Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][CH:21]([C:23](O)=[O:24])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl.CN(C)CCCN=C=NCC.CN(C=O)C>O>[Cl:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][CH:21]([C:23]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:24])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15]
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCC(C(=O)O)C4)cc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCC(C(=O)N2CCOCC2)C4)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 455.1 %

Procedure:
A mixture of the compound obtained in Example 37 (500 mg), morpholine (99 mg), N,N-dimethylaminopyridine (13 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (197 mg), and DMF (10 ml) was stirred at room temperature for 10 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel to obtain 1-{[3-chloro-4-(4-methoxyphenyl)-7-[(4-morpholinyl)carbonyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione (2.6 g, 92%) from the eluates with ethyl acetate. It was recrystallized from chloroform-hexane. Colorless prisms. Melting point 170-171° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([N:6]1[CH:10]=[C:9]([C:11](=[O:21])[C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:8]=[CH:7]1)(=[O:5])=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]([CH3:22])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([OH:21])[C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:8]=[CH:7]1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1cnc(C(=O)c2c(Cl)cc(Cl)cc2Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)n1cnc(C(O)c2c(Cl)cc(Cl)cc2Cl)c1
Reaction time: 0.5 h

Procedure:
1-(Dimethylsulphamoyl)-4-(2,4,6-trichlorobenzoyl)imidazole (2.6 g) in dry tetrahydrofuran (15 ml) was added over 30 seconds to lithium aluminium hydride (110 mg) in dry tetrahydrofuran (15 ml) with cooling. The mixture was stirred at 5° for 30 minutes. Water (0.110 ml ), aqueous sodium hydroxide (15%: 0.110 ml) and water (0.330 ml) were added and the mixture stirred for 15 minutes at room temperature. The mixture was filtered and the precipitate washed with tetrahydrofuran. The filtrate and washings were evaporated under reduced pressure and the residue washed with diisopropyl ether and dried under reduced pressure to give 1-(dimethylsulphamoyl)-4-(2,4,6-trichloro-α-hydroxybenzyl)imidazole, as an off white solid. To this product (1.92 g) in dry tetrahydrofuran (40 ml) was added sodium hydride (170 mg; 80g in oil), with stirring, under nitrogen. Trimethylsilyl chloride (0.7 ml) was added to this mixture at 30° to give the trimethyl silyl ether. The mixture was then cooled to - 70° and butyllithium (2.2 ml; 2 5M in hexane) added. The mixture was stirred at -78° for 30 minutes, dimethylformamide (0.5 ml) added and the mixture allowed to warm to room temperature. The mixture was poured into ice/water, stirred for 30 minutes and the solid collected and dried to give crude 1-(dimethylsulphamoyl)-2-formyl-4-[(2,4,6-trichloro-α-(trimethylsilyloxy)benzyl]imidazole. This was then then treated with hydroxylamine hydrochloride in a similar manner to step (b) in Example 1, to give crude 1-(dimethylsulphamoyl)-2-(hydroxyiminomethyl)-4-(2,4,6-trichloro-α-hydroxybenzyl)imidazole. This was then treated with trifluoroacetic anhydride in a similar manner to step (c) in Example 1, to give crude 2-cyano-1-(dimethylsulphamoyl)-4-(2,4,6-trichloro-α-hydroxybenzyl)imidazole, as an off white solid.
Reaction SMILES: [CH:1]1([CH:4]([O:7][C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=2[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12])[C:5]#[CH:6])[CH2:3][CH2:2]1>C(N(CC)C1C=CC=CC=1)C>[CH:1]1([CH:4]2[CH:5]=[CH:6][C:9]3=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:8]3[O:7]2)[CH2:3][CH2:2]1
Reactant: C#CC(Oc1cc(C(=O)OC)cc(OC)c1OC)C1CC1
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)c1cc(OC)c(OC)c2c1C=CC(C1CC1)O2
Temperature: 200 °C
Reaction time: 5 h

Procedure:
33.5 g of methyl (RS)-3-(1-cyclopropyl-prop-2-ynyloxy)-4,5-dimethoxy-benzoate were dissolved in 330 ml of N,N-diethylaniline, heated to 200° C. under argon and stirred at 200° C. for a further 5 hrs. The solvent was distilled off at 90° C./1 mbar and the residue was extracted: 2×1.5 l of diethyl ether, 2×1.5 l of 1N HCl, 2×1.5 l of saturated NaCl. The oil obtained was purified by silica gel chromatography with toluene, then toluene/ethyl acetate 9:1. Crystallization was effected from diethyl ether and hexane. Methyl (RS)-2-cyclopropyl-7,8-dimethoxy-2H-1 -benzopyran-5-carboxylate was obtained as white crystals.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH2:11])[CH2:4]2.C[O-].[Na+].C(O)(=O)C.C([BH3-])#N.[Na+].[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:32]=1)[N:29]([CH2:37][CH:38]=O)[N:28]=[CH:27]2>CO>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:32]=1)[N:29]([CH2:37][CH2:38][NH:11][C@H:5]1[CH:6]3[CH2:9][CH2:10][N:3]([CH2:8][CH2:7]3)[CH2:4]1)[N:28]=[CH:27]2
Reactant: COC(=O)c1cc(Cl)cc2cnn(CC=O)c12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: C[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc2cnn(CCN[C@@H]3CN4CCC3CC4)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
(S)-Quinuclidin-3-amine dihydrochloride (355 mg, 1.8 mmol) was stirred in MeOH (5 mL) at room temperature while sodium methoxide (25 wt % in MeOH, 0.8 mL, 3.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. Glacial acetic acid (0.2 mL, 4.1 mmol) was added to neutralize the basicity of the mixture. Sodium cyanoborohydride (224 mg, 3.6 mmol) was added, followed by methyl 5-chloro-1-(2-oxoethyl)-1H-indazole-7-carboxylate (472 mg, 1.9 mmol) from Step C above in MeOH (8 mL). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h). The reaction mixture was concentrated and absorbed onto silica gel and purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-methyl 5-chloro-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate as a light yellow solid (525 mg, 77%): 1H NMR (500 MHz, CD3OD) δ 8.17 (s, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 4.80 (t, J=6.5 Hz, 2H), 4.02 (s, 3H), 3.50-3.38 (m, 1H), 3.25-3.05 (m, 4H), 3.05-2.90 (m, 3H), 2.65-2.55 (m, 1H), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 2H), 1.90-1.75 (m, 2H), 1.65-1.55 (m, 1H); MS (ESI+) m/z 363 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24](CC4C=CC(OC)=CC=4)[C:17]=23)[C:12]([CH3:34])=[CH:11][N:10]=1.FC1C=CC(F)=CC=1C1C=C(NC2C3C(=CN(CC4C=CC(OC)=CC=4)N=3)N=CC=2)C(C)=CN=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[C:12]([CH3:34])=[CH:11][N:10]=1
Reactant: COc1ccc(Cn2ncc3nccc(Nc4cc(-c5cc(F)ccc5F)ncc4C)c32)cc1
Agent: COc1ccc(Cn2cc3nccc(Nc4cc(-c5cc(F)ccc5F)ncc4C)c3n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(-c2cc(F)ccc2F)cc1Nc1ccnc2cn[nH]c12
Temperature: 70 °C

Procedure:
N-(2-(2,5-Difluorophenyl)-5-methylpyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-7-amine and N-(2-(2,5-difluorophenyl)-5-methylpyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine and trifluoroacetic acid (35.0 mL) were combined and heated at 70° C. for 3 hours. The reaction was then cooled and concentrated to give a residue which was dissolved in dichloromethane (75 mL) and added with stirring to a saturated sodium bicarbonate solution (50 mL) to give a solid. The solid was collected by filtration and dissolved in ethyl acetate (500 mL) which was extracted with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to give title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (3H, s) 7.09 (1H, d, J=4.80 Hz) 7.26-7.36 (2H, m) 7.50 (1H, s) 7.75 (1H, ddd, J=9.54, 6.13, 3.28 Hz) 8.24 (1H, d, J=1.26 Hz) 8.35 (1H, d, J=5.05 Hz) 8.43 (1H, s) 8.50 (1H, s) 13.03 (1H, s). MS [M+H] found 338.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[O:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccccc1Oc1ccccc1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccccc2N2CCNCC2)cc1
Temperature: 100 °C
Yield: 64.2 %

Procedure:
1-Bromo-2-phenoxybenzene (432 mg, 1.73 mmol), piperazine (299 mg, 3.47 mmol), Pd2(dba)3 (48 mg, 0.052 mmol), BINAP (54 mg, 0.087 mmol) and NaOt-Bu (249 mg, 2.60 mmol) were dissolved in toluene (10 mL) in a reaction vessel and refluxed at 100° C. for 20 hours. After the reaction was completed, the reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography (MC:mixture solution (MC:MeOH:H2O:NH3=80:20:1:1)=6:1) to obtain 283 mg of the target compound (1.11 mmol, 64.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][CH2:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)OCc2ccccc2)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OCc2ccccc2)OC(C)(C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and benzyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:9]=2)[C:4](=[O:16])[NH:3]1.I[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=2)[C:4](=[O:16])[N:3]1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24]
Reactant: Cc1ccncc1I
Reactant: CC1Cc2ccc(C(F)(F)F)cc2C(=O)N1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1C(=O)c2cc(C(F)(F)F)ccc2CC1C
Temperature: 110 °C
Yield: 3.6 %

Procedure:
3-Methyl-7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-43d: 200 mg, 0.872 mmol) was reacted with 3-iodo-4-methyl-pyridine (287 mg, 1.308 mmol), K3PO4 (463 mg, 2.18 mmol), trans-N,N′-dimethyl-cyclohexane-1, 2-diamine (40 mg), CuI (20 mg) and 1,4-dioxane (5 mL). The resulting mixture was refluxed for 64 hours at 110° C. to afford the crude product. Purification by column chromatography on silica gel (90% ethylacetate in hexane) followed by preparative HPLC afforded 10 mg of the product (3.58% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl-:15].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:2]3[CH:7]=[CH:6][C:5]([Cl:15])=[CH:4][CH:3]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Clc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 203.1 %

Procedure:
A suspension of 4-(4-Bromo-phenyl)-piperidin-4-ol (4.02 g, 15.7 mmol) in chlorobenzene (30 ml) was added dropwise to a suspension of aluminium chloride (7.32 g, 54.9 mmol) in chlorobenzene (10 ml) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours, quenched by addition of ice then methyl t-butyl ether added. After stirring for 1 hour the precipitate was collected by filtration washed with water, methyl t-butyl ether and water to afford the title compound (5.59 g, 92% yield). LC/MS: (PS-B3) Rt 3.57 [M+H]+ 350, 352.
Reaction SMILES: [N+]([O-])(O[CH:4]1[O:17][C@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]([O:7][C:8](=[O:10])[CH3:9])[C@H:5]1[N:23]=[N+:24]=[N-:25])=O.[Cl:27]CCl>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[C:8]([O:7][C@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[O:17][C@H:4]([Cl:27])[C@@H:5]1[N:23]=[N+:24]=[N-:25])(=[O:10])[CH3:9]
Reactant: ClCCl
Reactant: CC(=O)OC[C@H]1OC(O[N+](=O)[O-])[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@H](Cl)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 48 h

Procedure:
An about 1:2 mixture of the α- and β- anomers of 3,4,6-tri-O-acetyl-2-azido-2-deoxy-D-galactopyranosyl nitrate (0.377 g, 1.01 mmole) was dissolved in acetonitrile (6 ml) containing tetraethylammonium chloride (0.924 g, 5.05 mmole) and the solution was left at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (25 ml), washed with water (25 ml) and dried. Evaporation of the solvent in vacuo left a syrup (0.325 g) which showed doublets with spacings of 9.0 and 3.5 Hz at δ 5.15 and 6.20 p.p.m., respectively in the p.m.r. spectrum measured in CDCl3. These signals are assigned to the β- (XXIII) and α-anomers (XXII) for 3,4,6-tri-O-acetyl-2-azido-2-deoxy-D-galactopyranosyl chloride, respectively. Judging from the relative intensities of the signals, the product consisted of a near 10:1 mixture of the α- and β-anomers, (XXII) and (XXIII) respectively.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:23]([O-:28])([N+]([O-])=O)=[O:24]>C(Cl)(Cl)Cl>[N+:23]([C:11]1[O:10][C:9]2[C:12]3[C:17]([C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:8]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O-:28])=[O:24]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)c1cc2c(-c3ccccc3)coc2c2ccccc12
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc2c(-c3ccccc3)c([N+](=O)[O-])oc2c2ccccc12
Temperature: 20 °C
Reaction time: 24 h

Procedure:
The product of Step A is dissolved partially in 125 ml. of hot chloroform, and 1 g. of dinitrogen tetraoxide is added. The mixture is stirred at 20° C. for about 1 day. The mixture is evaporated to provide a residue which is triturated with isopropyl alcohol. The residue is separated by filtration and recrystallized from acetic acid to provide light yellow crystals of 2-nitro-3-phenylnaphtho-[1,2-b]furan-5-carboxylic acid, m.p. 286°-288° c. (dec.).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([CH2:20][CH:21]=[O:22])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[Cl:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:23][CH:20]([C:17]1([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH2:19][CH2:18]1)[CH:21]=[O:22]
Reactant: COc1ccc(C2(CC=O)CC2)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2(C(Cl)C=O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
L-Proline (10 mg, 0.1 mmol) was added to a solution of [1-(4-methoxyphenyl)cyclopropyl]acetaldehyde (100 mg, 0.53 mmol) in chloroform (1 mL) at 0° C. followed by addition of N-chlorosuccinimide (84 mg, 0.63 mmol). The reaction mixture was stirred at ambient temperature for 2 h. The mixture was diluted with hexanes and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate in hexanes (0-10%) to afford the desired product.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH:12]([CH:25]([OH:37])[CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:13]([NH:21][C:22]([CH3:24])=[O:23])[C:14]([O:16]C(C)(C)C)=[O:15].FC(F)(F)C(O)=O>ClCCl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH:12]([C:25](=[O:37])[CH2:26][NH:27][S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])[CH:13]([NH:21][C:22]([CH3:24])=[O:23])[C:14]([OH:16])=[O:15]
Reactant: CC(=O)NC(C(=O)OC(C)(C)C)C(C(O)CNS(=O)(=O)c1ccccc1)N1CCc2ccccc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC(C(=O)O)C(C(=O)CNS(=O)(=O)c1ccccc1)N1CCc2ccccc2C1=O
Yield: 74.8 %

Procedure:
A solution of 3-(1, 2, 3, 4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-5-benzenesulfonylamino-4-hydroxy-pentanoic acid, tert-butyl ester (0.44 g, 0.48 mMol) and 15 mL of trifluoroacetic acid in 15 mL of dichloromethane was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure. Crystallization from dichloromethane/ether/hexane gave 0.17 g of 3-(1,2,3,4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-5-benzenesulfonylamino-4-oxo-pentanoic acid.
Reaction SMILES: [C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)(O)=[O:2].C(=O)(O)[O-]>C1COCC1>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH:4]([CH2:1][OH:2])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)#[N:22]
Reactant: COC(=O)c1ccc(CCC(CCCCC#N)C(=O)O)cc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC(CO)CCCCC#N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
33 ml of a 1 M borane-THF complex solution (33 mmol) are added dropwise to a solution of 5 g (16.48 mmol) of methyl 4-(3-carboxy-7-cyanoheptyl)benzoate from Example 92A in 62 ml of THF at −15° C., and the solution is stirred at this temperature for 2 hours. Then a further 16 ml of 1 M borane-THF complex solution are added dropwise, and stirring is continued for 45 minutes. The reaction mixture is then warmed to 0° C. and stirred at this temperature for 1 hour. After reaction is complete, 100 ml of saturated bicarbonate solution are added to the reaction mixture, and the solvent is concentrated to dryness. The residue is taken up in ethyl acetate and water, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and again freed of solvent. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1→1:3→100% ethyl acetate). 2.4 g (93% purity, 47% yield) of a colorless solid are obtained.
Reaction SMILES: C([O:3][C:4](=[O:21])/[CH:5]=[CH:6]/[CH:7]=[CH:8]/[C:9]1[S:13][C:12]2[CH:14]=[CH:15][C:16]([N:18]([CH3:20])[CH3:19])=[CH:17][C:11]=2[CH:10]=1)C.NO.[OH-].[K+].CO.Cl>C1COCC1.O>[CH3:20][N:18]([CH3:19])[C:16]1[CH:15]=[CH:14][C:12]2[S:13][C:9](/[CH:8]=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:21])=[O:3])=[CH:10][C:11]=2[CH:17]=1
Reactant: CCOC(=O)/C=C/C=C/c1cc2cc(N(C)C)ccc2s1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc2sc(/C=C/C=C/C(=O)O)cc2c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of (2E,4E)-5-(5-dimethylaminobenzo[b]thiophen-2-yl)-penta-2,4-dienoic acid ethyl ester (540 mg, 1.8 mmol) in dry THF (10 mL) was added at 0° C. an aqueous solution of hydroxylamine (50%, 1.1 mL, 16.6 mmol). To this mixture was added a solution of potassium hydroxide in methanol (2.9 mL, 1M, 2.9 mmol) over a period of 40 minutes at 0° C. The mixture was stirred at 20° C. for 2 hours, and water (10 mL) was then added. The solution was acidified to pH 5 by addition of concentrated hydrochloric acid (10 M, CAUTION), then extracted with ethyl acetate (50 mL). The organic layer was washed with brine (25 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a solid which was recrystallised from ethanol to give the title compound (367 mg, 71%) as an orange solid, mp 195° C. (decomp.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][C@@H:17]2[CH3:29])[N:3]=1.Br.[CH3:31][C@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][C@@H:17]3[CH3:29])[N:3]=[C:2]([N:33]3[CH2:34][CH2:35][CH2:36][C@@H:32]3[CH3:31])[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: C[C@H]1CCCN1
Reactant: C[C@H]1CN(c2ncccc2Cl)CCN1c1cc(-c2ccc(F)c(Cl)c2)nc(Cl)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CN(c2ncccc2Cl)CCN1c1cc(-c2ccc(F)c(Cl)c2)nc(N2CCC[C@@H]2C)n1

Procedure:
Dissolve 2-chloro-4-(3-chloro-4-fluorophenyl)-6-((S)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl)pyrimidine (45 mg, 0.1 mmol) and (S)-2-methylpyrrolidine hydrobromide (0.2 mmol, prepared essentially as described by Nijhuis et. al. (1989) J. Org. Chem. 54:209-216) in CH3CN; 2.0 mL) under nitrogen atmosphere. Add K2CO3 (55 mg, 0.4 mmol) and heat at 80° C. for 20 hours. Concentrate under vacuum, dilute with water (5.0 mL), extract with EtOAc (3×3 mL) and dry with MgSO4. Filter, and concentrate under vacuum to afford crude product. Purify by flash column chromatography using 10-20% EtOAc/hexane to afford the title product as viscous oil. NMR (CDCl3) δ1.31 (3H, d, J=2.1), 1.41(3H, d, J=2.3), 1.62 (2H, m), 1.93 (3H, m), 3.00 (2H, m), 3.35 (1H, t), 3.65 (2H, m), 3.81(2H, m), 4.35 (1H, m), 4.68 (1H, bs), 6.22 (1H, s), 6.87 (1H, m), 7.16 (1H, t), 7.61 (1H, m), 7.88 (1H, m), 8.06 (1H, m), 8.20 (1H, m). Mass spec m/z=501.22.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: Nc1ncc2cc(-c3cccc(Cl)c3Cl)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1cccc(Cl)c1Cl

Procedure:
Following the general procedure of Example 2, 0.502 g of 6-(2,3-dichlorophenyl)-pyrido[2,3-d]-pyrimidine-2,7-diamine from Example 83 was reacted with 0.206 mL of tert-butyl isocyanate. The product is purified by silica gel chromatography eluting with a gradient of CHCl3 :EtOAc (98:2) to CHCl3 :EtOAc (1:2) to afford the title compound; mp 356-358° C.