Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH2:25])([CH3:19])([CH3:18])[CH3:17].CCN(CC)CC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH:25][S:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:14])=[O:13])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
Powdered 1-chloro-isoquinoline-5-sulfonyl chloride (10.0 g, 38.2 mmol) is added in portions to a stirred solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (7.33 g, 45.8 mmol) and NEt3 (10.7 mL, 76.4 mmol) in anhydrous CH2Cl2 (200 mL) at 0° C. under nitrogen. The resultant mixture is allowed to stir at ambient temperature for 4 hours. The mixture is concentrated and chromatographed on silica gel (gradient 0-5% CH3OH in CH2Cl2) to give 13.8 g (35.8 mmol, 94% yield) of the title compound as foam. ESIMS: m/z 386 [(M+H)+, 35Cl], 388 [(M+H)+, 37Cl]. Analysis for C16H20ClN3O4S: calcd: C, 49.80; H, 5.22; N, 10.89; found: C, 49.70; H, 5.22; N, 10.72.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C@@H:12]([NH2:14])[CH3:13])[CH:6]=1.C(N(CC)CC)C.CN1CCCC1=O.C(N[CH2:38][C@@H:39]([C:48]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[C:54]2[C:49]=1[CH:50]=[CH:51][C:52](=[O:66])[NH:53]2)[O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])C1C=CC=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C@@H:12]([NH:14][CH2:38][C@@H:39]([C:48]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[C:54]3[C:49]=2[CH:50]=[CH:51][C:52](=[O:66])[NH:53]3)[O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(C[C@H](C)N)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1cccc(C[C@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Yield: 21.7 %

Procedure:
A solution of [3-((S)-2-aminopropyl)phenyl]acetic acid methyl ester (632 mg, 3.05 mmol) and triethylamine (1.27 mL, 9.15 mmol) in N-methylpyrrolidinone (3.4 mL, 35 mmol) was added to 8-benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethylsilanyloxy)-ethyl]-1H-quinolin-2-one (1.5 g, 3.0 mmol) (see, e.g., U.S. Patent Publication No. 2006/0035931 A1, published Feb. 16, 2006). The resulting mixture was microwaved (300 watts) at 100° C. for 1.5 h. The mixture was then diluted with EtOAc (20 mL) and this solution was washed repeatedly with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% MeOH in DCM) to give the title compound (400 mg, 20% yield) as a yellow oil.
Reaction SMILES: F[C:2](F)(F)S(O)(=O)=O.[CH2:9]([OH:12])[CH2:10][CH3:11].CC[O:15][CH2:16][CH3:17]>>[CH2:9]([O:12][CH2:2][CH:16]([OH:15])[CH3:17])[CH2:10][CH3:11].[CH2:9]([O:12][CH2:2][CH2:16][CH3:17])[CH2:10][CH3:11]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCCO
Reactant: CCOCC
Product: CCCOCC(C)O
Product: CCCOCCC
Yield: 11 %
Yield: 15 %

Procedure:
Homogenous catalysts have a distinct advantage in that the application of mechanistic understanding can allow rational tuning of catalyst structure and reaction conditions to optimize activity, selectivity and lifetimes. Schlaf and coworkers have explored the reduction of terminal vicinal diols to n-alcohols using homogeneous Ru ionic hydrogenation catalysts and through these studies have provided insight into various factors that control deoxygenation selectivity. The use of diol models, which are less reactive than their polyol analogs, enabled kinetic analysis and more thorough characterization of product profiles. The most selective of the Ru hydrogenation catalysts was [Cp*Ru(CO)2(H2)][OTf], which achieved a 54% yield of 1-propanol in sulfolane solvent at 110° C. and 710 psi H2 using trifluoromethanesulfonic acid (HOTf) as the catalyst for the initial dehydration step. In addition to the 1-propanol hydrogenation product, the formation of several ether condensation products was observed, including significant yields of propylene glycol propyl ether (11%) and di-n-propyl ether (15%). The overall selectivity for reduction of the secondary hydroxyl group is 99%. The high regioselectivity of the ruthenium catalyst was impressive, but the catalyst is deactivated by water, which is a byproduct of the reaction. The active Ru dihydrogen complex is deprotonated by water to yield an inactive dimer. This catalyst decomposition makes it impractical for use with inherently wet glycerol from biodiesel production. Several ruthenium containing ionic hydrogenation catalysts with N-donor ligands have demonstrated greater solubility and stability in aqueous solution, however significant thermal decomposition and/or reduced selectivities were observed.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]=[O:5].Cl.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[NH:14])=[CH:11][CH:10]=1.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22](O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]2[N:15]=[C:4]([O:5][C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:28])([F:27])[F:18])[CH:25]=3)[CH:3]=[CH:2][N:14]=2)=[CH:11][CH:10]=1
Reactant: O=CC=C(Cl)Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: N=C(N)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: FC(F)(F)c1cccc(Oc2ccnc(-c3ccc(Cl)cc3)n2)c1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35 ml), is slowly added to a mixture consisting of a 4-chlorobenzamidine hydrochloride (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (40 mmoles) and dimethoxyethane (40 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein is completed additional 4-chlorobenzamidine hydrochloride (1 mmoles) is added. The reaction mixture is stirred for 3 hours under reflux and subsequently cooled down to ambient temperature over night and filtered through silica. The organic phase is concentrated in vacuo. The residue was purified by chromatography on Al2O3 (petrol ethers/ethyl acetate: 20/1) to yield 2.79 g (80%) of the pure product having a melting point of 92° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.[CH3:18][O:19][C:20]1[C:29]([O:30][CH3:31])=[N:28][C:27]2[C:26]([CH:32]=O)=[CH:25][C:24]([N+:34]([O-:36])=[O:35])=[CH:23][C:22]=2[N:21]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>ClCCl.C(O)C>[CH3:18][O:19][C:20]1[C:29]([O:30][CH3:31])=[N:28][C:27]2[C:22](=[CH:23][C:24]([N+:34]([O-:36])=[O:35])=[CH:25][C:26]=2[CH2:32][NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([OH:10])=[O:9])[N:21]=1
Reactant: N[C@H]1CCCC[C@H]1C(=O)O
Reactant: COc1nc2cc([N+](=O)[O-])cc(C=O)c2nc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nc2cc([N+](=O)[O-])cc(CN[C@H]3CCCC[C@H]3C(=O)O)c2nc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
105 mg (0.588 mmol) of cis-2-amino-cyclohexanecarboxylic acid and 82 μl (0.588 mmol) of triethylamine are added in succession to a solution of 129 mg (0.490 mmol) of 2,3-dimethoxy-7-nitro-quinoxaline-5-carbaldehyde in 1 ml of dichloromethane and 2 ml of ethanol. After 3 hours' stirring at room temperature, 1 g of anhydrous sodium sulfate is added to the suspension and the mixture is stirred for a further 20 hours at room temperature. The thick suspension is diluted with 0.5 ml of ethanol and 46 mg (1.23 mmol) of sodium borohydride are added. After 3 hours' stirring, there are added 0.5 ml of acetone and 10 minutes later 0.3 ml of acetic acid and filtration is carried out. The filter residue is washed with ethanol and dichloromethane. The filtrate is chromatographed on silica gel first with dichloromethane/ethyl acetate (97:3) and then with dichloromethane/methanol/glacial acetic acid (90:9:1). The title compound is obtained in the form of a white powder.
Reaction SMILES: C(Cl)(Cl)=O.Cl.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:19]([O:21][CH3:22])=[O:20])([CH3:18])[CH2:16][NH:15][N:14]=2)=[CH:9][CH:8]=1.[C:23](Cl)(=[O:25])[NH2:24].N[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1>C(OCC)(=O)C.C(N(CC)CC)C.C(#N)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([NH:24][C:23]([N:15]2[CH2:16][C:17]([C:19]([O:21][CH3:22])=[O:20])([CH3:18])[C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)=[N:14]2)=[O:25])=[N:29][CH:30]=1
Reactant: COC(=O)C1(C)CNN=C1c1ccc(Cl)cc1
Reactant: NC(=O)Cl
Reactant: Nc1ccc(Cl)cn1
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C1(C)CN(C(=O)Nc2ccc(Cl)cn2)N=C1c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To 10 ml of acetonitrile containing 4.5 ml of 2.5M phosgene in ethyl acetate was added a slurry of 2.9 g (10 mmole) of 3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole hydrochloride 2.0 g (20 mmole) of triethylamine and 20 ml of acetonitrile. After stirring for 10 minutes the carbamoyl chloride was judged to have been formed and then 1.5 g (11 mmole) of 2-amino-5-chloropyridine was added with an additional 2 g of triethylamine. After stirring for 18 hours the mixture was partitioned between ether and water, washed with brine, dried over magnesium sulfate, filtered concentrated, and chromatographed yielding N-(5-chloropyrid-2-yl)-3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide, mp 130°-146° C. NMR data was consistent with the structure.
Reaction SMILES: [Br:1][CH:2]([Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:3].C([Si](Cl)(Cl)Cl)CCCC.[CH2:23]([N:30]([CH3:32])[CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(=O)CC>[Br-:1].[CH2:23]([N+:30]([CH3:32])([CH3:31])[CH:2]([Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:3])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCO[Si](OCC)(OCC)C(C)Br
Reactant: CN(C)Cc1ccccc1
Agent: CCCCC[Si](Cl)(Cl)Cl
Solvent: CCC(C)=O
Product: CCO[Si](OCC)(OCC)C(C)[N+](C)(C)Cc1ccccc1
Product: [Br-]

Procedure:
In a manner like that used for the preparation of alpha-bromoethyltriethoxysilane, alpha-bromoamyltriethoxysilane is prepared in two steps from amyltrichlorosilane (commercially available). One-quarter mole of alpha-bromoamyltriethoxysilane (78.5g) is refluxed for 12 hours with 0.25 moles (33.75g) of benzyldimethylamine in 125 ml. of 2-butanone. The product, alpha-(benzyldimethylammonio)ethyltriethoxysilane bromide is isolated by removing the solvent under vacuum.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH:42]3[CH2:47][CH2:46][C:45]4([CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)[CH2:44][CH2:43]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1>>[CH:28]1([C:31]2[C:32]([O:41][CH:42]3[CH2:47][CH2:46][C:45]4([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]4)[CH2:44][CH2:43]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([NH:64][S:61]([CH:58]2[CH2:60][CH2:59]2)(=[O:63])=[O:62])=[O:38])[CH2:30][CH2:29]1
Reactant: O=C(O)c1cc(C2CC2)c(OC2CCC3(CCCCC3)CC2)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OC2CCC3(CCCCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoic acid, and making variations as required to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a white solid (0.034 g, 34%): 1H NMR (300 MHz, DMSO-d6) δ11.78 (s, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.00 (d, J=13.3 Hz, 1H), 4.61-4.55 (m, 1H), 3.11-3.03 (m, 1H), 2.08-1.99 (m, 1H), 1.84-1.73 (m, 2H), 1.68-1.50 (m, 4H), 1.38-1.23 (m, 11H), 1.12-1.07 (m, 5H), 0.92-0.85 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 450.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:23])=[O:9])=[C:6]([F:11])[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(Br)c(C(=O)O)c2F)CC1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCCCC1CCC(c2ccc(Br)c(C(=O)OC)c2F)CC1
Yield: 101.6 %

Procedure:
17.1 g (46.0 mmol) of trans-6-bromo-2-fluoro-3-(4-pentylcyclohexyl)-benzoic acid were dissolved in 70 ml of acetone, 7.66 g (55.4 mmol) of potassium carbonate and 3.14 ml (50.6 mmol) of methyl iodide were added, and the mixture was refluxed overnight. The batch was filtered, and the solvent was distilled off, giving 18 g (100%) of methyl 6-bromo-2-fluoro-3-(4-pentylcyclohexyl)benzoate as a colourless oil, which was reacted further without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (400 mg) obtained in Example 59 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (0.34 g) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and ethyl bromoacetate (0.15 ml) was added to the mixture. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (50 ml), and the crystals precipitated were recovered by filtration. The crude crystals obtained were washed with water, ethanol and ether in succession, and recovered by filtration to obtain the title compound (410 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[N:21]1([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:25]=[CH:24][CH:23]=[CH:22]1>C(Cl)Cl.O>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:22]1[N:21]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:25]=[CH:24][CH:23]=1)=[O:9]
Reactant: Cc1ccsc1C(=O)O
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ccsc1C(=O)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a stirred solution consisting of 3-methyl-2-thiophenecarboxylic acid (21.0 g) in dry DCM (1.51) was added oxalyl chloride (21.0 ml) at room temperature under nitrogen. After stirring for 1 hour at room temperature, the reaction mixture was cooled to -10° C. and tin (IV) chloride (17.3 ml) was added. The resulting solution was stirred for 10 minutes (-10° C.) at which time 2-(1H-pyrrol-1-yl)-1H-isoindole-1,3(2 H)dione (31.3 g) was added in three portions. After stirring for 1 hour in the cooling bath, the reaction mixture was poured into cold water and the layers separated. The organic phase was washed twice with 5% HCl (aq.) and dried (MgSO4). Filtration and concentration gave the crude product. Purification via preparative HPLC (silica gel, DCM) afforded 12.5 g of the product as a solid, m.p. 221°-223° C.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].C1COCC1.[CH:12]1([CH2:17][C:18](Cl)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>>[CH:12]1([CH2:17][C:18]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
136 ml of a 1 M solution of potassium tert-butoxide in THF (136 mmol) were cooled to 0° C., and 21.0 g (143.2 mmol) of cyclopentylacetic chloride were added dropwise. After the addition had ended, the suspension was warmed to RT and stirred overnight and then added to saturated aqueous ammonium chloride solution. The mixture was extracted three times with diethyl ether. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The desired product was isolated from the residue by kugelrohr distillation (1.6 mbar/160-180° C.). This gave 17.58 g of the target compound (66.6% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:6]=2[CH:20]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Temperature: 90 °C
Yield: 15.6 %

Procedure:
(S)-1-[6-Fluoro-1-(3-fluorophenyl)-1H-benzoimidazol-2-yl]ethylamine (0.45 g, 1.64 mmol) was dissolved in n-butanol (10 mL) and 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.39 g, 1.64 mmol) and DIPEA (1.45 mL, 8.24 mmol) were added. The reaction mixture was heated at 90° C. overnight. The resultant mixture was allowed to cool to RT and was concentrated in vacuo. The residue was passed down an Isolute® SCX-2 cartridge, eluting with DCM, MeOH and 2M NH3 in MeOH to afford crude product. This material was purified by column chromatography (silica gel, gradient 0-7.5% MeOH in DCM) to afford 185 as an off-white solid (100 mg, 20%). LCMS (Method K): RT 3.52 min [M+H]+ 392.0 1H NMR (DMSO-d6, 400 MHz): δ 8.09 (1H, s), 8.05 (1H, s), 7.91 (1H, s), 7.68 (1H, dd, J=8.80, 4.85 Hz), 7.58-7.47 (2H, m), 7.42 (1H, d, J=7.91 Hz), 7.32-7.23 (1H, m), 7.09 (1H, td, J=9.32, 2.48 Hz), 6.92 (1H, dd, J=8.93, 2.50 Hz), 5.63-5.47 (1H, m), 1.58 (3H, d, J=6.82 Hz)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH:35]=[CH2:36]>>[CH2:34]([N:37]1[CH2:42][CH2:41][N:40]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:39][CH2:38]1)[CH:35]=[CH2:36]
Reactant: C=CCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: C=CCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 3 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 5 equivalents of 1-allylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[OH:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[OH:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH3:23])[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:31][CH2:30]1
Reactant: COc1ccccc1CNC1=Nc2ccc(NC(=O)CCl)cc2CO1
Reactant: OCCN1CCNCC1
Solvent: CC#N
Product: COc1ccccc1CNC1=Nc2ccc(NC(=O)CN3CCN(CCO)CC3)cc2CO1
Yield: 244.4 %

Procedure:
Prepared from 2-chloro-N-[2-(2-methoxy-benzylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 26 step A) (50 mg, 0.129 mmol, HPLC 0.889 min 81%) and 1-(2-hydroxyethyl)piperazine (1 ml, 8 mmol) in acetonitrile (3 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (143 mg, 79%, HPLC 0.379 min), MS (ISP) m/e=454.3 [(M+H)+].
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.Br.[N:14]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][C:26]([OH:28])=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.[C:30]1([C:36]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:44][CH2:43][C@@H:42]([F:45])[C@@H:41]3[C@H:37]2[CH2:38][NH:39][CH2:40]3)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl.C(N(CC)CC)C>[C:46]1([C:36]2([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:44][CH2:43][C@@H:42]([F:45])[C@@H:41]3[C@H:37]2[CH2:38][N:39]([C:26](=[O:28])[CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:40]3)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Br
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1N1CCCC1)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h
Yield: 16.6 %

Procedure:
0.28 cm3 of triethylamine and 0.32 g of carbonyldiimidazole are added to a solution, cooled to 4° C., of 0.57 g of (2-pyrrolidinophenyl)acetic acid hydrobromide in 20 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.67 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride in 20 cm3 of dry dichloromethane and 0.28 cm3 of triethylamine is added. The reaction mixture is stirred at room temperature for 24 hours and then diluted with 100 cm3 of dichloromethane, washed twice with 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.5 cm, height 38 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30 by volume) and collecting fractions of 20 cm3. Fractions 26 to 54 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from an acetonitrile and diisopropyl oxide mixture (25/75 by volume). 0.16 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoro-2-[(2-pyrrolidinophenyl)acetyl]perhydroisoindole is obtained in the form of white crystals; melting point 170° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=C=O.[NH:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1>>[OH:31][CH:29]1[CH2:30][N:27]([C:10]([C@@H:9]2[CH2:13][C:14](=[O:16])[CH2:15][N:8]2[C:6]([NH:17][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[O:7])=[O:12])[CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: Cc1cccc(N=C=O)c1
Reactant: OC1CNC1
Product: Cc1cccc(NC(=O)N2CC(=O)C[C@H]2C(=O)N2CC(O)C2)c1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-oxoproline, 1-isocyanato-3-methylbenzene, and 3-azetidinol the title compound was obtained in 73% purity by LC/MS. MS(ESI+): m/z=318.0.