Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]([CH3:48])[CH2:38][CH2:39][CH2:40][N:41]([CH3:47])[CH2:42][CH2:43][CH2:44][NH:45][CH3:46].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:45]([CH2:44][CH2:43][CH2:42][N:41]([CH2:40][CH2:39][CH2:38][N:37]([CH3:36])[CH3:48])[CH3:47])[CH3:46])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CNCCCN(C)CCCN(C)C
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N(C)CCCN(C)CCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 56.2 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in CH2Cl2 (1 mL) were added N-[3-(dimethylamino)propyl]N,N′-dimethyl-1,3-propanediamine (0.004 mL, 0.02 mmol) and triethylamine (0.05 mL, 0.36 mmol). The resultant solution was stirred at room temperature over night. The reaction mixture was concentrated. Separation via a HPLC followed by treatment with t-amino SPE cartridge then provided the title compound as a white solid (7 mg, 29%). LC-MS m/z 609 (M+H)+; 1H-NMR (MeOD) δ 1.29 (d, 6H), 1.95 (m, 4H), 2.33 (s, 3H), 2.75 (s, 3H), 2.78 (s, 3H), 2.92 (s, 3H), 3.17 (m, 6H), 3.50 (m, 2H), 4.15 (s, 2H), 4.23 (m, 1H), 7.19 (m, 2H), 7.48 (d, 1H), 7.55 (m, 1H), 7.71 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: Br[C:2]1[N:3]([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=3[S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][N:6]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]1([C:2]2[N:3]([CH2:7][C:8]3[CH:9]=[C:10]([C:14]4[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=4[S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=3)[CH:4]=[CH:5][N:6]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3Br)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccccc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
To a solution of 3-[3-(2-bromoimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (58.5 mg, 0.115 mmol; see Example 11(b)) in toluene (5 mL) and ethanol (0.5 mL) was added phenyl boronic acid (55.9 mg, 0.458 mmol), Pd(PPh3)4 (7.9 mg, 6.88 μmol), NaOH (0.46 mL, 0.688 mmol, 1.5 M aq), and the reaction mixture was stirred for 4 h at 90° C. Another portion of phenyl boronic acid (20.0 mg, 0.164 mmol) and Pd(PPh3)4 (2.0 mg, 1.7 μmol) were added and the reaction was stirred overnight at 90° C. The reaction mixture was diluted with EtOAc (30 mL) and washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using EtOAc:hexane (8:2) as eluent to give the sub-title compound in 49% yield (28.4 mg, 0.056 mmol).
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:15])([F:14])[CH:8]([OH:13])[C:9]([F:12])(F)[F:10].[C:16]([O:21][CH2:22][C:23](=[O:25])[CH3:24])(=[O:20])[C:17]([CH3:19])=[CH2:18].Cl.[O:27]1CCCC1>CCCCCC>[C:16]([O:21][CH2:22][C:23]([CH3:24])([OH:25])[C:9]([F:12])([F:10])[C:8]([OH:27])([OH:13])[C:7]([F:15])([F:14])[F:6])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)OCC(C)=O
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=C(C)C(=O)OCC(C)(O)C(F)(F)C(O)(O)C(F)(F)F
Temperature: 5 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
In a nitrogen atmosphere at 5° C., 1290 ml of 1.6M butyllithium in hexane was added to a mixture of 168 g of 1,1,1,3,3,3-hexafluoro-2-propanol and 1200 g of tetrahydrofuran, followed by one hour of stirring at 5° C. Then 142 g of 2-oxopropyl methacrylate was added at 5° C. The mixture was stirred for 10 hours, after which dilute hydrochloric acid was added to quench the reaction and neutralize the reaction mixture. This was followed by conventional aqueous work-up and purification by silica gel column chromatography, collecting 253 g of the product (yield 82%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.CCN(C(C)C)C(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[NH2:36].[C:42]([O-:45])(O)=O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:9])[C:42]([NH:36][C:35]2[CH:37]=[C:38]([O:40][CH3:41])[CH:39]=[C:33]([O:32][CH3:31])[CH:34]=2)=[O:45])[CH:3]=1
Reactant: O=C([O-])O
Reactant: CNc1cc(Cl)ncn1
Reactant: COc1cc(N)cc(OC)c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)N(C)c2cc(Cl)ncn2)cc(OC)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a stirred solution of 6-chloro-N-methylpyrimidin-4-amine (1 g, 6.965 mmol) in dioxane (10 mL) was added DIPEA (3.6 mL, 20.895 mmol) and triphosgene (0.81 g, 2.786 mmol) under argon atmosphere at 0° C. The resulting mixture was stirred for 1 h at 70° C., and then allowed to cool to room temperature. The resulting mixture was added via cannula to a solution of 3,5-dimethoxyaniline (1.2 g, 8.358 mmol) and DIPEA (1.2 mL, 6.965 mmol) in dioxane (4 mL) under argon atmosphere at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. After completion of the reaction by TLC (Hexanes:EtOAc, 7:3), reaction mixture was diluted with ethyl acetate and a saturated aqueous solution of NaHCO3. The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic phase washed with brine, dried on Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (Hexanes:EtOAc, 70:30) to afford 1-(6-chloropyrimidin-4-yl)-3-(3,5-dimethoxyphenyl)-1-methylurea (1.1 g, yield: 50%) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 12.38 (s, 1H), 8.71 (s, 1H), 6.99 (s, 1H), 6.79 (d, 2H), 6.26 (t, 1H), 3.81 (s, 6H), 3.45 (s, 3H); MS (ESI): 323.10 [M+H]+.
Reaction SMILES: [Na].[C:2]1([CH2:8][CH2:9][SH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:32]([C:33](=[O:35])[CH2:34][C@:17]12[CH3:18])[C@:30]1([CH3:31])[C:25](=[CH:26][C:27](=[O:36])[CH:28]=[CH:29]1)[CH2:24][CH2:23]3)(=O)=O>C(O)C>[C:2]1([CH2:8][CH2:9][S:10][C@@H:16]2[CH2:21][CH2:20][C@H:19]3[C@H:22]4[C@H:32]([C:33](=[O:35])[CH2:34][C@:17]23[CH3:18])[C@:30]2([CH3:31])[C:25](=[CH:26][C:27](=[O:36])[CH:28]=[CH:29]2)[CH2:24][CH2:23]4)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Reactant: SCCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2SCCc1ccccc1

Procedure:
To 2.25 gm. of sodium metal dissolved in 180 ml. of ethanol is added 8 ml. of β-phenylethyl mercaptan followed by 3 gm. of 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione. Heat the reaction at reflux for 48 hours. Obtain a residue in a manner similar to that described in Example 1A. Chromatograph the residue on a 300 gm. silica gel column eluting with chloroform/ethyl acetate (2:1). Combine the desired fractions as determined by thin layer chromatography, evaporate and crystallize the resultant residue from ether/hexane to obtain the title compound; m.p. 112°-115° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.C(OC=[CH:24][C:25](=[O:32])[CH2:26][C:27]([O:29]CC)=O)C.[C:33](O)(=O)C>>[OH:29][C:27]1[N:3]2[N:4]=[CH:5][C:6]([C:7]3[CH:8]=[CH:9][C:10]([S:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=3)=[C:2]2[N:1]=[CH:33][C:26]=1[C:25](=[O:32])[CH3:24]
Reactant: Nc1n[nH]cc1-c1ccc(Sc2ccccc2)cc1
Reactant: CC(=O)O
Reactant: CCOC=CC(=O)CC(=O)OCC
Product: CC(=O)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Temperature: 25 °C

Procedure:
A mixture of 534 mg of 3-amino-4-(4-phenylthiophenyl)pyrazole, 484 mg of ethyl ethoxymethyleneacetoacetate, and 15 ml of acetic acid was stirred at room temperature. The precipitate was filtered 30 minutes later, and washed with n-hexane. The mixture of the obtained precipitate, 290 mg of sodium methoxide and 50 ml of toluene was concentrated in vacuo, and 2N hydrochloric acid, methylene chloride and ethyl acetate were added to the residue, and after separating, the organic layer was dried with over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was recrystallized in methylene chloride-ethyl acetate (=1:1), and the title compound was obtained (350 mg)
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1>CC(C)=O>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][Br:19])[CH:22]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: BrCc1cccc(CBr)c1
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCc3cccc(CBr)c3)cc2s1
Yield: 91.7 %

Procedure:
To a solution of 2-cyano-6-hydroxybenzothiazole (1.04 g) in 30 mL of acetone was added potassium carbonate (1.63 g), followed by α, α′-dibromo-m-xylene (4.7 g). The resultant solution was stirred at RT for 1 hour and the solvent was removed under reduced pressure. The residue was resuspended in dichloromethane and washed with water. The aqueous phase was extracted with more dichloromethane (2×) and the organic extracts were combined, dried over sodium sulfate, and purified by flash chromatography using dichloromethane. 1.945 g of product was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[O:5][C:6]=1[Br:7].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:44][CH:45]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:44][CH:45]([CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:10])[O:5][C:6]=1[Br:7]
Reactant: O=C(O)c1cc(Br)c(Br)o1
Reactant: CC(C)(C)OC(=O)NCC(N)Cc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(Cc1ccccc1)NC(=O)c1cc(Br)c(Br)o1
Reaction time: 16 h
Yield: 107 %

Procedure:
To a solution of 4,5-dibromo-2-furancarboxylic acid (2.81 g, 10.4 mmol), PyBrOP (5.6 g, 12.0 mmol) and diisopropylethyl amine (4.2 mL, 24.0 mmol) in DCM (70 mL) at 25° C. was added 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (2.0 g, 8.0 mmol). After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, hexanes/EtOAc, 2:1) affording the title compound (4.3 g, 82%) as a white solid: LC-MS (ES) m/z=503 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[CH:7]=1.O(C1C=CC(N)=CC=1)C1C=CC=CC=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)[NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:59][CH:58]=2)C)=CC=1)C(O)=O)C>>[CH3:20][O:19][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([CH3:14])([C:16](=[O:18])[NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:59][CH:58]=2)[CH3:15])[CH:7]=1)[C:3]([OH:2])=[O:21]
Reactant: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)O)c1)OC
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Agent: Nc1ccc(Oc2ccccc2)cc1
Product: CO[C@@H](Cc1cccc(OC(C)(C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)c1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (EXAMPLE 56, step 2) and 4-phenoxy-phenyl amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C28H31NO6 [M−H]−: 476.
Reaction SMILES: C([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:11]=2)[C:6]1=O)(C)(C)C.[CH:20]([Mg]Br)([CH3:22])[CH3:21].[NH2:25][NH2:26].C1(P(ON)(C2C=CC=CC=2)=O)C=CC=CC=1>>[NH2:25][N:26]1[N:5]=[C:6]([CH:20]([CH3:22])[CH3:21])[C:7]2[C:12](=[CH:11][C:10]([C:15]([F:16])([F:17])[F:18])=[CH:9][CH:8]=2)[C:13]1=[O:14]
Reactant: CC(C)[Mg]Br
Reactant: NN
Reactant: CC(C)(C)N1C(=O)c2ccc(C(F)(F)F)cc2C1=O
Agent: NOP(=O)(c1ccccc1)c1ccccc1
Product: CC(C)c1nn(N)c(=O)c2cc(C(F)(F)F)ccc12

Procedure:
The crude 2-tert-butyl-5-(trifluoromethyl)isoindoline-1,3-dione was treated with isopropylmagnesium bromide and hydrazine using a method similar to that described in Example 1A, followed by treatment with O-(diphenylphosphoryl)hydroxylamine using a method similar to that described in Example 1B to give the title compound. LC/MS (APCI) m/z 272 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([C:21]#[N:22])([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].C(O)C.N>[Ni].CO.ClCCl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:22][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(C)c(C)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CC1(c2ccc(C)c(C)c2)CNC(=O)C1
Reaction time: 48 h

Procedure:
Combine 3-cyano-3-(3,4-dimethylphenyl)pentanedioic acid diethyl ester (56 g, 177 mmol) and ethanol (500 mL) in a Parr bottle. Add Raney nickel (50 g) and an aqueous concentrated ammonia solution (85 mL). Hydrogenate at 50° C. and 100 psi for 48 h. Filter through a celite pad and rinse the solids with ethanol. Evaporate the filtrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 6% methanol/dichloromethane to give the title compound.
Reaction SMILES: S(Cl)(Cl)=O.CC1C(C)=CC=CC=1C(O)=O.CC1C(C)=CC=CC=1C(Cl)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.[CH3:49][C:50]1[C:55]([CH3:56])=[CH:54][CH:53]=[CH:52][C:51]=1[C:57]([N:59]=[C:60]=[S:61])=[O:58]>C1(C)C=CC=CC=1.C(O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:60]([NH:59][C:57](=[O:58])[C:51]2[CH:52]=[CH:53][CH:54]=[C:55]([CH3:56])[C:50]=2[CH3:49])=[S:61])=[CH:44][CH:43]=1
Reactant: Cc1cccc(C(=O)N=C=S)c1C
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: Cc1cccc(C(=O)Cl)c1C
Agent: Cc1cccc(C(=O)O)c1C
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4C)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,3-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,3-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 2,3-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml), and a solution of 2,3-dimethyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (81 mg, yield 98%).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]3=[C:15]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[CH:16]=2)[N:11]=[CH:10]1.C(N(CC)CC)C.ClC1C=C(C=CC=1)C(OO)=[O:44]>ClCCl>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]3[CH:28]=[CH:29][CH:30]=[CH:31][C:13]3=2)[C:18](=[O:19])[NH:9][CH:10]=1.[OH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]3=[C:15]([CH2:20][C:21]3[CH:22]=[N+:23]([O-:44])[C:24]([CH3:27])=[CH:25][CH:26]=3)[CH:16]=2)[N:11]=[CH:10]1
Reactant: Cc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccccc23)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccccc23)c[n+]1[O-]
Product: O=c1[nH]cnc2c1ccc1ccccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-[(1S,2S)-2-hydroxycyclohexyl]-6-[6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one was prepared as described in Example 2. To a suspension of 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one hydrochloride (0.050 g, 0.12 mmol) in 0.6 mL of dichloromethane was added triethylamine (0.012 g, 0.12 mmol). Upon dissolution of the suspension, 3-chloroperoxybenzoic acid (0.031 g, 0.13 mmol) was added and the mixture was stirred at rt for 15 h. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium carbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% methanol in dichloromethane, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 416.1967 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.99-8.96 (m, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.79-7.76 (m, 1H), 7.65-7.59 (m, 2H), 6.91 (d, J=8.1 Hz, 1H), 4.61 (br s, 1H), 4.31 (s, 2H), 4.00 (br s, 1H), 2.50-2.40 (m, 1H), 2.41 (s, 3H), 2.26-2.21 (m, 1H), 2.06-1.98 (m, 1H), 1.98-1.82 (m, 3H), 1.58-1.40 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1>>[ClH:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH:28][S:16]([C:14]2[O:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH:21]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)o2)c(C)[nH]c1=O
Reactant: NCCc1cccnc1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCc3cccnc3)o2)c(C)[nH]c1=O
Product: Cl
Yield: 34 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-sulfonyl chloride is reacted with (2-pyridin-3-yl)ethylamine as described in Step 5, Example 24 to give the title compound as a solid (34% yield). LC/MS: RT 2.00 min; m/e 388 (M+H); 1H NMR (δ, ppm): 8.75 (2H), 7.90-8.36 (3H), 7.45 (1H, s), 7.13 (1H, d); 6.68 (1H, d), 3.27 (2H), 2.96 (2H), 2.36 (3H, s), 2.40 (2H), 1.11 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].[NH:35]([C:39]1[S:40][CH:41]=[C:42]([CH2:44][S:45][CH2:46][CH2:47][NH2:48])[N:43]=1)[C:36]([NH2:38])=[NH:37]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH2:17][CH2:18][NH:19][C:23]([NH:48][CH2:47][CH2:46][S:45][CH2:44][C:42]2[N:43]=[C:39]([NH:35][C:36]([NH2:38])=[NH:37])[S:40][CH:41]=2)=[O:24])[CH3:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.29 g (0.97 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil: MS (+FAB method): m/z (rel. int. [%])=560 ([M+H]+, 8), 78 (100); IR (KBr): 1659 cm-1 (C=O). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt in an ethanol/ether solvent mixture; m.p.: 132° C. (ethanol/ether).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:7]([Cl:10])([Cl:9])=[CH2:8]>C(Cl)Cl>[Cl:9][C:7]([Cl:10])=[CH:8][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: C=C(Cl)Cl
Solvent: ClCCl
Product: CC(C)C(=O)C=C(Cl)Cl
Temperature: 25 °C
Yield: 1.7 %

Procedure:
To a solution of 53.5 gm (0.5 mole) of isobutyryl chloride and 45 gm (0.27 mole) of ferric chloride in 50 ml of methylene chloride cooled to 50°, and maintained below 10°, was added, with stirring, 53.2 gm (0.55 mole) of vinylidene chloride over a 1 hour period. After the addition, the reaction mixture was allowed to warm to room temperature for 3 hours before being poured over 100 gm of crushed ice. The layers were separated, and the organic solution was washed three times with 50-ml portions of water before being dried over magnesium sulfate. After being filtered, the solution was diluted with 50 ml of methylene chloride. The diluted solution was washed twice with dilute aqueous potassium carbonate and then with water before being distilled under reduced pressure, yielding 1.4 gm of crude 1,1-dichloro-4-methyl-1-penten-3-one; b.p., 41°-62°/4.1-4.7mm. The presence of the dichloroketone was established by gas chromatographic analysis, complimented by the mass spectrum of the gc component believed to be the dichloroketone, the mass spectrum of which showed a parent peak at m/e 166 and a fragmentation pattern consistent with 1,1-dichloro-4-methyl-1-penten-3-one.
Reaction SMILES: [C:1]1([C:7]([CH3:18])([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C)(C)C.N.[H][H]>[Ru].[Pd].O>[C:1]1([C:7]([CH3:18])([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CCCC#N)(CCCC#N)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Ru]
Agent: N
Solvent: O
Solvent: CC(C)(C)O
Product: CC(CCCCN)(CCCCN)c1ccccc1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
A one liter autoclave was charged with 50 g 0.21 mol of a dinitrile consisting essentially of 5-phenyl-5-methylnonanedinitrile. Also charged to the reactor was 300 mL 237 g t-butyl alcohol, 25 mL water, 5 g of 5 percent by weight ruthenium on alumina, and 2 g of 5 percent by weight palladium on alumina. The reactor was flushed with nitrogen and charged with 70 g 4.1 mol of ammonia. The reactor was pressured to 1200 psig with hydrogen and heated with stirring at 170° C. for two hours. Hydrogen uptake indicated only reduction of nitrile groups to amino groups had taken place thus producing the aralkylenediamine, 5-phenyl-5-methyl-1,9-nonanediamine.