Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[C:25]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:1][C@@H:2]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=2)[C:3]([O:5][CH3:6])=[O:4])=[O:34])=[CH:36][CH:37]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(C#N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Prepared using General Procedure 3: To the solution of (S)-methyl 2-amino-3-(4-cyanophenyl)propanoate (789.2 mg, 3.32 mmol) in DCM (15 mL) and DIEA (1.29 g, 9.96 mmol) was added 4-(tert-butyl)benzoyl chloride (981.3 mg, 4.99 mmol) at RT. The reaction was stirred for 2 h and the reaction was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 1.06 g (88%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate. LCMS-ESI (m/z) calculated for C22H24N2O3: 364.2. found 365.3 [M+H]+, tR=3.55 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=8.0 Hz, 1H), 7.85-7.60 (m, 4H), 7.49 (dd, J=15.1, 8.4 Hz, 4H), 4.85-4.60 (m, 1H), 3.65 (s, 3H), 3.30-3.23 (m, 1H), 3.18 (dd, J=13.7, 10.6 Hz, 1H), 1.29 (s, 9H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.[O:25]=[C:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:31][C:32](O)=[O:33]>>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([NH:22][C:32](=[O:33])[CH2:31][N:27]4[CH2:28][CH2:29][CH2:30][C:26]4=[O:25])[CH2:20][CH2:21]3)=[CH:23][CH:24]=2)[CH2:2]1
Reactant: NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: O=C(O)CN1CCCC1=O
Product: O=C(CN1CCCC1=O)NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Compound 289 is synthesized from Intermediate M and (2-Oxo-pyrrolidin-1-yl)-acetic acid according to the procedure used to synthesize Example 261. (LC/MS method 16: ES+ m/z 451.4 [M+H]+, Rt=2.51 min)
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][N:31]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH:32]1[CH2:36][CH2:35][O:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:40]4[CH2:39][CH2:38][CH:37]([N:31]([CH3:30])[CH:32]5[CH2:36][CH2:35][O:34][CH2:33]5)[CH2:42][CH2:41]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CN(C1CCNCC1)C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N(C)C4CCOC4)CC3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (72 g, 0.19 mmol), methylpiperidin-4-yl(tetrahydrofuran-3-yl)amine (42 mg, 0.23 mmol) and 4 Å powdered molecular sieves (200 mg) in DCE (5 mL) was stirred at room temperature for 6.5 h before the addition of sodium triacetoxyborohydride (81 mg, 0.38 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 390 as a cream solid (55 mg, 53%). LCMS (Method G): RT 4.96 min [M+H]+ 546.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.99 (m, 1 H); 7.77-7.73 (m, 1 H); 7.29-7.23 (m, 2 H); 4.34 (m, 4 H); 3.96 (m, 1 H); 3.91-3.69 (m, 12 H); 3.45-3.26 (m, 3 H); 2.97 (d, J=11.3 Hz, 2 H); 2.51 (m, 1 H); 2.26 (s, 3 H); 2.16 (t, J=11.3 Hz, 2 H); 2.03 (m, 1 H); 1.89 (m, 2 H); 1.76 (s, 2 H); 1.66 (m, 1 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: S(Cl)([Cl:3])=O.[I:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1>CN(C=O)C.ClCCl>[I:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([Cl:3])=[O:15])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (39.53) and DMF (2 drops) were added to a solution of 4-iodophenylacetic acid (26.2 g), in dichloromethane (150 ml). The reaction mixture was stirred at ambient temperature for 18 hours and the solvent removed by evaporation to give 4-iodophenylacetyl chloride as an oil (23 g) which was purified by vacuum distillation; b.p. 118-119° C. (0.35 mmMg)
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[F:28][C:29]1[C:35]([F:36])=[CH:34][C:32]([NH2:33])=[C:31]([O:37][CH3:38])[CH:30]=1>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:33][C:32]2[CH:34]=[C:35]([F:36])[C:29]([F:28])=[CH:30][C:31]=2[O:37][CH3:38])=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: COc1cc(F)c(F)cc1N
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 4,5-difluoro-2-methoxyaniline (commercially available; CAS RN 1017779-71-3) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. White solid (80%). MS (ESI): m/z=425.027 [M+H]+.
Reaction SMILES: C[Al](C)C.CO[C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[C:23]([CH3:24])=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30]>C1(C)C=CC=CC=1.O>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH:30][C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[C:23]([CH3:24])=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8]
Reactant: COC(=O)c1sccc1Nc1ncnc2[nH]cc(C)c12
Reactant: NCc1cccc(Cl)c1
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c[nH]c2ncnc(Nc3ccsc3C(=O)NCc3cccc(Cl)c3)c12
Temperature: 70 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
Trimethyl aluminum (0.35 mL, 0.69 mmol, 2M in toluene) was added to a solution of 3-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester (50 mg, 0.17 mmol) and 3-chlorobenzylamine (0.11 mL, 0.87 mmol) in toluene (2 mL), and stirred overnight at 70° C. The reaction mixture was cooled to room temperature, diluted with H2O and EtOAC, and filtered through an Extrelut column. The column was washed with EtOAC and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 100% EtOAC in hexanes to provide the desire product (34 mg, 49% yield) as an off-white solid. LC-MS (M+H=398, obsd.=398).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:24]2)[O:12]1.[BH3-]C#N.[Na+].[CH3:43][C:44](O)=O.CC=O>CO.O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH2:43][CH3:44])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:24]2)[O:12]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Reactant: CC(=O)O
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a mixture of benzyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (3.76 g, 7.2 mmol) and NaBH3CN (5.9 g, 93.6 mmol) in MeOH (40 mL) was added AcOH to adjust to pH=6. Then, 40% MeCHO (8.7 mL, 122.5 mmol) was added and the mixture was stirred at 30° C. for 1.5 h. Water (15 mL) was added and the mixture was concentrated in vacuo. Then, the mixture was extracted with DCM (30 mL×3). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by SGC (DCM: MeOH=100:1-20:1) to obtain the target (2.6 g, yield: 66%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.26 (s, 1H), 8.23 (m, 1H), 7.37-7.28 (m, 5H), 6.24 (s, 1H), 5.52-5.49 (m, 1H), 5.10-5.06 (m, 3H), 4.41-4.40 (m, 1H), 3.20-2.90 (m, 2H), 2.80-2.60 (m, 2H), 2.12-1.77 (m, 4H), 1.74-1.60 (m, 3H), 1.39 (s, 3H), 1.26-1.22 (m, 3H), 0.94-0.89 (m, 3H) ppm; ESI-MS (m/z): 551.3 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12])#[C:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].O>CN1CCCC1=O>[CH2:3]([C:2]1[NH:12][C:6]2[C:5]([CH:1]=1)=[CH:10][CH:9]=[C:8]([F:11])[CH:7]=2)[CH3:4]
Reactant: CCC#Cc1ccc(F)cc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1cc2ccc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The reaction was carried out under an argon atmosphere. 21 g (0.13 mol) 2-but-1-ynyl-5-fluoro-phenylamine were added to 30 g (0.27 mol) potassium tert.butoxide in 120 mL N-methyl-2-pyrrolidinone and the mixture was stirred for 4 h at RT. The reaction mixture was mixed with water and extracted with diethyl ether. The organic phase was dried and evaporated down. The residue was purified on silica gel.
Reaction SMILES: Cl.O[CH2:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][N:5]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][N:5]=1
Reactant: OCc1nccc2c1CCCC2
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ClCc1nccc2c1CCCC2
Temperature: 50 °C

Procedure:
To a solution of l-hydroxymethyl-5,6,7,8-tetrahydroisoquinoline hydrochloride (0.42 g) in chloroform (10 ml) was added dropwise a solution of thionyl chloride (1.1 ml) in chloroform (5 ml) at room temperature and heated for 2 hours at ca. 50° C. The reaction mixture was concentrated in vacuo and the residue was taken up with ethyl acetate. The organic layer was washed with saturated sodium carbonate aqueous solution, dried over sodium sulfate, filtered and concentrated in vacuo to give 1-chloromethyl-5,6,7,8-tetrahydroisoquinoline (0.22 g) as a brown oil.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.[Si:14]([O:21][C@H:22]([CH2:27][O:28][CH3:29])[C:23](OC)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O>[Si:14]([O:21][C@H:22]([CH2:27][O:28][CH3:29])[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][N:11]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: Cc1ccc(N)nc1
Reactant: COC[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium (2.5M in hexanes) (2.04 mL, 3.26 mmol) was added dropwise to a stirred solution of 5-methylpyridin-2-amine (CAS 1603-41-4) (353 mg, 3.26 mmol) in THF (10 mL) cooled to 10° C. under nitrogen. The resulting solution was stirred at ambient temperature for 10 minutes and then added to a solution of (R)-methyl 2-(tert-butyldimethylsilyloxy)-3-methoxypropanoate C5b (810 mg, 3.26 mmol) in THF (10 mL) at 10° C. The resulting solution was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with saturated ammonium chloride (50 mL), water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. Purification by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane provided (R)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(5-methylpyridin-2-yl)propanamide (300 mg). 1H NMR (400 MHz, CDCl3) δ 0.15 (3H, s), 0.16 (3H, s), 0.88 (9H, s), 2.12 (3H, s), 3.46 (3H, s), 3.61-3.65 (2H, m), 4.35-4.42 (1H, m), 7.47 (1H, d), 8.19 (1H, d), 8.20 (1H, s), 8.97 (1H, s), m/z (ESI+) (M+H)+=325; HPLC tR=3.08 min.
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][CH:20]3[O:24]C(=O)[N:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21]3)[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3>C1COCC1.O>[Br:18][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:19][CH:20]([OH:24])[CH2:21][NH:22][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:8]3[C:16]([C:15]=2[CH:14]=1)=[CH:17][C:5]([Br:4])=[CH:6][CH:7]=3
Reactant: O=C1OC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CN1c1ccccn1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: OC(CNc1ccccn1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 168 h
Yield: 82.1 %

Procedure:
LiOH.H2O (0.0076 g, 0.182 mmol, 10 equiv) was added to 5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(pyridin-2-yl)oxazolidin-2-one (0.0091 g, 0.0182 mmol) in a mixture of 208 μL THF and 23 μL H2O (v/v=9:1). The mixture was stirred at room temperature for 7 days. The reaction mixture was purified by silica gel chromatography using CH2Cl2/EtOAc as elute to afford 0.0071 g white solid as product, yield 41.0%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].[CH:14]([Mg]Br)=C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:14])[CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1cccc(F)c1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
A solution of 3-fluoro-N-methoxy-N-methylbenzamide (16 g, 87.4 mmol) in THF (150 mL) was cooled to −78° C. Vinylmagnesium bromide (120 mL, 120 mmol) was added slowly. The mixture was stirred at −78° C. for 10 min, at rt for 3 h, and quenched by addition of 1 N aq HCl (100 mL) at 0° C. The aqueous layer was extracted with EtOAc (100 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography to afford 1-(3-fluorophenyl)ethanone (9.7 g, yield: 75%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[CH2:19]([SH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([S:26][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1cccnc1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1cccnc1SCc1ccccc1
Yield: 78.5 %

Procedure:
10 g of 2,3-dichloropyridine, 11.2 g of anhydrous potassium carbonate and 100 ml of dimethylsulfoxide were mixed to obtain a suspension. To this suspension, 10 ml of a dimethylsulfoxide solution of 10.1 g of benzyl mercaptan was dropwise added over a period of about 20 minutes at 110° C. Then, the mixture was reacted at a temperature of from 120 to 130° C. for about 1.5 hours. Thereafter, the reaction product was put into water and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate. Then, methylene chloride was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 12.5 g of oily 2-benzylthio-3-chloropyridine.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]1=O>>[CH3:2][C:1]1[S:3][C:11]2[CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=2[N:4]=1
Reactant: CCOC(=O)C1CCCC(Br)C1=O
Reactant: CC(N)=S
Product: CCOC(=O)C1CCc2sc(C)nc2C1

Procedure:
The compound is prepared by action of thioacetamide on 2-bromo-5-ethoxycarbonyl cyclohexanone (II), as described in Example 1. B.P.0.4 =116°-120° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[CH2:12][C@H:11]([NH:13][C:14]3[N:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:10]2)[C:3]=1[NH2:24].[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:24][C:3]1[C:2]([C:32]2[CH:33]=[CH:34][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:30][CH:31]=2)=[N:7][CH:6]=[N:5][C:4]=1[NH:8][C@H:9]1[CH2:12][C@H:11]([NH:13][C:14]2[N:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10]1
Reactant: Nc1c(Cl)ncnc1N[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ncnc(N[C@H]3C[C@H](Nc4ncc5ccccc5n4)C3)c2N)cc1
Temperature: 120 °C

Procedure:
6-chloro-N4-(trans-3-(quinazolin-2-ylamino)cyclobutyl)pyrimidine-4,5-diamine (from example 13 step 2, 0.045 g, 0.132 mmol), tetrakis(triphenylphosphine)palladium (0.015 g, 0.013 mmol), (4-methoxycarbonylphenyl)boronic acid (0.036 g, 0.197 mmol), and potassium carbonate (0.073 g, 0.527 mmol) were combined with dioxane (2 mL) and water (0.5 mL) and sealed in a vial under argon. The reaction was heated at 120° C. for 25 minutes in the microwave. The crude product was partitioned between water (100 mL) and ethyl acetate (100 mL) and the organic phase dried with magnesium sulfate. Purification using silica chromatography (0-8% (2N ammonia in methanol) in dichloromethane) gave the desired methyl 4-(5-amino-6-((trans-3-(quinazolin-2-ylamino)cyclobutyl)amino)pyrimidin-4-yl)benzoate (0.039 g, 0.088 mmol, 67.1% yield) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH2:10][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[C:13]1([C@H:11]2[CH2:10][O:9][C:8]([C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[O:1][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:12]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(C2=N[C@@H](c3ccccc3)CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(C2=N[C@@H](c3ccccc3)CO2)c1
Reaction time: 12 h
Yield: 100.2 %

Procedure:
To a vigorously stirred mixture of 4,5-dihydro-2-(3-hydroxyphenyl)-4(S)-phenyloxazole (2.04 g, 8.5 mmol) and potassium carbonate (2.36 g, 17 mmol) in DMF (40 ml) was added dropwise over 5 min. a solution of ethyl bromoacetate (1.71 g, 10.2 mmol) in DMF (5 ml) at ambient temperature. The reaction mixture was stirred for 12 h and then poured into water (100 ml). The mixture was extracted with diethyl ether (3×50 ml), and the combined extracts were washed with brine (50 ml), dried (MgSO4) and concentrated under reduced pressure to afford title compound (2.77 g, quant.) as a pale yellow liquid.
Reaction SMILES: C[Mg+].[Br-].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>CCOCC>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)=[CH:16][CH:15]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1ccc(CBr)cc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: Clc1ccc(Cc2c[nH]c3ccccc23)cc1
Yield: 29.1 %

Procedure:
To a vigorously stirred solution of 30 mL of 3M MeMgBr in ether was added dropwise a solution of 10 g of indole in 100 mL of ether. After addition was finished, the mixture was heated to reflux for 30 minutes and treated with 22 g of p-chlorobenzyl bromide. The reaction mixture was refluxed for 3 hours, quenched with 50 mL of saturated aqueous solution of NH4Cl, and extracted with 200 mL of ether. The ether layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel flash chromatography eluted with toluene to give 6 g of the title compound as a beige solid.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.O>[C:1]([N:5]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccco1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccco1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N'-t-butyl-N-(2-furoyl)hydrazine (1.0 g) was dissolved in 10 ml toluene and 2 ml water. 50% aqueous sodium hydroxide (1.0 g) was added followed by benzoylchloride (0.8 g). After stirring for 14 hours at room temperature, the solid product, N'-t-butyl-N-(2-furoyl)-N'-benzoylhydrazine, was removed by filtration and washed with water. m.p. 160-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:18][O:19][CH:20]([O:26][CH3:27])[CH2:21][C:22](OC)=[O:23].C[O-].[Na+].[Na]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:21]([CH:20]([O:26][CH3:27])[O:19][CH3:18])[C:22]2=[O:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=Cc1cccnc1Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)CC(OC)OC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: COC(OC)c1cc2cccnc2n(-c2cc(Cl)cc(Cl)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
A solution of 42.7 g of 2-(3,5-dichlorophenyl)aminonicotinaldehyde, prepared in Example 29, in 500 ml of tetrahydrofuran containing 35.6 g of methyl 3,3-dimethoxypropionate, and a solution of sodium methylate prepared from 5.5 g of sodium in 100 ml of methanol, are stirred for 24 h at room temperature. The reaction mixture is subsequently concentrated under vacuum, water is then added and the crystals formed are filtered off, washed carefully with water and dried to give 44.25 g of 1-(3,5-dichlorophenyl)-1,2-dihydro-3-dimethoxymethyl-2-oxo-1,8-naphthyridine in the form of white crystals melting at 190° C. Yield 75.7%.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([C:7](O)=[O:8])[N:6]=1.CN(C=O)C.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([C:7]([Cl:24])=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Cl)c(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of 2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (1.47 g, 6.70 mmol) in CH2Cl2 (30 mL) cooled at 0° C. was added DMF (26 μL, 0.34 mmol) and oxalyl chloride (0.73 mL, 8.38 mmol). The reaction was allowed to warm to ambient temperature and stirred for 4 h. The solution was concentrated in vacuo to provide 2-methyl-5-phenyl-1,3-thiazole-4-carbonyl chloride as a yellow-orange oil which gave a mass ion (ES+) of 236.3. 1H NMR δ (ppm) (CDCl3): 7.42-7.46 (5H, m), 2.78 (3H, s).