Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Cl.[S:6]([O-:9])([O-:8])=[O:7].[Na+:10].[Na+].O>COCCOC>[CH3:1][O:2][CH2:3][CH2:4][S:6]([O-:9])(=[O:8])=[O:7].[Na+:10]
Reactant: COCCCl
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COCCS(=O)(=O)[O-]

Procedure:
To a solution of 2-chloroethyl methyl ether (Acros, 68.0 mL) in 1,2-dimethoxyethane (DME) (250 mL) was added sodium sulfite (103 g) and water (250 mL). The reaction mixture was heated at reflux for 18 hours. The solvent was removed in vacuo and the residue was extracted with methanol (500 mL). The solid was removed by filtration and washed with methanol (250 mL). The combined filtrate and washings were evaporated in vacuo to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:14]([C:4]1[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][CH:5]=1)[C:13]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=1[F:11])=[CH:5][NH:6]2
Reactant: Clc1cccc2[nH]ccc12
Reactant: O=Cc1ccc(F)cc1F
Product: Fc1ccc(C(c2c[nH]c3cccc(Cl)c23)c2c[nH]c3cccc(Cl)c23)c(F)c1

Procedure:
The compound Bis(4-chloroindol-3-yl)-(2,4-difluorophenyl)methane was prepared following procedure A, starting from 4-chloro indole and 2,4-difluoro benzaldehyde. LC: Tr 2.63 min, MS: 427 (M+H)+
Reaction SMILES: [Si]([O:18][C@@H:19]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:33]2[CH2:32][CH2:31][C@@:29]2([CH3:30])[C@H:25]3[CH2:26][CH2:27][C@@H:28]2[C:38]#[C:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[C:43]1([CH3:46])[CH:44]=[CH:45][C:40]([C:39]#[C:38][C@H:28]2[CH2:27][CH2:26][C@H:25]3[C@H:24]4[C@H:33]([CH2:32][CH2:31][C@:29]23[CH3:30])[C@:34]2([CH3:37])[C@H:21]([CH2:20][C@H:19]([OH:18])[CH2:36][CH2:35]2)[CH2:22][CH2:23]4)=[CH:41][CH:42]=1
Reactant: Cc1ccc(C#C[C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O[Si](c6ccccc6)(c6ccccc6)C(C)(C)C)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C#C[C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3α-(t-butyldiphenylsilyloxy)-17β-[2-(4-tolyl)ethynyl]-5α-androstane (80 mg, 0.13 mmol) in anhydrous tetrahydrofuran (5.2 mL) was treated with a 1M solution of (n-Bu)4N+F− (2.6 mL, 2.6 mmol) and the resulting solution was stirred at RT for 48 h. Work up of the reaction was accomplished as in Example 2. Purification by flash column chromatography using dichloromethane as eluent afforded the desired product named above.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:6][C:7]1[O:8][C:9]2[CH:15]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: Nc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(S(=O)(=O)Cl)cc2o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
7.5 ml of chlorosulfonic acid was stirred at room temperature under an inert atmosphere (nitrogen). 5 g of 2-aminobenzoxazol (7-2) was added in small portions. The temperature was kept between 30-60° C. during the addition of 7-2. The mixture was heated to 80° C. for 2 hours. 5.3 g of thionyl chloride was added drop wise, keeping the temperature at 65° C. The mixture was stirred during 2 hours. After cooling to 0° C. 0.10 ml of ethyl acetate and 10 ml of a solution of sodium carbonate (1N) were added. The organic layer was separated from the water layer and this latter was extracted with ethyl acetate. The combined organic layers were dried over calcium chloride, yielding 7.8 g (90%) of 2-amino-6-chlorosulfonylbenzoxazole (7-3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH:9]([CH2:15][C:16]2[O:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH:9]([CH2:15][C:16]2[O:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionate (3.3 g, 9.16 mmol) in methanol (9.2 ml) was added 2N aqueous sodium hydroxide solution (9.2 ml,18.4 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionic acid (2.43 g, 80%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[CH:8]=[C:7]3[O:13][CH2:14][O:15][C:6]3=[CH:5][C:4]=2[N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>CN1C(=O)CCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[CH:8]=[C:7]4[O:13][CH2:14][O:15][C:6]4=[CH:5][C:4]=3[N:3]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1nc(Cl)nc2cc3c(cc12)OCO3
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(N)c3cc4c(cc3n2)OCO4)CC1
Yield: 39 %

Procedure:
A mixture of 6-chloro-[1,3]dioxolo[4,5-g]quinazolin-8-ylamine (0.9 g, 4.02 mmol equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.61 g, 8.05 mmol, 2.0 equiv; commercially available) in anhydrous NMP (8 mL) and triethylamine (2 mL) was heated by microwave irradiation to 170° C. for 1 h. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified with column chromatography on silica eluting with a gradient of toluene/ethyl acetate (4:1→2:1) providing 0.6 g (39%) of the title compound. MS (ISP): 388.4 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:25])=[C:7]([C:16]([I:24])=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[C:18]=1[I:19])[C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])(=[O:3])[CH3:2].[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1O)([O-:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>>[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:14][C:13](=[O:15])[CH2:12][CH2:11][NH:10][C:8](=[O:9])[C:7]1[C:6]([I:25])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:18]([I:19])=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[C:16]=1[I:24])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)NCCC(=O)O)c1I
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)NCCC(=O)Oc2ccccc2[N+](=O)[O-])c1I

Procedure:
Following the procedure of example 33 the product is synthesized from 13.7 g (20 mMol) N-(3,5-diacetamido-2,4,6-triiodobenzoyl)-β-alanine, 3.5 g (25 mMol)-o-nitrophenol and 5 g (24 mMol) N,N'-dicyclohexylcarbodiimide. Yield 11 g (68%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][NH2:31])=[CH:29][C:24]=2[N:23]=[CH:22]1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][NH:31][C:2]3[C:3]4[CH2:11][N:10]([C:12]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=5[C:14]#[N:15])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:29][C:24]=2[N:23]=[CH:22]1
Reactant: NCc1ccc2ocnc2c1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5ocnc5c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (100 mg, 0.35 mmol) and benzo[d]oxazol-5-ylmethanamine (150 mg, 0.41 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) was subjected to microwave irradiation at 185° C. for 2.5 h. The reaction mixture was concentrated and purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% CH3CN-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:16]=1)[C:8](N(OC)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg]Br.Cl>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([C:8](=[O:9])[CH3:22])[CH:14]=[C:15]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: COCCOc1cc(C(=O)N(C)OC)cc(C(C)(C)C)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cc(C(C)=O)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-tert-Butyl-N-methoxy-5-(2-methoxyethoxy)-N-methylbenzamide (O3.043; 1.35 g) was dissolved in THF (40 ml), methylmagnesium bromide (3.05 ml, 3 M in ether) was added dropwise at 0° C. and then the mixture was stirred at RT for 2 h. Then the mixture was admixed with 1 N hydrochloric acid (50 ml), diluted with water and extracted by shaking three times with EA. Then the combined EA phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-30% in 30 min). 1.0 g of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[Cl:25][C:26]1[C:27]([NH2:41])=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[NH2:41][C:27]1[N:28]=[CH:29][C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)=[CH:31][C:26]=1[Cl:25]
Reactant: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cnc(N)c(Cl)c2)OC1(C)C
Product: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N)c(Cl)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 0.075 mmol) and 3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (stage 148.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.53 min (Method A); M+H=485 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.94 (s, 1H), 8.51-8.49 (m, 1H), 8.08-8.04 (m, 1H), 7.96-7.92 (m, 1H), 7.72-7.69 (m, 1H), 7.39-7.36 (m, 1H), 6.74 (s, br, 2H), 3.80 (s, 3H), 3.58 (s, 3H), 2.08 (s, 3H), 1.89 (s, 3H))
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.[CH:16](I)([CH3:18])[CH3:17].O>CN(C=O)C>[CH:16]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1)([CH3:18])[CH3:17]
Reactant: CC(C)I
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(C(C)C)c2ccccc12
Reaction time: 7 h
Yield: 77.8 %

Procedure:
In DMF (8.0 ml) was suspended sodium hydride (60% in oil, 275.2 mg, 6.881 mmol). To the resulting suspension was added methyl indole-3-carboxylate (401.8 mg, 2.294 mmol) at 0° C. under stirring. After stirring for further 45 minutes at the same temperature, isopropyl iodide (0.34 ml, 3.440 mmol) was added to the reaction mixture. Stirring was then conducted for 1.5 hours at 0° C. and for 7 hours at room temperature. Water was added to the reaction mixture to terminate the reaction, followed by extraction with ethyl acetate. The extract was washed successively with 1N HCl and saturated saline, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (3:1, v/v) eluate fractions, methyl 1-isopropylindole-3-carboxylate (387.6 mg, 78%) was obtained as a light yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([S@:23]([NH2:25])=[O:24])([CH3:22])([CH3:21])[CH3:20]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14](/[CH:17]=[N:25]/[S@@:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:24])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C[C@H]1CC[C@H](CCOCc2ccccc2)CC1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C/[C@H]1CC[C@H](CCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (trans-4-(2-(benzyloxy)ethyl)cyclohexanecarbaldehyde (6.45 g, 26.18 mmol) and (R)-(+)-tert-butylsulfinamide (3.49 g, 28.8 mmol) in THF (66 mL) was added titanium(IV) ethoxide (8.78 mL, 41.89 mmol) under N2. The resulting solution was stirred at rt for 20 h and quenched by addition of saturated NaHCO3 solution dropwise. The mixture was vigorously stirred for 30 min and filtered through a pad of Celite, concentration. Purification by flash column chromatography (eluent: 20% EtOAc in hexanes to 30%) gave the titled product (8.38 g, 92%). LC/MC: 350.1 (MH)+.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[C:27]([CH2:30][C:31]1[N:32]2[CH:38]=[N:37][CH:36]=[C:33]2[S:34][CH:35]=1)(=[O:29])[NH2:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:37]3[CH:36]=[C:33]4[S:34][CH:35]=[C:31]([CH2:30][C:27](=[O:29])[NH2:28])[N+:32]4=[CH:38]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: NC(=O)Cc1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(CC(N)=O)[n+]4c3)[C@H](C)[C@H]12
Yield: 3.9 %

Procedure:
The same procedure as in Example 1 was repeated except that 95 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 70 mg of 3-carbamoylmethylimidazo[5,1-b]thiazole were used, thereby obtaining 4.1 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: CS(=O)c1ccc(C(=O)CBr)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)c1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Yield: 54.6 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (399 mg). and 2-bromo-4'-methylsulphinylacetophenone (784 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for one hour, when the resulting suspension was chilled in ice. The collected solid was crystallised from ethanol to give the title pyrimidinone (509 mg,); m.p. 219°-220°; λmaxEtOH 233.5 nm (ε 17920), 332 nm (ε 2060), λinf 266 nm (ε 9280).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([NH2:23])=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:36][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][C:21]([NH2:23])=[O:22])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(N)=O

Procedure:
4-[2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanamide (4.3 g, 14 mmol) was treated with mCPBA (6.1 g, 27 mmol), concentrated ammonium hydroxide (50 mL of 29%), and p-toluenesulfonyl chloride (4.6 g, 24 mmol) according to a modification of the method described in Part E of Example 3. The mCPBA addition was carried out at 0° C., and the reaction was carried out in dichloromethane (150 mL). At the end of the reaction the layers were separated, and saturated aqueous sodium bicarbonate (100 mL) and 5% aqueous sodium hydroxide (10 mL) were added to the organic layer. The aqueous layer was extracted with dichloromethane (1.3 L), and the combined extracts were dried over potassium carbonate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol containing 4 mL/L of ammonium hydroxide) followed by recrystallization five times from ethanol containing a small amount of water. The resulting solid was recrystallized from water:acetonitrile (5:L), dried overnight in a vacuum oven at 70° C., triturated with 25% aqueous ammonium hydroxide, diluted with water, isolated by filtration, recrystallized from ethanol:water, and dried overnight in a vacuum oven at 70° C. to provide 0.4704 g of 4-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanamide as tan crystals, mp 233-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C.[S:23](=O)(=[O:26])([OH:25])[OH:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:13]=[C:12]([S:23]([OH:26])(=[O:25])=[O:24])[S:11][CH:10]=2)=[O:8])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)c2ccsc2)cc1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2csc(S(=O)(=O)O)c2)cc1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
9.7 g (0.05 mol) of product from Step A was dissolved in 75 ml CH2Cl2 and cooled to -10° C. Then, 15.3 g (0.15 mol) acetic anhydride was added dropwise followed by the dropwise addition of 5.9 g (0.06 mol) concentrated sulfuric acid. The resulting mixture was stirred at room temperature overnight.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=O)[CH:21]([C:24](=O)[CH3:25])[CH2:20][CH2:19][CH2:18][C:8]=2[N:9](C(OC(C)(C)C)=O)[CH:10]=1)=[O:5])[CH3:2].C(O)(=O)C.[CH:31]([NH2:33])=[NH:32]>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22]3[N:32]=[CH:31][N:33]=[C:24]([CH3:25])[C:21]=3[CH2:20][CH2:19][CH2:18][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: N=CN
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(C(C)=O)CCC2
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2c1-c1ncnc(C)c1CCC2
Temperature: 120 °C
Yield: 36 %

Procedure:
Bismuth (III) chloride (0.1 mmol) and sodium iodide (0.3 mmol) are transferred to a dried flask under nitrogen and 5 mL of a mixture of CH2Cl2/ether (9/1) is added by a syringe. This is followed by the addition of acetyl chloride (2.2 mmol) and the suspension is stirred for 5 min at RT. 4-trimethylsilanyloxy-7,8-dihydro-6H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2 mmol) in 5 mL of the same solvent mixture is added. After 2 hours at RT, the mixture is quenched with 20 mL saturated NaHCO3 solution and extracted several times with CH2Cl2. The organic layers are combined, dried over Na2SO4 and evaporated in vacuo yielding 5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester as an oil (86%). LRMS 363.4 found (M+1) 364.2 Step 3: In a sealed tube are 5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.1 mmol) and formamidine acetate (5.5 mmol) and 10 mL EtOH. The mixture is heated at 120° C. for 48 hours. The solvent is evaporated in vacuo and the residue is taken up in CH2Cl2 and washed two times with NaHCO3 (aq). The organic layer is dried over Na2SO4 and evaporated in vacuo and the residue chromatographed using 10% MeOH in CH2Cl2 as mobile phase to yield 7-Methyl-3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid ethyl ester (36%). LRMS 271.1 found (M+1) 272
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1)(=O)=O.[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1.CN(C)C=O>C(O)(C)C>[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Reactant: CC1CCCCN1
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CC1CCCCN1[C@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Temperature: 25 °C

Procedure:
A stirred solution of (R)-1-(6-(4-cyanophenyl)benzo[d]thiazol-2-yl)pyrrolidin-3-yl methanesulfonate (Reference Example 14b, 20 mg, 0.050 mmol), 2-methylpiperidine (0.029 mL, 0.25 mmol), and N,N-dimethylformamide (0.01 mL) in isopropanol (0.50 mL) was heated at 150° C. under microwave irradiation for 15 minutes. The reaction mixture was cooled to room temperature, concentrated, and purified by silica gel chromatography (100:0 to 70:30 dichloromethane/ethyl acetate, then 98:2 to 92:8 dichloromethane/methanol). Fractions containing product were combined and concentrated under reduced pressure to give 4-(2-435)-3-(2-methylpiperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yl)benzonitrile. 1H NMR (300 MHz, CD2Cl2) δ ppm 1.06-1.12 (m, 3H), 1.37-1.45 (m, 2H), 1.54-1.61 (m, 1H), 1.67-1.77 (m, 2H), 2.01-2.16 (m, 2H), 2.19-2.29 (m, 1H), 2.35-2.51 (m, 1H), 2.63-2.70 (m, 1H), 2.81-2.95 (m, 1H), 3.36-3.50 (m, 1H), 3.50-3.79 (m, 5H), 7.55 (s, 2H), 7.72 (s, 4H), 7.88 (s, 1H); MS (ESI) m/z 403 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:10]([C:11]([CH3:13])=[CH2:12])[CH2:9][CH2:8][C:7]=1[CH3:14])[CH:3]=[O:4].C>O1CCOCC1.[Pd]>[CH3:1][CH:2]([CH2:5][C:6]1[CH:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][C:7]=1[CH3:14])[CH:3]=[O:4]
Reactant: C=C(C)C1CCC(C)=C1CC(C)C=O
Agent: [Pd]
Solvent: C1COCCO1
Product: CC1=C(CC(C)C=O)C(C(C)C)CC1
Yield: 94.2 %

Procedure:
19.2 g (0.1 Mole) of 2-methyl-3-(2-methyl-5-isopropenyl-cyclopent-1-en-1-yl)-propanal in 100 ml of dioxan were reduced by catalytic hydrogenation in the presence of traces of palladium over charcoal. After absorption of 2,300 ml of hydrogen (10 hours) the reaction mixture was filtered and the clear filtrate evaporated under reduced pressure. The obtained residue was then distilled to give 18.3 g of the desired aldehyde; bp. 45°-50°/0.1 Torr; nD = 1.4710; d20 = 0.9069;