Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=2[N:7]=1
Reactant: Cc1nc2cc(F)ccc2s1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2sc(CBr)nc2c1
Yield: 20.4 %

Procedure:
A mixture of 5-fluoro-2-methyl-1,3-benzothiazole (500 mg, 2.99 mmol), NBS (600 mg, 3.37 mmol) and AIBN (125 mg, 0.76 mmol) in carbon tetrachloride (25 ml) was heated at reflux for 20 hours under nitrogen with stirring. The solution was then concentrated to give a residue which was purified by silica gel column chromatography using 1% ethyl acetate in petroleum ether to afford 2-(bromomethyl)-5-fluoro-1,3-benzothiazole as a yellow solid (150 mg, 20%). 1H NMR (400 MHz, CDCl3): δ 7.81 (dd, J=8.8, 5.2 Hz, 1H), 7.70 (dd, J=9.2, 2.4 Hz, 1H), 7.23-7.16 (m, 1H), 4.80 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[N:30](COCC[Si](C)(C)C)[N:29]=[CH:28][C:27]=1B(O)O>>[CH:20]1([CH:16]([N:5]2[C:4]3[N:3]=[C:2]([C:27]4[CH:28]=[N:29][NH:30][C:26]=4[C:22]4[S:21][CH:25]=[CH:24][N:23]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH3:17])[CH2:19][CH2:18]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: C[Si](C)(C)CCOCn1ncc(B(O)O)c1-c1nccs1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3cn[nH]c3-c3nccs3)nc2N1C(C)C1CC1

Procedure:
The title compound was prepared similarly to the methods described in Example 5, with Intermediate SS instead of Intermediate B and with 5-(thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ylboronic acid (Boronic Acid 1) instead of pyridin-4-ylboronic acid. The resulting coupling product is then deprotected by the method described in Example 331 to give the title compound. LCMS: 410.1 m/z (M+H)+; ret. Time: 7.64 min. (Analytical Method C).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([C:10](=[O:24])[CH2:11][CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1)[CH:7]1[CH2:9][CH2:8]1)[CH3:2]>[Pd].CCO>[NH3:6].[CH3:2][CH2:1][OH:3].[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([C:10](=[O:24])[CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][N:17]=[C:18]2[C:23]=1[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:7]1[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CN(C(=O)CCCc1ccnc2ncccc12)C1CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)CCCc1ccnc2c1CCCN2)C1CC1
Product: N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of ester 23-4 (600 mg, 1.75 mmol), 10% Pd/C (300 mg) and EtOH (30 ml) was stirred under hydrogen atmosphere (1 atm) at ambient temperature for 20 h. The catalyst was removed by filtration through celite and then the filtrate was concentrated. Flash chromatography (silica, 50%/EtOAc/sat. NH3 -EtOH) gave ester 23-5 as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([NH:28][C:29]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:30])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:39])[CH:4]=1)#[N:2].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>>[C:45]([O:44][C:42](=[O:43])[CH2:41][N:14]([C@H:11]1[CH2:12][CH2:13][N:9]([CH2:8][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[S:7][CH:6]=2)[C:10]1=[O:39])[S:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][C:22]([NH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[CH:23][CH:24]=2)[CH:19]=1)(=[O:17])=[O:16])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc4ccc(NC(=O)OCc5ccccc5)cc4c3)C2=O)cs1
Product: CC(C)(C)OC(=O)CN([C@H]1CCN(Cc2csc(C#N)c2)C1=O)S(=O)(=O)c1ccc2ccc(NC(=O)OCc3ccccc3)cc2c1

Procedure:
The title compound is prepared from N-Cbz-7-aminonaphthalene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide as described in EXAMPLE 141, Part D using tert-butyl bromoacetate in place of benzyl bromide. The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc/CH2Cl2 to 10% EtOAc/CH2Cl2 to provide the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:34])[F:35])=[CH:29][CH:28]=1)(=[O:32])=[O:31])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccc(OC(F)(F)F)cc2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 4-(trifluoromethoxy)benzenesulfonyl chloride (29 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (6 mg, 21%) as a white solid. MS (ESI+) for C19H19F3N2O4S m/z 429 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:21])[C:9]([OH:20])([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:3]1.[Br:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOCC>C(Cl)(Cl)Cl.C(#N)C>[Br-:22].[OH:20][C:9]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[C:8]([O:7][CH:4]1[CH2:5][CH2:6][N+:2]([CH3:1])([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:3]1)=[O:21]
Reactant: BrCCCOc1ccccc1
Reactant: CN1CCC(OC(=O)C(O)(c2cccs2)c2cccs2)C1
Solvent: CC#N
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: C[N+]1(CCCOc2ccccc2)CCC(OC(=O)C(O)(c2cccs2)c2cccs2)C1
Product: [Br-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.66 g (0.002 mol) of 2-hydroxy-2,2-dithien-2-ylacetic acid 1-methylpyrrolidin-3-yl ester (Intermediate I-7) were dissolved in 9 ml of CHCl3 and 6 ml of acetonitrile. 1.6 ml of (3-bromopropoxy)benzene (2.15 g, 0.01 mol) were added and the mixture was stirred during 72 hours at room temperature under N2 atmosphere. Solvents were evaporated. Ether was added to the residue and the mixture stirred to obtain a solid. The solid was treated with ether several times, filtered and washed with ether. The yield was 0.75 g (69.4%) of the title compound as a mixture of four stereoisomers.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)c1ccccc1
Product: Cc1ccc(N)c(C(=O)c2ccccc2)c1
Yield: 49.3 %

Procedure:
The procedure was in the same manner as described in example 15, except that the starting material was benzoic acid instead of p-chlorobenzoic acid and p-toluidine instead of 4-chloroaniline. The title compound was obtained as yellow needle crystal, and yield 49.3%, m.p. 64-66° C.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=1[F:21])(=[O:5])=[O:4])[CH3:2].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][C:9]=1[F:21])(=[O:5])=[O:4])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(CNS(=O)(=O)CC)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)NCc1ccc(C(C)C(=O)O)cc1F
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a solution of ethyl 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoate (60 mg, 0.189 mmol) in tetrahydrofuran and water co-solvent, sodium hydroxide (19 mg) was added at room temperature. The mixture was stirred for overnight and extracted with ethyl acetate, dried over magnesium sulfate, the solvent was evaporated in vacuo. It was purified by column chromatography to give 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoic acid (55 mg).
Reaction SMILES: [C:1]([C:3]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].C(N(CC)CC)C.[CH3:17][N:18]=[C:19]=[O:20]>C(#N)C>[C:1]([C:3]1([NH:9][C:19]([NH:18][CH3:17])=[O:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2]
Reactant: CN=C=O
Reactant: C#CC1(N)CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#CC1(NC(=O)NC)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 g (8 mmol) 1-ethynylcyclohexylamine and 2 mL (15 mmol) triethylamine in 10 mL acetonitrile is combined at ambient temperature with 0.5 g (9 mmol) methylisocyanate. The colourless suspension is stirred overnight at ambient temperature and then evaporated down. The residue is taken up in dichloromethane and washed with aqueous potassium carbonate solution. The organic phase is dried and evaporated down. Yield: 1.4 g (colourless solid)
Reaction SMILES: COC1C=C(N[N:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15])C=CC=1OC.[NH2:18][C:19]1[CH:20]=[C:21]([O:27][CH3:28])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1.C(#N)CC#N.O.[NH2:35][NH2:36]>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([NH:18][N:12]=[C:13]2[C:14]([NH2:15])=[N:36][N:35]=[C:16]2[NH2:17])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(NN=C(C#N)C#N)cc1OC
Reactant: NN
Reactant: COc1ccc(N)cc1OC
Solvent: O
Solvent: N#CCC#N
Product: COc1ccc(NN=C2C(N)=NN=C2N)cc1OC
Temperature: 25 °C

Procedure:
4-[(3,4-dimethoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 115 mg (0.5 mmol) of 2-[(3,4-dimethoxyphenyl)hydrazono]malononitrile, which was derived from 4-aminoveratrole (153 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared. Very little solid had formed after heating the reaction at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 46 mg (35%) of the compound as a mustard coloured solid.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl[CH2:46][C:47]1[O:48][C:49]([CH3:52])=[N:50][N:51]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:46][C:47]3[O:48][C:49]([CH3:52])=[N:50][N:51]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nnc(CCl)o1
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: Cc1nnc(Cn2nnc3c(N4CC(F)(F)C(F)(F)C4)nc(C(C)(C)C)nc32)o1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole and isolated as light-yellow gum. MS (m/e): 415.3 (MH+).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:9].[Na+].S(=O)(=O)(O)O.I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O>[Cl:9][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[O:7][CH3:8]
Reactant: [Cl-]
Reactant: COc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1Cl
Temperature: 80 °C
Yield: 2 %

Procedure:
Anisole (1 mmol) was treated with sodium chloride (1.2 mmol) in acetonitrile: water (2:1, 6 ml). 20% Sulfuric acid (5 ml) and sodium periodate (20 mol %) was added to reaction mixture. The mixture was heated at 80° C. under inert atmosphere for 4 h. The product was purified by column chromatography to give 4-chloroanosole (25%) and 2-chloroanisole (2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([C:21](=[O:23])[CH3:22])=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccc(C(C)=O)cc4)CC3)nc2c1
Yield: 87 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 87%). 1H NMR (200 MHz, CDCl3): δ 2.54-2.58 (m, 3H), 3.49-3.67 (m, 4H), 3.87-3.96 (m, 6H), 4.12-4.16 (m, 4H), 6.87-7.03 (m, 2H), 7.19-7.31 (m, 3H), 7.62-7.66 (m, 1H), 7.89-7.97 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([CH3:24])=[CH:18][C:19]=2[CH3:23])[N:14]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([CH3:24])=[CH:18][C:19]=2[CH3:23])[N:14]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Cc1cc(C)c2ccc(N)nc2n1
Solvent: c1ccncc1
Product: Cc1cc(C)c2ccc(NS(=O)(=O)c3ccccc3Cl)nc2n1

Procedure:
At an internal temperature of 40° to 50° C., 7.5 g (35.5 mmol) of 2-chlorobenzenesulfonyl chloride was slowly dripped, while stirring, into a suspension of 4.1 g (23.6 mmol) of commercially available 2-amino-5,7-dimethyl-1,8-naphthyridine in 100 ml of anhydrous pyridine.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH2:10][C:11]([F:14])([CH3:13])[CH3:12])C1C=CC=CC=1.[C:22]([OH:25])(=[O:24])[CH3:23]>CO.[Pd]>[C:22]([OH:25])(=[O:24])[CH3:23].[F:14][C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][NH2:8]
Reactant: CC(C)(F)CCN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(F)CCN

Procedure:
Treat a solution of N,N-dibenzyl-3-fluoro-3-methylbutan-1-amine (18.03 g, 63.2 mmol) in MeOH (150 mL) and acetic acid (7.23 mL, 126 mmol) with 10% Pd/C (3.36 g, 3.16 mmol) and hydrogenate (345 kPa) for 2.5 days. Add additional palladium on carbon (1 g) and hydrogenate the mixture (345 kPa) overnight. Filter the mixture through diatomaceous earth, rinse well with MeOH and concentrate the filtrate to dryness to afford the title compound. MS (m/z): 106.1 (M-AcOH+1).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:17]#[N:18].[C:23]([N:42]1[CH:46]=[C:45]([CH2:47][CH2:48][CH:49]=[O:50])[N:44]=[CH:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCOC(C)=O>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[C:21]=1[CH:49]([OH:50])[CH2:48][CH2:47][C:45]1[N:44]=[CH:43][N:42]([C:23]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:46]=1)[C:17]#[N:18]
Reactant: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(F)c(C(O)CCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c(F)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (0.53 mL, 3.75 mmol) is dissolved in 5 mL THF and cooled down to −78° C. To this is added n-BuLi (2.3 mL, 1.6M in hexanes). After 15 min, a solution of 3,5-difluorobenzonitrile (0.52 g, 3.75 mmol) and THF (5 mL) is added and the solution maintained at that temperature for 0.5 h before adding a solution of 3-(1-trityl-1H-imidazol-4-yl)propionaldehyde and THF (20 mL). After 2 h, the solution is diluted with EtOAc and quenched with saturated aqueous NH4Cl. The mixture is then partitioned between EtOAc and saturated aqueous NH4Cl. The organic is dried (Na2SO4) and evaporated. The residue is purified via flash column chromatography (EtOAc/hexanes 2:8→EtOAc) to give 3,5-difluoro-4-[1-hydroxy-3-(1-trityl-1H-imidazol-4-yl)-propyl]benzonitrile as a yellow powder. MS (ESI) m/z 506.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[N:19]=[CH:18][C:17]=2[N:31]2[CH:35]=[CH:34][C:33]([C:36](O)=[O:37])=[CH:32]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:39]([O:46][CH2:47][CH2:48][NH2:49])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C>[Si:39]([O:46][CH2:47][CH2:48][NH:49][C:36]([C:33]1[CH:34]=[CH:35][N:31]([C:17]2[C:16]([NH:15][CH2:14][CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)=[CH:21][C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)=[N:19][CH:18]=2)[CH:32]=1)=[O:37])([C:42]([CH3:44])([CH3:45])[CH3:43])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C(=O)O)c2)C1
Reactant: CC(C)(C)[Si](C)(C)OCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C(=O)NCCO[Si](C)(C)C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.9 %

Procedure:
1-(4-((1-(tert-Butoxycarbonyl)piperidin-3-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (80 mg, 0.154 mmol) was dissolved in DMF (1.5 mL). 2-(tert-Butyldimethylsilyloxy)ethanamine (41 mg, 0.230 mmol), N-ethyldiisopropylamine (30 mg, 0.230 mmol), 1-hydroxy benzotriazole hydrate (31 mg, 0.230 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (44 mg, 0.23 mmol) were added to the solution and the reaction mixture was stirred for 14 h at room temperature. The solution was partitioned between dichloromethane and water. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and evaporated to give tert-butyl 3-((5-(3-(2-(tert-butyldimethylsilyloxy)ethylcarbamoyl)-1H-pyrrol-1-yl)-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (80 mg, 78%) which was used in the next step without purification.
Reaction SMILES: CN(CCOCCOCCOCCC(OC(C)(C)C)=O)[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][CH2:11][N:12]([CH3:55])[C:13](=[O:54])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:53])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:15]=1)=[O:4].[CH3:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96][CH2:97][CH2:98][NH2:99]>>[CH3:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96][CH2:97][CH2:98][NH:99][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][CH2:11][N:12]([CH3:55])[C:13](=[O:54])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)=[O:53])[CH:15]=1)=[O:4]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCN
Reactant: CN(CCN1CCC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Product: COCCOCCOCCOCCOCCOCCOCCOCCNC(=O)[C@@H]1CCCN1CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of tert-butyl 2-methyl-1-((S)-1-(2-(N-methyl-3 ((4-(piperidin-1-yl)-2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzamido)ethyl)pyrrolidin-2-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate Example 190, using 2,5,8,11,14,17,20,23-octaoxapentacosan-25-amine in place of tert-butyl 5,8,11-trioxa-2-azatetradecan-14-oate. MS (ES, m/z): 1094.47 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH2:18]>N1C=CC=CC=1>[S:13]([O:4][CH2:3][CH:2]([CH3:1])[CH2:5][O:6][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:14])=[O:18])([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CO)CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)COS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
2-Methylpropane-1,3-diol (50 g, 555 mmol) was dissolved in 555 ml pyridine and cooled to 0° C. p-Toluenesulfonyl chloride (212 g, 1110 mmol) was added and stirring was continued over night. 200 ml H2O was added and the reaction was extracted with DCM (2×1L). The combined organic extracts were dried over MgSO4 and evaporated. The product was recrystallized from EtOH/Hex and the product was obtained as a white solid. MS m/z: 399.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[Br:13]Br.O>C(O)(=O)C>[Br:13][C:8]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]=1
Reactant: BrBr
Reactant: COc1ccc(C=O)cc1OC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)c(C=O)cc1OC
Reaction time: 8 h

Procedure:
3,4-Dimethoxybenzaldehyde (398.8 g) is dissolved in acetic acid (1.8 liter), and thereto is added dropwise bromine (136 ml) at room temperature over a period of four hours. The mixture is stirred overnight, and thereto is added dropwise slowly again bromine (60 ml), and the mixture is stirred overnight. The reaction solution is added to water (7 liters), and the precipitated crystals are collected by filtration, washed with water, and dissolved in chloroform (2 liters). The chloroform solution is washed, dried, concentrated, and the residue is crystallized from dilsopropyl ether to give 6-bromo-3,4-dimethoxybenzaldehyde (470 g) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.C([N:21]1[CH2:25][CH2:24][NH:23][C:22]1=O)(=O)C>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:5]2[C:22]1[NH:23][CH2:24][CH2:25][N:21]=1
Reactant: CC(=O)N1CCNC1=O
Reactant: Clc1ccc2[nH]c(Cc3ccccc3)cc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc2[nH]c(Cc3ccccc3)c(C3=NCCN3)c2c1
Temperature: 60 °C

Procedure:
A mixture of 2.42 g (10 mmol) 5-chloro-2-benzylindole and 1.28 g (10 mmol) 1-acetyl-imidazolidine-2-one (0.1 mol) is added to phosphorus oxychloride (10 ml) and heated to 60° C. for 5 hours. After evaporation of phosphorus oxychloride the residue is treated with ethanol (14 ml) and heated to reflux for 3.5 hours. Ethanol is evaporated. The residue is purified by chromatography to obtain the hydrochloride. The base is obtainable by treatment with 2N sodium hydroxide to pH 11. The solid is filtered off and dried in vacuo. Hydrochloride, m.p. 299-300° C., M.S. (Ei 70 ev) m/Z M=309.