Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])=[O:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:12]([C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[F:21])=[C:3]([CH:1]=[O:2])[CH:4]=1)=[O:7]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C=O)c1
Temperature: 90 °C
Yield: 100.6 %

Procedure:
To a round bottle flask, was added methyl 3-formyl-4-(trifluoromethylsulfonyloxy)benzoate (6300 mg, 20 mmol), 2-fluoro-5-methoxyphenylboronic acid (10 g, 61 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA), potassium phosphate tribasic (6.6 mL, 81 mmol) (granular) and tetrakis(triphenylphosphine)palladium (2.3 g, 2.0 mmol). The flask was flushed with nitrogen, DME was added, and the mixture was heated at 90° C. for 6 hours. The reaction mixture was diluted with EtOAc and water. The organic phase was washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to give a residue which was purified by chromatography to give the product as a yellow solid (5.80 g, 100%). MS ESI m/e: 289.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=[N:8][OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.Br[CH2:14][C:15]1[CH:40]=[CH:39][C:18]([C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:38])[C:30]2[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][CH:31]=2)=[O:20])=[CH:17][CH:16]=1>>[CH3:1][C:2]1([CH3:12])[CH2:7][CH:6]([N:8]([CH2:14][C:15]2[CH:40]=[CH:39][C:18]([C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:8]([CH:6]4[CH2:7][C:2]([CH3:12])([CH3:1])[NH:3][C:4]([CH3:11])([CH3:10])[CH2:5]4)[OH:9])=[CH:32][CH:31]=3)=[O:20])=[CH:17][CH:16]=2)[OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1
Reactant: O=C(OCCCCCCOC(=O)c1ccc(CBr)cc1)c1ccc(CBr)cc1
Reactant: CC1(C)CC(=NO)CC(C)(C)N1
Product: CC1(C)CC(N(O)Cc2ccc(C(=O)OCCCCCCOC(=O)c3ccc(CN(O)C4CC(C)(C)NC(C)(C)C4)cc3)cc2)CC(C)(C)N1

Procedure:
from 2,2,6,6-tetramethylpiperidin-4-one oxime and hexamethylene di-(4-bromomethylbenzoate)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([NH:11]C=O)=[C:7]([C:14](=O)[CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:6]=1)[CH3:2].Cl.[NH2:28][OH:29]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([C:14](=[N:28][OH:29])[CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC=O)c(C(=O)CCNC(=O)OC(C)(C)C)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(N)c(C(CCNC(=O)OC(C)(C)C)=NO)c1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
A solution of ethyl-4-formylamino-3-[3'-(N-tert-butyloxycarbonylamino)propionyl]benzoate (7.04 g, 20 mmol) and hydroxylamine hydrochloride (7.65 g, 110 mmol) in pyridine (200 ml), was heated at reflux for 15 hours. After this time the solution was cooled to ambient temperature and the solvent evaporated in vacuo. The residue was chromatographed (eluent 1:1 petrol:ethyl acetate) to give the title oxime (5.0 g, 71%) as a solid. m.p. 138°-140° C. NMR δ (250 MHz, CDCl3) 1.40 (12H, m), 3.13 (2H, t, J=7 Hz), 3.40 (2H, m), 4.31 (2H, q, J=7 Hz), 5.19 (1H, br s), 6.11 (2H, br s), 6.66 (1H, d, J=9 Hz), 7.73 (1H, dd, J=9 and 2 Hz), 8.10 (1H, br s), 10.46 (1H, br s).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>CCCCO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:29][CH2:28][C:25]2[CH:26]=[N:27][C:22]([CH3:21])=[CH:23][CH:24]=2)[N:10]=1
Reactant: Cc1ccc(CN)cn1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNc2nc(F)nc3[nH]cnc23)cn1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.4 g, 2.3 mmol) in n-BuOH (50 ml) under an argon atmosphere at 0° C., was added DIEA (2.5 ml, 14.7 mmol) followed by (6-methylpyridin-3-yl)methanamine (0.36 g, 2.95 mmol). The reaction mixture was stirred at this temperature for 1 h and then allowed to return to room temperature and stirred for 4 h, it was still seen incomplete, hence heated the reaction to 100° C. and left at that temperature for 8 h. The solvent was evaporated in vacuo and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→90:10), to afford the product as a white solid; Yield: 0.38 g (65%) δH CDCl3, 250 MHz) 2.44 (3 H, s, CH3), 3.66-3.57 (2 H, m, NHCH2), 4.63 (1H, s, br, NH), 7.25 (1 H, d, J 7.5, ArH), 7.71 (1 H, dd, J 2.5, 7.5, ArH), 8.14 (1 H, s, ArH), 8.49 (1 H, s, ArH), 9.07 (1 H, s, br, NH); δC (CDCl3, 250 MHz) 159.12 (C), 158.62 (C), 157.61 (C), 155.56 (C), 147.44 (CH), 146.99 (CH), 136.32 (C), 123.05 (2×CH), 119.42 (C), 41.64 (CH2), 18.47 (CH3); m/z 259.2 (M+H)
Reaction SMILES: CC[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:20][CH3:21])=[CH:9][C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=O.[OH-].[K+]>C(O)C.O.C(Cl)(Cl)Cl>[CH3:3][NH:5][C:6]1[S:7][C:8]([CH2:20][CH3:21])=[CH:9][C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: CCC(=O)Nc1sc(CC)cc1C(=O)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(NC)s1
Temperature: 95 °C
Yield: 67.5 %

Procedure:
To a solution of 26.0 g of 2-(N-methylacetylamino)-3-(o-chlorobenzoyl)-5-ethylthiophene in 520 ml of ethanol, is added 5.85 g of potassium hydroxide in 164 ml of water. The mixture is heated at 95°C for 1 hour, then evaporated under reduced pressure to a residue. Water is added to the residue and extracted with dichloromethane. The dichloromethane extracts are washed with water, dried over sodium sulfate, then evaporated under reduced pressure to give crystals, which are chloromatographed on silica gel using chloroform as an eluent to give 15.26 g of 2-(N-methylamino)-3-(o-chlorobenzoyl)-5-ethylthiophene as crystals having a melting point of 100° - 102°C (after recrystallization from ether); yield 67.5%.
Reaction SMILES: [CH2:1]([CH:5]([Sn])C=C(CCCC)CCCC)[CH2:2]CC.Br[C:18]1[C:19]([F:38])=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24]1[C:27]([CH2:36][CH3:37])([CH2:31][C:32]([O:34][CH3:35])=[O:33])[O:28][CH2:29][CH2:30][C:23]2=1>C1C=CC=CC=1.[Pd].CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:36]([C:27]1([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:24]2[NH:25][C:26]3[C:22]([C:23]=2[CH2:30][CH2:29][O:28]1)=[CH:21][CH:20]=[C:19]([F:38])[C:18]=3[CH2:5][CH:1]=[CH2:2])[CH3:37]
Reactant: CCCCC(=CC([Sn])CCCC)CCCC
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1c(Br)c(F)ccc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=CCc1c(F)ccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Temperature: 80 °C
Reaction time: 42 h
Yield: 78 %

Procedure:
According to the procedure of Kosugi et al, Chem. Letters 301 (1977) tetrakis-(triphenylphosphine) palladium [0] (60 mg) was added to a mixture of tributylallyltin (1.75 g, 0.0053 mol) and 8-bromo-1-ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-1-acetic acid, methyl ester (1.6 g, 0.0043 mol) in benzene (4.0 mL) under N2. The sealed tube was then heated to 80° C. for 15 hours, more palladium catalyst was added (30 mg), and heating continued for 42 hours at 110°-120° C. The cooled reaction mixture was diluted with Et2O, then filtered through a glass wool plug. The ether was washed twice with brine, then dried (MgSO4) to yield an oil that was purified via flash chromatography. Using 1:7 EtOAc:hexane to afford 1.12 g, (~78%) of 1-ethyl-7-fluoro-1,3,4,9-tetrahydro-8-(2-propenyl)-pyrano[3,4-b]indole-1-acetic acid, methyl ester as a colorless oil. The oil was dissolved in ethanol (40 mL) and 1N sodium hydroxide added (15 mL). The mixture was heated to reflux for 2 hours then cooled and concentrated. 1N HCl was added and the aqueous solution extracted with ether. The ether layers were washed (brine), dried (MgSO4) and concentrated to yield a foamy oil. This was purified by flash chromatography on SiO2 -pretreated with 2% H3PO4 -MeOH. Using 1:2 EtOAc:hexane to give 1 g (73%) of 1-ethyl-7-fluoro-1,3,4,9-tetrahydro-8-(2-propenyl)-pyrano[3,4-b]indole-1-acetic acid as a colorless oil which crystallized from toluene:petroleum ether, m.p. 123°-125° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH2:18][CH2:19][NH2:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH2:18][CH2:19][NH:20][C:28]([NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCN1Cc2ccccc2CC1Cc1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(NCCN1Cc2ccccc2CC1Cc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a solution of 30 mg of 2-[3-benzyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 1-f) in 1 mL of methylene chloride was added 13.8 mg of phenyl isocyanate at room temperature, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction liquid was concentrated under reduced pressure. The residue obtained was purified using PLC (chloroform:methanol=10:1) to obtain 32.2 mg (yield 60%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH2:32])[CH:30]=2)[CH:25]=[CH:24][N:23]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH:32][C:10](=[O:12])[C@@H:9]([N:8]([CH3:17])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH:30]=2)[CH:25]=[CH:24][N:23]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Nc1ccc2ccncc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccc2ccncc2c1)N(C)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To (S)-2-(tert-butoxycarbonyl(methyl)amino)-4-methylpentanoic acid in DMF was added EDC, DMAP and isoquinolin-7-amine. This mixture was stirred for 4 hours and the reaction was washed with NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, Hexanes/EtOAc) gave pure (S)-tert-butyl 1-(isoquinolin-7-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate (E87).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([Cl:24])=[CH2:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].C([NH+](CC)CC)C.Cl>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([Cl:24])=[CH2:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:27][N:26]=[N:25][N:18]=2)=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: C=C(Cl)COc1ccc(Br)cc1CN(CC)c1ccc(C#N)cn1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: C=C(Cl)COc1ccc(Br)cc1CN(CC)c1ccc(-c2nnn[nH]2)cn1
Temperature: 120 °C
Yield: 104.2 %

Procedure:
2-[N-(5-Bromo-2-(2-chloroprop-2-en-1-yloxy)benzyl)-N-ethylamino]-5-cyanopyridine (reference example 7) (0.40 g, 0.96 mmol), in sieve-dried N-methyl pyrrolidone (10 ml) was treated with sodium azide (189 mg, 12.9 mmol) followed by triethylammonium chloride (208 mg, 1.49 mmol) and the mixture heated at 120° C. (oil bath) for 8 hours. The red solution was taken into ice/water (12 ml), acidified to pH 1-2 with concentrated hydrochloric acid, extracted with ethyl acetate (×2) and the combined extracts washed with water (×2), dried (MgSO4) and evaporated to give a pale red gum (0.45 g). The gum was presorbed to silica (1.2 g) and purified by MPLC to give a colourless title compound as a gum which solidified (135 mg, 31%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[S:40][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:37]=1.C(N(CC)CC)C.NCCN(CCN)CCN>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[S:41]([C:39]2[S:40][C:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=3)=[CH:37][CH:38]=2)(=[O:42])=[O:43])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Agent: NCCN(CCN)CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccc(-c3ccccn3)s2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (15 mg, 0.038 mmol), prepared in Step A of Example 13a, 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (5 eq), and triethylamine (5 eq), in CH2Cl2 (1-2 mL) was stirred at room temperature for 72 h. Additional 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (5 eq) and triethylamine (5 eq) were added and the reaction was stirred for 24 h followed by addition of tris(2-aminoethyl)amine on polymer support. The reaction was stirred for 24 h and the resin was removed by filtration with the aid of CH2Cl. The organic solution was washed sequentially with 5.5% aqueous HCl and saturated NaHCO3 solution. The organic solution was concentrated and was used in Step B without further purification.
Reaction SMILES: [C:1]([C:3](=[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:4][CH2:5][C:6]([O:8]CC)=[O:7])#[N:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C:3](=[C:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCOC(=O)CCC(C#N)=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=C(C#N)CCC(=O)O)c2ccc(OC)cc2)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
3.6 g of ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate was dissolved in 10 ml of dioxane and 3 ml of a 5N aqueous solution of NaOH was added thereto. The obtained mixture was stirred at 60° C. for five hours. After the completion of the reaction, the reaction mixture was acidified and extracted with ethyl acetate. Thus 3.2 g of the title compound having the following physicochemical properties was obtained. This product could be further purified by recrystallizing from ethyl acetate/hexane.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([N:14]2[C:18]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:17][N:16]=[N:15]2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].C(=O)(O)[O-].[Na+]>O1CCCC1.Cl.[Cl-].[Na+].O>[CH3:22][S:19]([C:18]1[N:14]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([CH:7]=2)[CH:2]=[O:1])[N:15]=[N:16][N:17]=1)(=[O:20])=[O:21]
Reactant: COc1ccc(-n2nnnc2S(C)(=O)=O)cc1C1OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nnnc2S(C)(=O)=O)cc1C=O
Yield: 44.4 %

Procedure:
1-(3-[1,3]Dioxolan-2-yl-4-methoxy-phenyl)-5-methanesulfonyl-1H-tetrazole (800 mg) in tetrahydrofuran (13 ml) and hydrochloric acid (2N, 7.5 ml) was stirred at room temperature for 1.5 h. The solution was basified with sodium bicarbonate solution (8%), saturated with brine (50 ml), extracted with ether (3×50 ml), dried (N2SO4) and evaporated to give the title compound as an orange solid (307 mg). T.l.c. (Ethyl acetate/cyclohexane (1:1)), Rf=0.5
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[O:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[ClH:36]>>[ClH:36].[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[O:29][CH2:30][C:31]([OH:33])=[O:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)COc1c(-c2ccccc2)nc2ccccc2c1C(=O)N[C@@H](CC)c1ccccc1
Agent: Cl
Product: CC[C@H](NC(=O)c1c(OCC(=O)O)c(-c2ccccc2)nc2ccccc12)c1ccccc1

Procedure:
0.35 g (0.7 mmol) of (S)-N-(α-ethylbenzyl)-3-(ethoxycarbonylmethoxy)-2-phenyl quinoline-4-carboxamide (compound of Example 1) were dissolved in 20 ml of 37% HCl and the reaction mixture was refluxed under magnetical stirring for 20′. The solution was evaporated in-vacuo to dryness and the crude product was triturated with warm EtOAc/i-PrOH to yield 0.17 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:18][C:19]1[C:24]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1cccnc1Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccnc4Cl)nc23)CC1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.054 mMol 2-chloro-3-pyridinecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [F:1][CH:2]([F:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9]3[O:15][CH2:14][O:13][C:10]=3[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:4]1.Cl>O>[F:22][CH:2]([F:1])[N:3]1[C:12]2[C:7](=[CH:8][C:9]3[O:15][CH2:14][O:13][C:10]=3[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1
Reactant: CCOC(=O)c1cn(C(F)F)c2cc3c(cc2c1=O)OCO3
Agent: Cl
Solvent: O
Product: O=C(O)c1cn(C(F)F)c2cc3c(cc2c1=O)OCO3
Yield: 97.9 %

Procedure:
A mixture of 27.5 g of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester and 600 ml of 6 N hydrochloric acid is heated under reflux for 1.5 hours. The mixture is diluted with 1 liter of water, cooled, and filtered. The solid product is triturated with cold ethanol and filtered to give 24.5 g of the desired product, m.p. 327°-8° C. (dec). Anal. Calc'd for C12H7F2O5 ; C:50.89, H:2.49, N:4.95--Found; C:50.95, H:2.54, N:4.84.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][CH:9]([CH3:26])[CH2:10][C@@H:11]([NH3+:25])[B:12]1[O:20][C@H:19]2[C@:14]([CH3:24])([C@H:15]3[CH2:21][C@@H:17]([CH2:18]2)[C:16]3([CH3:23])[CH3:22])[O:13]1.[C:27]([NH:34][C@H:35]([C:39](O)=[O:40])[CH:36]([CH3:38])[CH3:37])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:30]([O:29][C:27](=[O:28])[NH:34][C@H:35]([C:39](=[O:40])[NH:25][C@H:11]([B:12]1[O:20][C@H:19]2[C@:14]([CH3:24])([C@H:15]3[CH2:21][C@@H:17]([CH2:18]2)[C:16]3([CH3:23])[CH3:22])[O:13]1)[CH2:10][CH:9]([CH3:26])[CH3:8])[CH:36]([CH3:37])[CH3:38])([CH3:31])([CH3:33])[CH3:32]
Reactant: CC(C)C[C@@H]([NH3+])B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1

Procedure:
The title compound is prepared as described in step B of example 1 but using (S)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylammonium trifluoroacetate ((C) in Synthetic Scheme 1) (for preparation see Kettner, C. A. and Shenvi, A. B. J. Biol. Chem. 1984, 259, p. 15106–15114 and Matteson, D. S. and Sadhu, K. M. J. Am. Chem. Soc. 1981, 103, p. 5241–5242) (2.395 g, 6.32 mMol), Boc-L-valine (1.373 g, 6.32 mMol), TBTU (2.23 g, 6.95 mMol, 1.1 equiv), DIEA (3.3 mL, 18.95 mMol, 3.0 equiv) and DMF (24 mL).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[C:15][Si](C)(C)C)=[CH:11][CH:12]=2)[C@H:7]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C#C[Si](C)(C)C)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)[C@H](Nc1ccc(C#N)cn1)C[C@H](C)N2C(C)=O
Reaction time: 0.5 h

Procedure:
6-(((2S,4R)-1-Acetyl-2-methyl-6-((trimethylsilyl)ethynyl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 10) (1.69 g, 4.20 mmol) was treated with tetrabutylammonium fluoride (1M in THF, 4.62 ml, 4.62 mmol) and THF (18 ml) and the solution stirred at ambient conditions for 30 min. The reaction was concentrated in vacuo, diluted with water (25 ml) and extracted with DCM (3×30 ml). The organics were combined, being dried (hydrophobic frit) and the solvent evaporated in vacuo. The residue was purified by chromatography on a silica cartridge (100 g) eluting with an ethyl acetate/cyclohexane gradient (0-75%). The appropriate fractions were collected and the solvent evaporated in vacuo to give 6-(((2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (990 mg) as a yellow foam. LCMS (formate), Rt 0.92 min, MH+ 331.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([CH:7]([NH:10][C:11]1[C:12]([N+:25]([O-:27])=[O:26])=[CH:13][C:14]([CH2:21][CH:22]=[N:23]O)=[C:15]([CH3:20])[C:16]=1[N+:17]([O-:19])=[O:18])[CH2:8][CH3:9])[CH3:6]>O1CCCC1>[CH2:5]([CH:7]([NH:10][C:11]1[C:12]([N+:25]([O-:27])=[O:26])=[CH:13][C:14]([CH2:21][C:22]#[N:23])=[C:15]([CH3:20])[C:16]=1[N+:17]([O-:19])=[O:18])[CH2:8][CH3:9])[CH3:6]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(CC=NO)c(C)c1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(CC#N)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A solution of thionyl chloride (25.0 ml) in tetrahydrofuran (THF; 100 ml) is added at <20° C. to a solution of {5-[(1-ethylpropyl)amino]-4,6-dinitro-o-tolyl}acetaldehyde oxime (12.0 g; 0.037 mol) in THF (160 ml). The reaction mixture is stirred overnight at room temperature, filtered, and the filtrate concentrated in vacuo to leave an oil which crystallizes, when seeded, to afford the title product (9.8 g), an orange solid. A sample is purified for analysis, melting point 59°-60° C.