Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([CH2:21][CH:22]=[CH2:23])=[C:9]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:41])C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[C:7]1[CH:8]=[C:9]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]([CH2:21][CH:22]2[CH2:23][O:41]2)=[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCc1c(OCc2ccccc2)cc(C(=O)OC(C)(C)C)cc1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(CC2CO2)c(OCc2ccccc2)c1
Yield: 57.9 %

Procedure:
To a solution of 4-allyl-3,5-bis-benzyloxy-benzoic acid tert-butyl ester (200d) (125 g, 0.29 mol) in CH2Cl2 was added m-CPBA (100 g, 0.58 mol) in several portions. The mixture was refluxed overnight. The solid was filtered and washed with CH2Cl2. The combined filtrates were washed with saturated aqueous Na2S2O4 (250 mL) and brine (250 mL). The organic layer was dried over Na2SO4 and concentrated to give a yellow oil. The crude oil was purified by flash column chromatography (EtOAc/petroleum ether=1/20) to give the title compound (75 g, 57.8%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.40 (m, 12H), 5.09 (s, 4H), 3.53 (dd, 1H), 3.17 (m, 1H), 2.80 (dd, H), 2.63 (t, 1H), 2.51 (dd, 1H), 1.60 (s, 9H).
Reaction SMILES: I[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[C:3]4[C:8]([C:9]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[C:10]5[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]5)=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: OB(O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc(-c3c4ccccc4c(-c4ccccc4)c4ccccc34)cc2)cc1
Yield: 45 %

Procedure:
1.0 g (2.63 mmol) of 9-iodo-10-phenylanthracene, 542 mg (2.70 mmol) of 4-(4-bromophenyl)phenylboronic acid, 46 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium, 3 mL (6 mmol) of potassium carbonate solution (2.0 mol/L), and 10 mL of toluene were stirred for 9 hours at 80° C. After reaction, toluene was added, and it was filtered through florisil®, celite, and alumina. The filtrate was washed with water and saturated saline, and then dried with magnesium sulfate. After natural filtering, the filtrate was concentrated, and when recrystallization was performed with a mixture of chloroform and hexane, 562 mg of 9-[4-(4-bromophenyl)phenyl]-10-phenylanthracene (PBA) that was a target substance and was a light brown solid was obtained in a yield of 45% (Synthesis Scheme (e-2)).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(Cc1ccccn1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccccn1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[methyl(2-pyridinylmethyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 35) (527 mg, 1.12 mmol) in dichloromethane (20 ml) was treated with trifluoroacetic acid (10 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue was azeotroped from toluene. The residue was dissolved in a saturated aqueous solution of sodium hydrogen carbonate (3 ml) and the pH was adjusted to pH 4 with aqueous citric acid solution (10%w/v). The aqueous phase was extracted with ethyl acetate (×2) and the combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a yellow oil (456 mg)
Reaction SMILES: C([O:8][C:9](=[O:40])[CH2:10][CH2:11][NH:12][C:13](=[O:39])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:38])[C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:37])[NH:26]C(OCC2C=CC=CC=2)=O)=[CH:21][CH:20]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]([NH:17][CH2:16][CH2:15][CH2:14][C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:40])=[O:8])=[O:39])=[O:38])=[CH:24][CH:23]=1)(=[NH:26])[NH2:37]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(C(=O)NCCCC(=O)NCCC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc(C(=O)NCCCC(=O)NCCC(=O)O)cc1
Yield: 79.4 %

Procedure:
512 mg of N-[4-[p-[N-(benzyloxycarbonyl)amidino]benzamido]-butyryl]-β-alanine benzyl ester and 170 mg of Pd/C in 10 ml of acetic acid were stirred under hydrogen. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in water and the solution was evaporated. The residue was suspended in water, adjusted to pH 7 using ammonia, filtered with suction, washed with water and dried. 239 mg of N-[4-(p-amidinobenzamido)butyryl]-β-alanine, m.p. >250° C., MS: 321 (12, M+H), were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:29]1[C:37]2[C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[S:34][C:33]=2[C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:32]3[C:33]4[S:34][C:35]5[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=5[C:37]=4[CH:29]=[CH:30][CH:31]=3)=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Product: O=C(O)c1c(-c2ccccc2)c2cc(Nc3cccc4c3sc3ccccc34)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate and 4-dibenzothiopheneboronic acid according to the procedure of Example 1 Step 3 as a black solid: 1H NMR (DMSO-d6) δ 5.82 (s, 2 H), 7.00-8.20 (m, 27 H); MS (ESI) m/z 525 (MH+); HRMS calcd. for C34H25N2O2S: 525.1637; found (ESI+): 525.1622; Anal. calcd. for C34H24N2O2S.0.3ACN: C, 74.88; H, 4.89; N, 5.81. Found: C, 75.14; H, 4.53; N, 5.82.
Reaction SMILES: C1(P(C2C=CC=CC=2)(=O)O[C:9]([CH3:40])=[C:10]([N:24]2[C:30](=[O:31])[CH:29]3[CH:25]2[S:26][C:27]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:28]3)[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])C=CC=CC=1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>O1CCCC1>[O:33]([CH2:32][C:27]1[S:26][CH:25]2[CH:29]([C:30](=[O:31])[N:24]2[C:10](=[C:9]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH3:40])[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[N:28]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C1COCCN1
Reactant: CC(OP(=O)(c1ccccc1)c1ccccc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Solvent: C1CCOC1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 6 h

Procedure:
To a stirred solution of 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-1-(p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl diphenylphosphinate (1.34 g.) in tetrahydrofuran (20 ml.) at 0°-5° C. was added morpholine (0.38 ml.). After stirring for 6 hours at 0°-5° C., the solvent was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in essentially quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond and was identical to that produced in example 8.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:11]1([NH:17][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1NC1CCCCC1

Procedure:
A mixture composed of 0.1 mol (15.85 g) of 2-chloro-3-nitropyridine and 0.1 mol (11.50 ml) of cyclohexylamine is heated at 120° C. for 4 hours in 250 ml of DMF in the presence of potassium carbonate (13.81 g). The solution is then extracted with 200 ml of ether and the organic phase is washed three times with water. After drying over magnesium sulphate, the ether is evaporated off.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccccc3)nc12

Procedure:
From phenylacetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.Br[C:14]1[CH:23]=[N:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:20]2[CH:21]=[N:22][CH:23]=[CH:14][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccncc1Br
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: COC(=O)c1ccncc1NCc1ccc(C(F)(F)F)cc1
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield from 4-(trifluoromethyl)benzylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.95 (d, 1H, J=5.0 Hz), 7.93 (br s, 1H), 7.65 (d, 1H, J=5.0 Hz), 7.60 (d, 2H, J=8.1 Hz), 7.47 (d, 2H, J=8.1 Hz), 4.58 (d, 2H, J=5.9 Hz) 3.91 (s, 3H). [M+H] calc'd for C15H13F3N2O2, 311. Found 311.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=[O:8])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1.[OH-].[Li+].O.Cl>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)c(Br)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
400 mg (1.10 mmol) of the compound from Example 4A are provided in 19 ml of tetrahydrofuran, and 263 mg (11.0 mmol) of lithium hydroxide and 19 ml of water are added at room temperature. The mixture is stirred at room temperature overnight, a 1N aqueous hydrogen chloride solution is then added until an acidic pH is achieved, the mixture is extracted with ethyl acetate and the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated. 190 mg of the title compound having a purity of 86% (44% of theory) are obtained.
Reaction SMILES: C(Cl)(Cl)Cl.CCCCCC.[CH:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[CH2:27][C:28](N)=[O:29].CC(C)=[O:33].CCCCCC>>[CH:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[CH2:27][C:28]([OH:29])=[O:33]
Reactant: CC(C)=O
Reactant: NC(=O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
3.0 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionamide is refluxed in a mixture of 20 ml. of acetic acid and 30 ml. of concentrated hydrochloric acid for 3 hours. The solution is cooled and poured into water. The mixture is extracted with ethyl acetate and the extract is washed, dried and evaporated to yield 90% of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid., m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C. Use of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:16][C:15]2[C:14]3[C:13]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]4)=[N:12][CH:11]=[N:10][C:9]=3[S:8][C:7]=2[CH2:6][CH2:5]1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:44][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C=O)C>[C:27]([O:26][C:25]([NH:24][CH:21]1[CH2:20][CH2:19][CH:18]([O:17][C:13]2[C:14]3[C:15]4[CH2:16][C@H:4]([CH2:3][C:2]([OH:44])=[O:1])[CH2:5][CH2:6][C:7]=4[S:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:23][CH2:22]1)=[O:31])([CH3:28])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@H](CCO)CC4)CC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@H](CC(=O)O)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added tert-butyl N-(4-[[(12R)-12-(2-hydroxyethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (129 mg, 0.29 mmol, 1.00 equiv) in 4 mL of DMF. Then PDC (639 mg, 1.70 mmol, 6.00 equiv) was added and the resulting solution was stirred overnight at room temperature. The reaction was then quenched with water and extracted with 4×40 mL of CHCl3/isopropanol (3:1). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to provide 2-[(12R)-3-[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetic acid (98 mg, 74%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:10]F>C(#N)C>[Cl:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][C:5]([F:10])=[CH:6][N:7]=1
Reactant: N#Cc1nccnc1Cl
Reactant: FF
Solvent: CC#N
Product: N#Cc1nc(F)cnc1Cl
Temperature: 25 °C

Procedure:
In 15 mL of acetonitrile was dissolved 0.3 g of 3-chloro-2-pyrazinecarbonitrile. At an ice-cooled temperature, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced into the solution at a rate of 45 mL per minute for a period of 20 minutes. Then, while elevating the temperature from the ice-cooled temperature to room temperature, nitrogen gas was introduced over a period of one hour. The reaction mixture was concentrated under reduced pressure and the oily product thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=10:1] to obtain 0.12 g of 3-chloro-6-fluoro-2-pyrazinecarbonitrile as a colorless oily product.
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH:24]([CH3:26])[CH3:25])[CH2:5][CH2:6][C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:8](N)=[O:9])[CH3:3].[H][H]>C(O)(=O)C.[Pt]=O>[CH3:3][CH:2]([N:4]([CH:24]([CH3:26])[CH3:25])[CH2:5][CH2:6][C:7]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:8](=[O:9])[N:13]2[CH:12]([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11]1)[CH3:1]
Reactant: CC(C)N(CCC(Cc1ccccn1)(C(N)=O)c1ccccc1)C(C)C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)N(CCC1(c2ccccc2)CC2CCCCN2C1=O)C(C)C
Yield: 55.6 %

Procedure:
A solution of 11.0 g (31 mmol) of the title product of Example 2 was hydrogenated at room temperature in 200 ml of glacial acetic acid using hydrogen at 60 psi over 1 g of platinum oxide catalyst. After catalyst was removed by filtration, the solvent was removed in vacuo and the residue redissolved in ice/water. The aqueous solution was made basic with dilute aqueous sodium hydroxide and extracted with diethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel afforded 5.9 g of the title compound as an analytically pure oil.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[CH2:27][C:28]#[N:29]>>[C:28]([CH2:27][N:5]1[CH2:6][CH2:7][C:3]([O:2][CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:4]1)#[N:29]
Reactant: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCNC1
Reactant: N#CCCl
Product: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCN(CC#N)C1
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 3, 3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]pyrrolidine was reacted with 2-chloroacetonitrile to give 1-(cyanomethyl)-3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]pyrrolidine in 45% yield, m.p. 76°-77° C. (recrystallised from methanol).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[CH:19][C:20]#[N:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]#[N:21])[CH:15]=[CH:16][C:17]1=2
Reactant: CC(C)(C)OC(=O)NC1CCCc2cc(C=CC#N)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC=Cc1ccc2c(c1)CCCC2N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of [6-(2-cyano-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-carbamic acid tert-butyl ester (2.7 g, 9.05 mmol) in DCM (40 mL) was added TFA (15 mL). The resulting mixture was stirred at RT for 1 h. Solvent was removed. The residue was redissolved in EtOAc. The organic layer was washed with sat. NaHCO3, H2O, brine, dried over MgSO4 and removed solvent. The crude product was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH (2M NH3) mixture (97:3) gave final compound (1.6 g, 89%). MS m/z: 199.3 (M+H). Calc'd. for C13H14N2-198.26.
Reaction SMILES: [C:1]([C:3]1(O)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[CH3:9][NH:10][CH2:11][CH:12]=[CH2:13]>>[CH2:11]([N:10]([C:3]1([C:1]#[CH:2])[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:9])[CH:12]=[CH2:13]
Reactant: C=CCNC
Reactant: C#CC1(O)CCCC1
Product: C#CC1(N(C)CC=C)CCCC1

Procedure:
In analogy to example 37.5 and 37.6, 1-Ethinylcyclopentanol and N-Methyl-allylamine were converted to yield Allyl-(1-ethynyl-cyclopentyl)-methyl-amine as colorless oil, MS: 163 (M).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.Cl.[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>C(#N)C.O>[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:3]=2)[CH2:22][CH2:21]1
Reactant: NC1CCC(F)(F)CC1
Reactant: Cc1nc(NCc2ccccn2)nc(Cl)c1C
Agent: Cl
Solvent: CC#N
Solvent: O
Product: Cc1nc(NCc2ccccn2)nc(NC2CCC(F)(F)CC2)c1C
Yield: 41 %

Procedure:
A solution of 4-chloro-5,6-dimethyl-N-(pyridin-2-ylmethyl)pyrimidin-2-amine (200 mg, 0.8 mmol, Example 29, Step C) and (4,4-difluorocyclohexyl)amine hydrochloride (172 mg, 1 mmol) in acetonitrile (5 mL) was refluxed overnight. The reaction mixture was diluted with water (50 mL) and a formed precipitate was collected by filtration. The crude material was purified by HPLC (column: YMC-PACK ODS-AQ C18, 250 mm×20 mm, 10 μm; gradient: 20-50% acetonitrile in 0.02% trifluoroacetic acid/water over fifteen minutes; 50-100% acetonitrile in 0.02% trifluoroacetic acid/water over five minutes; flow rate: 25 mL/min; temperature: 25° C.) to afford 114 mg, 25% of the titled compound as the trifluoroacetic acid salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.45-1.55 (m, 4H), 1.70-1.82 (m, 2H), 1.88 (s, 3H), 1.90-2.00 (m, 2H), 2.25 (s, 3H), 3.90 (bs, 1H), 4.70 (d, J=5.37 Hz, 2H), 7.38 (t, J=6.25 Hz, 1H), 7.47 (d, J=7.52 Hz, 1H), 7.64 (d, J=7.52 Hz, 1H), 7.90 (t, J=7.52 Hz, 1H), 8.46-8.52 (m, 1H), 8.57 (d, J=4.57 Hz, 1H), 12.78 (bs, 1H); MS (ESI) m/z 348.8 (M+1)+. N4-(4,4-Difluorocyclohexyl)-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine trifluoroacetate was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1) to afford 58 mg (68%) of the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.40-1.51 (m, 2H), 1.60-1.71 (m, 3H), 1.81 (bs, 4H), 1.90-1.98 (m, 2H), 2.07 (s, 3H), 3.76-3.84 (m, 1H), 4.46 (d, J=5.91 Hz, 2H), 5.84 (d, J=7.25 Hz, 1H), 6.70-6.75 (m, 1H), 7.10-7.22 (m, 1H), 7.24 (d, J=7.79 Hz, 1H), 7.67 (t, J=7.52 Hz, 1H), 8.45 (d, J=4.30 Hz, 1H); MS (ESI) m/z 348.8 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([I:9])=[CH:7][C:6]([C:10](=[O:17])[CH2:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][C:4]=1[F:18]>>[NH2:2][C:3]1[C:8]([I:9])=[CH:7][C:6]([CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:5][C:4]=1[F:18]
Reactant: CC(C)(C)NCC(=O)c1cc(F)c(N)c(I)c1
Agent: Cl
Product: CC(C)(C)NCC(O)c1cc(F)c(N)c(I)c1

Procedure:
m.p. of the hydrochloride: 207°-209° C. (decomp.), was prepared from 4'-amino-2-tert.butylamino-3'-fluoro-5'-iodo-acetophenone analogous to Example 49.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][C:19](=[O:25])[CH2:20][CH2:21][C:22](O)=[O:23])=[O:5].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C=O>[Cl:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:25])=[O:5]
Reactant: O=C(O)CCC(=O)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c(NN3C(=O)CCC3=O)ccnc12)c1c(Cl)cccc1Cl
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-4-[2-(3-carboxypropanoyl)hydrazino]quinoline (138 mg) in dimethylformamide (3 ml) were added 1-hydroxybenzotriazole (45.9 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (65.1 mg) at ambient temperature, and the mixture was stirred at the same temperature overnight. To the mixture was added water, and the resulting precipitates were collected by filtration to give 8-(2,6-dichlorobenzoylamino)-4-(2,5-dioxopyrrolidin-1-ylamino)quinoline (72 mg).