Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[N:11]\[OH:12]
Reactant: O=Cc1cccc(F)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O/N=C\c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a suspension of 3-fluorobenzaldehyde (6.75 g, 54 mmol) and hydroxylamine hydrochloride (4.16 g, 60 mmol) in ethanol (4.3 mL) and water (13 mL) was added ice (25 g). Then a solution of sodium hydroxide (5.5 g, 138 mmol) in water (6.5 mL) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 30 min stirring at room temperature a white solid precipitated and the resulting mixture was then diluted with water and acidified with HCl (4 N). The white precipitate was then filtered off, washed with water and dried under high vacuum to afford the title compound (7.0 g, 93%) which was obtained as a white solid. MS m/e (EI): 139.1 [M].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:21])=[N:7][C:8]2[CH:9]=[C:10]3[O:20][CH2:19][CH2:18][O:17][C:11]3=[CH:12][C:13]=2[C:14]=1[CH2:15]Cl)=[O:4].C(Cl)Cl.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:21])=[N:7][C:8]2[CH:9]=[C:10]3[O:20][CH2:19][CH2:18][O:17][C:11]3=[CH:12][C:13]=2[C:14]=1[CH2:15][N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)=[O:4]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1c(Cl)nc2cc3c(cc2c1CCl)OCCO3
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(Cl)nc2cc3c(cc2c1CN1CCN(C)CC1)OCCO3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 4-necked 5-L round-bottom flask is equipped with a mechanical stirrer and 250-mL addition funnel. Under nitrogen, the flask is charged with 7-chloro-9-chloromethyl-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester (Intermediate 6, 340 g, 1.04 mol), and methylene chloride (2L). To the stirred solution is added N-methylpiperazine (237 mL, 2.14 mol) over 10 min. After the addition is complete, the reaction mixture is stirred at ambient temperature for 15 h. The reaction mixture is poured into water (3 L) and the organic layer is separated. The aqueous layer is extracted with methylene chloride (3×2 L). The combined organic layers are washed with brine (2 L), dried over anhydrous sodium sulfate and concentrated in vacuo. The resultant thick brown slurry is successively treated with methylene chloride (300 mL) and hexane (1.5 L). The mixture is swirled at 0° C. for 30 min. The precipitate is collected on a Buchner funnel, washed with hexane (1 L) and dried in vacuo. at 30° C. yielding 7-chloro-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro[1,4]dioxino [2,3-g]quinoline-8-carboxylic acid methyl ester as a yellow powder: mp 143 ° C. 1H NMR (CDCl3, 200 MHz) d 2.28 (s, 3H), 2.38-2.49 (m, 8H), 3.81 (s, 2H), 3.96 (s, 3H), 4.59 (s, 2H), 4.40 (s, 4H), 7.45 (s, 1H), 1H). Elemental analysis: Calculated for C19H22CIN3O4: C 58.24, H 5.66, N 10.72. Found: C 58.08, H 5.72, N 10.63.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH:19]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:20][C:21]#[N:22])[CH:18]=3)[N:11]3[CH:29]=[CH:30][N:31]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C1C[O:35][CH2:34][CH2:33]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(=O)(O)[O-].[Na+].CCOC(C)=O>[C:34]([N:26]1[CH2:27][CH2:28][CH:23]([CH:19]([N:17]2[CH:18]=[C:14]([C:12]3[N:11]4[CH:29]=[CH:30][N:31]=[C:10]4[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=4)[N:13]=3)[CH:15]=[N:16]2)[CH2:20][C:21]#[N:22])[CH2:24][CH2:25]1)(=[O:35])[CH3:33]
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CCNCC4)c3)n2)cn1
Reactant: C1CCOC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(CC#N)n2cc(-c3nc(-c4cnn(C)c4)cc4nccn34)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-(piperidin-4-yl)propanenitrile hydrochloride (10.0 mg, 0.021 mmol) was suspended in THF (211 μL, 0.0211 mmol). To this was added triethylamine (8.81 DIPHOS, 0.0632 mmol) to free-base. Acetic anhydride (2.38 μL, 0.0253 mmol) was added and the reaction mixture stirred at ambient temperature for 30 minutes. The reaction mixture was then diluted in saturated sodium bicarbonate and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated in vacuo. Purification of the resulting crude material by reverse phase HPLC using 0-100% acetonitrile/water gradient afforded the title compound (7.2 mg, 77% yield). MS (apci) m/z=444.3 (M+H).
Reaction SMILES: C(OC([N:8]([C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([F:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.ClC1C2C=CC=C(S(Cl)(=O)=[O:42])C=2C(F)=CN=1.ClC1C2C=CC=C(S(Cl)(=O)=O)C=2C(Br)=CN=1>>[OH:42][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([F:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(F)c23)C1
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)ncc(F)c12
Agent: O=S(=O)(Cl)c1cccc2c(Cl)ncc(Br)c12
Product: CN[C@H]1CCN(S(=O)(=O)c2cccc3c(O)ncc(F)c23)C1
Product: Cl

Procedure:
(S)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-1-(1-chloro-4-fluoro-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 27a) can be prepared by using 1-chloro-4-fluoro-5-isoquinolinesulfonyl chloride in the method of Example 35-1, Step A instead of 1-chloro-4-bromo-5-isoquinolinesulfonyl chloride, and then used in the method of Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:9]1[N:10]([CH2:23][CH2:24]O)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:21])[C:12]=2[N:22]=1)[CH2:6][CH2:7][CH3:8].CN(C)C=O>C1(C)C=CC=CC=1>[CH2:5]([C:9]1[N:10]([CH2:23][CH2:24][Cl:3])[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:21])[C:12]=2[N:22]=1)[CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCO
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCl
Yield: 76.5 %

Procedure:
Thionyl chloride (3.8 g, 32 mmol) was added to a solution of 2-butyl-1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.7 g, 13 mmol) in toluene containing a catalytic amount of N,N-dimethylformamide. The reaction mixture was heated to reflux and then capped. When analysis by high performance liquid chromatography indicated that the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in warm methanol and then combined with concentrated ammonium hydroxide (5 mL). The mixture was chilled. The resulting precipitate was isolated by filtration, washed with cold methanol and then dried under vacuum overnight to provide 3.01 g of 2-butyl-1-(2-chloroethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([C:6]([Cl:9])=[CH:7][CH:8]=1)[NH2:5].[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][CH3:17])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: COS(=O)(=O)OC
Reactant: Nc1c(Cl)ccc(Br)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1c(Cl)ccc(Br)c1F
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 65.3 %

Procedure:
3-Bromo-6-chloro-2-fluoroaniline (1.2 g, 5.2 mmol) was dissolved in THF (12 mL) in a 100 mL round bottomed flask and treated with tetra-N-butyl ammonium bromide (0.015 g, 0.05 mmol) and powdered sodium hydroxide (0.83 g, 20.9 mmol) with stirring. After 5 minutes, the dark mixture was treated with dimethyl sulfate (1.3 g, 10.4 mmol) and the mixture heated at 60° C. for 2 hours. Analysis by TLC (hexanes: ethyl acetate/20:1) indicated some starting material remained. Added additional dimethyl sulfate (0.66 g, 5.2 mmol) and continued heating for 1.5 hour then stirred at room temperature overnight. The reaction was partitioned between diethyl ether and water and the layers separated and the aqueous phase extracted with ether. The combined ether layers were washed with water and dried (MgSO4). Filtration, concentration and purification by flash silica gel chromatography (hexanes) gave N-(3-bromo-6-chloro-2-fluorophenyl)-N-methylamine (0.81 g) as a colorless oil: 1H NMR (300 MHz, CDCl3): δ 6.93 (dd, 1H, J=8.4), 6.83 (dd, 1H), 4.00 (bs, 1H), 3.09 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[O:11])=[CH:4][CH:3]=1.Cl.Cl.[F:30][C:31]([F:41])([F:40])[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:14](=[O:15])[NH:16][CH2:17][C:18](=[O:20])[N:37]2[CH2:36][CH2:35][N:34]([CH2:33][CH2:32][C:31]([F:40])([F:41])[F:30])[CH2:39][CH2:38]2)=[O:11])=[CH:6][CH:7]=1
Reactant: FC(F)(F)CCN1CCNCC1
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccn1)NC(=O)/C=C/c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(Cl)cc1)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(CCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a mixture of [[(2S)-2-[[(2E)-3-(4-chlorophenyl)-2propenoyl]amino]-3-(2-pyridyl)propanoyl]amino]acetic acid (38.8 g), 1-(3,3,3-trifluoropropyl)piperazine dihydrochloride (25.5 g), 1-hydroxybenzotriazole (14.9 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.1 g) in N,N-dimethylformamide (250 ml) was added dropwise N,N-diisopropylethylamine (38.3 ml) at 10° C. over 50 minutes. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ice-cold saturated aqueous sodium hydrogencarbonate solution (750 ml). The mixture was extracted three times with ethyl acetate (total 2500 ml) and washed successively with water (500 ml×3) and brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent; 12% methanol in ethyl acetate) to give the title compound (37.0 g) as a white amorphous solid, which was recrystallized from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=2[O:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: COc1ccc(Nc2nc(Cl)nc3ccccc23)c(OC)c1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 2,4-dimethoxyaniline by a procedure similar to example 28 (92% yield). 1H NMR (CDCl3): 8.59 (d, J=8.7 Hz, 1H), 8.22 (s, broad, 1H), 7.75-7.81 (m, 3H), 7.52 (ddd, J=8.4, 6.6 and 2.1 Hz, 1H), 6.52-6.59 (m, 2H), 3.95 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O:12]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]=O)=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1.N1CCCCC1.C(O)(=O)C>CC(O)C>[C:10]([CH2:9][CH2:8][O:7][C:1](=[O:6])[C:2](=[CH:22][C:20]1[CH:19]=[CH:18][C:17]2[O:12][CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)[C:3](=[O:4])[CH3:5])#[N:11]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CC(=O)CC(=O)OCCC#N
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc2c(c1)OCCO2)C(=O)OCCC#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-cyanoethyl acetoacetate (5.00 g, 32.2 mmol), 1,4-benzodioxan-6-carboxaldehyde (5.29 g, 32.2 mmol), piperidine (137 mg, 1.61 mmol) and acetic acid (97 mg, 1.6 mmol) in 70 ml of 2-propanol was stirred at r.t. for 48 hrs. After evaporation of solvent, the product was purified by chromatography (SiO2, AcOEt: Hexane, 60:10). 2-[(3,4-Ethylenedioxyphenyl)methylene]-3-oxobutanoic acid 2-cyanoethyl ester was obtained as a yellowish oil (2.64 g, 27% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.CC#[N:16]>>[Cl:1][C:2]1[C:7]([C:8]([NH2:16])=[O:9])=[C:6]([F:11])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC#N
Product: COc1ccc(Cl)c(C(N)=O)c1F
Yield: 85 %

Procedure:
Synthesised from commercially available 6-chloro-2-fluoro-3-methoxybenzenecarboxylic acid according to Method A, scheme 1. Yield 85%, mp 154-156° C., HPLC-MS (method 1): m/z 245 [M+H+CH3CN]+, Rt=2.37 min.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9](=[O:38])[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH:26]=3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:6]=[CH:5][N:4]=1.C(N(CC)C(C)C)(C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50].[O:53]1[CH2:58][CH2:57]OCC1>>[CH3:2][C:3]1[CH:8]=[C:7]([C:9](=[O:38])[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:26][CH2:27][NH:28][C:58](=[O:53])[CH:57]=3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:6]=[CH:5][N:4]=1.[CH3:48][S:49]([N:28]1[CH2:27][CH:26]=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([CH3:2])[CH:8]=3)=[O:38])=[CH:20][CH:21]=2)[CH2:30][CH2:29]1)(=[O:51])=[O:50]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc2C)ccn1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)C[C@H](c2ccc(C3=CC(=O)NCC3)cc2)c2ccccc2C)ccn1
Product: Cc1cc(C(=O)C[C@H](c2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2C)ccn1
Yield: 16 %
Yield: 35 %

Procedure:
Hydrogen chloride solution (4 M in 1,4-dioxane, 1.5 mL, 6.0 mmol) was added at room temperature to a solution of (R)-tert-butyl 4-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolyl-propyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (example 372, step 1; 200 mg, 403 μmol) in 1,4-dioxane (4 mL), then after 2 h the reaction mixture was evaporated. The residue was suspended in dichloromethane (8 mL), then treated with N,N-diisopropylethylamine (312 mg, 2.42 mmol) and methanesulfonyl chloride (92 mg, 805 μmol) at 0° C. The ice bath was removed, then after 16 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient, then dichloromethane-methanol 9:1) gave the title compound (27 mg, 16%; light brown foam, MS (ESI+): m/z=411.2 ([M+H]+)) and (R)-3-[4-(1-methane sulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (66 mg, 35%).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:8]1[CH:13]=[C:12]([C:14](=O)[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)[CH:5]([CH3:7])[CH3:6].CO>O.[OH-].[Na+]>[CH2:4]([C:8]1[CH:13]=[C:12]([C:14](=[N:2][OH:3])[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: CC(=O)c1cc(C)nc(CC(C)C)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NO)c1cc(C)nc(CC(C)C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A solution of hydroxylamine hydrochloride (120 mg, 1.732 mmol) in water (0.5 mL) and 1 N aq. NaOH (1.2 mL) is added to 1-(2-isobutyl-6-methyl-pyridin-4-yl)-ethanone (276 mg, 1.44 mmol). The solution is stirred at 80° C. for 2 h, MeOH is added to maintain homogeneity of the mixture. The mixture is cooled to rt and the precipitate that forms is collected, washed with water and dried in vacuo to give 1-(2-isobutyl-6-methyl-pyridin-4-yl)-ethanone oxime (258 mg) as a white solid; 1H NMR (D6-DMSO): δ 0.88 (d, J=6.5 Hz, 6 H), 1.98-2.10 (m, 1 H), 2.13 (s, 3 H), 2.45 (s, 3 H), 2.56 (d, J=7.0 Hz, 2 H), 7.22 (s, 1 H), 7.27 (s, 1 H), 11.54 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:13])[C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:21][OH:22].CN([CH:26]=[O:27])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[CH:10]1([CH2:9][O:8][C:5]2[C:4]([F:13])=[CH:3][C:2]([C:21]([O:27][CH3:26])=[O:22])=[CH:7][N:6]=2)[CH2:12][CH2:11]1
Reactant: Fc1cc(Br)cnc1OCC1CC1
Reactant: CN(C)C=O
Reactant: CO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cnc(OCC2CC2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-2-(cyclopropylmethoxy)-3-fluoropyridine (2.49 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (832 mg), triethylamine (2.82 mL), methanol (2 mL) and DMF (20 mL) was stirred overnight at 80° C. under a carbon monoxide atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.75 g).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19]([O:21]C)=[O:20])#[N:2].[OH-].[Li+].O>CO.Cl>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19]([OH:21])=[O:20])#[N:2]
Reactant: COC(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1c(C(=O)O)n(-c2cccc(F)c2)c2ccccc12
Yield: 97.3 %

Procedure:
Methyl 3-cyano-1-(3-fluorophenyl)-1H-indole-2-carboxylate (0.13 g, 0.44 mmol) was treated with 1.0 M lithium hydroxide in water (0.66 mL, 0.66 mmol) in methanol (3 mL) at room temperature for 3 hours. The reaction was diluted with 1 N HCl and extracted with EtOAc. The extracts were combined, washed with brine, dried over MgSO4 and concentrated to give the desired acid (0.12 g, 97%). LCMS calculated for C16H10FN2O2(M+H)+: m/z=281.1. Found: 281.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>O1CCOCC1.O.O>[CH2:17]([NH:19][C:20]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5])=[O:21])[CH3:18]
Reactant: CCN=C=O
Reactant: Cc1cccc(N)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cccc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To an ice cooled solution of 2-amino-6-methylbenzoic acid (500 mg, 3.3 mmol) and sodium bicarbonate (277 mg, 3.3 mmol) in 9 mL of dioxane/water (2:1) was added ethyl isocyanate (281 mg, 3.96 mmol). The reaction was slowly warmed to room temperature while stirring overnight. The reaction mixture was diluted with water and extracted with EtOAc. The acueous fraction was acidified with 2N HCl and extracted with EtOAc. The organic fraction was dried (MgSO4), filtered, and evaporated under reduced pressure affording 272 mg of 2-[[(ethylamino)carbonyl]amino]-6-methylbenzoic acid used directly in the next reaction: 1H-NMR (300 MHz, d6-DMSO) δ 1.02 (t, J=7 Hz, 3H), 2.32 (s, 3H), 3.03 (m, 2H), 6.67 (d, J=8 Hz, 1H), 6.87 (br. t, 1H, exchangeable), 6.99 (t, J=8 Hz, 1H), 7.79 (d. J=8 Hz, 1H), 9.46 (br. s, 1H, exchangeable).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[Br:12][CH:13]([CH3:17])[C:14](Br)=[O:15]>>[Br:12][CH:13]([CH3:17])[C:14]([NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2])=[O:15]
Reactant: CC(Br)C(=O)Br
Reactant: CCc1cccc(CC)c1N
Product: CCc1cccc(CC)c1NC(=O)C(C)Br
Yield: 80 %

Procedure:
Following the procedure described in Example 8A using 2,6-diethylaniline and 2-bromopropionyl bromide the desired intermediate was obtained in 80% yield. Recrystallized from abs. methanol it melted at 197°-199° C.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.C(#N)C.[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>CCOCC>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH2:28][CH3:29])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCN1CCCC1CN
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CCOCC
Solvent: CC#N
Product: CCN1CCCC1CNC(=O)CCn1cnc2c(=O)[nH]cnc21
Reaction time: 17 h
Yield: 43.1 %

Procedure:
3-(1.6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (250 mg. 1.06 mol) (AIT-0027) was placed into a 10 ml round bottom flask equipped with a magnetic stirring bar, reflux condenser and CaCl2 drying tube. Then 3 ml acetonitrile and 280 mg (2.18 mmol) 2-(aminomethyl)-1-ethyl-pyrrolidine were added and the solution was heated to reflux. Not all of the ester dissolved at reflux, but as the reaction proceeded, the solution became homogeneous. Reflux was continued for 17 hours, at which time the solvent had completely evaporated. The residue was treated with acetonitrile and allowed to cool. A white precipitate had formed. Ether was added and the solution was stirred to wash the precipitate. The solution was filtered by Buchner vacuum filtration and the precipitate was washed with ether. Upon drying, 300 mg (0.94 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]propanamide (AIT-0029) was obtained as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[C:14](=[O:15])[NH:13][C:12]3[N:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10]2(=[O:21])=[O:20])[CH:6]=[C:5]([O:22][CH3:23])[N:4]=1.[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[C:26]=1[CH2:27]O.CN(C(/N=N/C(N(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COC1C=C(N2C(=O)N(CC3C(C)=CC(F)=CN=3)C3C=CC=CC=3S2(=O)=O)C=C(OC)N=1>C(Cl)Cl>[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[C:26]=1[CH2:27][N:13]1[C:12]2[N:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10](=[O:21])(=[O:20])[N:9]([C:7]2[CH:6]=[C:5]([O:22][CH3:23])[N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[C:14]1=[O:15]
Reactant: OCc1c(F)cc(F)cc1Cl
Reactant: COc1cc(N2C(=O)Nc3ncccc3S2(=O)=O)cc(OC)n1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: COc1cc(N2C(=O)N(Cc3ncc(F)cc3C)c3ccccc3S2(=O)=O)cc(OC)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(N2C(=O)N(Cc3c(F)cc(F)cc3Cl)c3ncccc3S2(=O)=O)cc(OC)n1
Yield: 50 %

Procedure:
The title compound (74 mg, 0.15 mmol) was prepared from 2-(2,6-dimethoxypyridin-4-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (IntF3) (101 mg, 0.30 mmol), 2-chloro-4,6-difluorobenzyl alcohol (IntA22) (59 mg, 0.33 mmol), TMAD (57 mg, 0.33 mmol) and triphenyl phosphine (86 mg, 0.33 mmol) in DCM (3 mL) using the methods of (162).