Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8](Br)[CH:9]=1)=[O:4].[Br:14][C:15]1[CH:16]=[C:17]([S:22][OH:23])[CH:18]=[N:19][C:20]=1[Cl:21].CN(C=[O:28])C>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([S:22]([C:17]2[CH:18]=[N:19][C:20]([Cl:21])=[C:15]([Br:14])[CH:16]=2)(=[O:28])=[O:23])[CH:9]=1)=[O:4]
Reactant: CN(C)C=O
Reactant: OSc1cnc(Cl)c(Br)c1
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c([N+](=O)[O-])s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester (5.0 g, 19.9 mmol) was dissolved into DMF (20 mL) and cooled to 0° C. To this was added a solution of 5-bromo-6-chloro-pyridine-3-sulphenic acid (Example 118, step a) (1.8 g, 6.6 mmol) in DMF (20 mL) dropwise for 2 hours. The reaction was then warmed to RT and allowed to continue to stir for an additional 2 hours. The reaction was concentrated in vacuo and purified by SiO2 flash column chromatography (Biotage—40 M, 25% EtOAc in hexanes). The product was isolated as a white solid (2.5 g, 48%). ESI-MS (m/z): Calcd. for C11H6BrClN2O6S2: 440.8 (M+H); found: 441.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([F:9])[CH:4]=1.[C:10]([O-:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].CCOCC>CN(C=O)C>[F:9][C:5]1[CH:4]=[C:3]([CH2:2][O:18][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: Fc1cc(CBr)ccn1
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(OCc1ccnc(F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
The mixture of 4-Bromomethyl-2-fluoro-pyridine (35) (4.85 g, 25.5 mmol) and sodium benzoate (5.51 g, 38.25 mmol) in DMF (60 ml) was stirred at room temperature for 3 hr. Ether was then added and the mixture was washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexane (1:4)) to afford 4.68 g (79%) of a colorless oil; 1H NMR (200 MHz, CDCl3) δ: 5.41 (2H, s), 7.11 (1H, m), 7.45-7.66 (3H, m), 8.08-8.12 (2H, m), 8.23 (1H, d, J=5.4 Hz); m/z (EI): 231 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:21]#[N:22])([CH3:20])[CH3:19])[N:13]=2)[CH:3]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:21]#[N:22])([CH3:20])[CH3:19])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C#N)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C(C)(C)C#N)n2)c(C(N)=O)nn1
Temperature: 120 °C
Reaction time: 18 h
Yield: 35.2 %

Procedure:
A resealable pressure tube was charged with 6-chloro-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (200 mg, 631 μmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (135 mg, 631 μmol) in NMP (2.00 mL). The reaction mixture was heated in an oil bath with stirring at 120° C. for 18 h. Then added more tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (135 mg, 631 μmol) in small portions during 7 hours and reaction continued for 18 h. The solvent was distilled off under high vacuum. The residue was dissolved in dichloromethane containing few drops of methanol and then purified by flash column (spherical silica 20-45 μM, 50 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to yield tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (110 mg, 222 μmol, 35.2% yield) as a yellow foam. 1H NMR (CHLOROFORM-d) δ: 11.48 (s, 1H), 8.82 (br. s., 1H), 8.00-8.11 (m, 1H), 7.62 (t, J=7.9 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 5.53-5.85 (m, 2H), 5.06 (d, J=8.3 Hz, 1H), 4.47 (br. s., 1H), 3.80-3.99 (m, 1H), 1.24-1.93 (m, 23H); LC-MS 495.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]#[N:16].[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C.O>[Br:1][C:2]1[C:3]([NH:9][C:15]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)=[NH:16])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: N#Cc1cccs1
Reactant: Nc1ncc(Br)nc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: N=C(Nc1ncc(Br)nc1Br)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A stirred solution of 3,5-dibromo-pyrazin-2-ylamine (500 mg, 1.98 mmol), thiophene-2-carbonitrile (260 uL, 2.04 mmol) and AlCl3 (232 mg, 1.74 mmol) in dichloroethane (5 ml) was heated at 115° C. overnight. The mixture was allowed to cool to room temperature and diluted with water (5 mL). After 30 minutes, the resulting precipitate was collected and purified by column chromatography (SiO2, THF) to afford 488 mg (68%) of N-(3,5-dibromo-pyrazin-2-yl)-thiophene-2-carboxamidine as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.22 (t, J=3.9 Hz, 1H), 7.83 (dd, J=4.8 Hz, 1H), 7.99 (d, J=4.1 Hz, 1H), 8.49 (s, 1H), 8.88 (br. s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)=[N:8]2)[CH2:5][CH2:4][NH:3]1.[H-].[Na+].[C:31]([O:35][C:36]([CH:38]=C1CCCCCC1N1C(=O)C=CC(C2C(C3C=CC=CC=3)=NN3C=CC=CC=23)=N1)=[O:37])(C)(C)[CH3:32].BrCC(OCC)=O>CN(C)C=O.O>[CH2:31]([O:35][C:36]([CH2:38][N:3]1[CH2:4][CH2:5][CH:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)=[N:8]2)[C:2]1=[O:1])=[O:37])[CH3:32]
Reactant: CC(C)(C)OC(=O)C=C1CCCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: O=C1NCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1=O
Reaction time: 0.5 h
Yield: 633.2 %

Procedure:
To a solution of 3-[2-(2-oxopyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (740 mg) in N,N-dimethylformamide (5 ml) was added 60% sodium hydride in mineral oil (120 mg) at O° C. After the mixture was stirred for 30 minutes, to this was added ethyl 2-bromoacetate (0.22 ml). After the reaction mixture was stirred at 0° C. for 1 hour, it was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (CHCl3 -CHCl3 :MeOH (30:1)) to give 3-[2-(1-ethoxycarbonylmethyl-2-oxopyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.7 g) (yellow oil).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1(O)[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:5]([O:7][CH3:8])=[O:6].[OH:20]C1C2C(=CC=CC=2)C=CC=1C(=O)C(OC)=O.Cl.CON>CO>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(=O)c1ccc2ccccc2c1O
Reactant: CON=C(C(=O)OC)C1(O)C=Cc2ccccc2C1
Agent: CON
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccc2ccccc2c1O
Yield: 77 %

Procedure:
Preparation of methyl 2-hydroxy-2-naphthylglyoxylate O-methyl oxime ##STR53## 69 g (0.26 mol) of methyl 1-hydroxy-2-naphthylglyoxylate and 44 g (0.53 mol) of O-methylhydroxylamine hydrochloride are introduced into 800 ml of methanol and heated to reflux temperature for 6 h with stirring. The mixture is then concentrated, the residue is taken up in ethyl acetate, and the solution is washed with H2O, dried over sodium sulfate and concentrated again. 52 g (0.20 mol) of methyl 1-hydroxy-2-naphthylglyoxylate O-methyl oxime are obtained (77% yield).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17](=[N:19][OH:20])[NH2:18])=[C:4]2[CH2:3]1.[Cl:21][CH2:22][C:23](OC(=O)CCl)=O>CN(C)C=O>[Cl:21][CH2:22][C:23]1[O:20][N:19]=[C:17]([C:16]2[N:15]=[CH:14][N:5]3[C:6]4[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=4[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=23)[N:18]=1
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2ccccc2C1=O
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Yield: 70.5 %

Procedure:
4.60 g (16.95 mmol) 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime were stirred with 3.19 g (18.65 mmol) of chloroacetic anhydride in 25 ml of N,N-dimethylformamide at room temperature for 30 minutes and at 105° for 2 hours. The reaction mixture was evaporated, the residue was dissolved in methylene chloride and the solution was washed with saturated sodium bicarbonate solution. After drying over magnesium sulfate the solution was concentrated and the crystalline residue was chromatographed on silica gel while eluting with ethyl acetate. There were obtained 3.94 g (70%) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 208°-209°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([CH2:20][O:21][C:6]=2[CH:5]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].Br[C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2C=1C1(C3=CC4OCOC=4C=C3OC1)[C:28](=O)[NH:29]2.Br.BrCC1C=NC=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:33]([CH2:25][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]3([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][C:6]=4[O:21][CH2:20]3)[C:11]2=[O:19])[CH:28]=1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Agent: Br
Agent: BrCc1cccnc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cccnc2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using 6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-(pyridin-3-ylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained, which was treated with 4.0 M HCl in dioxane to give the title compound (70%) as a white solid: mp 151-153° C.; 1H NMR (300 MHz, CD3OD) δ 9.07-8.61 (m, 3H), 8.19-8.04 (m, 1H), 7.42-6.71 (m, 7H), 5.28 (s, 2H), 5.05 (d, 1H), 4.86 (d, 1H); 13C NMR (75 MHz, CD3OD) δ 179.43, 163.5, 151.8, 147.0, 142.9, 142.4, 142.2, 133.0, 130.6, 129.3, 128.9, 125.5, 125.4, 125.3, 114.9, 110.5, 104.9, 82.0, 58.9, 42.0; MS (ES+) m/z 413 (M+1).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.CN(C(ON1N=[N:28][C:23]2[CH:24]=[CH:25][CH:26]=[N:27][C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:37](N(CC)C(C)C)(C)[CH3:38]>CN(C=O)C>[N:27]12[CH2:26][CH2:25][CH:24]([CH2:37][CH2:38]1)[C@@H:23]([NH:28][C:10]([C:2]1[S:1][C:9]3[C:4](=[N:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=1)=[O:12])[CH2:22]2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc2ncccc2s1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ncccc2s1

Procedure:
35 mg (0.20 mmol) of thieno[3,2-b]pyridine-2-carboxylic acid, 58.3 mg (0.29 mmol) of R-3-aminoquinuclidine dihydrochloride, 111.4 mg (0.29 mmol) of HATU, 138.8 mg (1.07 mmol) of N,N-diisopropylethylamine and 1.5 ml of DMF are reacted according to the general procedure (variant A). The reaction mixture is purified by preparative
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:13]([C:17]1[S:21][C:20](=[NH:22])[N:19]([CH2:23][CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)[CH:18]=1)([CH3:16])([CH3:15])[CH3:14].N>>[C:13]([C:17]1[S:21]/[C:20](=[N:22]\[C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])/[N:19]([CH2:23][CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)[CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC(Cn2cc(C(C)(C)C)sc2=N)C1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: N
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CC1CN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared according to the procedure described in Example 54A by substituting 5-chloro-2-methoxybenzoic acid for Example 26B and the product of Example 63A for Example 16A. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.34 (s, 9H) 1.44 (s, 9H) 3.10-3.30 (m, 1H) 3.77 (dd, J=9.12, 5.16 Hz, 2H) 3.90 (s, 3H) 4.05 (t, J=8.53 Hz, 2H) 4.37 (s, 2H) 6.63 (s, 1H) 6.91 (d, J=8.73 Hz, 1H) 7.33 (dd, J=8.72, 2.78 Hz, 1H) 7.89 (d, J=2.78 Hz, 1H). MS (DCI/NH3) m/z 494.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:6]([NH:16][C:17](=O)[CH2:18][C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[CH:5]=1.Cl.O>O1CCOCC1>[CH2:12]([CH:11]([N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:25])=[CH:5][C:6]=2[N:16]=[C:17]1[CH2:18][C:19]1[O:23][N:22]=[CH:21][CH:20]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cc1ccno1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCC(CC)n1c(Cc2ccno2)nc2cc(C(=O)O)ccc21
Temperature: 130 °C
Yield: 88.4 %

Procedure:
To 1.06 g 4-(1-Ethyl-propylamino)-3-(2-isoxazol-5-yl-acetylamino)-benzoic acid methyl ester were added 7.5 ml of 4M hydrochloric acid in dioxane. The reaction mixture was heated to 130° C. for 20 min in a microwave reactor. After cooling to rt 2 ml of water were added and the reaction was again heated to 130° C. for 20 min. The reaction was concentrated and the residue purified by chromatography (silica, ethyl acetate/heptane) to yield 0.85 g (90%) of 1-(1-Ethyl-propyl)-2-isoxazol-5-ylmethyl-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.CN(C=O)C.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[CH3:20]
Reactant: CCNCC
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)c1cc(C)c2nnc(N)n2n1
Reaction time: 264 h

Procedure:
6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 250 mg) was dissolved in abs. DMF (2 ml) and admixed with diethylamine (7 ml). Thereafter, the reaction mixture was placed into a heating block at 80° C. with stirring for 11 days. The solvent was then drawn off and the residue was admixed with a little water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (met. A), and the clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 100 mg of the title compound were obtained.
Reaction SMILES: C([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=2)[CH:8]=1)=[O:6])(C)C.Br[C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[CH:31][CH:32]=1.BrC1C=NC2C(C=1)=CC=CC=2>>[O-:33][N+:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:25]#[C:24][C:20]2[CH:19]=[C:18]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][N:11]=4)[C:16](=[O:17])[C:7]([C:5]([NH2:4])=[O:6])=[CH:8]3)[CH:23]=[CH:22][CH:21]=2)[CH:28]=1
Reactant: [O-][n+]1cccc(Br)c1
Reactant: C#Cc1cccc(-n2cc(C(=O)NC(C)C)c(=O)c3cccnc32)c1
Agent: Brc1cnc2ccccc2c1
Product: NC(=O)c1cn(-c2cccc(C#Cc3ccc[n+]([O-])c3)c2)c2ncccc2c1=O

Procedure:
Following the procedure of example 19, but substituting the 1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin4-one-3-carboxamide from Step 3 for N-Isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and 3-bromopyridine N-oxide for 3-bromoquinoline, the 1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin4-one-3-carboxamide was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[Br:17][C:18]1[C:19]([Cl:29])=[C:20]([CH2:25][C:26](Cl)=[O:27])[C:21]([Cl:24])=[CH:22][CH:23]=1>C(#N)C>[Br:17][C:18]1[C:19]([Cl:29])=[C:20]([CH2:25][C:26]([NH:1][C:2]2[N:3]=[CH:4][S:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[O:27])[C:21]([Cl:24])=[CH:22][CH:23]=1
Reactant: COC(=O)c1scnc1N
Reactant: O=C(Cl)Cc1c(Cl)ccc(Br)c1Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1scnc1NC(=O)Cc1c(Cl)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.8 %

Procedure:
2.0 g (12.64 mmol) of methyl 4-amino-1,3-thiazole-5-carboxylate were dissolved in 20 acetonitrile, and 2.05 ml (25.29 mmol) of pyridine were added. After 5 min of stirring at room temperature, a solution of 4.21 g (13.91 mmol) of (3-bromo-2,6-dichlorophenyl)acetyl chloride (obtained from (3-bromo-2,6-dichlorophenyl)acetic acid, see WO9736868) in 10 ml of acetonitrile was added dropwise. The reaction mixture was stirred at RT for 12 h. The precipitate formed was filtered off, washed with water and dried under reduced pressure. The resulting mother liquor was concentrated by evaporation, dissolved in chloroform and chromatographed (ethyl acetate/n-heptane: 20/80 to 80/20). This gives a total of 4.01 g of methyl 4-{[(3-bromo-2,6-dichlorophenyl)acetyl]amino}-1,3-thiazole-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH2:22][CH2:23][C:24]#[N:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([NH:25][CH2:24][C:23]#[N:22])=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: N#CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)NCC#N)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 34.3 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), 2-aminoacetonitrile (3.64 mg, 0.065 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (3.8 mg, 33.8%). 1H NMR (400 MHz, CD3OD) δ 0.85-0.97 (m, 3 H) 1.02 (d, J=6.57 Hz, 1 H) 1.07 (d, J=6.32 Hz, 2 H) 2.53 (dt, J=11.18, 6.54 Hz, 1 H) 3.52-3.86 (m, 2 H) 4.89-5.04 (m, 1 H) 5.07 (d, J=11.37 Hz, 1 H) 5.51 (d, J=10.86 Hz, 1 H) 7.80-7.89 (m, 1 H) 8.13-8.34 (m, 1 H). [M+H] calc'd for C16H16ClN5O2, 346; found, 346.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>ClCCl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[F:30])(=[O:39])=[O:38])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2F)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.36 mmol) and pyridine (114 mg, 1.44 mmol) in anhydrous dichloromethane (5 mL) was added 2-fluorobenzene-1-sulfonyl chloride (70.1 mg, 0.36 mmol) at ice-bath. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give N-(2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)phenyl)-2-fluorobenzenesulfonamide. LC/MS m/e obsd. (ESI+) [(M+H)+] 478.90.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][C:9]([C:16]([OH:18])=[O:17])=[CH:8]2.[NH:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>O>[ClH:1].[CH3:20][N:19]([CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][C:9]([C:16]([OH:18])=[O:17])=[CH:8]2)[CH3:21]
Reactant: COc1cc2[nH]c(C(=O)O)cc2cc1OCCCl
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2[nH]c(C(=O)O)cc2cc1OCCN(C)C
Product: Cl
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
A mixture of acid 18 (300 mg, 1.11 mmol), 40% aqueous Me2NH (2.81 mL, 22.2 mmol), Na2CO3 (295 mg, 2.78 mmol), and water (20 mL) was stirred at 100° C. for 1.5 h. After cooling to room temperature the solvent was removed in vacuo, the residue was dissolved in water (15 mL), and the resulting solution was acidified with 2 M HCl. Then, the solution was evaporated to dryness and the resulting crude product was purified by column chromatography on silica gel (MeOH/CH2Cl2, 10:1, 1% conc. HCl) to provide a green solid which was dissolved in water. Insoluble silica gel was removed by filtration, the water was removed under reduced pressure and the residue was dried in vacuo to give 19 (343 mg, 98%) as a grey-green solid. 1H NMR (300 MHz, DMSO-d6): δ=2.87 (s, 6 H, NMe2), 3.49 (t, J=5.0 Hz, 2 H, 2′-H2), 3.82 (s, 3 H, OMe), 4.34 (t, J=5.0 Hz, 2 H, 1′-H2), 6.94 (s, 1 H, 7-H), 6.97 (d, J=1.8 Hz, 1 H, 3-H), 7.23 (s, 1 H, 4-H), 10.99 (sbr, 1 H, NH+), 11.50 (sbr, 1 H, NH), 12.60 (sbr, 1 H, CO2H) ppm; 13C NMR (50.3 MHz, DMSO-d6): δ=42.7 (NMe2), 55.2 (C-2′), 55.6 (OMe), 64.5 (C-1′), 94.8 (C-7), 106.2 (C-4), 107.5 (C-3), 119.7 (C-3a), 127.0 (C-2), 133.2 (C-7a), 143.4 (C-5), 149.4 (C-6), 162.4 (C═O) ppm; MS (70 eV, EI): m/z (%)=278 (7) [M−HCl]+, 58 (100) [CH2NMe2]+; C14H19ClN2O4 (314.76): calcd. 278.1267 [M−HCl]+, found 278.1267.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][CH:19]([O:27][CH3:28])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[OH:26]>CC#N>[CH3:28][O:27][CH:19]([O:18][CH3:17])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[O:26][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CBr)nc1
Reactant: COC(OC)c1ccncc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(OC)c1ccncc1OCc1ccc(C#N)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 6-(bromomethyl)pyridine-3-carbonitrile (3 g, 15.23 mmol, 1.00 equiv) in CH3CN (100 mL). Potassium carbonate (4.24 g, 30.68 mmol, 2.00 equiv) and 4-(dimethoxymethyl)pyridin-3-ol (2.83 g, 16.73 mmol, 1.10 equiv) were added to the reaction mixture. The resulting solution was stirred for 2 h at 50° C., and then it was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) as eluent to furnish 1.4 g (32%) of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carbonitrile as a red solid.