Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>>[CH2:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NC(=O)C1CCNCC1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCN1CCC(C(N)=O)CC1
Yield: 102.8 %

Procedure:
Prepared from isonipecotamide (4.04 g, 31.6 mmol), 1-iodohexane (6.7 g, 31.6 mmol) and potassium carbonate (4.36 g, 31.6 mmol) according to the procedure used for Example 8 (Step A) to give 6.9 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([OH:13])[CH2:3][O:4][CH:5]([CH2:7][O:8][CH:9]([CH2:11][OH:12])[CH3:10])[CH3:6].[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([CH:1]([C:21](=[O:22])[C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:25][CH:24]=2)[CH:2]([OH:13])[CH2:3][O:4][CH:5]([CH2:7][O:8][CH:9]([CH2:11][OH:12])[CH3:10])[CH3:6])=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CC(O)COC(C)COC(C)CO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: CC(CO)OCC(C)OCC(O)C(C(=O)c1ccc([N+](=O)[O-])cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 89 %

Procedure:
Tripropylene glycol (57.6 g, 0.3 mole) was treated with p-nitrobenzoyl chloride (116 g, 0.625 mole), following the general procedure described in Example 1, Part A. The product, bis-(4-nitrobenzoyl)-tripropylene glycol (131 g), was obtained as a viscous yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][C:31](O)=[O:32])=[CH:24][CH:23]=1.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:34][C:35](=[O:36])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30][C:31]([N:17]2[CH2:18][CH2:19][CH2:20][C@@H:15]([C:7]3[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=3)[CH2:16]2)=[O:32])=[CH:24][CH:23]=1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.7 %

Procedure:
(R)-1-(3-Methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (0.29 mmol, 79 mg) in DMF (15 mL) was added to (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.32 mmol, 115 mg) and N-methylmorphine (1.16 mmol, 0.13 mL). The reaction mixture was stirred at rt for 5 min and then added HATU (0.32 mmol, 122 mg) and kept stifling at rt overnight. The reaction mixture was poured into H2O, extracted with EtOAc. The extract was washed with H2O, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by preparative LC/MS (35-60% CH3CN in H2O) to afford tert-butyl (R)-1-(4-bromophenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (6A) (0.26 mmol, 160 mg, yield: 89.7%). ESI-MS: m/z 614.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1)=[C:7]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[C:6]([CH3:31])=[CH:5]2>[Pd].CCOC(C)=O.CCO>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1)=[C:7]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[C:6]([CH3:31])=[CH:5]2
Reactant: Cc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1cccc(O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(CCC(=O)O)cc2)c1-c1cccc(O)c1
Reaction time: 14 h
Yield: 434.3 %

Procedure:
A 1:1 EtOAc/EtOH solution (4 mL) of (2E)-3-(4-{[6-hydroxy-2-(3-hydroxyphenyl)-3-methyl-1-naphthalenyl]oxy}phenyl)-2-propenoic acid (251) (0.041 g, 0.01 mmol, 1 equiv) was treated with 5% Pd—C (0.027 g, 0.02 mmol, 0.1 equiv) and the reaction vessel was equipped with an H2-filled balloon. After 14 h at ambient temperature, the crude mixture was filtered through a pad of Celite. Concentration gave a light pink solid that was purified by radial chromatography (SiO2, 1 mm plate, 90:10; CHCl3/MeOH) to afford the title compound (252) as a pink solid (0.018 g, 44%). 1H NMR (CD3OD, 400 MHz) δ 7.58 (d, J=9.0 Hz, 1H), 7.40 (s, 1H), 7.07-7.03 (m, 2H), 6.95-6.89 (m, 3H), 6.62 (dd, J=8.1, 2.3 Hz, 1H), 6.55-6.52 (m, 2H), 6.43 (d, J=8.5 Hz, 2H), 2.75 (t, J=7.7 Hz, 2H), 2.34 (t, J=7.3 Hz, 2H), 2.17 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[C:15]1(=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[CH2:16]1.N1CCCCC1.Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8]([CH:16]2[C:15](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:24])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CC(=O)c2ccccc21
Reactant: CCC(Oc1ccc(Cl)cc1)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCC(Oc1ccc(Cl)cc1)C(=O)C1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 18.1 %

Procedure:
5.8 G of 2-(4-chlorophenoxy)butyryl chloride (0.025 mol) are added dropwise, with stirring and whilst cooling with an ice bath at 0°C and working under nitrogen, to 3.65 g (0.025 mol) of indane-1,3-dione in 20 ml of pyridine containing two drops of piperidine. After stirring the mixture for 18 hours, it is poured onto ice and acidified with hydrochloric acid, and the resulting mixture is ectracted with chloroform. After evaporating the solvent, the residue is crystallised from ethyl acetate to give 1.55 g of pure 2-[2'-(4"-chlorophenoxy)butyryl]indane-1,3-dione, melting point 132°C. Empirical formula: C19H15O4Cl; molecular Weight: 342.79; Elementary analysis:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([NH2:21])=[O:20])[C:5]2=[O:22].[CH2:23](N(CC)CC)[CH3:24].C([B-](F)(F)F)=C.[K+]>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([CH:23]=[CH2:24])=[CH:11][CH:10]=3)[C:5](=[O:22])[C:6]([C:19]([NH2:21])=[O:20])=[CH:7]2)=[CH:13][CH:14]=1
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=C[B-](F)(F)F
Solvent: CCCO
Solvent: ClCCl
Product: C=Cc1ccc2c(c1)c(=O)c(C(N)=O)cn2-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of compound E (450 mg, 1.25 mmol), triethylamine (174 μL, 1.25 mmol), and Pd(dppf)Cl2 CH2Cl2 (18.2 mg, 0.025 mmol) in 1-propanol (8.3 mL) was added potassium vinyltrifluoroborate (200 mg, 1.50 mmol). The reaction was purged with argon and stirred at 100° C. for 16 hours. The reaction was filtered over Celite® and washed very well with a 5% MeOH in DCM solution and concentrated in vacuo to give 385 mg (100%) of the title compound that was used without further purification. ES-MS [M+1]+: 309.2.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH2:4]Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:4][C:3]2[C:6]([O:11][CH3:12])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=2[F:1])=[C:16]([O:21][CH3:22])[CH:15]=1
Reactant: COc1ccc(F)c(F)c1CCl
Reactant: COc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1OCc1c(OC)ccc(F)c1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of 2,3-difluoro-6-methoxybenzyl chloride (7.65 g), 4-chloro-2-methoxyphenol (6.34 g), potassium carbonate (8.29 g) and sodium iodide (1.2 g) in N,N-dimethylformamide (20 mL) was stirred at 80° C. for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/diethyl ether=5/1), and collected by filtration. The collected solids were washed with the same solvent, and dried under reduced pressure to give the title compound (8.6 g).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:11]=2)[C:6](=[O:19])[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]1[OH:25])C.C(N1C2C(=CC=C(C3C=NC=CC=3)C=2)C(=O)C(C(O)=O)=C1)C.[H-].[Na+].CI>>[OH:25][C:4]1[N:3]([CH3:1])[C:12]2[C:7]([C:6](=[O:19])[C:5]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8][CH:9]=[C:10]([C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)[CH:11]=2
Reactant: CCOC(=O)c1c(O)n(CC)c2cc(-c3ccncc3)ccc2c1=O
Agent: CCn1cc(C(=O)O)c(=O)c2ccc(-c3cccnc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CCOC(=O)c1c(O)n(C)c2cc(-c3ccncc3)ccc2c1=O

Procedure:
Ethyl 1,4-dihydro-2-hydroxy-1-methyl-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylate was prepared from 7.20 g dioxobenzoxazine of Example 38, part (a), 1.66 g 60% sodium hydride and 1.95 ml methyl iodide according to the procedure of Example 38, part (b), and was obtained (4.50 g) as a yellow solid, m.p. about 184° C(decompn.).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[Cr](O)(O)(=O)=O.C(O)(C)C>N1C=CC=CC=1.[OH-].[K+]>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:3][CH:4]=[O:5]
Reactant: CC(CCO)CCCC(C)(C)C
Agent: O=[Cr](=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CC(CC=O)CCCC(C)(C)C
Reaction time: 2 h

Procedure:
Five grams of 3,7,7-trimethyloctan-1-ol in 50 ml. of dry pyridine is added to a mixture of chromic acid (5 g.) in pyridine (50 ml.) with stirring. After two hours, isopropanol (10 ml.) is added and after a further 30 minutes, the mixture is diluted with 0.5% aqueous potassium hydroxide solution and extracted with ether. The ethereal extract is washed, dried and evaporated to yield 3,7,7-trimethyloctan-1-al.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[N:8]([CH3:14])[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CS(O[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][CH2:34]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>ClCCl.CO>[C:43]([O:42][C:40](=[O:41])[NH:39][CH:36]1[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[C:7](=[O:15])[N:8]([CH3:14])[C:9]2=[O:13])[CH2:34][CH2:35]1)([CH3:46])([CH3:45])[CH3:44]
Reactant: COc1ccc2c(=O)n(C)c(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C)c(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Yield: 18.5 %

Procedure:
7-Methoxy-3-methylquinazoline-2,4(1H,3H)-dione (Intermediate 112, 523 mg, 2.5 mmol) was deprotonated with lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 1.9 mL, 1.9 mmol) and alkylated with 2-{4-[tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6, 3.4 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 200 mg (18%) of the product as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([N:29]2[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]2)[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([N:29]3[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]3)[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OC1CCN(c2cccc(Br)n2)C1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(N4CCC(O)C4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (200 mg, 0.64 mmol) and 1-(6-bromopyridin-2-yl)pyrrolidin-3-ol (132 mg, 0.54 mmol) as the starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[CH:18][C:17](=[O:20])[C:8]4[CH:9]=[C:10]([O:15]C)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[CH:18][C:17](=[O:20])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.3 %

Procedure:
10-bromo-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (3.2 g) obtained in Example 58 was suspended in anhydrous methylene chloride (500 ml), and boron tribromide (25 g) was added dropwise at room temperature. The mixture was stirred at room temperature for 12 hours and the reaction mixture was poured into ice water (1 L) and the crystals precipitated were recovered by filtration. The methylene chloride layer of the filtrate was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The two types of crystals thus obtained were combined, and the above-described procedure was repeated. The reaction mixture was poured into ice water (1 L), and the crystals precipitated were recovered by filtration. The crude crystals obtained were washed with a mixed solution of chloroform and methanol at an elevated temperature and recovered by filtration to obtain the title compound (2.4 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH3:28].CO>N1C=CC=CC=1>[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](=[O:31])[O:26][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[S:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)[CH3:28]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)s2)cc1OC
Solvent: CO
Solvent: c1ccncc1
Product: CCN(CC)C(=O)OC1CCN(c2ccc(/C=C(\C#N)c3ccc(OC)c(OC)c3)s2)CC1
Yield: 21.4 %

Procedure:
Compound 6 (150 mg) was dissolved in pyridine (1 mL), and diethylcarbamoyl chloride (55 mg) was added to the solution, followed by stirring under reflux for 2 hours. After completion of reaction, methanol was added to the reaction mixture, followed by stirring for 30 minutes. The solvent was evaporated to dryness, and the residue was extracted with chloroform and purified water. The organic layer was dried over sodium sulfate anhydrate, and the solvent was evaporated to dryness. The residue was recrystallized from ethyl acetate, to thereby yield the target product (yield: 40.6 mg, 21.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:14])[CH:6]=[C:7]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:8]=1.Cl[CH2:16][CH2:17][C:18](Cl)([CH3:20])[CH3:19].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH:11]([CH3:12])[CH3:13])[CH:6]=[C:5]2[C:4]=1[CH:16]=[CH:17][C:18]([CH3:20])([CH3:19])[O:14]2
Reactant: COc1cc(O)cc(OCC(C)C)c1
Reactant: CC(C)(Cl)CCCl
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: COc1cc(OCC(C)C)cc2c1C=CC(C)(C)O2
Temperature: 125 °C
Reaction time: 60 h
Yield: 69 %

Procedure:
A mixture of 3.9 g (20 millimoles) of 3-methoxy-5-isobutoxy-phenol, 2.8 g (20 millimoles) of 1,3-dichloro-3-methyl-butane and 0.26 g (1 millimole) of bis-(acetyl-acetonato)-nickel is heated at 125° C. for 8 hours. The mixture is cooled, the solvent removed, the residue taken up in 40 ml of anhydrous benzene and 0.8 g (3.5 millimoles) of DDQ (dichloro-dicyano-benzoquinone) are added. The mixture is heated to boiling for 60 hours. The solution is filtered, the filtrate evaporated and the residue purified as described in Example 3. Thus 3.6 of the desired compound are obtained in the form of a colorless oil, yield 69%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10](/[CH:11]=[CH:12]/[CH:13]=[N+](C)C)=[C:4]2[CH:3]=1.C(=O)(O)[O-:26].[K+].O>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10](/[CH:11]=[CH:12]/[CH:13]=[O:26])=[C:4]2[CH:3]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2/C=C/C=[N+](C)C)cc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nn3ccc(Br)cc3c2/C=C/C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (E)-N-(3-(5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)allylidene)-N-methylmethanaminium (470 mg, 1.22 mmol) in methanol (5 mL) was added a 15% solution of potassium bicarbonate (5 mL) and the mixture was stirred at room temperature for 1 h. Water was added and methanol was evaporated under reduced pressure. Filtration of the precipitate afforded 322 mg of the title compound. LCMS m/z 357.0, 359.0 (M+H)+, ret. time=2.70 min.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4](O)=[O:5].C[N:16](C=O)C.C(Cl)(=O)C(Cl)=O>C1COCC1>[Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1c([N+](=O)[O-])ccc(F)c1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1c([N+](=O)[O-])ccc(F)c1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
2-Bromo-3-fluoro-6-nitrobenzoic acid (Example 134f) (24.83 g, 94.0) mmol, (mixture of two regioisomers) was dissolved in anhydrous THF (200 mL) under a nitrogen atmosphere at room temperature. Anhydrous DMF (0.75 mL) was added and the obtained mixture was cooled to 0° C. Oxalyl chloride (12.3 mL, 141 mmol) was slowly added and the reaction mixture was stirred at 0° C. for 10 min, and at room temperature for a further 2 h. The reaction was evaporated to dryness, suspended in anhydrous THF (100 mL) and added slowly to concentrated ammonium hydroxide (350 mL) at 0° C. After stirring for 45 minutes at 0° C. the mixture was extracted with CH2Cl2 (5×100 mL), and the organic extractions were then discarded. At this point the desired regioisomer existed as an insoluble precipitate in the aqueous layer, which was collected by filtration to give 10.3 g (42%) of 2-bromo-3-fluoro-6-nitrobenzamide which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (dd, J=8.8, 4.4 Hz, 1H), 8.10 (broad s, 1H), 7.95 (broad s, 1H), 7.66 (dd, J=9.6, 7.6 Hz, 1H).
Reaction SMILES: COCC1CCCCN1C1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[N:30]=1.[CH2:47]([CH:54]1[CH2:58][CH2:57][CH2:56][NH:55]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[CH2:47]([CH:54]1[CH2:58][CH2:57][CH2:56][N:55]1[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[N:30]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1ccc(CC2CCCN2)cc1
Agent: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCC3Cc3ccccc3)n2)c1

Procedure:
B26 was prepared following the procedure reported for B4 using A1 and rac-2-benzylpyrrolidine. It was obtained as a white crystalline solid; yield: 160 mg (42%). 1H NMR (300 MHz, d6-DMSO, 300K) δ 1.67-1.92 (m, 4H), 2.57-2.77 (m, 1H), 3.03-3.21 (m, 1H), 3.42-3.62 (m, 2H), 4.20 (2 s, 2H), 4.28-4.48 (m, 1H), 6.88 (bs, 2H), 6.93-7.08 (m, 1H), 7.12-7.38 (m, 6H), 7.58 and 7.71 (2 m, 1H), 7.82-8.01 (m, 1H), 8.23 and 8.30 (2 s, 1H), 9.66 (bs, 1H). MS (ES) C21H24N6O2S requires: 424. found: 425 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10](=O)[C@@H:11]([F:23])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:31]([NH:38][C@H:10]1[C@@H:11]([F:23])[CH2:12][C@@H:13]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@:9]1([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:15][C@H:14]2[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)C(=O)[C@@H](F)C[C@@H]1N2Cc1ccccc1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@@H](NCc3ccccc3)[C@@H](F)C[C@@H]1N2Cc1ccccc1
Temperature: 50 °C
Yield: 31.7 %

Procedure:
(1R*,3S*,5S*,6R*)-8-Benzyl-3-fluoro-1-phenyl-6-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-2-one (Description 36a; 1.68 g, 4.1 mmol), titanium iso-propoxide (1.8 mL, 6.2 mmol) and benzylamine (520 μL, 4.7 mmol) were heated together at 85° C. for two hours, then cooled and diluted with methanol (30 mL). The solution was then heated to 50° C. and sodium borohydride (1.06 g, 28 mmol) was added portionwise over 4 hours. After addition was complete, the solution was heated for a further 16 hours, then cooled and poured into aqueous sodium hydroxide solution (100 mL, 1M). The suspension formed was extracted with ethyl acetate (2×100 mL) and the extracts were dried (MgSO4). Concentration in vacuo gave a gum which was purified by silica chromatography to give the title compound (651 mg, 1.3 mmol).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[O:12])=[C:6]([O:21][CH3:22])[CH:5]=1.CO.O.[OH-].[Li+]>O>[CH3:22][O:21][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)Nc2cnc(C)cn2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1NC(=O)Nc1cnc(C)cn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a stirred suspension of 3-methoxy-4-[3-(5-methyl-pyrazin-2-yl)-ureido]-benzoic acid methyl ester (7.15 g, 22.6 mmol) in 3:1 MeOH:H2O (226 mL) at RT under N2 was added lithium hydroxide monohydrate (9.5 g, 226 mmol) as a solid and the mixture heated to 65° C. After reaching temperature, the suspension gradually became a bright yellow solution. After about 4 hours a precipitate formed but the reaction was continued overnight. After cooling to RT, MeOH was removed by rotovap and the aqueous suspension diluted with 100 mL H2O and neutralized to pH=5 with concentrated HCl. As pH=5 was approached, the suspension turned from yellow to white. The suspension was then filtered through paper on a large ceramic funnel. The filtration went very slowly, taking several hours. The filter cake was washed twice with H2O. When most of the H2O was removed, the residue was dried under high vacuum in a dessicator overnight to give the free acid as a white solid (6 g, 88%). 1H-NMR (400 MHz, d6-DMSO) δ 8.79 (br s, 1H), 8.36 (d, 1H), 8.22 (s, 1H), 7.57 (d, 1H), 7.51 (s, 1H), 3.97 (s, 3H), 2.42 (s, 3H).