Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37](O)=[O:38])=[CH:33][CH:32]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:78][CH2:79][C:80]([NH:82][C@@H:83]([C:91]([OH:93])=[O:92])[CH2:84][CH:85]1[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]1)=[O:81]>CN(C=O)C>[Si:1]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH:22]=2)[C@@H:13]1[C:31]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([NH:78][CH2:79][C:80]([NH:82][C@@H:83]([C:91]([OH:93])=[O:92])[CH2:84][CH:85]2[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]2)=[O:81])=[O:38])=[CH:40][CH:41]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)O)cc1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)NCC(=O)N[C@H](CC2CCCCC2)C(=O)O)cc1)c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 0.08 h

Procedure:
{4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 8) (25.1 mg, 0.040 mmol) was dissolved in DMF (1 ml, dry). N-methylmorpholine (13 μl, 121 mmol) was added and the reaction mixture was stirred at 30° C. for five minutes. TBTU (20.1 mg, 0.063 mmol) was added and the reaction mixture was stirred at 30° C. for 1 hour. Glycyl-3-cyclohexyl-D-alanine (12.5 mg, 0.055 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was purified with preparative HPLC on a C8 column. A gradient from 10 to 100% MeCN in 0.1M NH4OAc buffer was used as eluent. Most of the MeCN was removed under reduced pressure. The residue was diluted with water and lyophilised to give the title compound, M/z: 921 (M−1).
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6])[CH3:3].CC1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.ClC(Cl)(Cl)C(=N)O[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][O:1][C@H:2]([C@H:4]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6])[CH3:3])=[CH:35][CH:36]=1
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Reactant: COC(=O)[C@@H](CCC(C)C)[C@H](C)O
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: COC(=O)[C@@H](CCC(C)C)[C@H](C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.7 %

Procedure:
To a solution of (S)-methyl 2-((S)-1-hydroxyethyl)-5-methylhexanoate (5.00 g, 26.6 mmol) and ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (camphorsulfonic acid, CSA; 0.617 g, 2.66 mmol) in DCM (53.1 mL) was added 4-methoxybenzyl 2,2,2-trichloroacetimidate (8.27 mL, 39.8 mmol) at 0° C. The reaction mixture was removed from the cold bath and stirred at room temperature for 17 h. Hexane (50 mL) was added to the reaction and the precipitate was removed by filtration. The solids were washed with hexanes (2×10 mL), Celite® (2 scoopula tip-fulls) was added to the combined filtrate and washes, and the solvent was removed under reduced pressure. The resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (80 g SiO2, 0→35% EtOAc/hexanes) to afford the title compound (6.3 g, 20.4 mmol, 77%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.24-7.16 (m, 2H), 6.89-6.79 (m, 2H), 4.49 (d, J=11.2 Hz, 1H), 4.33 (d, J=11.1 Hz, 1H), 3.75 (s, 3H), 3.74-3.62 (m, 4H), 2.49 (ddd, J=10.7, 8.2, 4.0 Hz, 1H), 1.62-1.40 (m, 3H), 1.23-1.16 (m, 3H), 1.16-1.03 (m, 2H), 0.87 (d, J=3.9 Hz, 3H), 0.85 (d, J=3.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.03, 159.10, 130.63, 129.14, 113.62, 76.16, 70.71, 55.11, 52.64, 51.25, 36.58, 27.97, 26.00, 22.69, 22.17, 17.08; ESIMS m/z 331 ([M+Na]+).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[CH2:18]([C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
A mixture of ethyl isonipecotate (65 mmol; 10.2 g), anhydrous potassium carbonate (195 mmol; 26.9 g) and benzyl bromide (78 mmol; 13.36 g) in anhydrous N,N-dimethylformamide (100 ml) was stirred at 70° C. for 18 hours. After cooling, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3×200 ml). The combined organic phases were washed with saturated NaCl solution (3×100 ml), dried over sodium sulfate and evaporated under reduced pressure. A crude product was obtained, which was purified on a column of alumina (eluting with chloroform) to give 13.84 g (86%) of pure product as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[C:38]([O:39][CH3:40])=[CH:37][C:27]([C:28]([NH:30][C@@H:31]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]2)=[O:29])=[C:26]([F:41])[CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[C:38]([O:39][CH3:40])=[CH:37][C:27]([C:28]([NH:30][C@@H:31]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]5)=[O:29])=[C:26]([F:41])[CH:25]=4)=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(F)cc1N
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCCC1)CC1(CC1)C(=O)N2C
Yield: 39.7 %

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 103 mg, 0.32 mmol), 4-amino-2-fluoro-5-methoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide (Intermediate 182; 87 mg, 0.32 mmol) and p-toluenesulphonic acid monohydrate (154 mg, 0.81 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140° C. for 3 hours. The mixture was cooled and absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (70 mg, 40%).
Reaction SMILES: O[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccccc2)cs1
Product: Clc1nc(-c2ccccc2)cs1

Procedure:
To 80 ml of phosphorus oxychloride were added 7.7 g (43 mmol) of 2-hydroxy-4-phenylthiazole, followed by heating at 100°-105° C. for 2 hours. The solvent was then distilled off from the reaction mixture under reduced pressure. Ice water was added to the residue, followed by extraction with ethyl ether. The ether layer was washed with water. After purification by silica gel column chromatography (solvent: hexane/ethyl acetate=5/1), the title compound was obtained as pale yellow crystals.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17]([CH2:19][C:20]#[N:21])[CH:18]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17]([C:19]2[N:3]=[N:2][N:1]([C:4]3[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=3[Cl:11])[C:20]=2[NH2:21])[CH:18]=1
Reactant: COc1ccc(Cl)cc1CC#N
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1nnn(-c2ccc(Cl)cc2Cl)c1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2,4-dichloro-benzene (0.9 g, 1 eq) and commercial (5-chloro-2-methoxy-phenyl)-acetonitrile (1.04 g, 1.2 eq) in ethanol (10 ml) kept under nitrogen, a solution of sodium methoxide (0.388 g, 1.5 eq) in ethanol (10 ml) is added drop-wise (20 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (40 ml), washed with water (2×50 ml), dried over MgSO4 and evaporated to dryness. The yellow solid residue (0.820 g) is purified by crystallization from a mixture of dichloromethane and hexane (1:1), to afford the title compound as white solid (0.480 g, 28% yield). M.p. 153.5-154.7° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[C:6]=1[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: Cc1cc2ccccc2o1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)c2c(C)oc3ccccc23)cc1

Procedure:
2-Methylbenzofuran (7.25 g., 0.055 mol.) was acylated with 15.7 g. (0.092 mol.) of anisoyl chloride according to the procedure described in Example 10 to give 2-methyl-3-(4'-methoxybenzoyl)benzofuran.
Reaction SMILES: [Cl:1][C:2]([O:4]C(Cl)(Cl)Cl)=O.[F:9][C:10]([F:46])([F:45])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:14][N:15]([C@@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[N:30]=2)[NH:25][C@H:24]([CH2:36][CH3:37])[CH2:23]1)[C:16]1[N:17]=[N:18][N:19]([CH3:21])[N:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:46][C:10]([F:9])([F:45])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1)[CH2:14][N:15]([C:16]1[N:17]=[N:18][N:19]([CH3:21])[N:20]=1)[C@@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:33])([F:34])[F:35])[N:30]=2)[N:25]([C:2]([Cl:1])=[O:4])[C@H:24]([CH2:36][CH3:37])[CH2:23]1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Add trichloromethyl chloroformate (0.36 mL, 3.02 mmol) to a solution of (2R,4S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (1.67 g, 3.02 mmol) and triethylamine (0.84 mL, 6.04 mmol) in toluene (19 mL). Stir the mixture at room temperature under nitrogen for 3 h, then add more triethylamine (0.50 mL, 3.6 mmol) and trichloromethyl chloroformate (0.21 mL, 1.8 mmol). Stir the mixture overnight. Evaporate the solvent and purify the residue by silica gel chromatography (elution with hexane/ethyl acetate) to afford the title compound (1.83 g, 98%). MS (ES+): 616 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]4[C:21](=[O:28])[C:22](=[O:27])[C:23]=4OCC)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][NH2:30].O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]4[C:21](=[O:28])[C:22](=[O:27])[C:23]=4[NH:30][CH3:29])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Temperature: 25 °C

Procedure:
A mixture of 0.8 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-ethoxy-cyclobut-3-ene-1,2-dione, 15 mL of 33 % methylamine, 5 mL of water, and 5 mL of ethanol was refluxed for 5 hr. The mixture was cooled to room temperature and the solid was collected and washed with ethanol and ether giving 0.45 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-methylamino-cyclobut-3-ene-1,2-dione as a yellow powder: mass spectrum (m/e): M+H 426.0.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[O:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[O:27][C:24]([CH2:25][NH:26][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(CN)o1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Product: Cc1ccc(CNc2cccc3nc(NC(=O)c4cccnc4)nn23)o1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and 5-methylfurfurylamine (1.0 mL) as an off-white solid (40 mg, 37%). HPLC, 2.38 min. Rt: (purity 98.6%). LC/MS, M−(ESI): 347.1.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[CH:8]=1.CN(C)[CH:17]=[O:18]>O1CCCC1>[CH2:13]([C:9]1[CH:8]=[C:7]([CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=1)[CH3:14]
Reactant: CCc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cccc(CO)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (34 ml of a 2.5M solution in hexanes) was added to a solution of 1-bromo-3-ethylbenzene (15 g) in tetrahydrofuran (320 ml) at −78° C. After 1 hour N,N-dimethylformamide (15 ml) was added. The mixture was stirred at −78° C. for 1 hour and allowed to warm to room temperature. The mixture was quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in methanol (250 ml) and treated with sodium borohydride (1.51 g) portionwise. The mixture was stirred at room temperature for 16 hours, quenched with 2M HCl (100 ml) and stirred for 4 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and 2M HCl. The organic phase was dried (MgSO4), evaporated and the residue purified by chromatography eluting with 5-10% ethyl acetate in isohexane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([Cl:19])=[N:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:20])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([O:34][CH3:35])=[CH:29][C:28]=1[O:36][CH3:37])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([Cl:19])=[N:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:23][C:24](=[O:25])[NH:26][C:27]2[CH:32]=[C:31]([Cl:33])[C:30]([O:34][CH3:35])=[CH:29][C:28]=2[O:36][CH3:37])[C:9]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccnc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3c(Cl)nccc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vial is charged with (5-Chloro-2,4-dioxo-1,4-dihydro-2H-pyrido[4,3-d]pyrimidin-3-yl)-acetic acid tert-butyl ester (53.1 mg, 0.17 mmol), 2-Bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (58.1 mg, 0.187 mmol), and Cs2CO3 (124.3 mg, 0.34 mmol). The mixture is treated with DMF (3 ml) and the solution stirred at RT overnight. The reaction mixture is treated with water and the product extracted with EtOAc (3×10 ml). The organic extracts are combined and washed with water (2×10 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude material is purified using flash column chromatography with an eluent system of isohexane:EtOAc to give the title compound; [M+H]+ 539.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:35])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:34])[CH:17]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])=[N:23][O:24][C:25]=3[CH3:26])=[O:20])[C@H:5]2[S:4]1.[CH3:36][N:37]1[C:41]([SH:42])=[N:40][N:39]=[N:38]1>P([O-])([O-])([O-])=O.CC(C)=O>[CH3:36][N:37]1[C:41]([S:42][CH2:2][C:3]2([CH3:35])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]3[C:16](=[O:34])[CH:17]([NH:18][C:19]([C:21]4[C:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[Cl:33])=[N:23][O:24][C:25]=4[CH3:26])=[O:20])[C@H:5]3[S:4]2)=[N:40][N:39]=[N:38]1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CBr)S[C@H]12
Reactant: Cn1nnnc1S
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CSc3nnnn3C)S[C@H]12

Procedure:
By treating in the similar manner as described in Example 11 using 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate and 1-methyl-IH-tetrazole-5-thiol in a mixture of pH 6.85 phosphate buffer and acetone, there was obtained amorphous 2,2,2-trichloroethyl 2-(1-methyl-IH-tetrazol-5-yl)thiomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate. Infrared Absorption Spectrum (Nujol) 3300, 1780, 1770, 1665 cm-1.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=5)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O[N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[N:38]1.C(N=C=NCCCN(C)C)C.O>ClCCl>[N:37]1([O:32][C:31](=[O:33])[C:30]2[CH:29]=[CH:28][C:27]([N:24]3[CH2:23][CH2:22][N:21]([C:18]4[CH:17]=[CH:16][C:15]([N:12]5[CH2:13][CH2:14][CH:9]([C:3]6[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=6)[CH2:10][CH2:11]5)=[CH:20][CH:19]=4)[CH2:26][CH2:25]3)=[CH:35][CH:34]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[N:38]1
Reactant: O=C(O)c1ccc(N2CCN(c3ccc(N4CCC(c5ccccc5)CC4)cc3)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(On1nnc2ccccc21)c1ccc(N2CCN(c3ccc(N4CCC(c5ccccc5)CC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 60.9 %

Procedure:
To a suspension of 4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic acid dihydrochloride salt (0.62 g) and 1-hydroxybenzotriazole (0.2 g) in dichloromethane (12 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.22 g) and stirred for 22 hours at ambient temperature. The reaction mixture was added to a mixture of water and dichloromethane. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic acid benzotriazol-1-yl ester (0.41 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([S:14]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:7].CN(C=O)C.I[CH2:36][CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:36]([N:17]([S:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6]([O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])=[O:7])[CH:9]=1)(=[O:15])=[O:16])[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1)[CH2:37][CH3:38]
Reactant: CCCI
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(c1ccc(C(=O)OC)cn1)S(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a mixture of 500 mg of methyl 6-{[(3-{[2-(trimethylsilyl)ethoxy]carbonyl}phenyl)sulfonyl]amino}nicotinate and 10 mL of DMF were added 0.300 mL of 1-iodopropane and 400 mg of potassium carbonate, followed by stirring at 80° C. for 5 hours. The reaction mixture was left to stand to cool and then water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to obtain 200 mg of a methyl 6-{propyl[(3-{[2-(trimethylsilyl)ethoxy]carbonyl}phenyl)sulfonyl]amino}nicotinate as a colorless oily substance. ESI+: 479
Reaction SMILES: [H-].[Na+].Cl[CH2:4][O:5][CH3:6].O.[CH:8](=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11]>CN(C)C=O>[CH3:6][O:5][CH2:4][O:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[CH:8]=[O:16]
Reactant: O=Cc1ccccc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccccc1C=O
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
In N,N-dimethylformamide (20 mL) was dissolved 5.01 g (41.1 mmol) of commercially available salicylaldehyde, 1.80 g (45.0 mmol) of 60% sodium hydride was added to the solution in an ice bath, and after stirring the mixture in an ice bath for 10 minutes, 3.43 mL (45.2 mmol) of chloro(methoxy)methane was gradually added dropwise to the mixture and the resulting mixture was stirred in an ice bath for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 6.54 g (39.4 mmol, Yield: 95.9%) of 2-(methoxymethoxy)benzaldehyde.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]1([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][CH2:4][C:5]1[N:19]([CH2:20][C:21]2([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(CNc2c(N)cnc3ccccc23)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(NC(=O)OC(C)(C)C)CCCCC1
Yield: 37 %

Procedure:
Ethoxyacetyl chloride (9.00 g, 73.4 mmol) was reacted with tert-butyl 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclohexylcarbamate (27.2 g, 73.4 mmol) according to the method described in Part E of Example 9 and the resulting product was treated according to the method described in Part E of Example 9. After the solvent was removed to yield an oil, the oil was dissolved in ethanol (300 mL) and water (30 mL). Sodium hydroxide (4.3 g, 108 mmol) was added and the solution was heated at reflux for 6 h. The volatiles were removed under reduced pressure and the resulting brown oil was partitioned between dichloromethane (500 mL) and water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a brown oil. Purification by flash chromatography (silica gel, 30% ethyl acetate/hexanes) provided tert-butyl 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexylcarbamate as a brown solid (11.9 g, 38%).