Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[NH2:30])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=O)[CH3:32]>>[CH3:31][C:32]1[N:23]([CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[N:30]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Product: Cc1nc2cnccc2n1CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 30 %

Procedure:
N*4*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-3,4-diamine (60 mg, 0.15 mmol) and acetic anhydride (˜1 mL) were stirred at reflux for 18 hours. The reaction mixture was quenched with ˜1 mL water, then basified with dilute sodium carbonate solution then extracted with DCM (2×20 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1 by volume) to provide the title compound as a brown oil (19 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 1.78-1.82 (m, 6H), 1.97-2.10 (m, 5H), 2.23 (m, 2H), 2.54 (m, 4H), 2.62 (t, 2H), 3.40 (m, 2H), 3.82 (m, 2H), 4.00 (t, 2H), 4.07 (s, 2H), 6.80-6.88 (m, 4H), 7.00 (d, 1H), 8.30 (d, 1H), 8.92 (s, 1H). LRMS ESI+ m/z 435 [MH]+.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[C:14]([C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[OH:25])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.Cl>>[C:26]1([C:12]2[CH:13]=[C:14]([C:16]([CH3:17])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH:15]=[C:10]([C:2]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)([CH3:1])[CH3:3])[C:11]=2[OH:25])[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Reactant: O=C1CCCCC1
Agent: Cl
Product: CC(C)(c1ccccc1)c1cc(C2=CCCCC2)c(O)c(C(C)(C)c2ccccc2)c1
Reaction time: 19 h
Yield: 3.2 %

Procedure:
A mixture consisting of 66.1 g (0.20 mol) of 2,4-bis(1-methyl-1-phenylethyl)phenol and 9.8 g (0.10 mol) of cyclohexanone is melted together and is then saturated, with stirring, with hydrochloric acid gas at 40-45° C. After 19 hours, another 9.8 g (0.10 mol) of cyclohexanone are added. The reaction mixture is saturated again with hydrochloric acid gas and is then stirred for 21 hours. The reaction mixture is diluted with petroleum ether and washed with water. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is chromatographed over silica gel using the solvent system hexane/ethyl acetate=39:1, giving 1.3 g (2%) of 2-cyclohexen-1-yl-4,6-bis(1-methyl-1-phenylethyl)phenol as a thick yellowish oil (compound (110), Table 1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][CH:11]([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(#N)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][N:10]([C:16]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26])[CH:11]([CH3:12])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NCCNC(=O)OC(C)(C)C
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)N(CCNC(=O)OC(C)(C)C)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A mixture of (2-Isopropylamino-ethyl)-carbamic acid tert-butyl ester (100 mg, 0.5 mmol), rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (185 mg, 0.5 mmol) and K2CO3 (138 mg, 1 mmol) in DCM (1 mL) and acetonitrile (2 mL) was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography to give 180 mg rac-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-carbamic acid tert-butyl ester. MS: [M+H]+=492
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]O.[H-].[Na+].F[C:10]1[CH:11]=[C:12]([CH:20]([NH:22][CH:23]2[CH2:25][CH2:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.O>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:10]1[CH:11]=[C:12]([CH:20]([NH:22][CH:23]2[CH2:25][CH2:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: COCCCO
Reactant: CC(NC1CC1)c1cc(F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCc1cc(C(C)NC2CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-methoxy-1-propanol (0.14 mL) in N,N-dimethylformamide (3.0 mL) was added 60% oil-based sodium hydride (97 mg), and the mixture was stirred at room temperature for 10 minutes. Then, thereto was added dropwise a solution of N-{1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}cyclopropylamine (300 mg) in N,N-dimethylformamide (1.0 mL), and the mixture was heated to stir at 40° C. for 4 hours. After cooling to room temperature, thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1→2/3) to give N-{1-[3-(3-methoxypropyl)-5-(trifluoromethyl)phenyl]ethyl}cyclopropanamine [REx(31-1)] (227 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[NH:14][C:13]3=[CH:15][S:16][CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=1.Cl[C:19]([O:21][CH:22]=[CH2:23])=[O:20]>>[CH:22]([O:21][C:19]([N:11]1[C:12]2=[CH:17][S:16][CH:15]=[C:13]2[N:14]=[C:10]1[S:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:20])=[CH2:23]
Reactant: C=COC(=O)Cl
Reactant: Cc1ccc(CSc2nc3cscc3[nH]2)nc1
Product: C=COC(=O)n1c(SCc2ccc(C)cn2)nc2cscc21
Yield: 41.5 %

Procedure:
In analogy to Example 15 1.5 g of crude product were obtained from 2.1 g (8 mmol) of 2-(5-methyl-2-picolylmercapto)-1H-thieno[3,4-d]imidazole and 0.85 g (0.72 ml, 8 mmol) of vinyl chloroformate and were chromatographed on SiO2 (CH2Cl2 /MeOH 50:1). 1.1 g of title compound were obtained by crystallization from diisopropyl ether. Melting point 78°-80° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][O:10][C:11]1[C:16]2[C:17](=[O:27])[N:18]3[CH2:25][C@H:24]([OH:26])[CH2:23][C@H:19]3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=[CH:13][C:12]=1[O:28][CH3:29].N1C=CN=C1.O>CN(C=O)C>[CH3:9][O:10][C:11]1[C:16]2[C:17](=[O:27])[N:18]3[CH2:25][C@H:24]([O:26][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:23][C@H:19]3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=[CH:13][C:12]=1[O:28][CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc2c(c1OC)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Solid TBDMS Chloride (8.22 g, 54.44 mmol) was added in one portion to a solution of 4 (7.23 g, 24.74 mmol) and imidazole (8.42 g, 123.72 mmol) in anhydrous DMF (75 mL) and allowed to stir at room temperature for 16 hours. The reaction mixture was poured into water (500 mL) and filtered to afford the crude product (5), which was purified by recrystallisation from EtOH (800 mL) as fine white needles (6.995 g, 17.21 mmol, 70%). 1H NMR (270 MHz, CDCl3) δ 10.06 (s, 1H, NH), 7.37 (s, 1H, ArH), 6.68 (s, 1H, ArH), 4.19-4.14 (m, 1H, 2), 4.06-4.01 (m, 1H, 11a), 3.90 (s, 3H, OMe), 3.88 (s, 3H, OMe), 3.69-3.63 (m, 2H, 3), 2.85-2.80 (m, 1H, 1), 2.05-2.01 (m, 1H, 1); 13C NMR (67.8 MHz, CDCl3) δ 170.4, 170.2, 165.9, 152.1, 145.8, 145.6, 131.1, 130.7, 118.1, 111.9, 104.3, 104.1, 69.2, 69.1, 56.0, 55.9, 55.7, 54.3, 54.0, 35.0, 25.8, 25.7, 25.6, 17.9, −3.0, −3.5, −4.9, −5.0.
Reaction SMILES: [N+](=[CH:3][C:4]([CH:6]([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])=[N-].S(=O)(=O)(O)[OH:32]>O1CCOCC1.O>[C:4]([CH:6]([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:5])[CH2:3][OH:32]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)C=[N+]=[N-])OC(C)=O
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)CO)OC(C)=O
Yield: 96 %

Procedure:
A clear, yellow solution of ethyl 8-diazoacetyl-12-acetoxyheptadecanoate (8.4 g., 0.02 mole) in dioxane (50 ml.) is vigorously stirred at 20° and treated with 2N sulfuric acid (30 ml.) added dropwise over 5 minutes. The resulting turbid solution is warmed to and maintained at 65° for 30 minutes. The reaction solution is cooled to 20°, diluted with water to a total volume of one liter and extracted with ether (5 × 200 ml.). The organic extract is washed with water (2 × 200 ml.), 5% aqueous sodium bicarbonate (200 ml.), water (200 ml.), and saturated brine (2 × 200 ml.), dried over sodium sulfate and filtered. Evaporation (in vacuo at 40°-65°) of the filtrate gives the title compound as a deep yellow oil (7.9 g., 96%), pmr (CDCl3) δ 0.86 (3H,t), 1.28 (27H,e), 2.0 (3H,s), 2.25 (3H,t), 3.36 (H,b), 4.10 (2H,q), 4.21 (2H,s) and 4.84 (H,b).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](=[S:17])[NH2:16])=[CH:11]2.[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C:33]#[C:34][CH3:35].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:17][CH:34]([CH2:33][C:32]([O:37][CH2:38][CH3:39])=[O:36])[CH2:35][N:16]=1)=[CH:11]2
Reactant: CC#CC(=O)OCC
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(COC)COC)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 52 %

Procedure:
A mixture of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (940 mg), ethyl 2-butynoate (0.6 mL), tributylphosphine (0.5 mL), tetrahydrofuran (15 mL) and toluene (20 mL) was stirred at 60° C. for 50 min. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate/hexane=0/5/95 to 5/95/0, volume ratio) to give the title compound (610 mg, 52%) as a yellow amorphous solid. MS 578 (MH+).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[CH2:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)C.[OH-].[Na+]>C1COCC1>[O:11]=[C:12]([CH2:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: CCOC(=O)Cc1cccc(C)c1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(CC(=O)CC#N)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.5 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 11 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of m-tolyl-acetic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids and then extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered. The organic layer is concentrated in vacuo, and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-oxo-4-m-tolyl-butyronitrile in the amount of 2.5463 gms.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[F:16][C:13]([F:14])([F:15])[C:8]1([C:9]([F:10])([F:11])[F:12])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:19](=[O:21])[O:17]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1C(O)(C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C(C(F)(F)F)(C(F)(F)F)O1
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a stirred solution of 2-(2-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.20 g, 16.20 mmol) in THF (160 mL) was added triphosgene (4.80 g, 16.20 mmol). The reaction was stirred overnight, quenched with ammonium chloride solution (sat.) and extracted several times with ethyl acetate. The organic layer was dried over magnesium sulfate and triturated with ether/hexane to give 2.78 g of 4,4-bis(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as a tan solid (60%). 1H NMR (DMSO-d6): δ 11.37 (s, 1H), 7.62 (m, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.11 (dd, J=8.0, 0.8 Hz, 1H). MS (ESI) m/z 284 ([M−H]−); HRMS: calcd for C10H5F6NO2, 285.0224; found (ESI_FT), 286.0299; Anal. Calcd for C10H5F6NO2: C, 42.12; H, 1.77; N, 4.91. Found: C, 42.63; H, 1.79; N, 4.72.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.O.O.O.O.O.[OH-].C[N+](C)(C)C.Br[CH2:34][CH2:35][OH:36].Cl>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:34][CH2:35][OH:36])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Oc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: OCCOc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Temperature: 50 °C
Yield: 95.7 %

Procedure:
To 4-(6-chloro-2,3-dihydro-indol-1-yl)-quinazolin-7-ol (125 mg, 0.42 mmol; from Example 65) in DMF (2 mL) was added H2O (50 μL), K2 CO3 (s) (116 mg, 0.84 mmol), and tetramethylammonium hydroxide pentahydrate (15 mg, 0.08 mmol) followed by 2-bromoethanol (39 μL, 0.46 mmol). The mixture was stirred at 50° C. under N2(g) and aliquots of 2-bromoethanol (3×20 μL) were added at 24 hour invervals. Extractive workup and chromatography analogous to that described in Example 1 followed by conversion to the HCl salt as outlined for Example 2 afforded 76 mg (53%) of product. (M.P. 215°-217° C.; LC-MS: 342 (MH+); anal. RP18-HPLC RT: 4.09 min.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:23])=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:23])=[C:18]([NH:19][S:30]([C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1cccnc1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2F)c(-c2ccnc(Cl)n2)s1
Yield: 75.3 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline (3 g, 8.6 mmol) and pyridine-3-sulfonyl chloride (1.68 g, 9.5 mmol) the title compound of Step A was obtained (2.1 g, 75.3% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.97-9.01 (br, 1H), 8.76-8.79 (m, 1H), 8.35 (d, J=5.3 Hz, 1H), 8.08-8.12 (m, 1H), 7.68-7.74 (m, 1H), 7.40-7.44 (m, 1H), 7.22-7.34 (m, 3H), 6.69 (d, J=5.3 Hz, 1H), 3.29-3.38 (m, 1H), 1.44 (d, J=6.8 Hz, 6H). MS (ES+): 490 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34].CN(C=O)C>[Cu](I)I.O>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][CH2:26][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=2[C:13]2[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1=2
Reactant: Clc1ccccc1CCBr
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2Cl)CCN(C)CC1
Temperature: 90 °C
Reaction time: 12 h
Yield: 14.2 %

Procedure:
The title compound was prepared by following general procedure 4. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1.0 mmol) was taken with copper iodide (19 mg, 0.1 mmol), L-praline (23 mg, 0.2 mmol), potassium phosphate tribasic (426 mg, 2.0 mmol), 1-(2-bromoethyl)-2-chlorobenzene (219 mg, 1.0 mmol) and DMF was added, the reaction was stirred at 90° C. under argon atmosphere for 12 h and monitored by LCMS. After completion of the reaction water was added and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase chromatography to afford 50 mg of the title compound (10.7%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][C:29](Cl)=O.C(N(CC)CC)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])[C:29]([CH2:28][CH2:27][O:26][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Reactant: COCCC(=O)Cl
Solvent: CCN(CC)CC
Product: COCCc1nc2cnc3cc(Br)ccc3c2n1CCCN1CCCC1=O

Procedure:
1-[3-(7-Bromo3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one was treated according to the methods described in Parts B, C, and D of Examples 152-156. 3-Methoxypropionyl chloride was used in Part C, and triethylamine (1.3 equivalents) was added to the reaction mixture. The crude product obtained in Part D was purified by flash chromatography on silica gel (eluting sequentially with 100:0 and 92.5:7.5 chloroform:methanol) followed by recrystallization from acetonitrile. The crystals were washed with acetonitrile and diethyl ether and dried in a vacuum oven at 60° C. to provide 1-{3-[7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light grey solid.
Reaction SMILES: [CH:1]([N:4]([CH:17]([CH3:19])[CH3:18])[CH2:5][CH2:6][CH:7]([C:14](=[O:16])N)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[N+]([O-])(O)=O.[CH2:24]([OH:26])[CH3:25]>>[CH:1]([N:4]([CH:17]([CH3:19])[CH3:18])[CH2:5][CH2:6][CH:7]([C:14]([O:26][CH2:24][CH3:25])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(CCC(C(N)=O)c1ccccc1)C(C)C
Reactant: CCO
Solvent: O=[N+]([O-])O
Product: CCOC(=O)C(CCN(C(C)C)C(C)C)c1ccccc1

Procedure:
N,N-Diisopropyl-3-carbamyl-3-phenylpropanamine (26.5 g 0.100 mol) was added into aqueous ethanol (90%, 300 mL) containing conc. HNO3 (13.3 g, 0.21 mol) and refluxed for five days. Most of the solvent was evaporated under reduced pressure and the residue was mixed with water/diethyl ether. The organic phase was washed once with water. The combined aqueous phases were made alkaline (11 M NaOH) and extracted twice with diethyl ether. The combined organic phases were then dried (Na2SO4) and the solvent evaporated. The crude product was chromatographed on silica (petroleum ether-triethylamine, 97/3), to afford the title compound as a colourless liquid, 20.1 g (68.7%): 1H NMR (CDCl3) δ0.96 (m, 12H), 1.21 (t, 3H), 1.81 (m, 1H), 2.22 (m, 1H), 2.40 (t, 2H), 3.66 (dd, 1H), 4.12 (m, 2H), 7.20-7.32 (m, 5H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.O[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>C(Cl)Cl>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:25]=[CH:24][C:23]([O:19][C:17](=[O:18])[C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:21][CH:20]=3)=[CH:28][CH:27]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(OC(=O)c3ccc(OCCCO)cc3)cc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 2 (10 g, 32.21 mmol), 4′-hydroxy-biphenyl-4-carbonitrile (6.35 g, 32.53 mmol), and toluenesulfonic/4-(dimethylamino)pyridine complex (0.95 g, 3.22 mmol) in anhydrous methylene chloride (100 mL) was added N,N-dicyclohexylcarbodiimide (6.98 g, 33.82 mmol) under argon. The reaction mixture was stirred at 40° C. overnight. Upon filtering off the white residues, the filtrate was diluted with additional methylene chloride. The solution was then washed with water. The silyl ether of the title compound was purified by flash column chromatography on silica gel with gradient elution from 0 to 2% acetone in methylene chloride. The silyl-protected compound was hydrolyzed in tetrahydrofuran: water:acetic acid (80 mL: 80 mL: 240 mL) overnight. The volume of the solution was reduced by 50% via evaporation under reduced pressure. Methylene chloride was added to the slurry for washing sequentially with H2O, a 10% NaHCO3 solution and brine before drying over anhydrous MgSO4. The crude product resulting from evaporation of the solvent was purified by recrystallization from ethanol to yield 3 (10.71 g, 89%). 1H NMR spectral data (400 MHz, CDCl3): δ 2.10 (quintet, 2H, —CH2—), δ 3.95 (t, 2H, —CH2OAr), δ 4.25 (t, 2H, HOCH2—), δ 7.00–8.25 (m, 12H, aromatic rings).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:23][CH3:24].N1C=CC=CC=1.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37](Cl)=[O:38]>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:38])[CH2:36][C:32]4[S:31][CH:35]=[CH:34][CH:33]=4)=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)Cc1cccs1
Reaction time: 8 h
Yield: 32.3 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (31 mg, 0.096 mmol) was dissolved in dichloromethane (1 mL). Pyridine (1 mL) was added followed by 2-(2-thienyl)ethanoyl chloride (14 uL, 0.113 mmol). After stirring overnight, another 14 uL of 2-(2-thienyl)ethanoyl chloride was added and the reaction mixture was stirred overnight. The solvent was removed and the residue was purified by preparative thin layer chromatography eluting with dichlormethane/methanol (95:5) to give N1-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2-(2-thienyl)acetamide (14 mg, 0.031 mmol). 1H NMR (DMSO-d6) δ 1.89 (m, 6H), 2.25 (m, 2H), 3.82 (s, 3H), 3.99 (s, 2H), 5.19 (bs, 2H), 5.21 (m, 1H), 6.93 (s, 1H), 6.94 (s, 1H), 7.06 (m, 3H), 7.31 (m, 1H), 8.02 (s, 1H), 8.32 (s, 1H), 8.42 (d, J=8.22 Hz, 1H). LC/MS MH+=448.