Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]2[CH:6]=[CH:7][C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[N:10]([C:12](=[O:14])[CH3:13])[CH2:11][C:4]=2[N:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)(=[O:23])[CH3:22].C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:12]([N:10]1[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[CH:7]=[CH:6][C:5]2[CH:19]=[CH:20][C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:21](=[O:23])[CH3:22])=[N:3][C:4]=2[CH2:11]1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: CC(=O)N1Cc2nc(Cl)ccc2C=Cc2ccccc21
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)c1ccccc1-c1ccc2c(n1)CN(C(C)=O)c1ccccc1C=C2
Yield: 92 %

Procedure:
The title compound (6.1 mg, 92%) was prepared from 55C (5.0 mg, 0.018 mmol) and 2-acetylphenylboronic acid (2.9 mg, 0.018 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.363 min; LCMS Found: (M+H)+=369.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14])=[C:2]=[O:3].[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>C1COCC1>[CH3:19][C:16]([NH:15][C:2](=[O:3])[NH:1][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14])([CH3:20])[CH2:17][OH:18]
Reactant: CC(C)(N)CO
Reactant: COC(=O)c1ccc(N=C=O)c(C)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)NC(C)(C)CO)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.70 g (29.8 mmol) methyl 4-isocyanato-3-methyl-benzoate are dissolved in 100 ml THF and a solution of 2.86 ml (30.0 mmol) 2-amino-2-methyl-propan-1-ol in 25 ml THF is added dropwise. The mixture is stirred for 2 hours at ambient temperature and then evaporated down i. vac. The residue is further reacted without any more purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:34])[C:20]([OH:33])([C:25]3[CH:26]=[N:27][C:28]([O:31]C)=[CH:29][CH:30]=3)[C:21]([F:24])([F:23])[F:22])=[C:15]([Cl:35])[CH:14]=2)[CH:9]=[CH:10][C:11]=1[Cl:12])=[O:5])C.Cl.[OH-].[Na+]>O1CCOCC1.O1CCCC1.CO>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:34])[C:20]([OH:33])([C:25]3[CH:30]=[CH:29][C:28](=[O:31])[NH:27][CH:26]=3)[C:21]([F:24])([F:23])[F:22])=[C:15]([Cl:35])[CH:14]=2)=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: CC(c1ccc(-c2ccc(Cl)c(C(=O)O)c2)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F

Procedure:
In analogy to Example 175, step 6, 4,3′-dichloro-4′-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxy-pyridin-3-yl)-1-methyl-propyl]-biphenyl-3-carboxylic acid ethyl ester (Example 180) was treated first with aqueous HCl in dioxane, followed by aqueous NaOH in tetrahydrofuran/methanol to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=484.1 [M−H+].
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([N:14]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl>[N:32]1([C:38]([N:22]2[CH2:21][CH2:20][CH:19]([CH2:18][N:14]([CH:10]3[CH2:9][CH2:8][C:7]4[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[CH2:11]3)[CH2:15][CH2:16][CH3:17])[CH2:24][CH2:23]2)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice-cold solution of (7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-ylmethyl-propyl-amine, as prepared in Example 4, (400 mg, 1.2 mmol) and triethylamine (170 μl, 1.4 mmol, 1.2 eq.) in methylene chloride (40 mL) under an inert atmosphere morpholine-4-carbonyl chloride (170 μL, 1.4 mmol) was added dropwise. The ice bath was removed and the reaction was stirred at room temperature for 4 h. The methylene chloride was washed 2 times with water (30 mL), dried (MgSO4), filtered, and concentrated to afford morpholin-4-yl-(4-{[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidin-1-yl)-methanone as a clear oil (540 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([F:19])([F:18])[F:17])[CH2:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.N1C=CC=CC=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(=O)NC(=O)CCC1>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([O:8][S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([F:18])([F:17])[F:19])[CH2:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1CC(C(F)(F)F)CC(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C1CCCC(=O)N1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1CC(C(F)(F)F)CC(=O)N1c1cc(OS(=O)(=O)c2ccccc2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a solution of N-(4'-chloro-2'-fluoro-5'-hydroxyphenyl)-3-(trifluoromethyl)glutarimide (1.64 g, 5.05 retool, Compound 19) in about 20 ml of methylene chloride was added via syringe nearly 2.5 eq. of pyridine (1 ml) which had been freshly distilled from CaH2. Then a solution of benzenesulfonyl chloride (0.64 ml, 5.0 mmol) in 4.5 ml of methylene chloride was slowly added dropwise to the reaction mixture with ice bath cooling. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. Then there was added 0.17 g of additional glutarimide and the reaction mixture was stirred at room temperature for an additional 12 hours. The reaction mixture was poured into 50 ml of water and the layers were separated. The organic layer was evaporated in vacuo and the residue was dried in the vacuum oven (20-50 Torr, 50° C.). The resulting brown solid was rinsed with approximately 5 ml of methylene chloride and suction filtered to yield 1.9 g (82% yield) of the desired product as an off-white powder (m.p. 214°-215° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15])([O-:3])=[O:2].[Cl:18][C:19]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][C:19]1[CH:28]=[CH:27][C:26]([NH:29][S:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:16])=[O:15])=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 45.3 %

Procedure:
In a similar fashion using route 14 general procedure 27, 2-nitro-4-trifluoromethylbenzenesulfonyl chloride (Intermediate 461) (1.24 g, 4.29 mmol), 5-chloro-quinolin-8-ylamine (Intermediate 27) (0.64 g, 3.58 mmol), DMAP (cat.), pyridine (0.86 ml, 10.7 mmol) and DCM (5 ml) gave the title compound (700 mg, 45%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.N1(C2C=CN=CC=2)CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(O)CCCCCCCBr
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: O=C(CCCCCCCBr)OCc1ccccc1
Yield: 100.2 %

Procedure:
This compound was prepared from 8-bromooctanoic acid (2.23 g; 10.0 mmol), benzyl alcohol (1.19 g; 11.0 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 2.27 g; 11.0 mmol), and 4-pyrrolidinylpyridine (50 mg) in dry dichloromethane (50 mL) using Procedure A. 3.14 g (100%) product was obtained (clear oil that eventually solidified on standing).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:14]=[C:13](F)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7].O>C1COCC1>[F:3][C:4]1[CH:14]=[C:13]([NH:2][CH3:1])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CN
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1F
Reaction time: 3 h

Procedure:
A solution of MeNH2 in THF (21.6 mL; 2 M; 43.3 mmol) was added dropwise to a solution of ethyl 2,4-difluoro-5-nitrobenzoate (5.0 g; 21.6 mmol) in THF (70 mL) at −5° C. The mixture was left over night at rt whereafter an additional portion of MeNH2 in THF (10.0 mL; 2 M; 21.6 mmol) was added at 0° C. After 3 h at rt, water was added and the mixture was concentrated. The resulting precipitate was filtered off and dried to give the sub-title compound. Yield: 5.0 g (96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]([N:12]=[C:13]=[O:14])([F:11])[F:10]>C1(C)C=CC=CC=1>[C:2]1([NH:1][C:13]([NH:12][C:9]([F:11])([F:10])[F:8])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C=NC(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)NC(F)(F)F
Reaction time: 1 h

Procedure:
A solution of aniline (93.12 grams; 1.0 mol) in toluene (200 ml) is charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and gas inlet tube. Trifluoromethyl isocyanate (111 grams; 1.0 mol) is slowly bubbled into the reaction medium with vigorous stirring. The temperature of the reaction mixture is kept below about 50° C. After the addition is completed the reaction mixture is stirred for an additional period of about 1 hour. After this time the toluene is stripped from the reaction mixture under reduced pressure. The residue is then recrystallized to yield N-phenyl-N'-trifluoromethyl urea.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24](O)=[O:25])=[CH:14][CH:13]=1>>[NH2:10][CH2:9][C@H:4]1[C@@H:3]([CH2:1][CH3:2])[CH2:8][CH2:7][CH2:6][N:5]1[C:24]([C:19]1[N:20]=[C:21]([CH3:23])[S:22][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)=[O:25]
Reactant: CCc1cccnc1C#N
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: CC[C@H]1CCCN(C(=O)c2nc(C)sc2-c2ccc(F)cc2)[C@H]1CN

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using 3-ethylpicolinonitrile and 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) 361.1 (M+H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:38])[CH:25]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH2:26][S:27]2)=[CH:22][CH:21]=1.O>O1CCCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([C:24]2([OH:38])[C:23]3[C:28](=[CH:29][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[S:27][CH2:26][CH:25]2[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CSc3cc(OC)ccc3C2(O)c2cccc(C3OCCO3)c2)cc1
Reaction time: 0.83 h
Yield: 50 %

Procedure:
To a solution of 2-(3-bromophenyl)-1,3-dioxolane (3.04 g, 13.28 mmol) in dry tetrahydrofuran (35 ml) was added n-butyl lithium (8.37 ml, 13.316 mmol, 1.59 mol/l tetrahydrofuran solution) dropwise as −78° C. over 10 minutes and stirred for 50 minutes at the same temperature. Then to the reaction mixture was added 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (2 g, 6.658 mmol) dissolved in tetrahydrofiuran at the same temperature over 10 minutes. The reaction mixture was stirred for 6 h at −78° C. and followed at −10C for 2 h. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=8:1 to 7:3) to give 1.50 g (yield: 50%) of the title compound as a colorless oil. In this reaction, 0.77 g (38%) of the unreacted starting compound was recovered.
Reaction SMILES: [CH2:1]=[O:2].[CH:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[N:16]3[C:12](=[N:13][N:14]=[CH:15]3)[CH2:11][N:10]=2)=[CH:7][CH:8]=1>>[OH:2][CH2:1][C:15]1[N:16]2[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:9]([C:6]3[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=3)=[N:10][CH2:11][C:12]2=[N:13][N:14]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Reactant: C=O
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 1.5 h

Procedure:
The TLC test indicated that the reaction was not yet complete so another 1 g of paraformaldehyde was added 45 minutes after the first. Heating of the reaction mixture was continued at 125° C. After 1.5 hours total heating, a second TLC sample was taken and analyzed as above and it indicated that the estazolam was almost all consumed. To ensure complete reaction, another 0.5 g of paraformaldehyde was added and heating of the mixture was continued at 125° C. for another 45 minutes (2.25 hours total heating time), at which time testing by TLC analysis indicated reaction was substantially complete to form 1-(hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]([N:7]([CH3:15])[CH2:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)([CH3:6])[C:3]([OH:5])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[H-].[Na+].[NH2:51][C:52]1[S:56][C:55]([C:57]([CH3:61])([CH3:60])[C:58]#[N:59])=[N:54][N:53]=1>CN(C=O)C>[C:58]([C:57]([CH3:61])([CH3:60])[C:55]1[S:56][C:52]([NH:51][C:3](=[O:5])[C:2]([CH3:1])([N:7]([CH3:15])[CH2:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH3:6])=[N:53][N:54]=1)#[N:59]
Reactant: CN(CC1CCOCC1)C(C)(C)C(=O)O
Reactant: CC(C)(C#N)c1nnc(N)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1CCOCC1)C(C)(C)C(=O)Nc1nnc(C(C)(C)C#N)s1
Reaction time: 0.5 h
Yield: 10.9 %

Procedure:
To 270 mg (1.25 mmol) of 2-methyl-2-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-propionic acid (intermediate 3) in DMF (3 mL) are added 450 μL (2.58 mmol) DIPEA and 480 mg (1.26 mmol) HATU. In a second flask 110 mg sodium hydride (60% dispersion in oil; 2.75 mmol) are added to 215 mg (1.27 mmol) 2-(5-amino[1,3,4]thiadiazol-2-yl)-2-methyl-propionitrile (intermediate 6) in DMF (3 mL). After 10 min this mixture is added to the activated acid. The reaction mixture is stirred for additional 30 min, then filtered and purified by HPLC-MS to afford 50 mg of N-[5-(cyano-dimethyl-methyl)-[1,3,4]thiadiazol-2-yl]-2-methyl-2-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-propionamide.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[C:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:31][CH2:32][CH:27]([C:23]2[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:16])[CH3:33])[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1cccc(OCCCCCl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(=O)c1cccc(OCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-[3-(4-chlorobutoxy)phenyl]ethanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 437.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[O:19])=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[O:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2cc(C(=O)O)on2)cc1)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 86.6 %

Procedure:
3-{4-[3-(2-Fluoro-phenyl)ureido]-phenyl}-isoxazole-5-carboxylic acid ethyl ester (4.6 g) was dissolved in THF (92 ml). 1M aqueous NaOH solution (65 ml) was added and stirred at RT for 15-20 minutes. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to get off white solid, which was crystallized from CH2Cl2 to yield 3.68 g (86%) white solid. MS (ES+): m/z 342 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ 9.33 (s, 1H), 8.63 (s, 1H), 8.13 (m, 1H), 7.89 (d, 2H), 7.7 (s, 1H), 7.6 (d, 2H), 7.23 (m, 1H), 7.13 (m, 1H), 7.02 (m, 1H).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH3:14][O:15][CH:16]([O:26][CH3:27])[C:17]1[CH:18]=[C:19]([Br:25])[C:20]([CH3:24])=[N+:21]([O-])[CH:22]=1.CO.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C(Cl)Cl>[CH3:14][O:15][CH:16]([O:26][CH3:27])[C:17]1[CH:18]=[C:19]([Br:25])[C:20]([CH2:24][OH:4])=[N:21][CH:22]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(OC)c1cc(Br)c(C)[n+]([O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(OC)c1cnc(CO)c(Br)c1
Temperature: 77 °C
Yield: 82.9 %

Procedure:
Trifluoroacetic anhydride (0.191 mL, 1.353 mmol) was added to a solution of 5-[bis(methyloxy)methyl]-3-bromo-2-methylpyridine 1-oxide (118.2 mg, 0.451 mmol) in EtOAc (3 mL) at 0° C. and the mixture was heated at 77° C. in a sealed tube for 6 h and at room temperature overnight. Methanol (0.262 mL, 6.47 mmol) was added and the mixture was stirred at room temperature, and after stirring for 20 min, DCM and 10% Na2CO3 solution were added. Extraction, drying (Na2SO4), and filtration afforded {5-[bis(methyloxy)methyl]-3-bromo-2-pyridinyl}methanol (98 mg, 83%) as a brown oil pure enough to be used in the next step.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:18][C:19]1[C:20]2[CH2:28][N:27]([C:29]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=3[C:31]#[N:32])[CH2:26][CH2:25][C:21]=2[N:22]=[CH:23][N:24]=1)[C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[N:15][CH:16]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.CCOC(C)=O>C1COCC1>[OH:8][CH2:9][C@@H:10]([NH:18][C:19]1[C:20]2[CH2:28][N:27]([C:29]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=3[C:31]#[N:32])[CH2:26][CH2:25][C:21]=2[N:22]=[CH:23][N:24]=1)[C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13][CH:12]=1
Reactant: Cc1ccc(N2CCc3ncnc(N[C@H](CO[Si](C)(C)C(C)(C)C)c4cnc(C)nc4)c3C2)c(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CO)c4cnc(C)nc4)c3C2)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-(4-(2-(tert-butyldimethylsilyloxy)-1-(2-methylpyrimidin-5-yl)ethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (630 mg, 1.22 mmol) in THF (10 mL) was added 1M TBAF in THF (5 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then treated with water and EtOAc. The organic layer was washed with aq. NaHCO3 and brine, dried (MgSO4), and concentrated. The residue was washed by ethyl ether to yield a light colored solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]#[N:11].O1CCO[CH:14]1[C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:10]#[N:11])=[CH:14][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][N:19]=2)[N:24]=1
Reactant: Nc1cccnc1C1OCCO1
Reactant: N#CCC(=O)c1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cc2ncccc2nc1-c1ccccc1F
Temperature: 120 °C

Procedure:
3-(2-Fluorophenyl)-3-oxopropanenitrile (1.5 g, 9.2 mmol) and 2-(1,3-dioxolan-2-yl)-3-pyridinamine (1.68 g, 10.12 mmol) were dissolved in toluene (100 mL). To the mixture was added catalytic amount of p-TSA (300 mg) and the reaction flask equipped with Dean-Stark assembly was heated for 4 h at 120° C. After completion of reaction, the reaction mixture was treated with water and ethyl acetate. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a thick oily mass. The oily mass was then purified by silica gel column chromatography using 20% of ethyl acetate and hexane as eluent to give 2-(2-fluorophenyl)-1,5-naphthyridine-3-carbonitrile: 1H-NMR (CDCl3) δ: 7.2-7.0 (m, 3H), 7.8-7.4 (m, 3H), 8.4 (d, 1H), 9.1 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH:6]([C:8]2[N:9]=[CH:10][O:11][CH:12]=2)O)[N:3]=[CH:2]1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl>[O:1]1[CH:5]=[C:4]([CH:6]([C:8]2[N:9]=[CH:10][O:11][CH:12]=2)[N:30]2[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]2)[N:3]=[CH:2]1
Reactant: OC(c1cocn1)c1cocn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(c2cocn2)c2cocn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
A round bottom flask was charged with bis(oxazol-4-yl)methanol (200 mg, 1.20 mmol), CH2Cl2 (3 mL), and DIPEA (412 μL, 2.41 mmol). The solution was cooled to 0° C. and MsCl (112 μL, 1.45 mmol) was added dropwise. After stirring 0° C. for 30 min, more MsCl (100 μL, 1.29 mmol) was added. After an additional 30 min at 0° C., the reaction was quenched with brine and extracted with CH2Cl2 (3×). The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure yielding the crude alkyl chloride. The crude intermediate was dissolved in CH2Cl2 (3 mL) and treated with tert-butyl piperazine-1-carboxylate (224 mg, 1.20 mmol) and stirred at room temperature. After 48 h at room temperature, the reaction was quenched with brine and extracted with CH2Cl2 (3×). The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (100% CH2Cl2 to 4% MeOH in CH2Cl2) yielding tert-butyl 4-(bis(oxazol-4-yl)methyl)piperazine-1-carboxylate (114 mg, 28%) as a light brown oil. 1H NMR 400 MHz (CDC3) δ 7.87 (s, 2H), 7.69 (s, 2H), 4.78 (s, 1H), 3.45-3.37 (m, 4H), 2.53-2.40 (m, 4H), 1.39 (s, 9H). LCMS (ESI, m/z): 335 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C:11]([O:12][CH3:13])=[N:10][C@H:9]([CH:14]([CH3:16])[CH3:15])[C:8]([O:17][CH3:18])=[N:7]1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C:11]([O:12][CH3:13])=[N:10][C@H:9]([CH:14]([CH3:16])[CH3:15])[C:8]([O:17][CH3:18])=[N:7]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCCCBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCCCN=[N+]=[N-]
Reaction time: 8 h

Procedure:
1-Bromo-4-[(2R,5S)-3,6-dimethoxy-2-isopropyl-2,5-dihydro-5-pyrazinyl]-butane (3.81 g, 11.95 mmol) were dissolved in 40 ml DMF and 3.25 g NaN3 (50 mmol) and 0.1 g NBu4I were added. The solution was kept between 70° and 80° C. overnight and diluted with 50 ml water. After extraction with chloroform the organic layers were collected and dried (MgSO4). The residue was purified by flash chromatography (hexane/ethyl acetate 9/1).