Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:11]=1[N:12]1[CH2:43][CH2:42][C:15]([CH3:44])([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([CH3:41])[O:22][C:23]2[CH:24]=[C:25]([CH3:40])[CH:26]=[CH:27][C:28]=2[CH2:29][O:30][CH2:31]3)[CH2:14][CH2:13]1)[C:7]([O-:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:11]=1[N:12]1[CH2:13][CH2:14][C:15]([CH3:44])([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([CH3:41])[O:22][C:23]2[CH:24]=[C:25]([CH3:40])[CH:26]=[CH:27][C:28]=2[CH2:29][O:30][CH2:31]3)[CH2:42][CH2:43]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(c1)O[C@@H](C)CCCCOC1(C)CCN(CC1)c1c([C@H](OC(C)(C)C)C(=O)[O-])c(C)nc3cc(nn13)COC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2c(c1)O[C@@H](C)CCCCOC1(C)CCN(CC1)c1c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(nn13)COC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 112.6 %

Procedure:
(2S)-2-(tert-Butoxy)-2-[(20S)-4,16,20,26-tetramethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl]acetate (22 mg, 0.035 mmol) was dissolved in MeOH (1 mL). To this was added 1N sodium hydroxide (0.138 mL, 0.138 mmol) and the mixture heated to 60° C. (oil bath temperature). After stirring for 3 hrs the mixture was transferred to a separatory funnel and acidified with 1N HCl. The solution was then extracted with ethyl acetate and the organic layer dried over Na2SO4. After filtration the solvent was removed to under vacuum to provide 24 mg of the title compound as a powder. LCMS (M+H)=609.2.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1)(=[O:38])[CH3:37]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C[C@H]1F
Reactant: CC(=O)Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@H](F)C1

Procedure:
Starting from N-[(1S*,2R*,4S*)-4-amino-2-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f73) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:12]=[C:7]1[NH:8][C:9]2[N:10]=[CH:11][C:2](/[CH:15]=[CH:14]/[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:3][C:4]=2[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.3 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (12.99 g, 57 mmole), tert-butyl acrylate (34 mL, 232 mmole), DIEA (21.2 mL, 122 mmole), Pd(OAc)2 (1.3 g, 5.8 mmole) and P(o-tol)3 (3.5 g, 11.5 mmole) in propionitrile (200 mL) and DMF (50 mL) was purged with Ar, then was heated at reflux. After 18 h the reaction was allowed to cool to room temperature and was concentrated to dryness. The residue was purified by flash chromatography on silica gel (2-4% MeOH/CHCl3). The resulting residue was triturated with 1:1 Et2O/petroleum ether, collected, and dried, and the resulting material was triturated with 1:1 MeOH/H2O, collected, and dried, to give the title compound (7.09 g, 45%) as an off-white solid: 1H NMR (400 MHz, d6-DMSO) δ 10.70 (s, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.04 (s, 1H), 7.50 (d, J=16.0 Hz, 1H), 6.51 (d, J=16.0 Hz, 1H), 2.89 (t, 2H), 2.53 (t, 2H), 1.48 (s, 9H); MS (ES) m/e 275.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH2:23][C:22]=4[CH:36]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:23][C:22]=4[CH:36]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CCOC(=O)CCCN1CCOc2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CN(CCCC(=O)O)CCO4)no2)cc1C#N
Reaction time: 3 h
Yield: 27.8 %

Procedure:
Ethyl 4-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]butanoate (Preparation 80) (0.084 g, 0.171 mmol) was dissolved in Ethanol (2 ml). Then 2N NaOH (1 ml, 2.000 mmol) was added and the reaction left standing at RT for 3 hours. Ethanol was removed by evaporation and the resulting residue dissolved in EtOAc and water, acidified with acetic acid and the phases separated. The organic phase was dried (MgSO4), evaporated and triturated with ether. Drying under vacuum overnight at 50° C. yielded the title compound (22 mg) as a white solid. δH (d6DMSO, 400 MHz): 1.37 (6H, d), 1.66 (2H, t), 2.22 (2H, t), 2.45 (2H, m), 3.01 (2H, m), 3.82 (2H, s), 4.07 (2H, m), 4.95 (1H, m), 7.14 (1H, d), 7.54 (1H, d), 7.89 (1H, dd), 7.96 (1H, d), 8.38 (1H, dd), 8.50 (1H, d); MS (ES): C25H26N4O5 requires 462; found 463 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[CH3:23]C(C)([O-])C.[K+].FC(F)(F)S(OC)(=O)=O.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:15][CH3:23])=[CH:16][CH:17]=[C:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Reactant: CC(C)(C)[O-]
Agent: COS(=O)(=O)C(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reaction time: 0.17 h

Procedure:
Codeinone (300 mg) was added to a stirred suspension of potassium tert-butoxide (153 mg) in N,N-dimethylformamide (5 ml) at room temperature. After 10 minutes, methyl trifluoromethanesulphonate (164 mg) was added dropwise to the suspension. The solution was stirred for 5 minutes, diluted with ethyl acetate (30 ml), and then poured into water (50 ml). The aqueous phase was removed, and the organic phase was dried with sodium sulphate and evaporated, producing an orange solid. Analysis by HPLC against pure thebaine gave a thebaine content of 10%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]([CH:17]([O:23][CH2:24][CH2:25][N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[C:31]([O:35][C:36](=[O:43])[C@H:37]([CH2:39][CH2:40][S:41][CH3:42])[NH2:38])([CH3:34])([CH3:33])[CH3:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]([CH:17]([O:23][CH2:24][CH2:25][N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:14]=[CH:13][C:9]=2[C:10]([NH:38][C@@H:37]([CH2:39][CH2:40][S:41][CH3:42])[C:36]([O:35][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:43])=[O:12])=[CH:4][CH:3]=1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(C(OCCn2ccnc2)c2nccs2)cc1-c1ccc(F)cc1
Product: CSCC[C@H](NC(=O)c1ccc(C(OCCn2ccnc2)c2nccs2)cc1-c1ccc(F)cc1)C(=O)OC(C)(C)C
Yield: 63 %

Procedure:
The title compound was prepared from 2-(4-fluorophenyl)4-[1-(thiazol-2-yl)-2-(imidazol-1-yl)ethoxymethyl]benzoic acid by a similar method to that used for Example 1 but using L-methionine tert-butyl ester in place of L-methionine methyl ester.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[C:15]2C=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2O)=[C:9]([F:25])[CH:8]=1.Cl>N1C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:14](=[O:24])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][C:5]=3[O:4][C:2]2=[O:3])=[C:9]([F:25])[CH:8]=1
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(O)c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(=O)n(-c3ccc(Cl)cc3F)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl chloroformate (0.1 mL, 1.2 mmole) was added dropwise to a stirred solution of compound 2a (0.295 g, 1 mmole) in dry pyridine (8 mL) at 0° C. The mixture was refluxed for 2 hr. After 16 hr stirring at room temperature, the pH of the reaction mixture was adjusted to pH=6 from 1 M HCl(aq). The resulting white mixture was cooled to obtain solid compound. The product was filtered off and recrystallized from hot ethanol. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[N:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[C:40](B(O)O)[CH:39]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[N:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[C:40]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7]4[N:15]=[CH:16][CH:17]=[CH:18][C:6]=4[N:5]3[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]3([NH2:30])[CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:39]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC1(c2ccc(-c3c(-c4cnc5ccccc5c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 160 °C
Yield: 65.8 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol), quinolin-3-ylboronic acid (31 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.3 mg, 0.01 mmol) and K3PO4 (72 mg, 0.27 mmol) in DMF/water (0.9 mL, 6:1, v/v) was heated at 160° C. under microwave irradiation for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by HPLC. To the fraction, conc. HCl (3 ml) and methanol (3 ml) were added and the residue was evaporated after 24 h. The residue was purified by HPLC to give the titled compound as a white solid (30 mg, 55%). 1HNMR (DMSO-d6) 400 MHz δ: 8.85 (d, J=2.3 Hz, 1H), 8.63 (s, 1H), 8.48 (d, J=2.3 Hz, 1H), 8.24 (s, 1H), 8.11 (dd, J=4.6, 1.7 Hz, 1H), 8.03 (dd, J=8.0, 1.7 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.93 (d, J=7.4 Hz, 1H), 7.73 (t, J=7.4 Hz, 1H), 7.60 (t, J=7.4 Hz, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.38 (t, J=8.6 Hz), 7.31 (d, J=7.4 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.15 (t, J=8.0 Hz, 1H), 6.96 (dd, J=8.0, 1.7 Hz, 1H), 6.77 (dd, J=8.0, 4.6 Hz, 1H), 2.47-2.41 (m, 2H), 2.24-2.17 (m, 2H), 2.10-2.02 (m, 1H), 1.77-1.68 (m, 1H); LCMS: 507 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C[C:12]1[N:17]=[C:16]([C:18](O)=O)[CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:18])[N:17]=2)[OH:8])=[CH:5][CH:4]=1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C(O)c2cccc(C)n2)cc1

Procedure:
To a boiling solution of 50 g of 4-methoxybenzaldehyde in 50 ml of p-cymeme is added 11.2 g of 6-methylpicolinic acid. After heating for 3 hours, the reaction is cooled and extracted with 2N HCl. The acidic extracts are washed with ether, made basic with ammonia and extracted with ether. Concentration of the dried ether extracts gives 4-methoxyphenyl-(6-methyl-2-pyridyl)carbinol.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:9](=[O:10])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([CH2:7][C:16]2[C:11]([C:9]([OH:10])=[O:8])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OC(c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccccc1Cc1ccccc1

Procedure:
A mixture of 55.2 g. of 3-phenyl phthalide (0.263 mole), 600 ml. ethanol and 5.9 g. of 10% Pd/C is hydrogenated at room temperature and 50 psi until 1 equivalent of H2 is absorbed. The catalyst is removed by filtration and the solvent removed in vacuo and the residue triturated in petroleum ether to give α-phenyl-o-toluic acid; m.p. 101°-104° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:8]=1)[NH2:5].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[N:26]=[C:25]([CH:27]2[CH2:29][CH2:28]2)[CH:24]=[CH:23][N:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:27]1([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([NH:5][C:4]3[CH:6]=[C:7]([C:9]4[S:13][CH:12]=[N:11][CH:10]=4)[CH:8]=[C:2]([CH3:1])[CH:3]=3)[N:26]=2)[CH2:29][CH2:28]1
Reactant: Cc1cc(N)cc(-c2cncs2)c1
Reactant: Clc1nccc(C2CC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cncs2)c1
Temperature: 100 °C
Yield: 74.5 %

Procedure:
A 20 mL microwave vial was charged with 3-methyl-5-(1,3-thiazol-5-yl)aniline (500 mg, 2.63 mmol), cesium carbonate (2.99 g, 9.20 mmol), 2-chloro-4-cyclopropylpyrimidine (Intermediate 29, 406 mg, 2.63 mmol), and dioxane (10.4 mL). The system was purged and flushed with argon (3×) before adding XantPhos (228 mg, 0.394 mmol) and palladium(II) acetate (59 mg, 0.263 mmol). The system was then purged and flushed with argon (3×) before sealing and heating to 100° C. for 2 h. Upon completion the mixture was cooled to room temperature, diluted with ethyl acetate, filtered through celite washing with ethyl acetate, and concentrated under reduced pressure. Purification by column chromatography on silica gel (0-60% ethyl acetate in hexanes) provided 603 mg (1.96 mmol, 74%) of 4-cyclopropyl-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine as a yellow solid. MS ESI: [M+H]+ m/z 309.2.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH2:4]1)#[N:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CCC[C@H](C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CCC[C@H](C#N)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
In a 25 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-3-cyanocyclohexyl)-amide (48 mg, 0.085 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1.2 mL, 15.6 mmol) was added and the orange reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (3 mL) and ethylenediamine (0.50 mL, 7.4 mmol) was added. The light yellow reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was sequentially washed with water, ethyl acetate, and hexanes to afford 35 mg (95%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-3-cyanocyclohexyl)-amide as an off-white solid. MS: [M+Na]+=474; 1H NMR (DMSO-d6) δ: 12.79 (br. s., 1H), 9.08 (s, 1H), 8.46 (s, 1H), 8.40 (d, J=8.7 Hz, 1H), 8.08 (d, J=7.9 Hz, 1H), 8.00 (d, J=0.8 Hz, 1H), 7.37 (dd, J=8.5, 1.1 Hz, 1H), 4.17 (s, 3H), 4.01-4.31 (m, 1H), 3.30-3.49 (m, 1H), 2.24 (d, J=13.2 Hz, 1H), 2.07 (d, J=12.1 Hz, 1H), 1.59-1.94 (m, 5H), 1.36-1.59 (m, 1H).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].C(O)(=O)C.[CH3:16][NH:17][NH2:18]>C(OC)(C)(C)C>[CH3:16][N:17]1[C:5]([OH:6])=[CH:4][C:3]([CH:2]([F:11])[F:1])=[N:18]1
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CNN
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: Cn1nc(C(F)F)cc1O
Temperature: 5 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
166 g (1 mol) of ethyl difluoroacetoacetate are initially charged in 500 ml of methyl tert-butyl ether, and 60 g of acetic acid are added. After the mixture has been cooled to 5° C., 119 g of methylhydrazine are added in 40% aqueous solution. The mixture is stirred at 22° C. for a further 20 h. The phases are separated, and the organic phase is washed with 200 ml of water and dried over MgSO4. After the solvent has been removed under reduced pressure, 140 g of the product are obtained as a yellow solid with an m.p. of 133° C. and a purity of 96%. Yield 91%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][C:9]([C:17]#[N:18])=[C:10]([N:12]=[CH:13][N:14](C)C)[CH:11]=1.[CH3:21][O:22][C:23](=[O:31])[CH2:24][C:25]1[CH:29]=[C:28](N)[NH:27][N:26]=1>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]2[C:9]([C:17]([NH:18][C:28]3[NH:27][N:26]=[C:25]([CH2:24][C:23]([O:22][CH3:21])=[O:31])[CH:29]=3)=[N:14][CH:13]=[N:12]2)=[CH:8][C:7]=1[O:19][CH3:20]
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OCCCCl
Reactant: COC(=O)Cc1cc(N)[nH]n1
Solvent: CC(=O)O
Product: COC(=O)Cc1cc(Nc2ncnc3cc(OCCCCl)c(OC)cc23)[nH]n1
Yield: 72.9 %

Procedure:
N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (230 mg, 0.78 mmol) in acetic acid (0.7 ml) was heated with methyl(5-amino-1H-pyrazol-3-yl)acetate (110 mg, 0.74 mmol) at reflux for 1 hour. The mixture was cooled, the acetic acid was evaporated in vacuo, and the residue purified by chromatography on silica gel, eluting with methanol:ammonia:dichloromethane (9:1:90), to yield methyl (5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)acetate (219 mg, 69% yield) as a cream solid:
Reaction SMILES: [Si](O[CH:9]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:10]1)(C(C)(C)C)(C)C.C[Si]([Br:25])(C)C>C(Cl)Cl>[Br:25][CH:9]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:10]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(F)cc2)O1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: Fc1ccc(C2CCC(Br)O2)cc1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
2-(t-Butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (202, 593 mg, 2.0 mmol) was mixed in 10 mL of dry methylene chloride (degassed by bubbling argon prior to use). This solution was cooled to -70° C. While stirring at the same temperature under dry argon, trimethylsilyl bromide (290 μL, 2.2 mmol) was added dropwise. The stirring was continued for an additional 1.5 h to produce 2-bromo-5-(4-fluorophenyl) tetrahydrofuran (203) which was not isolated and was used in subsequent chemistry without further purification (see below).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5]C=O)[CH3:4].[CH3:8][C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[C:10](=[O:12])C.Cl>CCOCC.C1C=CC=CC=1>[CH3:13][C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:8])[C:10](=[O:12])[CH2:4][CH:3]=[O:5]
Reactant: CC(=O)C(C)(C)c1ccccc1
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(C)(C(=O)CC=O)c1ccccc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 8.8 g. of 50% NaH oil dispersion in 150 ml. of dry benzene was treated at 25° C. with 13.6 g. of ethylformate in 20 ml. of dry benzene under N2. Over a period of a half hour, 14.9 g. of 3-methyl-3-phenyl-2-butanone in 80 ml. of dry benzene was added at 0° C. After stirring at 40° C. for 4 hours, the mixture was diluted with 250 ml. of ether, treated with ice and acidified with hydrochloric acid. The acidic solution ws extracted with ether and the ether extract was washed with brine, sodiuim bicarbonate solution, washed again with brine and dried. The solvent was evaporated and the residue was distilled under reduced pressure to afford 14.8 g. of the title product as an oil, B. P. 83°-84°/0.2 mm., λmaxfilm 3.5 (broad) 5.75, 5.90, 6.12, 6.30, 6.70, 6.80, 6.95, 7.31, 7.94, 8.18, 9,38, 12,60, 13.05 and 14.28 μ.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Mg+2].[Cl-].[Cl-].[Cl:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)=[O:15].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>CC(C)CC(O)C.OCC(CO)O>[Cl:12][CH2:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[OH:15]
Reactant: O=C(CCl)c1cccc(Cl)c1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CC(C)CC(C)O
Solvent: OCC(O)CO
Product: O[C@@H](CCl)c1cccc(Cl)c1
Reaction time: 24 h

Procedure:
For the conversion, a mixture of 20 ml of a buffer (100 mM potassium phosphate, pH=8.5, 1 mM MgCl2, 10% glycerol), 20 g 2-chloro-1-(3-chlorophenyl)ethane-1-one dissolved in 80 ml 4-methyl-2-pentanol, 10 mg NAD and 20 000 U recombinant oxidoreductase from Pichia stipidis DSMZ 3651 was incubated at room temperature for 24 h with constant thorough mixing. After 24 h, more than 99% of the 2-chloro-1-(3-chlorophenyl)ethane-1-one used had been reduced. Subsequently, the 4-methyl-2-pentanol phase containing the product was separated from the aqueous phase, filtered, and the product (R)-2-chloro-1-(3-chlorophenyl)ethane-1-ol was obtained by distillation.
Reaction SMILES: [N+:1]([C:4]1[C:5](/[CH:14]=[N:15]/[S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[C:5]([CH2:14][NH:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2]
Reactant: CC(C)(C)S(=O)/N=C/c1ccc2cccnc2c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)S(=O)NCc1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.9 %

Procedure:
A solution of 2-methyl-propane-2-sulfinic acid 1-(8-nitro-quinolin-7-yl)-meth-(E)-ylideneamide (Intermediate 208) (400 mg, 1.3 mmol) in MeOH (8 ml) under a nitrogen atmosphere was cooled to 0° C. Sodium borohydride (1.24 g, 3.3 mmol) was added and the mixture was allowed to warm to room temperature while stirring for 16 h. The reaction mixture was concentrated in vacuo and the residue was diluted with sat. sodium bicarbonate solution (15 ml), extracted with EtOAc followed by 10% MeOH/DCM. The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (411 mg, 100%). The material was used in the next step without purification.