Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:23]2[C:24]([F:41])=[C:25]([NH:29][S:30]([C:33]3[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=3[F:40])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:5]=[CH:4][N:3]=1.[NH3:42]>CO>[NH2:42][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:23]2[C:24]([F:41])=[C:25]([NH:29][S:30]([C:33]3[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=3[F:40])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: N
Solvent: CO
Product: CS(=O)(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(N)n3)s2)CC1
Yield: 30 %

Procedure:
Following a procedure analogous to Example 51, Step B using N-(3-{5-(2-chloro-4-pyrimidinyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (0.140 g, 0.217 mmol) and 7M ammonia in MeOH (25 mL) the title compound was obtained (0.041 g, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (br. s., 1H), 7.84 (d, J=5.3 Hz, 1H), 7.63-7.73 (m, 1H), 7.37-7.48 (m, 1H), 7.17-7.34 (m, 4H), 6.58 (br. s., 2H), 5.65 (d, J=5.2 Hz, 1H), 3.60 (br. s., 4H), 3.26 (br. s., 4H), 2.92 (s, 3H). m/z (ES+): 626 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][O:10]C(=O)C)=[C:6]([CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[C:16]2[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:5]=[CH:4][N:3]=1.O.[NH2:28][NH2:29]>CCO>[F:26][C:25]1[C:20]([C:16]2[N:15]([CH2:14][C:6]3[C:7]([CH2:8][CH2:9][OH:10])=[C:2]([NH:28][NH2:29])[N:3]=[CH:4][N:5]=3)[CH:19]=[CH:18][N:17]=2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OCCc1c(Cl)ncnc1Cn1ccnc1-c1ncccc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ncnc(Cn2ccnc2-c2ncccc2F)c1CCO
Temperature: 70 °C

Procedure:
A mixture of 163 (1.72 g, 4.6 mmol) and hydrazine monohydrate (0.95 g, 19 mmol) in EtOH (20 mL) is heated at 70° C. overnight. The solvent is removed in vacuo and the residue is triturated with ethyl acetate and ethyl ether. Filtration gives the product (164) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[N:4][C:5]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:31]>C(Cl)Cl>[Cl:19][C:6]1[C:5]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[N:4][C:3]([F:25])=[C:2]([Cl:1])[C:7]=1[S:8]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:17])[CH3:18])[CH:10]=1)=[O:31]
Reactant: CC(C)c1cc(Sc2c(Cl)c(F)nc(NCC(=O)O)c2Cl)ccc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)c1cc(S(=O)c2c(Cl)c(F)nc(NCC(=O)O)c2Cl)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
To a solution of 3,5-dichloro-2-fluoro-4-(3-isopropyl-4-hydroxyphenylthio)-6-hydroxycarbonylmethylaminopyridine (25 mg, 0.06 mmol) in CH2Cl2 (1.5 mL) was added 3-chloroperoxy-benzoic acid (11 mg). The mixture was left to stir overnight (ca. 15 h) at ambient room temperature. The product was extracted with EtOAc (25 mL). The organic extract was washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. The isolated crude product was purified by preparative HPLC (from 50% B to 100% B for 10 min, Solvent A=90% H2O-10% MeOH-0.1% TFA Solvent B=10% MeOH-90% H2O-0.1% TFA, at 20 mL/min using column YMC ODS S5 20×100 mm) to afford 16.5 mg (64%) of title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[C:11]=2C(OC)=O)[C:5]([CH3:8])=[CH:6][N:7]=1.CO>S(=O)(=O)(O)O.O>[CH3:1][C:2]1[C:3]2[N:4]([N:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nn2c(C)cnc(C)c2c1C(=O)OC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2c(C)ncc(C)n2n1
Temperature: 180 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A solution of dimethyl 4,7-dimethylpyrazolo[1,5-a]pyrazine-2,3-dicarboxy late (900 mg, 3.42 mmol) in sulfuric acid (4 mL) and water (1 mL) was stirred and heated to 180° C. After stirring for 2 h at that temperature, the reaction mixture was cooled, and 40 mL of methanol (MeOH) was added. The mixture was refluxed at 70° C. for 2 h. Then the mixture was concentrated to dryness. The residue was treated with water and adjusted with saturated sodium bicarbonate solution to pH 8, then extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated to give 560 mg (80% yield) of the title compound as a yellow solid. ESI MS: m/z 206.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=0.8 Hz, 1H), 7.36 (s, 1H), 4.03 (s, 3H), 2.77 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:16]([O:18]C)=O)[S:14][CH:15]=2)=[O:9])[CH:3]=1.O.[NH2:21][NH2:22]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:16]([NH:21][NH2:22])=[O:18])[S:14][CH:15]=2)=[O:9])[CH:3]=1
Reactant: NN
Reactant: COC(=O)c1cc(NC(=O)c2cc(Br)ccn2)cs1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(NC(=O)c2cc(Br)ccn2)cs1
Yield: 101.9 %

Procedure:
The methyl 4-(4-bromopicolinamido)thiophene-2-carboxylate (2.7 g, 6.9 mmol) was dissolved in ethanol, hydrazine hydrate (1.4 mL, 28 mmol) was added and the reaction was refluxed overnight. The reaction mixture was concentrated, and the solids were suspended in acetonitrile and filtered to afford 2.4 g (70%) 4-bromo-N-(5-(hydrazinecarbonyl)thiophen-3-yl)picolinamide as a white solid. M+1=341.1
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11]N)[C:4]=2[O:3]1.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.Cl>C(O)C.O1CCOCC1>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]3[C:17]4[CH2:16][NH:15][CH2:20][CH2:19][C:18]=4[NH:11][C:10]=3[C:4]=2[O:3]1
Reactant: NNc1cccc2c1OC(F)(F)O2
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: FC1(F)Oc2ccc3c4c([nH]c3c2O1)CCNC4
Temperature: 110 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
The (2,2-difluoro-benzo[1,3]dioxol-4-yl)-hydrazine (753 mg, 4.00 mmol) and 4-piperidone hydrochloride (543 mg, 4.00 mmol) in ethanol (10 mL) were heated to reflux for 45 min. The 4M HCl in dioxane (2 mL) was added and heating continued for 2 h. A sample was removed and after bubbling HCl gas briefly was heated in the microwave to 110° C. for 10 min. The rest of the material was processed in 5 batches and the combined black reactions filtered, washed with a little water and then precipitation with Et2O:Hexane 1:2 (c.f. 10 mL) before drying the resulting grey solid (147 mg, 13% yield)
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][OH:29])[O:22][C@@H:13]2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:10])[C:4](=[O:30])[CH2:3]1.[C:32]1([C:38](Br)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:31])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][C:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[O:22][C@@H:13]2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:10])[C:4](=[O:30])[CH2:3]1
Reactant: CC(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](O)[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 66.9 %

Procedure:
A mixture of Benzyl 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-α-D-glucopyranoside (100 mg, 0.23 mmol), triphenylmethylbromide (149 mg, 0.46 mmol) in DMF/pyridine 1:1 (2 ml) was stirred at 100° C. for 15 h. The reaction mixture was evaporated, the residue was taken up in CHCl3 (10 ml), washed with water (3 ml), dried over MgSO4 and concentrated. The residue was purified by chromatography using CHCl3/MeOH 10:1 as the mobile phase to give Benzyl 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-6-O-triphenylmethyl-α-D-glucopyranoside (14) (104 mg, 64%).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C:6]=1I.[CH2:19]([Li])CCC.IC>C1COCC1>[I:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C:6]=1[CH3:19]
Reactant: Cc1nc(I)c(I)n1-c1ccc(C(F)(F)F)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1nc(I)c(C)n1-c1ccc(C(F)(F)F)cc1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
4,5-Diiodo-2-methyl-1-(4-trifluoromethyl-phenyl)-1H-imidazole (1.0 g, 2.1 mmol) was dissolved in 15 ml THF and cooled to −75° C. n-Butyllithium (1.6M in Hexane) (1.60 ml, 2.5 mmol) was added, and the mixture stirred for 60 min at −75° C. Iodomethane (0.19 ml, 3.0 mmol) was added and stirring was continued 30 min. at −75° C. and then 1 h without dry ice bath. The reaction mixture was quenched with sat. NaHCO3− solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 100:0→60:40 gradient) and by recrystallization from little ethyl acetate and cyclohexane. The desired compound was obtained as a white solid (197 mg, 26%), MS: m/e=367.0 (M+H+).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][C:30]1([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31]1.C[O-].[Na+].CO.Cl>O>[C:26]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][C:30]2([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31]2)=[O:7])[N:9]=1)#[N:27]
Reactant: NCC1(C(=O)O)CCC1
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(OC3CCCCC3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCC2)c(O)c2ccc(OC3CCCCC3)cc12
Yield: 35.2 %

Procedure:
A mixture of 1-cyano-7-cyclohexyloxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (20 mg, 0.054 mmol) and 1-aminomethyl-cyclobutanecarboxylic acid (37 mg, 0.22 mmol) in 0.5 M NaOMe/MeOH solution (0.84 mL, 0.42 mmol) was microwaved at 120° C. for 2 h. Reaction mixture was diluted with water (50 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried. Crude product was purified by silica gel chromatography, eluting with 10-100% EtOAc/hexanes, to provide the title compound 8 mg (0.019 mmol) in 35% yield. LC-MS ESI−: 422.03 (M−1)−.
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[C:4]2[C:13]3[CH:12]=[C:11]([O:14][CH3:15])[C:10]([C:16]4[C:17]([CH3:22])=[N:18][O:19][C:20]=4[CH3:21])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:23]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN1C(=O)CCC1>[CH3:22][C:17]1[C:16]([C:10]2[C:11]([O:14][CH3:15])=[CH:12][C:13]3[C:4]4[N:3]([C@@H:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH3:25])[C:2]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[N:23][C:5]=4[CH:6]=[N:7][C:8]=3[CH:9]=2)=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: C1CCNCC1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n([C@H](C)c3ccccc3)c12
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(N3CCCCC3)n([C@H](C)c3ccccc3)c12
Temperature: 150 °C
Yield: 53.6 %

Procedure:
2-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline (30 mg, 0.069 mmol) (for a preparation see Intermediate 12) was dissolved in NMP (0.5 ml), piperidine (0.2 ml, 2.020 mmol) was added and the mixture was heated at 150° C. for 30 min, then cooled, added to water (10 ml) and extracted with EtOAc (10 ml). The solvent was washed with water (2×10 ml), dried and evaporated. The residue was dissolved in DCM (2 ml), loaded onto a 10 g silica column, eluted with 2M methanolic ammonia/DCM (0-10%) and product-containing fractions evaporated in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-2-(1-piperidinyl)-1H-imidazo[4,5-c]quinoline (18 mg, 0.037 mmol, 53.9% yield) as a amber solid. LCMS (formate) Rt 1.05 min, MH+ 482
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.[Ag]=O>[CH3:9][N:10]([C:6]1[CH:7]=[CH:8][C:1](=[O:2])[C:3](=[O:4])[CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1O
Reactant: CNc1ccccc1
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CN(C1=CC(=O)C(=O)C=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2.2 g (0.02 mole) catechol and 2.0 g (0.019 mole) N-methylaniline were dissolved in 80 ml acetone. Then 18.8 g (0.08 mole) silver oxide was added followed by 20 g anhydrous sodium sulfate. The mixture was stirred at room temperature for 10 minutes and filtered. The residue was washed with several portions of acetone totaling 50 ml. The filtrate was diluted with ligroin (bp 60°-80° C.) and the solid was filtered and washed with ligroin to give 2.6 g (60%). Thin-layer chromatography on Eastman chromogram silica gel sheets showed essentially a single spot with traces of impurities.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[N:19]2[C:15]([S:16][C:17]3[CH2:23][CH2:22][CH2:21][CH2:20][C:18]=32)=[N:14][CH:13]=1)=O)C>C1COCC1>[N:14]1[CH:13]=[C:12]([CH2:10][OH:9])[N:19]2[C:18]3[CH2:20][CH2:21][CH2:22][CH2:23][C:17]=3[S:16][C:15]=12
Reactant: CCOC(=O)c1cnc2sc3c(n12)CCCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc2sc3c(n12)CCCC3
Yield: 88.2 %

Procedure:
A suspension of LiAlH4 (2.1 g) in THF (100 mL) was treated with 5,6,7,8-Tetrahydro-imidazo[2,1-b]benzothiazole-3-carboxylic acid ethyl ester (Formula F-4) (5.6 g) and reacted at 25° C. for 5.5 hours. The reaction was quenched by serial additions of water and 15% sodium hydroxide and the mixture was filtered. Evaporation of the filtrate gave 5,6,7,8-Tetrahydro-imidazo[2,1-b]benzothiazole-3-methanol (Formula F-5) (4.11 g), m.p. 182-183° after crystallization from iso-propanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[C:10](=[O:15])[CH:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:14][CH2:13][CH2:12]1
Reactant: BrBr
Reactant: Cc1ccc(C)c(C2CCCCC2=O)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C)c(C2CCCC(Br)C2=O)c1
Temperature: 25 °C
Yield: 115.2 %

Procedure:
2-(2,5-Dimethyl-phenyl)-cyclohexanone (51 mg, 0.25 mmol) was dissolved in chloroform (1 mL). To this solution bromine (42.3 mg, 0.27 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (81 mg) which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=[N:44][C:39]2[CH:40]=[CH:41][CH:42]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(CN)CC1>CN(C=O)C>[CH:40]1([CH2:39][NH:44][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([B:11]3[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:16])([CH3:17])[O:15]3)[CH:4]=2)[CH2:42][CH2:41]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (Intermediate 17)(2.0 g, 7.63 mmol), DIPEA (4 ml, 22.89 mmol) and HATU (3.05 g, 8.02 mmol) were dissolved in DMF (20 ml) and stirred at room temperature for 15 mins. Cyclopropylmethylamine (568 mg, 8.01 mmol) was added and the reaction stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250 ml) and water (50 ml). The organic phase was washed with hydrochloric acid (2N, 50 ml) and aqueous sodium bicarbonate (1M, 50 ml), then dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane/ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to give N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (1.73 g). LCMS: retention time 3.47 min, MH+ 316. NMR: δH [2H6]-DMSO 8.54,(1H, t), 8.11, (1H, d), 7.82,(1H, dd), 7.26,(1H, d), 3.12,(2H, t), 1.32,(12H, s), 1.03,(1H, m), 0.42,(2H, m), 0.22,(2H, m).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9]>>[Cl:5][C:6]1[C:7]([C:8]([Cl:3])=[O:9])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccnc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
1131 g (9.5 mol) of thionyl chloride were slowly added dropwise at 90° C. to 500 g (3.17 mol) of 2-chloronicotinic acid. The reaction mixture was stirred for 1 hour at 90° C. and freed from thionyl chloride under reduced pressure (“high vacuum”) at approximately 40° C. This gave 561 g (100%) of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4](=[O:6])[CH3:5].O1[CH2:11][CH2:10][CH2:9][CH2:8]1.[H-].[Na+].BrCCCCBr>C(Cl)Cl>[CH3:1][S:2][C:3]1([S:4](=[O:6])[CH3:5])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCOC1
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: BrCCCCBr
Solvent: ClCCl
Product: CSC1(S(C)=O)CCCC1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Formaldehyde dimethyl mercaptal S-oxide (1.49g) was dissolved in 15 ml. of tetrahydrofuran, and with ice cooling, 665 mg of sodium hydride was added. The mixture was stirred for 30 minutes with ice cooling, and then 2.936g of 1,4-dibromobutane was added. The mixture was stirred for 1 hour with ice cooling, for 24 hours at room temperature, and then for 44.5 hours at 50° C. Then, 100 ml. of methylene chloride was added, and the insoluble matter was separated. The filtrate was concentrated at reduced pressure, and the residue was separated by column chromatography (silica gel, eluted with 20% AcOEt-CH2Cl2, AcOEt, and MeOH) to afford 985 mg of cyclopentanone dimethyl mercaptal S-oxide. Also, 463 mg of formaldehyde dimethyl mercaptal S-oxide was recovered. The yield was 46%, and the conversion was 67%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(OCC)C.C([Mg]Br)C=C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[C:37]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:36]=[CH:35][C:34]=2[C:44]2[O:45][C:46](=[O:54])[C:47]3[CH:53]=[CH:52][N:51]=[CH:50][C:48]=3[N:49]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[C:37]([N:39]3[CH2:40][CH2:41][CH2:42][CH2:43]3)[CH:36]=[CH:35][C:34]=2[C:44]([NH:49][C:48]2[CH:50]=[N:51][CH:52]=[CH:53][C:47]=2[C:46]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[O:54])=[O:45])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2-c2nc3cnccc3c(=O)o2)CC1
Reactant: Nc1ccc(Cl)cn1
Agent: C=CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2cnccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A solution of 2-amino-5-chloropyridine (52 mg, 0.4 mmol) in THF (10 mL) was cooled to 0° C. and treated with a 1 M diethyl ether solution of allylmagnesium bromide (0.4 mL). The mixture was stirred for 5 minutes before adding 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-pyrido[3,4-d][1,3]oxazin-4-one (100 mg, 0.2 mmol). The reaction mixture was stirred overnight at ambient temperature then concentrated to dryness under vacuum. The residue was treated with brine (5 mL) and CHCl3 (20 mL). The layers were separated and the organic layer was chromatographed using 1% MeOH in CHCl3 to give 125 mg (0.2 mmol, 99%) of product as a solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1>C(Cl)Cl>[C:1]([O:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc(Oc2ccc(O)cc2)cc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
Acetylchloride (1.5 mL, 21 mmol) is added to a solution of 4-(4-hydroxyphenoxy)benzoic acid (2.3 g, 10 mmol) and TEA (2.9 mL, 21 mmol) in CH2Cl2 (50 mL). The reaction is stirred for 16 hours at room temperature. The reaction mixture is diluted with CH2Cl2 and washed three times with saturated NaHCO3. The organic layer is dried (MgSO4), filtered and concentrated in vacuo. The resulting material is dissolved in dioxane (6 mL). Aqueous LiOH (1N, 930 μL) is added, and the reaction is allowed to stir for one hour at room temperature. The reaction mixture is poured into CH2Cl2 and washed twice with KHSO4. The organic layer is dried (MgSO4), filtered and concentrated in vacuo to give 4-(4-acetoxyphenoxy)benzoic acid (1.5 g, 87%). 1H NMR (300 MHz, DMSO) δ 12.80, 7.96, 7.23-7.13, 7.04, 2.29.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:7][C:8]=1[CH:9]=O)#[N:2].O.[NH2:23][NH2:24]>CO>[C:1]([C:3]1[C:8](=[CH2:9])[NH:7][C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]=1[NH:23][NH2:24])#[N:2]
Reactant: NN
Reactant: CCOC(=O)c1cc(C#N)c(C=O)nc1N1CCCCC1
Solvent: O
Solvent: CO
Product: C=C1NC(N2CCCCC2)=C(C(=O)OCC)C(NN)=C1C#N
Temperature: 25 °C

Procedure:
28.7 g of 5-cyano-6-formyl-2-piperidinyl-3-pyridine-carboxylic acid, ethyl ester (0.1 mol) are dissolved in 100 ml of methanol. 5.5 g of hydrazine hydrate are added and the solution is stirred at room temperature over night. The title compound is filtered off and recrystallized from methanol. Yield 20.5 g (68%); m.p. 168°-170° C.