Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([C:32](=[O:38])[C:33](OCC)=[O:34])[CH:31]=1.Cl>ClCCl.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:33](=[O:34])[C:32](=[O:38])[C:30]3[CH:31]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=3[OH:39])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C(=O)c1cc(Cl)ccc1O
Reactant: COc1ccc(CCc2ccc(N)cc2)cc1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CCc2ccc(NC(=O)C(=O)c3cc(Cl)ccc3O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
Under an argon atmosphere, a tetrahydrofuran (20 ml) solution of 4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine (2.50 g, 9.72 mmol) is cooled to 0° C. n-Butyllithium (2.3M, 4.2 ml, 9.72 mmol) is added, and the resulting solution is stirred for 15 minutes. A tetrahydrofuran (10 ml) solution of ethyl 5-chloro-2-hydroxy-α-oxobenzenacetate (0.74 g, 3.24 mmol) is then added, after which the solution is allowed to warm to ambient temperature over a 30 minute period. The contents are then poured into 5% hydrochloric acid (100 ml) and extracted into ethyl acetate. The organics are washed with 10% sodium bicarbonate and brine, then dried (sodium sulfate), and concentrated to give 1.51 g of a crude solid. Chromatography (Kieselgel 60, dichloromethane) affords N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-2-hydroxy-5-chloro-α-oxobenzeneacetamide (0.86 g, 61%), mp 128°-130° C.
Reaction SMILES: [Br:1][C:2]1[C:13]([F:14])=[CH:12][C:5]2[S:6][C:7](C(O)=O)=[CH:8][C:4]=2[CH:3]=1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[Br:1][C:2]1[C:13]([F:14])=[CH:12][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cc2cc(Br)c(F)cc2s1
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: Fc1cc2sccc2cc1Br
Yield: 54.4 %

Procedure:
Using analogous reaction condition and reagents as described in Example 25 for the preparation of I-25c above, 5-bromo-6-fluorobenzo[b]thiophene-2-carboxylic acid (I-28c: 240 mg 0.875 mmol) in DMA (4 mL) and DBU (0.523 mL, 3.503 mmol) were heated in microwave to afford the crude product. Purification by column chromatography on silica gel (100% hexane) afforded 110 mg of the product (55% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O.Br[CH2:46][C:47]1[CH:48]=[N:49][O:50][C:51]=1[CH3:52].BrCC1OC(C(F)(F)F)=CC=1>>[CH3:52][C:51]1[O:50][N:49]=[CH:48][C:47]=1[CH2:46][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Cc1oncc1CBr
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1oncc1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 4-(bromomethyl)-5-methylisoxazole to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (25%) as a white solid: mp 159-161° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.39-6.91 (m, 4H), 6.50 (s, 1H), 6.11 (s, 1H), 5.94 (d, 1H), 5.85 (ABq, 2H), 4.95 (ABq, 2H), 4.78 (ABq, 2H), 2.37 (s, 3H); MS (ES+) m/z 377.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:11]([C:4]2[C:5]([C:8]([N:32]3[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:29][CH2:30][CH2:31]3)=[O:10])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][O:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=1[C:25]([F:26])([F:27])[F:28]
Reactant: c1ccc2c(c1)NCCO2
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCN(c1cc(Cl)cnc1C(=O)N1CCOc2ccccc21)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 56.2 %

Procedure:
To a mixture of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (112 mg, 0.244 mmol), 100 mg (0.70 mmol) of 3,4-dihydro-2H-benzo[1,4]oxazine, and 0.174 mL (1.0 mmol) of DIEA in CH2Cl2 (2.5 mL) was added 0.19 mL 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate). After 3 h the reaction mixture was directly purified via flash column (50% EtOAc in hexane) to afford 79 mg of 4-chloro-N-[5-chloro-2-(2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide as a white powder. MS m/z: 576.38 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:10]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[CH:9]=[C:8]([I:16])[C:4]=2[CH:5]=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.[CH3:25][C:26]([Si:29](OS(C(F)(F)F)(=O)=O)([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([Si:29]([CH3:31])([CH3:30])[O:13][CH2:12][C:11]([N:10]1[C:3]2[C:2]([F:1])=[CH:7][N:6]=[CH:5][C:4]=2[C:8]([I:16])=[CH:9]1)([CH3:14])[CH3:15])([CH3:28])([CH3:27])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(CO)n1cc(I)c2cncc(F)c21
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-1-yl)-2-methyl-propan-1-ol (Preparation 72, 4.5 gm, 13.47 mmol) in DCM (90 mL) were added 2,6-lutidine (3.91 mL, 33.65 mmol) and tert-butyl dimethylsilyl trifluoromethanesulfonate (4.62 gm, 17.51 mmol) at 0° C. The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with DCM. The organic layer was washed with water, brine, dried over sodium sulphate, and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with 10-12% EtOAc in Hexane to afford the title compound as off white solid (45%, 2.7 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH2:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].O=[CH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:4]([C@H:3]1[C:8](=[O:9])[NH:10][CH:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[NH:2]1)[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)COC(=O)CCC=O
Reactant: CC(C)C[C@H](N)C(N)=O
Agent: Cl
Product: CC(C)COC(=O)CCC1NC(=O)[C@H](CC(C)C)N1

Procedure:
L-Leucinamide hydrochloride (3.2 g, 19.2 mmol) and isobutyl 4-oxobutanoate (3 g, 18.96 mmol) were reacted together according to the procedure of example 5A to give the title compound, 1.7 g (33%).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:16][C:3]1=2.[SH:29][CH:30]([CH3:34])[C:31]([OH:33])=[O:32]>>[C:31]([CH:30]([S:29][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:16][C:3]1=2)[CH3:34])([OH:33])=[O:32]
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Reactant: CC(S)C(=O)O
Product: CC(SC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21)C(=O)O

Procedure:
11-Hydroxy-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and 2-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][N:16]([CH3:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][N:25]=3)=[C:19]([CH3:33])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:43][C:44]([F:55])([F:54])[C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Pt].[C]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][N:16]([CH3:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[N:25]=[CH:26][C:27]([NH:30][C:49](=[O:50])[C:48]4[CH:52]=[CH:53][C:45]([C:44]([F:43])([F:54])[F:55])=[CH:46][CH:47]=4)=[CH:28][CH:29]=3)=[C:19]([CH3:33])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N(C)CC(=O)N2CCN(Cc3ccccc3)CC2)ccc1Oc1ccc([N+](=O)[O-])cn1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: [Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(N(C)CC(=O)N2CCN(Cc3ccccc3)CC2)ccc1Oc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cn1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a suspension of 1-(4-benzylpiperazin-1-yl)-2-{methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}ethanone (2.85 g, 6.0 mmol) in ethyl acetate (30 mL) was added 5% platinum-carbon (0.30 g) under a nitrogen atmosphere, and the resulting solution was stirred for 3 hours at 40° C. under a hydrogen atmosphere. The platinum-carbon was separated off with Celite, and the filtrate was concentrated. The residue was dissolved in THF (30 mL), and to this solution was added triethylamine (1.26 mL, 9.1 mmol) under ice cooling. To the resulting solution was then added dropwise 4-(trifluoromethyl)benzoyl chloride (1.16 mL, 7.8 mmol). This reaction solution was stirred overnight, then a saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The resulting product was then recrystallized from a mixed solvent consisting of diisopropyl ether-acetone, to thereby yield 1.37 g of the title compound.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[S:15]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][C:28]([CH3:32])([CH3:31])[C:29]#[N:30])[C:22](=O)[C:21]12OCCC[O:34]1)(=[O:17])=[O:16])C1C=CC=CC=1.N.C1COCC1>[Ni].CCO>[OH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[S:15]([C:18]1[CH:26]=[CH:25][C:24]2[N:23]3[CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][N:30]=[C:22]3[C:21](=[O:34])[C:20]=2[CH:19]=1)(=[O:17])=[O:16]
Reactant: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCC[C@H]3COCc3ccccc3)ccc21
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CN=C2C(=O)c3cc(S(=O)(=O)N4CCC[C@H]4CO)ccc3N2C1
Temperature: 132 °C
Yield: 84.3 %

Procedure:
A mixture of 3-[5′-({(2S)-2-[(benzyloxy)methyl]pyrrolidin-1-yl}sulfonyl)-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′(2′H)-yl]-2,2-dimethylpropanenitrile (3.00 g, 5.56 mmol), wet Raney Nickel (3.18 g) in 2M EtOH.NH3 (180 mL) and THF (30 mL) was hydrogenated at 54 lb/in2 H2 for 22 hr. The reaction was filtered through Sulka Floc and the filtrate was poured into a steel pressure vessel and heated to 132° C. for 18 hr. After cooling to room temperature the reaction was concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (98.5/1/0.5) to give the title compound as a white solid (1.77 g, 60% ). NMR (400 MHz, DMSO-d6): consistent.
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.[CH3:70][CH:71]([CH3:75])[C@@H:72]([NH2:74])[CH3:73]>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:74][C@@H:72]([CH3:73])[CH:71]([CH3:75])[CH3:70])=[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: CC(C)[C@H](C)N
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N[C@@H](C)C(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

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 (31 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and (2S)-3-methyl-2-butanamine (10.5 uL, 0.09 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, 40%). LC-MS m/z 591 (M+H)+.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][C@H:24]([C:34]([O:36][CH3:37])=[O:35])[CH2:25][CH2:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].Cl.ClC(OCC(C)C)=O>>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@H:24]([C:34]([O:36][CH3:37])=[O:35])[CH2:25][CH2:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 88 %

Procedure:
Condensation of ZPheOH (3.00 g.) and HGlu(tBu)OMe hydrochloride salt (2.54 g.) by the mixed anhydride method using isobutyl chloroformate gave ZPhe-Glu(tBu)OMe in 88% yield. Debenzyloxycarbonylation of ZPhe-Glu(tBu)OMe (4.30 g.) by hydrogenation with palladium catalyst gave HPhe-Glu(tBu)OMe, which was not isolated but immediately condensed with BocPro-PheOH (3.12 g.) using dicyclohexylcarbodiimide and hydroxysuccinimide, affording BocPro-Phe-Phe-Glu(tBu)OMe in 22% yield. Hydrazinolysis of BocPro-Phe-Phe-Glu(tBu)OMe (1.09 g.) gave BocPro-Phe-Phe-Glu(tBu)NHNH2 in 58% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.1 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (40 mg, 0.1020 mmol), 4-dimethylaminopyridine (6.2 mg, 0.0508 mmol) and piperidine (17 mg, 0.2000 mmol) were dissolved in methylene chloride (5 ml), then WSC-HCl (59 mg, 0.3077 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=2:1) to give the title compound (16 mg, 0.0348 mmol, 34%).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].C(O)(=[O:17])C>C1COCC1.O>[CH2:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH:9]=[O:17])[NH:5][C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1CC
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1[nH]c(C=O)c(C)c1CC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 3-ethyl-4,5-dimethyl-1H-pyrrole-2-carboxylate (Salor-Aldrich) (0.0147 g, 0.077 mmol) in acetic acid (5 mL), THF (4 mL) and water (4 mL) was added ceric ammonium nitrate (0.169 g, 0.31 mmol) and the reaction was stirred at ambient temperature. After 1.5 h, the reaction was poured into water (10 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic layers were washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated. The resultant residue was purified by normal phase chromatography. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 9.78 (s, 1H); 4.36 (q, J=7.1 Hz, 2H); 2.76 (q, J=7.6 Hz, 2H); 1.62 (s, 3H); 1.38 (t, J=7.1 Hz, 3H); 1.13 (t, J=7.6 Hz, 3H). HRMS (ES) exact mass calculated for C11H16NO3 (M+H+): 209.1052. Found 209.1050.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[CH2:15][CH:16]([OH:37])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>>[C:31]1([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH:16]([OH:37])[CH2:15][NH:1][C:2]3[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[N:7]4)[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc(N)c2cccnc12
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: COc1ccc(NCC(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2cccnc12
Yield: 11.6 %

Procedure:
Following the same procedure as in Example 27, reaction and treatment were carried out using 1.81 g of 5-amino-8 methoxyquinoline and 1.23 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine to obtain 200 mg of 5-[3-(4-diphenylmethylpiperazine- 1-yl)-2-hydroxy-propylamino]-8 methoxyquinoline.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:3]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:24][S:25]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:3]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(-c2ccc3nc(N4CC[C@H](O)C4)sc3c2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Reaction time: 8 h

Procedure:
A stirred, 0° C. solution of (S)-4-(2-(3-hydroxypyrrolidin-1-yl)benzo[d]thiazol-6-yl)benzonitrile (Reference Example 13b, 75 mg, 0.23 mmol) in pyridine (2.5 mL) was treated with methanesulfonyl chloride (0.022 mL, 0.280 mmol). The ice bath was removed and stirring was continued at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give (S)-1-(6-(4-cyanophenyl)benzo[d]thiazol-2-yl)pyrrolidin-3-yl methanesulfonate that was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 2.36-2.50 (m, 1H), 2.53-2.63 (m, 1H), 3.10 (s, 3H), 3.84-4.15 (m, 4H), 5.47-5.52 (m, 1H), 7.60 (dd, J=2, 8 Hz, 1H), 7.67-7.75 (m, 4H), 7.79 (d, J=8 Hz, 1H), 7.85 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 400 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:39])[C:32]3[N:36]=[C:35]([CH3:37])[NH:34][C:33]=3[CH:38]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][C:35]1[NH:34][C:33]2[CH:38]=[C:29]([O:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)[CH:30]=[C:31]([CH3:39])[C:32]=2[N:36]=1
Reactant: Cc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(C)[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.16 g (0.59 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.15 g (0.55 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2,4-dimethyl-1H-benzimidazole and 0.21 mL (1.2 mmol) DIPEA were combined in 2.0 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].OO.C(=O)([O-])[O-:34].[K+].[K+]>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:16](=[O:27])[C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])(=[O:34])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C(N)=O)c2)cc1
Reaction time: 24 h
Yield: 166.6 %

Procedure:
To a solution of N1-(3-cyanobenzoyl)-N2-(4-tert-butylbenzoyl)-1,2-benzenediamine (200 mg, 0.5 mmol) in methyl sulfoxide (10 mL) was added 30% hydrogen peroxide solution (0.5 mL, 5.8 mmol) and potassium carbonate (17 mg, 0.13 mmol). After stirring for 24 h, the reaction mixture was diluted with water (20 mL), filtered, washed with water, and dried to give 90 mg (43%) of the title compound as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:12]N)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].O.Cl.C(O[CH:19](OCC)[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29])C>C(O)C>[CH3:11][O:10][C:9]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[O:3][CH3:2])[NH:12][CH:19]=[C:20]2[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29]
Reactant: COc1ccc(NN)cc1OC
Reactant: CCOC(CCCN1CCCCC1=O)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc2[nH]cc(CCN3CCCCC3=O)c2cc1OC
Yield: 21.7 %

Procedure:
One dissolves 54 g of 3,4-dimethoxy phenylhydrazine hydrochloride in a mixture of 750 mls of ethanol, 750 mls of water and 350 mls of 5% hydrochloric acid. It is heated under a reflux, and then one adds over a period of 5 minutes a solution of 63 g of 1-(4,4-diethoxybutyl)-2-piperidone in 250 mls of ethanol. After heating under a reflux for 2 hours and then cooling, one eliminates the ethanol by distillation under reduced pressure (20 mm of mercury) and then extracts successively with 500 mls, 300 mls and 200 mls of methylene chloride. The combined organic phases are washed with 500 mls of water and then 500 mls of a saturated solution of sodium bicarbonate, dried over magnesium sulphate and evaporated to dryness under reduced pressure (20 mm of mercury). The residue (58 g) is chromatographed over 1 kg of silica gel contained in a column with a diameter of 6 cm, collecting fractions of 500 mls and eluting with ethyl acetate containing 1.5% of methanol. Fractions 31 to 43 are combined and evaporated to dryness. In this way one obtains 17 g of 1-[2(5,6-dimethoxy-3-indolyl) ethyl]-2-piperidone in the form of a thick yellow oil which slowly crystallises.