Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22]([O:24]C)=[O:23])[CH:9]=1)(=[O:3])[CH3:2].C(C1CCNCC1)C1C=CC=CC=1>CS(C)=O>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22]([OH:24])=[O:23])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(=O)Nc1cc(NCCNC(C)=O)nc(-c2ccccc2)n1
Agent: c1ccc(CC2CCNCC2)cc1
Solvent: CS(C)=O
Product: CC(=O)NCCNc1cc(NC(=O)C(=O)O)nc(-c2ccccc2)n1
Yield: 68.7 %

Procedure:
Methyl [(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetate (50 mg) was dissolved in DMSO (420 μl) with stirring. To this were added 4-benzylpiperidine (74 μl) and activated powdered 4 angstrom molecular sieves and the mixture left to stir at room temperature for 5 hrs. After this time the reaction was filtered and first dichloromethane (1.6 ml) then PS-NCO (0.58 g) were added and the mixture left to stir for 1 hr. The resulting slurry was filtered, then partitioned between dichloromethane (20 ml) and water (20 ml), and the aqueous layer extracted with dichloromethane (2×20 ml). The combined organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Further purification via column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (94:6 v/v) furnished the title compound (33 mg).
Reaction SMILES: [N-:1]=[C:2]=S.C(Cl)(Cl)=S.NC(N)=S.[CH:12]1([N:18]=[C:19]=[N:20]C2CCCCC2)C[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>ClCCl.C1COCC1>[NH2:20][C:19]1[NH:18][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[N:1]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: [N-]=C=S
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: S=C(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of an isothiocyanate (prepared by reacting the corresponding amine with thiophosgene) and a suitably substituted phenylenediamine in dry dichloromethane was stirred at rt overnight and evaporated to dryness. The resulting thiourea was then purified by e.g. column chromatography or reacted further as crude material. Thus, the thiourea was dissolved in THF, added a coupling reagent such as dicyclohexylcarbodiimide (DCC), and stirred at reflux temperature overnight. Aqueous NaHCO3 was added and the solution extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give the crude 2-aminobenzimidazole which was subsequently purified by column chromatography or preparative LCMS.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[NH:8][C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=1)=[O:6])C.[OH-].[Na+]>O>[CH2:12]([C:9]1[NH:8][C:7]([C:5](=[O:6])[C:4]([OH:14])=[O:3])=[CH:11][CH:10]=1)[CH3:13]
Reactant: CCOC(=O)C(=O)c1ccc(CC)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C(=O)C(=O)O)[nH]1
Yield: 83.8 %

Procedure:
A mixture of 5-ethyl-2-pyrrolylglyoxylic acid ethyl ester (1.95 g.) and sodium hydroxide (0.44 g.) in water (25 ml.) was heated on a steam bath for 1.5 hours. The mixture was cooled, filtered and the filtrate was acidified with 2 N hydrochloric acid. The solid was filtered off, washed with a little water, dried and crystallized from toluene to give 5-ethyl-2-pyrrolylglyoxylic acid (1.40 g.), M.P. 126°-128°). Found: C, 57.55; H, 5.53; N, 8.70. C8H9NO3 requires: C, 57.48; H, 5.43; N, 8.38%.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:27]([OH:28])=[CH:26][C:9]2[C@H:10]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:11]([OH:16])[C:12]([CH3:15])([CH3:14])[O:13][C:8]=2[CH:7]=1)=[O:4].[Cl-].[NH4+]>CO.[OH-].[Na+]>[OH:16][C@@H:11]1[C@@H:10]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]2[CH:26]=[C:27]3[C:6]([NH:5][C:3](=[O:4])[CH2:2][O:28]3)=[CH:7][C:8]=2[O:13][C:12]1([CH3:15])[CH3:14]
Reactant: CC1(C)Oc2cc(NC(=O)CCl)c(O)cc2[C@H](NCCc2ccccc2)[C@H]1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2cc3c(cc2[C@H](NCCc2ccccc2)[C@H]1O)OCC(=O)N3
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of 2-chloro-N-[(3R*,4S*)-3,6-dihydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-7-yl]-acetamide (120 mg, 0.30 mmol) in methanol (1.2 mL), aqueous sodium hydroxide solution (1 mol/L, 1.5 mL) was added at room temperature, and the resulting mixture was stirred for 4 hours. Upon the completion of the reaction, saturated aqueous ammonium chloride solution was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium hydroxide solution (1 mol/L) and then with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=1/1) and the aimed product was obtained (yield: 72%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=2)=[CH:11][N:10]=[C:9]1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[CH:33]=1.CCN(CC)CC>CN1C(=O)CCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:38][C:34]1[CH:33]=[C:32]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[C:13](=[O:14])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:9]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)=[N:10][CH:11]=3)=[CH:16][C:17]=2[F:22])[CH:37]=[CH:36][N:35]=1
Reactant: O=c1c(-c2ccc(O)c(F)c2)cnc(Nc2ccc(F)cc2)n1Cc1ccccc1
Reactant: Nc1cc(Cl)ccn1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cc(Oc2ccc(-c3cnc(Nc4ccc(F)cc4)n(Cc4ccccc4)c3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
3-benzyl-5-(3-fluoro-4-hydroxyphenyl)-2-(4-fluorophenylamino)pyrimidin-4(3H)-one (731.4 mg, 1.804 mmol) and 4-chloropyridin-2-amine (473.7 mg, 3.685 mmol) were dissolved in NMP (8.0 ml) and Et3N (1.25 ml, 8.97 mmol) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (190 C) and stirred under nitrogen. After 19 hours, more 4-chloropyridin-2-amine (409 mg, 3.20 mmol), DMAP (286.5 mg, 2.345 mmol), Et3N (0.50 ml, 3.6 mmol) were added, followed by NMP (1.0 ml). Stirring was continued at 190 C. After 23 hours, the reaction was cooled to room temperature, diluted with DCM, and washed with water (2×50 ml). The aqueous extracts were combined and extracted with DCM. Some MeOH (˜10%) was also used to help solubilize the biphasic mixture. All the organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on silica gel (˜3 inches, DCM->50:1->20:1 DCM/MeOH) to afford the desired 5-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-benzyl-2-(4-fluorophenylamino)pyrimidin-4(3H)-one, which was taken on to the next step. MS (ESI pos. ion) m/z: 498 (MH+). Calc'd exact mass for C28H21F2N5O2: 497.
Reaction SMILES: [H-].[H-].[H-].[H-].[Al+3].[Li+].[CH3:7][C:8]1[CH:13]=[C:12]([OH:14])[C:11]([CH3:15])=[CH:10][C:9]=1[S:16]C#N>O1CCCC1>[CH3:7][C:8]1[CH:13]=[C:12]([OH:14])[C:11]([CH3:15])=[CH:10][C:9]=1[SH:16]
Reactant: Cc1cc(SC#N)c(C)cc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(S)c(C)cc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 250 ml three-necked flask, to a stirred mixture of lithium aluminum tetrahydride (LiAlH4, 1.0 g, 26.3 mmol) and tetrahydrofuran (40 ml) was added dropwise a solution of 2,5-dimethyl-4-hydroxy-phenyl thiocyanic acid (1.2 g, 6.7 mmol) in 20 ml tetrahydrofuran at 0° C. After 30 min of stirring at 0° C., the mixture was allowed to warm up to room temperature and then stirred for another 1 hour at room temperature. The reaction was quenched by adding ethanol (10 ml). The value of pH of the mixture was adjusted to 3-4 by adding 6 M hydrochloric acid in an ice water bath, and then the aqueous phase was extracted with ethyl acetate (3×60 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtrated, and evaporated in vacuo to yield the crude product of 2,5-dimethyl-4-hydroxy-mercaptobenzene (yellow liquid).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:48])[C:15]([C:23]3[N:24]=[C:25]([NH:28][C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[S:26][CH:27]=3)=[N:16][O:17]C(C)(OC)C)[C:11](=[O:49])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].C(NCC)C.CC(C)=O.Cl>O>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:48])[C:15]([C:23]3[N:24]=[C:25]([NH:28][C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[S:26][CH:27]=3)=[N:16][OH:17])[C:11](=[O:49])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCNCC
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 21 g of the product of Step A, 80 ml of acetone and 27 ml of 2 N hydrochloric acid was stirred at room temperature for 90 minutes and 55 ml of water were added thereto with stirring. The acetone was evaporated under reduced pressure and 140 ml of ethyl acetate were added with stirring. The decanted aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with half saturated aqueous sodium chloride solution, was dried and vacuum filtered to obtain the syn isomer of 3-methyl-7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyiminoacetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([CH2:14][CH:15]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:36][CH2:35][C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[NH:32][C:31]3=[O:41])[CH2:26][CH2:25]2)=[O:23])[C:16]([O:18]CC)=[O:17])=[CH:6][C:5]=1[Cl:42]>CCO>[NH2:3][C:4]1[C:9]([C:10]([F:12])([F:13])[F:11])=[CH:8][C:7]([CH2:14][CH:15]([NH:21][C:22]([N:24]2[CH2:25][CH2:26][CH:27]([N:30]3[CH2:36][CH2:35][C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[NH:32][C:31]3=[O:41])[CH2:28][CH2:29]2)=[O:23])[C:16]([OH:18])=[O:17])=[CH:6][C:5]=1[Cl:42]
Reactant: CCOC(=O)C(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(Cl)cc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
45 mL of 1 M NaOH were added to a solution of 13.00 g (22.34 mmol) of ethyl 3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-propionate in 100 mL EtOH and the mixture was stirred, for 16 h at RT. EtOH was evaporated off i. vac., 45 mL of 1M HCl were added and the mixture was stirred for 15 min. The precipitate formed was filtered off, washed with water and dried i. vac. at 75° C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[C:47](=[O:48])[N:46]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[N:45]=[CH:44]3)=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:38]=[CH:39][C:40]([N:43]4[C:47](=[O:48])[N:46]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[N:45]=[CH:44]4)=[CH:41][CH:42]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CC1(C)OB(c2ccc(-n3cnn(COCC[Si](C)(C)C)c3=O)cc2)OC1(C)C
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ncn(-c2ccc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)cc2)c1=O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of compound 3a (108 mg, 0.246 mmol), compound 82c (206 mg, 0.246 mmol), PdCl2(dppf)-DCM (6.0 mg, 0.0074 mmol), and Argon-degassed aqueous 2M Na2CO3 (0.616 mL, 1.23 mmol) in Argon-degassed 1,4-dioxane (4 mL) was further degassed with Argon for 3 min and then stirred at 90° C. for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to a brown residue, which was purified by flash column chromatography on silica gel (40-100% EtOAc-DCM, followed by 100% EtOAc) to afford compound 82d as a hard white foam. Mass spectrum (LCMS, ESI pos.): Calcd. for C35H40N8O3Si, 649.3 (M+H). found 649.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:38]([C:41]1[CH:42]=[C:43]([N:47]=[C:48]=[O:49])[CH:44]=[CH:45][CH:46]=1)(=[O:40])[CH3:39]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:48]([NH:47][C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:38](=[O:40])[CH3:39])[CH:42]=2)=[O:49])[C@@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Reactant: CC(=O)c1cccc(N=C=O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(NC(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 18 h
Yield: 29.3 %

Procedure:
In a dry flask (3S,4R)-4-amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (43 mg, 0.10 mmol) was dissolved in tetrahydrofuran (2 mL) and then triethylamine (19 μL, 0.14 mmol) and 3-acetylphenylisocyanate (17 μL, 0.12 mmol) were added. After stirring for 18 hours, removed half of the reaction mixture for purification. The remainder of the reaction mixture was taken onto the next reaction without purification. The aliquot was purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (17 mg, 57%). 1H NMR (400 MHz, DMSO-d6, 120° C.), δ: 8.64 (s, 1H), 7.94 (m, 1H), 7.57 (d, J=8, 1H), 7.46 (d, J=8, 1H), 7.33 (t, J=8, 1H), 7.17 (m, 2H), 7.00 (t, J=9, 2H), 6.13 (d, J=8, 1H), 4.07 (m, 1H), 3.87 (m, 1H), 3.61 (m, 1H), 3.42 (dd, J=14, J′=4, 1H), 3.32 (m, 1H), 2.98 (m, 2H), 2.70 (m, 1H), 2.50 (m, 1H), 2.49 (s, 3H), 2.02 (m, 1H), 1.73 (m, 3H), 1.53 (m, 1H), 1.39 (s, 9H), 1.22 (m, 2H). HRMS (ESI), C32H42FN4O5 m+/z: calc.=581.3139, found=581.3149.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[N:10]=1)(=[O:8])=[O:7])(C)C>FC(F)(F)C(O)=O>[NH2:5][S:6]([C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=[C:11]([C:19]([F:21])([F:22])[F:20])[N:10]=1)(=[O:7])=[O:8]
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C(F)(F)F)nc1S(N)(=O)=O
Yield: 58 %

Procedure:
A solution of 0.95 g (2.79 mmol) of the product from Example 4 was stirred in 40 mL trifluoroacetic acid at room temperature overnight. The solution was evaporated to an oil which was triturated with ether to afford 0.46 g (58%) of a solid. m.p. 187°-188° C. 1H NMR (CDCl3) δ4.05 (3H, s), 5.5 (NH2), 7.95 (1H, d, J=8 Hz), 8.35 (1H, d, J=8 Hz); IR (mineral oil) 3390, 3280, 1725, 1340, 1140 cm-1.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]1[NH:17][C:18]([NH2:21])=[N:19][N:20]=1.[CH2:22]1[O:32][C:25]2([CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[O:24][CH2:23]1.O>C(O)(=O)C>[O:24]1[C:25]2([CH2:30][CH2:29][CH:28]([NH:21][C:18]3[NH:17][C:16]([CH3:15])=[N:20][N:19]=3)[CH2:27][CH2:26]2)[O:32][CH2:22][CH2:23]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cc1nnc(N)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
Sodium triacetoxyborohydride (32.4 g) was gradually added to a solution (150 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (10.0 g) and 1,4-cyclohexanedione monoethyleneketal (19.1 g) in acetic acid. The mixture was stirred at room temperature for 16 hr, water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue was solidified with diisopropyl ether, and the solid was collected by filtration, and dried to give the title compound (15.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5]2.O[CH2:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:28]=[CH:29][CH:30]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:32]([NH:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5]2)(=[O:34])[CH3:33]
Reactant: CC(=O)Nc1cccc(CO)c1
Reactant: COC(=O)[C@H]1c2ccc(O)cc2CCN1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1c2ccc(OCc3cccc(NC(C)=O)c3)cc2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
To a mixture of (R)-2-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (99 mg, 0.32 mmol),N-(3-(hydroxymethyl)phenyl)acetamide (53 mg, 0.32 mmol)and PPh3 (92 mh, 0.35)in THF(2 mL) at 0° C. was added DEAD (60 μL, 0.38 mmol). The reaction mixture was warmed to room temperature and stirred overnight. It was concentrated and purified by preparative HPLC (Phenomenex 20×100 mm eluting with 0-100% MeOH/H2O (90% in H2O) gradient over 8 min with flow rate 25 mL/min) to yield (R)-2-tert-butyl 1-methyl 6-(3-acetamidobenzyloxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate as a white solid(39 mg, 27%). HPLC retention time (Method C)=3.59 min. LC/MS (ESI) (M+H)+=477.26. 1H NMR (CDCl3, 400 MHz), 1:1 rotamers, δ ppm 1.47 (s, 5H), 1.49 (s, 4H), 2.71-2.98 (m, 2H), 3.60-3.84 (m, 2H), 3.70 (s, 3H), 5.03 (s, 2H), 5.37 (s, 0.5H), 5.53 (s, 0.5H), 6.74 (s, 1H), 6.82 (dd, J=8.59, 2.53 Hz, 1H), 7.15 (d, J=7.58 Hz, 1H), 7.29-7.39 (m, 2H), 7.46 (d, J=8.08 Hz, 1H), 7.58 (br. s., 1H).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:30][CH2:31][C@H:32]4[CH2:36][CH2:35][CH2:34][O:33]4)[C:16]4[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.Cl>CO>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:30][CH2:31][C@H:32]4[CH2:36][CH2:35][CH2:34][O:33]4)[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC[C@H]3CCCO3)c2C1
Agent: Cl
Solvent: CO
Product: c1ncc(-c2ccc(Nc3nc4c(c(NC[C@H]5CCCO5)n3)CNCC4)cc2)o1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butyl 2-(4-(oxazol-5-yl)phenylamino)-4-((tetrahydrofuran-2-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (323 mg, 0.66 mmol) was dissolved in methanol (3 mL). Hydrochloric acid (0.020 mL, 0.66 mmol) was added and the reaction mixture was stirred at 80° C. for 1 h. The solvent was evaporated under reduced pressure and the crude was used as such in the subsequent step. MS (ES+) m/z 393.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[N:11]=[C:10]([O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([NH2:20])=[C:15]([CH3:21])[CH:14]=2)[CH:9]=[CH:8][N:7]=1.CO.CO[CH:30](OC)[N:31]([CH3:34])[CH2:32][CH3:33]>>[Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[N:11]=[C:10]([O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([N:20]=[CH:30][N:31]([CH2:32][CH3:33])[CH3:34])=[C:15]([CH3:21])[CH:14]=2)[CH:9]=[CH:8][N:7]=1
Reactant: CCN(C)C(OC)OC
Reactant: Cc1cc(Oc2ccnc(Oc3cccc(Cl)c3C)n2)c(C)cc1N
Solvent: CO
Product: CCN(C)C=Nc1cc(C)c(Oc2ccnc(Oc3cccc(Cl)c3C)n2)cc1C
Temperature: 45 °C
Reaction time: 20 h

Procedure:
To a mixture of 293 mg (0.7 mmol) of 4-[2-(3-chloro-2-methyl-phenoxy)-pyrimidin-4-yloxy]-2,5-dimethyl-phenylamine in 20 ml methanol 182 mg (1.05 mmol) of N-(dimethoxymethyl)-N-methyl-ethanamine (77% pure) was added. The reaction mixture was stirred for 20 hrs at 45° C. The reaction mixture was dried over magnesium sulfate concentrated in vacuo and yielded 290 mg (76%) with a purity of 78%; log P (pH 2.3)=2.08.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[Cl-].C(C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C.[Cl:38][C:39]1[CH:44]=[CH:43][C:42](I)=[CH:41][C:40]=1[CH3:46]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH:2]([C:1]#[N:5])[C:3]#[N:4])=[CH:41][C:40]=1[CH3:46]
Reactant: N#CCC#N
Reactant: Cc1cc(I)ccc1Cl
Agent: [Pd]
Agent: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C(C#N)C#N)ccc1Cl
Temperature: 25 °C

Procedure:
A solution of malononitrile (1.79 mL, 28.4 mmol) in THF (6 mL) was added dropwise over 25 minutes to a vigorously stirred, ice-cooled suspension of NaH (60% dispersion in mineral oil, 1.70 g, 42.6 mmol) in THF (40 mL) under a nitrogen atmosphere. The resulting slurry was allowed to warm to room temperature. Meanwhile tris(dibenzylideneacetone)dipalladium(0) (167 mg, 0.182 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (151 mg, 0.36 mmol) were combined in THF (5 mL) and warmed to 60° C. for 10 minutes, then cooled to room temperature. This solution and 2-chloro-5-iodotoluene (3.66 g, 14.2 mmol) were added to the malononitrile solution with THF (40 mL) rinse, and the grey mixture was heated at reflux under nitrogen for 37 hours, then cooled to room temperature and concentrated under vacuum. Water (50 mL) was added to the residue and the mixture was extracted with CH2Cl2 (2×40 mL). The aqueous phase (pH˜10) was made acidic (pH˜3) by addition of 10% HCl (10 mL) and extracted again with CH2Cl2 (2×40 mL). The combined organic extract was concentrated and the residual red-brown oily residue was purified by flash chromatography (silica gel, eluted with hexanes-EtOAc, 90:10-70:30) to provide the title compound as a tan solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.44 (s, 3H) 5.00 (s, 1H) 7.27 (dd, J=8.1, 2.4 Hz, 1H) 7.37 (d, J=2.4 Hz, 1H) 7.47 (d, J=8.1 Hz, 1H).