Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]([F:10])=[C:8](O)[C:7]([NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])=[C:6]([C:18]#[N:19])[C:5]=1[CH3:20])(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([C:4]1[C:9]([F:10])=[C:8]2[O:14][C:13]([CH:15]3[CH2:17][CH2:16]3)=[N:12][C:7]2=[C:6]([C:18]#[N:19])[C:5]=1[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c(C#N)c(NC(=O)C2CC2)c(O)c1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Temperature: 25 °C
Yield: 71.5 %

Procedure:
N-(4-Acetyl-2-cyano-5-fluoro-6-hydroxy-3-methylphenyl)cyclopropanecarboxamide (I-81) (200 mg, 0.72 mmol) was dissolved in toluene (4 ml), pyridinium p-toluenesulfonate (40 mg, 0.14 mmol) was, added, followed by heating under reflux for 21 hours. After cooling to room temperature, this was diluted with ethyl acetate, washed with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluted with a mixed solvent of n-hexane/ethyl acetate (3:1, v/V) to obtain the entitled compound (133 mg, 71%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:25]([NH:24][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:26])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and phenyl isocyanate (33 μL, 0.30 mmol) in THF (10 mL) are reacted according to method C yielding the title product as colorless needles after column chromatography with hexane-EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[CH:7]2
Reactant: Brc1cccc2cc[nH]c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
7-Bromoindole(0.37 g, 1.9 mmol) was dissolved in dry DMF. K2CO3 (0.52 g, 3.8 mmol) and methyliodide (0.13 mL, 2.08 mmol) were added. The reaction was stirred at room temperature for 5 days, after which H2O (20 mL) was added, the water phase was extracted with Et2O (3×20 mL), and the combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by chromatography, eluent EtOAc:petroleum ether 1:20 to give 7-bromo-1-methylindole as a crystalline compound.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[CH:14]=[C:15]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[C:24]([O:23][C:21]([NH:20][CH2:19][CH2:18][CH2:17][O:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:35])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:28][C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:14]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCCCNC(=O)OC(C)(C)C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCOc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
A solution of [4-(3-tert-butoxycarbonylamino-propoxy)-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (4 mg) in THF/H2O (1 mL, 1:1) was treated with LiOH (1.4 mg) at 0° C. and the reaction was stirred at room temperature for 2 h. The mixture was acidified to pH 3 with 1N HCl and purified by preparative HPLC to give the title compound (1.5 mg) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.40 (s, 1H), 8.28-8.27 (m, 1H), 8.14-8.13 (m, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H), 5.63-5.59 (m, 1H), 4.05 (t, 2H), 3.23-3.20 (m, 2H), 3.18-3.16 (m, 1H), 2.39-2.31 (m, 1H), 1.96 (t, 2H), 1.40 (s, 9H). MS calcd for (C21H26BN3O8+H-Boc)+: 360.2. MS found: (M+H-Boc)+=360.2.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[C:28]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[N:29]=2)[N:26]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C=O.C(=O)([O-])O.[Na+]>[CH:33]1([C:31]([NH:30][C:28]2[N:29]=[C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]4[CH:18]=[C:17]([NH:16][C:7]([C:5]5[O:4][N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:38]=[CH:37][CH:36]=4)=[N:26][N:25]3[CH:27]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)O)on1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of 3-methylisoxazole-5-carboxylic acid (87 mg, 0.679 mmol) in tetrahydrofuran (2.0 mL) were added N,N-dimethylformamide (1 drop) and oxalyl chloride (75.8 μL, 0.88 mmol), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL), and added to a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (140 mg, 0.453 mmol) in tetrahydrofuran (12 mL). Then, triethylamine (138 mg, 1.36 mmol) was added to the mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted three times with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→80/20) and precipitated from ethyl acetate/hexane to give the title compound (42 mg, 22%) as a white powder.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[CH2:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)=[CH2:3].[H][H]>[Pt]=O.C(O)(=O)C>[CH:2]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:1]
Reactant: C=C(C)[C@@H]1CC=C(C(=O)O)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)C1CCC(C(=O)O)CC1
Yield: 93 %

Procedure:
Platinum oxide (200 mg) as a catalyst was suspended in acetic acid (20 ml), and then (s)-(-)-perillic acid (2 g, 12 mmole) was added. The mixture thus obtained was stirred for 8 hours at room temperature under a current of hydrogen gas. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to a dryness. The matter was recrystallized from methanol-water to obtain 4-isopropyl cyclohexane carboxylic acid (1.9 g, yield 93%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH:29][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[O:14][CH3:13])=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: COc1ccccc1CN
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNc2cccc3nc(NCc4ccccc4OC)ccc23)c1

Procedure:
The title compound, MS: m/e=400.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-bromo-2-chloroquinoline, 2-methoxybenzylamine and 3-methoxybenzylamine.
Reaction SMILES: [C:1]([NH:5][CH:6]([OH:10])[C:7]([OH:9])=[O:8])(=[O:4])[CH:2]=[CH2:3].[CH3:11]OC(OC)OC.COC.C1(C=CC(O)=CC=1)O>CO>[CH3:11][O:10][CH:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:7]([OH:9])=[O:8]
Reactant: COC(OC)OC
Reactant: C=CC(=O)NC(O)C(=O)O
Agent: COC
Agent: Oc1ccc(O)cc1
Solvent: CO
Product: C=CC(=O)NC(OC)C(=O)O
Reaction time: 72 h

Procedure:
45 parts of acrylamidoglycolic acid, 90 parts trimethylorthoformate, 0.045 parts of the mono methyl ether of hydroquinone and 35 parts of methanol are mixed in a flask equipped with a stirrer, condensor and thermometer. The mixture was heated at a bath temperature of 60°-65° C. for 24 hours. A small amount of insoluble material was filtered off and discarded. The filtrate was stripped of solvent under vacuum and a rubbery substance was obtained. This material was extracted with ether with stirring for 3 days. The solid which was insoluble in the ether was filtered off and was further extracted with acetone. The acetone was removed to yield 24 g of crude AGME (Mp. 100-102.5).
Reaction SMILES: [I:1][C:2]#[C:3][CH:4]1[CH2:6][CH2:5]1.[F:7][C:8]([F:20])([F:19])[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[CH2:12][N:13]=[N+:14]=[N-:15]>>[CH:4]1([C:3]2[N:15]=[N:14][N:13]([CH2:12][C:11]3[CH:16]=[CH:17][CH:18]=[C:9]([C:8]([F:7])([F:20])[F:19])[CH:10]=3)[C:2]=2[I:1])[CH2:6][CH2:5]1
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Reactant: IC#CC1CC1
Product: FC(F)(F)c1cccc(Cn2nnc(C3CC3)c2I)c1

Procedure:
Synthesized from (iodoethynyl)cyclopropane and 3-trifluoromethyl-benzylazide using general procedure; 0.589 g, 1.498 mmol, 96%; mp=129-134° C. (dec.); IR (υ[cm−1]) 3087, 3011, 1453, 1325, 1165, 1122, 1074, 777, 701; 1H NMR (600 MHz, CDCl3) δ=7.57-7.56 (m, 2H), 7.45 (t, J=7.7, 1H), 7.39 (d, J=7.7, 1H), 5.57 (s, 2H), 1.78-1.72 (m, 1H), 1.06-1.01 (m, 2H), 0.99-0.93 (m, 2H); 13C NMR (151 MHz, CDCl3) δ=153.8, 135.6, 131.7 (q, J=32.6), 131.4, 129.7, 125.6 (q, J=3.7), 125.0 (q, J=3.9), 124.0 (q, J=272.3), 77.9, 53.7, 7.8, 7.5; HRMS (ESI-TOF) (m/z): [M+Na]+ calcd for C13H11F3IN3Na, 415.9847; found 415.9847.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:31][CH2:32][CH2:33][CH2:34]Br>C(#N)C>[Br:31][CH2:32][CH2:33][CH2:34][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1
Reactant: BrCCCBr
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1nccc(-c2cc(NCCCBr)c3cc(OC)ccc3c2)n1
Temperature: 65 °C
Reaction time: 10 h

Procedure:
A mixture of 4-(4-amino-6-methoxy-2-naphthyl)-N-methylpyrimidin-2-amine (33), synthesized according to General Procedure B Steps 1-3 (1.00 g, 3.2 mmol) and acetonitrile (10 mL) was treated with N,N-diisopropylethylamine (1.2 mL, 7.1 mmol) followed by 1,3-dibromopropane (7.3 mL, 71.4 mmol). The resulting mixture was stirred at 65° C. for 10 h. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated (rotary). The crude compound was purified by column chromatography (silica gel) using 75% ethyl acetate/hexanes as the eluent to afford 4-(4-((3-bromopropyl)amino)-6-methoxynaphthalen-2-yl)-N-methylpyrimidin-2-amine (189) (0.55 g). LC/MS (m/z): 402 [M+H]
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH3:7][CH:8]1OC(C)OC(C)O1.[CH:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=1)([CH3:18])[CH3:17].C(O)=O>O>[Br:1][C:2]1[S:3][C:4]([CH:7]([NH:25][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([CH:16]([CH3:18])[CH3:17])=[CH:20][CH:21]=2)[CH3:8])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(C(N)=O)cc1
Reactant: Brc1cccs1
Reactant: CC1OC(C)OC(C)O1
Solvent: O=CO
Solvent: O
Product: CC(C)c1ccc(C(=O)NC(C)c2ccc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.5 %

Procedure:
2-Bromothiophene (8.15 g, 0.05 mol), paraldehyde (2.20 g, 0.017 mol) and 4-isopropylbenzamide (1.63 g, 0.01 mol) were added to formic acid (10 ml) and stirred at a room temperature for three hours. Water (50 ml) was added to the reaction mixture. The mixture was extracted with chloroform (50 ml), subjected to a silica gel column chromatography (eluent: chloroform) and recrystallized from chloroform/petroleum benzine (1:2) to obtain the entitled compound (0.3 g) as a colorless needle-shape crystal. Yield: 8.5%. Melting point: 108° C.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[O:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>C(OCC)C>[O:8]1[CH:12]2[CH:11]=[CH:10][CH:9]1[CH:3]1[C:4](=[O:6])[NH:5][C:1](=[O:7])[CH:2]12
Reactant: O=C1C=CC(=O)N1
Reactant: c1ccoc1
Solvent: CCOCC
Product: O=C1NC(=O)C2C3C=CC(O3)C12
Temperature: 25 °C
Reaction time: 70 h
Yield: 46.1 %

Procedure:
A mixture of maleimide (Sigma-Aldrich, St. Louis Mo.; 2.0 g, 0.0206 moles) and furan (Sigma-Aldrich, St. Louis Mo.; 7.49 mL, 0.103 moles) in anhydrous ethyl ether (50 mL) was stirred for 70 hours at room temperature under an argon atmosphere. A white precipitate formed during the reaction and was filtered off and dried under reduced pressure giving 1.57 g of white crystals. NM (d6-DMSO): Mixture of exo- and endo-isomers (37:63) of ETPI: Exo-3,6-Epoxy-1,2,3,6-tetrahydrophthalimide: 2.85 ppm (s, —CH, 2H), 5.25 ppm (s, —CH, 1H), 6.55 ppm (s, —CH═CH—, 2H), Endo-3,6-Epoxy-1,2,3,6-tetrahydrophthalimide: 3.48 ppm (s, —CH, 2H), 5.11 ppm (s, —CH, 2H), 6.49 ppm (s, —CH═CH, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH2:3]1.CCN(C(C)C)C(C)C.[Cl:23][C:24]1[C:25]([C:31]#[N:32])=[N:26][CH:27]=[C:28](Cl)[N:29]=1>C1COCC1>[Cl:23][C:24]1[N:29]=[C:28]([NH:1][C@@H:2]2[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH2:3]2)[CH:27]=[N:26][C:25]=1[C:31]#[N:32]
Reactant: CN(C)C(=O)N1CCCC[C@@H](N)C1
Reactant: N#Cc1ncc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCCC[C@@H](Nc2cnc(C#N)c(Cl)n2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
(R)-3-Amino-N,N-dimethylazepane-1-carboxamide (508) (˜200 mg crude) was dissolved in THF (7 mL), and DIEA (0.30 mL, 1.7 mmol) was added, followed by 3,5-dichloropyrazine-2-carbonitrile (100 mg, 0.57 mmol). The reaction was stirred at RT for 12 hours. The solvents were removed under reduced pressure, and the residue was purified by silica column chromatography (MeOH, DCM) to give (R)-3-(6-chloro-5-cyanopyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide (509) (53 mg, 0.16 mmol, 14% yield over 3 steps).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3][C:2]1=[O:12].Br[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:25])=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21].COC(C1C=C(C=CC=1)CN1C2C(=CC=CC=2)C(=O)NC1=O)=O>>[F:25][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[NH:3][C:2]2=[O:12])=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Reactant: COC(=O)c1cc(CBr)ccc1F
Agent: COC(=O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Product: COC(=O)c1cc(Cn2c(=O)[nH]c(=O)c3ccccc32)ccc1F

Procedure:
The title compound was prepared from quinazoline-2,4(1H,3H)-dione and methyl 5-(bromomethyl)-2-fluorobenzoate using a procedure similar to those described for the synthesis of compound of Example 1. 1H NMR (DMSO-d6): 11.75 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.84 (d, J=6.9 Hz, 1H), 7.67-7.55 (m, 2H), 7.32-7.21 (m, 3H), 5.32 (s, 2H), 3.81 (s, 3H). MS: m/z 329.1 [M+H]+.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[CH:14](N(C)CCN(C)C)=[O:15].C([Li])CCC.[I:28]I>COCCOC.C1COCC1>[I:28][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([O:7][CH3:6])[C:13]=1[CH:14]=[O:15]
Reactant: II
Reactant: COc1ccccn1
Reactant: CN(C)CCN(C)C=O
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COCCOC
Product: COc1nccc(I)c1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 5-liter three-necked round bottom flask was equipped with an overhead mechanical stirrer under nitrogen, the flask was charged with THF (1 L) and cooled to −78° C. To this stirred solution was added tert-butyllithium (1.7 M solution in pentane) (800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at −78° C. The mixture was stirred for 1 h at −78° C. To the mixture was added N-formyl-N,N′,N′-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at −78° C. The reaction mixture was stirred for ca. 30 min at −78° C. before warming to −23° C. over ca. 30 min. To the mixture at −23° C. was added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5 M solution in hexane) (800 mL, 2.0 mol). The resulting mixture was stirred for ca. 2 h during which time the reaction mixture turned deep green. A 12-L 4-necked round flask was charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution was cooled to −78° C. The contents of the 5-L flask were transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12-L flask at −78° C. After the addition was complete, the reaction mixture was stirred for an additional 1 h at −78° C. The cooling bath was removed and the mixture was allowed to warm to about 0° C. and treated with 2 L of water and 2 L of 1 N hydrochloric acid. Methyl t-butyl ether (2 L) was added and the layers were separated. The aqueous layer was extracted with 2×1 L of methyl t-butyl ether. The combined organic layers were washed with saturated Na2S2O3 (1.2 L), brine (1.2 L), dried over Na2SO4. After concentration in vacuo, the thick slurry was diluted with hexane (1 L). The mixture was cooled with an ice/water bath for ca. 30 min. The precipitate was filtered and dried in vacuum to yield the title compound as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 10.22 (s, 1H), 7.86 (1H, d, J=5.3 Hz), 7.54 (1H, d, J=5.3 Hz), 4.06 (3H, s). LCMS (M+H)+ m/z 364 (t=2.26 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:18])=O)[N:15]=3)[S:10][C:3]=12.C(Cl)(=O)C(Cl)=O.[CH3:25][NH2:26]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([NH:26][CH3:25])=[O:18])[N:15]=3)[S:10][C:3]=12
Reactant: O=C(O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazole-4-carboxylic acid 43a (0.123 g, 0.41 mmole) in CH2Cl2 cooled at 0° C. was added 2.0 M oxalyl chloride in CH2Cl2 (0.520 ml, 1.04 mmole) and DMF (2 drops). The reaction mixture was stirred at room temperature for 1 h, concentrated and dried. The residue was taken into CH2Cl2 (10 ml), and 2.0 M methylamine in CH2Cl2 (0.250 ml, 0.492 mmole) was added. The reaction mixture was stirred at room temperature for 1 h, and then partitioned between H2O (100 ml) and CH2Cl2 (2×100 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 2-8% CH3OH in CH2Cl2 to give yellow solid (0.116 g, 91%). 1H NMR (300 MHz, CDCl3) δ8.62 (1H, d, J=5.1 Hz), 8.19 (1H, s), 7.96 (1H, s), 7.33 (1H, d, J=5.1 Hz), 3.06 (3H, d, J=4.9 Hz); ESIMS (MH+): 309.95.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[NH:11]([C:15]1[O:19][N:18]=[C:17]([CH2:20][S:21][CH2:22][CH2:23][NH2:24])[N:16]=1)[C:12]([NH2:14])=[NH:13].[NH3:25]>>[NH2:25][C:7]1[C:3]([NH:24][CH2:23][CH2:22][S:21][CH2:20][C:17]2[N:16]=[C:15]([NH:11][C:12]([NH2:14])=[NH:13])[O:19][N:18]=2)=[N:4][S:5](=[O:10])[N:6]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: N=C(N)Nc1nc(CSCCN)no1
Reactant: N
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)N=C2N)no1

Procedure:
When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide is successively treated with an equimolar amount of 2-[(5-guanidino-1,2,4-oxadiazol-3-yl)methylthio]ethylamine and excess ammonia, the title compound is thereby produced.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:39]=[CH:38][C:29]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:28][CH:27]=2)=[N:16]1.[CH2:40]([N:42]([CH2:45]C)CC)[CH3:41].[OH2:47]>C1COCC1>[CH2:40]([NH:42][C:45]([N:35]1[CH2:36][CH2:37][N:32]([C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26](/[CH:25]=[CH:24]/[C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][N:16]=3)=[CH:39][CH:38]=2)[CH2:33][CH2:34]1)=[O:47])[CH3:41]
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: O
Reactant: CCN(CC)CC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: C1CCOC1
Product: CCNC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A solution of dihydrochloride of Compound 18 (400 mg, 1.09 mmol) in THF (20 mL) was added with triethylamine (0.42 mL, 3.01 mmol) and ethylisodyanate (117 mg, 1.65 mmol), followed by stirring at room temperature for 3 hours. The reaction mixture was added with water, and deposited crystal was collected by filtration and was dried to obtain Compound 59 (218 mg, 55%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([C:17]#[N:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:24][NH2:25].C(N(C(C)C)CC)(C)C.O>C(O)CC>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:21]([Cl:20])[CH:22]=1)=[CH:13][C:12]([C:17]#[N:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: COc1ccc(CN)cc1Cl
Reactant: CCOC(=O)c1cnc2ccc(C#N)cc2c1Cl
Agent: Cl
Solvent: O
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2ccc(C#N)cc2c1NCc1ccc(OC)c(Cl)c1
Yield: 97.9 %

Procedure:
To 10.0 g (38.4 mmol) 4-chloro-6-cyanoquinoline-3-carboxylic acid ethyl ester was added 10.4 g (50 mmol, 1.5 eq) 3-chloro-4-methoxybenzyl amine hydrochloride and 35 mL (228 mmol, 6 eq) diisopropylethylamine (Aldrich, 99.5+%). The mixture was dispersed in 200 mL n-propanol and brought to reflux for two hours. The solution was then poured into 500 mL water. The resulting precipitate was filtered, then washed with 500 mL water, then twice washed with 50 mL absolute ethanol to yield 14.87 g (37.6 mmol, 97% yield) of the title compound as a white fiberous solid after codistilling with absolute ethanol: mp: 161-162° C.; LC/MS (M/Z) 396 [M+H] observed, 97% purity.