Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([O:21]CC=C)=O)=[N:7][C:6]=2[CH:25]=1.NC[C@@H]1[C@H](C)CCCN1C([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[N:44]1[N:48]=[C:47]([CH3:49])[CH:46]=[N:45]1)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[N:44]3[N:48]=[C:47]([CH3:49])[CH:46]=[N:45]3)=[O:21])=[N:7][C:6]=2[CH:25]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanone. ESI-MS (m/z): 479 [M+1]+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:22][CH:21]([CH3:23])[CH:14]([C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(C)I
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(c1nc(N2CCOCC2)cc(=O)[nH]1)C(C)C

Procedure:
The product is prepared according to the procedure described in example 67, using 600 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 1 and 0.29 ml of 2-iodopropane in place of the methyl iodide, and replacing the potassium carbonate with cesium carbonate. After purification by silica column chromatography, eluent: 900505 CH2Cl2/CH3CN/MeOH, 20 mg of ethyl 3-methyl-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]butanoate are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[H][H].CC(=CCCC(CCO)C)C.CC(=CCCC(CC=O)C)C>>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: CC(C)=CCCC(C)CC=O
Agent: CC(C)=CCCC(C)CCO
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Temperature: 80 °C

Procedure:
Example 1 was repeated using L-isopulegol with a purity of 97.1% and 84% ee, which was introduced at a rate of 24.5 g/h (total amount 466 g) into the reactor at a hydrogen pressure of 40 bar. The main reactor (MR) was heated to 80° C., the postreactor to 70° C. The L-isopulegol used had the following composition: L-isopulegol: 97.1 GC % by weight, citronellol: 0.05 GC % by weight, citronellal: 0.40 GC % by weight, isopulegol isomer: 0.45 GC % by weight, secondary components: 0.34 GC % by weight. L-menthol (84% ee) was obtained in an amount of 468 g, corresponding to a rate of 24.6 g/h. The chemical purity of the L-menthol output is shown in Table 3.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.[C:18](Cl)([N:20]=[C:21]=[O:22])=[O:19]>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[O:15][C:21](=[O:22])[NH:20][C:18](=[O:19])[C:13]=3[CH2:12][O:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: O=C1CCOCC1c1ccc(C(F)(F)F)cc1
Reactant: O=C=NC(=O)Cl
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(C(F)(F)F)cc1)COC2

Procedure:
3-(4-(trifluoromethyl)phenyl)dihydro-2H-pyran-4(3H)-one (Intermediate Z(2)) was reacted as described in Intermediate X(3) with carbonisocyanatidic chloride to give 8-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (Intermediate Z(3)).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:14][CH2:13][C:1]1[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)COc1ccc(CBr)cc1
Yield: 56.1 %

Procedure:
To a solution of the methyl 2-(p-tolyloxy)acetate (3.10 g, 17.2 mmol) in carbon tetrachloride (60 mL) was added N-bromosuccinimide (3.57 g, 20 mmol) followed by benzoyl peroxide (463 mg, 1.9 mmol). The resulting solution was heated at reflux overnight, and then diluted with methylene chloride. The mixture was washed with brine, dried on MgSO4, and concentrated. The resulting colorless oil was purified by chromatography on silica gel (Hexane/ethyl acetate 9/1) to afford a colorless oil (2.5 g, 56%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.Cl.[CH3:26][O:27][C:28](=[O:38])[C@H:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH2:30].CS(C)=O.C(N(CC)CC)C>C(#N)C>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:30][CH:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([O:27][CH3:26])=[O:38])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CS(C)=O
Product: COC(=O)C(Cc1ccccc1)NC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C

Procedure:
0.500 g (1.519 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 0.328 g (1.519 mmol) of L-phenylalanine methyl ester hydrochloride were placed in a 25 ml round bottom flask equipped with a magnetic stirring bar. 3 ml of dimethylsulfoxide was added and the solution was stirred to dissolve as much solid as possible at room temperature. Then 159 mg (1.571 mmol) of triethylamine was added and the solution was stirred at room temperature (20° C.) for one hour. 10 ml of acetonitrile was added to the stirring solution. The solution was triturated with ether until a white precipitate had formed. The solution was filtered to remove the triethylamine hydrochloride. The mother liquor was again treated with ether to produce a precipitate. The mixture was filtered and the white solid was washed with ethyl ether and dried. This yielded 0.465 g of a white solid. The white solid material was added to 22 ml ethanol/H2O 9:1 and was heated to dissolve the compound. After allowing to cool to room temperature, ether was added until just before the cloud point. The solution was placed in a refrigerator overnight. Upon filtration and washing with ether, 0.235 g of 2-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]-3-phenylpropanoic acid, methyl ester (AIT-0085) as a white crystalline material was obtained. m.p. 186°-191° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:19])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([Cl:19])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1

Procedure:
A solution of thionyl chloride (30 ml) and 3-nitro-5-(trifluoromethyl)benzoic acid (10 g) was heated to reflux for 2 h. The reaction mixture was concentrated under reduced pressure and treated with toluene (10 ml) which was then removed under reduced pressure to afford 3-nitro-5-(trifluoromethyl)benzoyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]([F:26])[CH3:25])=[O:10])[C:2]1C=CC=C[CH:3]=1.[H][H]>CO.Cl.[Pd].C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]([F:26])[CH3:25])=[O:10])[CH:2]=[CH2:3]
Reactant: CC(F)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCC(C)F
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-2-(2-fluoropropyl)oxymethyl-4-methanesulfonyloxypyrrolidine (950 mg) in a mixture of methanol (20 ml) and concentrated hydrochloric acid (one drop) was hydrogenated under atmospheric pressure of hydrogen in the presence of 30% palladium on carbon as a catalyst at ambient temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to give a residue, which was dissolved in a mixture of ethyl acetate (100 ml) and water (40 ml). The aqueous layer was separated and tetrahydrofuran (40 ml) was added thereto To the solution was added dropwise allyl chloroformate (320 μl) while keeping the pH between 8-9 with 4N sodium hydroxide at 0° C. and the mixture was stirred at the same condition for one hour after addition of allyl chloroformate (320 μl). The mixture was extracted with ethyl acetate (100 ml), washed with brine (50 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (100 ml) eluting with a mixture of hexane and ethyl acetate (2:1 V/V) to give (2S,4R)-1-allyloxycarbonyl-2-(2-fluoropropyl)oxymethyl-4-methanesulfonyloxypyrrolidine (360 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[C:20]3[CH:19]=[C:18]4[C:21]([CH3:29])([CH3:28])[C:22]5[C:27]([C:17]4=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:5]=[C:4](Br)[N:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:31]1([C:2]2[CH:7]=[C:6]([N:8]3[C:20]4[CH:19]=[C:18]5[C:21]([CH3:29])([CH3:28])[C:22]6[C:27]([C:17]5=[CH:16][C:15]=4[C:14]4[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=4)=[CH:26][CH:25]=[CH:24][CH:23]=6)[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4cc(Br)nc(Br)c4)c3cc21
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: [Na+]
Solvent: COCCOC
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4cc(-c5ccccc5)nc(-c5ccccc5)c4)c3cc21

Procedure:
25 g (48 mmol) of 10-(2,6-dibromopyridin-4-yl)-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene and 12.9 g of phenylboronic acid (106 mmol) are suspended in 300 ml of ethylene glycol dimethyl ether. 75 ml of a 2 M Na2CO3 solution are added to the reaction mixture. 2.8 g (2.4 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 12 h. After cooling, the precipitated solid is filtered off with suction and washed with water and ethanol and dried. The residue is extracted with hot toluene and recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. Yield: 15 g, 60% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].C(N(CC)CC)C.C1COCC1.[C:48]([O:51][CH2:52][C:53](Cl)=[O:54])(=[O:50])[CH3:49]>C(OCC)(=O)C>[C:48]([O:51][CH2:52][C:53]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]1)=[O:54])(=[O:50])[CH3:49]
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.6 %

Procedure:
To a mixture of the compound of Example 77 (200 mg, 0.423 mmol), triethylamine (122 μL, 0.880 mmol) and THF (10 mL) was added acetoxyacetyl chloride (47.3 μL, 0.440 mmol) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate), and the obtained solid was recrystallized from ethyl acetate-THF to give the title compound (171 mg, 75%) as a white powder.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:31](=[CH:32][CH:33]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:18][N:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3](O)=[O:4].[NH2:34][CH2:35][CH2:36][OH:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.CO>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:31](=[CH:32][CH:33]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[C:20]([C:21]([F:22])([F:24])[F:23])=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:18][N:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([NH:34][CH2:35][CH2:36][OH:37])=[O:4]
Reactant: O=C(O)C(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CN1CCOCC1
Product: O=C(NCCO)C(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (Preparation 131B, isomer 2, 25 mg, 0.055 mmol) in DMF (1 mL) was added 2-aminoethanol (5.02 mg, 0.082 mmol), BOP (31.5 mg, 0.071 mmol), and 4-methylmorpholine (33.2 mg, 0.329 mmol). The reaction mixture was stirred for 30 min. Methanol was added and it was purified by prep HPLC (Phenomenex 21.2×250 mm, Solvent A: 90% water with 10% MeOH and 0.1% TFA, Solvent B: 90% MeOH with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 30 min, 20 mL/min, 220 nM) to yield 2-hydroxy-N-(2-hydroxyethyl)-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetamide (18 mg, 0.036 mmol, 65.3% yield) as a white solid: product HPLC ret. time=8.66 min (condition G); LC/MS M+1=500.04; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (1H, t, J=5.72 Hz), 7.87 (1H, d, J=7.92 Hz), 7.80 (2H, d, J=7.26 Hz), 7.63-7.76 (3H, m), 7.44-7.53 (2H, m), 6.34 (1H, d, J=4.84 Hz), 4.98 (1H, d, J=4.62 Hz), 4.71 (1H, t, J=5.50 Hz), 3.43 (2H, q, J=5.94 Hz), 3.11-3.24 (2H, m), 3.04 (4H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>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.O1CCOCC1.O>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:3]=2)[CH:19]=[N:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cn1
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: Cn1cc(-c2cc(Oc3ccc(N)nc3)ncn2)cn1
Temperature: 90 °C
Yield: 67.9 %

Procedure:
A mixture of 5-((6-chloropyrimidin-4-yl)oxy)pyridin-2-amine (0.50 g, 2.25 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.47 g, 2.25 mmol), and Cs2CO3 (1.46 g, 4.49 mmol) in 5:1 dioxane/water (6 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.26 g, 0.23 mmol), sparged again with Ar and heated at 90° C. overnight. The mixture was cooled to RT, the solids removed via filtration, washed with dioxane and the filtrate concentrated to dryness. The residue was treated with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to dryness. The material was treated with EtOAc and the resulting solid collected via filtration to afford 5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-amine (0.41 g, 68%). 1H NMR (400 MHz, DMSO-d6): δ 8.60 (d, 1 H), 8.44 (s, 1 H), 8.12 (s, 1 H), 7.78 (d, 1 H), 7.28 (m, 2 H), 6.48 (d, 1 H), 5.94 (s, 2 H), 3.88 (s, 3 H); MS (ESI) m/z: 269.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[N:24]=[C:25](OS(C(F)(F)F)(=O)=O)[C:26]3[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:27]=3[N:28]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1.Cl>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:26]3[CH2:32][NH:31][CH2:30][CH2:29][C:27]=3[N:28]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1
Reactant: Nc1ccccc1
Reactant: COc1cc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3c(c(Nc4ccccc4)n2)CNCC3)ccc1-n1cnc(C)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
Aniline (0.032 g, 0.34 mmol) was added to a solution of tert-butyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.2 g, 0.34 mmol, Example 7a) in DMF (2 mL). The solution was stirred at 70° C. for 1 h. HCl 2M aq (2 ml) was added and the solution heated to 76° C. for 1 h. Solvent was concentrated under reduced pressure and purified on preparative HPLC to give N2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (0.060 g, 41.0%). MS (ESI+)/(ESI−) m/z 428/426
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([CH:12]([OH:14])[CH3:13])=[C:10]([Cl:15])[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([C:12](=[O:14])[CH3:13])=[C:10]([Cl:15])[N:9]=[C:8]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:22][CH:23]=1
Reactant: CC(O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
3.7 g of 1-[3-(4-bromobenzyl)-5-chloro-2-phenyl-3H-imidazol-4-yl]ethanol is dissolved in 20 ml of acetic acid and slowly treated at 15° C. with a solution of 15.6 g of (NH4)2Ce(NO3)6 in 30 ml of water. The mixture is stirred at 10° C. for 30 minutes, then allowed to warm to RT. It is diluted with 200 ml of water and adjusted to pH=5 using NaHCO3, and the product is filtered off with suction. Chromatography once each with DIP and MTB yields 2.0 g of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[C-:27]#[N:28].[K+]>C(Cl)Cl.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:27]#[N:28])[CH:7]=[CH:8][CH:9]=1
Reactant: C1COCCN1
Reactant: [C-]#N
Reactant: O=Cc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: CCCCCC
Solvent: ClCCl
Product: N#CC(c1cccc(F)c1)N1CCOCC1

Procedure:
As in Example 35, the following reactions are carried out. m-Fluorobenzaldehyde is reacted with p-toluenesulfonic acid, morpholine and KCN to give α-(m-fluorophenyl)-4-morpholineacetonitrile as crystals (from CH2Cl2 -hexane) m.p. 74°-75° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:21][C:16]2[C:15]([NH2:22])=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccccc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
To a solution of 1.0 g 1-benzyl4-piperidone and 1.14 g of 1,2-phenylenediamine in 15 mL of THF was added two spatula tips of molecular sieves 4Å. After stirring at room temperature for 10 minutes, 1.34 g of sodium triacetoxyborohydride was added and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with 50 mL of CH3OH and diluted with EtOAc. After filtering molecular sieves, the filtrate was concentrated under reduced pressure. The residue was partitioned between 50 mL of EtOAc and 30 ml saturated NaHCO3 aqueous solution. After separating layers, the aqueous phase was extracted with 2×50 mL EtOAc. The combined organic phases were washed with 15 mL of brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 100% EtOAc, then 90% EtOAc in CH3OH to give 666 mg of the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ1.56 (m, 2H), 2.07 (m, 2H), 2.18(m, 2H), 2.87 (d, J=11.6 Hz, 2H), 3.29(m, 1H), 3.56(s, 2H), 6.69 (m, 3H), 6.72(m, 1H), 7.25-7.61(m, 5H). ESI-MS 282 (M+H); HPLC A: 1.92 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:2]1.C(O)(=[O:18])C.CS(C)=O.Cl>O>[O:18]=[C:2]1[CH:3]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1
Reactant: CC(=O)O
Reactant: COC(=O)CCc1c[nH]c2ccccc12
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCC1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
A mixture of methyl 3-indolepropionate (5.00 g, 0.0246 mol), acetic acid (10 mL), dimethylsulfoxide (26 mL, 0.369 mol, 15 eq.) and concentrated hydrogen chloride (37%) (22 mL, 0.738 mol, 30 eq.) was stirred at ambient temperature for 2.5 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (30% ethyl acetate in hexanes) to afford the title compound as an oil (5.28 g, 98%); 1H NMR (DMSO-d6); 62.03-2.10 (m, 2H); 2.32-2.39 (m, 2H); 3.46 (t, J=6.4 Hz, 1H); 3.54 (s, 3H); 6.81 (d, J=7.6 Hz, 1H); 6.93-6.97 (m, 1H); 7.15-7.17 (m, 1H); 7.24 (d, J=7.6 Hz, 1H);
Reaction SMILES: I[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3].[NH:22]([CH3:24])[CH3:23]>C(Cl)Cl.CCO>[CH3:23][N:22]([CH3:24])[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3]
Reactant: CC(I)c1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: CNC
Solvent: ClCCl
Solvent: CCO
Product: CC(c1cccc2c1ccn2S(=O)(=O)c1ccccc1)N(C)C

Procedure:
A solution of 4-(1-iodoethyl)-1-(phenylsulfonyl)-1H-indole (40 mg, 97.3 μmol; Intermediate 99) in CH2Cl2 (1.5 mL) was treated with Me2NH (174 μL of a 5.6 M solution in EtOH, 973 μmol) at rt for 1 h. The reaction mixture was concentrated in vacuo, the obtained residue taken up with MeOH/THF and purified by prep. HPLC (System B, 30-60% MeCN, 50 mM NH4HCO3) to yield the title compound as a white, waxy solid (10.6 mg, 11% over two steps). MS (ESI+) for C18H20N2O2S m/z 329 (M+H)+.