Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])[N:10]=[C:9]1[NH2:20])=O)(C)(C)C.[N:21]([CH2:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])=[N+:22]=[N-:23]>>[NH2:20][C:9]1[NH:8][CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[N:23]=[N:22][N:21]([CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[CH:19]=2)[N:10]=1
Reactant: [N-]=[N+]=NCC(=O)Nc1ccccc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: Nc1nc(CCCCCc2cn(CC(=O)Nc3ccccc3)nn2)c[nH]1
Yield: 52.4 %

Procedure:
Following the general procedure, 2-amino-4-hept-6-ynyl-imidazole-1-carboxylic acid tert-butyl ester (0.075 g, 0.270 mmol) was reacted with 2-azido-N-phenyl-acetamide (0.072 g, 0.410 mmol) and afforded 0.050 g (51% yield) of 2-{4-[5-(2-amino-1H-imidazol-4-yl)-pentyl]-[1,2,3]triazol-1-yl}-N-phenyl-acetamide hydrchloride. 1H NMR (400 MHz, CD3OD) 8.53 (s, 1H), 7.59 (d, J=7.6, 2H), 7.31 (t, J=7.2, 2H), 7.11 (t, J=7.2, 1H), 6.50 (s, 1H), 5.62 (s, 2H), 3.96 (s, 1H), 2.89 (bs, 2H), 2.50 (t, J=6.8, 2H), 1.79 (bs, 2H), 1.66 (bs, 2H), 1.45 (bs, 2H); 13C NMR (100 MHz, CD3OD) δ 164.3, 148.6, 139.2, 130.1, 128.9, 125.9, 121.2, 109.8, 55.7, 28.9, 25.3, 24.7; HRMS (ESI), calculated for C18H23N7O (MH+) 353.1964. Found 353.1968.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O.C1COCC1>[CH2:17]([O:16][C:14]([N:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of azetidin-3-ol hydrochloride 7 (25 g, 0.23 mol) in water (150 mL) and THF (300 mL) was added K2CO3 (63.1 g, 0.46 mol). The mixture was stirred for 30 min. at 20-25° C. Then benzyl chloroformate (40.9 g, 0.24 mol) was added within 30 min. at 0-5° C. followed by stirring the mixture overnight at 20-25° C. THF was removed on a rotavap at 30° C./vacuum and the mixture was extracted with ethyl acetate (2×150 mL). The combined organic layer was washed with water (1×50 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate-heptanes 1:1 and 4:1 to yield 8 as a clear oil (47.3 g, 100%). 1H NMR (300 MHz, CDCl3): δ 3.72 (1H, d, J=6.2 Hz), 3.85 (2H, dd, J=9.5, 4.4 Hz), 4.17 (2H, dd, J=9.5, 6.7 Hz), 4.49-4.57 (1H, m), 5.06 (2H, s), 7.31-7.38 (5H, m); 13C NMR (75 MHz, CDCl3): δ 59.2, 61.6, 66.9, 127.9, 128.1, 128.5, 136.5, 156.6; IR: (film) 3406, 1686, 1438 cm−1; ES-HRMS m/z: (M++1H) calcd. for C11H14NO3 208.0968. found 208.0967.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(Cl)cc3Cl)CC2)cc1
Solvent: O=CO
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 30.3 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(2,4-dichlorobenzyl)-1-piperidinecarboxamide formate (0.30 g, 0.64 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.233 g, 0.577 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.145 g, 0.175 mmol).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:27])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@@H:50]([NH2:57])[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:57][C@@H:50]2[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@H:47]([O:46][C:43]3[CH:44]=[CH:45][C:40]4[N:41]([C:37]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]5[CH3:30])=[N:38][N:39]=4)[CH:42]=3)[CH2:48][CH2:49]2)=[O:27])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: C[C@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Temperature: 70 °C
Reaction time: 7.5 h
Yield: 60.6 %

Procedure:
A solution of Intermediate 151c (102 mg, 0.22 mmol) in 1,4-dioxane (2.0 mL) was treated with Intermediate 81d (75 mg, 0.20 mmol) and DIPEA (0.043 mL, 0.25 mmol) and the mixture was stirred at 70° C. for 7.5 h then at 50° C. for 64 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. The gum was purified by FCC, using 0-10% MeOH in DCM to give the title compound as a yellow glass (84 mg, 61%). LCMS (Method 3): Rt 3.75 min, m/z 693.5 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([F:32])[CH:26]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](=[O:23])[NH:29][C:28]1[CH:30]=[CH:31][C:25]([Br:24])=[CH:26][C:27]=1[F:32])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Reactant: Nc1ccc(Br)cc1F
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Br)cc1F

Procedure:
(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (4.45 g, 12.9 mmol) was dissolved in 50 mL dry CHCl3 under an Ar atmosphere, added 4-bromo-2-fluoroaniline (2.45 g, 12.9 mmol), EEDQ (3.8 g, 15 mmol), and triethylamine (2.6 mL, 19.3 mmol). Reaction was refluxed for 6 hours, cooled and concentrated. Redissolved in EtOAc (250 mL), washed with 10% HCl (2×200 mL), 0.1M NaOH (2×200 mL), water, brine, dried with MgSO4, filtered and concentrated to yield title compound. (5.5 g, 82%) APCI (AP−): 515.1, 517.1 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C@@H:6]1[CH3:18])=[O:4].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([Cl:30])[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[Cl:31])[N:23]=[CH:22][N:21]=[C:20]2[NH:1][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C@@H:6]1[CH3:18])=[O:4]
Reactant: Clc1cc2ncnc(Cl)c2cc1Cl
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)CCN1C(=O)CN
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)CCN1C(=O)CNc1ncnc2cc(Cl)c(Cl)cc12

Procedure:
tert-Butyl (2S,3R)-1-(2-(6,7-dichloroquinazolin-4-ylamino)acetyl)-2-methylpyrrolidin-3-ylcarbamate was synthesized from tert-butyl (2S,3R)-1-(2-aminoacetyl)-2-methylpyrrolidin-3-ylcarbamate and 4,6,7-trichloroquinazoline using general procedure M. RP-HPLC (Table 1, Method d) Rt 5.67; m/z: (M+H)+ 454.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[C:13]([C:16]1[CH:17]=[C:18]([C:22](O)=[O:23])[CH:19]=[N:20][CH:21]=1)(=[O:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:13]([C:16]1[CH:17]=[C:18]([C:22]([NH:12][C:6]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=2[NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:23])[CH:19]=[N:20][CH:21]=1)(=[O:15])[CH3:14]
Reactant: Nc1ccc(F)cc1NC1CC1
Reactant: CC(=O)c1cncc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cncc(C(=O)Nc2ccc(F)cc2NC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.082 g, 0.495 mmol) in dichloromethane were added the title compound from Step A (0.090 g, 0.545 mmol), HATU (0.207 g, 0.545 mmol), HOAt (0.074 g, 0.545 mmol), and diisopropylethylamine (0.35 mL, 1.98 mmol). The reaction was stirred at room temperature for 1 hour, then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (30-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 314.14 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.33 (s, 1 H), 9.29 (s, 1 H), 8.72 (s, 1 H), 8.02 (br s, 1 H), 7.19-7.16 (m, 1 H), 6.91 (d, J=10.5 Hz, 1 H), 6.50-6.47 (m, 1 H), 4.64 (br s, 1 H), 2.69 (s, 3 H), 2.45-2.44 (m, 1 H), 0.78-0.77 (m, 2 H), 0.52-0.51 (m, 2 H).
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[CH2:7]([O:9][C:10]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][C:11]=1[C:12]#[N:13])[CH3:8]>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH2:26]2)(=[O:20])=[O:19])=[CH:14][C:11]=1[C:12]([NH2:6])=[NH:13])[CH3:8]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1C#N
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=N)N
Temperature: 25 °C
Yield: 28.6 %

Procedure:
Trimethylaluminium (10 mL, 2 Molar solution in hexanes) was added dropwise to a slurry of ammonium chloride (1.07 g, 0.02 Mol) in toluene (15 mL) at 0° C. The mixture was stirred without cooling until gas evolution stopped. 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)benzonitrile (the compound of Preparation 7) (3.23 g, 0.01 Mol) was then added and was washed in with toluene (5 mL) before the reaction was stirred at 80° C. for 40 h. After cooling to room temperature silica gel (15 g) and dichloromethane (100 mL) were added. The mixture was then filtered and the solids were washed with dichloromethane/methanol mixtures. The combined filtrate and washings were evaporated and the residue was chromatographed over silica gel using dichloromethane methanol mixtures to afford 1.08 g, 28.6% of the title compound. M/Z=found 341 (M+H). 1H NMR (CD3OD) 1.28 (t, 3H) 1.49 (t, 3H) 2.97 (q, 2H) 3.14 (br, s, 4H) 3.33(br, s, 4H) 4.32 (q, 2H) 7.45(d, 1H) 7.96 (d, 1H) 8.05 (dd, 1H).
Reaction SMILES: N1(C[N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)CCCC1.C([Li])CCC.[CH3:17][C:18]([C:21]1[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:24]=[C:23]([C:32](N(OC)C)=[O:33])[N:22]=1)([CH3:20])[CH3:19]>O1CCCC1.C1CCCCC1>[CH3:20][C:18]([C:21]1[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:24]=[C:23]([C:32]([C:11]2[CH:10]=[CH:9][NH:8][N:7]=2)=[O:33])[N:22]=1)([CH3:17])[CH3:19]
Reactant: c1cnn(CN2CCCC2)c1
Reactant: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C(=O)c2cc[nH]n2)nc(C(C)(C)C)c1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 1-(1-pyrrolidinomethyl)pyrazole (0.64 g, 4.2 mmol) (See Katritzky, A. R.; Rewcastle, G. W.; Fan, W-Q; J. Org. Chem 1988, 53, 5688) in tetrahydrofuran (10 mL) at -78° C. under nitrogen atmosphere is added a 2.1M solution of n-butyllithium (2.0 mL, 4.20 mmol) in cyclohexane. The resulting mixture is stirred 1 hour at -78° C. and warmed to ~0° C. After stirring 0.5 hours at 0° C., this mixture is cannula transferred to a solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide in tetrahydrofuran (10 mL) at ~0° C. This reaction mixture is warmed to room temperature and stirred 16 hours. After quenching with aqueous saturated ammonium chloride solution, the mixture is extracted with ethyl acetate and the combined extracts washed with brine. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The organic residue is purified by flash chromatography (SiO2, 10% methanol/hexane) followed by recrystallization from isopropanol and water to give 0.22 g (43%) of title compound as a mixture of tautomers, mp 156°-161° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[C:19](O)(=[O:30])[CH2:20][C:21]1[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:23](O)=[O:24].CO>C(O)C>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([N:1]3[C:19](=[O:30])[CH2:20][C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:24])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: CO
Solvent: CCO
Product: O=C1Cc2ccccc2C(=O)N1C1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C

Procedure:
4-Amino-1-[2-(indol-3-yl)ethyl]piperidine (2.43 g, 0.01 mol) and homophthalic acid (1.80 g, 0.01 mol) were heated at 160° (external temperature) for 3 hours then cooled to room temperature, giving a glass. This was dissolved in refluxing methanol and a small quantity of ethanol then cooled at 5° C. overnight. The title compound was deposited as a tacky solid which was collected and dried (0.82 g, 21.2%). The hydrochloride was formed by treatment of the base overnight with ethereal HCl, m.p. 186°-188°.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([C:15]2[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[N:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:12])[F:14])[N:8]=[C:7]([C:15]2[N:20]=[CH:19][C:18]([NH:21][C:31](=[O:32])[CH2:30][Cl:29])=[CH:17][CH:16]=2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOc1cc(C(F)(F)F)nc(-c2ccc(NC(=O)CCl)cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 57 (0.100 g, 0.337 mmol) in THF (5 mL), at 0° C. was added triethylamine (0.051 g, 0.506 mmol) and chloroacetylchloride (0.057 g, 0.506 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 50% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>C(#N)C>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1CCN1CCOCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.100 g, 0.303 mmol), cesium carbonate (0.296 g, 0.909 mmol), and 4-(2-chloroethyl)morpholine (0.059 g, 0.394 mmol) were suspended in acetonitrile (4 mL). The reaction was stirred at 60° C. overnight. H2O (25 mL) was added and the resulting precipitate was collected by filtration. The solid was subjected to chromatography (silica gel, ethyl acetate with 10% methanol) afforded an off-white solid (0.040 g, 30%). 1H NMR (400 MHz, CDCl3) δ 7.55 (app q, J=7.92 Hz, 1H), 6.93 (app t, J=8.39 Hz, 1H), 6.84 (app t, J=9.40 Hz, 1H), 5.95 (s, 1H), 5.18 (s, 2H), 4.16 (app t, J=6.78 Hz, 2H), 3.68 (s, 4H), 2.65 (app t, J=6.38 Hz, 2H), 2.54 (s, 4H), 2.43 (s, 3H). ES-HRMS m/z 443.0743 (M+H C19H21BrF2N2O3 requires 443.0776).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)=[CH:6][N:5]=[C:4]([NH2:16])[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl.O>[CH3:15][S:14]([C:10]1[N:9]=[C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([NH2:16])=[N:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1)=[O:25]
Reactant: CSc1nccc(-c2cnc(N)nc2C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: Cc1nc(N)ncc1-c1ccnc(S(C)=O)n1
Yield: 17.2 %

Procedure:
To a suspension of 4′-Methyl-2-methylsulfanyl-[4,5]bipyrimidinyl-2′-ylamine (19) (380 mg, 1.629 mmol) in DCM (3.258 mL) was added mCPBA (402 mg, 1.629 mmol). The reaction turned to a brown solution, and immediately the reaction was complete. The reaction mixture was diluted with DCM and water. The organic layer was washed with saturated sodium bicarbonate and brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash chromatography with a gradient of 2-10% MeOH in DCM to give the desired product (70 mg, 17%). MS (ES+): m/z=250.1 (100) [MH+]. HPLC: tR=0.64 minute over 3 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][NH:6][C:7](=[O:18])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=1[O:16][CH3:17].[CH2:20](O)[CH2:21][CH2:22]C.C1(C)C=CC=CC=1>CCCCO.CCCCO.CCCCO.CCCCO.[Ti].CO.C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:19])[CH2:4][O:5][NH:6][C:7](=[O:18])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=1[O:16][CH3:17])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCO
Reactant: COC(=O)CONC(=O)c1c(Cl)ccc(Cl)c1OC
Agent: [Ti]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCOC(=O)CONC(=O)c1c(Cl)ccc(Cl)c1OC
Temperature: 85 °C

Procedure:
To 161.8 g. of methyl[(3,6-dichloro-2-methoxybenzoyl) aminooxy]acetate was added 80 g. of n-butyl alcohol, 600 ml. of toluene, and 9.5 g. of titanium n-butoxide. The mixture was stirred and heated to 85° C. for 2 hours to drive off a methanol/toluene mixture. The heat was then maintained at 95°-100° C. to distill off n-butanol/toluene. The reaction mixture was cooled to 40° C. and 150 ml. of 1 M. HCl added. The mixture was then washed with 1 M. HCl, water, then saturated NaHCO3 solution, and then dried over MgOS4, filtered, and evaporated in vacuo to yield the title product as a white solid, m.p. 68°-71° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:37][C:38]1[CH:43]=[CH:42][C:41]([C@H:44]([NH2:46])[CH3:45])=[CH:40][CH:39]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([NH:46][CH:44]([C:41]1[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=1)[CH3:45])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(COCc1cc(C(=O)O)cc(C2(C#N)CCCC2)c1)(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: C[C@@H](N)c1ccc(F)cc1
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: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C2(C#N)CCCC2)c1)c1ccc(F)cc1

Procedure:
A solution of 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid (10.25 mg, 0.021 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.0085 mL, 0.063 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (12 mg, 0.025 mmol) and diisopropylethylamine (0.012 mL, 0.07 mmol) in 0.2 mL DMF was stirred at rt overnight. Purification by reverse phase preparative HPLC (5-95% MeCN/H2O containing 0.1% TFA, C18 PRO YMC 20×150 mm) gave 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)-N-(1-(4-fluorophenyl)ethyl)benzamide which was subsequently dissolved in 0.2 mL CH2Cl2 and 0.5 mL TFA. The reaction mixture was stirred for 1 h and concentrated. Lyophilization gave 3-((2-amino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)-N-(1-(4-fluorophenyl)ethyl)benzamide as the TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.93 (d, J=8.0 Hz, 1H), 7.92 (app d, J=1.6 Hz, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.42 (m, 2H), 7.28 (m, 3H), 7.18 (m, 2H), 7.05 (m, 2H), 5.25 (m, 1H), 4.70 (m, 2H), 3.44 (A of AB, d, J=10.1 Hz, 1H), 3.38 (B of AB, d, J=10.1 Hz, 1H), 3.09 (d, J=13.4 Hz, 1H), 2.86 (d, J=13.4 Hz, 1H), 2.50 (m, 2H), 2.18 (m, 2H), 2.03 (m, 4H), 1.58 (d, J=7.0 Hz, 3H), 1.25 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: [N-]=[N+]=NCc1cncc2cccnc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cncc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.1 g (5.9 mmol) 8-azidomethyl-1,6-napthyridine in 20 mL THF was added 2 mL H2O and 3 g PPh3. The resulting solution was alloed to stir overnight at room temperature, then concentrated in vacuo. Purification by flash chromatography (50×140 mm silica gel, linear gradient 5-20% (10% NH4H in MeOH):CH2Cl2) yielded 8-aminomethyl-1,6-napthyridine. 1H NMR (CDCl3, 400 MHz) δ 9.22 (s, 1H); 9.13 (dd, 1H, J=4.3 and 1.8 Hz); 8.70 (s, 1H); 8.32 (dd, 1H, J=8.24 and 1.83 Hz); 7.61 (dd, 1H, J=8.24 and 4.3 Hz); 4.40 (s, 2H).