Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21]([O:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[C:21]([O:25][C:26]([NH:28][CH2:29][C:30](=[O:31])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 544.2 %

Procedure:
A 10 L three-necked, round-bottomed flask was charged with diisopropylamine (531 g, 5.25 mol) in THF (3 L) and cooled to −78° C. n-BuLi (2.5M, 2 L, Shangyu hualun-chem, China) was added slowly into the reaction mixture at −78° C. under nitrogen. After the addition was completed, the reaction mixture was warm up to 0° C. slowly and keep at this temperature for 20 min, then cooled to −78° C. and tert-butyl acetate (580 g, 5 mol, Sigma-Aldrich) in THF (1.0 L) was added slowly at −78° C. and stirred at this temperature for 2 h. In a separated 5 L round-bottomed flask, 2-((tert-butoxycarbonyl)amino) acetic acid (280 g, 1.6 mol, Shanghai Chiralchemicals Inc, China) was dissolved in THF (1500 mL), cooled to −30° C., and treated with 1,1′-carbonyldiimidazole (285 g, 1.76 mol). The mixture was stirred for 30 min at −30° C., then this solution was added dropwise to the cooled (−78° C.) above solution previously prepared. After 1 h, the reaction mixture was quenched with aq. 4 N NH4Cl (5 L). Similarly another 5 batches were carried out on 280 g scale. The batches were combined and the solvent was removed in vacuo. The residue was diluted with EtOAc (35 L) and successively washed with water (9 L), brine (9 L) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil (2.38 kg, 90% yield) which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:17][C:18](=[O:20])[CH3:19])[CH3:16])=[CH:11][CH:10]=1
Reactant: CC(N)c1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.9 %

Procedure:
Triethylamine (2.8 mL) was dropped to the solution of 1-(4-bromophenyl)ethanamine (2.0 g, 10.0 mmol), and acetic anhydride (1.53 g, 15.0 mmol) in dichloromethane (30 mL) at room temperature. Then the mixture was stirred at room temperature for 12 hours. The mixture was washed with sodium hydroxide solution (40 mL, 0.5M) and water (40 mL). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:5) to give N-(1-(4-bromophenyl)ethyl)acetamide (2.2 g, 91%) as a white solid. 1H NMR (300 MHz, d6-DMSO): δ 8.27 (d, J=4.8 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 1H), 4.94 (m, 1H), 2.12 (s, 3H), 1.45 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:14][CH:15]=O.[H-].[Na+].[Cl:19][C:20]1[C:25]2[N:26]=C(S(C)(=O)=O)[N:28]=[CH:29][C:24]=2[CH:23]=[CH:22][N:21]=1>C1COCC1>[Cl:19][C:20]1[C:25]2[N:26]=[C:15]([NH:14][C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=4)=[CH:7][C:2]=3[CH3:1])[N:28]=[CH:29][C:24]=2[CH:23]=[CH:22][N:21]=1
Reactant: Cc1cc(-c2cnn(C)c2)ccc1NC=O
Reactant: CS(=O)(=O)c1ncc2ccnc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 121.1 %

Procedure:
To a cooled (0° C.) suspension of N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation 99, 40 mg, 0.186 mmol) in THF (4 mL) was added NaH (60% dispersion in oil, 12 mg, 0.297 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C. and 8-chloro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 97, 59 mg, 0.242 mmol) was added. The reaction mixture was stirred for 18 hours, whilst slowly warming to room temperature. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc (30 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (30 mL) and DCM (30 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-5% MeOH in EtOAc to give the title compound (79 mg, 97%).
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[CH:4]=[CH:3]1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].C(OCC)(=O)C>N1C=CC=CC=1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: CC(C)C(=O)Cl
Reactant: Cn1ccc2ccc(N)cc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
To a solution of 1-methyl-1H-indol-6-amine (45 mg, 0.31 mmol) in pyridine (2 mL) at room temperature was added isobutyryl chloride (35 μL, 0.34 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed three times with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 24.3 mg (36%) of the title compound (LCMS RT=5.73 min, MH+ 217.2)
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:10]=[C:9]([N:11]([CH3:17])[CH2:12][C@@H:13]2[CH2:15][C@H:14]2[CH3:16])[N:8]=[C:7]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=1)=[O:4])[NH2:2].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:32]1[C:43](O)=[O:44])=[O:30])([CH3:27])([CH3:26])[CH3:25].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-]>ClCCCl>[CH3:17][N:11]([CH2:12][C@@H:13]1[CH2:15][C@H:14]1[CH3:16])[C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:8]=1)[C:3]([NH:1][NH:2][C:43]([C@H:32]1[C@@H:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][CH2:35][CH2:36][N:31]1[C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[O:44])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](c2ccccc2)[C@@H]1C(=O)O
Reactant: C[C@@H]1C[C@H]1CN(C)c1cc(C(=O)NN)cc(N(C)S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@@H]1C[C@H]1CN(C)c1cc(C(=O)NNC(=O)[C@H]2[C@@H](c3ccccc3)CCCN2C(=O)OC(C)(C)C)cc(N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-[4-(hydrazinocarbonyl)-6-(methyl[(trans-2-methylcyclopropyl)methyl]amino)pyridin-2-yl]-N-methylmethanesulfonamide (3A.3b-1, 59.0 mg, 0.17 mmol) in 1,2-dichloroethane (2 ml) were added cis-1-(tert-butoxycarbonyl)-3-phenylpiperidine-2-carboxylic acid (Intermediate 1A.5, 45.9 mg, 0.15 mmol), 1-hydroxybenzotriazole (23.2 mg, 0.16 mmol), diisopropylethylamine (0.090 ml, 0.52 mmol), and polystyrene bound carbodiimide (246 mg, 0.34 mmol, 1.31 mmol/g). The reaction mixture was allowed to stir gently at room temperature for 18 h. Macroporous carbonate resin (360 mg, 0.68 mmol, 2.74 mmol/g) was added to the reaction, and the mixture was again allowed to stir gently for 18 h. The reaction mixture was filtered and concentrated in vacuo to yield tert-butyl cis-2-[(2-{2-(methyl[(trans-2-methylcyclopropyl)methyl]amino)-6-[methyl(methylsulfonyl)amino]isonicotinoyl}hydrazino)carbonyl]-3-phenylpiperidine-1-carboxylate.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([CH3:36])[CH:27]=1)#[N:25]>C(Cl)Cl>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:6]2[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]2)(=[O:34])=[O:33])=[C:28]([CH3:36])[CH:27]=1)#[N:25]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reaction time: 8 h
Yield: 104.2 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (2.79 g, 13.91 mmol, supplier Antlantic Scitech) in DCM (80 mL), DIPEA (3.64 mL, 20.87 mmol) was added under argon atmosphere at room temperature then 4-cyano-2-methylbenzenesulfonyl chloride (3 g, 13.91 mmol) was added at 0° C. The ice bath was removed and the reaction mixture was stirred overnight. The reaction mixture was partitioned between DCM (30 ml) and aqueous sodium bicarbonate (2×20 ml). The organic phase was washed with HCl (2×20 ml) and water (2×20 ml) then it was dried (phase separator) and concentrated under vacuum to give the title compound (5.5 g) as a yellow viscous liquid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].[CH2:9]=[C:10]1[CH2:13][CH2:12][C:11]1=[CH2:14]>ClCCl>[CH3:3][C:2]12[C:1](=[O:8])[O:7][C:5](=[O:6])[CH:4]1[CH2:14][C:11]1[CH2:12][CH2:13][C:10]=1[CH2:9]2
Reactant: C=C1CCC1=C
Reactant: CC1=CC(=O)OC1=O
Solvent: ClCCl
Product: CC12CC3=C(CC3)CC1C(=O)OC2=O
Reaction time: 1272 h

Procedure:
Into a 500-mL, single-neck round bottom glass flask containing a magnetic stirring bar was weighed 96.62 grams (0.862 moles) of citraconic anhydride. The flask was then fitted with a three-neck adapter to which was attached a thermometer, a condenser and a 250-mL addition funnel. To the funnel was added 86.0 grams of a distilled dimethylenecyclobutane (DMCB) cut containing 90.2% (by GC) 1,2-isomer (77.6 grams, or 0.968 moles, of 1,2-dimethylenecyclobutane). The flask was purged with dry nitrogen. The DMCB was then added dropwise to the citraconic anhydride with stirring. No temperature increase due to reaction exotherm was evident. When the DMCB addition was complete, the mixture was allowed to stand for 53 days at room temperature to complete the reaction. At the end of this period, gas chromatography revealed that the peak corresponding to unreacted citraconic anhydride had essentially disappeared. The product was then dissolved in dichloromethane and filtered to remove insoluble gelatinous material. Dichloromethane and unreacted volatiles were removed at 60° C. on a rotary evaporator to yield a crystalline product. The crude yield was 156.18 grams (94%). 152 g of product was then recrystallized from 165 grams of cyclohexane with strong stirring. Yield of recrystallized MBODA was 132.17 grams (80%). Melting point was 64°-68° C. The 1H and 13C NMR spectra of the product were consistent with the following structure; no impurities were seen in the product by NMR except for a small amount of cyclohexane. ##STR6##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:16]=[C:15]3[NH:40][C:41](=[O:68])[C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]3)=[CH:44][C:43]=2[N:55]([CH:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)[C:56](=[O:61])[C:57]([F:60])([F:59])[F:58])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>O1CCOCC1.CO>[F:8][C:6]1[CH:5]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[NH:40][C:41](=[O:68])[C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]3)=[CH:44][C:43]=2[N:55]([CH:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)[C:56](=[O:61])[C:57]([F:59])([F:60])[F:58])(=[O:10])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(S(=O)(=O)c5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A mixture of N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide (2.4 g, 2.53 mmol), 4N hydrochloric acid in 1,4-dioxane (35 mL), methanol (50 mL) and 1,4-dioxane (15 mL) was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure and the residue dissolved in dichloromethane, washed with water, brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/acetone 1:1 as the eluant affording the title compound as a pale yellow solid (1.43 g, 80% yield).
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]1=[O:20])#[N:2].Cl.N[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[C:24]=1[SH:31]>C(O)C>[F:29][C:27]1[CH:26]=[C:25]([F:30])[C:24]2[S:31][C:1]([CH2:3][N:4]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[S:7][CH:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]3=[O:20])=[N:2][C:23]=2[CH:28]=1
Reactant: Nc1cc(F)cc(F)c1S
Reactant: CCOC(=O)CC1Sc2ccccc2N(CC#N)C1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1Sc2ccccc2N(Cc2nc3cc(F)cc(F)c3s2)C1=O
Reaction time: 15 h
Yield: 76 %

Procedure:
Ethyl 2-(4-cyanomethyl-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl)acetate (580 mg) and 474 mg of 2-amino-4,6-difluorothiophenol hydrochloride were added to 4 ml of anhydrous ethanol, the mixture was heated to reflux under argon atmosphere. After 15 hours, the solvent was distilled off. Water was added to the mixture, and extracted with ethyl acetate. After the drying of the organic layer over anhydrous magnesium sulfate, the solvent was distilled off. The resulting oily matter was subjected to alumina column chromatography. Elution with hexane-ehtyl acetate gave 660 mg of the title compound. The structural formula and physical data of this compound are shown in Table 19.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9](OC)=[O:10])=[CH:5][CH:4]=1)#[N:2].O.[NH2:16][NH2:17]>>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([NH:16][NH2:17])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)COc1ccc(C#N)cc1
Reactant: NN
Solvent: O
Product: N#Cc1ccc(OCC(=O)NN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of methyl (4-cyanophenoxy)acetate (3.52 g, 18.4 mmol) in MEOH (100 mL) was added hydrazine hydrate (8.9 mL). After stirring for 1 h at rt, a solid precipitated out. Filtration, washing with MeOH (5 mL) and water (4×10 mL) and drying under vacuo at 50° C. overnight gave the title compound (2.63 g, 75%) as a white solid in 98.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][CH2:19][O:20][C:21]1[N:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[N:22][C:21]([O:20][CH2:19][F:18])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1cnc(OCF)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCF)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-fluoromethoxy-pyrazine-2-carboxylic acid (CAS 1174321-00-6) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=396.2 [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][CH2:34][CH2:33][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][CH2:34][CH2:33][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][CH2:34][CH2:33][CH2:32]1
Reactant: CC1(CO)CCCCC1
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)CCCCC1)(C(=O)OCC1(C)CCCCC1)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-methylcyclohexyl-methanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 0.84 (s, 6H, CH3, CH3), 1.09 (d, J=6.4 Hz, 3H, CH3), 1.1-1.4 (m, 20H, cyclohexyl), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, 1H, CH), 6.35 (d, J=4.17 Hz, 1H, OH), 6.85 (dd, J=7.9, 1.32 Hz, 1H, Ar--H), 7.07 (s, 1H, Ar--H), 7.09 (d, J=8.35 Hz, 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 641 (M+); Analysis for: C36H48ClNO7 ×HCl: Calc'd: C, 63.71; H, 7.28; N, 2.06; Found: C, 63.72; H, 7.03; N, 1.91.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](OS(C)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-:19].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([Br:19])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)C(OS(C)(=O)=O)c1cc(Cl)cc(Cl)c1
Reactant: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Br)c1cc(Cl)cc(Cl)c1
Yield: 102.5 %

Procedure:
A solution of methyl 2-(3,5-dichlorophenyl)-2-mesyloxyacetate (8.2 g) in dimethylformamide (30 ml) was treated with potassium bromide (4.0 g) at 50° C. for 1.5 hours. The reaction mixture was partitioned between water (200 ml) and ethyl acetate (300 ml). The organic phase was separated and washed twice with water (2×200 ml) and finally with saturated brine solution (200 ml). The ethyl acetate solution was dried and concentrated to dryness giving crude methyl 2-(3,5-dichlorophenyl)-2-bromoacetate (8 g). Filtration through a column of silica gel using dichloromethane as eluent gave the pure substance as an oil (7.4 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:12][C:13]([NH2:25])([CH3:24])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=1>>[OH:4][CH:2]([CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:25][C:13]([CH3:24])([CH3:12])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: COc1ccc(CC(C)(C)N)cc1F
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2)cc1F

Procedure:
Using the method of Example 6, supra, phenyl glycidyl ether (150 mg, 1.1 mmol) and 1,1-dimethyl-2-(3-fluoro-4-methoxyphenyl)ethylamine (197 mg, 1 mmol) were used to prepare the title compound. The title compound crystallized on standing to yield 169 mg of small crystals: GC/EI-MS, m/z (rel. int.) 332 (M+ -15,0.1), 209 (16), 208 (100), 139 (13), 133 (5), 114 (7), 107 (6), 77 (11), 71 (12), 70 (20), 58 (9).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[C:4]([F:13])[CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:19])=[O:11])=[C:4]([F:13])[CH:3]=1
Reactant: CO
Reactant: O=C(O)C=Cc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(Br)cc1F

Procedure:
The 3-(4-bromo-2-fluorophenyl)-2-propenoic acid obtained (17.1 g, 0.0698 mol) is taken up in 250 ml of methanol and 0.5 ml of concentrated sulphuric acid and heated for 12 h at reflux. Evaporation is carried out under vacuum and the residue purified by chromatography on silica (eluent: 1/1 hexane/ethyl acetate). Yd.: 14.7 g (81%) M.p. : 63°-65° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]([C:31](OC4C=CC=CC=4)=[O:32])C(=O)OC4C=CC=CC=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:31]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:32])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: C1COCCN1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCOCC4)c3)ccc21
Temperature: 25 °C
Reaction time: 9 h
Yield: 68.5 %

Procedure:
Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (20 g, 38 mmol) synthesized in Production example 5-2 was dissolved in N,N-dimethylformamide (190 ml); morpholine (13.3 mg, 153 mmol) was added thereto; and the reaction system was stirred at room temperature for 9 hours. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate and a small amount of tetrahydrofuran; this suspension was filtrated with silica gel; and ethyl acetate and three different ratio of solvent mixtures of ethyl acetate:methanol=20:1, 10:1, and 5:1 were eluted through the gel. The filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether (40 ml); hexane (200 ml) was added thereto; and precipitated insoluble syrupy portion was removed from the solution; and the resultant solution was concentrated again under reduced pressure. The residue was dissolved in ethyl acetate (300 ml) and was allowed to stand at room temperature. After the crystals were precipitated, the crystals were filtered off, washed with ethyl acetate, and dried to yield the crude crystals of the title compound (10.3 g). 9 g of this crude crystals was suspended in a mixture of tetrahydrofuran (3 ml) and N,N-dimethylformamide (3 ml each); this suspension was diluted with ethanol (60 ml); and the crystals were filtered off, washed with ethanol and dried to yield the title compound as colorless crystals (7.70 g, 19 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[C:8]1([S:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCCCSc1ccccc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCCSc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using [(5-chloropentyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 411.1 (M+H)+.