Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[SH:9].[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[C:10]1([C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:9][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:3]=2[CH2:2][OH:1])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1ccncc1S
Solvent: CN(C)C=O
Product: OCc1ccncc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 24.6 %

Procedure:
4-hydroxymethyl-3-mercaptopyridine (100 mg, 0.71 mmol) was dissolved in DMF (5 mL) and diisipropylethylamine (0.12 mL, 0.71 mmol) was added followed by triphenylmethylchloride (197 mg, 0.71 mmol). After 30 min. the reaction mixture was partitioned between water and ethyl acetate, and the organic layer was thoroughly washed with water and dried with anhydrous sodium sulfate. Purification by radial chromatography on silica gel produced pure title material (67 mg, 25% yield). 1H NMR (CDCl3) δ 4.17 (s, 2H), 7.20-7.40 (m, 15H), 7.42 (d, 1H, J=6), 8.22 (s, 1H), 8.40 (d, 1H, J=6).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:45]1([C:44]([NH:8][C@@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and benzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13](=O)[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13](=[S:27])[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2ccccc2N(C(=O)CN2CCCCC2)c2ncccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: O=C(CN1CCCCC1)N1c2ccccc2NC(=S)c2cccnc21

Procedure:
In the manner given in Example 1, 6,11-dihydro-11-(piperidinoacetyl)-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 6,11-dihydro-11-(piperidinoacetyl)-5H-pyrido-[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(O)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(O)cc2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-hydroxyacetophenone (0.722 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF (116 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 204° C.; 1H NMR (250 MHz, DMSO-d6) δ 3.96 (s, 2 H), 6.55 (s, 1 H), 6.88 (d, 2 H), 7.39 (m, 5 H), 7.63 (d, 2 H), 10.28 (s, 1 H), 11.75 (bs, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=C(C)O[N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.[C:29]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30]1>>[C:23]([C:21]1[CH:20]=[CH:19][C:3]([CH2:4][NH:5][C:6](=[O:18])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=2)=[C:2]([NH:1][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:22]=1)(=[NH:27])[NH2:24]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Reactant: O=C1CCCC1
Product: COc1cc(C(=O)NCc2ccc(C(=N)N)cc2NC2CCCC2)cc(OC)c1C

Procedure:
Compound 1g (50 mg, 0.13 mmol) was reductively aminated with cyclopentanone (0.012 mL, 0.14 mmol) and subsequently hydrogenated following a procedure analogous to the preparation of compound 11a, to give example 12. ESI-MS m/e 411.4 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:32])=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: CN1CCN(C(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)CC1
Yield: 74.1 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 1-methylpiperazine (available from Aldrich Chemical Company, Inc.; 62 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(4-methyl-piperazine-1-carbonyl)-biphenyl-2-carboxylic acid (86 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (br s, 1H), 9.97 (br s, 1H), 8.47 (s, 1H), 8.39 (s, 1H), 8.34 (s, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.48-7.57 (m, 4H), 3.25-3.44 (m, 8H), 2.81 (br s, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:19]=[CH:18][C:12]2[N:13]=[C:14]([CH2:16]Cl)[NH:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:27]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][CH:37]2[C:46]3[N:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH2:40][CH2:39][CH2:38]2)=[CH:31][CH:30]=1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:47][NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][N:36]([CH2:16][C:14]2[NH:13][C:12]3[CH:18]=[CH:19][C:9]([C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[N:15]=2)[CH:37]2[C:46]3[N:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH2:40][CH2:39][CH2:38]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: O=C(c1ccccc1)c1ccc2nc(CCl)[nH]c2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)c1ccc2[nH]c(CN(Cc3ccc(CNCc4ccccn4)cc3)C3CCCc4cccnc43)nc2c1
Yield: 75.9 %

Procedure:
A solution of 5-benzoyl-2-chloromethylbenzimidazole (284 mg, 1.05 mmol), N-(tert-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (476 mg, 1.04 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.08 mmol) were stirred at 80□ C in DMF (4 mL) for 16 hours. The reaction was then cooled, concentrated under reduced pressure and diluted with CH2Cl2 (35 mL) and saturated aqueous NaHCO3 (40 mL). The phases were separated and the aqueous phase was washed with CH2Cl2 (2×25 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (1×40 mL), dried (NaSO4), filtered and concentrated under reduced pressure. Purification of the resultant oil by flash chromatography on silica gel (96:4 CH2Cl2/MeOH) provided the desired alkylated product (468 mg, 65%) as an orange oil.
Reaction SMILES: B.O1CCCC1.[C:7]([O:11][C:12]([N:14]1[CH2:22][CH2:21][CH:17]([C:18](O)=[O:19])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C([O-])([O-])=O.[K+].[K+]>O>[C:7]([O:11][C:12]([N:14]1[CH2:22][CH2:21][CH:17]([CH2:18][OH:19])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Borane-tetrahydrofuran (1 M, 25 mL, 25 mmol) was added slowly to N-tert-butoxycarbonylisonipecotic acid (5.73 g, 25 mmol), as prepared in the preceding step, in tetrahydrofyiran (50 mL) at 0° C. (ice-bath) over 30 min. The mixture was stirred at 0° C. overnight and then warmed up to room temperature for 6 h. Water (10 mL) was added slowly and then K2CO3 (5 g in 50 mL water) was added. The mixture was extracted with ethyl acetate (3×50 mL). The organic phase was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as white crystals (4.55 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 1.13 (m, 2 H), 1.42 (s, 9 H), 1.67 (m, 4 H), 2.67 (t, 2 H, J=12.5 Hz), 3.46 (d, 2 H, J=3.0 Hz), and 4.09 (d, 2 H, J=3.6 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[N:5]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][C:48]([Cl:51])=[CH:49][CH:50]=1>O1CCOCC1>[Cl:51][C:48]1[N:47]=[CH:46][C:45]([CH2:44][NH:43][C:2]2[N:3]=[C:4]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[N:5]=[C:6]([NH:8][N:9]=[CH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=3)[N:7]=2)=[CH:50][CH:49]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: Fc1ccc(Nc2nc(Cl)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Fc1ccc(Nc2nc(NCc3ccc(Cl)nc3)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
{4-Chloro-6-[N′-(4-trifluoromethoxybenzylidene)hydrazino]-1,3,5-triazin-2-yl}-(4-fluoro-3-trifluoromethylphenyl)amine (XXI) (2.54 g, 5.14 mmol) was dissolved in dioxane (25 mL). To this solution was added diisopropylethylamine (1.8 mL, 10.3 mL) followed by 3-aminomethyl-6-chloropyridine (0.52 mL, 5.17 mmol). The reaction was allowed to stir overnight at room temperature. The solvent was removed under vacuum and the residue dissolved in ethyl ether (40 mL). This solution was rinsed with brine, dried over magnesium sulfate, filtered and concentrated to give a dark yellow oil which was purified by column chromatography (silica, gel, hexane/EtOAc), to afford desired product 2 (0.93 g, 32% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[O:13][CH3:14].[CH3:15][S:16]([CH2:19][C:20]#[N:21])(=[O:18])=[O:17]>N1CCCCC1.C(O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[C:20]#[N:21])=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: COc1cc(C=O)ccc1OCCO
Reactant: CS(=O)(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=C(C#N)S(C)(=O)=O)ccc1OCCO

Procedure:
A mixture of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde (0.98 g, 0.005 mol), (see Example 1 of U.S. Pat. No. 4,707,537, supra), methylsulfonylacetonitrile (0.60 g, 0.005 m), ethanol (10 mL) and piperidine (5 drops) is heated at reflux for 1 hour, during which time the product crystallizes. The reaction mixture is allowed to cool and the very pale yellow product is collected by filtration, washed with ethanol and dried in air. The yield of product is 1.05 g (70.9%). Mass spectrometry supports the following structure: ##STR22## In methylene chloride the product has an absorption maximum at 362 nm.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([CH2:24][CH3:25])[CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:12][CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[N:3]=[CH:4]3)(=[O:22])=[O:21])=[C:16]([CH2:24][CH3:25])[CH:15]=1
Reactant: CCc1cc(Br)ccc1S(=O)(=O)Cl
Reactant: Cn1ncc2cc(CN)ccc21
Product: CCc1cc(Br)ccc1S(=O)(=O)NCc1ccc2c(cnn2C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from (1-methyl-1H-indazol-5-yl)methanamine and 4-bromo-2-ethylbenzene-1-sulfonyl chloride.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Br:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]1>>[Br:24][C:20]1[CH:19]=[C:18]([F:25])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:40][CH2:39][CH2:38][CH2:37][N:34]3[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]3)=[O:29])[S:14][N:13]=2)=[C:22]([F:23])[CH:21]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: NC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)Oc1ccccc1
Product: CN1CCN(CCCNC(=O)Nc2snc(OCc3c(F)cc(Br)cc3F)c2C(N)=O)CC1

Procedure:
The title compound was prepared from [3-(4-bromo-2,6-difluoro-benzyloxy)-4-carbamoyl-isothiazol-5-yl]-carbamic acid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 1. MS (APCl, m/z): 547 and 549 [M+H]+.
Reaction SMILES: [C:1]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].ClC(OCC)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>>[C:19]1([NH:18][C:9]([C:6]2([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][CH2:8]2)=[O:11])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)Nc2ccccc2)CC1

Procedure:
1-Carboethoxycyclopropanecarboxylic acid (3.95 grams, 0.025 mole), ethyl chloroformate (2.71 grams, 0.025 mole) and aniline (2.33 grams, 0.025 mole) were reacted sequentially in the presence of triethylamine (2.53 grams, 0.025 mole) in a manner similar to that described for ethyl 1-(4-chloro-2-ethylphenylamlnocarbonyl)cyclopropanecarboxylate in Example XXXIII to give ethyl 1-(phenylaminocarbonyl)cyclopropanecarboxylate which was then hydrolyzed in a manner similar to that described in Example VII to give 2.42 grams (0.01 mole) of 1-(phenylaminocarbonyl)cyclopropanecarboxylic acid having a melting point of 178° C.-181° C. NMR analysis of the product indicated the following:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH-:9].[O:10]=[C:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:24](O)=O)[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH3:8][C:4]1[C:3]2[N:9]=[C:24]([C:19]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:11](=[O:10])[C:23]=4[CH:22]=[CH:21][CH:20]=3)[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(N)c1[NH-]
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2[nH]c(-c3cccc4c3-c3ccccc3C4=O)nc12

Procedure:
The procedure used in Example 68 is followed. In a 250 ml round-bottomed flask under an argon atmosphere, reflux, for 6 hours, a suspension of 5 g of (2-amino-6-methylphenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid, obtained in the previous stage, in 100 ml of acetic acid. After cooling, bring to dryness under reduced pressure. Take the residue up in 25 ml of water then bring to pH=8 by addition of a saturated aqueous solution of sodium hydrogen carbonate. The precipitate that formed is filtered off, washed with water, and made into a paste with diisopropyl ether, and in this way, we obtain 4.7 g of 4-(4-methyl-1H-benzimidazol-2-yl)-9H-fluoren-9-one, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].Cl.C([O-])(O)=O.[Na+].[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: CC(C)(O)C(=O)O
Reactant: OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(O)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
2-Hydroxyisobutyric acid (15 gm) was dissolved in benzyl alcohol (80 mL) at 0° C. and the solution was saturated with HCl gas. This solution was stored at rt overnight and then was poured into sat. NaHCO3 solution. This was extracted twice with CHCl3 and the combined organic extracts were dried (Na2SO4), filtered and evaporated to dryness. The residue so obtained was fractionally distilled and the title compound was obtained as a fraction that boiled at 85°-100° C. at 0.2 mm.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][N:15]1[C:19]([CH:20]=O)=[CH:18][N:17]=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:14][N:15]1[C:19]([CH2:20][N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[CH:18][N:17]=[CH:16]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1cncc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1cncc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
N-Boc-piperazine (0.930 g, 5.0 mmol, 1.1 eq) was dissolved in 1,2-DCE (14 mL). To this solution, 1-methyl-1H-imidazole-5-carboxaldehyde (0.500 g, 4.54 mmol, 1 eq) was added followed by the portionwise addition of sodium triacetoxyborohydride (1.35 g, 6.36 mmol, 1.4 eq). The mixture was stirred at room temperature for 4 h and was then washed with a saturated aqueous solution of NaHCO3. The organic layer was dried (MgSO4), and the solvent removed in vacuo. The crude mixture was redissolved in 18 mL of DCM and gently stirred overnight in the presence of PS-isocyanate (2 g, loading: 1.58 mmol/g). The mixture was filtered off, and the resin washed with DCM (2×10 mL). The solvent was removed in vacuo and the resulting mixture was purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane to give the title compound (0.280 g, 22%); 1H-NMR (500 MHz, CDCl3): δ 1.45 (s, 9H, C(CH3)3), 2.28-2.40 (m, 4H, piperazine N(CH2)2), 3.38 (m, 4H, piperazine N(CH2)2), 3.44 (s, 2H, NCH2), 3.66 (s, 3H, imidazole Me), 6.87 (s, 1H, imidazole 4-H), 7.40 (s, 1H, imidazole 2-H); GC-MS (Cl, m/z): Rt=4.89 min—281 [(M+H)+, 100%].
Reaction SMILES: CS(I)(C)(C)=O.[CH3:7][C:8]([O-:11])([CH3:10])[CH3:9].[K+].[Br:13][C:14]1[CH:33]=[CH:32][C:17]2[O:18]CC(=O)C3[S:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:23][C:22]=3[C:16]=2[CH:15]=1>ClCCl>[Br:13][C:14]1[CH:33]=[CH:32][C:17]2[O:18][CH2:7][C:8]3([C:10]4[S:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:23][C:22]=4[C:16]=2[CH:15]=1)[CH2:9][O:11]3
Reactant: CCOC(=O)c1nc2c(s1)C(=O)COc1ccc(Br)cc1-2
Reactant: CC(C)(C)[O-]
Agent: CS(C)(C)(=O)I
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1nc2c(s1)C1(COc3ccc(Br)cc3-2)CO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of S,S-dimethylmethanesulfinyl iodide (1.15 g, 5.23 mmol, 1.60 equiv), t-BuOK (4 mL, 1.20 equiv) in dichloromethane (5 mL) at room temperature After 30 minutes a solution of ethyl 9-bromo-4-oxo-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate (1.2 g, 3.26 mmol, 1.00 equiv) in dichloromethane (10 mL) was added slowly. The resulting solution was stirred for 5 h at room temperature, quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:19) to give 600 mg (48%) of the titled compound as a off-white solid; LC-MS 382,384[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:41]1[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(CCCNc2c(F)cc(F)c3oc(-c4ccc(NC(=O)C(C)(C)C)c(F)c4)cc(=O)c23)CC1
Temperature: 50 °C
Reaction time: 6.6 h
Yield: 80.1 %

Procedure:
612 mg (1.16mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one obtained in Example 129 (2) was dissolved in 30 mL of dimethylformamide under argon atmosphere, 1.30 mL (11.6 mmol) of 1-methylpiperazine was added and the mixture was stirred at 50° C. for 6.6 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to give 493 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-[3-(4-methylpiperazin-1-yl)propylamino]-4H-1-benzopyran-4-one (yield: 80%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][C:19](=[O:23])[CH2:18]2)[CH:13]=[CH:12][C:11]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:37]([CH3:39])[CH3:38]>CN(C=O)C>[C:1]([O:5][C:6](=[O:33])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH:37]([CH3:39])[CH3:38])[C:19](=[O:23])[CH2:18]2)[CH:13]=[CH:12][C:11]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Br
Reactant: CN(Cc1cc(CN2CCNC(=O)C2)ccc1Oc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(Cc2ccc(Oc3ccc(Cl)c(Cl)c3)c(CN(C)C(=O)OC(C)(C)C)c2)CC1=O
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of [2-(3,4-dichloro-phenoxy)-5-(3-oxo-piperazin-1-ylmethyl)-benzyl]-methyl-carbamic acid tert-butyl ester 79 mg, 0.16 mmol) in DMF (3.2 mL) at 0° C. was added NaH (90%, 7.6 mg). After 30 min, 2-bromopropane (15 μL, 0.16 mmol) was added and the reaction was allowed to come to rt and stir overnight. The mixture was quenched with satd. aq. NaHCO3 and extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by FCC to provide the title compound (35 mg, 41%). MS (ESI): mass calcd. for C27H35Cl2N3O4, 535.20; m/z found, 536.2 [M+H].