Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1>C1COCC1.CCOC(C)=O>[Br:2][CH2:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1
Reactant: CC(C)(C)C(=O)COc1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)COc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Add phosphorous tribromide (1.45 g, 5.34 mmol) slowly to a solution of 1-(4-hydroxymethyl-phenoxy)-3,3-dimethylbutan-2-one (1.08 g, 4.85 mmol) in anhydrous THF under nitrogen at 0° C. Stir at 0° C. for 1 h and then raise to ambient temperature. Stir overnight. Dilute with EtOAc, wash with saturated aqueous NaHCO3, brine, dry over Na2SO4, filter and concentrate. Purify the residue by chromatography on silica gel eluting with EtOAc:hexane (1:6) to provide the title compound (1.152 g, 83%). MS (ES+) m/z: 205 (M-Br)+.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14](I)[N:15]=[C:5]3[C:4]=2[CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.C[N:27](C)[CH:28]=[O:29]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:28]([NH2:27])=[O:29])[N:15]=[C:5]3[C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1cc2c(cn1)OCCn1cc(I)nc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: NC(=O)c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Temperature: 70 °C

Procedure:
A mixture of 10-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (2056 mg, 5.916 mmol), bis(triphenylphosphine)palladium(II) chloride (2.10E2 mg, 0.300 mmol) and hexamethyldisilazane (7.488 mL, 35.50 mmol) in 60 ml of N,N-Dimethylformamide was subjected to carbonylation at 1 atm with CO from balloon. The reaction mixture was heated at 70° C. for 1 h. The mixture was concentrated in vacuum, the residue partitioned between ethyl acetate and 1 M aqueous sodium carbonate. The organic extracts were washed with water, brine, dried over magnesium sulfate, concentrated in vacuum and purified on a 12 g silica column eluting with 0-5% MeOH in DCM to give 1300 mg (83%). MS (ESI+): 265.0. 1H NMR (500 MHz, DMSO) δ 8.37 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.70 (s, 1H), 7.25 (s, 1H), 4.56 (s, 4H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3([CH2:20][CH2:19][N:18](C(OCC4C=CC=CC=4)=O)[CH2:17][CH2:16]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([N:3]1[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCn1ncc2c1-c1ccccc1OC21CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCn1ncc2c1-c1ccccc1OC21CCNCC1
Yield: 100 %

Procedure:
Benzyl 1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (530 mg, 1.3 mmol) was stirred in methanol (9.5 mL) with Pd/C (70 mg, 0.070 mmol) under a balloon of hydrogen for 16 h. The reaction was filtered through a syringe filter and the solvent evaporated to give 1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (350 mg, 99%). ESI-MS m/z calc. 269.2, found 270.5 (M+1)+; Retention time: 0.80 minutes (3 min run).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[N:12][C:11]=1[CH3:18].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([CH:25]=[CH:26][CH:27]=[O:28])=[CH:23][CH:22]=1>O1CCCC1>[OH:28][CH:27]([CH:26]=[CH:25][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:30][CH:29]=1)[CH2:18][C:11]1[C:10]([CH3:9])=[N:15][C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=1
Reactant: COc1ccc(C=CC=O)cc1
Reactant: Cc1nc(C)c(C)nc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C=CC(O)Cc2nc(C)c(C)nc2C)cc1
Temperature: 25 °C

Procedure:
To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly a solution of tetramethylpyrazine (13.6 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of p-methoxycinnamaldehyde (17.8 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The reaction product mixture is then worked up according to the procedures of Example I to provide the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([CH:10]([C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:11][CH2:12][CH3:13])=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CCCC=O
Product: CCCC(c1c[nH]c2ncccc12)c1c[nH]c2ncccc12
Yield: 15 %

Procedure:
ST 1436 was prepared as described in example 2/2 from 7-azaindole and butyraldehyde. The reaction, however, was heated under reflux for 48 hours. The end product was isolated and purified chromatographically on a silica column eluting with a CH2Cl2:CH3COCH3 gradient ranging from 9:1 to 4:6. Yield 15%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11](O)(=[O:16])[CH2:12][CH:13]=[CH:14][CH3:15]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[O:9][CH3:10])[C:11](=[O:16])[CH2:12][CH:13]2[CH2:14][CH3:15]
Reactant: COc1ccccc1OC
Reactant: CC=CCC(=O)O
Product: CCC1CC(=O)c2cc(OC)c(OC)cc21
Temperature: 60 °C

Procedure:
A mixture of 1,2-dimethoxy-benzene (Compound 47a) (21.9 mL, 0.170 mole) and pent-3-enoic acid (Compound 47b) (25.5 g, 0.255 mole) was stirred under argon in an ice bath. Polyphosphoric acid (230 g, 1.05 mole) was added slowly. After addition was complete, the ice bath was removed and the reaction heated for 16 hours at 60° C. The reaction was added to ice water and extracted with dichloromethane. The organic extracts were washed with 3N NaOH, water, brine and dried over Na2SO4. The solvent was then removed in vacuo to yield a red oil containing the crude title compound. The crude material was purified on a silica gel column using dichloromethane as eluent. The pure fractions were combined and concentrated to yield the racemic mixture of the title compound as an off-white solid. MS m/z 221 (M+H)+;
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl>>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OC1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Reaction time: 1 h
Yield: 25.4 %

Procedure:
To a solution of tetrahydrofuran-3-ol (500 mg, 5.68 mmol) in Py (5 ml), 4-methylbenzene-1-sulfonyl chloride (1623 mg, 8.51 mmol) was added, and the mixture and stirred at Rt for 1 hour. The mixture was poured into HCl 1M and extracted with AcOEt (2×). The organic phase was dried over Na2SO4 and evaporated under reduced pressure to give 350 mg of the title compound (26% yield).
Reaction SMILES: C([O-])=O.[NH4+].[OH:5][C:6]1[CH:7]=[C:8]([CH2:15][C:16]([NH:18][C:19]2[N:24]=[CH:23][C:22]([CH:25]([CH3:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)=[O:17])[CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O>[Pd].C(O)C>[NH2:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:15][C:16]([NH:18][C:19]2[N:24]=[CH:23][C:22]([CH:25]([CH3:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)=[O:17])=[CH:7][C:6]=1[OH:5]
Reactant: COC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(O)c2)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)CC(C)c1ccc(NC(=O)Cc2ccc(N)c(O)c2)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Ammonium formate (1.7 g) and 10% palladium on charcoal were added to a solution of (RS) methyl 3-{6-[2-(3-hydroxy-4-nitrophenyl)-acetylamino]-pyridin-3-yl}-butanoate (180 mg, Reference Example 15) in ethanol (15 mL). The mixture was stirred at 60° C. for 1 hour, then cooled to room temperature and then filtered through a pad of diatomaceous earth. The filter pad was washed with ethanol. The combined filtrate and washings were evaporated and the residue was dissolved in ethyl acetate. This solution was washed with water, then dried over magnesium sulphate and then evaporated to give the title compound (134 mg) as a pale brown oil which was used without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:4][N:3]=[CH:2]1.O.NN.Cl>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCn1ccnc1

Procedure:
A mixture of 0.2 mole of 2-[4-(1H-imidazol-1-yl)butyl]-1H-isoindole-1,3(2H)-dione, 0.22 mol. of hydrazine hydrate and 400 ml. of ethanol was heated on the steam bath for 3 hours and then treated with 400 ml. of 3N HCl and heated at reflux for an additional 2 hours. The insoluble material was filtered off and the mother liquor was concentrated to a low volume and again filtered. The remainder of the volatile material was distilled off and the residue was treated with saturated potassium carbonate solution. The 1H-imidazole-1-butanamine was extracted into methylene chloride and further purified by distillation on a Kugelrohr apparatus. In like manner from the appropriate 2-[w-(1H-imidazol-1-yl)alkyl]-1H-isoindole-1,3(2H)-dione were prepared 1H-imidazole-1-pentanamine, 1H-imidazole-1-hexanamine, 1H-imidazole-1-heptanamine and 1H-imidazole-1-octanamine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Li])CCC.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1.CCCCCC>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Brc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of 2-bromoquinoline (2.0 g, 9.61 mmol) in tetrahydrofuran (10 mL) was added dropwise to a mixture of n-butyllithium in hexane (4.2 mL of a 2.5 M solution) and tetrahydrofuran (10 mL) at −65° C. under N2, and the mixture was stirred at this temperature for 1 hour. A solution of t-butyl-4-oxo-1-piperidine carboxylate (1.92 g, 9.61 mmol) in tetrahydrofuran (10 niL) was added dropwise over 3 minutes., after the addition, the reaction was slowly warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with sat. ammonium chloride (15 mL); the resulting mixture was stirred at ambient temperature for 10 minutes. The organic layer was separated, washed with water (20 mL), brine (20 mL), dried over magnesium sulfate. Concentration yielded 4-hydroxy-4-quinolin-2-yl-piperidine-1-carboxylic acid tert-butyl ester (3.16 g, 98%) as a yellow oil which was used without further purification. 1H NMR CDCl3 δ 8.20 (d, J=9 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.73 (t, J=8 Hz, 1H), 7.55 (t, J=7 Hz, 1H), 7.42 (d, J=9 Hz, 1H), 5.94 (brd s, 1H), 4.23-4.00 (m, 2H), 3.70 (t, J=6 Hz, 1H), 3.40-3.22 (m, 2H), 2.42 (t, J=6 Hz, 1H), 2.13-1.98(m, 2H), 1.49 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](=[S:18])[NH:13][C:12]=2[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14]([S:18][CH3:21])=[N:13][C:12]=2[CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=S)CCC2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSC1=Nc2cc(NC(=O)OC(C)(C)C)ccc2CCC1
Reaction time: 12 h
Yield: 42.1 %

Procedure:
A solution of (2-thioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-carbamic acid tert-butyl ester (5.0 g, 17.1 mmol) and potassium carbonate (4.7 g, 34.0 mmol) in acetone (400 mL) was treated with iodomethane (2.5 mL, 5.7 g, 40.0 mmol). The mixture was stirred for 12 h and concentrated. The residue was partitioned between water (100 mL) and DCM (200 mL). The aqueous phase was extracted again with DCM and the combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography with DCM/MeOH (9:1) to give (2-methylsulfanyl-4,5-dihydro-3H-benzo[b]azepin-8-yl)-carbamic acid tert-butyl ester (2.2 g, 7.2 mmol, 42%): 1H NMR (300 MHz, CDCl3) δ 7.1 (m, 3H), 2.92 (t, 1H), 2.81 (t, 1H), 2.55 (s, 3H), 2.4 (q, 2H), 2.32 (q, 2H), 1.6 (s, 9H); MS (m/e) 307 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.[C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Br:13][C:9]1[N:8]=[C:7]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:21])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
At −78° C. a 2.5 M solution of n-butyl lithium in hexanes (18.6 mL, 46.4 mmol, 1.1 equiv) was added dropwise to 2,6-dibromopyridine (1) (10.0 g, 42.2 mmol, 1.0 equiv) in THF (780 mL). The solution was then stirred for 20 min at which point benzophenone (8.07 g, 44.3 mmol, 1.05 equiv) was added. The reaction was allowed to stir an additional 0.5 hr at −78° C., at this time the cooling bath was removed and the reaction allowed to warm room temperature. The reaction was stirred at room temperature for 1 hr and quenched with saturated sodium bicarbonate (250 mL). The layers were separated and the aqueous layer extracted with dichloromethane (250 mL). The combined organic layers were dried over sodium sulfate and absorbed onto silica gel (30 g) by concentration under reduced pressure. This material was then purified on a silica gel column (300 g) by eluting with heptanes (2 L), ethyl acetate (2%) in heptanes (2 L) and finally ethyl acetate (5%) in heptanes (2 L). The desired product was isolated pure in 35% yield (5.0 g). A second fraction (5.4 g) of product and benzophenone was also isolated.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:30][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc(-c2cn[nH]c2)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cnn(Cc3ccc(OCc4ccccc4)cc3)c2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To a solution of 3-(1H-pyrazol-4-yl)-pyridin-2,6-diamine (25 mg, 0.14 mmol) described in Manufacturing Example 36-1-2 in N,N-dimethylformamide (10 mL) was added sodium hydride (8.6 mg, 0.22 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 4-Benzyloxybenzyl chloride (49.9 mg, 0.22 mmol) was then added and stirred for 30 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate only) to obtain the title compound (24.0 mg, 45%).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)CCN
Product: CC(C)CCNS(=O)(=O)c1ccc(Br)cc1
Yield: 98 %

Procedure:
Starting materials: isoamylamine and 4-bromobenzenesulfonyl chloride. Yield 98% as a white solid: 1H NMR (CDCl3) δ 7.71 (d, J=9 Hz, 2H), 7.62 (d, J=9 Hz, 2H), 4.26 (br s, 1H), 2.82 (t, J=7 Hz, 2H), 1.52 (m, 1H), 1.30 (q, J=7 Hz, 2H), 0.86 (s, 3H), 0.84 (s, 3H); 13C NMR (CDCl3) δ 139.3, 132.6, 128.8, 127.7, 41.7, 38.6, 25.6, 22.8, 22.4; MS (ESP) m/z 306, 308 (M++1).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][CH2:13][CH:14]([OH:18])[CH2:15][CH2:16][CH3:17])=[CH2:11])=[CH:6][CH:5]=1.N1C=CC=CC=1>ClCCl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH2:11][Br:1])[CH2:12][CH2:13][CH:14]([CH2:15][CH2:16][CH3:17])[O:18]2)=[CH:8][CH:9]=1
Reactant: C=C(CCC(O)CCC)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1CCC(CBr)(c2ccc(Cl)cc2)O1
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
A solution of bromine (1.28 g) in dichloromethane (25 ml) was added dropwise over 15 minutes to a stirred solution of 2-(4-chlorophenyl)-5-hydroxyoct-1-ene (1.9 g) and pyridine (0.63 g) in dichloromethane (25 ml) at 0° to 5° C. (decolourisation of bromine and mild exotherm). The cooling bath was removed and the mixture was stirred for a further 30 minutes, then washed successively with water, dilute hydrochloric acid, aqueous sodium bicarbonate, and water, then dried over magnesium sulphate and concentrated under reduced pressure to give 2-(4-chlorophenyl)-2-bromomethyl-5-prop-1-yltetrahydrofuran (2.6 g) as a red oil, 1H nmr (CDCl3): δ3.9 (2H, singlet, CH2Br).
Reaction SMILES: [CH2:1]([O:15][C:16]([C:18]1[CH:22]=[CH:21][S:20][C:19]=1[CH:23]=O)=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:25][C:26]([C:28]([NH2:30])=[S:29])=[S:27]>>[CH2:1]([O:15][C:16]([C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]1[S:27][C:26]2[N:25]=[C:23]([C:19]3[S:20][CH:21]=[CH:22][C:18]=3[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:17])[S:29][C:28]=2[N:30]=1)=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NC(=S)C(N)=S
Reactant: CCCCCCCCCCCCCCOC(=O)c1ccsc1C=O
Product: CCCCCCCCCCCCCCOC(=O)c1ccsc1-c1nc2sc(-c3sccc3C(=O)OCCCCCCCCCCCCCC)nc2s1
Temperature: 200 °C

Procedure:
To a 25 mL flask were added 0.978 g (2.8 mmol) of tetradecyl-2-formylthiophene-3-carboxylate and 110 mg (0.9 mmol) of dithiooxamide. This mixture was heated to 200° C. for 2 hours. The resulting mixture was purified by column chromatography using a mixture of hexane and dichloromethane to give the desired compound. The NMR data were obtained and were consistent with those of the desired compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10]C)=[O:9])[CH2:3][CH2:2]1.[CH3:12][C:13]([CH3:15])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.Cl>[CH:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1)([CH3:15])[CH3:12]
Reactant: COC(=O)CC1CCNCC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCC(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-piperidineacetate (0.6 g, 3.82 mmol) was dissolved in methylene chloride (20 mL), acetone (1 mL), acetic acid (0.26 mL) and sodium triacetoxyborohydride (1.21 g, 5.73 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated, and work-up according to a conventional method gave a crude product. The obtained crude product was dissolved in 6 N aqueous hydrogen chloride solution, and the mixture was stirred overnight at 80° C. The solvent was evaporated to give the title compound, which was used for the synthesis of A-22.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10]1[CH:26]=[CH:25][C:13]([C:14]([NH:16][CH:17]([N:22]=[C:23]=[O:24])[C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])=[CH:12][CH:11]=1>C1COCC1>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][CH:17]([NH:22][C:23]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])=[O:24])[C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])=[CH:25][CH:26]=1
Reactant: Cc1ccc(C(=O)NC(N=C=O)C(Cl)(Cl)Cl)cc1
Reactant: Nc1ccccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(NC(=O)Nc2ccccc2F)C(Cl)(Cl)Cl)cc1
Reaction time: 2 h

Procedure:
A solution of 2-fluoroaniline (132 mg, 1.40 mmol) in THF (8 mL) at ambient temperature was treated with a solution of Example 43A (386 mg, 1.26 mmol) in THF (1.5 mL). The reaction mixture was stirred for 2 hours and concentrated to a nominal volume. The white solids which precipitated from solution were collected by filtration and washed with diethyl ether. Recrystallization from 25% ethyl acetate/hexanes provided the desired product as a white solid.
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[C:22]([CH3:34])[CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:37]1([C:43]2[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:43]1([C:37]2[CH:38]=[CH:39][C:40]([C:2]3[CH:36]=[CH:35][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:25]=[CH:24][C:23]([N:26]6[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]6)=[C:22]([CH3:34])[CH:21]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:11]=4)=[CH:4][CH:3]=3)=[CH:41][CH:42]=2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: Cc1cc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)ccc1N1CC(=O)NS1(=O)=O
Product: Cc1cc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C4CCCCC4)cc3)cc2)ccc1N1CC(=O)NS1(=O)=O

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-2-methyl-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (61 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (41 mg, 0.2 mmol) to give 5-{4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-2-methyl-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)(Cl)Cl>[NH2:20][C:10]1[C:9]2[N:8]=[C:7]([CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=2[N:11]=1
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNS(C)(=O)=O
Temperature: 0 °C
Yield: 37.4 %

Procedure:
A suspension of 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (3.27 g, 8.7 mmol) and triethylamine (3.82 mL, 11.3 mmol) in chloroform (165 mL) was cooled to 0° C. A cold solution of methanesulfonyl chloride (1.37 mL, 9.6 mmol) in chloroform (10 mL) was slowly added. The reaction was allowed to warm to ambient temperature after 15 minutes. Additional triethylamine (3.74 mL) and methanesulfonyl chloride (2.12 mL) were added over the course of several days to drive the reaction to completion. The reaction was concentrated under reduced pressure, and the residue was partitioned between 1% aqueous sodium carbonate and chloroform. The aqueous layer was adjusted to pH 13 with the addition of saturated aqueous sodium bicarbonate and 50% aqueous sodium hydroxide. The precipitate was isolated by filtration, air-dried, and combined with material from another run. The crude product was recrystallized from isopropanol:water (15 mL/g:1.5 mL/g) and dried in a drying oven for several days to provide 1.48 g of N-{4-[4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide as a white solid.