Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.[Br:12][C:13]1[C:14]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:15][C:16](Cl)=[N:17][CH:18]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:12][C:13]1[C:14]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:15][C:16]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:17][CH:18]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Br)n[nH]1
Temperature: 165 °C
Yield: 47 %

Procedure:
To a microwave vial was added (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 369 mg, 2.08 mmol), 5-bromo-2-chloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 38, 500 mg, 1.73 mmol), and DIEA (468 mg, 3.8 mmol). Anhydrous n-BuOH (5 mL) was added, and the vial was heated in microwave oven at 165° C. for 5 hours. The reaction mixture was concentrated. The resulting residue was separated by silica gel column to afford desired product (320 mg, 47%). LC-MS, 393 (M+1). 1H NMR δ 12.02 (s, 1H), 8.82 (s, 2H), 7.94 (s, 1H), 7.48 (s, 0.55H), 5.90 (s, 0.41H), 5.09 (s, 1H), 2.19 (m, 3H), 1.49 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](OC(C)(C)C)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O.[C:33]([O:37][C:38]([N:40]1[CH2:47][C:46]2[C:45](C(O)=O)=[N:44][NH:43][C:42]=2[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[C:3]([C:22]([F:23])([F:24])[F:25])=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:45]3[C:46]4[CH2:47][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:41][C:42]=4[NH:43][N:44]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(C(=O)O)c2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1Cc2[nH]nc(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (9, 0.100 g, 0.27 mmol) in CH2Cl2 (10 mL) was added TFA (2 mL). The mixture was stirred at ambient temperature for 1 h and was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and to this solution was added 5-(tert-butoxycarbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid (0.073 g, 0.28 mmol), HBTU (0.191 g, 0.43 mmol), and N,N-diisopropylethylamine (0.11 g, 0.864 mmol). The mixture stirred at ambient temperature for 16 h and was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-90% EtOAc in hexanes) to give tert-butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (37) as a white solid (0.132 g, 91%): 1H NMR (300 MHz, CDCl3) δ 10.39 (br, 1H), 7.38-7.30 (m, 1H), 7.15-7.08 (m, 1H), 4.80-4.26 (m, 6H), 3.26-3.20 (m, 2H), 2.92 (br, 1H), 1.96-1.66 (m, 4H), 1.51 (s, 9H); MS (ESI+) m/z 501 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(N(CC)CC)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[CH3:1][N:2]([S:18]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)(=[O:20])=[O:19])[NH2:3]
Reactant: CNN
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
Into a 100 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, and dropping funnel under an atmosphere of nitrogen was added THF (25 mL), methylhydrazine (2.53 g, 2.92 mL, 55 mmol), and triethylamine (4.35 g, 43 mmol). The temperature of the mixture was lowered to approximately 5° C. and crude 4-chlorophenylsulfonyl chloride (10.5 g, 50 mmol, contained 4-chlorophenyl sulfonic acid) dissolved in 25 mL of THF was added dropwise at a rate such that the temperature did not rise over 10° C. The cooling bath was removed and the mixture was allowed to warm to stir overnight at RT. Ether (100 mL was added to the reaction mixture and the resulting slurry was washed with water (50 mL), brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo to give 5.4 g (49% yield) of 2-methyl-2-[(4-chlorophenyl)sulfonyl] hydrazine. 1H NMR (CDCl3) δ 7.8 (d, 2H), 7.6 (d, 2H), 3.6 (s, b, 2H), 2.9 (s, 3H).
Reaction SMILES: [F:1][CH:2]1[CH2:4][CH:3]1[N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12](F)[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O>[F:1][CH:2]1[CH2:4][CH:3]1[N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]1
Reactant: O=C(O)c1cn(C2CC2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4F)c3c2F)CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
In 3 ml of dimethyl sulfoxide was dissolved 60 mg of 1-(2-fluorocyclopropyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. After addition of 100 mg of N-methylpiperazine, the mixture was stirred at 110° C. for 1 hour. The solvent was removed, and the residue was distributed between chloroform and water. The chloroform layer was dried, and the solvent was removed by distillation. The residue was crystallized from chloroform-ethanol to yield 25 mg of the product. m.p. 251°-253° C. (dec.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:20][CH2:19][CH:10]3[N:11]([CH2:16][CH2:17][CH3:18])[CH2:12][C:13](=O)[CH:14]=[C:9]3[C:7]=2[CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:20][CH2:19][CH:10]3[N:11]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14][CH:9]3[C:7]=2[CH:8]=1
Reactant: CCCN1CC(=O)C=C2c3cc(OC)ccc3OCC21
Agent: [Pd]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCO
Product: CCCN1CCCC2c3cc(OC)ccc3OCC21

Procedure:
9-Methoxy-4-propyl-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridin-2-one is heated with lithium aluminium hydride in ether. The resulting product is hydrogenated in ethanol in the presence of 10% palladium on carbon catalyst to give 9-methoxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][C:5]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:6]=1[CH2:7][N:8]=[C:9]=[O:10].CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:9]([NH:8][CH2:7][C:6]1[CH:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:5]=1[CH3:4])=[O:10])[NH2:3]
Reactant: Cc1ccc(-c2ccccc2)cc1CN=C=O
Reactant: CNN
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2)cc1CNC(=O)N(C)N
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
254 mg (5.52 mmol) of methylhydrazine was dissolved in 10 ml of anhydrous toluene, and the mixture was cooled to 0° C. Tot this solution was slowly dropped while stirring a solution prepared by dissolving 1.12 g (5.02 mmol) of 2-methyl-5-phenylbenzyl isocyanate in 20 ml of anhydrous toluene. In this operation, the temperature of the reaction solution was controlled in the range from 0 to 5° C. After completion of dropping, the solution was stirred at 0° C. for 1 hour, further, stirring was continued for 2 hours at room temperature. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=1/1, then, 1/2 (v/v), then only ethyl acetate), to obtain 1.28 g (4.75 mmol) of 2-methyl-4-(2-methyl-5-phenylbenzyl) semicarbazide having a melting point of 91.6° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:13]([CH3:14])=[C:12]([C:15]3[N:19]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[N:18]=[CH:17][CH:16]=3)[C:11](=[O:28])[N:10]([CH3:29])[C:9]2=[O:30])[CH:5]=[CH:6][CH:7]=1.[C:31](OCC)(=O)[CH3:32]>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C[CH2-].C[CH2-].[Zn+2]>[CH3:29][N:10]1[C:11](=[O:28])[C:12]([C:15]2[N:19]([C:20]3[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=3)[N:18]=[CH:17][CH:16]=2)=[C:13]([CH3:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH2:31][CH3:32])[CH:3]=2)[C:9]1=[O:30]
Reactant: CCOC(C)=O
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [CH2-]C
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCc1cccc(-n2c(C)c(-c3ccnn3-c3ccc(C#N)cc3)c(=O)n(C)c2=O)c1
Temperature: 60 °C

Procedure:
To a solution of 4-[5-[1-(3-bromophenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 34) (15.5 mg) and bis(tri-t-butylphosphine)palladium (1.0 mg) in tetrahydrofuran (1.0 ml) was added zinc diethyl (1.0 M normal hexane solution, 0.06 ml) and the resulting mixture was stirred at 60° C. for thirty minutes. To the reaction mixture was added ethyl acetate (30 ml) and the mixture was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography to afford 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-ethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (3.6 mg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.C(N(CC)CC)C.[CH3:35][C:36]([CH3:38])=O>ClC(Cl)C>[CH:36]([NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)([CH3:38])[CH3:35]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CC(C)=O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (400 mg, 1.256 mmol) in dichloroethane (10 mL) under nitrogen atmosphere was added acetic acid (180.5 mg, 2.76 mmol), triethylamine (306.4 mg, 2.76 mmol) and acetone (80.2 mg, 1.38 mmol). The mixture was stirred for 1 h at ambient temperature and NaHB(OAc)3 (601 mg, 2.76 mmol) was added. After stirring overnight, the reaction mixture was filtered over celite, concentrated in vacuo and purified by column chromatography on silica gel eluting with DCM:MeOH:NH3 (89:10:1) to give the title compound as an oil (282 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.13 (d, 2H), 6.82 (d, 2H), 3.96 (t, 2H), 3.68 (m, 2H), 3.49 (m, 2H), 2.61 (s, 2H), 2.56 (t, 2H), 2.46 (m, 5H), 2.04 (m, 2H), 1.94 (m, 2H), 1.84 (m, 2H), 1.72 (m, 4H), 1.19 (s, 1H), 0.83 (d, 6H).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=1[S:2]([OH:5])(=[O:4])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cccc(OC)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)O)c(OC)c1

Procedure:
To a solution prepared by adding 57 ml of chlorosulfonic acid to 250 ml of chloroform, was added dropwise 50 g of 1,3-dimethoxybenzene at a temperature below 5° C. with stirring. After stirring at 5° C. for 30 minutes, the crystals thus-precipitated were collected by filtration and washed with 100 ml of chloroform.
Reaction SMILES: C1(=O)[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]([C:19]([OH:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[C:14]([C:19]([OH:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: NCc1ccccc1-c1ccccc1C(=O)O
Temperature: 40 °C
Yield: 75.4 %

Procedure:
A suspension of 10.0 g (28 mmol) of 2′-phthalimidomethylbiphenyl-2-carboxylic acid in 450 ml of methanol was treated with 20 ml of hydrazine hydrate and heated at 40° C. for 1.5 h. The reaction mixture was concentrated and the residue was taken up in 250 ml of methylene chloride. After filtering off undissolved 2,3-dihydrophthalazine-1,4-dione, the mother liquor was concentrated and 4.8 g of 2′-aminomethylbiphenyl-2-carboxylic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C@@:14]([OH:16])([CH3:15])[C:13]([CH3:18])([CH3:17])[O:12][C:11]3[CH:19]=[CH:20][C:21]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32]C)[CH:27]=4)(=[O:25])=[O:24])=[CH:22][C:10]2=3)[CH:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C@@:14]([OH:16])([CH3:15])[C:13]([CH3:18])([CH3:17])[O:12][C:11]3[CH:19]=[CH:20][C:21]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=4)(=[O:25])=[O:24])=[CH:22][C:10]2=3)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cccc(S(=O)(=O)c2ccc3c(c2)[C@@H](Nc2ccnc(Cl)n2)[C@](C)(O)C(C)(C)O3)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)Oc2ccc(S(=O)(=O)c3cccc(O)c3)cc2[C@@H](Nc2ccnc(Cl)n2)[C@]1(C)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
(3S,4R)-4-(2-Chloropyrimidin-4-yl)amino-3,4-dihydro-3-hydroxy-6-(3-methoxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (0.23 g) (see Preparation 19) was dissolved in dichloromethane (25 ml) (the flask was fitted with a calcium chloride drying tube) and boron tribromide (1 ml) was added. The mixture was stirred at room temperature for 24 hours and a precipitate was formed. The dichloromethane was decanted off, the solid taken up in 1N aqueous sodium hydroxide and washed with ethyl acetate. The aqueous phase was acidified to give a gum which was collected and dried under reduced pressure at 70° C. to yield (3S,4R)-4-(2-chloropyrimidin-4-yl)amino-3,4-dihydro-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (0.123 g) as a white solid, m.p.>280° C. LRMS m/z=475 (m)+.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14](O)=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].N1C=CC=CC=1.[F:27]C1N=C(F)N=C(F)N=1>C(Cl)Cl>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([F:27])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)F
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a solution of (2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoic acid (9) (1.7 g, 6.1 mmol) in DCM (20 mL) was added pyridine (0.53 g, 6.7 mmol), followed by 2,4,6-trifluoro-1,3,5-triazine (0.86 g, 6.4 mmol) dropwise. The reaction mixture was stirred for 4 h and TLC indicated completion of the reaction. The reaction mixture was washed with 10% aqueous citric acid and brine, dried over Na2SO4, and concentrated to provide the title compound (1.7 g, 100%) as red oil. 1H NMR (300 MHz, DMSO) δ ppm 0.86 (t, J=6.7 Hz, 3H), 1.16-1.38 (m, 4H), 1.57 (m, 2H), 3.03 (m, 1H), 3.87 (m, 2H), 4.91 (s, 2H), 7.41 (m, 5H).
Reaction SMILES: [OH2:1].[OH-].[Na+].[C:4]([C:6]([NH:11][C:12]([C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])=O)([CH3:10])[CH:7]([CH3:9])[CH3:8])#[N:5].Cl>C(Cl)Cl>[CH:7]([C:6]1([CH3:10])[NH:11][C:12]([C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[N:5][C:4]1=[O:1])([CH3:9])[CH3:8]
Reactant: CC(C)C(C)(C#N)NC(=O)c1ncccc1C(=O)O
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)C1(C)NC(c2ncccc2C(=O)O)=NC1=O

Procedure:
To a stirred mixture of 20 mL of water and 8.40 g (0.105 mol) of 50% sodium hydroxide solution is added 7.83 g (0.030 mol) of 2-[(1-cyano-1,2-dimethylpropyl)aminocarbonyl]nicotinic acid. External heating is applied to raise the temperature to 70°-75° C. where it is maintained for five hours. After cooling the reaction mixture to 20°-30° C., 50 mL of methylene chloride is added and the pH is adjusted to 3.0 by the addition of 37% hydrochloric acid. The organic layer is separated and the solvent is removed by distillation to give 6.71 g of solid 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)nicotinic acid which is 90% pure in 77% yields.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=1.[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][NH2:18]>C(O)C.C(OCC)(=O)C>[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=1
Reactant: CC(C)(C)CCN
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)cnc1NCCC(C)(C)C
Temperature: 150 °C

Procedure:
A solution of ethyl 2-chloro-5-fluoro-3-pyridinecarboxylate (0.300 g, 1.47 mmol) in ethanol (3.0 mL) was treated with (3,3-dimethylbutyl)amine (0.210 mL, 1.58 mmol). The mixture was heated to 150° C. for 0.5 h in a Biotage Initiator microwave synthesizer. The solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo. The title compound was obtained as an amber oil (0.347 g, 88%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 6.61 (d, J=3.0 Hz, 1H), 6.30 (dd, J=8.8, 3.0 Hz, 1H), 6.24 (br. s., 1H), 2.80 (q, J=7.1 Hz, 2H), 1.88-1.99 (m, 2H), −0.02-0.09 (m, 2H), −0.14 (t, J=7.2 Hz, 3H), −0.53 (s, 9H). MS(ES+) m/e 269 [M+H]+.
Reaction SMILES: O1CCC[CH2:2]1.Cl(O)(=O)(=O)=O.C[CH:12]([CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[C:20]([CH:22]=[CH2:23])[CH3:21])[CH:13]=[O:14]>O>[CH3:2][C:16](=[CH:17][CH2:18][CH:19]=[C:20]([CH:22]=[CH2:23])[CH3:21])[CH2:15][CH2:12][CH:13]=[O:14]
Reactant: C=CC(C)=CCC=CCC(C)C=O
Reactant: C1CCOC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: C=CC(C)=CCC=C(C)CCC=O

Procedure:
A solution of 13.4 g. (53 mM) of the C12 -aldehyde diethylacetal, prepared according to the method described in paragraph c), 250 ml. of tetrahydrofuran, 60 ml. of water and and 0.5 ml. of 72% perchloric acid was left for 20 hours at room temperature under nitrogen. Water was added and the mixture was extracted with pentane (3x). The organic layers were washed with 5% NaHCO3 and water, dried over sodium sulphate and evaporated. The remaining oil was distilled to yield 9.2 g. (99%) of 4 methyl-8-vinyl-4,7-nonadienal, b.p. 73°-75°/0.3 Torr. IR(CHCl3): 2720, 1720, 1640, 1605, 995, 905 cm-1. NMR(CCl4): 1.4 - 1.8 ppm (m, 6 H), 2.2 - 2.5 ppm (m, 4H), 2.78 ppm (t, J = 7 cps, 2 H), 4.6 - 5.5 ppm (m, 4 H), 6.20 ppm (about 75%) / 6.64 ppm (about 25%) (2 d of d, J = 10 and 17 cps, 1 H), 9.55 ppm (t, J = about 1.5 cps, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:14][OH:15]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]=[O:15]
Reactant: O=c1c(Br)c(CO)nc2ccc(F)cn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=Cc1nc2ccc(F)cn2c(=O)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
A mixture of 3-bromo-7-fluoro-2-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (5.6359 g, 20.64 mmol) and manganese(IV) oxide (17.94 g, 206.4 mmol) in toluene (137.6 mL) was heated to reflux. After 3 h, the mixture was cooled to rt and filtered through a pad of Celite™. The pad was rinsed with DCM (1 L). The filtrate was concd under reduced pressure to give 3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde (2.4747 g, 44.24% yield) as a bright yellow solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 10.13 (1 H, s), 9.03-9.06 (1 H, m), 8.24 (1 H, ddd, J=9.8, 7.1, 2.7 Hz), 8.00-8.05 (1 H, m); Mass Spectrum (ESI) m/e=270.9 [M+1 (79Br)] and 273.0 [M+1 (81Br)].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:11](=[CH2:12])[CH2:10][CH2:9][CH2:8][C:7]1=O.[C:14]([CH2:16][C:17]([NH2:19])=[S:18])#[N:15].C(=O)([O-])[O-].[K+].[K+].[S]>CC(C)=O>[SH:18][C:17]1[C:16]([C:14]#[N:15])=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:12]=2[N:19]=1
Reactant: C=C1CCCC(=O)C1c1cccs1
Reactant: N#CCC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [S]
Solvent: CC(C)=O
Product: N#Cc1c(S)nc2c(c1-c1cccs1)CCCC2
Yield: 91.9 %

Procedure:
12.68 g (65.9 mmol) 2-thiophene-2-yl-methylene-cyclohexanone, 7.00 g (70.0 mmol) cyanthioacetamide and 10.00 g (72.4 mmol) potassium carbonate are refluxed in 100 ml acetone for 8 h. Then, 1.05 g (32.8 mmol) sulfur are added and refluxed for 12 h. The solvent is removed in vacuo and the residue is suspended in 600 ml ethanol/water (1:5). Following acidification with glacial acetic acid, the resulting precipitate is sucked off, washed with 200 ml water, suck dried and dried in vacuo at 50° C. 16.50 g (92%) 5,6,7,8-tetrahydro-2-mercapto-4-thiophen-2-yl-quinoline-3-carbonitrile is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(F)n1
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCc2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of (4-bromo-phenyl)-methanol (4.54 g, 24.3 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (999 mg, 25 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2-Fluoro-6-methylpyridine (1.8 g, 16.2 mmol) was then added to the reaction mixture on an ice bath (0° C.), and stirred for 5 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (3.65 g, 81%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)(=[O:21])=[O:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>>[ClH:28].[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([C:16]1[S:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:18][CH:17]=1)(=[O:20])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(S(=O)(=O)c3ccccn3)s2)CC1
Agent: Cl
Product: O=S(=O)(c1ccccn1)c1cnc(N2CCNCC2)s1
Yield: 99 %

Procedure:
Prepared in analogy to example 4 (d) from 4-[5-(pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester and hydrogen chloride solution. The crude material was purified by recrystallisation from ether to afford the title compound as an off-white crystalline solid (yield 99%). MS (m/e): 311.0 (M+H+, 100%).