Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[N:31]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[N:32]=[C:33]([I:34])[C:26]=12>CN(C1C=CN=CC=1)C.BrC1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[N:31]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[N:32]=[C:33]([I:34])[C:26]=12
Reactant: COc1ccc(Cn2nc(I)c3c(Cl)ccnc32)cc1
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 150 °C
Reaction time: 72 h
Yield: 77.1 %

Procedure:
A mixture of 5-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.009 g, 0.03 mmol, prepared in Example 45, step F), 4-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (0.010 g, 0.0250 mmol) and DMAP (0.006 g, 0.05 mmol) in bromobenzene (0.300 mL) under N2 was stirred at 150° C. for 3 days. The reaction was concentrated in vacuo to remove as much bromobenzene as possible and then purified directly by flash column chromatography, eluting with 10:1 CH2Cl2/MeOH. The desired product (0.013 g, 76%) was obtained as a yellow solid. LRMS (APCI pos) m/e 675 (M+1).
Reaction SMILES: ClC1C=CN=C2C=CSC=12.F[C:12]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[C:22](C(N(C)C)=O)[S:23][C:16]=12.[N+](C1C=CC(O)=CC=1)([O-])=O>>[N+:33]([C:31]1[CH:30]=[CH:29][C:13]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)=[CH:12][CH:32]=1)([O-:35])=[O:34]
Reactant: CN(C)C(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: Clc1ccnc2ccsc12
Agent: O=[N+]([O-])c1ccc(O)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3ccsc23)cc1
Yield: 89 %

Procedure:
Staring from the chloride 2, following the procedure described above for the synthesis of compound 6 (scheme 1, example 1) but substituting 2-fluoro-4-nitrophenol for 4-nitrophenol, title compound 212 was obtained in 89% yield. MS (m/z) 273.0 (M+H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([NH2:30])=[O:29])=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:36]>C(OCC)(=O)C>[ClH:36].[NH2:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([NH2:30])=[O:29])=[CH:15][CH:14]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.24 g, 0.5 mmol) in ethyl acetate, (5 mL) was added a solution of 4N hydrogen chloride in ethyl acetate (5 mL), and the obtained solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diisopropyl ether to give (E)-3-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenamide hydrochloride (0.20 g, 95.2%) as crystals.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.Br[C:18](=[CH:20][CH3:21])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:19][C:18]([C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1)=[CH:20][CH3:21]
Reactant: CC=C(C)Br
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC=C(C)c1ccc(N)nc1
Temperature: 90 °C
Yield: 39.8 %

Procedure:
A reaction flask was charged with 0.5 g (2.27 mmol) of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxa borolan-2-yl)-pyridin-2-ylamine, 0.31 g (2.50 mmol) of 2-bromo-but-2-ene, 1.48 g (4.54 mmol) of Cs2CO3 and 52 mg (0.045 mmol) of tetrakis(triphenylphosphine)palladium under nitrogen atmosphere. The solids were dissolved in a degassed toluene/ethanol mixture (20 mL, 1/1) and the reaction heated to 90° C. for 7 h. The reaction was quenched with water (5 mL) and TBME (5 mL). The reaction mixture was filtered. The filtrate was extracted with TBME (20 mL). The organic extract was washed with brine and concentrated under reduced pressure. The residue was purified twice by column chromatography (silica, eluent DCM, 0-50% ethyl acetate) to afford 134 mg of 5-(1-methyl-propenyl)-pyridin-2-ylamine. ES−MS: m/z 149 [M+H+];
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>FC(C1C=CC=CC=1)(F)F>[Br:25][CH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ncccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Temperature: 75 °C
Yield: 8.3 %

Procedure:
tert-Butyl 3-methyl-1H-pyrazolo[3,4-b]pyridin-1-carboxylate (6.6 g, 28.3 mmol) was added into trifluoromethylbenzene (300 mL), and heated to 75° C. Then NBS (5.04 g, 28.3 mmol) was added, and after 15 minutes AIBN (465 mg, 2.8 mmol) was added, and heated to 80° C. and reacted for 1 hour. It was cooled slowly to room temperature and reacted for 12 hours. It was filtered to remove solid. The filtrate was rotate evaporated to dryness, and chromatographed on a column (PE:EA=25:1) to obtain a white solid 730 mg, at a yield of 8.3%.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH2:20].Cl>O1CCOCC1>[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH:20][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CN1CCCC1CCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)NCCC2CCCN2C)cc1

Procedure:
The title compound was prepared as in Example 81 with 4-toluenesulfonyl chloride replacing 2-naphthalenesulfonyl chloride and with 2-(1-methyl-pyrrolidin-2-yl)-ethylamine replacing 2-pyrrolidin-1-yl-ethylamine. The hydrochloride salt was prepared by treatment with hydrogen chloride in 1,4-dioxan. 1H NMR (DMSO-d6) 7.62 (2H, d, 8.1), 7.47 (1H, t, 5.1), 7.37 (2H, d, 8.1), 2.86-2.70 (3H, m), 2.37 (3H, s), 2.09 (3H, s), 1.98-1.93 (2H, m), 1.7-1.49 (4H, m) 1.29-1.16 (2H, m). Microanalysis found C 52.52 H 7.30 N 8.53. C14H23ClN2O2S requires C 52.73 H 7.27 N 8.79.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5].[CH:15]([C:17]1[CH:18]=[CH:19][C:20]([O:37][CH3:38])=[C:21]([CH:36]=1)[CH2:22][O:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([NH:31][C:32](=[O:34])[CH3:33])=[CH:26][C:25]=1[CH3:35])=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>CCO>[CH3:38][O:37][C:20]1[CH:19]=[CH:18][C:17]([CH:15]2[N:6]([CH2:7][CH2:8][O:9][CH3:10])[C:4](=[O:5])[C:3]3[C:2](=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:1]2)=[CH:36][C:21]=1[CH2:22][O:23][C:24]1[C:25]([CH3:35])=[CH:26][C:27]([NH:31][C:32](=[O:34])[CH3:33])=[CH:28][C:29]=1[CH3:30]
Reactant: COCCNC(=O)c1ccccc1N
Reactant: COc1ccc(C=O)cc1COc1c(C)cc(NC(C)=O)cc1C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: COCCN1C(=O)c2ccccc2NC1c1ccc(OC)c(COc2c(C)cc(NC(C)=O)cc2C)c1
Yield: 50.8 %

Procedure:
2-amino-N-(2-methoxyethyl)benzamide (71.2 mg, 0.367 mmol), N-(4-(5-formyl-2-methoxybenzyloxy)-3,5-dimethylphenyl)acetamide (100 mg, 0.305 mmol) and 0.2 equiv of Yb(OTf)3 in 5 mL of EtOH were heated at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica-gel using 10-80% ethyl acetate in DCM to give the N-(4-(2-methoxy-5-(3-(2-methoxyethyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)benzyloxy)-3,5-dimethylphenyl)acetamide (77.9 mg, 0.155 mmol, 50.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.97 (s, 3 H), 2.09 (s, 6 H), 2.90 (ddd, J=13.5, 6.7, 6.5 Hz, 1 H), 3.19 (s, 3 H), 3.31-3.53 (m, 2 H), 3.74 (s, 3 H), 3.86-4.06 (m, 1 H), 4.63 (s, 2 H), 5.85 (d, J=2.3 Hz, 1 H), 6.53-6.69 (m, 2 H), 6.98 (d, J=8.6 Hz, 1 H), 7.12-7.22 (m, 3 H), 7.22-7.31 (m, 2 H), 7.47 (d, J=2.3 Hz, 1 H), 7.61 (d, J=6.7 Hz, 1 H), 9.67 (s, 1 H); LC/MS (electrospray+ve), m/z 504.2 (MH)+, Retention time t=5.27 min; Purity: UV220>98%, UV254>98%; HRMS (ESI): m/z calcd for C29H33N3O5 [M+H]+504.2496, found 504.2498.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:56])([F:55])[CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:52]2[CH2:53][CH2:54][CH:49]([C:48]([F:56])([F:55])[F:47])[CH2:50][CH2:51]2)=[O:23])=[CH:15]3)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(C(F)(F)F)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-trifluoromethylpiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:20]1([C:26]2[O:27][C:28](=[O:31])[CH2:29][N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5](/[C:6](=[C:29]2/[N:30]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:27][C:28]/2=[O:31])/[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CN=C(c2ccccc2)O1
Reactant: CS(=O)(=O)c1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(=C2\N=C(c3ccccc3)OC2=O)c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 22.9 %

Procedure:
A solution of 11 ml of titanium tetrachloride in 27 ml of carbon tetrachloride is added dropwise at -10° C. to 110 ml of anhydrous tetrahydrofuran. Once the addition is complete, a solution of 14.7 g of 4-chloro-4'-(methylsulphonyl)benzophenone (the preparation of which is described in the document W097/37984) in 50 ml of anhydrous tetrahydrofuran is added dropwise in keeping the temperature below 0° C. A mixture of 8.05 g of 2-phenyl-5(4H)-oxazolone, 16 ml of pyridine and 25 ml of anhydrous tetrahydrofuran is then added dropwise at 0° C. The mixture is stirred 2 hours at this temperature, then brought to ambient temperature and 50 ml of water are added. After decanting, the organic phase is washed with water then dried over magnesium sulphate and evaporated off under vacuum. The residue crystallises in an acetone/t-butyl methyl ether mixture and is chromatographed on silica in an acetone/dichloromethane mixture (0.3/10) to give 5 g of (E)-4-[1-(4-chlorophenyl)-1-[4-(methylsulphonyl)phenyl]methylene]-2-phenyl-5-oxazolone as crystals of melting point 226° C.
Reaction SMILES: CN(C)[CH2:3][CH2:4]C1C2C(O)=CC=C(F)C=2N(C)C=1.C([O:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]2[C:27]=1[C:28]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])=[CH:29][NH:30]2)C1C=CC=CC=1>>[CH3:40][N:38]([CH3:39])[CH2:37][CH2:36][C:28]1[C:27]2[C:26]([OH:25])=[CH:34][C:33]([F:35])=[CH:32][C:31]=2[N:30]([CH2:3][CH3:4])[CH:29]=1
Reactant: CN(C)CCc1cn(C)c2c(F)ccc(O)c12
Reactant: CN(C)CCc1c[nH]c2cc(F)cc(OCc3ccccc3)c12
Product: CCn1cc(CCN(C)C)c2c(O)cc(F)cc21

Procedure:
Following the procedures (step 7-8 scheme 1) used to prepare compound 1-9c, compound 1-7b was used as starting material to obtain compound 1-9b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:30])[C:11]([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH2:27][CH3:28])[C:21]=2[CH:29]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:30])[C:11]([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH2:27][CH3:28])[C:21]=2[CH:29]=1)([OH:16])[C:12]([F:13])([F:14])[F:15]
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OC)cc3Cl)C(F)(F)F)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(O)cc3Cl)C(F)(F)F)cc21
Yield: 102.6 %

Procedure:
In analogy to Example 56, step 4, 6-[2-(2-chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-ethyl-4H-benzo[1,4]oxazin-3-one (1.58 g) was reacted with 1M solution boron tribromide in dichloromethane, to give the title compound (1.57 g) as a light yellow solid. MS (m/e)=430.2 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[N:11]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:10](=[O:17])[C:9]2[C:4](=[CH:5][C:6]([C:22]([F:25])([F:24])[F:23])=[C:7]([C:18](=[O:21])[CH2:19][CH3:20])[CH:8]=2)[NH:3]1.[BH4-].[Na+].Cl>C1COCC1.CO.CCOC(C)=O.O>[OH:21][CH:18]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[C:22]([F:24])([F:23])[F:25])[NH:3][C:2](=[O:1])[N:11]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:10]2=[O:17])[CH2:19][CH3:20]
Reactant: CCC(=O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Yield: 77.3 %

Procedure:
To a solution of N-(2,4-dioxo-6-propionyl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (50 mg, 0.132 mmol) in THF (1 mL) and MeOH (1 mL) was added sodium borohydride (80 mg, 2.11 mmol). The resultant mixture was stirred for 20 h. After that time, it was then diluted with EtOAc and water and the pH was adjusted to 4-5 with an aqueous hydrochloric acid solution (1N). The organic phase was separated and washed once with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the crude product by flash chromatography (silica gel 60, DCM/MeOH 100:0→90:10) to afford N-[6-(1-hydroxy-propyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (39 mg, 0.102 mmol, 78%) as a white powder, m.p. 219-222° C., 1H-NMR (DMSO-d6, 400 MHz) 11.93 (br s, 1H), 10.38 (br s, 1H), 8.33 (s, 1H), 7.50 (s, 1H), 5.63 (m, 1H), 5.27 (m, 1 H), 3.17 (s, 3H), 1.60 (m, 2H), 0.93 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:5](=O)[C:4]([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[C:3]1[O:16]CC.[F:19][C:20]([F:27])([C:23]([F:26])([F:25])[F:24])[CH2:21][NH2:22]>C(O)C>[O:1]=[C:2]1[C:3](=[O:16])[C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)=[C:5]1[NH:22][CH2:21][C:20]([F:27])([F:19])[C:23]([F:26])([F:25])[F:24]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: CCOc1c(Nc2ccc(C#N)cc2)c(=O)c1=O
Solvent: CCO
Product: N#Cc1ccc(Nc2c(NCC(F)(F)C(F)(F)F)c(=O)c2=O)cc1
Yield: 71 %

Procedure:
4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile (1 g, 4.1 mmol) and 2,2,3,3,3-pentafluoropropylamine (3 mL) in ethanol were refluxed for 24 hours. The reaction mixture was filtered and the resulting solid was triturated with diethyl ether to give 1.0 g (71%) of 4-[3,4-dioxo-2-(2,2,3,3,3-pentafluoro-propylamino)-cyclobut-1-enylamino]-benzonitrile as a yellow solid: mp 272°-275° C. (dec); 1H NMR (DMSO-d6): δ 10.15 (br s, 1H), 8.19 (br s, 1H), 7.81 (d, 2H), 7.79 (d, 2H), 4.54 (dt, 2H). IR (KBr): 3185, 2239, 1804, 1672, 1608, 1565, 1548 cm-1 ; MS (m/z) 346 ([M+H]+).
Reaction SMILES: C([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[CH3:25][O:24][C:21]1[N:20]=[CH:19][C:18]([CH2:17][NH:16][C:15]2[C:10]3[CH2:9][NH:8][CH2:27][CH2:26][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CNc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CNc2ncnc3c2CNCC3)cn1
Reaction time: 72 h

Procedure:
A mixture of 6-benzyl-N-((6-methoxypyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (1.90 g, 5.26 mmol), MeOH (100 mL), and 10% Pd—C (600 mg) was hydrogenated at 1 atm for 3 days. LC-MS indicated complete conversion. Catalyst was filtered off and the filtrate was concentrated in vacuo to yield a light yellow foam.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:8]=O)=[C:5]([CH3:7])[N:6]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:17][C:18](=[O:20])[CH3:19])C=CC=CC=1.O>CS(C)=O>[CH3:1][C:2]1[S:3][C:4]([CH:8]=[CH:17][C:18](=[O:20])[CH3:19])=[C:5]([CH3:7])[N:6]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(C)c(C=O)s1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)C=Cc1sc(C)nc1C
Yield: 81.8 %

Procedure:
A solution of 2,4-dimethylthiazole-5-carboxaldehyde (2.0 g) and 1-triphenylphosphoranylidene-2-propanone (8.2 g) in dimethylsulphoxide (140 ml) was stirred at ambient temperature for 24 hr. The solution was poured into water (400 ml) and extracted with dichloromethane. The dried (Na2SO4) organic extract was evaporated and the residue was purified by column chromatography over silica with ethyl acetate/n-hexane (1:1 v/v) elution to give 1-(2,4-dimethyl-5-thiazolyl)but-1-en-3-one (2.1 g). Pmr spectrum (CDCl3 ; δ in ppm): 2.32 (3H, s); 2.49 (3H, s); 2.67 (3H, s); 6.30 (1H, d); 7.60 (1H, d).
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:38]2[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=2)=[S:45])=[C:28]([F:33])[CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1
Agent: O=C(N=C=S)c1ccc(F)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 83%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24]([OH:26])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[CH2:35]([N:37](CC)CC)C.CN>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24](=[O:26])[NH:37][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: ClCCl
Product: CNC(=O)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-carboxynitrobenzene (3.3 g) in dichloromethane (50 ml) were added isobutyl chloroformate (1.4 ml) and triethylamine (1.4 ml) in an ice bath and the mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture was added 40% aqueous methylamine (1.1 ml) and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol=19/1 as an eluant to give the desired compound (3.5 g, yield quantitative) as a yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1)=[CH:15]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:27]=1)=[CH:15]2
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2cc(-c3cc4cc(F)c(F)cc4[nH]3)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
4-Methoxybenzaldehyde (0.204 g, 1.5 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.405 g, 1.48 mmol) in methylene chloride (125 mL), followed by acetic acid (0.3 g, 1.5 mmol). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.31 g, 1.46 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2SO4. The solvent was evaporated to give a yellow oil. Recrystallization from methanol/water gave the product as off-white crystals (270 mg); mp 173-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[OH:15])=[CH:10][C:9]=2[F:25])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])=[CH:10][C:9]=2[F:25])=[CH:26][CH:27]=1
Reactant: OC(c1ccc(OCc2ccc(Cl)cc2)c(F)c1)c1c[nH]c2ncccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: O=C(c1ccc(OCc2ccc(Cl)cc2)c(F)c1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To [4-(4-chloro-benzyloxy)-3-fluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (P-1895, 17.7 mg, 0.046 mmol) in tetrahydrofuran (10.0 mL) was added Dess-Martin periodinane (23.5 mg, 0.056 mmol). The reaction was stirred at room temperature for 15 minutes. The reaction was concentrated, then purified with silica gel column chromatography eluting with 50% ethyl acetate in hexane to give a white solid (P-1897, 6.4 mg, 36.3%). MS (ESI) [M+H4]+=381.3.