Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][CH2:27][C@@H:28]([NH2:30])[CH3:29].CN1CCOCC1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:30][CH:28]([CH2:27][CH3:26])[CH3:29])=[O:20]
Reactant: CC[C@H](C)N
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: CN1CCOCC1
Product: CCC(C)NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.900 g, 2.47 mmol), S-(+)-sec-butylamine (0.235 g, 3.21 mmol), N-methylmorpholine (0.270 g, 2.67 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(sec-butyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.300 9, 27.8% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][C:14]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][N:15]=1.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[F:12][C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:20]([C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH3:13])[CH:19]=1)=[N:1]2
Reactant: Cc1cc(C=O)ccn1
Reactant: NC(=O)c1c(N)cc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)ccn1
Temperature: 115 °C

Procedure:
To a solution of 2-amino-4,6-difluoro-benzamide (0.71 g, 4.10 mmol) and 2-methyl-pyridine-4-carbaldehyde (0.50 g, 4.10 mmol) in N,N-dimethylacetamide (10 mL) were added NaHSO3 (58.5 wt %, 1.00 g, 5.70 mmol) and p-TSA (0.16 g, 0.08 mmol). The reaction mixture was heated at 115° C. for 30 hours, then cooled to room temperature. The solvent was removed under reduced pressure. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane) to afford 5,7-difluoro-2-(2-methyl-pyridin-4-yl)-3H-quinazolin-4-one as a light yellow solid. Yield: 0.30 g (26%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([CH:29]1[CH2:31][O:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][CH:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: c1ccc(CC2CO2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)Cc3ccccc3)CC1)O2

Procedure:
Compound 163 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-benzyloxirane and conditions outlined in procedure X. M.p.=70-73° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 7.35-7.2 (m, 5H), 3.95 (m, 1H), 2.95-2.8 (m, 5H), 2.75-2.65 (m, 3H), 2.5-2.35 (m, 3H), 2.1 (d, 2H), 1.95-1.75 (m, 2H); LCMS: 436 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7]1.[NH2:21][NH2:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([NH:21][NH2:22])=[O:14])[CH2:8][CH2:7]1
Reactant: CCOC(=O)CN1CCN(Cc2cccc(Cl)c2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2cccc(Cl)c2)CC1

Procedure:
Synthesized according to General Procedure C: 6{8} (6.78 g, 22.8 mmol, 1 equiv.), anhydrous hydrazine (2.9 mL, 91.4 mmol, 4 equiv.), ethanol (31.4 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{8} (5.04 g, 78%) as a light yellow oil. 1H-NMR (500 MHz, CDCl3): δ 8.15 (br s, 1H), 7.27 (br s, 1H) 7.21-7.12 (m, 3H), 3.82 (br s, 2H) 3.42 (s, 2H), 3.03 (s, 2H), 2.49 (br s, 4H), 2.41 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.3, 140.0, 134.0, 129.3, 128.8, 127.1, 126.9, 62.0, 60.4, 53.4, 52.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1
Yield: 80 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.057 g (80%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-3-carboxamide as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1(=O)[O:13][C:11](=O)[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[N:19]1C=CC=[CH:21][CH:20]=1>>[O:13]1[CH2:11][CH2:10][C:14]2[CH:15]=[CH:16][CH:17]=[C:9]([CH2:21][C:20]#[N:19])[C:8]1=2
Reactant: O=C1OC(=O)c2ccccc21
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Product: N#CCc1cccc2c1OCC2

Procedure:
A mixture of the oil, toluene (60 ml), pyridine (2.2 ml) and phthalic anhydride (4 g) was heated at 90°-95° C. for 4 hours. The resulting solution was cooled, washed with 10% aqueous potassium carbonate solution, then with dilute hydrochloric acid. The solution was then dried over sodium sulphate and the solvent removed in vacuo to yield an oil. The oil was distilled, (b.p. 120° C./1 mbar) to give 2,3-dihydrobenzo[b]furan-7-ylacetonitrile which rapidly solidified (16.97 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)[CH:26]=[CH:25][N:24]=[CH:23]1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:34]([CH2:33][C:30]1[CH:29]=[CH:28][C:27]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:32][CH:31]=1)[C:35]1[CH:36]=[CH:37][C:38]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:40]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(NCc2ccc(-n3ccnc3)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(-n3ccnc3)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 59.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.54 g) and {[4-(imidazol-1-yl)phenyl]methyl}(4-isopropylphenyl)amine (0.55 g) as starting materials, 5-benzyloxy-N-{[4-(imidazol-1-yl)phenyl]methyl-}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.62 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][CH2:24][OH:25])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:27][CH:28]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCCO)cc2c1O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCCO)cc2c1O
Yield: 44.9 %

Procedure:
A solution of the title compound of Example 94 (0.180 g), Pd/Ba2SO4 (10%, 75.3 mg), and pyridine (5 mL) in EtOAc (25 mL) is maintained under an atmosphere of H2 (balloon) for 3 hrs, then filtered over celite. The crude product is recrystallized from EtOAc/hexanes to afford 81.6 mg of the desired product as an off-white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CS([C:11]1[N:12]=[C:13]([O:27][CH2:28][CH2:29][CH3:30])[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[O:17][C:15]=2[N:16]=1)(=O)=O.[CH:31]1([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C=O)C>[CH:31]1([O:37][C:11]2[N:12]=[C:13]([O:27][CH2:28][CH2:29][CH3:30])[C:14]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=4)[O:17][C:15]=3[N:16]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Reactant: OC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1nc(OC2CCCCC2)nc2oc(-c3cccc(C)c3)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.5 %

Procedure:
113 mg of cesium carbonate and 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine were added to a solution of 29 mg of cyclohexanol in 3 ml of DMF. The mixture was stirred at room temperature for 18 h. After filtration, the solvent was distilled off in vacuo, and the product was isolated via preparative HPLC to yield 10 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[N:17]=[C:16](S(C)(=O)=O)[N:15]=[C:14]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:13]=1[C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[NH2:45][CH2:46][CH2:47][OH:48]>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[N:17]=[C:16]([NH:45][CH2:46][CH2:47][OH:48])[N:15]=[C:14]([NH:22][S:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[C:13]=1[C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(S(C)(=O)=O)nc2OCCOCc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(NCCO)nc2OCCOCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
##STR152## (1) A solution of N-[6-(2-benzyloxyethoxy)-5-(4-methylphenyl)-2-methylsulfonylpyrimidin-4-yl]-4-tert-butylbenzenesulfonamide obtained in Reference Example 11-(6) (300 mg) in 2-aminoethanol (4 ml) is heated with stirring at 120° C. for three hours. After cooling, to the reaction solution is added an aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=10:1), and recrystallized from isopropyl ether-n-hexane to give N-[6-{2-benzyloxyethoxy)-2-(2-hydroxyethylamino)-5-(4-methylphenyl)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (260 mg) as a crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C(=O)Cc2ccc(F)cc2)ccn1
Agent: CN(C)c1ccncc1
Product: CC(=O)Nc1cc(C(=O)Cc2ccc(F)cc2)ccn1

Procedure:
12.0 g of the compound (28) are suspended in 100 ml of acetic anhydride, a spatula tip of 4-dimethylaminopyridine is added and the reaction mixture is heated under reflux for 5 h. Most of the excess acetic anhydride is distilled off, the residue is hydrolyzed and the mixture is adjusted to pH 7 using conc. ammonia. The resulting clear precipitate (29) is filtered off and dried under reduced pressure over P2O5.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[Cl:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[Cl:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([NH:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])=[O:37]
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1cccc(CCl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NC(=O)c1cccc(CCl)c1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of (R)-2-Amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (30.5 mg, 0.092 mmol) in DCM (1 mL) cooled to 0° C. was added DIEA (17.4 μL, 0.1 mmol) followed by 3-chloromethyl benzoylchloride (14.2 μL, 0.1 mmol). Upon completion of addition, the reaction mixture was allowed to warm slowly to rt. where it stirred overnight. After this time, the solution was diluted with dichloromethane and quenched by the addition of aqueous NaHCO3. The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified via SiO2 chromatography to give the (R)-3-(chloromethyl)-N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)benzamide as a clear glassy solid (23.7 mg, 58% yield). MS found: 447.3 (M+), 449.3 (M+2).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.C[O:9][C:10]([C:12]1[C:17](C)=[CH:16][C:15]([Br:19])=[C:14](Cl)[N:13]=1)=[O:11]>>[Br:19][C:15]1[CH:16]=[CH:17][C:12]([C:10]([OH:11])=[O:9])=[N:13][C:14]=1[O:7][CH2:6][CH:3]1[CH2:5][CH2:4]1
Reactant: OCC1CC1
Reactant: COC(=O)c1nc(Cl)c(Br)cc1C
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
Sodium hydride (4.83 g, 0.12 mol) was added into cyclopropanemethanol (CAN 2516-33-8, 30 g) at 0° C. and the mixture was stirred at 0° C. for 1 h. Then to the mixture was added methyl 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (3 g, 12.75 mmol). The obtained solution was heated to 90° C. for 2 h. Then the mixture was evaporated to dryness, the residue was dissolved in 40 mL of water, and adjusted to pH=4 with hydrochloric acid (3 N), and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with water (2×30 mL) and brine (2×50 mL) then evaporated to dryness to obtain the product as a white solid (2.5 g, 76.7%); MS (EI): m/e=272.0 [MH+].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[S:63](Cl)(=[O:65])=[O:64])#[N:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([S:63]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[C:55]#[N:56])(=[O:65])=[O:64])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1S(=O)(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-cyanobenzenesulfonyl chloride as the starting materials in 50% yield. LCMS for C30H28ClN8O4S (M+H)+: m/z=631.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([C:18]([OH:20])=O)[NH:13]3)=[CH:5][CH:4]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:21]([N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:18]([C:12]2[NH:13][C:14]3[C:10]([CH:11]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:17]=[CH:16][CH:15]=3)=[O:20])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(-c2cccc3[nH]c(C(=O)O)cc23)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(Cc5ccccc5)CC4)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
128 (4.7 g, 17.6 mmol) and 1-benzyl-piperidin-4-ylamine (3.3 g, 17.6 mmol) are dissolved in DMF (70 ml) and after addition of TBTU (6.4 g, 19.4 mmol) and ethyldiisopropylamine (12 ml, 70.4 mmol) the mixture is stirred at room temperature for 2 h. Then the solvent is evaporated at high vacuum. The residue is dissolved in ethyl acetate washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layers are dried over sodium sulfate and evaporated under reduced pressure. The crude mixture is crystallized from methanol.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[O:5][CH2:6][CH2:7][N:8]=1.BrCCC(O)=[O:13].C1N=CN(C(N2C=NC=C2)=O)C=1.C(CN)O>>[OH:5][CH2:6][CH2:7][NH:8][C:4](=[O:13])[CH2:3][CH2:2][Br:1]
Reactant: BrCCC1=NCCO1
Reactant: O=C(O)CCBr
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: NCCO
Product: O=C(CCBr)NCCO

Procedure:
The required intermediate, 2-(2-bromoethyl)oxazoline, is prepared in a two-step process starting with 3-bromopropionic acid. Reaction of this acid with CDI followed by ethanolamine gives N-(2-hydroxyethyl)-3-bromopropionamide. Treatment of this compound with triphenylphosphine (PPh3) and DEAD in THF yields 2-(2-bromoethyl)oxazoline.
Reaction SMILES: C(OCC)(=O)CC(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:8]=1)=O.S(=O)(=O)(O)O.O.[C:32]([OH:35])(=[O:34])[CH3:33]>>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:9]2[CH:8]=[C:7]([CH2:6][CH2:33][C:32]([OH:35])=[O:34])[CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(=O)OCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCc1cccc(Cc2ccc(Cl)cc2)c1
Temperature: 25 °C

Procedure:
A solution of 15.2 g of ethyl 3-(p-chlorobenzoyl)-benzyl malonate in 50 ml of acetic acid was added to a solution of 50 ml of sulfuric acid and 50 ml of water and the mixture was refluxed under a nitrogen atmosphere for 20 hours and then cooled to room temperature. The mixture was poured into water and then extracted with methylene chloride. The organic phase was extracted with N sodium hydroxide and the alkaline phase was treated with activated carbon, filtered and acidified by addition at 10° C with stirring of 270 ml of N hydrochloric acid. The mixture was vacuulm filtered and the precipitate was washed with water and dried under reduced pressure to obtain 3.11 g of 3-(3'-p-chlorobenzyl-phenyl)-propionic acid which was used as is for the next step.
Reaction SMILES: C(OC([N:6]1[CH2:10][CH2:9][C@@H:8]([CH2:11][P:12]([O:17]CC)([O:14]CC)=[O:13])[C@@H:7]1[C:20]([O:22]CC)=[O:21])=O)C.[ClH:25]>>[ClH:25].[P:12]([CH2:11][CH:8]1[CH2:9][CH2:10][NH:6][CH:7]1[C:20]([OH:22])=[O:21])([OH:14])([OH:17])=[O:13]
Reactant: CCOC(=O)[C@H]1[C@H](CP(=O)(OCC)OCC)CCN1C(=O)OCC
Agent: Cl
Product: O=C(O)C1NCCC1CP(=O)(O)O

Procedure:
A solution of 2.7 g of cis and trans ethyl 1-ethoxycarbonyl-3-(diethylphosphonomethyl)pyrrolidine-2-carboxylate is heated under reflux with 6N hydrochloric acid for 6 hours to yield 3-(phosphonomethyl)-pyrrolidine- 2-carboxylic acid hydrochloride; NMR (D2O): 4.78, 4.40, 3.95, 3.83, 3.72, 3.20, 3.01, 2.78, 2.69 ppm.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:12](O)[CH2:13][OH:14].C(OCC)(OCC)OCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:9]([C:2]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:14][CH2:13][CH2:12][O:1]1)[CH2:10][CH3:11]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: O
Product: CCCC1(CC(=O)OCC)OCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A mixture of ethyl 3-oxohexanoate (5 g, 31.6 mmol), ethylene glycol (3.92 g, 63.2 mmol) and triethyl orthoformate (4.68 g, 31.6 mmol), and p-toluenesulfonic acid monohydrate (544 mg, 2.86 mmol) was stirred at room temperature for 29 hours and 10 minutes. To the reaction mixture, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (6.2 g, 97%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH3:12]CCCCC.C[Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of 4-fluoro-2-hydroxybenzoic acid (9.8 g, 62.3 mmol) in benzene (100 mL) and MeOH (20 mL) was cooled in an ice bath and a 2 M hexane solution of (trimethyl-silyl)diazomethane (50 mL) was added dropwise. The reaction was stirred overnight at ambient temperature, diluted with benzene (348 mL) and MeOH (39 mL), and treated with more of the (trimethylsilyl)diazomethane solution (15 mL). The mixture was concentrated in vacuo to dryness to give the title compound (10.4 g, 98%) as a solid.