH2:35][N:25]([C@@H:26]([CH3:34])[CH:27]([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])[C:23](=[O:24])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]1=2
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 57 mg (0.32 mmol) was coupled with (S)-tert-butyl 3-amino-4-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-4-oxobutanoate (Compound IV-18) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:16])[CH2:11][C:10]([O:14][CH3:15])([O:12][CH3:13])[CH2:9]2)=[CH:4][CH:3]=1.[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])N1C(OCC)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:16]3[C:18](=[O:17])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:27])[CH2:11][C:10]([O:14][CH3:15])([O:12][CH3:13])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC1(OC)CC(N)(c2ccc(Br)cc2)C1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC1(OC)CC(c2ccc(Br)cc2)(N2C(=O)c3ccccc3C2=O)C1
Temperature: 70 °C
Yield: 40.6 %

Procedure:
A mixture of 1-(4-bromophenyl)-3,3-dimethoxycyclobutanamine (0.66 g, 2.306 mmol), ethyl 1,3-dioxoisoindoline-2-carboxylate (0.56 g, 2.55 mmol) and triethylamine (1.3 ml, 9.33 mmol) in CHCl3 (15 ml) was heated at 70° C. for 16 h. The reaction mixture was concentrated to as dry as possible. Methanol (˜5 ml) was added. The solution was concentrated to dryness. Methanol (˜5 ml) was added again and the resulted solid was collected by filtration to afford product as a white solid (0.39 g). 1H NMR (500 MHz, CDCl3): 7.70 (dd, 2H), 7.60 (dd, 2H), 7.44 (dd, 2H), 7.37 (dd, 2H), 3.18 (m, 4H), 3.10 (s, 3H), 3.02 (s, 3H).
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([NH:4][CH2:5]3)C1)[CH2:9]2.C12NC(CCCC1)CCCC2>>[CH:11]12[CH2:1][CH2:9][CH:8]3[CH:10]([NH:4][CH2:5][CH:6]1[CH2:7]3)[CH2:3]2
Reactant: C1NC2CC3CC1CC(C3)C2
Agent: C1CCC2CCCCC(C1)N2
Product: C1CC2CC3CNC2CC13

Procedure:
4-azatricyclo [4.3.1.13,8 ]undecane; 11-azabicyclo[4.4.1]undecane;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.O=S(Cl)Cl.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[F:29])[C:22]([O:24][CH3:25])=[O:23].O>CC(N(C)C)=O>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:28]([F:29])=[C:19]([NH:18][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:13])[CH:20]=1
Reactant: COC(=O)c1ccc(F)c(N)c1
Reactant: O=C(O)c1cnc2cc(Br)ccn12
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
To the solution of compound 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 1) (1.26 Kg, 5.23 mol) in DMAC (15 L) was added dropwise SOCl2 (1.86 kg, 15.6 mol) at 10° C. in 30 min. To the resulting mixture warmed to 20° C. was added compound methyl 3-amino-4-fluorobenzoate (884 g, 5.23 mol) in DMAC (3.0 L) over 30 min. After addition, the reaction temperature went up to 30° C. HPLC showed the reaction went to completion within 5 min. To the reaction mixture was added water (20 L) over 20 min. The mixture was filtered and dried under vacuum to afford the title compound as a white solid;
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.Br[C:38]1[CH:39]=[CH:40][C:41](=[O:49])[N:42]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH:43]=1>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:38]3[CH:39]=[CH:40][C:41](=[O:49])[N:42]([CH2:44][C:45]([F:47])([F:48])[F:46])[CH:43]=3)=[CH:18][CH:19]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1ccc(Br)cn1CC(F)(F)F
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CC(F)(F)F)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 5-bromo-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.323 min, m/z=471.1; 1H NMR (CDCl3) 1.13 (s, 3H), 1.19 (s, 3H), 1.53 (d, 3H), 2.19-2.30 (m, 4H), 2.40 (m, 1H), 2.89 (m, 1H), 4.67 (m, 2H), 5.69 (m, 1H), 6.70 (d, 1H), 7.03 (d, 2H), 7.13 (d, 2H), 7.29-7.38 (m, 6H), 7.55 (d, 1H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([NH:25][C:26](=[O:39])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:29]=2[F:38])=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21]C(=O)C)[CH:12]=[CH:11]2)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:38][C:29]1[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([NH:25][C:9]1[C:8]([NH:7][CH2:6][CH2:5][OH:4])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]([CH2:19][CH2:20][OH:21])[C:14]2=[O:18])=[O:39]
Reactant: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1NC(=O)Cc1cccc(C(F)(F)F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Cc1cccc(C(F)(F)F)c1F)Nc1c(NCCO)ccc2c(=O)n(CCO)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with 2-(2-(2-acetoxyethyl)-5-(2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamido)-1-oxo-1,2-dihydroisoquinolin-6-ylamino)ethyl acetate (120 mg, 0.00022 mol), potassium carbonate (45 mg, 0.00033 mol) and methanol (3 mL, 0.07 mol) and 2 drops of water was added and the reaction stirred at room temperature for 30 minutes and was filtered over sodium sulfate and the solvent removed and the residue purified by flash chromatography to get the product as white solid. MS m/z=468.4 (M+H). 1H NMR (400 MHz ) δ 9.45 (s, 1H), 7.98 (d, J=8.95 Hz, 1H), 7.79 (t, J=7.45 Hz, 1H), 7.70 (t, J=7.09 Hz, 1H), 7.40 (t, J=7.83 Hz, 1H), 7.22 (d, J=7.83 Hz, 1H), 6.91 (d, J=9.08 Hz, 1H), 6.16 (d, J=7.73 Hz, 1H), 5.64 (t, J=5.72 Hz, 1H), 4.84 (t, J=5.33 Hz, 1H), 4.76 (t, J=5.48 Hz, 1H), 3.96 (s, 2H), 3.91 (t, J=5.27 Hz, 2H), 3.62-3.53 (m, 4H), 3.27 (q, J=6.15 Hz, 2H).
Reaction SMILES: [C:1](=O)([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:2]C(Cl)C.[F-:14].[K+].C1OCCOCCOCCOCCOCCOC1>>[F:14][C:1]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:2]
Reactant: CC(Cl)OC(=O)Oc1ccccc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Product: O=C(F)Oc1ccccc1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
A mixture of 11.6 g (0.058 mole) of freshly distilled 1-chloroethyl phenyl carbonate, 4.60 g (0.079 mole) of anhydrous KF (Aldrich), 0.80 g (0.003 mole) of 18-crown-6 ether (Aldrich) is prepared. The mixture is stirred and heated by means of an oil bath at 75° C. at a pressure of about 2.7 kPa. The reaction is allowed to proceed for 90 minutes during which the phenyl fluoroformate which is formed continuously evaporates and is removed by fractional distillation.
Reaction SMILES: Cl.[N+:2]([C:5]1[C:6]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:27](O)=[O:28].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O.O>[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:27]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:6]2[C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:13][CH2:14]1)=[O:28]
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: O=[N+]([O-])c1cccnc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(c1nc2ccccc2[nH]1)N1CCC(Nc2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A mixture of 3-nitro-N-(piperidin-4-yl)pyridin-2-amine hydrochloride (intermediate 58, 580 mg, 2.3 mmol), 1H-benzo[d]imidazole-2-carboxylic acid (365 mg, 2.3 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (365 mg, 2.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (516 mg, 2.7 mmol) and N-methylmorpholine (455 mg, 4.6 mmol) in dry dimethylformamide (15 mL) was stirred at room temperature overnight. The mixture was diluted with water (60 mL), and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the crude compound which was purified by silica chromatography to afford (1H-benzo[d]imidazol-2-yl)(4-((3-nitro-pyridin-2-yl)amino)piperidin-1-yl)methanone (600 mg, 1.64 mmol, 72.8% yield).
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[C:11](=[O:12])[CH:10]2[CH2:13][CH:7]([CH2:8][CH2:9]2)[C:6]1=[O:14])=O.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[S:21])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[S:21][CH:2]=[C:3]([CH:5]3[C:11](=[O:12])[CH:10]4[CH2:13][CH:7]([CH2:8][CH2:9]4)[C:6]3=[O:14])[N:22]=2)=[CH:18][CH:17]=1
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: O=C(CCl)C1C(=O)C2CCC(C2)C1=O
Solvent: Cc1ccccc1
Product: O=C1C2CCC(C2)C(=O)C1c1csc(-c2ccc(Cl)cc2)n1
Yield: 53.3 %

Procedure:
3-(2-chloro-acetyl)bicyclo[3.2.1]octane-2,4-dione (3.16 g, 14.7 mmol) and 4-chloro-thiobenzamide (2.53 g, 14.7 mmol) are mixed together in toluene (50 ml) and heated under reflux overnight. Therefore, the reaction mixture was evaporated to a black gum and the gum was absorbed onto silica and purified by flash chromatography eluting with a gradient of hexane/ethyl acetate to give 3-[2-(4-chloro-phenyl)thiazol-4-yl]bicyclo[3.2.1]octane-2,4-dione (2.6 g).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]([NH2:17])([C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7].C1COCC1.[Li+].[OH-]>CO.O>[CH3:7][CH:6]([CH3:8])[CH2:5][C:4]([NH2:17])([C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:3]([OH:18])=[O:2]
Reactant: COC(=O)C(N)(CC(C)C)C(=O)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(N)(C(=O)O)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.7 %

Procedure:
To a solution of 4-methyl-2-[pyridine-3-carbonyl]-amino-pentanoic acid methyl ester (0.80 g, 3.3 mmol), in methanol (8 mL), THF (3 mL) was added LiOH (0.7 g, 16.9 mmol), dissolved in water (9 mL). The mixture was allowed to stir at room temperature (25° C.) over 2.5 h. Methanol and THF was stripped off from the reaction mass, acidified the reaction mass using 1.5NHCl (pH=1). Extracted the reaction mass with ethyl acetate (100 mL) thrice and dried over sodium sulphate and concentrated to obtain product as pale yellow solid (0.45 g, 60%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:13][C:14]1[C:27]2[CH2:26][CH2:25][C@H:24]3[C@@H:19]([CH2:20][CH2:21][CH2:22][NH:23]3)[C:18]=2[CH:17]=[C:16]([F:28])[CH:15]=1>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:23]3[C@@H:24]4[C@H:19]([C:18]5[CH:17]=[C:16]([F:28])[CH:15]=[C:14]([F:13])[C:27]=5[CH2:26][CH2:25]4)[CH2:20][CH2:21][CH2:22]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: Fc1cc(F)c2c(c1)[C@@H]1CCCN[C@H]1CC2
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@H]2c3cc(F)cc(F)c3CC[C@@H]21
Yield: 70 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-7,9-difluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 70% of theory; TLC: rf=0.43 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=368 [M+H]+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[O:8][CH:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH3:10]>C(OC(=O)C)C>[Cl:5][C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[O:8][CH:9]([C:11]1[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=1)[CH3:10]
Reactant: O=C(Cl)Cl
Reactant: CC(Oc1ccccc1Cl)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: CC(Oc1ccccc1Cl)c1nnc(N=C=O)s1
Reaction time: 17 h

Procedure:
A 300 milliliter, 3-neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotometer was charged with 50 milliliters of ethyl acetate saturated with phosgene at 20° C. (approximately 0.5 mole of phosgene). An additional 100 milliliters of ethylacetate was added; 9.8 grams of 5-[1-(2-chlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole (prepared above) at a temperature from 0° C. to room temperature was added. The resulting solution was stirred for 17 hours with formation of an emulsion and then the flask was purged with nitrogen until no COCl2 was detected. The solution was filtered, and topped at 70° C. on a roto-vac to form 9.9 grams of a gooey yellow oil of 5-[1-(2-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: OS(O)(=O)=O.I([O-])(=O)(=O)=O.[Na+].[C:12]([OH:21])(=[O:20])[CH:13]([CH:15]([C:17]([OH:19])=O)O)O.C1(=O)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]C1.[OH-].[Na+].Cl>O.C(O)C>[O:19]=[C:17]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][C:15]1=[CH:13][C:12]([OH:21])=[O:20]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: O=C1CCc2ccccc21
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)C=C1Cc2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.1 %

Procedure:
To a solution of 1.3 mL of H2SO4 dissolved in 75 mL H2O was added 11.3 g (0.053 mol) of sodium periodate. The reaction mixture was cooled to 0° C. and 8.0 g (0.053 mol) of tartaric acid was added all at once and stirred for 15 min. at room temperature. 5.0 g (0.038 mol) of 1-indanone was added all at once followed by the dropwise addition of 19.0 g (0.24 mol) of 50% NaOH dissolved in 40 mL of H2O. A white precipitate was formed and 75 mL of ethanol was added. The reaction mixture was stirred at room temperature for 1 hour, acidified to pH ~2 with concentrated HCl and stirred for 18 hours at room temperature, filtered and dried to afford 3.3 g of a yellow solid.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].CCN(CC)CC.[Br:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1/[C:23](=[CH:33]\OC)/[C:24](=[O:32])[NH:25][C:26]2=[O:31].O>CN(C)C=O>[Br:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1/[C:23](=[CH:33]/[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([OH:2])[CH:4]=1)/[C:24](=[O:32])[NH:25][C:26]2=[O:31]
Reactant: COc1ccc(CN)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2cccc(Br)c21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CN/C=C2\C(=O)NC(=O)c3cccc(Br)c32)cc1O
Reaction time: 3.5 h
Yield: 86.4 %

Procedure:
A solution of 88.5 mg (0.468 mmol) of 3-hydroxy-4-methoxy-benzylamine hydrogen chloride in 1.8 mL of N,N-dimethylformamide (DMF) at RT under N2 is treated with 94.5 mg (0.936 mmol) of Et3N. (4E)-5-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (132 mg, 0.468 mmol) is added and the mixture is stirred for 3.5 h. Water is added and the product is collected, washed with H2O and Et2O and dried to give 163 mg (86%) of pale yellow amorphous solid: mp 204-206° C.; 1H NMR (DMSO-d6) δ 11.11 (s, 1H), 10.56 (m, 1H), 9.08 (s, 1H), 8.93 (d, 1H, J=13.6 Hz), 8.05 (d, 1H, J=6.9 Hz), 7.87 (d, 1H, J=6.9 Hz), 7.09 (m, 1H), 6.91 (d, 1H, J=8.07 Hz), 6.78 (m, 2H), 4.49 (d, 2H, J=5.37 Hz), 3.75 (s, 3H); HRMS (ESI) m/z calcd for C18H15BrN2O4 403.02880. found 403.02840 (M+H)+1.