Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Br:15][C:16]1[CH:17]=[C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(Br)c3)nc2c1
Temperature: 120 °C
Yield: 87.9 %

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (0.5 g, 2.55 mmol) in N,N-dimethylacetamide (30 mL) was added 3-bromo-benzaldehyde (0.32 mL, 2.80 mmol) followed by NaHSO3 (0.39 g, 3.82 mmol) and p-toluenesulfonic acid monohydrate (0.24 g, 1.27 mmol). The reaction was heated at 120° C. for 20 h. After that time it was cooled to room temperature (rt), concentrated under reduced pressure and diluted with water. The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was triturated with diethyl ether to give 2-(3-bromo-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one (0.81 g, 88%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.84 (d, J=7.0 Hz, 1H), 7.66 (d, J=7.0 Hz, 1H), 7.38 (t, J=7.0 Hz, 1H), 6.8 (s, 1H), 6.46 (s, 1H), 3.94 (s, 3H), 3.90 (s, 3H).
Reaction SMILES: Cl.[C:2]1([CH:8]([SH:14])[CH:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](O)(=O)C>C=O>[C:2]1([CH:8]2[S:14][CH2:15][NH:10][CH:9]2[C:11]([OH:13])=[O:12])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(C(=O)O)C(S)c1ccccc1
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Product: O=C(O)C1NCSC1c1ccccc1
Reaction time: 2.5 h
Yield: 88 %

Procedure:
A mixture of β-phenyl-DL-cysteine hydrochloride [HT Nagasawa et al, J. Med. Chem (1987) 30, 1373] (1.32 g, 5.65 mmol) in acetic acid (11 ml) and formaldehyde (37 wt % aqueous solution, 0.43 ml) was heated to 80° to give a cloudy solution that was cooled to 30° and stirred for 2.5 h, then stood at room temperature for 16 h. The white precipitate was collected by filtration, washed with Et2O and dried in vacuo to give the title compound (1.04 g, 88%). δH (DMSO-d6) 7.57-7.54 (2 H, m, Ar—H), 7.40-7.29 (3 H, m, Ar—H), 4.90 (1 H, d, CHα-Thiopro), 4.59 (2 H, d, J 9.3 Hz, NCH2S), 4.46 (1 H, d, J 9.8 Hz, CHPh). m/z (ESI, 60 V) 210 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:36])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:25]=4[O:31][C:32]([F:35])([F:34])[F:33])=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CN1CCOCC1.[CH:44]1([C:47](Cl)=[O:48])[CH2:46][CH2:45]1>ClCCl>[O:36]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([NH:30][C:47]([CH:44]5[CH2:46][CH2:45]5)=[O:48])[CH:27]=[CH:26][C:25]=4[O:31][C:32]([F:35])([F:33])[F:34])=[CH:20][CH:19]=3)=[O:17])=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)cc2)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Nc1ccc(CN2CCS(=O)(=O)CC2)cc1)c1ccc(-c2cc(NC(=O)C3CC3)ccc2OC(F)(F)F)cc1
Reaction time: 18 h
Yield: 90.9 %

Procedure:
5′-Amino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid [4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (50 mg) in dichloromethane (1 ml) containing N-methylmorpholine (0.03 ml) was treated with cyclopropanecarbonyl chloride (9 mg), the mixture being stirred for 18 h. The solvent was then evaporated and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 800:8:1 to 100:8:1 gave a colourless solid (46 mg).
Reaction SMILES: [C:1]([C:3]([C:12]#[N:13])=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)#[N:2].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=1[S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=1[S:23]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[C:3]([C:12]#[N:13])[C:1]#[N:2])=[CH:6][CH:7]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: N#CC(C#N)=Cc1ccc(O)cc1
Solvent: c1ccncc1
Product: N#CC(C#N)=Cc1ccc(OS(=O)(=O)c2cc(Cl)c(Cl)cc2Cl)cc1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
1.7 g of 4-(2,2'-dicyanovinyl)phenol and 2.7 g of 2,4,5-trichlorobenzenesulfonyl chloride were dissolved in 10 ml of pyridine and reacted at 80° C. for 30 minutes. Crystals were precipitated by cooling to the room temperature and adding water, filtered and recrystallized from toluene to obtain 3.5 g of 4-(2,2'-dicyanovinyl)phenyl 2,4,5-trichlorobenzenesulfonate as white crystals. Melting point=165-166° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]([S:12]([NH:15]C(=O)OC(C)(C)C)(=[O:14])=[O:13])[CH2:9][CH2:8][NH:7][C:6]=2[N:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[F:39])[N:24]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[C:11]2[N:10]([S:12]([NH2:15])(=[O:13])=[O:14])[CH2:9][CH2:8][NH:7][C:6]=2[N:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[F:39])[N:24]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)N1CCNc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1N(S(N)(=O)=O)CCN2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
96 mg (0.17 mmol) of the compound from example 41A were initially charged in dichloromethane (5 ml), then 0.13 ml (1.73 mmol) of trifluoroacetic acid were added and the reaction mixture was stirred at RT overnight. The mixture was concentrated, the residue was separated by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 52 mg (66% of theory) of the title compound in solid form.
Reaction SMILES: [CH:1]1([C:4]2[CH2:8][CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)NN=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>O>[CH:1]1([CH:4]2[CH2:8][CH:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:3][CH2:2]1
Reactant: Oc1cccc(C2CC(C3CC3)=NN2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc(C2CC2C2CC2)c1
Temperature: 250 °C
Yield: 67.7 %

Procedure:
To a 250 ml round bottom flask equipped with nitrogen inlet, thermometer, and reflux condenser was charged 5.0 g (0.0246 moles) of 3-cyclopropyl-5-(3-hydroxyphenyl)-2-pyrazoline, and 5.0 g of powdered sodium hydroxide (0.125 moles). The two solids were mixed thoroughly, then heated slowly to 250° C., under a rapid steam of nitrogen. The reaction mixture was heated continuously at 250° C. for a total of 2 hours, then cooled to ambient temperature. The resulting residue was the dissolved in 200 mls of water, then acidified to pH 2 with 1N aqueous hydrochloric acid. The acidic solution was extracted with 3×100 mls of ethyl ether, and the ether extract was washed with 2×100 mls of water, and 100 mls of saturated aqueous sodium chloride solution. The ether extract was the dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure with a rotary evaporator at 45° C. The resulting crude product was chrmoatographed on silica gel with a 15% ethyl acetate, 85% hexane mobile phase. The pure fractions were combined and concentrated under reduced pressure on a rotary evaporator to afford 2.9 g of the title compound 1-(3-hydroxyphenyl)-2-cyclopropyl cyclopropane as a pale yellow liquid at a 68% yield.
Reaction SMILES: Cl[CH2:2][C@@H:3]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH:4]([CH3:6])[CH3:5].[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[O:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C@@H:3]([CH:4]([CH3:6])[CH3:5])[CH2:2][O:24]1
Reactant: CC(C)CN[C@H](CCl)C(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1OC[C@H](C(C)C)N1CC(C)C

Procedure:
(L)-Valine methyl ester was reduced to (1S)-1-(hydroxymethyl)-2-methylpropylamine according to Method B1b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2,4diisopropyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (1S)-1-(hydroxymethyl)-N-isobutyl-2-methylpropylamine. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to give (1S)-1-(chloromethyl)-N-isobutyl-2-methylpropylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-oxazolidine.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([CH3:15])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([CH3:15])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(C)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Yield: 95 %

Procedure:
A mixture of 30 g of ethyl 1-cyclopropyl-6,8-difluoro-7-methyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 210 ml of glacial acetic acid, 160 ml of water and 23.5 ml of concentrated sulphuric acid is heated under reflux for 2 hours. The hot suspension is then poured onto ice and the precipitate is filtered off with suction, rinsed thoroughly with water and dried in vacuo at 100° C. 25.9 g of pure 1-cyclopropyl-6,8-difluoro-7-methyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 227°-229° C. are obtained in this manner.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[N:11]2)=[C:6]([CH2:18][NH:19][C@H:20]([P:22](=[O:27])([O:25][CH3:26])[O:23][CH3:24])[CH3:21])[CH:5]=1)([O-:3])=[O:2].[CH2:28](I)[CH3:29].CCN(C(C)C)C(C)C>C(#N)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[N:11]2)=[C:6]([CH2:18][N:19]([CH2:28][CH3:29])[C@H:20]([P:22](=[O:27])([O:23][CH3:24])[O:25][CH3:26])[CH3:21])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN[C@@H](C)P(=O)(OC)OC)c2nc1OC
Reactant: CCI
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN(Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12)[C@@H](C)P(=O)(OC)OC
Temperature: 55 °C
Reaction time: 18 h

Procedure:
3.4 g (8.5 mmol) of dimethyl (R)-N-(7-nitro-2,3-dimethoxyquinoxalin-5-ylmethyl)-α-aminoethylphosphonate, 8.9 ml (7.5 eq.) of ethyl iodide and 20.9 ml (14.5 eq.) of Hunig's base are mixed in 18 ml of acetonitrile and stirred at 55° C. for 18 hours. The reaction mixture is evaporated and slurried with ethyl acetate. The deposited solid is filtered off and washed with ethyl acetate. The title compound is obtained in the form of a yellow resin after evaporation of the filtrate and column chromatography using ethyl acetate/methanol (95:5) as eluent.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:14][N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: Oc1ccc(OCCCCBr)cc1
Reactant: CNc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCCOc1ccc(O)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
Compound 11a (0.20 g, 0.816 mmol) and compound N-methylaniline (0.176 mL, 1.63 mmol) were stirred in acetonitrile (10 mL) for 30 mins and then diisopropylethylamine (0.33 mL, 2.44 mmol) was added dropwise. The reaction was then stirred at 60° C. for 12 hours and monitored by TLC. The reaction mixture was concentrated and treated with formic acid to facilitate purification by column chromatography to isolate compound 11 as a colorless oil (0.12 g, 0.36 mmol, 46% yield). MS (ESI, positive) m/z calcd. for C17H22NO2 [M+H]+: 272.16451, found: 272.16452. 1H NMR (CDCl3, 400 MHz) δ 7.29 (t, J=7.2 Hz, 2H), 6.77-6.83 (m, 7H), 6.10 (bs, 1H), 3.92 (t, J=5.2 Hz, 2H), 3.41 (t, J=7.2 Hz, 2H), 2.97 (s, 3H), 1.70-1.81 (m, 4H).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH:8]([OH:10])[C:7]2[S:11][CH:12]=[CH:13][C:6]=2[CH2:5]1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1F>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[O:10][CH:8]1[CH2:9][N:4]([CH2:3][CH2:2][F:1])[CH2:5][C:6]2[CH:13]=[CH:12][S:11][C:7]1=2
Reactant: Fc1cccc(Cl)c1Cl
Reactant: OC1CN(CCF)Cc2ccsc21
Product: FCCN1Cc2ccsc2C(Oc2cccc(Cl)c2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 5-(2-fluoroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 17) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[CH3:6][C@H:7]1[CH2:12][C@@H:11](O)[C@H:10]([CH:14]([CH3:16])[CH3:15])[CH2:9][CH2:8]1.S(=O)(=O)(O)O>C1CCCCC1.O>[C:1]([O:5][CH:9]1[CH:10]([CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:12][CH:7]([CH3:6])[CH2:8]1)(=[O:4])[CH:2]=[O:3]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: O=CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCCCC1
Product: CC1CCC(C(C)C)C(OC(=O)C=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of aqueous glyoxalic acid (200 g; 50% w/v), L-menthol (632.4 g) and concentrated sulfuric acid (3.5 g) in cyclohexane (600 mL) was refluxed at 80° C. to 85° C. for 3 to 4 hours. Water (115 mL) was removed by azeotropic distillation using a Dean Stark trap. The resulting solution was allowed to cool to room temperature and diluted with de-ionized water (500 mL). The organic layer was separated and diluted with de-ionized water (800 mL). The pH of the resultant mixture was adjusted to 5 using aqueous sodium carbonate (10%; 15 ml). The organic layer was separated and washed twice with aqueous sodium bisulfite (2×70 g in 2×800 mL of de-ionized water). The pH of the organic layer was again adjusted to 5 using aqueous sodium carbonate (10%; 20 ml) and aqueous solution of formaldehyde (130 mL) was added to it in one hour at room temperature. The pH of the resultant mixture was again adjusted to 7.5 using aqueous sodium carbonate (10%; 15 ml) and stirred for about 6 hours at room temperature. The suspension obtained was filtered and washed with de-ionized water (2×200 mL) at room temperature. The wet mass obtained was suspended in de-ionized water (1000 mL) and stirred for 2 hours at 40° C. to 45° C. The resultant mixture was cooled to 20° C. to 25° C. and stirred at the same temperature for one hour. The suspension was filtered and washed with de-ionized water (200 mL) at room temperature to give menthyl glyoxalate as wet mass.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]#[N:14])[CH2:9][CH2:8]1.[OH:15][NH:16][C:17](=N)[CH:18]([CH3:20])[CH3:19].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:18]([C:17]1[N:14]=[C:13]([N:10]2[CH2:9][CH2:8][CH:7]([C@H:5]3[CH2:6][C@H:4]3[CH2:3][CH2:2][OH:1])[CH2:12][CH2:11]2)[O:15][N:16]=1)([CH3:20])[CH3:19]
Reactant: N#CN1CCC([C@H]2C[C@H]2CCO)CC1
Reactant: CC(C)C(=N)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
In a 500 ml RBF was added a solution of 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carbonitrile (15.3 g, 85 mmol) in 1:1 THF:EtOAc (150 ml). To this solution was added N-hydroxy-2-methylpropanimidamide (9.93 g, 97 mmol) as a solid and the resulting mixture was stirred to yield a clear solution. An addition funnel was added to the flask and the whole set up was set under nitrogen atmosphere. The solution was placed in an oil bath heated to 70° C. A 0.5M solution of zinc chloride (204 ml, 102 mmol) in THF was placed in the addition funnel and added over a 5 minute period to the reaction mixture. Upon complete addition, the resulting mixture was stirred at 70° C. for 2 hours. After 30 minutes the clear solution became cloudy. After 1 hour at 70° C., a thick white precipitate formed. TLC indicates consumption of the all starting material. The mixture was cooled to RT and the white solid was filtered off and washed with 1:1 THF:EtOAc (200 mL) and dried. The white solid in the fitted funnel was dissolved in 100 mL of DMF and drawn through by vacuum into a 250 ml RBF. To this solution was then added Tosic Acid (8.07 g, 42.4 mmol) and the resulting mixture stirred at 80° C. overnight. (LCMS after 2.5 hrs showed the reaction was ˜30-40% complete with no other by-products forming.) The mixture was allow to cool to room temperature and then was diluted with 150 mL of ethyl acetate. The mixture was placed in a separatory funnel and washed with sat'd sodium bicarbonate solution (150 mL). The aqueous was extracted once with ethyl acetate (100 mL) and the organics were combined. The organics were washed with 1M Na2CO3 (50 mL), followed by water (2×100 mL), and then brine (100 mL). The organics were dried over sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure. The residue was taken up in 50 mL DCM and loaded onto a Flash 75 system (silica gel column). Biotage Flash 75 purification was done eluting with 20-70% ethyl acetate/hexane for 4 column volumes followed by 70% ethyl acetate for 4 column volumes (total solvent 16 L). The fractions containing the product were collected and concentrated under reduced pressure to afford the pure product. LC/MS (m/z): 280 (M+H)+.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[N:9]=[C:10]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]([C:17](O)=O)=[N:12]2.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[N:9]=[C:10]([NH:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:11]([C:17]1[O:3][C:1]([CH3:2])=[N:4][N:5]=1)=[N:12]2
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1C(=O)O
Reactant: CC(=O)NN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2nc3cccc(Br)c3nc2NC(C)(C)C)o1
Temperature: 90 °C
Yield: 45 %

Procedure:
Acetic hydrazide (33 mg, 0.44 mmol) and 5-bromo-3-(tert-butylamino)quinoxaline-2-carboxylic acid (371a) (130 mg, 0.40 mmol) were combined in EtOAc (4 mL) to give a yellow solution. TEA (0.17 mL, 1.20 mmol) was added followed by 1-propanephosphonic acid cyclic anhydride (Aldrich; 50 wt. % solution in EtOAc, 0.59 mL, 1.00 mmol). The reaction was sealed and heated in an oil bath at 90° C. for 16 h. The reaction mixture was cooled to RT, partitioned between saturated NaHCO3 and EtOAc. The aq. layer was extracted with EtOAc and the combined organic layers were washed with brine, and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was adsorbed onto 1 g silica gel and purified by silica gel chromatography (12 g column) using a gradient of 0-20% EtOAc/hexanes to afford 8-bromo-N-(tert-butyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)quinoxalin-2-amine (67 mg, 0.18 mmol, 46% yield) as a yellow solid. m/z (ESI, +ve ion) 362.0/364.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][C@H:41]5[CH3:46])=[O:39])=[CH:34][N:33]=4)[C:28](=[O:47])[N:27]([CH3:48])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][C@H:41]5[CH3:46])=[O:39])=[CH:34][N:33]=4)[C:28](=[O:47])[N:27]([CH3:48])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 132d (120 mg, 0.18 mmol) in methanol/dichloromethane (4/4 mL) was added NaBH4 (15 mg, 0.60 mmol). The mixture was stirred at room temperature for 1 h and quenched with water (2 mL). It was then evaporated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 132 (60 mg, 50%) as a white solid. MS-ESI: [M+H]+ 654.3. 1H NMR (500 MHz, MeOD-d4) δ 8.94 (d, J=2.5 Hz, 1H), 8.61 (d, J=5.0 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H) 7.88 (d, J=1.5 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.72-7.69 (m, 1H), 7.65 (d, J=5.0 Hz, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 4.62-4.58 (m, 2H), 4.36-4.31 (m, 1H), 3.61-3.84 (m, 2H), 3.71-3.67 (m, overlap, 5H), 3.56-3.47 (m, 2H), 1.47 (s, 9H), 1.39 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][C:5]([O:9][CH2:10][CH3:11])=[CH:6][C:7]=1[Cl:8].Cl.Cl.Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[S:25][C:26]([CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][NH2:37])[CH2:32][CH2:31]2)=[CH:27][N:28]=1>>[NH2:1][C:2]1[C:3]([C:12]([NH:37][CH2:36][CH:33]2[CH2:34][CH2:35][N:30]([CH2:29][C:26]3[S:25][C:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[N:28][CH:27]=3)[CH2:31][CH2:32]2)=[O:14])=[N:4][C:5]([O:9][CH2:10][CH3:11])=[CH:6][C:7]=1[Cl:8]
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Reactant: CCOc1cc(Cl)c(N)c(C(=O)O)n1
Agent: Cl
Product: CCOc1cc(Cl)c(N)c(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)n1

Procedure:
According to the same procedure described in Example 16, using the compound prepared in Example 428 instead of 4-chloro-3-methoxybenzoic acid and the compound prepared in Example 214 instead of the compound prepared in Example 9, the title compound having the following physical data was obtained.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[C:9]([O:10][CH3:11])=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=[N:6][CH:5]=1.[OH-].[Na+]>CO.O>[CH3:11][O:10][C:9]1[C:4]([C:3]([OH:16])=[O:2])=[CH:5][N:6]=[CH:7][C:8]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cncc(C(=O)OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cncc(C(=O)O)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 5,3 g (23.5 mmol) of methyl-4-methoxy-5-methoxycarbonyl-nicotinate in 150 ml of methanol and 50 m. of water is added a solution of 0.94 g (23,5 mmol) of sodium hydroxide in 10 ml of water. The resulting mixture is stirred at room temperature overnight. The methanol is removed under vacuum, the aqueous solution is made slightly acidic and extracted with ethyl acetate. The combined organic phases are dried and filtered through silica. The filtrate is evaporated to near dryness and diluted with diisopropyl ether. A precipitate is obtained, filtered off and dried. There is obtained 2,83 g (57% yield) of a white solid (M+1=212).