Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]2[N:5]=[C:4]([SH:17])[N:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[CH2:18]([S:17][C:4]1[N:3]=[C:2]([OH:1])[N:7]2[N:8]=[CH:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]2[N:5]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: N#CCCCCc1cnn2c(O)nc(S)nc12
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCCCc1cnn2c(O)nc(SCc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of compound (3) (5.3 g, 21,3 mmol) in N-methylpyrrolidinone (30 mL) was degassed in vacuum for 5 min. Benzyl bromide (2.28 mL, 19. 1 mmol) and DIEA (4.4 mL, 25 mmol) were added and the reaction mixture was stirred at room temperature under vacuum for 30 min. Sol-vent was removed under reduced pressure and the residue was diluted with EtOAc. The acetate solution was washed with 1 M HCl followed by brine. Organic extract was dried over anhydrous Na2 SO4, filtered, and concentrated. The residue was triturated in a mixture solvent of hexane, ether and EtOAc, and filtered to give 5-(2-benzylsulfanyl-4-hydroxy-pyrazolo[1,5-a][1,3,5]triazin-8-yl)-pentanenitrile (4) as a solid (6.0 g. 93%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)[C:13]1=[O:26])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)[C:13]1=[O:26]
Reactant: COC(=O)c1ccc2ccn(CCCNC(=O)OC(C)(C)C)c(=O)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2ccn(CCCN)c(=O)c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.90 g, 2.5 mmol) in methylene chloride (20 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (10.0 mL, 40 mmol). The reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated to dryness to afford methyl 2-(3-aminopropyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate.HCl (0.74 g, quant.). LC-MS: (FA) ES+ 261.
Reaction SMILES: [CH3:1][O-].[K+].[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][C:15]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:14]=3[NH:13][C:12](=[O:22])[C:11]=2[CH:23]=1)([O-:6])=[O:5].IC>C(O)(C)(C)C.O1CCOCC1>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][C:15]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:14]=3[N:13]([CH3:1])[C:12](=[O:22])[C:11]=2[CH:23]=1)([O-:6])=[O:5]
Reactant: C[O-]
Reactant: Cc1ccc2c(c1)Oc1ccc([N+](=O)[O-])cc1C(=O)N2
Agent: [K+]
Solvent: CI
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: Cc1ccc2c(c1)Oc1ccc([N+](=O)[O-])cc1C(=O)N2C
Temperature: 60 °C
Reaction time: 4 h
Yield: 59.8 %

Procedure:
To a warm solution of 4.05 g potassium methoxide in 80 ml of t-butanol and 80 ml of dioxane was added 13.5 g (0.05 mol) of 2-nitro-7-methyldibenz[b,f][1,4]oxazepin-11(10H)-one. The resulting suspension was warmed to 60° C. for 15 minutes. Initially everthing went in solution, after several minutes a crystalline precipitate formed. To the stirred suspension was added 3.75 ml of iodomethane. The reaction mixture was stirred for 4 hours at 60° C., then concentrated to dryness in vacuo. The dark residue was suspended in water, acidified with acetic acid, concentrated in vacuo and then recrystallized from propanol to give 8.5 g (60% yield) of 2-nitro-7,10-dimethyldibenz[b,f][1,4]- oxazepin-11(10H)-one mp 156°-159°.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:20])[CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH:21]1([C:24]2[CH:33]=[C:32]([C:34](Cl)=[O:35])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH2:23][CH2:22]1>>[CH:21]1([C:24]2[CH:33]=[C:32]([C:34]([NH:20][CH:13]([C:10]3[CH:11]=[CH:12][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=3)[CH2:14][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[O:35])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH2:23][CH2:22]1
Reactant: CCCS(=O)(=O)c1ccc(C(N)CN2CCCC2)cc1
Reactant: O=C(Cl)c1cc(C2CC2)nc2ccccc12
Product: CCCS(=O)(=O)c1ccc(C(CN2CCCC2)NC(=O)c2cc(C3CC3)nc3ccccc23)cc1

Procedure:
{1-[4-(Propylsulphonyl)phenyl]-2-pyrrolidin-1-ylethyl}amine, the intermediate described in Example 47e, was reacted with 2-cyclopropylquinoline-4-carbonyl chloride (see above) under the conditions described in Example 47f. 1H NMR δ (400 MHz, CDCl3) δ 0.97 (3H, t, J=7.4 Hz), 1.07-1.11 (2H, m), 1.16-1.20 (2H, m), 1.66-1.77 (6H, m), 2.18-2.24 (1H, m), 2.48-2.50 (2H, m), 2.63-2.71 (3H, m), 2.91-3.02 (3H, m), 5.19-5.24 (1H, m), 7.29 (1H, s), 7.42-7.48 (2H, m), 7.56 (2H, d, J=8.3 Hz), 7.62-7.66 (1H, m), 7.82 (2H, d, J=8.3 Hz), 7.96 (1H, d, J=8.4 Hz), 8.13 (1H, d, J=8.3 Hz); m/z (ES+) 492 (M+H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=[O:9].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=[O:9])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: O=c1cccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)Cn1ccccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a suspension of 60% sodium hydride dispersion in mineral oil (220 mg, 5.5 mmol) in cold (0° C.) THF is added 2-pyridone (475 mg, 5.0 mmol) in THF (4 mL) and DMPU (2 mL) followed by ethyl bromoacetate (0.556 mL, 5.0 mmol), and the reaction is stirred at RT for 1 h. The reaction is quenched with water, and extracted with EtOAc. The organic layer is separated, evaporated, and the residue purified by chromatography on silica gel; elution with EtOAC:dichloromethane:heptane (50:30:20) gives 690 mg of the product 425. 1H NMR (CDCl3) δ 7.35 (m, 1H), 7.21 (d, 1H), 6.57 (d, 1H), 6.19 (t, 1H), 4.62 (s, 2H), 4.23 (q, 2H), 1.28 (t, 3H); MS: m/z 182 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][N:12]=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][C:20]=2[O:31][CH3:32])[N:10]=1.CCN(C(C)C)[CH:36]([CH3:38])[CH3:37].[Cl-].C[OH:44]>C(Cl)Cl>[C:15]([C:14]1[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:37](=[O:44])[CH:36]=[CH2:38])=[N:10][C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][C:20]=2[O:31][CH3:32])=[N:12][CH:13]=1)(=[O:17])[CH3:16]
Reactant: COc1cc(N2CCOCC2)ccc1Nc1ncc(C(C)=O)c(Nc2ccccc2N)n1
Reactant: CCN(C(C)C)C(C)C
Reactant: CO
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)Nc1ccccc1Nc1nc(Nc2ccc(N3CCOCC3)cc2OC)ncc1C(C)=O
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-(2-aminophenylamino)-2-(2-methoxy-4-morpholinophenylamino) pyrimidin-5-yl)ethanone (100 mg, 0.23 mmol) in DCM (10 ml), DIPEA (55 mg, 0.46 mmol) and acrolyl chloride (20.7 mg, 0.23 mmol) were added at −20° C., and the mixture was stirred for 30 min. TLC showed completion of starting material (TLC system: 5% methanol in DCM. (Rf): 0.5). The reaction mixture was diluted with DCM (20 mL) and washed with water (2×10 mL). The organic layer was separated, dried over sodium sulphate, and concentrated. Crude compound was purified by column chromatography using silica gel (100-200 mesh) with 3% methanol in DCM to obtain N-(2-(5-acetyl-2-(2-methoxy-4-morpholinophenylamino) pyrimidin-4-yl amino)phenyl) acrylamide as a pale yellow solid. Yield: (30 mg, 26%). MS: m/z 489.2 (ES+); 1HNMR (DMSO-d6) δ 11.25 (s, 1H), 9.76 (s, 1H), 8.77 (s, 1H), 8.73 (s, 1H), 8.10 (br s, 1H), 7.35 (d, 1H, J=8.4 Hz), 7.25 (br s, 1H), 0.06 (br t, 2H), 6.65 (s, 1H), 6.45 (m, 2H), 6.20 (dd, 1H, J=2.0, 17.2 Hz), 5.74 (dd, 1H, J=8.0 Hz), 3.72 (m, 7H), 3.12 (m, 4H, 3.24 (br s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=CC(CCC(O)=O)=CC=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC(C2N(CC3C=C(C=CC=3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.[CH3:73][O:74][C:75](=[O:85])[CH2:76][C:77]1[CH:82]=[CH:81][C:80]([CH2:83]Br)=[CH:79][CH:78]=1>>[CH3:73][O:74][C:75](=[O:85])[CH2:76][C:77]1[CH:78]=[CH:79][C:80]([CH2:83][N:12]2[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:31][CH3:32])=[CH:81][CH:82]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Product: COC(=O)Cc1ccc(Cn2c(-c3ccc(Cl)cc3OC)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and (4-bromomethyl-phenyl)-acetic acid methyl ester (CAS Reg. No. 7398-42-7). Brown sticky solid (15%). MS (Turbo Spray): m/z=457.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9]C(=O)[N:7]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:6]=2[CH:16]=1.O.[K]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:9])=[C:6]([NH:7][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:16]=1
Reactant: CN(C)CCn1c(=O)sc2ccc(Cl)cc21
Agent: [K]
Solvent: CCO
Solvent: O
Product: CN(C)CCNc1cc(Cl)ccc1S
Reaction time: 2 h
Yield: 79 %

Procedure:
After removal of the solvent under reduced pressure, the residue was dissolved in ethylacetate, and the solution was washed with aqueous sodium hydroxide. The ethylacetate extract was acidified with dilute hydrochloric acid and the aqueous layer was neutralized with saturated aqueous sodium bicarbonate and then the resulting oily substance was extracted with ethylacetate. The extract was washed with water, dried (Na2SO4) and evaporated to give 5-chloro-3-(2-dimethylaminoethyl)-2-benzothiazolinone (74.5 g) as prisms. m.p. 62.5-65.5° C. 5-Chloro-3-(2-dimethylaminoethyl)-2-benzothiazolinone (74.5 g) was added to a mixture of water (110 ml), ethanol (350 ml) and potassium hydroide (75.0 g). The solution was refluxed with stirring for two hours. After removal of the solvent under reduced pressure, the residual oil was dissolved in water, then the aqueous solution was washed with ether. The aqueous layer was washed and neutralized with 2N-acetic acid with weak stirring. The resulting light yellow precipitates were collected on a filter, washed with water and air-dried to give 4-chloro-2-(2 -dimethylaminoethylamino)-thiophenol (52.9 g) as prisms. m.p. 126-130° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.O.[NH2:12][NH2:13]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:12][NH2:13])=[O:9])[CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)C1CCOCC1
Solvent: CO
Solvent: O
Product: NNC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a round-bottom flask was added a solution of methyl tetrahydro-2H-pyran-4-carboxylate (compound 137.1, 5.00 g, 31.2 mmol, 1.00 equiv, 90%) in methanol (50 mL). Hydrazine hydrate (5.20 g, 83.2 mmol, 3.00 equiv) was added and the resulting mixture was stiffed overnight at 40° C. in an oil bath. After cooling to ambient temperature, the mixture was concentrated in vacuo to yield 4.00 g (80%) of tetrahydro-2H-pyran-4-carbohydrazide as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH:6]([OH:12])[C:7]([CH3:11])=[CH:8][CH2:9][CH3:10])[CH3:3].[CH3:13][O:14][C:15]([CH3:17])=[CH2:16]>Cl.CCCCCC>[CH3:13][O:14][C:15]([CH3:17])([O:12][CH:6]([C:7]([CH3:11])=[CH:8][CH2:9][CH3:10])[CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:16]
Reactant: CCC=C(C)C(O)CCC(C)C
Reactant: C=C(C)OC
Agent: Cl
Solvent: CCCCCC
Product: CCC=C(C)C(CCC(C)C)OC(C)(C)OC

Procedure:
10 g of 2,6-dimethyl-6-nonen-5-ol and 12 7 g of isopropenyl methyl ether are mixed and treated with 3 drops of concentrated hydrochloric acid. The mixture is subsequently held at reflux temperature for 15 hours, cooled, taken up in hexane and washed neutral with sodium hydrogen carbonate solution and water. After distillation of the solvent, there are obtained 14.1 g of crude 5-[1'-methoxy-1'-methyl-ethoxy]-2,6-dimethyl-6-nonene which are rectified in a water-jet pump vacuum (boiling point 109° C./12 Torr, nD20 =1.4379). The mixed acetal decomposes when subjected to gas chromatography and must therefore be tested for purity by thin-layer chromatography (elution agent: hexane/pentane/chloroform/ethyl acetate in the ratio 25:25:50:5); Rf =0.60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]([F:73])([F:72])[F:71])=[CH:66][N+:65]=1[O-]>[Fe].C(O)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]([F:72])([F:71])[F:73])=[CH:66][N:65]=3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1ccc(C(F)(F)F)c[n+]1[O-]
Agent: [Fe]
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)cn3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 8.7 %

Procedure:
The title compound was prepared by following the procedure described for Example-121 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), COMU (0.284 g, 0.663 mmol), DIPEA (0.085 g, 0.658 mmol), 2-amino-5-(trifluoromethyl)pyridine 1-oxide (Intermediate-41, 0.052 g, 0.292 mmol), DMF (5 mL), iron powder (0.100 g) and acetic acid (5.0 mL) to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.12 (s, 2H), 7.33 (m, 3H), 7.54 (s, 1H), 8.23 (d, J=8.7 Hz, 1H), 8.48 (d, J=8.70 Hz, 1H), 8.57 (s, 1H), 10.47 (s, 1H), 11.00-12.00 (s, 2H); MS [M]+: 520.18.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][C:3](=[O:11])[NH:4][C:5]=2[CH:10]=1)=[O:19]
Reactant: O=C1COc2ccccc2N1
Reactant: O=C(Cl)CCCCCBr
Product: O=C1COc2ccc(C(=O)CCCCCBr)cc2N1
Yield: 45.1 %

Procedure:
Using 2H-1,4-benzoxazin-3(4H)-one (15.0 g) and 6-bromohexanoyl chloride (25.8 g) according to the same method as that of Reference Example 1, the title compound (14.8 g) was obtained as colorless crystals.
Reaction SMILES: [S:1]=[C:2]1[NH:14][C:13](=[O:15])[C:5]2=[CH:6][C:7]3[C:12]([N:4]2[NH:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CI.[C:18]([O-])(O)=O.[Na+]>O1CCCC1>[CH3:18][S:1][C:2]1[NH:14][C:13](=[O:15])[C:5]2=[CH:6][C:7]3[C:12]([N:4]2[N:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=c1[nH]c(=S)[nH]n2c1cc1ccccc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nn2c(cc3ccccc32)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Into a round-bottom flask 2-thioxo-2,3-dihydro-1H-[1,2,4]triazino[1,6-a]indol-4-one (9.25 g, 0.04 mol) and methyl iodide (3.42 mL, 0.0549 mol) were combined in tetrahydrofuran (200 mL). The reaction was stirred at 45° C. for one hour. The solvent was removed under vacuum to give a solid, which was next stirred for 30 minutes with saturated aqueous NaHCO3 (100 mL). The solid was filtered and washed with water, then dried on high vacuum and further by azeotrop distillation with toluene to give 2-methylsulfanyl-3H-[1,2,4]triazino[1,6-a]indol-4-one (7 g, 71%), which was used in the next step without further purification. 1H-NMR (DMSO-d6) δ 12.28 (br s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.43 (m, 1H), 7.28 (m, 1H), 7.18 (s, 1H), 2.64 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:8]([CH3:9])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccccc1
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CC(=O)c1ccc(F)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of benzyl-methyl-amine (28.9 g) and triethylamine (33.8 mL) in dimethylformamide (600 mL) was added in 5 portions 2-chloro-1-(4-fluorophenyl)-ethanone (40 g) on an ice bath. After stirring at room temperature for 2 hours, ethyl acetate was added, and the salt that precipitated was removed by filtration, and the filtrate was concentrated. A crude purification was carried out by silica gel column chromatography (hexane/ethyl acetate), and the title compound (56.9 g) was obtained as a colorless oily matter.
Reaction SMILES: Cl.[N:2]1([C:7](=N)[NH2:8])C=CC=N1.CN(C=O)C.CCN(C(C)C)C(C)C.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>CCOCC>[OH:27][CH2:26][CH:25]([NH:24][C:7]([NH2:8])=[NH:2])[CH2:28][OH:29]
Reactant: NC(CO)CO
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: N=C(N)NC(CO)CO
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 1H-pyrazole-1-carboximidamide hydrochloride (12 g, 82 mmol) and DMF (40 mL) at RT was added DIPEA (19 mL, 110 mmol) and 2-aminopropane-1,3-diol (5.0 g, 55 mmol) and the reaction was stirred overnight. Et2O (15 mL) was added and the reaction was stirred for 10 min before the reaction was allowed to settle and the ether layer was decanted. The remaining crude oil was concentrated under high vacuum to afford 7.3 g (100%) of 1-(1,3-dihydroxypropan-2-yl)guanidine (296) which contained residual DMF.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10]([C:20]([O:22]CC)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][C:10]([C:20]([OH:22])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
To 3.2 g (0.0093 mol) of the product from Step A was added 100 mL methanol and 100 mL 1N sodium hydroxide. The reaction mixture was heated at reflux for 18 h, cooled to room temperature, poured into 200 mL water and extracted with ether (1×100 mL). The aqueous phase was acidified with concentrated HCl and extracted with ether (3×100 mL), washed with water (1×100 mL) and brine (1×100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 3.0 g of a yellow solid, mp 157-158° C. 1H NMR (CDCl3) δ: 1.6 (bs, 1H), 1.8-2.4 (m, 3H), 2.8 (d, 1H), 5.3 (bs, 1H), 7.0-7.4 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)#[CH:10].C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:10]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(I)cn1
Reactant: C#Cc1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cnc(Cl)nc2)cc1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A solution of 2-chloro-5-iodopyrimidine (600 mg, 2.5 mmol), 1-ethynyl-4-fluorobenzene (330 mg, 2.75 mmol), triethylamine (556 mg, 761 μl, 5.49 mmol), and bis(triphenyl-phosphine)palladium (II) chloride (175 mg, 250 μmol) in 7 ml of THF was purged with argon. Then copper (I) iodide (23.8 mg, 125 μmol) was added and the reaction was heated for 2 h at room temperature. The dark solution was filtered and the solids were washed with THF. The residue was taken up in ethyl acetate, adsorbed onto 3 g of silicagel which was loaded onto a 50 g prepacked flash chromatography column. After elution with a 0% to 20% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 505 mg (87%) of the title compound as an crystalline light yellow solid, MS: m/e=233.1, 235.1 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18](=[O:19])[N:9]2[CH2:10][CH2:11][C:12]3[C:17]([C:8]2=[CH:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:4].[OH-].[Na+]>O1CCOCC1>[O:19]=[C:18]1[N:9]2[CH2:10][CH2:11][C:12]3[C:17]([C:8]2=[CH:7][CH:6]=[C:5]1[C:3]([OH:4])=[O:2])=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: COC(=O)c1ccc2n(c1=O)CCc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc2n(c1=O)CCc1ccccc1-2
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 4-oxo-6,7-dihydropyrido[2,1,a]isoquinoline-3-carboxylic acid methyl ester (3-101-02) (252 mg) in dioxane (2.0 mL) was 2 mol/L aqueous sodium hydroxide solution (2.0 mL) at room temperature. After the reaction mixture was stirred for 1 h, and washed with diethyl ether, adjusted to be acidic with conc. hydrochloric acid. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted three times with ethylacetate and the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 4-oxo-6,7-dihydropyrido[2,1,a]isoquinoline-3-carboxylic acid (3-101-03) (209 mg, 88%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][CH:17]=[O:18])[C:12]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:11]=2[O:10][C@@H:9]1[CH3:24])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(OC(=O)C)C.CCCCCCC>O1CCCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][OH:18])[C:12]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:11]=2[O:10][C@@H:9]1[CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1Oc2ccc(F)cc2N(CC=O)C(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C[C@H]1Oc2ccc(F)cc2N(CCO)C(=O)[C@H]1NC(=O)OC(C)(C)C
Yield: 60.5 %

Procedure:
0.10 g (0.28 mmol) [(6R,7S)-2-Fluoro-6-methyl-8-oxo-9-(2-oxo-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester in 4 ml tetrahydrofurane were reduced with 0.02 g (0.34 mmol) sodium borohydride. Chromatography on silicagel with ethylacetate/heptane 8:2 yielded 0.06 g (56%) [(6R,7S)-2-fluoro-9-(2-hydroxy-ethyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester, MS m/e (%): 377.3 (M+Na+, 86), 355.2 (M+H+, 14), 255.3 (100).