Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:25]2[CH:30]=[C:29]([CH3:31])[C:28]([OH:32])=[C:27]([CH3:33])[CH:26]=2)([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:8]1=[O:34].[CH3:39]O>C1COCC1>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]2([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH3:39])=[C:27]([CH3:33])[CH:26]=3)[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][C:5]3[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=3[Cl:3])[C:8]2=[O:34])=[CH:21][CH:20]=1
Reactant: CO
Reactant: Cc1cc(C2(c3ccc([N+](=O)[O-])cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc(C)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(C)cc(C2(c3ccc(N)cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolve nickelous chloride (36 mg, 0.15 mmol) in methanol (3 mL). Add sodium borohydride (17 mg) followed 1-(2-chloro-benzyl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-3-(4-nitro-phenyl)-1,3-dihydro-indol-2-one (152 mg, 0.3 mmol) in THF (3 mL). Add additional sodium borohydride and stir at room temperature for 30 min. Concentrate to dryness and partition the resulting residue in water/ethyl acetate. Separate and extract aqueous with ethyl acetate (2×). Wash combined organic portions with brine and then dry (MgSO4), filter and concentrate in vacuo to give 145 mg of residue. Purify by flash chromatography (gradient of 10% EtOAc/hexanes to 50% EtOAc/hexanes) to give 97 mg (67%) of the title compound as a white foam. MS (ES): m/z=483 (M+1); 1H NMR(DMSO-d6): δ9.99 (s, 1H), 7.53 (m, 3H), 7.36-7.24 (m, 4H), 7.10 (t, J=8 Hz, 1H), 6.95 (m, 2H), 6.85 (m, 4H), 6.52 (d, J=8.5 Hz), 5.19 (bs, 2H), 5.06 (s, 2H) 3.65 (s, 3H), 2.16 (s, 6H).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].Br.Br.[NH:30]1[CH2:36][CH:35]([OH:37])[CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CC(O)C>[CH3:23][C:19]1[N:18]=[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([N:30]5[CH2:36][CH:35]([OH:37])[CH2:34][NH:33][CH2:32][CH2:31]5)[C:3]([C:24]([F:27])([F:25])[F:26])=[CH:4][CH:5]=4)[C:16]=3[CH:15]=2)[CH:22]=[N:21][CH:20]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)(F)F)c(F)n2)n1
Reactant: OC1CNCCNC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)(F)F)c(N3CCNCC(O)C3)n2)n1
Temperature: 120 °C
Yield: 10.8 %

Procedure:
A mixture of 1-[6-fluoro-5-(trifluoromethyl)-2-pyridyl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.213 mmol; 79.9 mg), 1,4-diazepan-6-ol dihydrobromide (1.07 mmol; 297 mg), and cesium carbonate (2.13 mmol; 696 mg) in DMSO (2 mL) and IPA (4 mL) in a sealed pressure vial was heated at 120° C. overnight. The mixture was cooled to room temperature, and then filtered through Celite®. The filtrate was concentrated and the residue was purified by reverse phase HPLC to afford 219 as an off-white solid (10.8 mg, 11%). 1H NMR (400 MHz, DMSO) δ 9.59-9.53 (s, 1H), 9.48-9.43 (s, 1H), 9.38-9.33 (s, 1H), 8.79-8.75 (s, 1H), 8.66-8.62 (s, 1H), 8.22-8.17 (d, J=8.5 Hz, 1H), 7.57-7.52 (d, J=8.5 Hz, 1H), 4.76-4.67 (s, 1H), 3.98-3.88 (d, J=10.4 Hz, 3H), 3.75-3.66 (d, J=14.1 Hz, 1H), 3.65-3.55 (dd, J=15.3, 8.4 Hz, 1H), 3.15-3.07 (m, 1H), 3.06-2.99 (m, 1H), 2.87-2.79 (dd, J=13.7, 3.4 Hz, 1H), 2.76-2.68 (dd, J=13.6, 5.8 Hz, 1H), 2.69-2.62 (s, 3H); MS (ESI) m/z: 471.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:5][NH:6][C:7]1[C:8]2[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:9]=2[N:10]=[C:11]([CH2:13]Cl)[N:12]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].C(OCC)(=O)C>CN(C=O)C.O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:5][NH:6][C:7]1[C:8]2[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:9]=2[N:10]=[C:11]([CH2:13][NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:12]=1
Reactant: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(CCl)nc12
Reactant: NCCCO
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(CNCCCO)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2 g of 7-(3-chloro-4-methoxybenzylamino)-5-chloromethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine in 10 ml of DMF is treated with 5 ml of 3-aminopropanol and stirred at room temperature for two hours. It is then diluted with water and extracted with ethyl acetate. The oily product obtained after customary work-up is dissolved in alcoholic HCl and treated with ethyl acetate until turbidity. The precipitated crystals are filtered off with suction and recrystallized from isopropanol/ethyl acetate. 3.1 g of 7-(3-chloro-4-methoxybenzylamino)-5-(3-hydroxypropylaminomethyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine are obtained in the form of its dihydrochloride.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9]
Reactant: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 45 °C
Yield: 91.7 %

Procedure:
To a suspension of 5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-vinyloxyethoxy)-amide (58.36 g, 0.12 mol) in methanol (600 mL) was added aqueous hydrochloric acid (242 mL, 1M, 0.242 mol). The reaction mixture was stirred and warmed to 45° C. for 1 hr during which time the solids dissolved. The reaction mixture was then cooled to room temperature, and concentrated in vacuo to remove the methanol. The resultant residue was treated with aqueous saturated sodium hydrogen carbonate and stirred at room temperature for 1 hr before collecting crude product by filtration, and drying at 55° C. over phosphorus (V) oxide under vacuum for 24 hr. The crude product was crystallized from IPA:H2O (1:1, v/v) (800 mL) with slow cooling and mechanical stirring. The product was collected by filtration and washed cold IPA:H2O (1:1, v/v) (100 mL) before being dried in vacuo at 55° C. to yield the title compound as a light brown solid (50.2 g, 90%). LCMS (Method A): RT=5.58 min, [M+H]+=457. 1H NMR (DMSO-d6, 400 MHz) 8.05 (1 H, s), 7.58 (1 H, dd, J=10.69, 1.92 Hz), 7.43 (1 H, s), 7.39 (1 H, d, J=9.33 Hz), 7.31-7.28 (1 H, m), 6.89 (1 H, d, J=9.31 Hz), 6.34 (1 H, t, J=8.68 Hz), 4.64 (1 H, s), 3.64 (2 H, t, J=4.78 Hz), 3.46 (2 H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH2:11]1[C:16](=O)[CH2:15][C:13](=[O:14])[CH2:12]1.[NH2:18][C:19]1[NH:23][N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[O:30])[CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:20]3[C:21](=[O:30])[N:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:23][C:19]=3[NH:18][C:16]3[CH2:11][CH2:12][C:13](=[O:14])[C:15]2=3)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: Nc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: O=C1CCC(=O)C1
Product: O=C1CCC2=C1C(c1ccc(F)c(Br)c1)c1c([nH]n(-c3ccccc3)c1=O)N2
Yield: 48.5 %

Procedure:
3-Bromo-4-fluorobenzaldehyde (0.3 g, 1.5 mmol), 1,3-cyclopentadione (0.15 g, 1.5 mmol), and 5-amino-2-phenyl-1,2-dihydropyrazol-3-one (0.26 g, 1.5 mmol) were processed as in Example 1. The resulting precipitate was chromatographed on silica gel eluting with 10% ethanol/CH2Cl2 to provide 0.32 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.26 (m, 2H), 2.63 (m, 2H), 4.86 (s, 1H), 7.21 (m, 3H), 7.4 (t, 2h), 7.51 (d, 1H), 7.67 (d, 2H),10.47 (s, 1H), 11.2 (s, 1H); MS (ESI−) m/z 438 (M−H)−; Anal. Calcd for C21H15N3FBrO2: C, 56.71; H, 3.51; N, 9.45. Found: C, 56.55; H, 3.86; N, 9.12.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C(=O)(OC(Cl)C)[O:8][C@:9]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[NH:26][C:27]([C@@]12C(C)(C)[C@@](C)(CC1)C(=O)O2)=[O:28])([C:14]#[C:15][CH:16]1[CH2:18][CH2:17]1)[C:10]([F:13])([F:12])[F:11].C(OC)(C)(C)C.O>CN(C)C=O>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]2[NH:26][C:27](=[O:28])[O:8][C@:9]([C:14]#[C:15][CH:16]3[CH2:18][CH2:17]3)([C:10]([F:13])([F:12])[F:11])[C:19]=2[CH:24]=1
Reactant: CC(Cl)OC(=O)O[C@@](C#CC1CC1)(c1cc(Cl)ccc1NC(=O)[C@@]12CC[C@@](C)(C(=O)O1)C2(C)C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
K2CO3 (13.3 g, 95.8 mmol) powder was added to a solution of (S)-2-(5-chloro-2-((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamido) phenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-yl 1-chloroethyl carbonate (7, R1 is 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptyl, R3 is 1-chloroethyl, 36.8 g, 63.9 mmol) in N,N-dimethylformamide (150 mL). The reaction mixture was stirred at room temperature overnight. Methyl t-butyl ether (300 mL) and water (300 mL) were added to the mixture, and the resulting layers were separated. The organic layer was washed with brine and evaporated to 60 mL then petroleum ether (200 mL) was added. The resulting mixture was filtered and rinsed with petroleum ether to give (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (Efavirenz, 1) as an off-white solid.
Reaction SMILES: [CH2:1]1[C@H:13]2[C@H:5]([NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:4][CH2:3][N:2]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19](O)(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S1C=CC=C1.[H][H]>CO.[Pd]>[C:20]1([CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C@H:13]3[CH2:1][N:2]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][CH2:4][C@@H:5]23)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: CCOC(=O)N1CC[C@H]2Nc3ccccc3[C@H]2C1
Reactant: O=C(O)c1ccccc1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CCOC(=O)N1CC[C@@H]2[C@H](C1)c1ccccc1N2Cc1ccccc1
Yield: 97.8 %

Procedure:
A mixture of intermediate 1 (22.46 g), benzoic acid (11.8 g) and thiophene (4%, 2 ml) in methanol (440 ml) was hydrogenated with palladium-on-carbon (10%, 3 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off. The filtrate was evaporated, yielding 30 g (99%) of (±)-ethyl cis-1,3,4,4a,5,9b-hexahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indole-2-carboxylate (intermediate 2).
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[C:16]([S:23][CH:24]([CH3:26])[CH3:25])[CH:15]=2)=[CH:10][CH:9]=1.[CH2:33](O)[CH3:34].Cl>>[ClH:1].[OH:2][C@H:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:33][CH3:34])=[O:21])=[C:16]([S:23][CH:24]([CH3:26])[CH3:25])[CH:15]=2)=[CH:12][CH:13]=1
Reactant: CC(C)Sc1cc(-c2ccc(CCNC[C@H](O)c3ccccc3)cc2)ccc1C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(-c2ccc(CCNC[C@H](O)c3ccccc3)cc2)cc1SC(C)C

Procedure:
The suspension of 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-4-biphenylcarboxylic acid hydrochloride in hydrogen chloride ethanol solution (5.5M, 1 ml) was stirred under reflux for 1.5 hours. The mixture solution was evaporated under reduced pressure and the resultant solid was washed with isopropyl ether to give ethyl 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-4-biphenylcarboxylate hydrochloride (37 mg).
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)c2ccccc2)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Benzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-benzoyloxy-2(1H)-pyrimidinone.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH2:17])[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH:17][C:28]([CH:25]4[CH2:27][CH2:26]4)=[O:29])[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1nc2ccc3c(c2o1)C(CCN)CC3
Reactant: O=C(Cl)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2ccc3c(c2o1)C(CCNC(=O)C1CC1)CC3
Reaction time: 0.25 h
Yield: 42.3 %

Procedure:
2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethanamine hydrochloride (100 mg, 0.396 mmol) and triethylamine (111 μL, 0.792 mmol) were dissolved in tetrahydrofuran (4 mL), cyclopropanecarbonyl chloride (43.1 μL, 0.475 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→80/20) to give the title compound (47.6 mg, yield 42%).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2O)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:18]=[O:19].S(=O)(=O)(O)O.[ClH:25]>C(O)(=O)C>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:11][Cl:25])[C:18]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C=O
Reactant: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 90 °C
Yield: 95 %

Procedure:
A mixture of 2-(2H-benzotriazol-2-yl)-4-methyl-phenol (100.0 g, 0.44 mol), paraformaldehyde (26.4 g, 0.88 mol), sulphuric acid (10.9 g, 110 mmol), conc. HCl (200 mL), and acetic acid (500 mL) is heated to 90° C. for six hours. The precipitated product is isolated by filtration and washed subsequently with AcOH, AcOH:heptane (1:1), and heptane and dried at 45° C. (95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]([CH3:14])[CH2:8][O:9][N:10]=C(C)C)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:14])[CH2:8][O:9][NH2:10])=[CH:15][CH:16]=1
Reactant: CC(C)=NOCC(C)Oc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(CON)Oc1ccc(Cl)cc1
Yield: 768.5 %

Procedure:
10 g (4.13 mmol) of acetone O-[2-(4-chloro-phenoxy)-propyl]-oxime and 31 g of 30% strength aqueous trifluoroacetic acid solution were heated for 83/4 hours at 80° C. at a reduced pressure of 430 mbar, similarly to experiment 3b, 100 g of water being continuously added dropwise to the reaction mixture and a water/acetone mixture being distilled off. The working up similarly to 3b) gave 6.4 g of 2-(4-chlorophenoxy)-propoxyamine in this case. Yield: 76%.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][C:5](OC2C=CC([N+]([O-])=O)=CC=2)=[N:4][S:3]1(=[O:21])=[O:20].Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C@@H:31]([NH2:33])[CH3:32]>ClCCl.C(N(CC)C(C)C)(C)C>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C@@H:31]([NH:33][C:5]1[O:6][C:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:22])[S:3](=[O:20])(=[O:21])[N:4]=1)[CH3:32]
Reactant: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Reactant: C[C@H](N)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC1=NS(=O)(=O)C(C)(C)C(C)(C)O1)c1ccccc1Cl
Yield: 81.4 %

Procedure:
Under inert gas, 200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 176 mg of (S)-1-(2-chlorophenyl)ethylamine hydrochloride were dissolved in 1 ml of dichloromethane and 0.21 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 50 ml of dichloromethane, washed three times with 30 ml of 10% aqueous ammonia solution, three times with 30 ml of 1 N aqueous hydrochloric acid and with 30 ml of saturated aqueous sodium hydrogencarbonate solution, dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (171 mg) with a molecular weight of 344.94 g/mol (C15H21ClN2O3S); MS (ESI): m/e=345 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35](=[O:40])[CH2:34]2.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[NH:36][C:35](=[O:40])[CH2:34]5)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc5c(c4)CC(=O)N5)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.9 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (100 mg, 0.24 mmol) and 5-aminoindolin-2-one (36 mg, 0.24 mmol) in dichloromethane (20 mL) were added 1-methyl-1H-imidazole (79 mg, 0.96 mmol) and EDCI (183 mg, 0.96 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 15 hours, the solid was collected by filtration and washed with methanol (4 mL) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-oxoindolin-5-yl)piperidine-3-carboxamide as a orange solid (68 mg, 51.8%). 1H NMR (300 MHz, DMSO): δ 10.31 (s, 1H), 9.87 (s, 1H), 9.67 (s, 1H), 8.86 (s, 1H), 7.68 (d, 1H, J=2.4 Hz), 7.53 (s, 1H), 7.37 (s, 1H), 7.35 (s, 1H), 6.83-6.81 (m, 1H), 6.75 (d, 1H, J=8.4 Hz), 4.82-4.67 (m, 2H), 3.71-3.65 (m, 6H), 3.48 (s, 2H), 3.12-2.95 (m, 2H), 1.98-1.74 (m, 5H). LC-MS: 546 [M+H]+, tR=1.493 min. HPLC: 98.74% at 214 nm, 98.67% at 25 4 nm, tR=3.60 min.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[Br:75][C:76]1[CH:81]=[CH:80][CH:79]=[C:78](/[CH:82]=[CH:83]/[C:84]2[CH:89]=[CH:88][CH:87]=[C:86]([O:90][CH3:91])[CH:85]=2)[N:77]=1>C(O)CC.O>[Br:75][C:76]1[N:77]=[C:78]([C@@H:82]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@H:83]([OH:12])[C:84]2[CH:89]=[CH:88][CH:87]=[C:86]([O:90][CH3:91])[CH:85]=2)[CH:79]=[CH:80][CH:81]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: COc1cccc(/C=C/c2cccc(Br)n2)c1
Reactant: CC(C)(C)OCl
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: COc1cccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)c2cccc(Br)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 107 %

Procedure:
To tert-butyl carbamate (688 mg, 5.88 mmol) in propanol (10 mL) was added sodium hydroxide (231 mg, 5.78 mmol) in water (20 mL) followed by tert-butyl hypochlorite (0.652 mL, 5.78 mmol). The solution was cooled to 0° C. and (DHQD)2PHAL (89 mg, 0.114 mmol) was added in propanol (3 mL) followed by (E)-2-bromo-6-(3-methoxystyryl)pyridine (550 mg, 1.90 mmol) in propanol (10 mL). To this was added potassium osmate dihydrate (27.9 mg, 0.076 mmol) as a solid in one portion. The reaction was allowed to gradually warm to room temperature overnight. The reaction was placed in a cool bath (ca. 15° C.) and quenched by addition of sodiumthiosulfate (1.1 g) in water (8 mL). The reaction was stirred at room temperature for 30 min. The reaction was diluted with 1:1 diethylether/ethyl acetate, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (20%-->50% EtOAc/Hex) gave 860 mg (107% yield) as a mixture of regioisomers. Mass spec.: 444.98 (MNa)+.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1([CH3:26])[C:11](=[O:12])[N:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)[C:9](=[O:25])[NH:8]1.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.CO>O>[CH3:6][C:7]1([CH3:26])[C:11](=[O:12])[N:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:14]=2)[C:9](=[O:25])[N:8]1[CH2:34][CH2:33][CH2:32][CH2:31][OH:30]
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCO
Temperature: 30 °C
Yield: 89.7 %

Procedure:
300 ml of dimethylformamide and 100 g of the product of Example 3 are introduced at 20°/22° C. and the reaction medium is maintained under agitation at this temperature for approximately 5 minutes then 98.5 g of 4-bromobutyl acetate then 20 g of soda are added and the whole is maintained under agitation and under a nitrogen atmosphere at +20°/+22° C. for approximately 22 hours. While maintaining agitation, at this temperature, 20 g of soda is added then over approximately 5 minutes 400 ml of methanol is added and the whole is maintained in this way for 1 hour. While leaving the temperature to rise, 500 ml of demineralized water at +20° C. is introduced under agitation, then the reaction medium is placed under agitation, 500 ml of demineralized water is added at +20° C. and the whole is maintained under agitation for 1 hour at 25°/30° C., then cooled down under agitation to +0°/+5° C., and maintained for 2 hours, followed by separating, washing with 4×100 ml of demineralized water and drying. Purification is carried out by adding 696 ml of methylene chloride at 20°/22° C. and washing with 3×232 ml of demineralized water then drying, 5.8 g of supra black is added, the medium is maintained under agitation at 20°±2° C. for 2 hours followed by filtering and rinsing with 2×116 ml of methylene chloride. After concentrating under agitation, 116 ml of denat. ethanol toluene is added at 20° C. then 174 ml of demineralized water is added. The reaction medium is cooled down under agitation to 20°/22° C., maintained under agiatation for 2 hours at this temperature then cooled down to 0°±2° C. and maintained for 1 hour under these conditions, followed by separating, washing with 2×58 ml of ethanol with 50% water at 0°/+2° C. and drying. In this way 111.5 g of expected product (white powder) is obtained. M.p.=102° C.