Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.O1CCCC1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:1][C@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc1
Temperature: 25 °C
Yield: 73207.6 %

Procedure:
To an ice-cooled solution of D-valine (50.5 g, 0.43 mol) and triethylamine (145 mL, 1.034 mol) in a 1:1 mixture of tetrahydrofuran and water (350 mL) was added 4-methoxybenzenesulfonyl chloride (88.2 g, 0.43 mmol). The reaction mixture was stirred and allowed to warm to room temperature overnight. The volatile organics were removed and the aqueous phase was extracted with diethyl ether. The aqueous phase was acidified to pH 3 with 10% hydrochloric acid and the product was extracted into ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, and then concentrated to give 2(R)-(4-methoxy-benzenesulfonylamino)-3-methylbutyric acid as a white solid (90.45 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[Br:7][C:8]1[CH:19]=[CH:18][C:11]([C:12](N(OC)C)=[O:13])=[CH:10][CH:9]=1.C([Li])(C)(C)C>C(OCC)(=O)C>[Br:7][C:8]1[CH:19]=[CH:18][C:11]([C:12]([C:2]2[CH:3]=[N:4][NH:5][CH:6]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Reactant: Brc1cn[nH]c1
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Br)cc1)c1cn[nH]c1

Procedure:
The title compound was prepared from 4-bromopyrazole and 4-bromo-N-methoxy-N-methylbenzamide following the general method of Method 1 using two equivalents of t-butyllithium as the base. The crude product was re-crystallized from ethyl acetate and petroleum ether affording 0.28 g (44% yield) of the title compound as colorless crystals: mp 213-215° C.; 1H NMR (300 MHz, CD3OD) δ 7.95 (br s, 2 H), 7.58 (m, 2 H), 7.51 (m, 2 H); 13C NMR (100.5 MHz, CD3OD) δ 190.3, 139.6, 138.8, 133.4, 132.1, 128.6, 123.1; MS (TSP) m/z 251, 253 (M+1).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:16]=[C:17]([CH:25]([OH:28])[C:26]#[CH:27])[CH:18]=[C:19]([Cl:24])[C:20]=1[N:21]([CH3:23])[CH3:22])([CH3:14])([CH3:13])[CH3:12]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:11]([C:15]1[CH:16]=[C:17]([CH:25]([OH:28])[C:26]#[C:27][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:18]=[C:19]([Cl:24])[C:20]=1[N:21]([CH3:22])[CH3:23])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1cc(Cl)c(N(C)C)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CN(C)c1c(Cl)cc(C(O)C#Cc2ccc(C(=O)O)cc2)cc1C(C)(C)C
Yield: 87.5 %

Procedure:
In a manner analogous to example 1 f, the process is carried out by a reaction of 200 mg (0.8 mmol) of 4-iodobenzoic acid with 300 mg (1.1 mmol) of 1-(3-tert-butyl-5-chloro-4-dimethylaminophenyl)prop-2-yn-1-ol in the presence of 8 mg (0.04 mmol) of copper iodide and 16 mg (0.02 mmol) of bis(triphenylphosphine)palladium chloride. 270 mg of 4-[3-(3-tert-butyl-5-chloro-4-dimethylaminophenyl)-3-hydroxyprop-1-ynyl]benzoic acid are obtained in the form of a whitish solid (Mp=120° C., yield=87%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[CH:6](O)[C:5](C)([CH3:18])[C:4]=2[CH:3]=1.II.Br.[C:23](O)(=O)C>>[Br:16][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:4](=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=3)[C:5]([CH3:18])=[C:6]([CH3:23])[C:7]=2[CH:8]=1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc2C1O
Reactant: CC(=O)O
Agent: Br
Agent: II
Product: Cc1c(C)c2cc(Br)ccc2c2ccc(Br)cc12

Procedure:
43.4 g (113 mmol) of 2,7-dibromo-9-hydroxy-10,10-dimethyl-9,10-dihydrophenanthrene were suspended in 610 ml of acetic acid. 780 mg of iodine and 3.5 ml of HBr in acetic acid were added, and the suspension was heated to reflux. The mixture was allowed to cool overnight with stirring. The residue was filtered off with suction and washed with water and methanol, giving 35.8 g (87.0% of theory) of the product.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](O)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Na].S(Cl)([Cl:22])=O.CN(C)C=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([Cl:22])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=S(Cl)Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 15.0 g (0.052 mol) of 4-(4-fluorophenoxy)benzenesulfonic acid□, sodium salt, in 150 mL of dry toluene was added 11.3 mL (0.155 mol, 3 equivalents) of thionyl chloride and 0.04 mL (0.5 mmol, 0.01 equivalents) of dimethylformamide. The resulting mixture was stirred at room temperature for 48 hours, filtered through diatomaceous earth, and concentrated under reduced pressure to 40 mL. This solution was used without further purification to prepare 1-[4-(4-fluorophenoxy)benzenesulfonylamino] cyclopentanecarboxylic acid benzyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH2:36]=[C:37]([CH2:40]O)[CH2:38][OH:39].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:36]=[C:37]1[CH2:38][O:39][C:32]2([CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:35][CH2:40]1
Reactant: C=C(CO)CO
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C1COC2(CCC(n3c(=O)c(Cc4ccc(-c5ccccc5C#N)cc4)c(CCC)n4ncnc34)CC2)OC1
Yield: 62.6 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.50 g), 2-methylidenepropane-1,3-diol (0.18 g), 4-methylbenzenesulfonic acid (0.020 g) and toluene (20 mL) was heated with a Dean-Stark apparatus under reflux for 21 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 64%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([Cl:11])[CH:3]=1.P(Br)(Br)Br.[CH:16]1(O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[H-].[Na+]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([CH2:9][O:10][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][C:7]=1[F:8]
Reactant: OCc1cc(F)c(Br)cc1Cl
Reactant: OC1CCCCC1
Agent: BrP(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1cc(COC2CCCCC2)c(Cl)cc1Br
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a solution of (4-bromo-2-chloro-5-fluorophenyl)methanol (5.00 g, 21.00 mmol) in dichloromethane (150 mL) was added phosphorous tribromide (8.53 g, 31.50 mmol) at 0° C. The clear reaction solution was stirred at the same temperature for 1 hour, then at an ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo to dryness to obtain viscous yellow liquid which was added to a stirred mixture of cyclohexanol (1.68 g, 16.80 mmol) and sodium hydride (60% dispersion in mineral oil, 1.93 g, 21.00 mmol,) in N,N-dimethylformamide (15 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 16 hours and quenched with addition of saturated ammonium chloride (100 mL). The organic layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered the solid. The filtrate was concentrated in vacuo to dryness. The residue was purified by flash column chromatography with ethyl acetate in hexanes (10%) to afford the title compound (2.60 g, 38%) as a viscous liquid: MS (ES+) m/z 320.9, 318.9 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:27][CH2:26][CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:20][CH2:21]1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: OCCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC(CCO)CC3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 4-Piperidineethanol (Aldrich)(85.6 mg; 0.66 mmol; 1 eq.) and triethylamine (0.19 ml; 1.33 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is crystallized in MeOH, affording Compound (28) as a brown solid (117.2 mg; 43%). 1H NMR (DMSO-d6, 300 MHz) δ 1.05-1.30 (m, 2H), 1.38 (m, 2H), 1.75 (m, 2H), 2.13 (s, 3H), 2.48 (s, 3H), 2.85 (m, 1H), 3.22 (m, 1H), 3.45 (m, 2H), 4.38 (t, J=6 Hz, 1H), 4.42 (m, 1H), 5.15 (m, 1H), 7.97 (s, 1H), 12.16 (s, 1H). M− (ESI): 393.21; M+ (ESI): 395.20. HPLC (method A), Rt: 2.69 min (purity: 95.7%).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:21])[CH:17]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:4][C:3]1=[O:22].[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.[Cl:36][CH2:37][CH2:38]Cl.C([BH3-])#N.[Na+]>C(O)C.CO.C(O)(=O)C>[Cl-:21].[Cl:36][CH2:37][CH2:38][N+:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([NH:1][N:2]3[CH2:7][CH2:6][N:5]([S:8]([C:11]4[CH:20]=[CH:19][C:18]5[C:13](=[CH:14][CH:15]=[C:16]([Cl:21])[CH:17]=5)[CH:12]=4)(=[O:9])=[O:10])[CH2:4][C:3]3=[O:22])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: ClCCCl
Reactant: NN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2cc[n+](CCCl)cc2)CC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-amino-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (33.98 g) and 1-(4-pyridyl)-4-piperidone (18.50 g) in ethanol (1 L)/1,2-dichloroethane (300 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 3 days. Any insolubles were filtered off and the reaction mixture was concentrated to obtain a residue, which was dissolved in methanol (1 L), combined with acetic acid (33.82 g) while cooling on ice, followed by sodium cyanoborohydride (17.06 g) and then stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate and brine, dried, concentrated and purified by a column chromatography on a silica gel (dichloromethane: methanol=10:1 to dichloromethane: methanol: triethylamine=40:2:1) and a column chromatography on a basic silica gel (tetrahydrofuran to methanol) to obtain the title compound (30 g) as a colorless amorphous material.
Reaction SMILES: CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C[N:17]([CH2:25][C@H:26]1[CH2:29][C@H:28]([O:30]C2C=CC(CN3CCCC3)=CC=2)[CH2:27]1)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].NC[C@@H]1C[C@H](O)C1.CCN(CC)CC>C1COCC1>[OH:30][C@@H:28]1[CH2:29][C@H:26]([CH2:25][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:27]1
Reactant: CN(C[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: NC[C@H]1C[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@@H](O)C1

Procedure:
(Boc)2O (4.42 g, 0.02 mol) was added to a solution of intermediate 9, cis-3-(aminomethyl)cyclobutanol (1.95 g, 0.019 mol) and Et3N (5.6 mL, 0.039 mol) in 20 mL absolute THF under stirring. The mixture was stirred at room temperature for 30 min, evaporated, and coevaporated with CCl4. The residue was recrystallized form ether to give the title compound (3 g, 77%) as yellow crystals. 1H NMR-data (DMSO-d6): 6.61-6.87 (m, 1H, NH); 4.85 (br.s, 1H, OH); 3.77-3.92 (m, 1H); 2.90 (t, 2H, CH2, J=6.1 Hz); 2.10-2.22 (m, 2H); 1.67-1.80 (m, 1H); 1.21-1.51 (m, 11H, CH2, Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([CH3:15])=[N:9]1.[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[CH:16]1([CH:13]([C:11]2[C:10]([CH3:15])=[N:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:12]=2)[OH:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1nn(-c2ccccc2Cl)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccc2Cl)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution (5 mL) of 1-(2-chlorophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (0.27 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (2.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.29 g, 79%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[Br:13]Br>>[Br:13][C:8]1[CH:7]=[C:6]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)O)cc1Br
Yield: 98.9 %

Procedure:
Proceeding as in Reference 14, but substituting 4-methoxyphenylacetic acid (16.6 g, 0.1 mol) and bromine (16.0 g, 0.1 mol), gave 3-bromo-4-methoxyphenylacetic acid (24.24 g, 98%) as a yellow powder.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH3:7][NH:8][C:9]([C:11]1[C:15]2[CH:16]=[C:17]([O:26][CH2:27][CH3:28])[C:18]([N:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH3:21])=[CH:19][C:14]=2[O:13][C:12]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:10]>C(#N)C>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:12]2[O:13][C:14]3[CH:19]=[C:18]([N:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH3:21])[C:17]([O:26][CH2:27][C:28]4[CH:14]=[CH:15][C:11]([C:1]([OH:2])=[O:4])=[C:12]([OH:13])[CH:29]=4)=[CH:16][C:15]=3[C:11]=2[C:9](=[O:10])[NH:8][CH3:7])=[CH:30][CH:31]=1
Reactant: CCOc1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2cc1N(C)S(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(OCc3ccc(C(=O)O)c(O)c3)cc12
Yield: 192.8 %

Procedure:
Preparation of compound 39(c) (5-(2,2-dimethyl-4-oxo-4H-benzo[1,3]dioxin-7-ylmethoxy)-2-(4-fluoro-phenyl)-6-(methanesulfonyl-methyl-amino)-benzofuran-3-carboxylic acid methylamide). Potassium carbonate (0.19 g, 1.38 mmol) and compound 39(b) (0.25 g, 0.917 mmol) were added to a solution of compound 38(d) (0.18 g, 0.459 mmol, which can be prepared according to Example 38 step d above), in acetonitrile (15 mL). The reaction mixture was refluxed for 4 hours and then concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with water. The organic layer was concentrated to a solid, which was triturated in 20% ethyl acetate/hexanes, filtered, and dried to provide 240 mg (90%) of the desired product as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13]C(SC)=[N:15][CH:16]=2)[N:11]([CH3:21])[C:10]1=[O:22].ClC1C=CC=C(C(OO)=[O:31])C=1.[CH3:34][S:35]([CH3:37])=[O:36].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:34]([S:35]([CH3:37])(=[O:31])=[O:36])=[N:15][CH:16]=2)[N:11]([CH3:21])[C:10]1=[O:22]
Reactant: CS(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1c(Cl)cccc1Cl)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
A solution of 3-(2,6-dichlorophenyl)-7-methylthio-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.1) (5 g, 14.1 mmol) in 200 mL of dichloromethane was cooled in ice and treated with 3-chloroperbenzoic acid (10 g, 28.9 mmol). The mixture was stirred at room temperature for 17 hours, then treated with 2 mL of dimethyl sulfoxide and left to stand for 10 minutes. Saturated aqueous sodium bicarbonate solution (100 mL) was then added and the phases were separated. The organic phase was dried over magnesium sulfate and filtered. Concentration of the filtrate under reduced pressure gave 5 g (92%) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (sulfone 1.2) as a white solid.
Reaction SMILES: C(S[C:9]1[N:13]=[C:12]([CH3:14])[N:11]([C:15]2[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=2)[N:10]=1)C1C=CC=CC=1.O.[S:26]([Cl:30])(Cl)(=[O:28])=[O:27]>ClCCl>[CH3:22][O:21][C:19]1[N:18]=[C:17]([O:23][CH3:24])[N:16]=[C:15]([N:11]2[C:12]([CH3:14])=[N:13][C:9]([S:26]([Cl:30])(=[O:28])=[O:27])=[N:10]2)[N:20]=1
Reactant: COc1nc(OC)nc(-n2nc(SCc3ccccc3)nc2C)n1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1nc(OC)nc(-n2nc(S(=O)(=O)Cl)nc2C)n1
Temperature: 5 °C

Procedure:
A solution of 3-benzylthio-1-(4,6-dimethoxy-1,3,5-triazin-2-yl)-5-methyl-1,2,4-triazole (6 g) in dichloromethane (60 ml) was treated with silica gel (14 g) 60-120 mesh and water (2.8 g). Sulphuryl chloride (10.6 ml) in dichloromethane (12 ml) was added dropwise with stirring whilst maintaining a temperature of 5° C. for 2 hours. The silica gel was filtered off, washed with dichloromethane (150 ml) and ethyl acetate (100 ml), and the combined washings were extracted with water and aqueous sodium bicarbonate. The organic layer was dried and evaporated at 40° C. in vacuo. The residue was triturated with ether and filtered to give 3 g of the desired product.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H](CC1C=CC=CC=1)C(O)=O)[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C@@H:26]1[C:32](=[O:33])[N:31]2[C@H:34]([C:38]([O:40][CH3:41])=[O:39])[CH2:35][CH2:36][CH2:37][C@@H:30]2[CH2:29][CH2:28][CH2:27]1>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]2[C@H:34]([C:38]([O:40][CH3:41])=[O:39])[CH2:35][CH2:36][CH2:37][C@@H:30]2[CH2:29][CH2:28][CH2:27]1)=[O:10])[C:9]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]2[C@H:34]([C:38]([O:40][CH3:41])=[O:39])[CH2:35][CH2:36][CH2:37][C@@H:30]2[CH2:29][CH2:28][CH2:27]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2CCC[C@H](N)C(=O)N21
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)O)Cc1ccccc1
Product: COC(=O)[C@@H]1CCC[C@@H]2CCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCC[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
Dimethyl (4S,7S,10aS,4′S,7′S,10a′S)-7,7′-(((2R,5R)-2,5-dibenzyl-1,6-dioxo-1,6-hexanediyl)diimino)bis(6-oxodecahydropyrido[1,2-a]azepine-4-carboxylate) was synthesized as described in General Procedure F using Intermediate 3 (10 mg, 0.031 mmol) and (4S,7S,10aS)-methyl 7-amino-6-oxodecahydropyrido[1,2-a]azepine-4-carboxylate (16 mg, 0.067 mmol) to give a white solid (8.0 mg, 34% yield). Anal. Calcd. for C44H58N4O8 m/z 770.5. found: 771.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1([CH2:37]O)[CH2:36][CH2:35][CH:34]=[CH:33][CH2:32]1.[K+].[Br-].Cl>>[CH3:30][C:31]1([CH2:37][O:24][C:23]([C:18]2([C:20]([O:22][CH2:30][C:31]3([CH3:37])[CH2:36][CH2:35][CH:34]=[CH:33][CH2:32]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:36][CH2:35][CH:34]=[CH:33][CH2:32]1
Reactant: CC1(CO)CC=CCC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC1(C)CC=CCC1)(C(=O)OCC1(C)CC=CCC1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 1-methylcyclohex-3-enylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 0.84 (s, 6H, 2×CH3), 1.09 (d, J=6.4 Hz, 3H, CH3), 1.25-1.4 (m, 4H, CH2), 1.6-1.65 (m, 2H, CH2), 1.8-2.0 (m, 6H, CH2), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 4.04 (m, 4H, OCH2, OCH2), 5.05 (m, 1H, CH), 5.55-5.65 (m, 4H, CH), 6.35 (d, J=4.17 Hz, 1H, OH), 6.85 (dd, J=7.9, 1.32 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.38-7.42 (m, 3H, Ar--H), 7.5 (s, 1H, Ar--H), 8.8 (brs, 1H, NH), 9.4 (brs, 1H, NH); IR (KBr, cm-1) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 638 (M+H)+ ; Analysis for: C36H44ClNO7 ×HCl: Calc'd: C, 64.09; H, 6.72; N, 2.08; Found: C, 64.69; H, 7.19; N, 1.67.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:34]>O>[C:22]([O:21][C:19]([N:11]([C:3]1[C:4]([CH3:10])=[CH:5][C:6]([C:8]#[N:9])=[CH:7][C:2]=1[NH:1][C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:34])[C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(C#N)cc(N)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCCCCCCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCOC(=O)Nc1cc(C#N)cc(C)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Di-t-butyl (2-amino-4-cyano-6-methylphenyl)imidodicarbonate (104 mg, 0.3 mmol) obtained in Step 2 was added with pyridine (0.24 mL, 3 mmol, 10 eq) and heptyl chloroformate (0.11 mL, 0.6 mmol, 2 eq), and the mixture thus obtained was stirred at room temperature for 10 minutes, followed by further stirring at 80° C. for 2 hours. Upon completion of the reaction, the resulting product was added with distilled water, and extracted with ethyl acetate. The organic layer thus obtained was dried over MgSO4, and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (EA:Hex=1:9) to obtain the title compound in a colorless liquid (146 mg, yield: 99%).