Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C@@H:8]3[C@@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@H:7]3[C:6]=2[CH:16]=1.F[C:18]1[CH:27]=[CH:26][N:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][C:22](=[O:28])[NH:23]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:28]=[C:22]1[NH:23][C:24]2[N:25]=[CH:26][CH:27]=[C:18]([O:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][C@@H:8]5[C@@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@H:7]5[C:6]=4[CH:16]=3)[C:19]=2[CH2:20][CH2:21]1
Reactant: O=C1CCc2c(F)ccnc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2Oc3ccc(O)cc3[C@H]21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1[C@H]2Oc3ccc(Oc4ccnc5c4CCC(=O)N5)cc3[C@H]21
Temperature: 120 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
The mixture of Intermediate III (400 mg, 1.8 mmol), 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) in DMF (20 mL) was stirred at 120° C. for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=3:1) to obtain the title compound (360 mg, 54.6%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH3:34])([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=1)[CH2:9][C:8]2=[O:35])(=[O:3])[CH3:2].[H][H]>CO.C1C=CC=CC=1.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:18])[CH3:19])[O:11][C:10]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)([CH3:34])[CH2:9][C:8]2=[O:35])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2=O

Procedure:
12.3 g of 6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)chroman-4-one (prepared as described in Preparation 19) were dissolved in a mixture of 200 ml of methanol and 20 ml of benzene, and then catalytically reduced for 6 hours at room temperature, in the presence of 2.4 g of 10% w/w palladium-on-carbon, under 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst was filtered off, and the filtrate was condensed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20](=[O:33])[C:21]([S:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][CH2:31][NH2:32])[N:29]=1)([CH3:23])[CH3:22])([CH3:18])([CH3:17])[CH3:16].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[C:15]([O:19][C:20](=[O:33])[C:21]([CH3:22])([S:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][CH2:31][NH:32][C:12]([C:10]2[CH:9]=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)=[O:14])[N:29]=1)[CH3:23])([CH3:17])([CH3:16])[CH3:18]
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNC(=O)c2cnn(-c3ccccc3)c2)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
1-Phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (4.1 g) synthesized in Reference Example 16 was dissolved in methanol (40 mL) and tetrahydrofuran (40 mL), aqueous sodium hydroxide solution (1 mol/L, 40 mL) was added, and the mixture was stirred at 60° C. for one hour. The reaction mixture was concentrated under reduced pressure, aqueous hydrochloric acid solution (1 mol/L, 50 mL) was added, and the precipitated solid was filtrated. The solid was dissolved in ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 1-phenyl-1H-pyrazole-4-carboxylic acid (2.5 g) as a white solid. This carboxylic acid (8.72 g) and 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (14 g) synthesized in Example 7 were dissolved in N,N-dimethylformamide (225 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (10.65 g) and 1-hydroxybenztriazole (HOBt) monohydrate (10.62 g) were successively added thereto, and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (16.2 g) as a white solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.[C:42]([O:46][C:47]([NH:49][C@@H:50]([CH2:54][S:55][S:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:51](O)=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43]>O1CCCC1>[C:42]([O:46][C:47](=[O:48])[NH:49][C@@H:50]([CH2:54][S:55][S:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:51]([NH:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:52])([CH3:44])([CH3:45])[CH3:43]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (2.52 g, 6.62 mmol), benzylamine (0.723 ml, 6.62 mmol) and N,N-diisopropylethylamine (1.153 ml, 6.62 mmol) were added to a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound tk91) (1.95 g, 6.30 mmol) in tetrahydrofuran (20 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (R)-tert-butyl(1-(benzylamino)-3-(tert-butyldisulfanyl)-1-oxopropan-2-yl)carbamate (Compound tk92) (2.357 g, 5.91 mmol, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>ClC(Cl)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:13]([NH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:20])[CH3:19]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COC(=O)c1ncccc1N
Solvent: CC(Cl)Cl
Product: CCOC(=O)CC(=O)Nc1cccnc1C(=O)OC
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 3-aminopicolinate (1.8 mL, 13.80 mmol) in dichloroethane (60 mL) was added ethyl 3-chloro-3-oxopropanoate (2.08 g, 13.80 mmol). The reaction was heated at reflux for 45 min. After this time the reaction was cooled to rt and partitioned between DCM (60 mL) and NaHCO3 (satd aq. solution, 30 mL). The separated aq. layer was extracted with DCM (40 mL) and the combined organic layer were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give methyl 3-(3-ethoxy-3-oxopropanamido)picolinate: LC-MS (ESI) m/z 267.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:25])[CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1>>[OH:25][CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:34]2[CH:35]=[CH:36][C:37]([C:40]3([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)=[CH:3][CH:4]=1)[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: COc1cccc(SCC(O)c2c(C)noc2-c2ccc(Br)cc2)c1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Product: COc1cccc(SCC(O)c2c(C)noc2-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(3-methoxy-phenylsulfanyl)-ethanol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:10][CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@@:14]3([CH2:22][C@@H:21]3[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:13]2=[O:30])[CH:9]=1)=[O:4].COC(C1N=CN(CCN2C3C(=CC=CC=3)[C@]3(C[C@H]3C3C=CC(Cl)=CC=3)C2=O)C=1)=O.O[Li].O>CO.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C@H:21]2[C@@:14]3([C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]([CH2:11][CH2:10][N:8]4[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[CH:7]4)[C:13]3=[O:30])[CH2:22]2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1cn(CCN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)cn1
Agent: COC(=O)c1cn(CCN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)cn1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(CCN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of methyl-1-(2-((1S,2R)-2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)ethyl)-1H-imidazole-4-carboxylate and methyl-1-(2-((1R,2S)-2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)ethyl)-1H-imidazole-4-carboxylate (0.07 mmol) in methanol (2 mL) and water (1 mL) was added LiOH.H2O (18 mg, 0.4 mmol) in one portion. The mixture was stirred at room temperature for 3 hours until the starting material was consumed. The mixture was concentrated under reduced pressure and acidified to pH˜3. The residue was dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as a white powder (26 mg, 88%). LC/MS m/e calcd. for C22H18ClN3O3: 407, observed (M+H)+: 408.8 1H NMR (400 MHz, MeOD) δppm 2.10 (dd, J=28.17, 8.46 Hz, 2 H) 3.10 (s, 1 H) 4.31 (s, 2 H) 4.86 (s, 2 H) 6.05 (d, J=7.33 Hz, 1 H) 6.75 (s, 1 H) 6.90-7.45 (m, 6 H) 7.86 (s, 1 H) 8.27 (s, 1 H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO[CH:12]([N:15]([CH3:17])[CH3:16])OC>>[CH2:8]([O:7][C:1](=[O:6])[C:2](=[CH:12][N:15]([CH3:17])[CH3:16])[C:3](=[O:4])[CH3:5])[CH3:9]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(C)=O
Yield: 99.3 %

Procedure:
Add ethyl acetoacetate (15 mL, 0.118 mol) to dimethoxymethyl-dimethyl-amine (19 mL, 0.142 mol) and reflux the mixture for 1 hr. Evaporate the mixture to give 2-dimethylaminomethylene-3-oxo-butyric acid ethyl ester (21.7 g, 99%).
Reaction SMILES: [CH:1]([N:4]([CH:25]([CH3:27])[CH3:26])[C:5](=[O:24])[CH:6]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([NH2:11])=O)([CH3:3])[CH3:2].O=S(Cl)Cl>CN(C=O)C>[C:9]([CH2:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:5]([N:4]([CH:25]([CH3:27])[CH3:26])[CH:1]([CH3:3])[CH3:2])=[O:24])#[N:11]
Reactant: CC(C)N(C(=O)C(c1cccnc1)C(CC(N)=O)c1ccccc1)C(C)C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)N(C(=O)C(c1cccnc1)C(CC#N)c1ccccc1)C(C)C

Procedure:
To a solution of N1,N1-diisopropyl-3-phenyl-2-pyridin-3-ylpentanediamide (90 mg, 0.245 mmol) in 1 mL DMF was added SOCl2 (0.5 mL) and heated at 90 C for 45 min. Concentrated (azeotroped 2× from benzene) and purified by r.p. HPLC. Desired fractions from HPLC were combined and the product was isolated as free base. White solid, single diastereomer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][CH:18]([C:22](=O)[CH3:23])[C:19](=O)[CH3:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][NH2:26]>CO.ClCCl>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[C:22]([CH3:23])=[N:25][NH:26][C:19]=2[CH3:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(Cc1cn(C(=O)OC(C)(C)C)c2ncccc12)C(C)=O
Reactant: NN
Solvent: ClCCl
Solvent: CO
Product: Cc1n[nH]c(C)c1Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Reaction time: 2 h

Procedure:
To 3-(2-acetyl-3-oxo-butyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (513, 1.20 g, 3.63 mmol) in methanol (15.0 mL), cooled to −20° C. under an atmosphere of nitrogen, was added hydrazine (0.128 g, 4.00 mmol) in dichloromethane (6.0 mL). The reaction was stirred for 2 hours. The reaction was concentrated to remove the solvents, and the residue was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 60% ethyl acetate in hexane to give a white solid (514, 1.0 g, 84.4%). MS (ESI) [M+H+]+=327.4.
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[CH:10][CH:9]=1)=[O:6])([CH3:4])[NH2:3].C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:4][C:2]1([CH3:1])[NH:3][C:31](=[O:33])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)=[CH:10][CH:9]=2)[C:5]1=[O:6]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(Oc2ccc(NC(=O)C(C)(C)N)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(Oc2ccc(N3C(=O)NC(C)(C)C3=O)cc2)c1
Reaction time: 0.5 h
Yield: 144 %

Procedure:
To a solution of 2-methyl-N1-(4-{[3-(methyloxy)phenyl]oxy}phenyl)alaninamide (Intermediate 72, 1.33 g) and triethylamine (3.70 mL, 26.6 mmol) in dry dichloromethane (80 mL) at 0° C. was added dropwise a solution of triphosgene (600 mg, 2.022 mmol) in dry dichloromethane (20 mL) and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with a saturated solution of ammonium chloride (100 mL) and two phases were separated. Aqueous layer was extracted with dichloromethane (100 mL) and the two organic phases were collected, dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography (Biotage system, 100 g SNAP cartridge) using as eluent a gradient and cyclohexane/ethyl acetate from 80/20 to 40/60 to afford the title compound as a white solid (950 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][O:27]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:31](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:31][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:12][CH:11]=3)[N:15]=[C:16]([NH:24][CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][O:27]3)[C:17]=2[CH2:23]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@H]4CCCO4)n2)CNCC3)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@H]4CCCO4)n2)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
(R)-N2-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (56 mg, 0.14 mmol) was dissolved in methanol (3 mL). Acetic acid (7.91 μL, 0.14 mmol) was added followed by formaldehyde (10.28 μL, 0.14 mmol) and sodium cyanoborohydride (8.68 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was evaporated under reduced pressure. The crude was purified by preparative HPLC yielding (R)-6-methyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (18.70 mg, 32.3%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[Cl:10][CH:11]([Cl:19])[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>>[Cl:10][CH:11]([Cl:19])[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1
Reactant: ClCc1ccc(Cl)nc1
Agent: Clc1ccc(C(Cl)Cl)cn1
Product: Cc1ccc(Cl)nc1

Procedure:
The present invention relates to the preparation of 5-aminomethyl-2-chloropyridines by reacting a mixture of 5-chloromethyl-2-chloropyridine and 5-dichloromethyl-2-chloropyridine with substituted amines. The mixture of 5-chloromethyl-2-chloropyridine and 5-dichloromethyl-2-chloropyridine is obtained by chlorination of 5-methyl-2-chloropyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15]>>[OH:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:12]=1[F:11]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: COc1ccc(O)c(N)c1
Product: COc1ccc(O)c(NC(=O)c2cc([N+](=O)[O-])ccc2F)c1

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-methoxyphenol (557 mg, 4.0 mmol) and 2-fluoro-5-nitrobenzoyl chloride (814 mg, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]1([C@H:20]([CH3:23])[CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>O>[C:14]1([C@H:20]([CH3:23])[CH2:21][NH:22][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: C[C@H](CN)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: C[C@H](CNC(=O)c1cnc2ccccc2n1)c1ccccc1
Yield: 74.9 %

Procedure:
Prepared from 2-quinoxaloyl chloride (0.47 g, 2.4 mmol), (S)-2-phenyl-1-propylamine (0.30 g, 2.2 mmol), pyridine (5 mL), and water (50 mL) yielding 0.48 g (74%) of (173):
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[O:22]1[C:24]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[OH:22][C:24]1([CH2:23][O:1][C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[O:5][CH2:6][CH2:7][N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Reactant: C1CCCC2(CCC1)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(OCC2(O)CCCCCCC2)c1
Temperature: 120 °C

Procedure:
The suspension of phenol 24 (1.0 g, 3.5 mmol), 1-oxa-spiro[2.7]decane (0.5 g, 3.2 mmol) and Cs2CO3 (1.14 g, 3.5 mmol) in DMSO (4 mL) was heated at 120° C. for 16 h. After completion of reaction, the mixture was quenched by the addition of 1N HCl and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (0 to 10% 7N NH3/methanol—CH2Cl2) afforded 2-(2-(3-(1-hydroxy-cyclooctylmethoxy)-phenoxy)-ethyl)-isoindole-1,3-dione as yellow oil. Yield (0.53 g, 35%): 1H NMR (400 MHz, CDCl3) δ 7.92-7.98 (m, 1H), 7.40-7.51 (m, 3H), 7.08-7.14 (m, 1H), 6.45-6.54 (m, 3H), 4.03 (s, 2H), 3.68-3.76 (m, 2H), 1.35-1.92 (m, 16H).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:24](=[CH:25][CH:26]=1)[C:17]1[CH:18]([O:22][CH3:23])[O:19][C:20](=[O:21])[C:16]=1[CH:15]=[CH:14]2)=[O:10])C1C=CC=CC=1>CCO.C1COCC1.[Pd]>[OH:10][C:9]([C:11]1[CH:12]=[C:13]2[C:24](=[CH:25][CH:26]=1)[C:17]1[CH:18]([O:22][CH3:23])[O:19][C:20](=[O:21])[C:16]=1[CH:15]=[CH:14]2)=[O:8]
Reactant: COC1OC(=O)c2ccc3cc(C(=O)OCc4ccccc4)ccc3c21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC1OC(=O)c2ccc3cc(C(=O)O)ccc3c21

Procedure:
A mixture of 7-benzyloxycarbonyl-1-methoxynaphtho[1,2-c]furan-3(1H)-one (33 mg, 0.095 mmol) and a catalytic amount of 10% Pd/C in 2 mL of EtOH was stirred at rt under an atmosphere of H2 (balloon) for 2 h. The mixture was then diluted with THF and filtered through a pad of Celite. The filtrate was then concentrated in vacuo. The crude material was dissolved in saturated aqueous NaHCO3 and washed with EtOAc. The aqueous layer was then acidified with 1 M aqueous HCl and extracted with EtOAc. The extract was dried over MgSO4 and concentrated in vacuo affording 19 mg (79%).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:14]([NH:22][NH2:23])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:23][N:22]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NNC(=O)c1ccccc1
Reactant: CCCCCNc1nc[nH]c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: CCCCCNc1nc[nH]c1-c1nc(-c2ccccc2)n[nH]1
Temperature: 170 °C
Reaction time: 14 h
Yield: 15.1 %

Procedure:
The mixture of 4-(pentylamino)-1H-imidazole-5-carbonitrile (200 mg, 1.12 mmol), benzohydrazide (229 mg, 1.68 mmol) and potassium carbonate (100 mg, 0.72 mmol) in 1-butanol (6 ml) in a sealed tube was stirred at 170° C. for 14 hours. The reaction was diluted with water and extracted with EtOAc three times. The combined organic layers was dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative LCMS (method A) to yield the desired product (50 mg, 17% yield). LCMS calculated for C16H21N6 (M+H): 297.2; found 297.1.
Reaction SMILES: [Li+].[BH4-].CO.[Br:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:16])([CH3:15])[C:10](OCC)=[O:11]>C(Cl)Cl>[Br:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][OH:11]
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)CCCBr
Yield: 101.5 %

Procedure:
Under argon, a suspension of LiBH4 (14.8 g, 646 mmol) in methylene chloride (600 mL) was stirred as methanol (25.6 mL, 20.2 g, 629 mmol) was added dropwise, taking care to keep the temperature below 30° C. To this mixture, a solution of ethyl 5-bromo-2,2-dimethylpentanoate (100.0 g, 392 mmol; prepared according to Kuwahara et al. Chem. Pharm. Bull 1997, 48, 1447) in methylene chloride (200 mL) was added dropwise over 20 minutes, and the solution was heated under reflux for 21 h. After chilling in an ice-bath, the reaction was quenched by adding H2O dropwise (100 mL). After the effervescence stopped, 2 N HCl (125 mL) was added dropwise and the solution was stirred until the effervescence ceased. The procedure was repeated with another portion of 2 N HCI (125 mL). The layers were separated, and the aqueous layer was extracted with an additional methylene chloride (500 mL). The two organic portions were combined and washed with 2 N HCl 9300 mL), then sat. NaHCO3 (300 mL). After drying the organics over Na2SO4, the solution was evaporated to yield the product as a light yellow oil (77.6 g, 91% yield). 1H NMR (d6-DMSO), d (ppm): 4.42 (s, 1H); 3.45 (t, 2 H, J=6.6); 3.08 (s, 2H); 1.84-1.69 (m, 2H); 1.27 (t, 2 H, J=8.3); 0.78 (s, 6H). 13C NMR (d6-DMSO), d (ppm): 69.7, 36.9, 35.7, 34.5, 27.4, 24.0.