Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][Cl:20].[I-].[K+]>CC(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:20][CH2:19][CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: ClCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCCl)cc1

Procedure:
To the solution of 27.83 g (0.2 Mol) of 4-nitro-phenol (Fluka 73560) in 420 mL of acetone is added 55.28 g (0.4 Mol) of potassium carbonate, 143.42 g (1 Mol) of 1-bromo-2-chloro-ethane, 0.55 g (0.0033 Mol) of potassium iodide and 0.28 g (0.00087 Mol) of tetrabutyl-ammonium bromide (Fluka 86860). The resulting suspension is refluxed for 67 h. After removing the solvent under reduced pressure, the residue is taken up into ethyl acetate and washed with water. The combined organic layers are dried (Na2SO4), filtered and concentrated under reduced pressure. After trituration of the residue with ligroin, the crystals are filtered off to obtain 1-(2-chloro-ethoxy)-4-nitro-benzene.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]2[C:15]=1C=C[C:18](=[O:32])[NH:19]2)[O:6][Si](C(C)(C)C)(C)C)=[N+:2]=[N-:3].C(OC1C=CC([C@@H](O)CBr)=CC=1NC=O)C1C=CC=CC=1>>[N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([NH:19][CH:18]=[O:32])[CH:15]=1)[OH:6])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Product: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 1, using Intermediate 9 as substrate. ES/MS calcd. C16H17N4O3+ 313.1. found m/z=313 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:42](O)=[O:43])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:42]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:43]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccn2)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccn3)sc2N)c1N1CC[C@@H](F)[C@@H](N)CC1
Yield: 68 %

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(pyridin-2-yl)thiazole-4-carboxylic acid gave 387 as an off-white solid (106 mg, 68% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.54 (d, J=4.6 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.81 (s, 1H), 7.76 (t, J=7.9 Hz, 1H), 7.29-7.20 (m, 1H), 6.27 (s, 2H), 4.90 (d, J=47.2 Hz, 1H), 3.73 (s, 3H), 3.58-3.33 (m, 3H), 3.23-3.11 (m, 2H), 2.44-2.22 (m, 1H), 2.11-1.92 (m, 2H), 1.87-1.76 (m, 1H). Exchangeable NH2 not observed. LCMS (ES+) m/z 431 (M+1)
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[N:27]=1.[Li+].[Cl-]>CN(C=O)C.[Cu]I.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:25][C:26]1[N:27]=[C:28]([C:2]2[C:10]3[C:5](=[CH:6][N:7]=[C:8]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(F)n1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(-c3cccnc3)ncc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(F)n2)c2cc(-c3cccnc3)ncc21
Temperature: 120 °C
Yield: 79.8 %

Procedure:
To a mixture of 3-iodo-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (GCP-P3-205-1) (200 mg, 0.44 mmol) and 2-fluoro-6-(tributylstannyl)pyridine (206 mg, 0.53 mmol) in 3 mL DMF, was added TEA 1 mL, LiCl (56 mg, 1.32 mmol) and CuI (84 mg, 0.44 mmol), and Pd(PPh3)4 (254 mg, 0.22 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 1 h, and the reaction was monitored by LCMS. Upon completion, the reaction mixture was extracted with 100 mL EtOAc, washed with 50 mL brine, and dried. The solvent was distilled off and the crude material was purified via flash chromatography, eluting with 5% to 30% ethyl acetate in heptane to afford 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine as a yellow solid (148 mg, 80%). ESI MS m/z=421.1 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH2:6][C:5]([CH3:10])([CH3:9])[C:4]=1[CH3:11]>C(O)C.[Ni]>[OH:1][CH2:2][CH:3]1[CH:8]=[CH:7][CH2:6][C:5]([CH3:10])([CH3:9])[CH:4]1[CH3:11]
Reactant: CC1=C(CO)C=CCC1(C)C
Agent: [Ni]
Solvent: CCO
Product: CC1C(CO)C=CCC1(C)C
Yield: 91.6 %

Procedure:
30.4 g of 1-hydroxymethyl-2,3,3-trimethyl-cyclohexa-1,5-diene were hydrogenated at 10°-12° in the presence of 1g of Raney-nickel in 300 ml of ethanol. 3.95 l of hydrogen were thus absorbed within 2.5 h. A filtration followed by evaporation and distillation gave 28.2 g of 1-hydroxymethyl-2,3,3-trimethyl-cyclohex-5-ene. nD =1.4862, d20 =0.9447
Reaction SMILES: [C:1]([C:6]1[S:10][C:9]([CH2:11][CH3:12])=[C:8]([CH:13]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].O1CCCC1.[OH-].[Na+]>C(O)C>[C:1]([C:6]1[S:10][C:9]([CH2:11][CH3:12])=[C:8]([CH:13]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc(C(Nc2ccc(C(=O)OC)cc2)C2CCCCC2)c(CC)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(=O)c1cc(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)c(CC)s1
Yield: 94.9 %

Procedure:
To a mixture of methyl 4-{[(5-butanoyl-2-ethylthiophen-3-yl)(cyclohexyl)methyl]amino}benzoate (316 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 and the mixture was stirred with heating under reflux for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (5 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (290 mg, 95%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)=[N:5][N:4]=[C:3]1[S:17][CH2:18][CH2:19][CH2:20][CH:21]=O.[CH2:23]([S:25]([C:28]1[CH:38]=[CH:37][C:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH2:36][C:30]=2[CH:29]=1)(=[O:27])=[O:26])[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:23]([S:25]([C:28]1[CH:38]=[CH:37][C:31]2[CH2:32][CH2:33][N:34]([CH2:21][CH2:20][CH2:19][CH2:18][S:17][C:3]3[N:2]([CH3:1])[C:6]([C:7]4[CH:8]=[C:9]5[C:14](=[CH:15][CH:16]=4)[N:13]=[CH:12][CH:11]=[CH:10]5)=[N:5][N:4]=3)[CH2:35][CH2:36][C:30]=2[CH:29]=1)(=[O:26])=[O:27])[CH3:24]
Reactant: CCS(=O)(=O)c1ccc2c(c1)CCNCC2
Reactant: Cn1c(SCCCC=O)nnc1-c1ccc2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc2c(c1)CCN(CCCCSc1nnc(-c3ccc4ncccc4c3)n1C)CC2
Reaction time: 8 h
Yield: 20.4 %

Procedure:
4-(4-Methyl-5-quinolin-6-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-butyraldehyde (0.1 g, 0.32 mmol) and 7-Ethanesulfonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.11 g, 0.45 mmol) were stirred at room temperature in dichloromethane (4 ml) for 20 min. Sodium triacetoxyborohydride (71 mg, 0.34 mmol) was then added and the mixture stirred overnight. The mixture was diluted with dichloromethane (50 ml) and washed with saturated sodium bicarbonate solution (30 ml). The aqueous was extracted with further dichloromethane (50 ml) and the combined organic portions were dried (Na2SO4), filtered and evaporated to give a yellow oil. Purification by silica gel chromatography (eluent 10% MeOH:EtOAc) which gave the title compound as a colourless oil (35 mg, 21%).
Reaction SMILES: [S:1]1[CH2:6][CH2:5]C(=O)[CH2:3][CH2:2]1.[CH:8](OC)([O:11][CH3:12])[O:9][CH3:10]>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>[CH3:10][O:9][C:8]1([O:11][CH3:12])[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1
Reactant: O=C1CCSCC1
Reactant: COC(OC)OC
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1(OC)CCSCC1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A mixture of tetrahydro-(4H)-thiopyran-4-one (15.0 g, 129 mmol), trimethyl orthoformate (28.3 mL, 258 mmol) and para-toluenesulfonic acid monohydrate (67 mg, 0.35 mmol) in methanol (40 mL) was refluxed for 1 hour. The reaction mixture was cooled to room temperature, 1 M NaOMe (0.35 mL, 0.35 mmol) was added and excess methanol and trimethyl orthoformate was removed by distillation (atmospheric pressure). Further distillation under reduced pressure afforded 4,4-dimethoxytetrahydro-(4H)-thiopyran (20.7 g, 99%). 1H NMR (DMSO) δ 3.07 (s, 6H), 2.56 (m, 4H), 1.84 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:22]1[N:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1)#[N:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:25]3[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[N:27][CH:26]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: N#Cc1ccc(C(=O)Cl)cn1
Product: N#Cc1ccc(C(=O)NCCCCn2cnc3c(N)nc4ccccc4c32)cn1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 6-cyanopyridine-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-cyanonicotinamide as an off white powder, m.p. 125.0-129.0° C. 1H NMR (300 MHz, DMSO-d6) δ 9.05 (dd, J=2.1, 0.8 Hz, 1H), 8.88 (t, J=5.6 Hz, 1H), 8.31 (dd, J=8.1, 2.1 Hz, 1H), 8.21 (s, 1H), 8.14 (dd, J=8.1, 0.8 Hz, 1H), 8.03 (m, 1H), 7.62 (dd, J=8;3, 1.1 Hz, 1H), 7.42 (m, 1H), 7.20 (m, 1H), 6.59 (broad s, 2H), 4.64 (t, J=6.9 Hz, 2H), 3.30 (m, 2H), 1.93 (m, 2H), 1.59 (m, 2H);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.CO[Na]>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:21])[CH:14]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:7]2=[O:9]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccnc1
Agent: CO[Na]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Br)cc2C(=O)C1c1cccnc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 5-bromo-2-[2-(pyridin-3-yl)acetamido]benzoate (3 g, 7.73 mmol, Intermediate 10: step a) and MeONa (11.7 mL, 31 mmol, 2.64 M in MeOH) in tetrahydrofuran (30 mL). The resulting solution was stirred overnight at 20° C. The solids were collected by filtration and washed with water (3×5 mL). The solids were dried under vacuum to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[S:24]([N:27]([CH2:29]Cl)[CH3:28])(=[O:26])=[O:25]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH2:28][N:27]([CH3:29])[S:24]([C:17]1[C:16]([Cl:15])=[CH:21][C:20]([Cl:22])=[CH:19][C:18]=1[Cl:23])(=[O:25])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCOCc1ccccc1
Reactant: CN(CCl)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(COCCCOCc1ccccc1)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
A soln. of 3-benzyloxy-1-propanol (4.08 g, 3.90 ml, 24.5 mmol) and tetra-n-butylammonium hydrogen sulfate (1.78 g, 5.25 mmol) in toluene (100 ml) was cooled in an ice-bath and 35% strength sodium hydroxide solution (49.0 g, 140 ml, 1.22 mol) was added. A soln. of 2,4,6-trichloro-N-chloromethyl-N-methylbenzenesulfonamide (7.10 g, 22 mmol) in MC (60 ml) was then slowly added dropwise. The mixture was then stirred at RT for 15-20 h. Thereafter, the phases were separated and the organic phase was washed neutral with water (6×50 ml) and saturated sodium chloride solution (2×40 ml), dried with Na2SO4 and concentrated i. vac. The crude product was purified by means of flash chromatography with cyclohexane/EtOAc (9:1).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([SH:16])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.[F:18][C:19]([F:37])([F:36])[C:20]1[CH:35]=[CH:34][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=2)=[CH:22][CH:21]=1>>[F:18][C:19]([F:36])([F:37])[C:20]1[CH:35]=[CH:34][C:23]([CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=2)[CH2:32][S:16][C:13]2[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:17])=[C:7]3[C:12]=2[O:11][CH2:10][CH2:9][CH2:8]3)=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccc(COc2cccc(CCl)c2)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCCO2
Product: O=C(O)COc1ccc(SCc2cccc(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester and 79B. MS m/z 519 (M+1).
Reaction SMILES: [N:1]1[N:2]2[CH2:11][CH2:10][CH2:9][C:3]2=[CH:4][C:5]=1[C:6](O)=[O:7].Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)(=O)C(Cl)=O.ClCCl.CN(C)C=O.O.C(#N)C>[CH3:16][O:15][N:14]([CH3:13])[C:6]([C:5]1[CH:4]=[C:3]2[CH2:9][CH2:10][CH2:11][N:2]2[N:1]=1)=[O:7]
Reactant: CNOC
Reactant: O=C(O)c1cc2n(n1)CCC2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CON(C)C(=O)c1cc2n(n1)CCC2
Temperature: 18.5 °C
Reaction time: 11 h

Procedure:
5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid, 3.8 g, 25 mmol) is slurried in 40 ml of 2M oxalyl chloride in dichloromethane, and to the slurry are added a few drops of dimethylformamide. The resulting mixture is stirred under a nitrogen atmosphere at 15-22° C. for 10-12 hours. The resulting acid chloride as a dark solution is evaporated to a dry residue. The residue is dissolved in toluene (50 ml) and evaporated once more to give the crude acid chloride. To a stirred mixture of the crude acid chloride in dichloromethane (100 ml) and N,O-dimethylhydroxylamine hydrochloride (2.7 g, 27.5 mmol) at 0-5° C. is added pyridine (4.7 g, 3.2 ml, 60 mmol) dropwise under a nitrogen atmosphere while maintaining the temperature about 0-5° C. The resulting stirred mixture is allowed to warm to 15-20° C. over a period of 4 hours and the reaction is monitored for completion by HPLC (Prodigy ODS3 4.6×150 mm column, using a 10 minutes gradient from 90:10 to 10:90 water/acetonitrile with 0.02% trifluoroacetic acid and UV detection at 254 nm. The retention time of the amide was 1.1 min). The mixture is washed with water (50 ml), concentrated, and purified on a short column of silica gel using elution with chloroform to give upon evaporation of volatiles N-Methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide, 4.1 g, 86%) as a light-brown crystalline solid, m.p. 45-50° C., which is characterized by NMR, mass spectrum, and elemental analysis.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8]O.N1C=CC=CC=1.P(Br)(Br)[Br:19]>C(OCC)C>[CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:19]
Reactant: BrP(Br)Br
Reactant: C[Si](C)(C)C#CCCCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[Si](C)(C)C#CCCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.8 %

Procedure:
To a mixture of 1-trimethylsilyl(hex-1-yn-6-ol) (32.6 g, 190 mmol) and pyridine (0.38 mL) dissolved in diethyl ether (100 mL) was added slowly phosphorus tribromide (7.1 mL, 75 mmol) in diethyl ether (20 mL). Upon addition a precipitate formed and the heterogeneous solution was stirred at room temperature overnight. The mixture was then heated at reflux for 2.5 hours and, upon cooling, was poured onto ice, washed with water, sodium bicarbonate solution, brine and dried (MgSO4). Evaporation of solvent under reduced pressure gave a residue which was distilled (b.p. 80° C., 3.5 mm Hg) to give 22 g (50%) of product. 1H NMR (CDCl3) δ: 0.14 (s, 9H), 1.64-1.72 (quintet, 2H), 1.91-2.02 (quintet, 2H), 2.27 (t, 2H), 3.44 (t, 2H) ppm.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[F:22][C:3]1[C:2]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:21][C:6]2=[N:7][C:8]3[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(C)CC4)cc3nc21
Yield: 38.9 %

Procedure:
7-Fluoro-1-methylamino-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under conditions analogous to Example 1 but starting from 1.93 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydrobenzo[ b][1,8]naphthyridine-3-carboxylic acid, 2.4 g of 1-methylpiperazine and 20 cm3 of pyridine. After recrystallizing twice from 15 cm3 of dimethylformamide each time, 0.9 g of 7-fluoro-1-methylamino-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 263°-264° C.
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)=[CH2:2].[I:11]Cl>CN(C)C=O>[I:11]/[CH:2]=[CH:1]/[C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1
Reactant: C=Cc1c[nH]c(=O)[nH]c1=O
Reactant: ClI
Solvent: CN(C)C=O
Product: O=c1[nH]cc(/C=C/I)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
5-vinyluracil (1.1 g, 8 mmoles) was dissolved in dry dimethylformamide (40 ml). To this solution was added a solution of iodine monochloride (1.28 g, 8 mmoles) in dry dimethylformamide (20 ml). The reaction mixture was allowed to stand, with occasional shaking, for 30 minutes and then heated at 100° for 30 minutes. The solution was then evaporated under reduced pressure to a brown oil to which was added water (20 ml). The resulting dark brown suspension was filtered and the brown solid collected and dried giving crude E-5-(2-iodovinyl)uracil (1.6 g, 76% yield). For the next stage this was not purified further.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>O.CN(C)C=O>[C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:14][CH2:13]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CC1
Reaction time: 3 h

Procedure:
The apparatus described in Example 1 was successively charged with 320 g diethyl malonate (2.0 mols), 1000 ml dimethylformamide, 1308 g of 1,2-dichloroethane (13.2 mols) and 664 g (4.8 mols) of finely comminuted potassium carbonate. While thoroughly stirring, the mixture was heated to 115° C., whereupon release of carbon dioxide and separation of water commenced. Over a period of 3 hours, another 320 g of diethyl malonate (2.0 mols) were metered into the reaction vessel through a dropping funnel. After 6 hours, when no more water separated out, the reaction was complete.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:12]=[C:13]=[S:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:15]([NH2:18])[CH2:16][NH2:17]>C(Cl)Cl.ClCl>[CH3:1][C:2]1[C:3]([NH:12][C:13]([NH:17][CH2:16][CH2:15][NH2:18])=[S:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1c(N=C=S)ccc2cccnc12
Reactant: NCCN
Agent: ClCl
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)ccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 8-methyl-7-quinolinylisothiocyanate (1.36 g) in CH2Cl2 (50 mL) is added dropwise to ethylene diamine (2.26 mL) in solution in CH2 Cl2 (50 mL). The mixture is stirred for 30 minutes at room temperature then rotary evaporated. The residue is suspended in CH2 Cl2 (50 mL) and ether (50 mL) and filtered. The precipitate is dried in vacuo to afford N-(8-methyl-7-quinolinyl)-N'-2-aminoethylthiourea as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)[C:5]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35](=[O:40])[CH2:34][CH2:33]2>C(O)CCC>[NH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]2[C:5]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[CH:4][N:3]=[C:2]([NH:29][C:30]3[CH:31]=[C:32]4[C:37](=[CH:38][CH:39]=3)[NH:36][C:35](=[O:40])[CH2:34][CH2:33]4)[N:7]=2)[CH2:13][CH2:12]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)ncc2-c2ccncc2)CC1
Solvent: CCCCO
Product: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2-c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (1-(2-chloro-5-(pyridin-4-yl)pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (80 mg, 0.20 mmol) and 6-amino-3,4-dihydroquinolin-2(1H)-one (50 mg, 0.30 mmol) in nBuOH (3 mL) was stirred at 116° C. for 20 h. It was concentrated in vacuo. The residue was dissolved in TFA (4 mL). After being stirred at room temperature for 30 min, TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound. MS 430.4 (M+H); UV 207.7, 264.5 nm.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC.Cl>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:15]([CH:3]=[CH:4][N:5]=[CH:13]2)=[CH:16][CH:17]=1
Reactant: COC(CN)OC
Reactant: COc1cccc(C=O)c1
Agent: Cl
Agent: FB(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc2ccncc2c1
Temperature: 5 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
Aminoacetaldehyde dimethyl acetal (81.9 mL) was added to a solution of 60.8 mL of 3-methoxy-benzaldehyde in 600 mL of toluene. The mixture was refluxed for 5 h using a Dean-Stark trap and subsequently cooled to 5° C. In a nitrogene atmosphere trifluoroacetic acid anhydride (209 mL) and borontrifluoride etherate (185 mL) were added in succession at such a rate, that the internal temperature was kept below 10° C. After stirring for 3 days at room temperature the the reaction mixture was poured on ice, 250 mL 2 N hydrochloric acid added and the organic layer extracted with 1 N hydrochloric acid. The pH value of the combined aqueous extracts was adjusted to pH 9 by adding concentrated aqueous ammonia. Extraction with ethyl acetate, followed by drying and removal of the solvent in vacuo gave 66.9 g (84%) of the title compound as a light brownish oil. EI-MS: 159 (M+).