Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[N:7]2)(=[O:32])=[O:33])=[CH:29][CH:30]=1
Reactant: c1ccc2c(C3CCCC3)n[nH]c2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)n2nc(C3CCCC3)c3ccccc32)cc1
Reaction time: 12 h
Yield: 45.7 %

Procedure:
Combine 3-Cyclopentyl-1H-indazole (2.168 g 11.640 mmole) with triethylamine (3.526 g, 34.92 mmoles) in 50 mls of dichloromethane. Dissolve 4-Chlorosulfonyl-benzoic acid methyl ester (4.085 g, 17.460 mmole) in dichloromethane 50 ml and add drop wise to solution at 0° C. Stir the reaction is for 12 hrs. Dilute the reaction and wash with NaHCO3. Dry organic layer over MgSO4 and concentrate. Purify the residue via column chromatography with a mixture of ethyl acetate and hexanes to isolate 2.046 g (Yield=48.5%) of the title compound: MS ES+ 385.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([NH:26][C:27](=O)[CH3:28])=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([NH:26][C:27](=[S:42])[CH3:28])=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31]
Reactant: CC(=O)Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: CC(=S)Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl

Procedure:
1 mmol of N-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]acetamide and 2 mmol of Lawesson's reagent were stirred in 2 ml of DME at 80° C. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain 1-{[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]amino}ethane-1-thione.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:9])[N:5]([CH3:8])[C:6]=1[CH3:7].BrC1N(C)C(C)=C(Br)N=1.C([Li])CCC.CI.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][N:37]3[C:40]([C:43]4[CH:44]=[C:45]([NH:49][C:50]([NH:52][CH2:53][C:54]([F:57])([F:56])[F:55])=[O:51])[CH:46]=[CH:47][CH:48]=4)=[CH:41][N:42]=[C:36]3[CH:35]=2)O1>>[F:57][C:54]([F:56])([F:55])[CH2:53][NH:52][C:50]([NH:49][C:45]1[CH:46]=[CH:47][CH:48]=[C:43]([C:40]2[N:37]3[CH:38]=[CH:39][C:34]([C:2]4[N:3]=[C:4]([CH3:9])[N:5]([CH3:8])[C:6]=4[CH3:7])=[CH:35][C:36]3=[N:42][CH:41]=2)[CH:44]=1)=[O:51]
Reactant: CC1(C)OB(c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)OC1(C)C
Reactant: Cc1nc(Br)c(C)n1C
Agent: Cc1c(Br)nc(Br)n1C
Agent: [Li]CCCC
Solvent: CI
Product: Cc1nc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)c(C)n1C

Procedure:
4-Bromo-1,2,5-trimethyl-1H-imidazole may be prepared from 2,4-dibromo-1,5-dimethyl-1H-imidazole by treatment with n-butyl lithium and methyl iodide as described in J. Org. Chem., 1994, 59, 5524. This may be coupled with 1-[3-(7-boronic acid-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea or 1-{3-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea according to procedure E3.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]([F:26])([F:25])[F:24])=[N:4][N:5]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Br:27][CH2:1][C:2]1[C:3]([C:23]([F:26])([F:24])[F:25])=[N:4][N:5]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)cc2)c1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(CBr)c2-c2ccccc2)cc1

Procedure:
To a solution of 4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide prepared in Example 201 (500 mg, 1.3 mmol) in carbon tetrachloride (9 mL) and benzene (4 mL) was added N-bromosuccinimide (285 mg, 1.6 mmol). The mixture was irradiated with a sunlamp for 3.5 hours. The reaction mixture was partitioned between dichloromethane and water and the organic solution was dried and concentrated to give the desired product, 412 mg (69%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:18]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:9]=3[S:8](=[O:27])[C:7]=2[CH:18]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)Sc1ccc(O)cc1C=C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)S(=O)c1ccc(O)cc1C=C2
Reaction time: 0.5 h

Procedure:
Suspend 50.2 mg. of 3-cyano-8-hydroxydibenzo[b,f]thiepine in 9 ml. of methylene chloride and add 40.6 mg. of m-chloroperbenzoic acid. Allow the mixture to stand at room temperature for 30 minutes. Separate the solids by filtration to obtain the title product (m.p., 241°-243° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1.CN(C)C=O>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:17][C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)Cc1ccc(I)cc1
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COc1cccc(C#N)c1)Cc1ccc(I)cc1
Temperature: 70 °C
Reaction time: 55 h

Procedure:
724 mg (6.08 mmol) of 3-cyanophenol and 1.12 g (8.1 mmol) of potassium carbonate were added to 1.6 g (0.60 mmol) of t-butyl [(1R)-2-chloro-1-(4-iodobenzyl)ethyl]carbamate and 25 ml of dimethylformamide, and they were stirred at 70° C. for 55 hours. The reaction liquid was diluted with water. After extraction with ethyl acetate, the organic layer was successively washed with water and saturated aqueous NaCl solution. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cccnc1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CC(=O)N2
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Cc1cccnc1)C(=O)N2
Yield: 75 %

Procedure:
Starting from 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-2H-indol-2-one and pyridine 3-carboxaldehyde and following the method described in Example 10, the desired compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.[CH3:25][Mg]Br.C(OCC)C>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([CH:23]([OH:24])[CH3:25])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 50 mL round bottom flask, 5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbaldehyde (0.5 g, 0.001457 mol) and THF (25 mL) was added and cooled to 0° C. To the flask was slowly added 1.5 M methyl magnesium bromide in diethyl ether (0.145 mL, 0.002186 mol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to provide the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 40% ethyl acetate in hexane [0.3 g, 57%]. 1H NMR (300 MHz, CDCl3): δ 8.05 (d, J=1.2 Hz, 1H), 7.83 (d, J=6.3 Hz, 1H), 7.71 (dd, J′=6.6, J″=1.2 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.40 (d, J=2.7 Hz, 1H), 4.91 (q, J=4.8 Hz, 1H), 3.89 (s, 8H), 1.63 (d, J=4.8 Hz, 3H). LC-MS (ESI): Calculated mass: 359. 1; Observed mass: 360.1 (RT: 1.58 min).
Reaction SMILES: CN(C)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:6].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1>CCO.O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)=[O:6])[CH3:23])=[CH:18][CH:17]=1
Reactant: CN(C)CCC(=O)c1cccc(F)c1
Reactant: C[C@H](N)c1ccc(Br)cc1
Solvent: CCO
Solvent: O
Product: C[C@H](NCCC(=O)c1cccc(F)c1)c1ccc(Br)cc1
Temperature: 80 °C
Yield: 20.3 %

Procedure:
A solution of 3-dimethylamino-1-(3-fluoro-phenyl)-propan-1-one (17 g, 0.087 mol) and (S)-1-(4-bromophenyl)-ethanamine (17 g, 0.087 mol) in a mixture of EtOH (50 mL) and H2O (50 mL) was refluxed at 80° C. overnight. The solvent was removed under vacuum, and the residue was purified by column chromatography to afford (S)-3-(1-(4-bromophenyl)-ethylamino)-1-(3-fluorophenyl)-propan-1-one (6.2 g, 20%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15]CC)=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-])=O.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[C:7]3[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3[nH]c(C(=O)O)c(-c4ccccc4)c3c2)cc1

Procedure:
The title compound was prepared from ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate and 4-tert-butylbenzene sulfonyl chloride followed the procedures of Example 1 Step 2 & Step 3 as a gray solid: 1H NMR (DMSO-d6) δ 1.25 (s, 9H, 7.05 (d, J=1.8 Hz, 1H, 7.10 (dd, J=8.9, 2.0 Hz, 1H, 7.26-7.45 (m, 6H, 7.54 (d, J=8.9 Hz, 2H, 7.57 (d, J=8.8 Hz, 2H, 9.81 (s, 1H, 11.79 (s, 1H, 12.42 (br s, 1H; MS (ESI) m/z 447 [M-H]−; HRMS calcd for C25H25N2O4S: 449.1533; found (ESI+): 449.1524; Anal. calcd for C25H24N2O4S.0.25H2O: C, 66.27; H, 5.45; N, 6.18. Found: C, 65.98; H, 5.34; N, 6.14.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:17])=[C:14]([OH:16])[CH:15]=1>CCO>[Cl:17][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)=[CH:15][C:14]=1[OH:16]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: Cc1ccnc(Cl)n1
Solvent: CCO
Product: Cc1ccnc(Nc2ccc(Cl)c(O)c2)n1
Temperature: 90 °C
Yield: 74 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-chloro-4-methylpyrimidine (69 mg, 0.54 mmol) and 5-amino-2-chlorophenol (77 mg, 0.54 mmol) in 10% aqueous EtOH (3 mL) was heated at 90° C. for 18 h. The title compound was obtained in 74% yield a (94 mg) and used for the next step without additional purification.
Reaction SMILES: C([O:5]O)(C)(C)C.[C:7]([O:11][C:12]([NH:14][C@@H:15]1[C@@H:20]([C:21]2[C:22]([C:38]([O:40][CH3:41])=[O:39])=[C:23]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:24]3[O:28][CH2:27][O:26][C:25]=3[CH:29]=2)[CH:19]=[CH:18][C@@H:17]([OH:42])[C@H:16]1[OH:43])=[O:13])([CH3:10])([CH3:9])[CH3:8]>CCCCCCCCCC.C1C=CC=CC=1.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[C:7]([O:11][C:12]([NH:14][C@H:15]1[C@H:16]([OH:43])[C@H:17]([OH:42])[C@@H:18]2[O:5][C@@H:19]2[C@@H:20]1[C:21]1[C:22]([C:38]([O:40][CH3:41])=[O:39])=[C:23]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]2[O:28][CH2:27][O:26][C:25]=2[CH:29]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)c1c([C@H]2C=C[C@@H](O)[C@@H](O)[C@@H]2NC(=O)OC(C)(C)C)cc2c(c1OCc1ccccc1)OCO2
Reactant: CC(C)(C)OO
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: CCCCCCCCCC
Solvent: c1ccccc1
Product: COC(=O)c1c([C@@H]2[C@@H](NC(=O)OC(C)(C)C)[C@H](O)[C@H](O)[C@@H]3O[C@@H]32)cc2c(c1OCc1ccccc1)OCO2
Temperature: 60 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
t-Butylhydroperoxide in decane (5M, 0.45 ml) was added to a solution of methyl 6-[(1R,4R,5S,6R)-6-(tert-butyloxycarbonylamino)-4,5-dihydroxy-2-cyclohexen-1-yl]-4-(phenylmethoxy)-1,3-benzodioxole-5-carboxylate (280 mg, 0.55 mmol) and vanadyl acetylacetonate (7 mg, 0.026 mmol) in benzene (10 ml). After stirring for 2 h at 60° C, the reaction mixture was concentrated under reduced pressure and subjected to chromatography (hexane/ethyl acetate, 1:5) to afford 129 mg (53%) of epoxide 16 and 42 mg of recovered starting material. 1H NMR (270 MHz, CDCl3) ε 7.27~7.40 (m, 5H), 7.04 (s, 1H), 5.99 (d, J=2.3 Hz, 2H), 5.68 (bd, J=7.3 Hz, 1H), 5.24 (AB, J=11.3 Hz, Δν=16.5 Hz, 2H), 4.28 (t, J=4.99 Hz, 1H), 3.83 (m, 4H), 3.35~3.46 (m, 3H), 3.07 (d, J=10.9 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: OCCO
Reactant: Cc1ccc(C=O)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C2OCCO2)cc1Br
Yield: 89.1 %

Procedure:
11.8 g (60 mmol) of 3-bromo-4-methylbenzaldehyde are placed in 150 ml of toluene in a round-bottomed flask and under nitrogen. 16.5 ml (300 mmol) of ethylene glycol and 571 mg (3 mmol) of para-toluenesulfonic acid are added. The mixture is refluxed for 36 hours and the water formed is separated out using Dean-Stark apparatus. At room temperature, the reaction medium is poured into saturated aqueous sodium hydrogen carbonate solution and then extracted with ether. The organic phase is dried over magnesium sulfate, filtered and evaporated. 13 g (89%) of the expected product are obtained in the form of a brown oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:70]1([C@@H:76]([NH2:78])[CH3:77])[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:78][C@H:76]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH3:77])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: C[C@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N[C@@H](C)c3ccccc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and [(1S)-1-phenylethyl]amine (12.9 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 45%). LC-MS m/z 625 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3]1=[O:21].[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C@:38](OS(C)(=O)=O)([CH2:44][CH2:45][CH2:46][CH3:47])C(OCC)=O)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:44][CH2:45][CH2:46][C@H:47]([NH:1][C@@H:2]2[CH2:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:3]2=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Reactant: CCCC[C@](OS(C)(=O)=O)(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1
Product: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H]1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 90 °C
Yield: 49.1 %

Procedure:
A mixture of 0.32 g of tert-butyl (RS)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate and 0.2 g of ethyl (R)-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate is heated at 90° C. for 30 minutes. After cooled, the mixture is separated and purified by silicagel column chromatography (hexane: ethyl acetate=2:1) to give 0.14 g of tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate as colorless oil from the first fraction.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.O.O[N:12]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A solution of 5-bromo-thiophene-2-carboxylic acid (4.51 g, 21.78 mmol), 3-hydroxybenzotriazole hydrate (3.24 g, 23.96 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (4.6 g, 23.96 mmol) in DMF (70 mL) is stirred at room temperature for 2 hours. The reaction mixture is then cooled to 0° C. and aq. 35% NH3 (2.2 mL) is added. The mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the residue dissolved in EtOAc, washed with 1N NaHCO3, and brine. The organic layers are combined, dried over MgSO4, filtered and concentrated to afford the title compound (3.78 g, 84%). HPLC (254 nm): Rt 2.46 min (96.5%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([OH:29])[C@H:14]([CH3:30])[O:13][C:12]1=[O:31])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:40]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:40]1([C:45]([O:29][C@@H:15]2[C@@H:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:17][CH2:18][CH2:19][C@H:11]([N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:32])[CH2:8][O:9][CH3:10])[C:12](=[O:31])[O:13][C@H:14]2[CH3:30])=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](O)[C@H](C)OC1=O
Reactant: O=C(Cl)C1CCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](OC(=O)C2CCCC2)[C@H](C)OC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A 20 mL vial was charged with tert-butyl((3S,7R,8R,9S)-8-hydroxy-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)(methoxymethyl)carbamate (200 mg, 0.443 mmol), CH2Cl2 (2215 μl), NEt3 (185 μl, 1.329 mmol) and DMAP (5.41 mg, 0.044 mmol). The reaction mixture was cooled to 0° C. in an ice bath under N2 and cyclopentanecarbonyl chloride (76 mg, 0.576 mmol) was added in one portion. The reaction became dark brownish-yellow. After stirring for 2 h, the reaction mixture was quenched by the addition of saturated aqueous NaHCO3. The mixture was extracted with CH2Cl2 (3×) and the combined organic layers were washed with brine, dried over MgSO4, concentrated, and purified by column chromatography on SiO2 (0→100% EtAOx/hexanes) to provide the title compound as a yellow solid (85 mg, 35.0%): 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J=8.5 Hz, 4H), 6.81 (d, J=8.4 Hz, 4H), 5.06-4.85 (m, 3H), 4.77 (d, J=11.6 Hz, 1H), 4.57 (dd, J=10.7, 6.0 Hz, 0H), 4.29-4.17 (m, 1H), 3.78 (s, 3H), 3.38-3.26 (m, 3H), 2.74 (p, J=8.0 Hz, 1H), 2.61 (dd, J=13.7, 3.7 Hz, 1H), 2.31 (dd, J=13.7, 11.1 Hz, 1H), 2.20-2.07 (m, 1H), 1.99-1.52 (m, 8H), 1.51-1.40 (m, 9H), 1.27 (d, J=5.8 Hz, 3H), 1.15-0.96 (m, 1H), 0.97-0.87 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 176.26, 173.56, 157.94, 155.49, 131.94, 129.59, 113.80, 81.21, 75.54, 72.72, 58.52, 55.43, 55.22, 44.32, 44.04, 35.77, 30.09, 30.00, 29.58, 28.20, 26.48, 25.72, 25.70, 19.09, 17.56; ESIMS m/z 570.5 ([M+Na]+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[C:5]([C:11]#[N:12])[CH:4]=1)#[N:2].CO.[H][H]>[OH-].[Na+].C1(C)C=CC=C(C)C=1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[C:7]([CH2:9][NH2:10])[CH:8]=1
Reactant: [H][H]
Reactant: N#Cc1cc(C#N)cc(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(C)c1
Solvent: CO
Product: NCc1cc(CN)cc(CN)c1
Yield: 79.1 %

Procedure:
In a 300 ml capacity, magnetic-stirring autoclave was sealed 15 g of 1,3,5-tricyanobenzene (MTN), together with 15 g of Raney nickel chromium catalyst (atomic ratio of Ni:Cr=49:1), 27 ml of methanol, 63 ml of m-xylene and 0.18 g of caustic soda. Hydrogen was charged under pressure into it at initial pressure of 100 kg/cm2G, and the reaction was carried out at 100° C., whereby 0.59 mole of hydrogen was absorbed for 35 minutes. The catalyst was filtered out, and the solvent was distilled off, followed by distilling under reduced pressure, thereby yielding 12.8 g of colorless crystals of 1,3,5-tris(aminomethyl)-benzene (MTA). The substance exhibited melting point of 49° to 51° C. and boiling point of 136° to 139° C./0.4 mmHg.
Reaction SMILES: C(Cl)(Cl)(Cl)F.[CH:6]([O:15][C:16](Cl)([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8].[F:20][C:21]([F:33])([F:32])[CH:22]([O:27]C(F)(F)F)[C:23]([F:26])([F:25])[F:24]>>[F:8][C:7]([F:10])([F:9])[CH:6]([O:15][C:16]([F:18])([F:17])[O:27][CH:22]([C:23]([F:26])([F:25])[F:24])[C:21]([F:33])([F:32])[F:20])[C:11]([F:14])([F:13])[F:12]
Reactant: FC(F)(Cl)OC(C(F)(F)F)C(F)(F)F
Reactant: FC(F)(F)OC(C(F)(F)F)C(F)(F)F
Solvent: FC(Cl)(Cl)Cl
Product: FC(F)(OC(C(F)(F)F)C(F)(F)F)OC(C(F)(F)F)C(F)(F)F

Procedure:
Fractionation of the combined products afforded 23.2 g of a mixture, boiling point up to 39.5° C., shown by 1H and 19F NMR and GC to contain mainly CFCl3 and (CF3)2CHOCF2Cl along with a small amount of trifluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether. There was then distilled 120.1 g, boiling point 40° to 45° C., identified by GC and NMR as chlorodifluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether. Next came 2.7 g, boiling point 75° to 79° C., of dichlorofluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether, identified by GC and NMR. Finally, there was obtained 24.4 g of 2,6-bis(trifluoromethyl)1,1,1,4,4,7,7,7-octafluoro-3,5-dioxaheptane, ((CF3)2CHOCF2OCH(CF3)2), boiling point 89° to 94° C. identified by GC and NMR analyses. NMR and mass spectroscopic (MS) analyses of (CF3)2CHOCF2OCH(CF3)2 are as follows: 1H-NMR (CDCl3) δ 4.78 (septet, JHF, 5.4 Hz, OCH(CF3)2); 19F-NMR (CDCl3) φ-60.9 (m, 2F, OCF2O), -74.3 (m, 12F, CF3). MS, m/e 364.966156 (M+ -F; mass meas. C7H2F13O2), 314.9808 (M+ -CF3), 216.983002 (mass meas. (CF3)2CHOCF2+), 150.9758 (CF3CHCF3+).