Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(NCC)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][OH:12])=[CH:3][CH:4]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: OCC#Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.8 %

Procedure:
A suspension of p-iodochlorobenzene [formula (VII), 7.15 g, 30.0 mmol], propargyl alcohol (1.75 mL, 30 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.21 g, 0.3 mmol), copper (I) iodide (29 mg, 0.15 mmol) and diethylamine (50 mL) was stirred under a N2 atmosphere at room temperature and dissolution occurred within 20 min. After 5 h, the diethylamine was removed, and the crude product was partitioned between water and ether. The ether phase was dried (brine), concentrated and flash chromatographed (4:1 petroleum ether: ethyl acetate) to provide 3-(4-chlorophenyl)-prop-2-yn-ol (compound of formula VIII, 4.09 g, 82%). This compound of formula (VIII) (3.47 g, 20.83 mmol) was suspended in dry ether (12 mL) and pyridine (0.42 mL) was added. The reaction mixture was cooled in an ice bath and a solution of phosphorus tribromide (1.0 mL, 10.42 mmol) in dry ether (6 mL) was added dropwise over a 15 min period. The reaction mixture was then stirred at room temperature for 2.5 h, cooled in an ice bath and crushed ice was added. The reaction mixture was added to water (200 mL) and extracted with ether (200 mL). The ether phase was washed with water, sat. aqueous NaHCO3 and brine. The extract was concentrated and flash chromatographed (9:1 petroleum ether:ethyl acetate) to provide the product as a white solid (3.38 g, 86%): mp 41°-43 ° C.; NMR (CDCl3): δ 7.37 (d, J=8.7 Hz, 2H, ArH), 7.27 (d, J=8.7 Hz, 2H, ArH), 4.16 (s, 2H, CH2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C([O-])(=O)C.[Na+].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:16](OC)=[O:17]>C(O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]2[C:16](=[O:17])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2)=[CH:21][CH:22]=1
Reactant: COC(=O)C(Br)c1ccc(F)cc1
Reactant: Nc1ccccc1S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2ccccc2SC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a suspension of 2-aminothiophenol (12.6 g) and sodium acetate (23.6 g) in ethanol (150 ml) is added methyl α-bromo-4-fluorophenylacetate (23.6 g), and the mixture is stirred at room temperature overnight. After the solvent is distilled off, water is added to the residue. The resulting precipitate is separated by filtration, washed, dried, and then recrystallized from tetrahydrofuran-n-hexane to give 2-(4-fluorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (21.7 g) as crystals. M.p. 216°-219° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:19][CH2:18][C:13]2=[N:14][O:15][C@@H:16]([CH3:17])[C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC[C@@H]1OC[C@]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=3[F:45])NOC[C@@H]2C1)C1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:19][CH2:18][C@:13]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=3[F:45])[NH:14][O:15][C@@H:16]([CH3:17])[C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc([C@]23CO[C@@H](COCc4ccccc4)C[C@H]2CON3)c(F)c1
Reactant: C[C@@H]1ON=C2CO[C@@H](COCc3ccccc3)C[C@H]21
Product: C[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@@H]12

Procedure:
The product, obtained as a yellow oil, was prepared from (3S,3aR,5R)-5-[(benzyloxy)methyl]-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C16) according to the general procedure for the synthesis of (3aR,5R,7aS)-5-[(benzyloxy)methyl]-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C5) in Preparation P1. Yield: 21.5 g, 57.2 mmol, 48%. LCMS m/z 376.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.98 (ddd, J=9.1, 9.1, 6.8 Hz, 1H), 7.28-7.40 (m, 5H), 6.87-6.93 (m, 1H), 6.80 (ddd, J=11.9, 8.6, 2.6 Hz, 1H), 4.60 (AB quartet, JAB=12.1 Hz, ΔνAB=19.9 Hz, 2H), 3.99-4.06 (m, 1H), 3.97 (dd, half of ABX pattern, J=12.9, 2.0 Hz, 1H), 3.80-3.88 (m, 2H), 3.56 (dd, half of ABX pattern, J=10.2, 6.3 Hz, 1H), 3.49 (dd, half of ABX pattern, J=10.2, 4.1 Hz, 1H), 2.81-2.87 (m, 1H), 2.04 (ddd, J=14.2, 7.6, 2.8 Hz, 1H), 1.48-1.59 (m, 1H), 0.79 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][CH:19]=1)=[O:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:16][CH:15]=1)=[O:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(CNC(=O)c2cnc(-c3ccccc3)nc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(CNC(=O)c2cnc(-c3ccccc3)nc2)c1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
Methanesulfonyl chloride (0.553 mmol) is added to a stirred solution of 2-phenyl-pyrimidine-5-carboxylic acid 3-amino-benzylamide (Example 115, 0.526 mmol) and triethylamine (1.05 mmol) in DCM (20 mL) at 0° C. The mixture is stirred at room temperature for an hour. The reaction mixture is quenched with 5% HCl and extracted with DCM (20 mL). The organic layer is separated, washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 0-5% MeOH in DCM to afford 2-(phenyl)-pyrimidine-5-carboxylic acid 3-methanesulfonylamino-benzylamide (200 mg) as a solid. MS: 383 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.41 (s, 3H), 4.76-4.72 (m, 2H), 7.00 (bs, N—H), 7.05-7.23 (m, 2H), 7.27-7.60 (m, 5H), 8.40-8.53 (m, 2H), 9.16 (s, 2H).
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])=[CH:11][CH:10]=2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.C(N(CC)CC)C.Cl[C:37](=[O:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>ClCCl>[C:37]([N:8]([CH2:7][CH2:6][N:5]1[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]2[C:1]1=[O:28])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]([F:22])([F:21])[CH:18]([F:19])[F:20])=[CH:13][CH:14]=1)([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:43]
Reactant: CCOC(=O)C(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCNc1ccc(OCC(F)(F)C(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(CCN1C(=O)c2ccccc2C1=O)c1ccc(OCC(F)(F)C(F)F)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To the mixture of the obtained N-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (3.2 g), triethylamine (1.2 ml) and dichloromethane (60 ml), was added dropwise a solution of ethyl chloroglyoxylate (0.9 ml) in dichloromethane (10 ml) at -65° C. The reaction solution was stirred for 1 hour at -40° C., and then ice-water (50 ml) was added thereto to fractionate. The dichloromethane layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-ethoxalyl-N-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (3.1 g) as colorless powdery crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2ccnc2)CC1

Procedure:
By a similar manner to Reference Example 29, 1-tert-butoxycarbonyl-piperidin-4-methanol (1.08 g, 5.0 mmol) was reacted with imidazole (1.02 g, 15 mmol) to give the titled compound as an amorphous-like substance 239 mg, 18%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:30])([F:29])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([S:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1)[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[ClH:31]>CO>[ClH:31].[F:30][C:4]([F:3])([F:29])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([S:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=1)[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(SC(Cn2ccnc2)c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
17.6 of 1N aqueous solution of sodium hydroxide were added to 1.79 g of methyl 4-[1-(2-trifluoromethylphenyl)-2-(imidazol-1-yl)ethylthio]benzoate (prepared as described in Example 37) in 17.6 ml of methanol, and the resulting mixture was stirred at room temperature for 4.5 hours. 8.8 ml of a 1N aqueous solution of sodium hydroxide were added to the reaction mixture and it was then neutralized with 1N aqueous hydrochloric acid, after which it was treated and purified by the same method as described in Example 16, to give 1.61 g of the title compound as colorless crystals, melting at 198°-202° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:18])=[N:16][N:17]=3)[N:14]=2)[CH:4]=1.[CH2:19]=[C:20]1[O:24][C:22](=[O:23])[CH2:21]1>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:18])=[N:16][N:17]=3)[N:14]=2)[CH:4]=1)[C:22](=[O:23])[CH2:21][C:20](=[O:24])[CH3:19]
Reactant: CNc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1

Procedure:
A mixture of 2.0 g of -N-methyl-3-(3-methyl-1,2,4-triazolo-[4,3-b]pyridazin-6-yl)benzenamine and 2.14 ml of diketene in 250 ml of dry toluene was heated to reflux for 2 days. The solution was concentrated in vacuo and the residue partitioned between 300 ml dichloromethane and 200 ml of water. The aqueous layer was extracted with 150 ml portions of dichloromethane. The organic layer and extracts were combined, dried and concentrated in vacuo. The residue was chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3). The fractions containing product were combined, evaporated in vacuo and the solid recrystalized from dichloromethane-hexane to give 1.15 g of tan crystals, mp 138°-141° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([CH:22]=[N:23][N:24]=3)[C:11](SC)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]1([CH2:37][C@H:38]([NH2:41])[CH2:39][NH2:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([CH:22]=[N:23][N:24]=3)[C:11]([NH:40][CH2:39][C@@H:38]([NH2:41])[CH2:37][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c2nncn12
Reactant: NC[C@@H](N)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N[C@H](CNc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c2nncn12)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 8-(4-fluorophenyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine (1.0 g, 3.0 mmole), potassium carbonate (1.5 g) and (2S)-3-phenylpropane-1,2-diamine (540 mg, 3.6 mmole) in 50 ml of DMF was stirred at room temperature (RT) for 48 hours. The reaction solution was poured into water (200 mL), and the resulting precipitate was filtered and washed with water. The crude product was purified by flash chromatography (3%-15% MeOH/NH3 in DCM) to provide 1-(8-(4-fluorophenyl)-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidin-5-yl)amino-2(S)-amino-3-phenylpropane was obtained as white solid; MS: m/z (M+H)+ 440.1; C25H22FN7 requir. 439.5.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C@@H:3]([NH:11][C@@H:12]([CH2:16][S:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([OH:15])=O)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.Cl.[NH2:40][C:41]1([C:44]#[N:45])[CH2:43][CH2:42]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:44]([C:41]1([NH:40][C:13](=[O:15])[C@@H:12]([NH:11][C@@H:3]([C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=2)[C:2]([F:1])([F:37])[F:38])[CH2:16][S:17][C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:43][CH2:42]1)#[N:45]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2(R)-[2,2,2-trifluoro-1-(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionic acid (21.58 g, 40 mmol; Reference D) and 1-aminocyclopropane-carbonitrile hydrochloride (OmegaChem, 6.16 g, 52 mmol) in DMF (75 mL) at rt was added DIPEA (Aldrich, 21 mL, 120 mmol) followed by solid HATU (ChemPacific, 19.77 g, 52 mmol) in one portion. This dark, homogeneous solution was allowed to stir at rt for 24 h. The reaction mixture was quenched by addition of 10% NaHCO3 (50 mL), followed by water (100 mL) and then extracted with EtOAc and the combined organics were washed with brine. Following drying over anhydrous MgSO4 and concentration in vacuo, the resulting dark oil was chromatographed on silica gel with 3/1 hex/EtOAc elution to afford a diastereomer mixture (ranging from 5.7/1 to 12/1) of N-(1-cyanocyclopropyl)-2-(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionamide and (9.83 g) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[N:15]1([CH2:20][CH2:21][OH:22])[CH:19]=[CH:18][N:17]=[N:16]1.O>CN(C)C=O>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:22][CH2:21][CH2:20][N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5]
Reactant: OCCn1ccnn1
Reactant: C=CCOc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(COCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
197 mg (8.21 mmol) 95% sodium hydride were given at −50° C. to a solution of 1.00 g (5.47 mmol) 1-allyloxy-4-chloromethyl-benzene and 619 mg (5.47 mmol) 2-(1H-[1,2,3]-triazol-1-yl)-ethanol in 9.0 ml N,N-dimethylformamide (DMF). The mixture was allowed to warm slowly to room temperature (r.t.), stirred overnight and 10 ml water was added. The formed oil was collected with 10 ml dichloromethane, the aqueous phase extracted with 10 ml dichloromethane and the combined organic phases dried over Na2SO4.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH3:14])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Brc1ccnc2ccncc12
Product: CN(C)c1ccnc2ccncc12

Procedure:
Paudler et al., J. Heterocyclic Chem. 2 (4), 393-8 (1965), show the synthesis and NMR spectra of various 4-substituted-1,6-naphthyridines, for example, the reaction of 4-hydroxy-1,6-naphthyridine with POBr3 or POCl3 to obtain 4-bromo-1,6-naphthyridine or 4-chloro-1,6-naphthyridine, respectively. Also shown is the reaction of 4-bromo-1,6-naphthyridine with dimethylamine to produce 4-dimethylamino-1,6-naphthyridine and the reaction 4-chloro-1,6-naphthyridine with piperidine or hydrazine to produce 4-(1-piperidinyl)-1,6-naphthyridine or 4-hydrazino-1,6-naphthyridine, respectively.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][CH2:18][CH2:19][SH:20]>>[C:1]1([NH:7][C:8]2[N:13]=[CH:12][C:11]([CH2:14][S:20][CH2:19][CH2:18][NH2:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(Nc2ccccc2)nc1
Reactant: NCCS
Agent: Cl
Product: NCCSCc1ccc(Nc2ccccc2)nc1

Procedure:
Following the procedure given in part C of Example 3, the title compound was prepared from 6-phenylamino-3-pyridinemethanol and 2-aminoethanethiol hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1.I([O-])(=O)(=O)=[O:26].[Na+]>CO>[CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:26])=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc2c(c1)N(c1ccccc1)C(=O)Cc1nnc(C)n1-2
Agent: [Na+]
Solvent: CO
Product: Cc1nnc2n1-c1ccc(S(C)=O)cc1N(c1ccccc1)C(=O)C2

Procedure:
3.36 g of 1-methyl-8-(methylthio)-6-phenyl-4-H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 2.14 g of sodium metaperiodate in 500 ml methanol is stirred at +5° C for 24 hours. The reaction is evaporated; the residue dissolved in methylene chloride, washed with water, dried and concentrated. The concentrate is chromatographed on silica gel (20-1000μ plates, 20 × 20 cm) using acetone-methanol (9:1) as eluting solvent. The band containing the product is removed, stirred with acetone-methanol (4:1) and the silica gel filtered off. The filtrate is evaporated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=4)=[N:19][C:18]=3[C:17]([O:34][CH3:35])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][CH2:38][CH2:39][NH:40][CH3:41]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([CH2:31][N:40]([CH2:39][CH2:38][O:37][CH3:36])[CH3:41])=[CH:27][CH:26]=4)=[N:19][C:18]=3[C:17]([O:34][CH3:35])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCOC
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Solvent: C1CCOC1
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c3s2)cc1
Temperature: 70 °C
Yield: 82.1 %

Procedure:
To a solution of 0.30 g (0.58 mMol) 4-[2-(4-chloromethyl-benzoylamino)-4-methoxy-benzothiazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 10 ml THF were added 0.16 g (1.75 mMol) N-(2-methoxyethyl)-methyl amine. The reaction mixture was heated to 70° C. for 5 h. The solvent was evaporated to dryness, the residue taken up in ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (dichloro methane/methanol 19:1) to yield 0.27 g (82%) of 4-[4-methoxy-2-(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzoylamino)-benzothiazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a white foam. ES-MS m/e (%): 567 ([M+H]+, 100).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:8]([O:24][CH3:25])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:8]([O:24][CH3:25])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH:23][C:38]([NH:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:39])=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(N)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)Nc4ccccc4)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 80 °C
Yield: 50.4 %

Procedure:
To an opaque yellow solution of 7-amino-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide (see Example 1) (30 mg, 0.07 mmol) in acetonitrile was added phenyl isocyanate (10 μL, 0.9 mmol). The reaction was heated to 80° C. for 12 h in a sealed tube, then cooled to room temperature. The product precipitated out directly to provide 20 mg (50%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([OH:24])=O)[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:25]=1.CN(C1C=CC=CN=1)C.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.[CH2:49]([O:51][C@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1)[CH3:50].C(O[C@H]1CCNC1)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([N:54]4[CH2:55][CH2:56][C@H:52]([O:51][CH2:49][CH3:50])[CH2:53]4)=[O:24])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:25]=1
Reactant: CCO[C@H]1CCNC1
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Agent: CN(C)c1ccccn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCO[C@H]1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2cc(Cl)ccc2CC3)C1
Reaction time: 3 h
Yield: 85 %

Procedure:
A suspension of 8.79 g (25 mmol) of 10-chloro-4-oxo-3-phenyl-6,7-dihydro-4H-benzo[a]quinolizine-1-carboxylic acid (X) in 125 ml of ethyl acetate was treated with 0.076 g (0.625 mmol) of dimethylaminopyridine and 3.49 g (27.5 mmol) of oxalyl chloride. The mixture was then stirred at 600 for 3 hours. The yellow solution (XI) was concentrated and the residue was taken up in 125 ml of toluene. This was treated either with 5.26 g (52 mmol) of triethylamine and 3.94 g (26 mmol) of (S)-3-ethoxypyrrolidine hydrochloride or with 2.63 g (26 mmol) of triethylamine and 3.0 g (26 mmol) of (S)-3-ethoxypyrrolidine and stirred for 4 hours. Subsequently, the solution was washed in succession with 100 ml of water, 100 ml of 1N HCl, 100 ml of 0.5N KHCO3 and then again with 100 ml of water. The individual aqueous phases were extracted with 100 ml of toluene and the combined organic extracts were dried with 20 g of Na2SO4. The residue obtained after filtration and concentration was dried at 50°/0.1 mbar/2 h. Compound I was obtained in 85% yield, based on the acid, after purification by recrystallization from acetone/water and acetone/hexane. M.p. 133°-134°.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH:6]([CH3:8])[CH:5]([CH3:9])[O:4]1.[CH3:10][C:11]([NH2:15])([CH3:14])[C:12]#[CH:13].[OH-].[Na+]>O>[CH3:10][C:11]([NH:15][CH2:2][CH:3]1[O:7][CH:6]([CH3:8])[CH:5]([CH3:9])[O:4]1)([CH3:14])[C:12]#[CH:13]
Reactant: C#CC(C)(C)N
Reactant: CC1OC(CBr)OC1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CC(C)(C)NCC1OC(C)C(C)O1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-4,5-dimethyl-1,3-dioxolane (20 grams) and 1,1-dimethylprop-2-ynylamine (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) is added and the resulting mixture is stirred for a period of about 30 minutes. The reaction mixture is then extracted with ether. The ether extract is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product N-(1,1-dimethylprop-2-ynyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)amine.