Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[C:18](O)(=[O:21])[CH2:19][OH:20].C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O>CN(C=O)C>[OH:21][CH2:18][C:19]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[O:20]
Reactant: O=C(O)CO
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CO)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 60 °C
Yield: 19.8 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (200 mg, 0.904 mol) and glycolic acid (83 mg, 1.085 mmol) in dry DMF (6 mL), EDC (191 mg, 1 mmol) and HOBt hydrate (154 mg, 1 mmol) were added and the reaction mixture was heated at 60° C. for 18 hrs. The solvent was evaporated in vacuo (45° C., 0.1 mbar) and the residue was dissolved in ethyl acetate (50 mL) and washed with water (2×25 mL). The organic phase was washed dried over sodium sulphate, filtered, the solvent evaporated in vacuo, the residue was triturated with DCM and further purified by preparative LCMS to afford 2-hydroxy-N-(3-(quinoxalin-2-yl)phenyl)acetamide (60 mg, 23% yield). LCMS calculated for C16H13N3O2 (M+H): 280.29. found 280. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.38 (1H, br.), 9.52 (1H, s), 8.62 (1H, m), 8.14-8.20 (2H, m), 8.05-8.08 (1H, m), 7.80-7.95 (3H, m), 7.55-7.60 (1H, m), 5.64 (1H, br), 4.08 (2H, s).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][CH2:4][C@H:3]1[NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CO.ClCCl>[OH:1][C@H:2]1[CH2:6][N:5]([CH:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH2:33][CH2:34]2)[CH2:4][C@@H:3]1[NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CNC[C@H]1O
Reactant: COc1ccc(N2CCC(=O)CC2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(N2CCC(N3C[C@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)[C@@H](O)C3)CC2)cn1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of rac-N-(2-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (50 mg, 0.152 mmol; prepared according to WO2004/050024A2), 1-(6-methoxypyridin-3-yl)piperidin-4-one (31 mg, 0.151 mmol) in methanol (4 mL) was added sodium triacetoxyborohydride (37 mg, 1.74 mmol) and stirred overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford N-[2-({(3S,4S)-4-hydroxy-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (73 mg, 93%) as a white solid. 1H-NMR (CD3OD) δ: 1.56-1.70 (m, 1H), 1.95-2.06 (m, 1H), 2.20-2.30 (m, 1H), 2.54-2.75 (m, 5H), 3.05-3.14 (m, 3H), 3.30-3.37 (m, 3H), 3.45-3.54 (m, 2H), 3.80-3.86 (s, 3H), 4.03-4.09 (m, 2H), 4.10-4.20 (m, 2H), 6.70-6.76 (in 1H), 7.40-7.50 (m, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.70-7.78 (m, 1H), 7.86 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.21 (s, 1H). MS m/z: 522 (M+1).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.N>C(O)(=O)C>[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:6]3[CH2:5][CH2:4][NH:3][CH2:8][CH:7]=3)=[CH:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCNCC1
Reactant: c1ccc(-n2ccc3ccccc32)cc1
Agent: Cl
Agent: N
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C1=C(c2cn(-c3ccccc3)c3ccccc23)CCNC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a heated (110° C.) mixture of 4-piperidone monohydrate hydrochloride (8.2 g), acetic acid (15 mL) and trifluoroacetic acid (30 mL) was added 1-phenyl-1H-indole (3.1 g) under nitrogen atmosphere over a period of 25 min. The mixture was stirred for 30 minutes at 120° C., then cooled and poured into ice. This was neutralized with conc. ammonia water under cooling and the product was extracted thrice with ethyl acetate. The combined extract was washed with water followed by saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was provided for the next reaction without further purification. Yield 63%. Amorphous.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH:4]=1)#[N:2].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.N.O>O1CCCC1>[C:1]([C:3]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:5]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:25])=[O:20])=[CH:21][CH:22]=2)[CH:4]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1cn(-c2ccc(C(=O)O)cc2)cc1-c1ccccc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cn(-c2ccc(C(N)=O)cc2)cc1-c1ccccc1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 4-(3-cyano-4-phenylpyrrole-1-yl)benzoic acid (0.14 g) in tetrahydrofuran (2.5 mL) was added 1,1′-carbonyldiimidazole (0.16 g). After stirring for 30 minutes, to this reaction mixture was added aqueous ammonia (28% solution 0.75 mL), and this mixture was stirred 2 hours. To this reaction mixture was added water (10 mL), the precipitated white solid was collected by filtration, and wash with methanol, dried to give the title compound (0.13 g).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[H][H]>CC(O)=O.[Pt](=O)=O>[ClH:1].[CH3:2][CH:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH:8]1[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: Cc1ccncc1C(=O)O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: CC1CCNCC1C(=O)O
Yield: 112.9 %

Procedure:
4-Methylnicotinic acid hydrochloride (5.00 g, 36.5 mmol, ASDI) and platinum (IV)oxide (0.35 g, 1.54 mmol) were shaken in AcOH (100 mL) at about 60 psi hydrogen for about 72 h. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to give 4-methylpiperidine-3-carboxylic acid hydrochloride (7.4 g, contained residual AcOH) that was carried forward without additional purification. To a solution of the acid (7.40 g, 36.4 mmol) and NaHCO3 (15.3 g, 182 mmol) in MeCN (75 mL) and water (125 mL) was added Boc2O (11.0 mL, 47.3 mmol). The reaction was stirred at about 25° C. for about 16 h. The reaction mixture was diluted with Et2O (100 mL) and acidified to pH 1 with 4N aqueous HCl. The layers were separated and the organic solution was washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. A white solid formed that was triturated with heptane and collected by vacuum filtration to give 1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (5.2 g, 58% over 2 steps): LC/MS (Table 2, Method a) Rt=2.01 min; MS m/z: 242 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]([OH:19])=[O:18])=[CH:12][N:7]3[CH:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:21].[CH:22]1([NH:25][CH2:26][CH:27]2[CH2:31][CH2:30]NC2)[CH2:24][CH2:23]1.[CH2:32]([N:34](CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]([OH:19])=[O:18])=[CH:12][N:7]3[CH:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([N:34]2[CH2:32][CH2:30][CH2:31][CH:27]2[CH2:26][NH:25][CH:22]2[CH2:23][CH2:24]2)[C:3]=1[F:21]
Reactant: C1CC(CNC2CC2)CN1
Reactant: CCN(CC)CC
Reactant: CC1COc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)C=O
Product: CC1COc2c(N3CCCC3CNC3CC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C

Procedure:
A mixture of 2.96 g (10 mmole) of 8-amino-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4]benzoxazine-6-carboxylic acid, 2.1 g (15 mmole) of N-cyclopropyl-3-pyrrolidinemethanamine, 3.03 g (30 mmole) of triethylamine and 100 ml of N,N-dimethylformamide is heated at 100° C. for four hours. The solvent is removed in vacuo and the residue triturated with water. The aqueous suspension is adjusted to pH 7.2 with 1.0M hydrochloric acid. The solid is removed by filtration, washed with water, and dried in vacuo to give 8-amino-9-fluoro-3-methyl-10-[(3-cyclopropylaminomethyl)-1-pyrrolidinyl]-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.
Reaction SMILES: [Li+].[BH4-].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12](OCC)=[O:13])=[CH:7][C:6]=1[O:18][CH3:19])#[N:4].O>C1COCC1>[OH:13][CH2:12][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[C:6]([O:18][CH3:19])[CH:7]=1)[CH3:17]
Reactant: CCOC(=O)C(C)c1ccc(C#N)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(C)CO)ccc1C#N
Reaction time: 12 h

Procedure:
LiBH4 (0.55 mL, 1.1 mmol, 2 M in THF) was added to a stirred solution of ethyl 2-(4-cyano-3-methoxyphenyl)propanoate (0.17 g, 0.73 mmol) in THF (25 mL) at 0° C. The resulting solution was stirred for 12 h. Water (15 mL) was added, and the resulting solution was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3→1:1) to give 4-(1-hydroxypropan-2-yl)-2-methoxybenzonitrile.
Reaction SMILES: [C:1]([C:3]1[NH:16][C:6]2=[N:7][CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=[C:5]2[CH:4]=1)#[N:2].CO.O1CCCC1.[OH-].[Li+]>O>[C:1]([C:3]1[NH:16][C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:5]2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1cnc2[nH]c(C#N)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc2cc(C(=O)O)cnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To ethyl 2-cyano-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (36 mg, 0.17 mmol) was added methanol (1 mL), tetrahydrofuran (1 mL), and water (1 mL), followed by 2 N aqueous lithium hydroxide (0.17 mL, 0.33 mmol). The reaction was stirred at room temperature overnight and was then concentrated. The crude was taken up in water and the pH was adjusted to 4 using 1 N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (3×). The combined organics were dried over sodium sulfate, filtered, and concentrated to provide the 2-cyano-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid. The title compound was then prepared by a method analogous to that described in Example 1, using 2-cyano-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid. −ESI (M−H) 415.1.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:50])([CH3:49])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C:23]#[C:24][CH2:25][C@:26]([NH:32]C(OC(C)(C)C)=O)([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:50])([CH3:49])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C:23]3[CH2:24][CH2:25][C@:26]([CH3:31])([C:27]([O:29][CH3:30])=[O:28])[N:32]=3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:52])[CH:8]=1
Reactant: COC(=O)[C@@](C)(CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)[C@@]1(C)CCC(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)=N1
Temperature: 20 °C
Yield: 100.4 %

Procedure:
Methyl (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)pyridin-2-yl]-2-[(tert-butoxycarbonyl)amino]-2-methylpent-4-ynoate (Intermediate 22, 1.23 Kg) was suspended in 6.2 L DCM at room temperature under inert atmosphere. The mixture was then heated to reflux (clear solution obtained at 30° C.). TFA (990 ml) was added dropwise over one hour. The resulting solution was stirred for at least 6 h at reflux and then was cooled to 20° C.±5° C. Water (6.15 L) was added and the biphasic mixture was stirred for 15 min. Layers were separated and the aqueous layer (top) was discarded. 6.1 L10% w/w aqueous potassium carbonate was added to the DCM layer and the biphasic mixture was stirred for 15 min. Layers were separated and the top layer (aqueous) was discarded. The DCM layer was dried over magnesium sulfate and was filtered. Acetonitrile (620 ml) was added to the above DCM solution and silver triflate (128.4 g,) was also charged to the vessel. The resulting mixture was then heated to reflux and stirred for 24 h. It was then cooled to 20° C. and quenched with 8.6 L. saturated ammonium chloride. The mixture was stirred for 1 h at 20° C. and was then cooled to 0° C. and stirred for 1 h. The silver chloride precipitate was then filtered cold and the resulting biphasic solution was allowed to warm to 20° C. Layers were separated. The top aqueous layer was discarded. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness under vacuum to give the title compound (1067.6 g).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10](=[O:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]=1[OH:27])([CH3:16])([CH3:15])[CH3:14].C=O.[CH2:30]1N2CN3CN(C2)CN1C3>CN(C)C=O.O>[C:23]([C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:18]=1[OH:27])[CH2:30][N:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][C:10]1=[O:12])([CH3:26])([CH3:25])[CH3:24]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=c1[nH]nc(-c2ccccc2)o1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: C=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Cn2nc(-c3ccccc3)oc2=O)cc(C(C)(C)C)c1O

Procedure:
40.5 g of 5-phenyl-1,3,4-oxadiazol-2-one (0.25 mol), 51.5 g of 2,6-di-tert.-butyl-phenol (0.25 mol), 8.2 g of paraformaldehyde (0.27 mol) and 0.7 g of hexamethylenetetramine in 150 ml of dimethylformamide and 15 ml of water are heated to 110°C for 15 hours, whilst stirring. A yellowish solution results, from which the 3-(3,5-di-tert.-butyl-4-hydroxybenzyl)-5-phenyl-1,3,4-oxadiazol-2-one (stabiliser No. 1) which is formed crystallises out on cooling to room temperature. The product is filtered off, washed with a little methanol and dried in vacuo at 70°C. Melting point: 164°C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]([F:24])=[CH:14][N:13]=3)=[CH:10][N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H]4CCNC4)C(F)=CN=3)=CN([S:58]([C:61]3C=CC(C)=CC=3)(=[O:60])=[O:59])C2=NC=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.N1CCOCC1>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:23][CH2:22][N:21]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:20]4)[C:15]([F:24])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCNC4)n3)c3cc(Cl)cnc32)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 50 °C
Yield: 37 %

Procedure:
To a stirred suspension of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-pyrrolidin-3-yl]pyrimidin-4-amine hydrochloride, 7c, (0.05 g, 0.10 mmol) in THF (1 mL) was added iPr2NEt (0.10 mL, 0.57 mmol) followed by methanesulfonyl chloride (0.04 mL, 0.57 mmol). The resulting homogenous light yellow mixture was heated at 50° C. for one hour at which time LCMS showed complete reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in methanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60° C. in sealed tube until LCMS showed reaction was complete. The resulting solution was quenched with aqueous saturated NH4Cl (0.5 mL) then evaporated to dryness. The residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 15.8 mg (37% yield) of 398, as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=O)=[C:4](Cl)[N:3]=1.Cl.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][NH2:27])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(CC)CC.Cl.[CH:36]12[O:43][CH:40]([CH2:41][CH2:42]1)[CH2:39][NH:38][CH2:37]2>C(Cl)Cl.C(O)C>[CH2:13]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[C:6]3=[N:7][C:2]([Cl:1])=[N:3][C:4]([N:38]4[CH2:37][CH:36]5[O:43][CH:40]([CH2:41][CH2:42]5)[CH2:39]4)=[C:5]3[CH:9]=[N:27]2)[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: C1CC2CNCC1O2
Reactant: NNC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (26.82 mmol) in CH2Cl2 (225 mL) is cooled to −78° C. To this is added a suspension of 1-benzyl-4-hydrazinylpiperidine hydrochloride (26.82 mmol) in Et3N (160.9 mmol), CH2Cl2 (25 mL), and ethanol (15 mL). The solution is allowed to stir at this temperature for 5 minutes, then warmed to room temperature and stirred for an additional 30 minutes, then concentrated in vacuo at 30° C. This dichloride intermediate is dissolved in ethanol (225 mL) and a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (24.14 mmol) in Et3N (160.9 mmol) and ethanol (20 mL) is added. The mixture is stirred at room temperature for 1 hour, concentrated, and purified by column chromatography (0-4% methanol in CH2Cl2) provides 3-(1-(1-benzylpiperidin-4-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane. (66%, MS=439.3 (M+H))
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>ClCCl.C1COCC1>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: CNOC
Reactant: O=C(O)c1cccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
2-Chloro-nicotinic acid (10.0 g, 63.5 mmol, 1.0 equiv) is suspended in dichloromethane (400 mL) and THF (100 mL). N,O-Dimethyl-hydroxylamine hydrochloride (6.81 g, 69.8 mmol, 1.1 equiv) and triethylamine (9.70 mL, 69.8 mmol, 1.1 equiv) are added, resulting in a clear solution. The mixture is cooled in an ice bath and EDCI (13.4 g, 69.8 mmol, 1.1 equiv) and HOAt (0.86 g, 6.35 mmol, 0.1 equiv) are added. The resulting mixture is stirred overnight at room temperature and concentrated in vacuo. The residue is redissolved in ethyl acetate (200 mL) and washed with 1N NaOH solution, twice with sat. NaHCO3 solution and brine. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. This gives 7.53 g of the title compound as a white solid. Yield: 59%
Reaction SMILES: [Br-].[Br-].[Br-].[Al+3].[F:5][CH:6]([F:33])[C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:25])([CH3:24])[C:14]([O:16]CC2C=CC=CC=2)=[O:15])[C:9](=[O:26])[C:8]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(OC)C=CC=CC=1>[N+](C)([O-])=O.ClCCl>[F:33][CH:6]([F:5])[C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:25])([CH3:24])[C:14]([OH:16])=[O:15])[C:9](=[O:26])[C:8]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C(=O)OCc1ccccc1)N1COC(C(F)F)=C(c2ccccc2)C1=O
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Product: CC(C)(C(=O)O)N1COC(C(F)F)=C(c2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
A solution of aluminium tribromide (3.85 g) in nitromethane was added in portions to a stirred solution of benzyl 2-(6-difluoromethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (1.93 g) and anisole (3.1 g) in dichloromethane at 0° C. under an inert atmosphere. The reaction mixture was stirred at 0° C. for 10 minutes and at ambient temperature for 2 hours and diluted with dichloromethane. The dichloromethane solution was washed in turn with 2 M hydrochloric acid and with water. The organic solution was extracted with 1 M sodium bicarbonate, the aqueous extract was then washed with diethyl ether and acidified to pH 1 with 2 M hydrochloric acid. The acidic solution was extracted with ethyl acetate, the extract was dried (magnesium sulphate) and evaporated under reduced pressure to give 2-(6-difluoromethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1, 3-oxazin-3-yl)-2-methylpropanoic acid (0.70 g) as a pink solid, m.p. 149-151° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([C:17]([O:19]CC)=[O:18])=[N:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=3[C:8]2=[O:24])=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO.O.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([C:17]([OH:19])=[O:18])=[N:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=3[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(F)cc1)C2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc(C(=O)O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 0.08 h

Procedure:
To a solution of ethyl 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (1.21 g, 3.38 mmol) in methanol (5 mL) and water (5 mL) and THF (5 mL) was added lithium hydroxide (0.425 g, 10.13 mmol). After 5 minutes, 1N HCl (3 equiv.) was added to the product mixture, which was then dried under vacuum to provide the crude title compound.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[S:11](Cl)(=[O:13])=[O:12]>O1CCCC1>[CH3:2][C:1]([NH:5][S:11]([C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)(=[O:13])=[O:12])([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of t-butylamine (8.35 g, 0.114 mol) in dry tetrahydrofuran (THF) (20 mL) cooled to 0° C. was added dropwise 2-thiophenesulfonyl chloride (5.0 g, 27.4 mmol). After the addition was completed, the reaction mixture was warmed to ambient temperature and stirred overnight. The mixture was extracted with ethyl acetate (3×80 mL) and the combined extracts were washed with water, dried over molecular sieves and concentrated. The residue was chromatographed on (silica, eluting with 25% ethyl acetate-hexane) to yield 5.62 g (94%) of solid: mp 80°-82° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:27][O:28][CH3:29]>C(Cl)(Cl)Cl>[CH3:27][O:28][CH2:29][N:3]1[CH:4]=[CH:5][S:1][C:2]1=[N:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(Nc2nccs2)n1
Reactant: COCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCn1ccsc1=Nc1cccc(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of 4.85 g (20.6 mmol) of methyl 6-(thiazol-2-ylamino)-pyridine-2-carboxylate, 7.20 ml (41.2 mmol) of N,N-diisopropylethylamine and 100 ml of chloroform was added 2.35 ml (30.9 mmol) of chloromethylmethyl ether followed by stirring at room temperature for 1 hour. The reaction mixture was washed with 100 ml of water for three times and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to about 20 ml in total and the resulting solid was filtered. The resulting solid was washed with ether and dried in vacuo to give 6.38 g (20.6 mmol) of the title compound as a white solid.