Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:22])[C:6]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]#[CH:15])[N:9]=[C:8]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:7]=1>C1COCC1>[CH3:21][CH:19]([S:16]([C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([NH:12][CH2:13][C:14]#[CH:15])[N:9]=1)[C:5]([OH:22])=[O:4])(=[O:18])=[O:17])[CH3:20]
Reactant: C#CCNc1cc(C(=O)OC)cc(S(=O)(=O)C(C)C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#CCNc1cc(C(=O)O)cc(S(=O)(=O)C(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Add 1 N lithium hydroxide (0.52 mL, 0.52 mmol) to a solution of 2-(propane-2-sulfonyl) -6-prop-2-ynylamino-isonicotinic acid methyl ester (0.102 g, 0.344 mmol) in THF (2 mL) at 0° C. Stir the mixture at room temperature for 3 h and acidify the solution to about pH =2 and concentrate the solvent to one half volume. Partition the residue between ethyl acetate and water, and extract the aqueous layer with ethyl acetate (2×10 mL). Wash the combined organic extract with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (85%).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8](O)=[O:9].[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[NH2:17].O>CC(N(C)C)=O>[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8]([NH:17][C:16]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:14]([CH3:13])[CH:15]=1)=[O:9]
Reactant: C[C@](O)(CBr)C(=O)O
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1cc(NC(=O)[C@@](C)(O)CBr)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
Thionyl chloride (0.48 ml, 6.6 mmol) was added dropwise to a solution of (2R)-3-Bromo-2-hydroxy-2-methylpropionic acid (1.0 g, 5.5 mmol) in 10 ml of DMA at −5 to −10° C. The mixture was stirred for 2 h, and a solution of 3-methyl-4-nitroaniline (0.83 g, 5.5 mmol) in 7 ml of DMA was added to the above mixture. The resulting mixture was stirred for 3 h at room temperature and poured into water (250 ml). The aqueous phase was extracted with ethyl acetate (4×50 ml), dried over Na2SO4 and evaporated. The yield of the desired compound was 2.5 g (contains also DMA), and it was used without further purifications. 1H NMR (DMSO-d6): 1.48 (3H, s), 2.53 (3H, s), 3.58 (1H, d, J=10.4 Hz), 3.82 (1H, d, J=10.4 Hz), 6.34 (1H, bs), 7.86 (1H, dd, J=9.0 Hz and 2.2 Hz), 7.91 (1H, d, J=2.2 Hz), 8.04 (1H, d, J=9.0 Hz), 10.09 (1H, bs).
Reaction SMILES: C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)OC1O)(=[O:3])C.[C:25]1([P:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:38]1([P:31](=[O:3])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 15 h

Procedure:
To a solution of the compound of Preparation A (0.927 mmol), dissolved in 40 ml of dry tetrahydrofuran, there are added 2,3,4,6-tetra-O-acetylglucopyranose (1.95 mmol) and triphenylphosphine (1.95 mmol). The reaction mixture is cooled to −78° C., and then DEAD (1.95 mmol) is added dropwise. The temperature is slowly raised to ambient temperature, and the reaction mixture is then stirred for a further 15 hours. After hydrolysis, the organic product is extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and filtered, and the solvent is evaporated off. After purification by chromatography on silica gel (cyclohexane/ethyl acetate: 65/35, and then toluene/ethyl acetate 3/2), the β-glycosylated compound is obtained in the form of yellow crystals and the α-glycosylated compound is obtained in admixture with triphenylphosphine oxide.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21]COC)=[CH:17][CH:16]=3)[CH:9]3[CH2:25][CH:26]([OH:28])[CH2:27][CH:8]3[C:7]=2[CH:6]=1.CO.C(Cl)Cl>C1COCC1.Cl.CCOC(C)=O>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([C@H:10]2[C@H:9]3[CH2:25][C@@H:26]([OH:28])[CH2:27][C@H:8]3[C:7]3[CH:6]=[C:5]([OH:4])[CH:14]=[CH:13][C:12]=3[O:11]2)=[CH:20][CH:19]=1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(O)CC32)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1ccc([C@@H]2Oc3ccc(O)cc3[C@@H]3C[C@H](O)C[C@@H]32)cc1
Yield: 75 %

Procedure:
Stir a solution of alcohol 25 (60 mg, 0.16 mmol) in 2 mL of THF and 2 mL of 3 M HCl overnight. Dilute the solution with EtOAc. Separate the aqueous solution and extract 2× with 10% MeOH in EtOAc. Wash the combined organic solutions with saturated aqueous sodium bicarbonate, brine, dry over Na2SO4, filter, and concentrate. Absorb to 1 g silica gel. Purify by silica gel chromatography (4 g silica gel, 0 to 10% MeOH/CH2Cl2 then 20% MeOH/CH2Cl2) to give 37 mg, (0.12 mmol, 79%) of alcohol 26. HPLC (Zorbax C18 column 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 7.79 min). LRMS(ES−) calcd for C18H15O4: 297.11; found: 297.29 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:21]3[C:20](=O)[CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]3[CH2:13][CH2:12][CH2:11][C:10](=[O:23])[C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(O)C.[BH4-].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]3[C:10](=[O:23])[CH2:11][CH2:12][CH2:13][C:14]=3[NH:15][C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC2=C1C(c1cccc(Cl)c1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1CCCC2=C1C(c1cccc(Cl)c1)C1=C(CCCC1)N2
Yield: 104.5 %

Procedure:
To a stirred 70° C. mixture of 9-(3-chlorophenyl)-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (5.0 g), ethanol (120 mL) and pyridine (40 mL) was added sodium borohydride (7.5 g) in two portions over six hours. The solvent was removed; the resulting yellow solid washed well with water and dried in vacuo to provide the title compound (5.0 g) as a yellow solid. Recrystallization from ethanol returned analytically pure material, mp 249°-250° C.; NMR: 1.41-1.51 (m,3, CH2), 1.60-1.88 (m,5, CH2), 2.09-2.15 (m,4, CH2), 2.39-2.45 (m,2, CH2), 4.17 (s,1, CH), 7.09-7.15 (m,3, Ar), 7.21-7.26 (m,1, Ar), 8.43 (s,1, NH). (CI, CH4) MS: m/z=314(M+1). Analysis for C19H20ClNO: Calculated C, 72.72; H, 6.37; N, 4.46; Found: C, 72.55; H, 6.48; N, 4.49.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=2[O:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1O
Reactant: CCOC(=O)CCCOc1ccccc1OCCCBr
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(N)nc(N)c1OCCCOc1ccccc1OCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
2,4-Diamino-6-ethyl-5-hydroxypyrimidine (0.4625 g, 3 mmol) was added to a stirred solution of lithium hydroxide monohydrate (0.4406 g, 10.5 mmol) in DMF (4 mL) and the reaction mixture was stirred at 25° C. for 1 hour. A solution of ethyl 4-(2-(3-bromopropoxy)phenoxy)butanoate (1.0357 g, 3 mmol) in DMF (1 mL) was added and the reaction mixture was left stirring at 25° C. overnight. DMF was partially removed under reduced pressure to give residue. The residue was diluted with water and extracted with dichloromethane. The aqueous layer was neutralized with dilute HCl to give white solid. Recrystallization with acetone afforded the desired diaminopyrimidine as white solid (0.6911 g, 59%, m.p. 204-206° C.). 1H NMR (400 MHz, DMSO-d6): 1.10 (3H, t, J=7.5 Hz), 1.91 (2H, m), 2.14 (2H, m), 2.31-2.39 (4H, m), 3.78 (2H, t, J=6.1 Hz), 3.96 (2H, t, J=6.4 Hz), 4.13 (2H, t, J=6.1 Hz), 5.60 (2H, s), 6.09 (2H, s), 6.86-6.90 (2H, m), 6.95-7.01 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[N:32]1([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:16]=[CH:15][C:14]4[NH:13][C:12]5[CH:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH2:19][C:11]=5[C:10]=4[CH:9]=3)=[CH:4][C:3]=2[C:28]([F:31])([F:30])[F:29])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Reactant: C1CCNC1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(N4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 120 °C
Yield: 32.4 %

Procedure:
A mixture of ethyl 2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (50.9 mg, 0.113 mmol), pyrrolidine (0.047 mL, 0.563 mmol), diacetoxypalladium (1.264 mg, 5.63 μmol), biphenyl-2-yl-di-tert-butylphosphine (3.36 mg, 11.0 μmol) and sodium 2-methylpropan-2-olate (27.1 mg, 0.282 mmol) in dioxane (3 mL) was heated under microwave irradiation at 120° C. for 2 h. The mixture was purified by HPLC. Fractions containing product were basified with 1 M NaHCO3 and concentrated. The residue was extracted with 0.5 M citric acid and CH2Cl2. The organics were dried over MgSO4, filtered, and concentrated to give the title compound as a white solid (17.8 mg). LCMS m/z=487.4 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].C([O-])(=O)C.[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15]>O.C(O)C>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[NH:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][S:5]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CSC(c2ccc([N+](=O)[O-])cc2)N1
Temperature: 0 °C
Yield: 87 %

Procedure:
3 g (17.08 mmoles) of L-Cysteine hydrochloride and 2.18 g (22.2 mmoles) of sodium acetate are dissolved in 75 ml of water. The solution is agitated vigorously during the addition by portions, of 3.10 g (20.5 mmoles) of 4-nitrobenzaldehyde in solution in 80 ml of 95% ethanol. A white precipitate rapidly appears in this pale yellow solution which forms abundantly. Agitation is maintained for one hour, the reaction mixture is then cooled down to 0° C. and filtered. The precipitate is successively rinsed with 200 ml of water, 100 ml of cold ethanol and 100 ml of ethyl ether. After drying a white powder is obtained with a yield of 87%. Melting point: 190-121° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[CH:6]=[C:7](\[CH3:10])/[CH2:8]Br)[CH3:2].[Cl:15][CH2:16][CH2:17][O:18][P:19]([O:24]CCCl)[O:20][CH2:21][CH2:22][Cl:23]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[CH:6]=[C:7](\[CH3:10])/[CH2:8][P:19]([O:20][CH2:21][CH2:22][Cl:23])([O:18][CH2:17][CH2:16][Cl:15])=[O:24])[CH3:2]
Reactant: CCOC(=O)C(/C=C(\C)CBr)NC=O
Reactant: ClCCOP(OCCCl)OCCCl
Product: CCOC(=O)C(/C=C(\C)CP(=O)(OCCCl)OCCCl)NC=O

Procedure:
8.2 g of E-5-bromo-2-formylamino-4-methyl-3-pentenoic acid ethyl ester and 19 ml of tris-(2-chloroethyl)-phosphite are stirred at a bath temperature of 70° for 20 hours. The resulting mixture is chromatographed on silica gel using ethyl acetate and ethyl acetate/isopropanol (7:1) as eluant, and the product is crystallised from ethyl acetate/diethyl ether. In this manner there is obtained E-2-formylamino-4-methyl-5-di(2-chloroethyl)phosphono-3-pentenoic acid ethyl ester, m.p. 47°-49°.
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.I[C:13]1[C@:14]2([CH2:31][CH2:30][C@H:29]3[C@@H:19]([CH2:20][CH:21]=[C:22]4[C@:27]3([CH3:28])[CH2:26][CH2:25][C@H:24]([OH:32])[CH2:23]4)[C@@H:16]2[CH2:17][CH:18]=1)[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:13]2[C@:14]3([CH2:31][CH2:30][C@H:29]4[C@@H:19]([CH2:20][CH:21]=[C:22]5[C@:27]4([CH3:28])[CH2:26][CH2:25][C@H:24]([OH:32])[CH2:23]5)[C@@H:16]3[CH2:17][CH:18]=2)[CH3:15])[CH:5]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(I)=CC[C@@H]12
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Diethyl(3-pyridyl)borane (3.23 g, 22 mmol) from Aldrich Chemical Co. Ltd. was added to a stirred solution of 17-iodo-androsta-5,16-dien-3β-ol (7.96 g, 20 mmol) in THF (120 ml) containing bis(triphenylphosphine)palladium (II) chloride (140 mg, 0.2 mmol). An aqueous solution of sodium carbonate (2M, 50 ml) was then added and the mixture heated, with stirring, by an oil bath at 80° C. for 48 h, and allowed to cool.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[NH2:2].[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15].Cl.C(=O)([O-])O.[Na+]>CCO>[NH2:15][C:14]1[N:1]([C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)[N:2]=[C:12]([C:11]([CH3:18])([CH3:17])[CH3:10])[CH:13]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(NN)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cn1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A solution of 5-hydrazino-2-methyl-pyridine (8.0 g, 65.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (10.0 g, 79.9 mmol) in EtOH (200 mL) containing 6 N HCl (6 mL) was refluxed for 17 h, then cooled to room temperature. Solid sodium hydrogen carbonate was added to neutralize the solution. The slurry was filtered. The filtrate was concentrated. Column chromatography (silica gel, 2.5″×5″, eluant=EtOAc) afforded the desired 5-amino-3-tert-butyl-1-(2-methylpyridine-5-yl)pyrazole (9.21 g, 62%) as a tan solid.
Reaction SMILES: Br[CH:2]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH3:11])[N:10]=1)=[O:4].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34]([SH:35])=[C:29]2[CH:28]=[N:27]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34]([S:35][CH:2]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:3]([NH:5][C:6]3[S:7][CH:8]=[C:9]([CH3:11])[N:10]=3)=[O:4])=[C:29]2[CH:28]=[N:27]1
Reactant: COCCOCCC(Br)C(=O)Nc1nc(C)cs1
Reactant: Sc1ncnc2c1cnn2-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCC(Sc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1nc(C)cs1
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A solution of 2-bromo-4-(2-methoxyethoxy)-N-(4-methyl-1,3-thiazol-2-yl)butanamide (104 mg, 0.308 mmol) in DMF (1 mL) was added to a stirred solution of 1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-thiol (81.0 mg, 0.308 mmol) and K2CO3 (51.1 mg, 0.370 mmol) in DMF (2 mL). The reaction mixture was kept at ambient temperature for 3 hrs (45° C. and 17 hrs for example 54, 55 and 56). Water and EtOAc were added, and the two phases were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined and washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with DCM/EtOAc:1/1) to give the title compound as a colourless viscous oil (145 mg), 1H NMR (300 MHz, CDCl3) δ 11.06 (br s, 1H), 8.93 (s, 1H), 8.30 (s, 1H), 7.62 (m, 1H), 7.49 (m, 3H), 6.51 (s, 1H), 5.14 (t, 1H), 3.77 (m, 1H), 3.67 (m, 1H), 3.59 (m, 2H), 3.50 (m, 2H), 3.33 (s, 3H), 2.60 (m, 1H), 2.27 (m, 4H), HRMS: calcd for (M+H+) C22H2435ClN6O3S2: 518.1040. Found: 519.1050.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.C1C(=O)N([Br:32])C(=O)C1>>[Br:32][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[NH:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)c1
Product: COc1cccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)cc2)c1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 207 using N-(3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesulfonamide and NBS (reaction time 30 min at room temperature). The crude product was purified by column chromatography on silica gel using ethyl acetate as eluent giving the final product, after recrystallization using hexane/ethyl acetate, in 75% yield, m.p. 140-144° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:26][CH:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH:14]2[CH2:13]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][CH:12]2[CH2:26][CH:15]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:18][CH:14]3[CH2:13]2)[C:5]([C:9]#[N:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(N)CC2C1
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3C#N)CC2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
To a solution of 2,4-dichloropyrimidine-5-carbonitrile (600 mg, 3.4485 mmol) and tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (936.8 mg, 4.139 mmol) in ethanol (50 mL) was added N,N-diethylethanamine (698.5 mg, 6.903 mmol). The mixture was stirred at rt for 3 h. Then it was concentrated under vacuo, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title product as yellow oil (332.5 mg, 26.50%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH:17]2Br>C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH:18]=[CH:17]2
Reactant: COc1ccc2c(c1)C(Br)CC2=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C=CC2=O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
DBU (9.2 mL, 61.7 mmol) was added to a solution of 5-methoxy-3-bromo-1-indanone (14.8 g, 61.7 mmol) in THF (100 mL) at −10° C. dropwise over 10 minutes. The resulting solution was stirred at −10° C. for 20 minutes, quenched via addition of saturated aqueous NH4Cl (100 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 5.4 g (55%—two steps) of the subtitle compound. 1H NMR (CDCl3 300 MHz) δ 7.42 (d, 1H), 7.38 (d, 1H), 6.62 (s, 1H), 6.60 (d, 1H), 5.89 (d, 1H), 3.85 (s, 3H) ppm. MS calculated for C10H8O2+H: 161, observed: 161.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]2[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39]2)(=[O:37])=[O:36])[C:25]([Cl:44])=[CH:24][N:23]=1>>[Cl:44][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]2[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39]2)(=[O:37])=[O:36])=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: C[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](C)C3)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[2-((S)-3-methyl-pyrrolidine-1-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.061 g, 47%). MP: 79-89° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.36 (s, 1H), 8.49 (d, J=8.3 Hz, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.93 (dd, J=8.0 Hz and 1.4 Hz, 1H), 7.56-7.49 (m, 2H), 7.25-7.20 (m, 2H), 6.64 (s, 1H), 3.87 (s, 3H), 3.43 (dd, J=9.6 Hz and 7.1 Hz, 1H), 3.40-3.33 (m, 1H), 3.30-3.22 (m, 3H), 3.14 (s, 3H), 2.98 (s, 3H), 2.91-2.86 (m, 2H), 2.79 (dd, J=9.5 Hz and 7.5 Hz, 1H), 2.74-2.63 (m, 6H), 2.25-2.10 (m, 1H), 1.95-1.87 (m, 1H), 1.43-1.33 (m, 1H), 0.86 (d, J=6.8 Hz, 3H). MS: 628.21 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:5]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)Oc1cc(F)c([N+](=O)[O-])cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 17 h
Yield: 96.6 %

Procedure:
A solution of 5-chloro-2-fluoro-4-[(1-methylethyl)oxy]-1-nitrobenzene (D83, 153 mg, 0.65 mmol) in dimethylformamide (5 ml) was treated with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (130 mg, 0.65 mmol) and diisopropylethylamine (0.113 ml, 0.65 mmol) and stirred at approx. 80° C. for 17 hrs. The mixture was concentrated under vacuum and the residue treated with water and extracted with diethyl ether (×2). The combined extract was dried (MgSO4) and concentrated under vacuum to afford the title compound as a yellow solid (260 mg, 97%).
Reaction SMILES: [OH-].[Na+].[NH:3]1CCC[C@H]1C(O)=O.[N-]=[N+]=[N-].[Na+].C(OC([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[C:30](Br)=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH:35]=[N:34][CH:33]=[CH:32]3)[CH2:24][CH2:23]1)=O)(C)(C)C>C(O)C.O.[Cu]I.C(OCC)(=O)C.O>[NH:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[C:30]([NH2:3])=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH:35]=[N:34][CH:33]=[CH:32]3)[CH2:24][CH2:23]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2Br)CC1
Agent: [Cu]I
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1c(OC2CCNCC2)ccc2cnccc12
Temperature: 95 °C
Reaction time: 2 h
Yield: 123.4 %

Procedure:
60 μL of 1N NaOH-solution, 6.9 mg (0.3 eq) of L-proline, 3.8 mg (0.1 eq) of CuI and 26 mg (0.4 mmol) of NaN3 were added to a solution of 82 mg (0.2 mmol) of 4-(5-Bromo-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (11) in 2 mL of ethanol/water (7/3). The mixture was heated to 95° C. for 3 h in a microwave reactor (CEM Discover). After cooling water and ethyl acetate were added and the mixture was filtered through a celite cartridge. After removal of the solvents by distillation the remainder was subjected to preparative HPLC. The N-Boc-protected intermediate was deprotected by treatment with 2 mL 5-6 N HCl in isopropanol for 2 h at room temperature. Then water was added and all solvents were removed by freeze drying to yield 18 mg of compound 31 as hydrochloride.