Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[O:6][C:7]2[C:13]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[O:6][C:7]2[C:13]([CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3=CCOCC3)c2o1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1nc2c(OC)ccc(C3CCOCC3)c2o1
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.4 %

Procedure:
To a stirred solution of 130 g (4.27 mmol) [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-benzooxazol-2-yl]-carbamic acid methyl ester in 250 ml methanol and 250 ml dichoromethane was added 1.00 g of 10% palladium on charcoal, and the mixture was then stirred for 10 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane/methanol (1/1), and the filtrate concentrated in vacuo to afford 1.30 g (100%) [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-carbamic acid methyl ester as an off-white solid. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[C:16]([CH3:30])[NH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=3)=[C:16]([CH3:30])[N:15]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:14]=2)=[O:12])=[CH:31][CH:32]=1)(=[O:4])=[O:3]
Reactant: Cc1[nH]cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c1-c1cccc(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (preparation 5, 50 mg, 0.108 mmol), K2CO3 (27 mg, 0.193 mmol) and benzyl bromide (0.015 mL, 0.129 mmol) in DMF (0.5 mL) is stirred for 30 min at 80° C. (microwave). The reaction mixture is diluted with MeOH, filtered and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 28 mg (47% of theory); ESI mass spectrum: [M+H]+=555; Retention time HPLC: 1.16 min (Z003—001).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][N:33]1[C:32]2[C:38]([CH3:40])=[CH:39][C:29]([NH:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[CH:30][C:31]=2[O:35][C:34]1=[O:36]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2
Temperature: 150 °C

Procedure:
90 mg (0.33 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 90 mg (0.31 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.87 mmol) DIPEA were combined in 1.5 mL DMF and stirred at 150° C. After the reaction had ended the reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and dried.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[C:19](Br)[C:12]2=[N:11][C:10]=1[C:27]1[O:28][C:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:30][N:31]=1)C1C=CC=CC=1.[Si]([I:44])(C)(C)C.CO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[F:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C:29]2[O:28][C:27]([C:10]3[N:11]=[C:12]4[C:19]([I:44])=[CH:18][C:17]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:16][N:13]4[C:14](=[O:15])[C:9]=3[OH:8])=[N:31][CH:30]=2)=[CH:34][CH:35]=1
Reactant: C[Si](C)(C)I
Reactant: O=c1c(OCc2ccccc2)c(-c2ncc(Cc3ccc(F)cc3)o2)nc2c(Br)cc(N3CCOCC3)cn12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: O=c1c(O)c(-c2ncc(Cc3ccc(F)cc3)o2)nc2c(I)cc(N3CCOCC3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of the product of example 3 (25 mg, 0.042 mmol) in acetonitrile (1 ml) was added idodotrimethylsilane (TMSI) (0.05 ml, 0.338 mmol) at room temperature. The mixture was stirred at room temperature for 8 hours, after which methanol (0.1 ml) was added to quench the reaction. Then saturated solution of Na2S2O3 was added drop-wise till a yellow solid was precipitated. The resulting solids were collected by filtration, washed with ethyl acetate to give the titled compound (13 mg, 60% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([C@@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]2=[O:25])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1>C(Cl)Cl>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([N:7]([CH2:6][C:5]2[CH:26]=[CH:27][C:2]([NH:1][C:40]([CH:37]3[CH2:39][CH2:38]3)=[O:41])=[CH:3][CH:4]=2)[C@@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]2=[O:25])(=[O:10])=[O:9])=[CH:16][CH:15]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(CN([C@@H]2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(CN([C@@H]2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1)C1CC1

Procedure:
N-(4-Amino-benzyl)-4-chloro-N-((R)-2-oxo-azepan-3-yl)-benzenesulfonamide (0.024 g, 0.06 mmol) was dissolved in CH2Cl2 (1 ml) and Hünig's base (0.01 ml, 0.07 mmol) and cyclopropanecarbonyl chloride (0.007 ml, 0.07 mmol) were added. After 30 min at r.t. the solvent was removed under reduced pressure and the residue dissolved in ethyl acetate and washed with 5% KHSO4/10% K2SO4, brine, dried (Na2SO4), filtered and concentrated. The crude was purified using preparative RP(C18) chromatography: lyophilisate 9 mg; MS: m/e=493.4 (MNH4+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:37][C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:40]3[CH2:41][CH2:42][C@@H:38]([F:37])[CH2:39]3)=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:20][CH2:19]4)=[CH:29][CH:28]=1
Reactant: F[C@@H]1CCNC1
Reactant: COCCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Product: COCCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CC[C@@H](F)C3)nc1)C2

Procedure:
The title compound was prepared by the method of Example 20 using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-(2-methoxyethoxymethyl)-4,4a,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, CHCl3-d): δ 8.55-8.44 (m, 1H), 7.50-7.39 (m, 3H), 7.19-7.11 (m, 2H), 6.41 (d, 1H), 6.27 (d, 1H), 5.46 (s, 1H), 5.33 (s, 1H), 4.15 (dd, 1H), 3.87 (dd, 2H), 3.73 (d, 1H), 3.68-3.55 (m, 7H), 3.38 (s, 3H), 3.25 (d, 1H), 3.14 (d, 1H), 2.80-2.69 (m, 1H), 2.39-2.25 (m, 3H), 2.17-2.03 (m, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].C1CCC(N=C=NC2CCCCC2)CC1.CN1CCOCC1>ClCCl>[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([NH:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)CCNC(=O)CNC(=O)OC(C)(C)C
Yield: 62 %

Procedure:
A solution of β-alanine ethyl ester hydrochloride salt (5) (3.07 g; 0.02 mmol), N-(tertbutoxycarbonyl)glycine (3.5 g; 0.02 mmol), DCCI (4.12 g; 0.02 mmol) and 4-methylmorpholine (2.2 ml) in dichloromethane (60 ml) was stirred overnight under argon atmosphere at ambient temperature. After filtration the residue was purified by flash chromatography eluting with dichloromethane/ethanol (96/4) to give ethyl 3-[(2-tertbutoxycarbonylaminoacetyl)amino]propanoate (6).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[O-]CC.[Na+].CN([CH:13]=[C:14]1[CH2:18][N:17](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][C:15]1=O)C>C(O)C>[CH3:3][C:2]1[N:4]=[CH:13][C:14]2[CH2:18][NH:17][CH2:16][C:15]=2[N:5]=1
Reactant: CC(=N)N
Reactant: CN(C)C=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ncc2c(n1)CNC2
Temperature: 85 °C

Procedure:
A solution of acetamidine hydrochloride (12.8 g, 135 mmol) and sodium ethoxide (59 mL, 157.5 mmol) in anhydrous ethanol (400 mL) was stirred under nitrogen for 15 min, and 4-[(dimethylamino)methylene]-1-tritylpyrrolidin-3-one from Step B (17.2 g, 45 mmol) was added. The resulting mixture was heated at 85° C. for 3.5 h, quenched with a solution of 5% aqueous citric acid (50 mL), and evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate solution. There was some insoluble solid material between the aqueous and the organic layers, which was filtered thorough a Celite pad and washed with ethyl acetate. The combined aqueous layers were extracted twice with ethyl acetate. The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated. The residue obtained was purified by chromatography on a Biotage Horizon® system (silica gel, 0-75% ethyl acetate/dichloromethane gradient) to yield the N-trityl protected derivative of the desired product. A portion of this trityl protected product (1.9 g, 5.0 mmol) was dissolved in 4N methanolic hydrogen chloride (20 mL) and stirred at room temperature for 2.5 h. The solution was evaporated and the residue was purified by chromatography on a Biotage Horizon® system (silica, 4.5-14% gradient of 10% concentrated aqueous ammonium hydroxide in methanol/dichloromethane) to yield the desired product. LC-MS=136.0 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[O:4][C:5]2[C:6](=[C:8]([C:12]([OH:14])=O)[CH:9]=[CH:10][CH:11]=2)[N:7]=1.Cl.Cl.[NH2:18][C@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1>>[N:21]12[CH2:20][C@@H:19]([NH:18][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:5]4[O:4][C:3]([N:2]([CH3:1])[CH3:15])=[N:7][C:6]=34)=[O:14])[CH:24]([CH2:25][CH2:26]1)[CH2:23][CH2:22]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: CN(C)c1nc2c(C(=O)O)cccc2o1
Agent: Cl
Product: CN(C)c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1

Procedure:
Following general procedure GP-C1, a mixture of 2-(dimethylamino)benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-(dimethylamino)benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][CH3:17])=[O:14].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>CC(N(C)C)=O>[C:21]([C:3]1[C:2]([NH:1][S:23](=[O:26])(=[O:25])[NH2:24])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][CH3:17])=[O:14])#[N:22]
Reactant: NS(=O)(=O)Cl
Reactant: CCNC(=O)N1CCCCC1COc1cccc(N)c1C#N
Solvent: CC(=O)N(C)C
Product: CCNC(=O)N1CCCCC1COc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.7 %

Procedure:
To a solution of 2-((3-amino-2-cyanophenoxy)methyl)-N-ethylpiperidine-1-carboxamide (Example 26b. 0.407 g, 1.35 mmol) in DMA (5 mL) was added sulfamoyl chloride (0.234 mg, 2.02 mmol) and the reaction mixture was stirred vigorously at r.t. for 2 h, then extracted with H2O/EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by Biotage purification system (120 g Silicycle column, DCM:THF=4:1 as eluent) to provide the desired product (0.606 g, 90%). MS 382 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13].[CH3:25][C:26](=O)[CH2:27][CH2:28][C:29](=O)[CH3:30].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([N:1]4[C:29]([CH3:30])=[CH:28][CH:27]=[C:26]4[CH3:25])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:23][CH:22]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(-n3c(C)ccc3C)cccc21

Procedure:
A mixture of methyl 2-(4-amino-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (140 mg), hexane-2,5-dione (166 mg) and 4-methylbenzenesulfonic acid (3 mg) in toluene (5 mL) was stirred under reflux for 30 min. Concentrated, the residue was purified by chromatography on silica gel column (5-15% ethyl acetate in hexanes) to give the title compound as a yellow solid. LC/MS m/z=421.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](OB(O)O)=[CH:5][CH:4]=1.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]3[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30](OS(C(F)(F)F)(=O)=O)[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1>>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]3[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2ccccc2OC1c1ccc2c(c1)OCO2
Reactant: COc1ccc(OB(O)O)cc1
Product: COC(=O)C1=C(c2ccc(OC)cc2)c2ccccc2OC1c1ccc2c(c1)OCO2

Procedure:
4-Methoxyphenyl boric acid and methyl 2-(benzo[1,3]dioxol-5-yl)-4-(trifluoromethanesulfonyloxy)-2H-chromen-3-carboxylate (III-5) synthesized from the compound (II-3) by a similar method as described in Reference Example 2 were reacted in a similar manner as described in Example 18 to give methyl 2-(benzo[1,3]dioxol-5-yl)-4-(4-methoxy-phenyl)-2H-chromen-3-carboxylate (Ia-4).
Reaction SMILES: [CH2:1]([C:5]1[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:31]3[S:32][CH:33]=[C:34]([C:36](N(OC)C)=[O:37])[N:35]=3)[CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:42][Mg]Br.O>O1CCCC1>[C:36]([C:34]1[N:35]=[C:31]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]3[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[S:32][CH:33]=1)(=[O:37])[CH3:42]
Reactant: CON(C)C(=O)c1csc(-c2ccc3nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccc(C)cc4)c3c2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1csc(-c2ccc3nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccc(C)cc4)c3c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a suspension of tert-butyl {[2-isobutyl-6-(4-{[methoxy(methyl)amino]carbonyl}-1,3-thiazol-2-yl)-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.23 g, 0.4 mmol) in tetrahydrofuran (10 ml) was added dropwise 3.0 M methylmagnesium bromide (0.4 ml, 1.2 mmol) at 0° C. After the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [6-(4-acetyl-1,3-thiazol-2-yl)-2-isobutyl-4-(4-methylphenyl)-3-quinolinyl]methylcarbamate (0.20 g, yield 95%) as white crystals.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.9 %

Procedure:
Cyclopentanemethanol p-toluenesulfonate was prepared by the following method: To a solution of cyclopentanemethanol (2.0 g, 20.0 mmol) and pyridine (2.9 ml, 36.3 mmol) in dichloromethane (20 ml) was added p-toluenesulfonyl chloride (3.46 g, 18.1 mmol). The mixture was stirred at room temperature for 24 h under nitrogen. The resulting mixture was washed with 2M hydrochloric acid and the aqueous layer separated and extracted with dichloromethane. The combined organics were dried over sodium sulphate and concentrated under reduced pressure to yield cyclopentanemethanol p-toluenesulfonate as a colourless oil (4.3 g, 17.0 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[N:15]=[C:14]2[CH2:23]Cl)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[C:37]2[C:32](=[CH:33][N:34]=[CH:35][CH:36]=2)[NH:31][N:30]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[N:15]=[C:14]2[CH2:23][N:31]2[C:32]3=[CH:33][N:34]=[CH:35][CH:36]=[C:37]3[C:29]([S:26]([CH3:25])(=[O:27])=[O:28])=[N:30]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(CCl)nc3cc(Cl)ccc32)C1
Product: CC(C)(C)OC(=O)N1CCC(n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1

Procedure:
3-[5-Chloro-2-(3-methanesulfonyl-pyrazolo[3,4-c]pyridin-1-ylmethyl)-benzoimidazol-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared in analogy to Example 2-1 by using 3-(5-chloro-2-chloromethyl-benzoimidazol-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine. MS obsd. (ESI+) [(M+H)+] 531.1.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:18]1[CH2:17][CH:16]2[CH2:20][CH:13]([C:9]3[N:8]=[C:7]4[N:6]([CH3:21])[C:5](=[O:22])[N:4]([CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:12]4=[CH:11][CH:10]=3)[CH2:14][CH:15]2[CH2:19]1)(=[O:36])[CH3:35]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC2CC(c3ccc4c(n3)n(C)c(=O)n4CC(C)(C)C)CC2C1
Reaction time: 0.08 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11-1, 50 mg, 0.15 mmol, 1.0 equiv), and DIPEA (0.080 mL, 0.45 mmol, 3.0 equiv) were added to anhydrous methylene chloride (2 mL). Stirred for 5 min and acetyl chloride (11.9 μL, 0.16 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 12-1 as a pale yellow oil. MS m/z (M+H): calculated=371.2443; observed=371.2440.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[CH3:13].[O:14]1CCCC1>>[OH:14][CH2:13][C:7]1[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][N:6]=1
Reactant: C1CCOC1
Reactant: Cc1ccnc(C)c1
Agent: [Li]CCCC
Product: Cc1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
n-Butyllithium (24 ml of a 1.6 N solution in hexanes, 38.4 mmol) was added to a stirred solution of 2,4-lutidine (4.28 g, 40 mmol) in tetrahydrofuran (70 ml) at −70° C. under an inert atmosphere. After 1 hour, air was bubbled through (for 1 hour), methanol (50 ml) was added and the reaction allowed to warm to ambient temperature. The reaction mixture was filtered and then evaporated in vacuo. Purification of the crude product by flash chromatography on silica gel, eluting with ethyl acetate, yielded 2-(hydroxymethyl)-4-picoline (700 mg, 14% yield) as a white solid. b) Sodium hydride (150 mg of an 80% dispersion in mineral oil, 5.00 mmol) was added to a stirred solution of 2-(hydroxymethyl)-4-picoline (590 mg, 5.00 mmol) in N-methylpyrrolidine (20 ml) at ambient temperature. 2-Fluoro-5-nitrotoluene (775 mg, 5.00 mmol) was added, the reaction was stirred for 18 hours at ambient temperature and the reaction was poured into water (60 ml). Collection of the yellow solid which precipitated, followed by drying in vacuo, yielded 2-((4-methyl-2-pyridyl)methoxy)-5-nitrotoluene (900 mg, 70% yield) as a yellow solid. c) 5% Platinum on carbon (50 mg) was added to a solution of 2-((4-methyl-2-pyridyl)methoxy)-5-nitrotoluene (750 mg, 2.91 mmol) in ethanol (150 ml) and the solution was stirred for 2 hours at ambient temperature under an atmosphere of hydrogen. Filtration of the reaction mixture, followed by solvent evaporation in vacuo, yielded 3-methyl-4-((4-methyl-2-pyridyl)methoxy)aniline (420 mg, 63% yield) as a yellow gum.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH2:12][N:11]([C@H](C2C=CC=CC=2)C)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH2:34]([O:33][C:31]([N:11]1[CH2:12][C@@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[CH2:10]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)C[C@H]2O[Si](C)(C)C(C)(C)C)CC1
Product: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O[Si](C)(C)C(C)(C)C)CC1

Procedure:
3-(S)-Tert-butyldimethylsilyloxy-4-(R)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]pyrrolidine (5.48 g, 13.15 mnmol) was dissolved in dry dichloroinethane (120 ml), and benzyl chloroformate (3.76 ml, 26.3 mmol) was added dropwise to the thus prepared solution which was cooled in an ice bath. After heating the reaction solution under reflux for 2 hours, dichloroinethane was evaporated under reduced pressure. Thereafter, the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=5:1, to thereby obtain 4.52 g (77%) of the title coinpound as a colorless oil.