Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH2:3]1.[CH2:16]=[CH:17][CH:18]=[CH2:19]>>[CH3:1][C:2]1([CH3:15])[CH2:3][CH:4]2[C:5]([C:12]([OH:14])=[O:13])([CH2:16][CH:17]=[CH:18][CH2:19]2)[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: C=CC=C
Reactant: CC1(C)CC=C(C(=O)O)c2ccccc21
Product: CC1(C)CC2CC=CCC2(C(=O)O)c2ccccc21
Yield: 32 %

Procedure:
The compound from Example 42 (8.5 g, 36.7 mmol) and butadiene were reacted in a Diels-Alder condensation as previously described to give after silica gel chromatography the title compound (3 g, 32% yield).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=1/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31](=[O:32])/[CH:30]=[CH:29]/[C:21]3[CH:22]=[C:23]([F:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=3[F:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: COc1cc(F)c(/C=C/C(=O)O)cc1F
Product: COc1cc(F)c(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)cc1F

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,5-difluoro-4-methoxy-phenyl)-acrylic acid. LC-MS-conditions 01b: tR=0.86 min; [M+H]+=402.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:10]([C:13]1[C:14](=[O:24])[O:15][C:16]([OH:23])=[C:17]([C:20](=O)[CH3:21])[C:18]=1[OH:19])(=[O:12])[CH3:11]>CO>[C:10]([C:13]1[C:14](=[O:24])[O:15][C:16](=[O:23])[C:17](=[C:20]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:21])[C:18]=1[OH:19])(=[O:12])[CH3:11]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: COc1ccc(N)cc1
Solvent: CO
Product: COc1ccc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)cc1

Procedure:
Similarly, equimolar amounts of p-methoxyaniline and 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one are refluxed in methanol to give, upon workup, 5-acetyl-4-hydroxy-3-[1-(p-methoxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 212°-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:31])[N:10]1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[OH:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:59]([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61].N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:59]([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:31])[N:10]1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[OH:38]
Reactant: O=C(NCCc1cccc(O)c1)C1c2ccccc2C(=O)N(C2CCCCC2O)C1c1ccc(Cl)cc1Cl
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](Oc1cccc(CCNC(=O)C2c3ccccc3C(=O)N(C3CCCCC3O)C2c2ccc(Cl)cc2Cl)c1)C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 121 %

Procedure:
To a mixture of 980 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(3-hydroxyphenyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 1160 mg of triphenylphosphine, 1080 mg of tert-butyl (2R)-2-hydroxypropanate, and 30 mL of THF was added 770 mg of diethyl azodicarboxylate at room temperature, followed by stifling for 12 hours. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 1460 mg of tert-butyl (2S)-2-(3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenoxy)propanate as a yellow solid.
Reaction SMILES: CS(O[C@H:6]1[CH2:9][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.O>[C:14]([O:13][C:11](=[O:12])[NH:10][C@H:8]1[CH2:9][C@@H:6]([N:18]=[N+:19]=[N-:20])[CH2:7]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N=[N+]=[N-])C1
Temperature: 85 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a solution of cis-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (29 g, 109 mmol) in DMF (100 mL) was added sodium azide (5.68 mL, 162 mmol) portionwise and the mixture stirred at 85° C. for 18 h. After cooling, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic was washed with water (2×100 mL) and brine, dried over Na2SO4 and evaporated in vacuo to give the desired product tert-butyl(cis-3-azidocyclobutyl)carbamate (22 g, 104 mmol, 95% yield) that was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.68 (br. s., 1 H), 3.87 (br. s., 1 H), 3.44-3.68 (m, 1 H), 2.75 (d, J=6.85 Hz, 2 H), 1.90 (q, J=9.19 Hz, 2 H), 1.44 (s, 10 H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:6]1[C:5]2[CH:12]=[CH:13][C:2]([F:1])=[CH:3][C:4]=2[C:9](=[O:10])[O:8][C:7]1=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccccc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
A solution of Compound 35 (3 g, 16.57 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 729 mg, 18.23 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat benzyl bromide (2.17 mL, 18.23 mmol) was added and the solution was further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 1.88 g (42%) of white solids. M.P. 95° C. 1H NMR (DMSO-d6): δ 5.29 (s, 2H), 7.26 (m, 2H), 7.35 (m, 5H), 7.40 (m, 2H), 7.64 (dt, J=2.9, 8.4 Hz, 1H), 7.82 (dd, J=3.2, 8.0 Hz, 1H). Anal. (C16H13NO3) C, H, N.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[C:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[C:10]2[Cl:27].[CH3:28][C:29]1[N:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:30]=1[CH:31]=[O:32]>C1COCC1>[Cl:27][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:31]([C:30]3[C:29]([CH3:28])=[N:36][C:35]([CH3:37])=[CH:34][CH:33]=3)[OH:32])[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C=O)c(C)n1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.84 mL, 2.1 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-3-(4-fluorobenzyl)-2-methoxyquinoline (0.826 g, 2.17 mmol, Intermediate 7: step d) in dry THF (11 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 2,6-dimethylnicotinaldehyde (0.23 mL, 1.8 mmol) in dry THF (3 mL) was added dropwise. The reaction was stirred for 5 minutes, then was removed from the cold bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The combined organic phases were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-3% MeOH-DCM) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.06 (d, J=1.9 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.45 (dd, J=8.6, 2.0 Hz, 1H), 7.26-7.21 (m, 2H), 6.97 (d, J=7.9 Hz, 1H), 6.94-6.89 (m, 2H), 6.07 (s, 1H), 4.22 (s, 2H), 4.05 (s, 3H), 3.77 (s, 1H), 2.46 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: CCCCCC.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[CH2:21]([O:28][C@@H:29]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[S:32][C:30]1([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH:67]=[O:68])[CH:62]=1)[OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C@@H:29]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[S:32][C:30]1([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH:67]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[OH:68])[CH:62]=1)[OH:31])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Brc1ccc(OC2CCOCC2)cc1
Reactant: O=Cc1cccc(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(OC2CCOCC2)cc1)c1cccc(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
2.6 M n-butylithium hexane solution (0.8 mL) was added to a mixture of 1-bromo-4-(4-tetrahydropyranyloxy)benzene (0.545 g, 2.12 mmol) and tetrahydrofuran (6 mL) at −78° C. After stirred for 1.5 hours, a tetrahydrofuran (8 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-(3-formylphenyl)-5-thio-D-glucopyranose (0.70 g, 1.06 mmol) was added and further stirred for three hours, and the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 2,3,4,6-tetra-O-benzyl-1-C-[3-[(4-(4-tetrahydropyranyloxy)phenyl)(hydroxy)methyl]phenyl]-5-thio-D-glucopyranose (0.67 g, 76%).
Reaction SMILES: Br[CH:2]1[CH2:6][O:5][N:4]([CH3:7])[C:3]1=[O:8].[C:9]([C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[CH:16]=[O:17])([CH3:12])([CH3:11])[CH3:10].C(Cl)Cl.Cl>C1C=CC=CC=1.[Zn]>[C:22]([C:19]1[CH:18]=[C:15]([CH:16]([OH:17])[CH:2]2[CH2:6][O:5][N:4]([CH3:7])[C:3]2=[O:8])[CH:14]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:20]=1[OH:21])([CH3:25])([CH3:23])[CH3:24]
Reactant: CN1OCC(Br)C1=O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: c1ccccc1
Product: CN1OCC(C(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 57 %

Procedure:
A mixture of 6 g (33.3 mmol) of 4-bromo-2-methyl-3-isoxazolidinone, 7 g (30 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 3.25 g (50 mmol) of zinc dust in 125 ml of benzene was refluxed with stirring. One hour later another 3 g of zinc dust was added and, after refluxing for an additional 17 hours, the reaction mixture was stirred for five minutes with 200 ml of methylene chloride and 150 ml of 0.5N hydrochloric acid. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to yield 10 g of crude material. This material was chromatographed on silica gel with 80% ethyl acetatehexane and recrystallized from ether-hexane to afford 5.7 g (17.1 mmol, 57%) of 4-[(3,5-di-tert-butyl-4-hydroxyphenyl)hydroxymethyl]-2-methyl-3-isoxazolidinone, mp 137°-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:24][CH:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:1][S:27]([CH:25]([CH3:26])[CH3:24])(=[O:29])=[O:28])=[CH:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Nc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)Nc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
151 mg of 4-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 105 μL of propane-2-sulfonyl chloride and 205 μL DIPEA in 500 μL DCM. The reaction mixture was evaporated, subjected to basic workup conditions and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1-methylethylsulfonamido)benzamide. MS (Q1) 430 (M)+.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH3:34][C:32]1[CH:33]=[C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][N:12]3[C:13]4[C:9](=[CH:8][C:7]([CH2:6][CH:5]([O:16][CH2:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:15][CH:14]=4)[CH:10]=[CH:11]3)[N:23]=2)[CH:29]=[C:30]([CH3:35])[CH:31]=1
Reactant: Cc1cc(C)cc(-c2nc(CCl)c(C)o2)c1
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cc(C)cc(C)c3)oc2C)c1)C(=O)O
Yield: 45 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(3,5-dimethyl-phenyl)-5-methyl-oxazole, the title compound was obtained in 45% yield as a pale yellow solid. MS: (M+H)+ 433.4.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][N:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[N:38]1[CH:37]=[CH:36][N:28]2[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:40][CH:39]=3)=[O:24])[CH2:26][C:27]=12
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 1.5 mmol of triethylamine. After stirring for 15 minutes, 1 mmol of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine is added and the mixture stirred for 5 hours. The reaction mixture is washed with water, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].[NH2:15][C:16]1[N:21]([CH3:22])[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[CH:17]=1>C(O)CC>[NH2:9][C:8]1[C:5]([C:6]#[N:7])=[C:4]([C:3]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:2]=2[Cl:1])[C:17]2[C:18](=[O:25])[N:19]([CH3:24])[C:20](=[O:23])[N:21]([CH3:22])[C:16]=2[N:15]=1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Solvent: CCCO
Product: Cn1c(=O)c2c(-c3ccc(Cl)cc3Cl)c(C#N)c(N)nc2n(C)c1=O

Procedure:
A mixture of 1a (150 mg, 0.6 mmol) and 6-amino-1,3-dimethyl uracil (200 mg, 1.2 mmol) in propanol (5 ml) was refluxed overnight, concentrated, redissolved in DCM, washed with 5% aqueous HCl, water, dried over Na2SO4, and concentrated to give the crude product 7-amino-5-(2,4-dichlorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (1b).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:23].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:23][C:3]1[CH:2]=[CH:11][C:10]([N:9]2[C:12]3[C:13](=[CH:14][C:15]([F:18])=[C:16]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:17]=3)[C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8]2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(Cl)c(F)cc2c1=O
Reactant: C1CNCCN1
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(N3CCNCC3)c(F)cc2c1=O

Procedure:
In the described fashion as Example 1(e), the above acid (7) R6 =H, R=p-fluorophenyl), after reacting with the piperazine, can give the desired 1-p-fluoro-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid (9) ##STR17## R=p-fluorophenyl) and its hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1Cl.[O:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[CH2:19][CH2:20]1)[NH2:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: C1CC(N2CCOCC2)CCN1
Product: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(Cl)c1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 3,4-dichloronitrobenzene and 4-morpholinopiperidine, the title compound was obtained, melting point: 220–223° C.
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH3:15].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].C(N(CC)CC)C>C(Cl)Cl>[C:17]([O:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH3:15])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)Cl
Reactant: CCC=CCCCCCCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCCCCCCC=CCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pentadeca-12-ene-1-ol (22.6 grams) is placed in a three-neck flask under a blanket of nitrogen. The entire reaction contents are cooled in an ice bath. Methacryloyl chloride (10.5 grams) dissolved in about 50 mL of methylene chloride is added slowly to the cooled pentadeca-12-ene-1-ol with vigorous stirring in about 2 hours. Triethylamine (11.5 g) dissolved in 25 mL of methylene chloride is subsequently added in about an hour. After addition of triethylamine, the solution is allowed to warm to ambient temperature and is stirred for another 4 hours in order to complete the reaction. The precipitated triethylammonium chloride is removed by filtration, and the filtrate is washed with brine solution (saturated NaCI) followed by washings with dil. NaOH and dil. HCl. The organic layer is dried with anhydrous magnesium sulfate and the solvent is removed in vacuo to yield pentadeca-12-ene-1-yl methacrylate in good yields. Pentadeca-12-ene-1-yl methacrylate is stabilized from polymerization by addition of approximately 10 ppm hydroquinone. The structure of the product is verified by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([OH:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([O:30][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Solvent: O
Product: CCCCCCCN(CCc1ccc(CC(OCc2ccccc2)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a solution of 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester (0.59 mmol, 250 mg) was added anhydrous CsOH (0.885 mmol, 148.6 mg) and freshly dried powdered 4 Angstrom molecular sieves (300 mg) followed by benzyl bromide (4.72 mmol, 0.56 mL). The mixture was allowed to stir for 16 hours. The mixture was poured into water and extracted with diethyl ether (3×). The organic layers were combined, washed with water (2×), brine (2×), dried over Na2SO4, and concentrated to a crude oil. The oil was purified by chromatography on silica gel (Merck silica gel 60, art#9385-3) eluting with 20% ethyl acetate in hexanes to give 2-benzyloxy-3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-propionic acid ethyl ester as a clear oil (180 mg, 58%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:11][S@@](C(C)(C)C)=O)[CH3:10].Cl>O1CCOCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([NH2:11])[CH3:10]
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1cccc(F)c1F
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
To a round bottom flask containing (R)—N—((S)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (786.8 mg, 3.01 mmol) was added Dioxane (10.000 mL). To this solution was added HCl in dioxane 4.0M (1.505 mL, 6.02 mmol) and the solution was allowed to stir 15 min at room temperature. The reaction mixture was concentrated, dissolved in Et2O 10 ml, and concentrated again. Et2O was again added and resulting mixture sonnicated and a solid material was filtered and dried to afford (S)-1-(2,3-difluorophenyl)ethanamine (0.4213 g, 2.176 mmol, 72.3% yield) as a white crystalline HCl salt. 1H NMR (400 MHz, D20) d ppm 1.55 (d, J=6.99 Hz, 3H) 4.71 (q, J=6.96 Hz, 1H) 7.10-7.26 (m, 3H); LCMS m/z 158.0 (M+H)+, Rt 0.37 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.O.O.[SH2:13].[Na].Cl>CCO.O>[S:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[SH:13])[CH:8]=[CH:9]1
Reactant: Clc1ccnc2ccsc12
Reactant: S
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Sc1ccnc2ccsc12
Temperature: 90 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
7-chlorothieno[3,2-b]pyridine (1.0 g, 5.9 mmol) in EtOH (15 mL) was treated with sodium hydrogen sulfide dihydrate (3.26 g, 35.4 mmol). The solution was heated at 90° C. overnight. An additional amount of sodium hydrogen sulfide dihydrate (3.26 g, 35.4 mmol) was added and the reaction stirred an additional 20 hours at reflux. The solution was cooled to ambient temperature and diluted with water (100 mL) to dissolve the solids. The solution was cooled to 0° C. and concentrated hydrochloric acid solution was added slowly to adjust the pH to 1. The solution was then filtered and the solid was dried under high vacuum to provide thieno[3,2-b]pyridine-7-thiol (0.73 g, 74% yield) as a yellow solid.