Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C[C:23]([CH3:25])=O>C(Cl)Cl>[Cl:2][C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:4][CH2:5][N:9]([CH2:23][CH3:25])[CH2:10][CH3:11])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(C)=O
Reactant: Clc1ncnc2[nH]c3ccccc3c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CCN(CC)CCn1c2ccccc2c2c(Cl)ncnc21
Yield: 82 %

Procedure:
A suspension of 4-chloroindolo[2,3-d]pyrimidine hydrochloride (407 mg, 2 mmol), 2-N,N-diethylaminoethyl chloride hydrochloride (413 mg, 2.4 mmol), anhydrous cesium carbonate (1.95 g, 6 mmol) and 4 molecular sieves (1.5 g) in acetone (6 mL) are heated at reflux under a nitrogen atmosphere for 1.5 h. The mixture is filtered through celite, washing the filter cake with acetone (4×10 ml), followed by concentration of the filtrate under reduced pressure affording a viscous amber oil, which is dissolved in CH2Cl2, (20 ml), and washed with water (2×25 mL), dried (MgSO4), and the solvent is removed in vacuo. The crude product is chromatographed on silica, eluting with 4% methanol/chloroform to give 4-chloro-9N-(2-(N,N-diethylamino)ethyl)indolo[2,3-d]pyrimidine (495 mg, 82%), as a pale yellow oil. 1H NMR (DMSO) δ8.79 (1H, s), 8.41 (1H, d, J=8.0 Hz), 7.66-7.58 (2H, m), 7.46-7.42 (1H, m), 4.57 (2H, t, J=6.8 Hz), 2.90 (2H, t, J=7.1 Hz), 2.63 (4H, d, J=7.0 Hz), 0.99 (6H, t, J=7.0 Hz).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]([N:7]1[CH2:11][C@@H:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C@@:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])([C:17]#[N:18])[C@H:8]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[F:34])=[O:6].[Li+].[OH-]>C1COCC1.CO>[Cl:33][C:29]1[C:28]([F:34])=[C:27]([C@@H:8]2[C@:9]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[F:26])([C:17]#[N:18])[C@H:10]([CH2:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:11][N:7]2[C:5](=[O:6])[CH2:4][C:3]([OH:35])=[O:2])[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)CC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1CN(C(=O)CC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
A mixture of methyl malonyl chloride (Aldrich, 127 mg, 0.93 mmol), DIPEA (Aldrich, 297.0 mg, 2.3 mmol) and rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (150 mg, 0.35 mmol) was stirred at rt overnight. The reaction mixture was concentrated and purified by RP-HPLC to give rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-3-oxo-propionic acid methyl ester (136.2 mg, 73.5%). In a manner similar to the method described in Example 8, rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-3-oxo-propionic acid methyl ester (120 mg, 0.23 mmol) was treated with 2 N LiOH (1.0 mL) in THF/MeOH (3 mL/1 mL) at rt for 3 hrs and purified by RP-HPLC to rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-3-oxo-propionic acid (21.2 mg, 18.2%). HRMS (ES+) m/z Calcd for C25H24Cl2F2N2O3+H [(M+H): 509.1205; Found: 509.1207.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])[CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+].C(O)C.Cl>O>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])[CH:16]=2)=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(C#Cc2cccc(S(=O)(=O)Nc3ncccc3C)c2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccnc1NS(=O)(=O)c1cccc(C#Cc2ccc(O)c(C(=O)O)c2)c1

Procedure:
Ethyl 2-hydroxy-5-[[3-[(3-methyl-2-pyridinylamino)sulfonyl]-phenyl]ethynyl]benzoate (4 g, 9.2 mmol) was added to a boiling solution of potassium hydroxide (6 g, 90 mmol) in water (100 ml). After 15 min ethanol (50 ml) was added and the solution acidified with hydrochloric acid, the product was collected by filtration and dried at 110° C. Yield 3.5 g, 93%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][O:27][C:28](=[O:31])[CH2:29]Br>CC(C)=O>[CH3:26][O:27][C:28](=[O:31])[CH2:29][N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:10]1
Reactant: Fc1ccc(-c2n[nH]c(-c3ccc(F)cc3)n2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reaction time: 24 h
Yield: 91.1 %

Procedure:
26.5 g 3,5-bis-(4-fluoro-phenyl)-1H-(1,2,4)triazole, 62.6 g K2CO3 and 15.7 g 2-bromoacetic acid methyl ester were dissolved in 1 L acetone and stirred for 24 h under reflux. K2CO3 was filtered and the solvent was removed to yield 30.8 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:45]([N+:49]1[N:53]=[C:52]([CH3:54])[S:51][C:50]=1[CH3:55])[CH2:46][CH2:47][CH3:48]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:8])/[CH:55]=[C:50]2\[S:51][C:52]([CH3:54])=[N:53][N:49]\2[CH2:45][CH2:46][CH2:47][CH3:48])=[CH:9][CH:10]=1
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 4-bromobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.85-0.94 (m, 3 H) 1.28-1.39 (m, 2 H) 1.67-1.80 (m, 2 H) 2.49 (s, 3 H) 4.20-4.23 (m, 2 H) 6.70 (m, 1 H) 7.64 (d, 2 H) 7.94 (d, 2 H); MS (ESI) m/z 353 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:27]([OH:29])=O)=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)[N:7]([CH3:25])[C:6]=2[CH:26]=1.[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:34][CH:32]([CH3:33])[CH2:31][NH:30][C:27]([C:3]1[C:2]([F:1])=[CH:26][C:6]2[N:7]([CH3:25])[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[N:9][C:5]=2[CH:4]=1)=[O:29]
Reactant: CC(O)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)c(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1F
Yield: 61.1 %

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-propyl)-amide (52 mg) was prepared by following General Procedure F starting from 6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 1-amino-2-propanol (15 mg), HBTU (80 mg), and DIEA (46 uL). LC/MS: m/z 484.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.93 (bs, 1H), 12.35 (bs, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.73 (d, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 4.79 (s, 1H), 3.86-3.75 (m, 1H), 3.61 (bs, 3H), 3.29-3.17 (m, 2H), 1.10 (d, 3H).
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[C:19]([NH2:24])([CH2:22][CH3:23])([CH3:21])[CH3:20]>>[CH3:20][C:19]([NH:24][C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:21])[CH2:22][CH3:23]
Reactant: CCC(C)(C)N
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Product: CCC(C)(C)Nc1c(-c2ccc(OC)cc2)c(=O)c1=O
Yield: 84.1 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and tert-amyl amine (0.48 mL, 4.11 mmol) were converted to the title compound (0.14 g, 84%) m.p.: 133-135° C.; 1H NMR (DMSO-d6) δ 8.28(br s,1H), 8.04(m,2H), 7.11(m,2H), 3.83(s,3H), 1.80(q,2H), 1.42(s,6H), 0.85(t,3H); IR (KBr) 2980, 1765, 1725, 1600, 1423, 1310, 1260, 1175, 1030, 850 cm−1; MS (m/z) 273 [M+].
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(O[C:39]1(O[Si](C)(C)C)[CH2:41][CH2:40]1)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([CH:39]5[CH2:41][CH2:40]5)[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncnn2c(C3CCN(C4CC4)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 29.2 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.244 mmol) was dissolved in methanol (3.5 mL). Acetic acid (140 uL, 2.44 mmol) was added followed by a small scoop of activated molecular sieves. [(1-ethoxycyclopropyl)oxy](trimethyl)silane (255 mg, 1.47 mmol) was added to the flask via syringe. Solid sodium cyanoborohydride was added (61 mg, 0.977 mmol) to the reaction which was then heated under nitrogen overnight. The mixture was partitioned between ethyl acetate (100 mL) and sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was washed with brine and then dried with sodium sulfate. The product was purified using column chromatography, eluent 2-3% (7N NH3 in Methanol)/dichloromethane to afford 32 mg (29%) of desired product. 1H NMR (300 MHz, dichloromethane-d2) δ 8.04 (s, 1 H), 7.89 (s, 1 H), 7.78-7.73 (m, 3 H), 7.60-7.40 (m, 4 H), 7.25 (d, 1 H), 6.63 (s, 1H), 5.62 (s, 2 H), 5.52 (bs, 2 H), 3.90 (m, 1H), 3.40 (m, 1H), 2.80 (m, 3 H), 2.40 (m, 1 H), 1.95 (m, 1 H), 1.75 (m, 1 H), 1.40-0.90 (m, 3 H); ES-MS m/z 450.2 [M+H]+, HPLC RT (min) 2.17.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:12]=1.Br[CH2:46][C:47]([O:49][CH3:50])=[O:48].C(N(C(C)C)CC)(C)C>CCO>[CH3:50][O:49][C:47](=[O:48])[CH2:46][N:20]1[CH2:21][CH2:22][N:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([F:42])([F:43])[F:44])[C:3]=3[Cl:2])[CH2:23][CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:12]=2)[CH2:18][CH2:19]1
Reactant: COC(=O)CBr
Reactant: FC(F)(F)c1cccc(CN(CCCOc2cccc(N3CCNCC3)n2)CC(c2ccccc2)c2ccccc2)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirring solution of (2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-piperazin-1-yl-pyridin-2-yloxy)-propyl]-amine hydrochloride (0.1 g, 0.16 mmol) in EtOH (6 ml) was added methyl bromo-acetate (16 uL, 0.17 mmol) and diisopropylethylamine (89 uL, 0.51 mmol). The reaction mixture was stirred for 10 h at RT and then concentrated. Purification by flash silica gel chromatograpy afforded the title compound as a clear oil, 47 mg (42%). MS (ESI) 681.2 (M+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=[C:16]([NH2:23])[C:15]=2[N:14]=[C:13]1[CH3:24].[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[NH2:23][C:16]1[C:15]2[N:14]=[C:13]([CH3:24])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:31]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:32])[C:20]=2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)N3CCOCC3)c2c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.9 %

Procedure:
Triethylamine (0.78 mL, 5.6 mmol) was added to a solution of 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.00 g, 4.3 mmol) in chloroform (50 mL). The solution was cooled in an ice bath and then 4-morpholinecarbonyl chloride (0.55 mL, 4.7 mmol) was added. After 15 minutes the reaction mixture was removed from the ice bath and allowed to stir at ambient temperature for 2 days. The reaction mixture was diluted with water (30 mL) and the pH was adjusted to 11 with potassium carbonate. The resulting precipitate was isolated by filtration and then recrystallized from isopropanol/water to provide 0.61 g of N-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]morpholine-4-carboxamide as a white solid, m.p. 128.9-129.7° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17]Cl.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[N:9]([CH2:17][C:16]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=3[O:14][CH3:13])[C:10]=2[N:11]=1
Reactant: COc1ccc(CCl)c(OC)c1
Reactant: O=C1COc2ccc(Br)nc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)COc3ccc(Br)nc32)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A suspension of 6-bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.412 g, 1.8 mmol) and 2,4-dimethoxybenzyl chloride (0.336 g, 1.8 mmol; freshly prepared according to U.S. Pat. No. 5,817,653) in DMF (5 mL) was treated with Cs2CO3 (1.76 g, 3 eq.). The mixture was stirred at rt for 2 h, partitioned between EA and water. The aq. phase was extracted with EA and the combined org. layers washed with water, and brine, dried over MgSO4 and concentrated. The residue was purified by FC (Hept/EA 1:1) to give the title intermediate as a colourless oil (0.61 g, 90% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11](C=O)[CH:10]=[N:9]2)[CH:5]=[C:4]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:3]=1.[C:26]([CH:31]=[C:32]1CCP(C2C=CC=CC=2)C1(C1C=CC=CC=1)C1C=CC=CC=1)([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11](/[CH:32]=[CH:31]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:10]=[N:9]2)[CH:5]=[C:4]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:3]=1
Reactant: CCOC(=O)C=C1CCP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CNc2cc(-n3ncc(C=O)c3C)nc(N)n2)cc1
Product: CCOC(=O)/C=C/c1cnn(-c2cc(NCc3ccc(OC)cc3)nc(N)n2)c1C

Procedure:
The compound obtained in (2) above weighing 3.50 g and 4.3 g of (carboethoxymethylene)triphenylphospholane were allowed to react and worked up in the same manner as in Example 57-(3) to give 3.22 g of the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]([C@@:18]2([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH2:20][O:19]2)[CH3:17])=[C:9](Cl)[N:8]=1>>[N:1]1([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]([CH3:17])[C@:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])([OH:19])[CH2:20][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[C:9]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[N:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H](n1cnc2c(Cl)nc(Cl)nc21)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnc2c(-n3cncn3)nc(-n3cncn3)nc21)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 14.6 %

Procedure:
Using 1H-1,2,4-triazole (59 mg) and (2S)-2-[(1R)-1-[2,6-dichloro-9(9H) -purinyl]ethyl]-2-(2,4-difluorophenyl) oxirane (168 mg), Compound 50 (21 mg) was obtained as a white powder by the same way as in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC.[F-].[Cs+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:15]=[CH2:16])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1nc(C(=O)OC)c(Cl)c(N)c1F
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A solution of methyl 4-amino-3,6-dichloro-5-fluoropyridine-2-carboxylate (8.00 g, 33.0 mmol), tributyl(vinyl)tin (13.27 g, 42.0 mmol) and cesium fluoride (11.19 g, 73.6 mmol) in dimethylformamide (250 mL) was sparged with nitrogen for 15 minutes. Dichlorobis(triphenylphosphine)palladium (II) (1.17 g, 1.6 mmol) was then added and the mixture was heated at 90° C. overnight. After cooling, the mixture was concentrated, taken up into ethyl acetate and filtered through a silica gel plug. The solvents were removed and the crude product was purified by column chromatography (50% ethyl acetate in hexane) to give methyl 4-amino-3-chloro-5-fluoro-6-vinylpyridine-2-carboxylate (5.13 g, 22.2 mmol), mp 68-71° C.
Reaction SMILES: [CH:1]1([N:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](=[O:11])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19]([C:22]1[CH:27]=[C:26]([SH:28])[CH:25]=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]=1[OH:33])([CH3:21])[CH3:20].C(N(CC)CC)C>CO>[CH3:32][C:29]([C:24]1[CH:25]=[C:26]([S:28][CH2:10][CH2:9][C:8]([N:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:11])[CH:27]=[C:22]([C:19]([CH3:21])([CH3:20])[CH3:18])[C:23]=1[OH:33])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)N(C1CCCCC1)C1CCCCC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SCCC(=O)N(C2CCCCC2)C2CCCCC2)cc(C(C)(C)C)c1O

Procedure:
The title compound of Example 3 (1.9 g, 0.008 mole), 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol(2 g, 0.008 mole) and triethylamine (0.5 ml) were stirred in methanol (25 ml) for about 12 hours. The solvent was removed in vacuo on a rotary evaporator, the crude material purified by chromatography on silica and recrystallized from hexane, m.p. ca. 168.5°-172° C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([O:11][CH3:12])=[N:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].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>[CH3:12][O:11][C:5]1[C:6]2[N:7]([CH:8]=[N:9][N:10]=2)[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[CH:3][N:4]=1
Reactant: OB(O)c1cccs1
Reactant: COc1ncc(Br)n2cnnc12
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: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cccs2)n2cnnc12
Temperature: 100 °C
Yield: 97.9 %

Procedure:
A 50 mL round bottom flask was charged with 5-bromo-8-methoxy-[1,2,4]triazolo[4,3-a]pyrazine (0.25 g, 1.1 mmol), thiophen-2-ylboronic acid (280 mg, 2.2 mmol), Pd(PPh3)4 (190 mg, 0.16 mmol), Cs2CO3 (530 mg, 1.6 mmol), 1,4-dioxane (11 mL) and water (4 mL). The resulting mixture was heated under N2 at 100° C. overnight. Work-up: the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL) and the filtrate was extracted with more EtOAc (10 mL×3). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a 1:50 methanol/dichloromethane, to afford 0.25 g (99%) of the product as a yellow solid. MS m/z: 233 (M+H+).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=1>CN(C)C=O>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[N:18]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccnc(-n2cnc3ccccc32)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
Benzimidazole (0.50 g) was dissolved in dimethylformamide (10 ml), and sodium hydride (60% purity, oily) (0.18 g) was added thereto at room temperature. After stirring for 1 hour, 2-chloro-4-methoxypyrimidine (0.62 g) was added at room temperature, followed by stirring for 3 hours. Ice water was added, followed by extraction with ethyl acetate, washing with a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.40 g of the desired product as a white powder (m.p. 114-116° C.).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]#[CH:31].C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:31][C:30]#[CH:29])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: C#CCOc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and propargyl bromide (53 uL, 0.47 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 39 as a colorless oil (20 mg).