Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[N:9]=2)[CH:7]=1.[S:28]1[CH:32]=[C:31]([N:33]([S:41]([C:44]2[CH:49]=[C:48]([F:50])[C:47](F)=[CH:46][C:45]=2[F:52])(=[O:43])=[O:42])C(=O)OC(C)(C)C)[N:30]=[CH:29]1.C(=O)([O-])[O-].[K+].[K+].[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62]>CS(C)=O.O>[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][C:47]2[C:48]([F:50])=[CH:49][C:44]([S:41]([NH:33][C:31]3[N:30]=[CH:29][S:28][CH:32]=3)(=[O:43])=[O:42])=[C:45]([F:52])[CH:46]=2)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[N:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(Cl)ccc3O)n2)CC1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cscn1)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccnc(N3CCNCC3)n2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
tert-Butyl 4-[4-(5-chloro-2-hydroxyphenyl)pyrimidin-2-yl]piperazine-1-carboxylate (Preparation 2, 48.6 mg, 0.11 mmol), tert-butyl 1,3-thiazol-4-yl[(2,4,5-trifluorophenyl)sulfonyl]carbamate (Preparation 45, 41.9 mg, 0.11 mmol) and potassium carbonate (21.9 mg, 0.16 mmol) were mixed in dimethylsulfoxide (1 mL) and shaken at ambient temperature for 18 hours. The reaction was diluted with water and the precipitate collected by filtration. The solid was dissolved in dichloromethane (2 mL), and dried over anhydrous magnesium sulfate. The mixture was filtered and trifluoroacetic acid (0.06 mL, 0.78 mmol) was added to the filtrate. After 2 hours the reaction was concentrated in-vacuo and purified by reverse phase HPLC to afford the title compound as a tan glass (52 mg).
Reaction SMILES: [CH:1]1[C:6]2[C:7]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[C:29](=O)(O)[O-].[Na+]>C(O)=O.O>[CH3:29][N:8]1[CH:7]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]1=2
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CCOC(=O)c1ccc(C2c3ccccc3Oc3ccccc3N2C)cc1
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
Title compound 4 (0.508 g, 1.48 mmol) was dissolved in formic acid (5.0 mL) and the mixture was cooled at 4° C. Sodium borohydride (0.502 g) was added and the reaction mixture was stirred at room temperature for 90 min. The mixture was diluted in water (50 mL) and solid sodium bicarbonate was added until alkaline (pH=8-9). This mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate and evaporated. The crude was purified by flash chromatography with 10% ethyl acetate in hexanes to afford title compound 7 (408 mg, 77%) as a colorless oil. LRMS (ESI): (calc) 359.15 (found) 360.3 (MH)+.
Reaction SMILES: [F:1][C:2]([F:40])([CH2:6][NH:7][C:8]([NH:10][C@@:11]([C:26]1[CH:31]=[C:30]([O:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])[CH:29]=[C:28]([F:39])[CH:27]=1)([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C:3]([OH:5])=O.C(Cl)(=O)OCC.CC[N:49](CC)CC.N>C(Cl)Cl>[F:1][C:2]([F:40])([CH2:6][NH:7][C:8]([NH:10][C@@:11]([C:26]1[CH:31]=[C:30]([O:32][C:33]([F:37])([F:38])[CH:34]([F:35])[F:36])[CH:29]=[C:28]([F:39])[CH:27]=1)([C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C:3]([NH2:49])=[O:5]
Reactant: O=C(NCC(F)(F)C(=O)O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Product: NC(=O)C(F)(F)CNC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
To a solution of (R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanoic acid (60 mg, 0.1 mmol) in CH2Cl2 (1 mL) at 0° C. was added ethyl carbonochloridate (10 uL, 0.1 mmol), followed by NEt3 (0.021 mL, 0.15 mmol) and NH3*H2O (0.1 mL, 2.6 mmol). The reaction mixture was stirred at rt for 30 min, then concentrated under reduced pressure and purified by prep HPLC (Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to yield (R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanamide as a white solid (12 mg, 21% yield). LCMS: RT=3.85 min [M+H] 576.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][OH:41]>CN(C=O)C>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([CH2:39][CH2:40][OH:41])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: OCCBr
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCN(CCO)CC3)c2)c2ccc(F)cc21
Temperature: 100 °C
Reaction time: 15 h
Yield: 68.7 %

Procedure:
To a mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 210 mg; 0.46 mmol), K2CO3 (189 mg; 1.37 mmol) and KI (3 mg; 0.018 mmol) in DMF (5 mL) was added 2-bromoethanol (115 mg; 0.92 mmol) under nitrogen. The reaction mixture was stirred at 100° C. for 15 hours, concentrated, and purified by preparative TLC (DCM/MeOH=10/1) to afford 148 mg (69%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[O:44][CH:45]=[CH:46][N:47]=2)=[CH:38][C:37]=1[CH3:48]>>[CH3:48][C:37]1[CH:38]=[C:39]([C:43]2[O:44][CH:45]=[CH:46][N:47]=2)[CH:40]=[C:41]([CH3:42])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(-c2ncco2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ncco6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-(4-bromo-3,5-dimethylphenyl)oxazole following a procedure analogous to that described in Step 2 of Intermediate 17. LC (method 11): tR=1.27 min; Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[N:3]=1.O.[NH2:11][NH2:12]>CCO>[NH:11]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[N:3]=1)[NH2:12]
Reactant: COc1nccc(Cl)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1nccc(NN)n1
Temperature: 85 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a stirred solution of 4-chloro-2-methoxypyrimidine (5.7 g, 39.4 mmol) in EtOH (100 mL) under Ar was added hydrazine hydrate (3.83 mL, 79 mmol) and the reaction mixture was heated up and stirred at 85° C. for 1 hr. Volatiles were removed under reduced pressure and the resulting crude material was purified by silica gel column chromatography (CH2Cl2/MeOH/1-5%/NH3 1%) to afford the title product (4.40 g, 31.4 mmol, 80% yield) as white solid. ESI-MS: 141 [M+H]+ (LC-MS 2); Rf=0.47 (CH2Cl2/MeOH 9:1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C=O)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>CCCCCC>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[C:27]([Cl:26])[CH:28]=1)=[O:15]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cccc(Cl)c2)cc1N
Yield: 32.6 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), DMF (0.5 mL, 6.46 mmol), and 3-chloroaniline (5.4 mL, 51.05 mmol). The reduction was performed as described but using DMF as the solvent to afford the product (2.29 g) after trituration in hexane; m.p. 144-146° C. after recrystallization from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=2I)=[O:19])[CH2:14][CH2:13]1.[CH3:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1>>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=2[N:34]2[CH:33]=[C:32]([CH3:31])[CH:36]=[N:35]2)=[O:19])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3I)CC2)c(F)c1
Reactant: Cc1cn[nH]c1
Product: Cc1cnn(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(S(C)(=O)=O)cc3F)CC2)c1
Yield: 29 %

Procedure:
The title compound was prepared according to the procedure described for example 294 from [4-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-(2-iodo-5-methanesulfonyl-phenyl)-methanone (compound CM) and 4-Methyl-1H-pyrazole (29% yield, yellow foam, MS (m/e): 521.3 (M+H, 100%)
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.Br.[Br:24][CH2:25][CH2:26][NH2:27].CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:27][CH2:26][CH2:25][Br:24])=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: NCCBr
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCBr)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
4-Azidobenzoic acid (1.62 g, 9.70 mmol), HOBt (662 mg, 5.15 mmol, 0.5 eq.) and 2-bromoethylamine hydrobromide (2.43 g, 11.6 mmol, 1.2 eq.) were dissolved in DMF (20 ml), WSC (2.28 g, 11.6 mmol, 1.2 eq.) was added, triethylamine (1.62 ml, 11.6 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was diluted with ethyl acetate (70 ml) and hexane (30 ml) and washed with 2% aqueous sodium carbonate solution, saturated aqueous sodium hydrogen carbonate solution, 10% aqueous sodium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 75 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated at 30° C. or below to give the title compound as a pale-brown solid (2.0 g).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Cl:24][C:25]1[CH:32]=[C:31](F)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].CC(C)([O-])C.[K+].O>C1COCC1>[Cl:24][C:25]1[CH:32]=[C:31]([CH:30]=[CH:29][C:26]=1[C:27]#[N:28])[O:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:23]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CCCCO)ccc21
Reactant: N#Cc1ccc(F)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc(NC(=O)CCCCOc3ccc(C#N)c(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.1 %

Procedure:
To a solution of the compound obtained in Step 1 (150 mg, 0.48 mmol) and 2-chloro-4-fluorobenzonitrile (75 mg, 0.48 mmol) in THF (6 mL) was added potassium t-butoxide (136 mg, 1.21 mmol), and the mixture was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 85% ethyl acetate/hexane) to give the title compound (79 mg, 0.178 mmol, 36.8%) as a white powder.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: BrB(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: -5 °C
Reaction time: 1.75 h
Yield: 18.1 %

Procedure:
5-Methoxy-1H-indole (5.6 g, 21.5 mmol) was reacted with 1.0 g (25 mmol) of 60% sodium hydride and then 3.0 mL (25 mmol) of benzyl bromide by the method described in Example 12, Part D to give crude 5-methoxy-1-(phenylmethyl)-1H-indole. This material was dissolved in 250 mL of methylene chloride, cooled to -5° C., 50 mL of 1M BBr3 /CH2Cl2 added, the cooling bath removed and the mixture stirred for 1.75 hours. Ice water was added and the mixture stirred. The organic layer was separated, washed with saturated NaCl, dried (Na2 SO4), and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% ether/hexane→ether to give 870 mg (19% overall yield) of crude 5-hydroxy-1-(phenylmethyl)-1H-indole.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C1COCC1>[C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH:17][C:41](=[O:43])[CH3:42])[N:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
To a stirred solution of 57 mg (0.123 mmol) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine in 5 mL of THF, 20 μL (0.123 mmol, 1 eq) of Huenig base and 11.6 μL (0.123 mmol, 1 eq) of acetic anhydride were added at 0° C. After 30 min., the reaction mixture was quenched by addition of an aqueous solution of NaHCO3 and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel gave 30 mg (48%) of (RS,SR)-N-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-acetamide as a light yellow solid, MS: 503 (MH+).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=O>CN(C=O)C>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:13]1[C:12]1[CH:15]=[CH:16][C:17]([OH:18])=[C:10]([Br:9])[CH:11]=1
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: Nc1ccccc1N
Solvent: CN(C)C=O
Product: Oc1ccc(-c2nc3ccccc3[nH]2)cc1Br
Yield: 79.4 %

Procedure:
In a DMF (3 mL) solvent, a mixture including 1,2-phenylenediamine (100 mg, 0.92 mmol), 3-bromo-4-hydroxybenzaldehyde (187.8 mg, 0.92 mmol), and Na2S2O5 (177.6 mg, 0.92 mmol) was mixed at a temperature of 80° C. for 1 hour. After cooling, DMF was removed therefrom under reduced pressure. Methylene chloride and water were added thereto to obtain a solid product, and the precipitate was filtered, and the filtered product was washed with methylene chloride, ethyl acetate, and water to obtain a solid Compound 56 (79.4%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:29][CH2:28]1>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH2:29][CH2:28]4)[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Product: CN(C(=O)c1cc2c(s1)-c1cc(N3CCC(N4CCOCC4)CC3)ccc1OC2)c1ccc(F)cc1F

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and 4-(4-piperidinyl)morpholine were reacted to give 127bp. 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 1H), 7.05-7.10 (m, 2H), 6.84-6.93 (m, 3H), 6.74 (m, 1H), 5.05 (s, 2H), 4.00 (m, 4H), 3.63-3.68 (m, 3H), 3.29-3.50 (m, 5H), 3.18 (m, 2H), 3.05 (m, 2H), 2.47 (m, 2H), 2.21 (m, 2H). LCMS (ESI) m/z: 526.1
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([C:11]1[O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2C=1C(O)=O)[CH2:8][CH2:9][CH3:10].CN(C=O)C>C(Cl)Cl>[CH2:7]([C:11]1[O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:1]=1[C:2]([Cl:4])=[O:3])[CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCc1oc2ccccc2c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Oxalyl chloride (6 mL, 68.8 mmol) was added under nitrogen at room temperature to a solution of 2-butyl-benzofuran-3-carboxylic acid (3.00 g, 13.7 mmol), prepared in the previous step, in 40 mL of methylene chloride. After the addition 10 μL of DMF was added and the reaction stirred at room temperature for 3 h. The solvent and the excess oxalyl chloride were removed under reduced pressure. To remove any residual oxalyl chloride the residue was taken up in benzene and then concentrated under reduced pressure to give 2-butyl-benzofuran-3-carbonyl chloride (3.00 g, 92%) as a white solid that was used in the next step without additional purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CCO>[Cl:10][C:4]1[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: C1CCNC1
Solvent: CCO
Product: N#Cc1cc(Cl)nc(N2CCCC2)c1
Temperature: 70 °C
Yield: 85.1 %

Procedure:
A solution of 2,6-dichloropyridine-4-carbonitrile 24 (4 g, 23.5 mmol) in abs. EtOH (10 mL) was added with pyrrolidine (1.15 mL, 1 mol eq) and the mixture was heated at 70° C. for 6 h. The solvent was removed under reduced pressure, water was added to the residue and the aqueous phase was extracted with EtOAc (3×40 mL). The combined organic phase was washed with brine (1×60 mL), dried over Na2SO4 and evaporated to afford 25A as a pale yellow deliquescent solid (4.2 g, 20 mmol, 87% Yield). 1HNMR (DMSO, 400 MHz) δ 2.00 (m, 4H), 3.42 (m, 4H), 6.39 (s, 1H), 6.61 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.[CH3:14][C:15]([CH3:17])=[O:16]>CCOCC>[Br:8][C:4]1[N:3]=[C:2]([C:15]([OH:16])([CH3:17])[CH3:14])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(O)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 2,6-dibromopyridine (1.0 eq.) in Et2O (0.2M) at −78° C. was added dropwise n-BuLi (1.05 eq.). The mixture was stirred at −78° C. for 45 min then acetone (1.5 eq.) was added. The final mixture was stirred for an extra 15 min at −78° C. and quenched with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (2×). The combined organic extracts were washed with, brine, dried over MgSO4, filtered and concentrated to afford the title compound as a white solid which was used as such.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1([C:31](Cl)=[O:32])[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:31]([C:18]1([CH2:17][CH2:16][CH2:15][CH2:14][Br:13])[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:32]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)c(OC)c1

Procedure:
Prepared analogously to Example 1 from 2,4-dimethoxybenzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[CH2:19][CH3:20])[C:5]1=[O:24])(=O)C.[N:25]1([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([NH:36]/[C:18](=[C:6]3\[C:5](=[O:24])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=4)/[CH2:19][CH3:20])=[CH:37][CH:38]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(CC)OCC
Reactant: Nc1ccc(CN2CCCCC2)cc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(/CC)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylene)-6-ethoxycarbonyl-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline Rf value: 0.9 (silica gel, methylene chloride/ethanol=5:1) C26H31N3O3
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.CN(C)C=O.Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>O>[N:2]1([O:1][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: CCCCCCCCCl
Reactant: On1nnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOn1nnc2ccccc21
Temperature: 135 °C

Procedure:
A mixture of 1-hydroxybenzotriazole (30.6 g), N,N-dimethylformamide (150 ml), 1-chlorooctane (32.7 g) and potassium carbonate (50 g) was heated at 135° C. for 0.5 hr. while stirring. The reaction mixture was poured into water and the resulting mixture was extracted with benzene. The benzene extract was dried and stripped of solvent by rotary evaporation and distillation to a pot temperature of 100 C. at a pressure of less than 0.1 mm of mercury. The product, n-octyl 1-benzotriazolyl ether was obtained as a clear yellow oil residue. The elemental analysis was as follows: