Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([C:23]2C=CC=CC=2)[CH2:8][CH2:7][N:6]([CH2:9][C@@H:10]([C:12]2[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=2[CH3:22])[OH:11])[CH2:5]1.Cl[C:30]1[N:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1>>[OH:11][C@H:10]([C:12]1[C:13]([CH3:22])=[C:14]2[C:15](=[CH:20][CH:21]=1)[C:16](=[O:19])[O:17][CH2:18]2)[CH2:9][N:6]1[CH2:7][CH2:8][C:4]([CH2:3][NH:2][C:30]2[CH:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][N:35]=2)([CH3:23])[CH2:5]1
Reactant: Cc1c([C@@H](O)CN2CCC(CN)(c3ccccc3)C2)ccc2c1COC2=O
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Product: Cc1c([C@@H](O)CN2CCC(C)(CNc3ccc(C#N)cn3)C2)ccc2c1COC2=O

Procedure:
6-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methylpyrrolidin-3-yl)methylamino)nicotinonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 18 starting from 5-[(R)-2-[3-(Aminomethyl)-3-phenylpyrrolidin-1-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 15] and 6-chloropyridine-3-carbonitrile.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([OH:13])[C:10]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH2:9]1[C:10]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:11]([OH:13])[CH2:12][NH:8]1
Reactant: OC1CN(Cc2ccccc2)CC12CCCC2
Agent: [Pd]
Solvent: CO
Product: OC1CNCC12CCCC2
Temperature: 45 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-benzyl-2-azaspiro[4.4]nonan-4-ol (20.00 g, 86.5 mmol) in MeOH (200 mL) was added Pd/C (10% wt, 3.00 g). The suspension was stirred at 45° C. under a H2 atmosphere overnight and filtered. The filtered cake was washed with EtOAc (50 mL×3). The filtrate was concentrated in vacuo to give the product as yellow oil (12.21 g, 100%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:25]=[CH:24][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH2:23])[CH2:18]2)=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+].[Cl-].[Na+]>ClC1C=CC=CC=1>[Cl:10][C:11]1[CH:25]=[CH:24][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:18]2)=[O:16])=[CH:13][CH:12]=1
Reactant: N[C@@H]1CCCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: O=C(N[C@@H]1CCCN(C(=O)c2ccc(Cl)cc2)C1)c1ccccc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 114.8 %

Procedure:
Benzoyl chloride (0.15 g) was added to the aqueous solution of (R)-1-(p-chlorobenzoyl)-3-aminopiperidine obtained in Example 14 (amount: 3 g), and the pH of the mixture was kept from 8.0 to 9.0 using sodium hydroxide. The mixture was stirred at 15° C. for 3 hours, and chlorobenzene (3 ml) and sodium chloride (0.5 g) were added thereto. The mixture was stirred at 90° C. for 10 minutes. The water layer was removed, and the solvent was evaporated under reduced pressure to obtain the title compound as yellow crystal (0.42 g, yield: 100%).
Reaction SMILES: Cl[C:2]([N:6](C)C)=C(C)C.[C:9]([O:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([C:25]([OH:27])=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl.C(N(CC)CC)C.Cl.CN.CN(C1C=CN=CC=1)C>[CH3:2][NH:6][C:25]([CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)c2ccccc21
Reactant: CC(C)=C(Cl)N(C)C
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)C1CN(C(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.35 ml of 1-chloro-N,N,2-trimethylpropenylamine is added to a solution of 0.59 g of 1-(tert-butoxycarbonyl)indoline-3(R,S)carboxylic acid in methylene chloride at 0° C. After 30 min, 0.93 ml of triethylamine, 0.23 g of methylamine hydrochloride and 4-DMAP, as a catalyst, are added and the mixture is stirred at room temperature for 3 h. The reaction mixture is then chromatographed directly over 80 g of silica gel (mobile phase J). This gives the title compound: Rf (P)=0.65.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[CH2:8][CH2:9]Cl)=[CH:4][CH:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>COCCOC.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[CH2:8][CH2:9][N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CN(CCCl)Cc1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: COCCOC
Product: CN1CCN(CCN(C)Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a solution of 73 (3.5 g, 13.3 mmol) in DME (20 ml) was added N-methylpiperazine (3.33 g, 2.5 eq, 33.3 mmol) and tetrabutylammonium bromide (cat). The reaction mixture was heated to reflux for 3 hrs, then cooled to RT and concentrated. The crude was dissolved in EtOAc, washed well with water and the organic phase was collected, dried over Na2SO4 and filtered then concentrated. Purification by column chromatography (20% MeOH in EtOAc+1% TEA) afforded 74 as colorless oil (3.0 g, 69% yield). MS (m/z): 326.0/328.0 (M+H).
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NC5C=CC(C6C=CC(CCCC=O)=CC=6)=CC=5)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:53][CH2:54][CH2:55][CH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][C:66]([S:69]([C:72]3[CH:73]=[C:74]4[C:79](=[C:80]([CH3:82])[CH:81]=3)[N:78]=[CH:77][C:76]([C:83]([NH2:85])=[O:84])=[C:75]4[NH:86][C:87]3[CH:92]=[CH:91][CH:90]=[C:89]([O:93][CH3:94])[CH:88]=3)(=[O:71])=[O:70])=[CH:65][CH:64]=2)=[CH:59][CH:58]=1>>[CH3:94][O:93][C:89]1[CH:88]=[C:87]([NH:86][C:75]2[C:74]3[C:79](=[C:80]([CH3:82])[CH:81]=[C:72]([S:69]([C:66]4[CH:65]=[CH:64][C:63]([C:60]5[CH:61]=[CH:62][C:57]([CH2:56][CH2:55][CH:54]=[O:53])=[CH:58][CH:59]=5)=[CH:68][CH:67]=4)(=[O:70])=[O:71])[CH:73]=3)[N:78]=[CH:77][C:76]=2[C:83]([NH2:85])=[O:84])[CH:92]=[CH:91][CH:90]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CCCO)cc5)cc4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCC=O)cc6)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CCC=O)cc5)cc4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 124, using Intermediate 66 as a substrate. ES/MS calcd. for C33H30N3O5S+ 580.2. Found m/z=580.3 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.I[Si](C)(C)C>C(#N)C>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][C:4]1([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:13])[CH2:12][C:3]1=[O:2]
Reactant: COC(=O)C1(CCC(C)C)C(OC)=CC(=O)c2ccccc21
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: COC(=O)C1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
To a solution of Example 178B (0.18 g, 0.6 mmol) in acetonitrile (2 mL) was added iodotrimethylsilane (TMSI) (0.13 mL, 0.9 mmol). The reaction solution was stirred at room temperature for 3 h. After which, additional 1.5 equivalents of TMSI (0.13 mL) were added and stirring was continued for 2 h. The solution was quenched with water (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (40%-80% ethyl acetate/hexane) afforded product as a white solid (0.11 g, 65%). 1H NMR (300 MHz, CDCl3) δ ppm 0.46 (m, 1 H), 0.79 (m, 7 H), 1.41 (m, 1 H), 2.29 (m, 1 H), 2.53 (m, 1 H), 3.60 (s, 3 H), 3.83 (m, 1 H), 6.11 (s, 1 H), 7.52 (m, 3 H), 8.12 (d, J=7.72 Hz, 1 H); MS m/z 289.0 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1([CH3:14])[NH:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>>[CH3:1][CH2:2][O:3][C:4]([C:6]1([CH3:14])[N:10]([C:22](=[O:24])[CH3:23])[CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5]
Reactant: CCOC(=O)C1(C)NC(C(=O)O)CS1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C)SCC(C(=O)O)N1C(C)=O

Procedure:
L-Cysteine hydrochloride monohydrate (100 g, 569 mmol) was dissolved in water (200 ml), and the pH of the solution was adjusted to 5.03 with 6N aqueous sodium hydroxide. The reaction mixture was heated to 40° C., ethyl pyruvate (76 ml, 684 mmol) was gradually added thereto, and the mixture was stirred at 40° C. for 3.5 hr to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by the area ratio of an HPLC chart to find about 55:45). After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. To the obtained ethyl acetate solution was added triethylamine (159 ml, 1141 mmol) under argon, and acetyl chloride (61 ml, 858 mmol) was slowly added dropwise thereto. The reaction mixture was heated under reflux for 4 hr to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by the area ratio of an HPLC chart to find about 95:5). After completion of the reaction, water (300 ml) was added thereto, and the pH of the mixture was adjusted to 1.0 with HCl. The aqueous layer was separated, and the organic layer was washed with water (300 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. The obtained ethyl acetate solution was concentrated until a weight of 500 g, to the residue was added heptane to allow recrystallization of the residue, and the crystals were washed with heptane/ethyl acetate=2/1, and dried at 50° C. under reduced pressure to give the trans form (mixture of (2R,4S)-form, (2S,4R)-form) of N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester as crystals (81 g, yield 55%).
Reaction SMILES: C[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC1(O)CCC1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20](=[O:28])[O:21]C1C=CC=CN=1>[NH4+].[Cl-]>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20](=[O:21])[O:28][C:3]1([CH3:2])[CH2:4][CH2:5][CH2:6]1
Reactant: CCCCCC
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: CC1(O)CCC1
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(OC(=O)Oc2ccccn2)CCC1
Reaction time: 0.08 h

Procedure:
To a slurry of KH (400 mg, 35% in oil, 3.5 mmol) was added 5 mL of hexane. It was stirred for 5 min, and then the hexane was removed. This process was repeated three times. THF (5 mL) was added to this prewashed KH, and then 1-methylcyclobutanol (200 mg, 2.3 mmol) was added at 0° C. The mixture was stirred (0° C. to rt) for 1 h, and then carbonic acid dipyridin-2-yl ester (753 mg, 3.5 mmol) was added. The mixture was stirred at rt for 4 h, and the reaction was diluted with sat. aq. NH4Cl. The mixture was then extracted with EtOAc, and the solvent was removed in vacuo to obtain 200 mg of the crude carbonic acid 1-methyl-cyclobutyl ester pyridin-2-yl ester as an orange solid. It was used directly in the next step without further purification.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7]>CC(O)=O>[Br:1][C:8]1[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:5]([O:4][CH3:3])[C:6]=1[NH2:7]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])cc(Br)c1N
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
47.64 g of bromine in 120 mL of AcOH was added dropwise to a solution of 47.64 g of 2-methoxy-4nitro-aniline in 240 ml of AcOH at 0° C. Upon addition a precipitate formed. Mixture was stirred for 30 minutes and then filtered. The precipitate was washed with satd. NaHSO3, water, and vaccum dried, giving 24 g of title compound as a bright yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:42][CH2:41][N:40]([C:37]5[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=5)[CH2:45][CH2:44]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: COc1ccc(N2CCN(C(=O)c3cccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)c3)CC2)cc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=621.98 (M+H+); retention time=0.92 minutes.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:18][CH2:17]1)[CH3:3].[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:44]([CH:47]2[C:51]([CH3:52])=[N:50][NH:49][N:48]2[CH3:53])=[CH:43][C:39]=1[C:40](O)=[O:41].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl.CO.ClCCl>[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:44]([CH:47]2[C:51]([CH3:52])=[N:50][NH:49][N:48]2[CH3:53])=[CH:43][C:39]=1[C:40]([N:27]1[CH2:28][CH2:29][C:25]([CH2:24][CH2:23][N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:8]3[N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:17][CH2:18]2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)=[O:41]
Reactant: COc1ccc(C2C(C)=NNN2C)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(C5C(C)=NNN5C)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 144 h

Procedure:
Combine 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (0.64 g, 1.2 mmol) and dichloromethane (12 mL). Add 2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoic acid (0.3 g, 1.2 mmol), 1-hydroxybenzotriazole hydrate (0.17 g, 1.23 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g, 1.5 mmol), and triethylamine (0.34 mL, 2.4 mmol). After 6 days, dilute the reaction mixture with dichloromethane and extract with a saturated aqueous sodium bicarbonate solution and then brine, dry the organic layer over MgSO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% methanol/dichloromethane and then 20% methanol/dichloromethane to give a residue. Combine the residue and dichloromethane, extract with water and then brine, dry over Na2SO4, and evaporate in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH3:26][CH:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:29]([CH:27]([CH3:28])[CH3:26])(=[O:31])=[O:30])=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a slurry of cis-2-(4-bromophenoxy)cyclopentanamine (1.43 g, 5.58 mmol) in methylene chloride (38.5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.40 mL, 9.36 mmol), then 4-(dimethylamino)pyridine (915 mg, 7.49 mmol). The reaction mixture was cooled to 0° C. and propane-2-sulfonyl chloride (0.937 mL, 8.38 mmol) was added drop-wise. The mixture was then allowed to warm to room temperature and stir for 18 hours. The reaction was treated with 1N aqueous hydrochloric acid, and the organic layer was washed with saturated aqueous sodium chloride solution, dried over calcium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Gradient: 0% to 15% ethyl acetate in heptane) to provide product as a colorless gum. Yield: 1.586 g, 4.38 mmol, 78%.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.C(O)C.[CH3:18][NH:19][NH2:20]>O>[CH3:18][N:19]([C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1)[NH2:20]
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Reactant: CNN
Solvent: O
Solvent: CCO
Product: Cc1cc(C)n(-c2ccc(N(C)N)nn2)n1

Procedure:
A mixture of 4.17 g (0.02 moles) of 3-chloro-6-(3,5-dimethyl-1-pyrazolyl)-pyridazine, 42 ml of ethanol and 2.3 g (0.05 moles) of methyl hydrazine is heated to reflux for 9 hours, and after cooling the mixture is poured into 100 ml of water. The solution is extracted with 3×50 ml of chloroform and the combined organic phases are dried over magnesium sulphate. After evaporation the residue is recrystallized from a 3:1 mixture of isopropanol and petroleum ether. Yield: 1.9 g (44.5%); m.p.: 93°-94° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21]C=CC=4)N=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.C(OC1C=CC(C(N(OC)C)=O)=C([F:48])C=1)C1C=CC=CC=1>>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[C:15]([F:48])[CH:14]=1)[C:18]1[CH:27]=[CH:26][CH:25]=[CH:20][CH:21]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1F
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1F

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 4-Benzyloxy-2-fluoro-N-methoxy-N-methyl-benzamide provided the title compound. MS: (M+H m/z=322.1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Cl:25][CH2:26][CH2:27][CH2:28]Br>>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:28][CH2:27][CH2:26][Cl:25])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Reactant: ClCCCBr
Product: CC(C)(C)c1cc(-c2nn(CCCCl)c3ncccc23)cc(C(C)(C)C)c1O

Procedure:
3-(3,5-Di-tertiary butyl-4-hydroxyphenyl)-1-(3-chloropropyl)-1H-pyrazolo[3,4-b]pyridine, melting at 107°-109° C. is prepared by reacting the compound of Example 1 with 3-chloropropyl bromide in a similar manner as Example 9, and recrystallizing from acetonitrile.
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][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]1([O:30][C:31](Cl)=[O:32])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[O:30][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)Oc1cccc2ccccc12
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)Oc1cccc2ccccc12

Procedure:
According to the general method of Example 7, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and chloroformic acid 1-naphthyl ester were combined to provide 1-naphthyl N-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a tan powder, m.p. 89.0-92.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.10 (d, J=7.4 Hz, 1H), 8.05 (t, J=5.8 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.66-7.45 (m, 6H), 7.30 (m, 1H), 7.19 (d, J=7.5 Hz, 1H), 6.72 (broad s, 2H), 4.67 (t, J=6.9 Hz, 2H), 3.17 (q, J=6.3 Hz, 2H), 1.96 (m, 2H), 1.59 (m, 2H); MS (EI) m/c 426.1929 (426.1930 calcd for C25H13N5O2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H]1CC[C@@H](O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
To a stirred, ice cold solution of 1.8 g of cis-4-hydroxy-cyclohexanecarboxylic acid ethyl ester, and 2.8 mL of triethylamine, in 25 mL of dichloromethane was added 0.85 mL of methane-sulfonyl chloride drop-wise over 10 min. The mixture was allowed to stir for 30 min, then concentrated under reduced pressure and diluted with 50 mL of ether and washed with 25 mL of 10% HCl, 25 mL of water, 25 mL of saturated sodium carbonate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude mesylate, 2.5 g, was used without further purification: 1H NMR (400 MHz, CDCl3) 4.92 (m, 1H), 4.15 (q, 2H), 3.02 (s, 3H), 2.4 (m, 1H), 2.05 (m, 2H), 1.92 (m, 2H), 1.62-1.4 (complex m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[C:6](\[Br:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:14]C(C)(C)C)=[O:13].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[C:6](\[Br:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: COC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Temperature: 20 °C
Yield: 105.7 %

Procedure:
A mixture of 3.3 g of the product of Step B, 30 ml of toluene and 0.33 g of p-toluene sulfonic acid monohydrate was refluxed until gas evolution ceased and was cooled to 20° C. and diluted with ether. The ether phase was washed with water, dried and evaporated to dryness at 40° C. under reduced pressure to obtain 2.9 g of (1R,cis) 2,2-dimethyl-3(Z)-[2-bromo-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylic acid.
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccncc4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OCc3ccncc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
Ethyl 3-[{[4-({cyclohexyl[3-methyl-5-(pyridin-4-ylmethoxy)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.17 g) synthesized in the above-mentioned (1) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (3.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol, was evaporated under reduced pressure, 1N hydrochloric acid (3.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.13 g, 77%) as a pale-yellow solid.