Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([O:17][CH3:18])[CH2:15][C:14](=[O:19])[CH2:13][CH:12]3[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N-:27]=[N+]=[N-].[Na+]>C(#N)C.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([O:17][CH3:18])[CH2:15][C:14](=[O:19])[NH:27][CH2:13][CH:12]3[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC1CC(=O)CC(c2ccc(Cl)cc2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: COC1CC(=O)NCC(c2ccc(Cl)cc2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 5.7 %

Procedure:
In a manner similar to the method described in example 2 (method A), rac-(1R,2S,6S)-6′-chloro-2-(4-chlorophenyl)-6-methoxyspiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (312 mg, 0.8 mmol) was reacted with NaN3 (104 mg, 1.6 mmole) in the presence of TiCl4 (1.0 M in CH2Cl2, 0.8 mL) (Aldrich) in acetonitrile (20 mL) to give rac-(3S,4R,5S)-6′-chloro-3-(4-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-5-methoxy-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (18.6 mg): HRMS (ES+) m/z Calcd for C20H18Cl2N2O3+H [(M+H)+]: 405.0767. Found: 405.0768; and rac-(3R,4R,5S)-6′-chloro-5-(4-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-methoxy-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (19.7 mg): HRMS (ES+) m/z Calcd for C20H18Cl2N2O3+H [(M+H)+]: 405.0767. Found: 405.0768.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[C:6]([Cl:15])[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C>C(Cl)Cl.C(OC(=O)C)C.C(OCC)C>[Cl:15][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[C:2]([NH:23][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=[C:4]([S:16][CH3:17])[N:5]=1
Reactant: NC1CCCC1
Reactant: CSc1nc(Cl)c(-c2ccccc2F)c(Cl)n1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)c(-c2ccccc2F)c(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.1 %

Procedure:
To a solution of 4,6-dichloro-5-(2-fluorophenyl)-2-methylthiopyrimidine (0.74 g, 256 mmol) in methylene chloride (1 ml) at room temperature under nitrogen atmosphere was added cyclopentyl-amine (1.01 ml, 10.24 mmol) and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then diluted with 1:1 v/v diethyl ether ethyl acetate (75 ml), washed with 1M aqueous hydrochloric acid (2×75 ml), saturated aqueous sodium bicarbonate solution (75 ml) and saturated brine (75 ml), dried over magnesium sulfate and concentrated in vacuo to afford a colorless syrup. The crude product was chromatographed on silica gel eluting with 95:5 v/v hexane: ethyl acetate to afford 0.87 g (100% yield) of the title compound as a white crystalline solid (melting point: 81-83° C.).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[NH:10][N:9]=1)=[O:7])C>CO>[CH3:17][CH:16]([CH3:18])[CH2:15][CH2:14][CH2:13][C:11]1[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=1
Reactant: CCOC(=O)c1cc(CCCC(C)C)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCCc1cc(C(=O)O)n[nH]1
Yield: 80.2 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 4.97 mmol) was added to a stirring, room temperature solution of 17 (0.2229 g, 0.994 mmol) in MeOH (12.4 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (20 min): The reaction was concentrated and then dissolved in 2.0 mL H2O. 10% aq. HCl was added dropwise until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.1565 g (80.2%) of 18. 1H (CD3OD, 400 MHz): δ 6.56 (1H, s), 2.68 (2H, t, J=7.6 Hz), 1.67 (2H, quint, J=7.8 Hz), 1.63-1.51 (1H, m), 1.23 (2H, dt, J=8.8, 7.1 Hz), 0.89 (6H, d, J=6.4 Hz) ppm. 13C (CD3OD, 100 MHz): δ 163.79, 149.69, 142.80, 107.65, 39.46, 28.92, 28.11, 26.90, 22.91 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.91; CH2 carbons: 39.46, 28.11, 26.90; CH carbons: 107.65, 28.92 ppm. HPLC: 8.579 min.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:23]([O:25]C)=[O:24])[CH2:8][CH2:7][N:6]([CH:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[Li+].[OH-].Cl>C1COCC1>[C:19]([O:18][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:9]([N:6]2[CH2:7][CH2:8][C:3]([O:2][CH3:1])([C:23]([OH:25])=[O:24])[CH2:4][CH2:5]2)[CH2:10][CH2:11]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)C1(OC)CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC1(C(=O)O)CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
tert-butyl 4-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.06 g, 0.17 mmol) was dissolved in THF (5 mL) at rt and 1M LiOH sol. (0.35 mL) was added. The reaction mixture was stirred at rt for 8 days. The pH was carefully adjusted to pH 6 by addition of concentrated hydrochloric acid, the solvents were removed in vacuo, to give 1-[1-(tert-butoxycarbonyl)azepan-4-yl]-4-methoxypiperidine-4-carboxylic acid which was used crude in subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CN1[CH:15]=[CH:14][C:12](=[O:13])N(C)C1=O.[O-]CC.[Na+:20].C(O)C>CO.ClCCl>[N:4]1[N:3]2[CH:15]=[CH:14][C:12]([O-:13])=[N:1][C:2]2=[CH:6][CH:5]=1.[Na+:20]
Reactant: Nc1cc[nH]n1
Reactant: Cn1ccc(=O)n(C)c1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: [O-]c1ccn2nccc2n1
Yield: 95 %

Procedure:
A mechanically stirred mixture of 3-aminopyrazole (9.38 g, 0.11 mM, 1.0 equiv), 1,3-dimethyluracil (14.7 g, 0.11 mM, 1.0 equiv) and 21% sodium ethoxide in ethanol (170 mL, 5.0 equiv) was heated to reflux. Within minutes, a heavy precipitate formed. After refluxing for 1 hour, 1,3-dimethyluracil could no longer be detected by thin layer chromatography (tlc) (92:8 dichloromethane (dichloromethane):MeOH). The reaction mixture was cooled, filtered, washed with cold ethanol and vacuum dried to give 13.47 g (95%) of sodium pyrazolo[1,5-a]pyrimidin-5-olate. LCMS (ESI) m+H=136.0; 1H NMR (400 MHz, DMSO-d6) δ: 8.0 (d, 1H), 7.43 (d, 1H), 5.65 (d, 1H), 5.37 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][N:11]=[C:10]([C:19]([OH:21])=O)[N:9]=2)=[CH:4][CH:3]=1.[CH:22]1([C:25]2[O:29][N:28]=[C:27]([CH2:30][NH2:31])[N:26]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[O:29][N:28]=[C:27]([CH2:30][NH:31][C:19]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13]([O:14][CH2:15][CH:16]4[CH2:17][CH2:18]4)=[CH:12][N:11]=3)=[O:21])[N:26]=2)[CH2:24][CH2:23]1
Reactant: O=C(O)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Reactant: NCc1noc(C2CC2)n1
Product: O=C(NCc1noc(C2CC2)n1)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid (example T) and [(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]amine (CAS Registry No. 1082420-52-7), LC-MS (UV peak area/ESI) 100%, 426.132 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12])[O:8][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([C:35]([F:36])([F:38])[F:37])[CH:28]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)c(C(F)(F)F)c3)cc2Cl)C(F)(F)F)cn(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a stirred solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5, 80 mg) in N,N-dimethylacetamide (1.5 ml) were added 4-fluoro-2-(trifluormethyl)benzaldehyde (63 mg) and cesium carbonate (208 mg). The mixture was stirred at room temperature for 3 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>0:1) to give the title compound (111 mg) as an off-white solid. MS (m/e)=548.2 [M+H+].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=3)[N:11]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:10]=2)O1.Cl[C:34]1[N:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[CH:37]=[CH:36][N:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:40]([C:38]1[CH:37]=[CH:36][N:35]=[C:34]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=3)[N:11]([S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=3)(=[O:23])=[O:24])[CH:10]=2)[N:39]=1)([CH3:42])[CH3:41]
Reactant: COC(=O)c1ccc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)c1ccnc(Cl)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)c(-c1nccc(C(C)C)n1)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 75.1 %

Procedure:
A brown mixture of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole-5-carboxylate (1.85 g, 4.06 mmol), 2-chloro-4-isopropylpyrimidine (0.700 g, 4.47 mmol) [CombiPhos Catalyst Inc.], potassium phosphate (2.59 g, 12.19 mmol), Pd2(dba)3 (0.15 g, 0.16 mmol), and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (X-Phos) (0.15 g, 0.32 mmol) in dioxane (15 mL) and H2O (3.00 mL) was purged with argon then heated in an oil bath at 100° C. for 3 h. The reaction was cooled to RT, diluted with EtOAc (100 mL), washed with NaOH (5 mL of 0.5 N) followed by brine (5 mL). The organic solution was dried and concentrated. Chromatographic purification of the brown residue (20-80% EtOAc/Hex) furnished methyl 3-(4-isopropylpyrimidin-2-yl)-1-tosyl-1H-indole-5-carboxylate (1.37 g, 75%) as a light-yellow solid. This material was used in next step without further purification. MS (ESI, pos. ion) m/z: 450.0 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:13][S:14][CH2:15][S:16](=[O:18])[CH3:17].CC(C)([O-])C.[K+].O>C(O)(C)(C)C.C(Cl)Cl>[CH3:17][S:16]([C:15]([S:14][CH3:13])=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)=[O:18]
Reactant: CC(C)Cc1ccc(C=O)cc1
Reactant: CSCS(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: O
Product: CSC(=Cc1ccc(CC(C)C)cc1)S(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.2 %

Procedure:
A mixture of 486 mg of p-isobutylbenzaldehyde and 450 mg of formaldehyde dimethyl mercaptal S-oxide was dissolved in 1 ml of t-butanol, and 2.0 ml of a t-butanol solution (0.608 N) of potassium t-butoxide was added. The mixture was stirred for 12 hours at room temperature. Water (0.5 ml) was added to the reaction mixture, and then 50 ml of methylene chloride was added. The mixture was dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and the filtrate was concentrated under reduced pressure. The oily residue was chromatographed on a column of silica gel using methylene chloride as an eluent to afford 701 mg of 1-methylsulfinyl-1-methylthio-2-(p-isobutylphenyl)ethylene in a yield of 87%.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([C:30]3[CH:31]=[N:32][C:33]([N:36]([CH2:46][C:47]4[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)[CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)=[N:34][CH:35]=3)[C:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:18][CH:17]=4)[C:11]=3[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>>[CH3:55][S:56]([N:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([N:13]3[C:11]4[N:12]=[C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[N:8]=[C:9]([C:30]5[CH:31]=[N:32][C:33]([N:36]([CH2:46][C:47]6[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=6)[CH2:37][C:38]6[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=6)=[N:34][CH:35]=5)[C:10]=4[CH2:15][CH2:14]3)=[CH:17][CH:18]=2)[CH2:25][CH2:26]1)(=[O:58])=[O:57]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCN4CCNCC4)cc3)cn2)cc1
Reactant: CS(=O)(=O)Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCN4CCN(S(C)(=O)=O)CC4)cc3)cn2)cc1

Procedure:
In the same manner as Example 1-D-143, using a crude product (80 mg) of 5-{2-morpholin-4-yl-7-[4-(2-piperazin-1-yl-ethyl)-phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine obtained in Example 1-D-143 and methanesulfonyl chloride (0.012 ml) instead of acetyl chloride, a crude product of 5-(7-{4-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine was obtained as a colorless solid (88 mg, 100%). Using a crude product (88 mg) of 5-(7-{4-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine, according to the above Deprotection method 2,5-(7-{4-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-ylamine was obtained as a colorless powder (26 mg, 43%).
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([O:8][NH:9][C:10](=[O:29])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][C:21]=2[F:28])[CH2:4][O:3]1.Cl>C(O)C>[CH2:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:12]2[C:13]([F:18])=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[C:10]([NH:9][O:8][CH:5]([CH2:6][OH:7])[CH2:4][OH:3])=[O:29])=[C:21]([F:28])[CH:22]=1)[CH3:27]
Reactant: CCc1ccc(Nc2c(C(=O)NOC3COC(C)(C)OC3)ccc(F)c2F)c(F)c1
Agent: Cl
Solvent: CCO
Product: CCc1ccc(Nc2c(C(=O)NOC(CO)CO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a stirring solution of the product of Example 33, Step C, N-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzamide (0.416 g, 0.980 mmol) in ethanol (5 mL) was added 1 molar aqueous hydrochloric acid solution (1 mL). After stirring for 1 hour at ambient temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water and twice with brine. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. The affording foam was crystallized in ethyl acetate and heptane to afford 2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-1-hydroxymethyl-ethoxy)-benzamide (0.318 g, 84.6%) as a white crystalline solid: m.p. 91–93° C.; 1NMR (400 MHz; CD3OD) δ 7.38 (1H, t, J=6.8 Hz), 6.85–6.96 (3H, m), 6.73–6.78 (1H, m), 3.86–3.82 (1 H), 3.64 (4H, d, J=4.9 Hz), 2.58 (2H, q, J=15.1, 7.6 Hz), 1.19 (3H, t, J=7.6 Hz); 19F-NMR (376 MHz; CD3OD) 8–132.4, −134.6, −147.2; MS(APCI+)=385; Anal.calcd/found for C18H19F3N2O4: C, 56.25/56.38; H, 4.98/4.81; N, 7.29/7.25.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][C:18]([O:17][CH3:16])=[O:27])=[CH:21][CH:22]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)([CH3:15])[CH3:14]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66, 95.0 mg, 0.45 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 131.0 mg, 0.45 mmol) in triethylamine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (111 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-8% EtOAc-hexanes) afforded 110.0 mg (70%) of the title compound as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11]
Reactant: O=C1NCc2c(Br)cccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1NCc2c(Br)ccc([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A 0° C. solution of Example 1C (5 g, 23.6 mmol) in 10 mL sulfuric acid was treated with a solution of concentrated nitric acid (1.55 mL, 24.7 mmol) in 10 mL sulfuric acid via addition funnel. The resulting mixture was stirred at 0° C. for 1 hour, warmed to room temperature, stirred overnight, poured over ice, and filtered. The filter cake was washed with water and diethyl ether and then dried to give 5.39 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 4.39 (s, 2H); 7.88 (d, J=8.1 Hz, 1H); 8.05 (d, J=8.5 Hz, 1H); 9.17 (s, 1H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][C:12](=[O:13])[C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([N:2]1[CH:1]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[C:12](=[O:13])[CH2:11][CH2:10][C:8]=32)=[N:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2c1ccc1[nH]ncc21
Solvent: CN(C)C=O
Product: O=C1CCc2c1ccc1nn(Cc3ccccc3)cc21
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a suspension of 7,8-dihydrocyclopenta[e]indazol-6(3H)-one (6.00 g, 34.8 mmol) in 60 mL of dimethylformamide was added benzyl bromide (5.40 mL, 45.5 mmol) and the mixture was heated to 100° C. After 15 hours, the solution was cooled to room temperature and partitioned between chloroform and saturated aqueous NaHCO3. The organic phase was washed with water (3×) and brine and dried over Na2SO4. The solution was concentrated to low volume under vacuum and flash chromatographed on silica gel eluting with EtOAc/dichloroethane (0:100 to 20:80) which removed a minor amount (˜10%) of the faster eluting regioisomer 3-benzyl-7,8-dihydrocyclopenta-[e]indazol-6(3H)-one and gave 2-benzyl-7,8-dihydrocyclopenta[e]indazol-6(2H)-one as a pale yellow solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([NH:17][C@@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][SH:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].[N+:25](/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O-:27])=[O:26]>C(#N)C>[C:10]([O:14][C:15]([NH:17][C@@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][S:20][CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][N+:25]([O-:27])=[O:26])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: COC(=O)[C@@H](CS)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@@H](CSC(C[N+](=O)[O-])c1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
Diisopropylethylamine (3.38 mL, 19.4 mmol) was added to a solution of methyl N-(tert-butoxycarbonyl)-D-cysteinate (3.04 g, 12.9 mmol) and □-trans-nitrostyrene (1.93 g, 12.92 mmol) in acetonitrile (80 mL). After 15 min, the reaction was concentrated. Purification by silica gel chromatography (100% hexanes→30% ethyl acetate/hexanes) gave the title compound (4.52 g).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]>CN(C)C=O>[CH2:1]([O:8][C:12]1[CH:17]=[C:16]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
Benzyl alcohol (5.4 g) is added slowly to a stirred suspension of sodium hydride (2 g, 60% dispersion in mineral oil) in dry dimethylformamide (100 mL). The mixture is stirred for 30 minutes then 2,4-difluoronitrobenzene (3.2 g) is added in one portion. The resulting black solution is stirred at room temperature for 18 hours ,evaporated and the residue partitioned between ether (200 mL) and water (100 mL). The organic phase is washed thoroughly with water, dried and evaporated. The residue is triturated with hot ethanol (50 mL) and the mixture cooled in an ice-bath. The insoluble material is purified by filtration through a bed of silica eluting with a mixture of dichloromethane and petroleum ether, b.p.40-60° C., (1:1 v/v). The filtrate is evaporated and the solid crystallised from ethanol to give 2,4-dibenzyloxynitrobenzene (2.3 g) as a cream coloured solid, m.p. 101-103° C. [Elemental analysis:- C,71.4; H,5.07; N,4.09%. Calculated:- C,71.6; H,5.11; N,4.18%].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([O:7][C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:5][N:6]=1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C>[Si:20]([O:15][CH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][CH:5]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncc(Oc2cccc(CO)c2)s1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Oc2cnc(N)s2)c1
Temperature: 60 °C
Yield: 39.1 %

Procedure:
[3-(2-aminothiazol-5-yl)oxyphenyl]methanol (1.70 g, 7.575 mmol), tert-butyldimethylchlorosilane (1.38 g, 9.189 mmol), and imidazole (0.625 g, 9.189 mmol) was taken in 20 mL of dry DMF and heated at 60° C. for overnight. TLC showed consumption of starting material. The reaction mixture was cooled to room temperature and poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the crude product which was purified by column chromatography using 5-30% ethyl acetate in hexanes to get pure title compound (0.998 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]([CH3:20])=[C:6]2[CH2:21][C:22]([NH2:24])=[O:23].B(Br)(Br)Br.C(Cl)Cl.O.C(OCC)(=O)C>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]([CH3:20])=[C:6]2[CH2:21][C:22]([NH2:24])=[O:23]
Reactant: CCCCCCCCn1c(C)c(CC(N)=O)c2cc(OC)ccc21
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCCn1c(C)c(CC(N)=O)c2cc(O)ccc21
Yield: 1.6 %

Procedure:
A solution of 1.03 g (3.1 mmol) of 5-methoxy-2-methyl-1-octyl-1H-indole-3-acetamide and 5 mL of 1M BBr3/methylene chloride in 50 mL of methylene chloride was stirred for 24 hours, poured into water and 150 mL of ethyl acetate added. The organic layer was separated, washed with NaHCO3 solution, dried (Na2SO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel by eluting with 5% MeOH/methylene chloride to give 16 mg (32% yield) of 5-hydroxy-2-methyl-1-octyl-1H-indole-3-acetamide.