Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:6]([OH:8])=[O:7])(=O)C>[OH-].[K+].C(O)C>[OH:4][C@@H:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:6]([OH:8])=[O:7]
Reactant: CCCCCCCCCCCCCC[C@H](OC(C)=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCC[C@H](O)C(=O)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
(S)-(+)-2-Acetoxyhexadecanoic acid (0.5 g; prepared by the method described in Agric. Biol. Chem., 54(12), 3337-3338, 1990) was dissolved in a solution of potassium hydroxide (1.0 g) in 50% aqueous ethanol was stirred at 70° C. for 2 hours. After the ethanol was evaporated, the reaction mixture was acidified with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated to give (S)-(-)-2-hydroxyhexadecanoic acid (407 mg). The product was dissolved in DMF (20 ml ), and N-hydroxysuccinimide (173 mg) and N,N'-dicyclohexylcarbodiimide (310 mg) were added to the solution. The mixture was stirred at room temperature for 12 hours and then filtered. 6-(4'-N-Glycyl-spicaminyl-amino)purine hydrochloride (0.60 g) and triethylamine (1.0 ml ) were added to the filtrate, and the mixture was stirred for 12 hours, concentrated and subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1 ) to give SPK271 in the yield of 97 mg. Substantially no contamination of the diastereomer was observed.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[N+]=[N-])[C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@:22]2([C:23]([O:25][CH3:26])=[O:24])[CH2:8][C:7]2([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(Br)cc1
Reactant: C=C(c1ccccc1)c1ccccc1
Product: COC(=O)[C@@]1(c2ccc(Br)cc2)CC1(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a flame-dried round bottom flask kept under a dry atmosphere of argon, was added Rh2(RDOSP)4 (0.01 equiv., 382 mg), 1,1-diphenylethlyene 11 (2.32 equiv., 8.16 mL), and dry degassed pentane (100 mL). A solution of freshly prepared methyl 2-(4-bromophenyl)-2-diazoacetate 12 (1.0 equiv., 5.1 g) in dry, degassed pentane (150 mL) was added to the former solution drop-wise over 3 hours at room temperature. The mixture was allowed to stir overnight, and then concentrated in vacuo. The crude material was purified using flash column chromatography eluting with a 50:1 mixture of hexanes/ethyl acetate to provide the desired product as a white foam (7.2 g, 88% yield, 98% ee). mp: 82-85° C.; Rf=0.55 (hexanes/ethyl acetate=7/1); [α]20 D −289.2° (c=1.17, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48-7.47 (m, 2H), 7.35-7.31 (m, 2H), 7.27-7.18 (m, 5H), 7.02-6.97 (m, 5H), 3.34 (s, 3H), 2.68 (d, J=5.5 Hz, 1H), 2.39 (d, J=5.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.9, 141.7, 139.1, 134.8, 133.5, 130.6, 129.8, 128.5, 128.3, 127.7, 126.9, 126.3, 121.1, 52.2, 44.6, 42.4, 22.6; IR (neat): 3057, 3024, 2947, 1724, 1490, 1217; HRMS (APCI) calcd for C23H20BrO2 (M+H)+ 407.06412. found 407.06432; HPLC (S,S-Whelk, 5% isopropanol in hexane, 0.8 mL/min, 1 mg/mL, 60 min, UV 254 nm) retention times of 10.6 min (major) and 50.9 min (minor), 98% ee. (S)-methyl 1-(4-bromophenyl)-2,2-diphenylcyclopropanecarboxylate was prepared by the same procedure with Rh2(S-DOSP)4 as the catalyst, [α]20D: 219.6° (c=1.32, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13]C(C#N)=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=1.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13][C:21]([C:20]([OH:23])=[O:22])=[CH:9][C:8]=2[C:15]([F:18])([F:16])[F:17])[CH:6]=1
Reactant: CC(=O)O
Reactant: Cc1cn(-c2ccc(C#N)cc2C(F)(F)F)cn1
Agent: Cl
Product: Cc1cn(-c2ccc(C(=O)O)cc2C(F)(F)F)cn1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzonitrile (1.01 g, 4 mmol), 6 mL of acetic acid and 3 mL of 12 M hydrochloric acid (37%) is shaken for 16 hours at 95° C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The resulting residue is evaporated twice with toluene, dissolved in water and the pH is adjusted to ˜5-6 by dropwise addition of 1M sodium hydroxide solution. The aqueous phase is extracted twice with ethyl acetate. The organic phase is dried (Na2SO4) and evaporated to yield the title compound as a pale yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[C:22]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:25]2[CH:36]=[CH:37][CH:38]=[CH:39][C:24]=2[N:23]=1>CC(O)C>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:26]2[C:25]3[CH:36]=[CH:37][CH:38]=[CH:39][C:24]=3[N:23]=[C:22]2[NH:18][C:17]2[CH:16]=[CH:15][C:14]([O:13][C:8]3[C:7]([CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:20][CH:19]=2)=[CH:33][CH:32]=1
Reactant: Nc1ccc(Oc2ncccc2C2CCOCC2)cc1
Reactant: COc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Solvent: CC(C)O
Product: COc1ccc(Cn2c(Nc3ccc(Oc4ncccc4C4CCOCC4)cc3)nc3ccccc32)cc1
Temperature: 170 °C

Procedure:
A glass microwave reaction vessel was charged with 4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)aniline (0.2573 g, 0.952 mmol) and 2-chloro-1-(4-methoxybenzyl)-1H-benzo[d]imidazole (0.312 g, 1.142 mmol) in IPA. The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 170° C. for 30 min. Solvent was evaporated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 10% to 80% EtOAc in hexane, to provide 1-(4-methoxybenzyl)-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. IC50 (uM) +++++.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]4)=[CH:20][CH:19]=3)[C:15]3[C:10](=[CH:11][C:12]([O:33][CH3:34])=[CH:13][CH:14]=3)[C:9]2=O)=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:33][CH3:34])[CH:11]=3)[CH:16]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)N(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of 2-(4-fluorophenyl)-6-methoxy-3-{4-[(2-piperidyl)ethoxy]benzyl}isoindolin-1-one (0.50 g, 1.05 mmol) in tetrahydrofuran (10 mL) under nitrogen was added a 1.5 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (2 mL, 3 mmol). After heating at reflux for 5 hours, the reaction was cooled to room temperature, 6 N HCl solution (6 mL) was added, and the reaction was stirred for 1 hour at room temperature. The mixture was basified with a saturated sodium bicarbonate solution and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 20-30% ethyl acetate/hexane) to provide the title compound (0.297 g, 61% yield): 1H NMR (CDCl3) 7.05 (t, 2H), 6.91 (d, 1H), 6.78 (dd, 1H), 6.61-6.72 (m, 7H), 5.24 (m, 1H), 4.30-4.41 (m, 3H), 4.15 (dd, 1H), 3.80 (s, 3H), 3.17 (t, 2H), 2.98-3.10 (m, 4H), 2.91 (m, 2H), 1.81 (m, 4H), 1.56 (m, 2H); ES-MS (m/z) 461 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].I[CH3:19].O>CN(C)C=O>[CH3:19][N:3]1[CH2:4][CH2:5][CH2:6][C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a solution of (R)-tert-butyl 2-oxopiperidin-3-ylcarbamate (642 mg, 3.00 mmol) in N,N-dimethylformamide (3 mL) at room temperature was added sodium hydride (132 mg, 3.3 mmol). The reaction mixture stirred for 30 min, then iodomethane (206 μL, 3.3 mmol) was added and stirring was continued for 1 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (100 mL), using a continuous extractor apparatus overnight. The organic extract was evaporated to dryness under vacuum and the crude residue was purified by SiO2 chromatography (23 g, CH2Cl2/MeOH/NH4OH, 100:0:0 to 94:5.7:0.3) to give 310 mg (45%) of (R)-tert-butyl 1-methyl-2-oxopiperidin-3-ylcarbamate as a colorless viscous oil.
Reaction SMILES: CS[C:3](=[N:12][CH2:13][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([Cl:11])[CH:5]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=[CH2:31])[C:27]([F:30])([F:29])[F:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[CH2:31][C:26]([C:21]3[CH:22]=[C:23]([Cl:25])[CH:24]=[C:19]([Cl:18])[CH:20]=3)([C:27]([F:28])([F:30])[F:29])[CH2:13][N:12]=2)=[CH:5][C:6]=1[Cl:11]
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(Cl)c1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CN=C(c2ccc(Br)c(Cl)c2)C1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (9.60 g, 27.4 mmol) in dry THF (100 mL) was added 2-(3,5-dichlorophenyl)-1,1,1-trifluoro-2-propene (8.94 g, 33.4 mmol) at −7° C. A solution of tetrabutyl ammoniumfluoride (5.32 mL, 1 M in THF, 5.33 mmol) was added at this temperature and the mixture was allowed to warm to room temperature over night. All volatiles were removed in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (9.50 g, 74%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29]OS(C)(=O)=O)[O:17][C@@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[I-:35].[Na+]>CN(C=O)C>[C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][I:35])[O:17][C@@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](SCC=Cc2ccccc2)O[C@H](COS(C)(=O)=O)[C@H]1OC(C)=O
Reactant: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](SCC=Cc2ccccc2)O[C@H](CI)[C@H]1OC(C)=O
Temperature: 70 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A suspension of 10 (2.0 g) and sodium iodide (1.0 g) in DMF (15 ml) is heated with stirring for 16 hours at 70° C. (bath temperature). The mixture is evaporated in vacuo to a residue, which is partitioned between chloroform and water. The organic layer is dried and evaporated to a syrup (2.0 g), which is put on a column of silica gel and eluted with CHCl3 --EtOAc (95:5, v/v). The title compound is isolated in 94% yield: m.p. 91°-92° C. (MeOH); [α]D27 +203±0.9° (C 1.06, CHCl3).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][CH2:9][C:10](Cl)=[O:11]>>[Br:8][CH2:9][C:10]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:11]
Reactant: OC1CCCCC1
Reactant: O=C(Cl)CBr
Product: O=C(CBr)OC1CCCCC1

Procedure:
The sub-title compound was prepared analogously to the procedure described in Example 32(i) above from cyclohexanol (1 g; 10 mmol) and bromacetylchloride (1 mL; 12 mmol).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[CH:12]([C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:27])[CH2:20][C:21]([CH3:26])([CH3:25])[O:22]2)=[C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]=1[C:34](=[O:46])[C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=1)([CH3:14])[CH3:13].CO>O1CCCC1>[OH:27][C@@H:19]1[C:18]2[C:23](=[CH:24][C:15]([CH:12]([CH3:13])[CH3:14])=[C:16]([C:34]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:43])[F:44])=[CH:37][CH:36]=3)=[O:46])[C:17]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:22][C:21]([CH3:25])([CH3:26])[CH2:20]1
Reactant: CC(C)c1cc2c(c(-c3ccccc3)c1C(=O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccccc3)c1C(=O)c1ccc(OC(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
72 μl (410 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 2.3 mg (20 μmol) of (1R,2S)-1-aminoindan-2-ol in 1.5 ml of tetrahydrofuran, and the mixture is stirred for 30 min. The mixture is then cooled to 0° C., and a solution of 49 mg (100 μmol) of 7-isopropyl-2,2-dimethyl-5-phenyl-6-[4-(trifluoromethoxy)benzoyl]-2,3-dihydro-4H-chromen-4-one (Example 32A) in 3.5 ml of tetrahydrofuran is slowly added dropwise. The mixture is allowed to thaw slowly and stirred at room temperature overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative HPLC (method 1) gives the target product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](O)[N:5]=[C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:20])[N:5]=[C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:3]=1
Reactant: N#Cc1ccc(Nc2nc(N)cc(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Nc2nc(N)cc(Cl)n2)cc1
Temperature: 25 °C

Procedure:
1900 ml of phosphorus oxychloride was added to a reaction vessel, to this was added 190 g of 4-(4-amino-6-hydroxypyrimidin-2-ylamino)benzonitrile under stirring at RT. The reaction mass was slowly heated to 80-85° C. and maintained at the same temperature for 16-18 hr. After completion of the reaction, phosphorous oxychloride was distilled off and stripped with 950 ml of ethyl acetate. 1900 ml of chilled water was slowly added to the reaction mass and its pH was adjusted to 9-10 with 950 ml of 50% aqueous potassium carbonate. The solid was filtered and dried under vacuum at 55-60° C. overnight.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:16][N:15]([C@H:25]([C@@H:36]([CH3:39])[CH2:37][CH3:38])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:14]1.C(N(CC)CC)C>C(Cl)Cl.CCOCC>[CH:12]([C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:16][N:15]([C@H:25]([C@@H:36]([CH3:39])[CH2:37][CH3:38])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:14]1)=[O:11]
Reactant: CC[C@H](C)[C@H](C(=O)OCc1ccccc1)N1C[C@H](CO)[C@@H](c2cccc(F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC[C@H](C)[C@H](C(=O)OCc1ccccc1)N1C[C@H](c2cccc(F)c2)[C@@H](C=O)C1
Reaction time: 0.25 h
Yield: 79.3 %

Procedure:
After cooling 0.605 g (4.767 mmole) oxalyl chloride in 30 mL DCM in a dry ice acetone bath under nitrogen, 0.748 g (9.569 mmole) DMSO in 5 mL DCM was added over 5 minutes. After stirring for 15 minutes, a solution of the alcohol (1.587 g, 3.987 mmole) from Step C above in 30 mL DCM was added over 20 minutes. After an additional 20 minutes, a solution of 2.017 g (19.935 mmole) triethylamine in 5 mL DCM was added over 5 minutes. The cooling bath was allowed to warm up overnight. The reaction mixture was transferred into a separatory funnel with ether and was washed with 1 N NaOH, water, and saturated brine. The organic layer was dried over sodium sulfate and concentrated to give 1.63 g crude product. FC on silica gel (5˜40% ethyl acetate in hexanes) gave 1.257 g title compound as a colorless oil. Rf: 0.44 (20% ethyl acetate in hexanes). 1H NMR (500 MHz) δ 9.64 (d, J=2.1 Hz, 1H), 7.33˜7.41 (m, 5H), 7.24˜7.27 (m, 1H), 6.90˜6.98 (m, 3H), 5.21 (AB d, J=12.2 Hz, 1H), 5.18 (AB d, J=12.2 Hz, 1H), 3.54˜3.58 (m, 1H), 3.26˜3.29 (m, 1H), 3.14˜3.22 (m, 3H), 2.89˜2.93 (m, 1H), 2.68˜2.71 (m, 1H), 1.86˜1.93 (m, 1H), 1.39˜1.47 (m, 1H), 1.04˜1.15 (m, 1H), 0.99 (d, J=6.7 Hz, 3H), 0.91 (t, J=7.5 Hz, 3H). Some starting material was also recovered (0.298 g). Rf: 0.13 (20% ethyl acetate in hexanes).
Reaction SMILES: C1(O[C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[CH3:23])CCCCC1.[CH2:24](OC(N1CCC[C@@H]1C(C1C2C(=CC=C(OC3CCCCC3)C=2)NC=1)=O)=O)C1C=CC=CC=1>>[CH3:24][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(OC3CCCCC3)cc12
Reactant: O=C(c1c[nH]c2ccc(OC3CCCCC3)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Product: Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1

Procedure:
(R)-5-Cyclohexyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole: from (R)-3-[(N-benzyloxycarbonylpyrrolidin-2-yl)carbonyl]-5-cyclohexyloxy-1H-indole (Example 2g).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH3:19])[N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:21][NH2:22]>C(O)CCC>[CH3:19][C:14]1[N:13]=[C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:21][NH2:22])=[O:2])[CH2:6][CH2:7]2)[CH:17]=[C:16]([CH3:18])[N:15]=1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cc(C)nc(C)n2)CC1
Solvent: O
Solvent: CCCCO
Product: Cc1cc(O[C@H]2CC[C@H](C(=O)NN)CC2)nc(C)n1

Procedure:
A mixture of trans-4-(2,6-dimethyl-pyrimidin-4-yloxy)-cyclohexanecarboxylic acid methyl ester (0.20 g, 0.76 mmol) and hydrazine hydrate (0.15 ml, 3.0 mmol) in n-butanol (0.5 ml) was heated at reflux over night. The reaction mixture was evaporated and dried in high vacuo (ca. 1-2 mbar) to give the crude title compound (0.19 g, 95%) as white solid, which was used in the next step without further purification. MS m/e: 265 (M+H+)
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][NH2:16]>O1CCCC1>[CH3:15][NH:16][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A suspension of 3.38 g of 5-chlorosulfonyl-2-oxindole in 10 mL 2M methylamine in tetrahydrofuran was stirred at room temperature for 4 hours during which time a white solid formed. The precipitate was collected by vacuum filtration, washed twice with 5 mL of water and dried under vacuum at 40° C. overnight to give 3.0 g (88% yield) of 5-methylaminosulfonyl-2-oxindole.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:51]=[CH:50][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)=[O:41])=[CH:38][CH:37]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([C:40]([NH:42][CH:43]5[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]5)=[O:41])=[CH:50][CH:51]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)cc2)CC1
Yield: 55.9 %

Procedure:
A mixture of 0.0562 g (0.17 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0485 g (0.255 mmole) of toluenesulfonic acid monohydrate, 0.0397 g (0.17 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 15 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to give 0.0501 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-262) as a white solid.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1.[C:24](=[O:26])=[O:25].Cl>C1COCC1>[Cl:16][C:17]1[C:22]([C:24]([OH:26])=[O:25])=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1
Reactant: Clc1cncc(Cl)n1
Reactant: O=C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ncc(Cl)nc1Cl
Reaction time: 0.5 h

Procedure:
To a THF solution of 2,2,6,6-tetramethylpiperidine was added n-butyllithium under ice cooling and was further added a THF solution of 2,6-dichloropyrazine at −78° C. After 30 minutes of stirring, dry ice was added to the reaction mixture and, after 30 minutes of stirring, 1 M hydrochloric acid was added thereto. Thereafter, purification in the usual way afforded 3,5-dichloropyrazine-2-carboxylic acid (pale yellow solid). FAB-MS: 191 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([Cl:25])[CH:19]=[C:18]2[CH3:26].N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:25][C:20]1[CH:19]=[C:18]([CH3:26])[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])[CH:16]=2)[N:21]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Cc1cc(Cl)nc2ccc(Br)cc12
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3nc(Cl)cc(C)c3c2)C1=O
Yield: 46.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 275.4 mg, 1.5564 mmol) was reacted with 6-bromo-2-chloro-4-methyl-quinoline (400 mg, 1.5564 mmol), 1,4-dioxane (10 mL), copper iodide (29.649 mg, 0.15564 mmol), trans-1,2-diamino cyclohexane (53.448 mg, 0.4668 mmol) and potassium carbonate (430 mg, 3.112 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 256 mg of the product (46.54% yield).