Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].C(N(CC)CC)C.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH:26]([CH2:28][NH:29][C:30]([C:32]3[S:33][C:34]([Cl:37])=[CH:35][CH:36]=3)=[O:31])[O:25][C:24]2=[O:38])=[CH:19][CH:18]=1>ClCCl>[Cl:37][C:34]1[S:33][C:32]([C:30]([NH:29][CH2:28][CH:26]2[O:25][C:24](=[O:38])[N:23]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[CH:22][CH:21]=3)[CH2:27]2)=[O:31])=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1ccc(N2CC(CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CN(c2ccc(NS(=O)(=O)CCCCl)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An ice-cooled solution of 26.4 mg (0.15 mmol) of 3-chloro-1-propanesulphonyl chloride and 0.03 ml (0.2 mmol) of triethylamine in 3.5 ml of absolute dichloromethane is admixed with 35 mg (0.1 mmol) of N-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl}-5-chloro-2-thiophene-carboxamide (from Example 149). After 30 min, ice-cooling is removed and the mixture is stirred at room temperature overnight, and 150 mg (about 5.5 eq.) of PS-trisamine (Argonaut Technologies) and 0.5 ml of dichloromethane are then added. The suspension is stirred gently for 2 h and filtered (the resin is washed with dichloromethane/methanol), and the filtrate is concentrated. The product is purified by preparative RP-HPLC. Yield: 19.6 mg (40% of theory),
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[S:10](=[O:19])(=[O:18])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[S:10](=[O:19])(=[O:18])[N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1cccnc1S(=O)(=O)Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccnc1S(=O)(=O)N(COCC[Si](C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenylsulfamoylnicotinic acid methyl ester (1.1 g), N,N-diisopropylethylamine (1.9 mL) and dichloromethane at 0° C. was treated with 2-(trimethylsilyl)ethoxymethyl chloride (0.67 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was cooled to 0° C., treated with additional (trimethylsilyl)ethoxymethyl chloride (0.30 mL), and stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and cyclohexane (0:1 to 1:0 by volume) to afford the title compound (1.6 g).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: OCc1ccccc1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)[C@@H](O)c1ccccc1
Temperature: 10 °C
Yield: 42 %

Procedure:
L-Mandelic acid (10 g.), 6.91 g. of benzyl alcohol, and 75 mg. of p-toluenesulfonic acid in 70 ml. of benzene was refluxed under a Dean-Stark trap for a total of 28 hours on 4 consecutive days. The crude benzyl ester was obtained by successively concentrating the liquor and cooling it to about 10° C. a number of times. The fractions melting between 97° C. and 105° C. were combined, dissolved in CHCl3 and washed twice with 15-ml. portions of 5% aqueous NaHCO3 solution. After evaporation of the CHCl3, the product was recrystallized from benzene to give benzyl L-mandelate, m.p. 104°-106° C., yield 42%.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.Cl>C(O)C.C(OCC)C>[CH2:1]([N:8]1[C:12]([CH2:13][NH2:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nnnn1Cc1ccccc1
Agent: Cl
Agent: NN
Solvent: CCOCC
Solvent: CCO
Product: NCc1nnnn1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of the solid isolated in Step B (7.88 g, 24.7 mmol) in ethanol (300 mL), hydrazine (1.58 g, 49.3 mmol) was added. The reaction mixture was then refluxed four hours. After cooling down to room temperature, the white solid from the solution was removed by filtration. The filtrate was concentrated. Acetonitrile (50 mL) was added to the residue. The precipitate from the solution was removed by filtration. The filtrate was concentrated to yield a colorless oil which was treated with 1 N HCl in diethyl ether to yield C-(1-benzyl-1H-tetrazol-5-yl)-methylamine as a white solid, as its corresponding HCl salt.
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH2:2]2.Cl[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.BrBr>[N:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:7]2[CH2:8][CH:1]3[O:9][CH:5]([CH2:4][N:3]([CH2:10][CH2:11][O:12][C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=4)[CH2:2]3)[CH2:6]2)=[CH:27][CH:28]=1
Reactant: ClCCCCc1ccncc1
Reactant: N#Cc1ccc(OCCN2CC3CNCC(C2)O3)cc1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCCN2CC3CN(CCCCc4ccncc4)CC(C2)O3)cc1
Yield: 57.3 %

Procedure:
4-[2-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethoxy]benzonitrile (0.80 g, 2.92 mmol, see preparation D above) was dissolved in MeCN (30 mL) and mixed with 4-(4-chlorobutyl)pyridine (0.74 g, 4.39 mmol, from step (i) above) and K2CO3 (1.62 g, 11.71 mmol). 1 drop of Br2 was added and the mixture was refluxed for 24 h. The mixture was filtered and evaporated. Purification by chromatography on silica, eluting with DCM:4% MeOH (satd. with ammonia), gave 0.68 g (57.2%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>C(O)C.O1CCOCC1>[ClH:29].[ClH:29].[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[N:16][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:20][CH:19]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(-c2cnc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(-c2cnc(NC3CCNCC3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.55 g, 1.43 mmol) in ethanol (10 mL) was added 4 M HCl in dioxane (10 mL) and the reaction mixture stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 285.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:11][CH2:12][CH:13]2[CH2:18][CH:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:16]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:15]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])[CH2:14]2)[CH:4]=1.[BH4-].[Na+].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[C:5]([O:11][CH2:12][CH:13]2[CH2:18][CH:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:16]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:15]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])[CH2:14]2)[CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2cc(OC)ccc2C=O)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2cc(OC)ccc2CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
4-Methoxy-2-(3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy)benzaldehyde (73.56 g, 69.8 mmol) was dissolved in THF-methanol (1100 ml+55 ml), and sodium borohydride (3.17 g, 83.8 mmol) was added at 0° C. After stirring the mixture at room temperature for 1.5 hr, 0.2N hydrochloric acid (150 ml) was added at 0° C. to quench the reaction. The solvent was evaporated to about half, and the residue was dissolved in chloroform (1400 ml), washed twice with 0.1N hydrochloric acid (700 ml), and twice with pure water (700 ml). The solvent was evaporated, and the residue was precipitated with methanol (800 ml), and washed with acetonitrile (800 ml) to give 4-methoxy-2-(3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy)benzyl alcohol (71.5 g, 67.7 mmol, 92% vs methyl 3,4,5-tris(octadecyloxy)cyclohexylcarboxylate).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:15]([CH2:18][CH3:19])(=[O:17])=[O:16].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.O>[CH2:18]([S:15]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:7]=1[CH:2]=[O:1])[C:11]#[N:12])(=[O:16])=[O:17])[CH3:19]
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1C1OCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: CCS(=O)(=O)c1cc(C#N)ccc1C=O
Temperature: 165 °C
Reaction time: 0.12 h

Procedure:
In an Emrys microwave, 4-(1,3-dioxan-2-yl)-3-(ethylsulfonyl)benzonitrile (1230 mg, 4.4 mmol) and pyridinium 4-toluenesulfonate (814 mg, 3.3 mmol; 0.75 eq.) in acetone/water (1:1, 20 ml) were heated with stirring at 165° C. for 7 min. The reaction mixture was then added to water (150 ml) and extracted with ethyl acetate (6×50 ml). The combined organic phases were then washed with saturated sodium chloride solution (30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 3:2). The title compound was isolated as a solid (0.89 g, 90% of theory).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Cl>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:19][N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]2)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
After dissolving 4-aminomethylpiperidine (13.7 g, 120 mmol) in acetonitrile (200 ml), potassium carbonate (11.057 g, 80 mmol) and 3,4-dichlorobenzyl chloride (7.818 g, 40 mmol) were added and the mixture was stirred at 60° C. overnight. After completion of the reaction, the reaction mixture was filtered and the solvent was distilled off. Purification was performed by silica gel column chromatography (dichloromethane/methanol/triethylamine=90/5/5) to obtain {1-[(3,4-dichlorophenyl)methyl]-4-piperidyl}methylamine. The compound was identified by LC-MS.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19](O)[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([S:32][C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Reactant: Cc1ccc(S)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Sc1ccc(C)cc1
Yield: 51.9 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using methyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-hydroxypropionate (389 mg), which is obtained in a similar manner to that described in Reference example 39(a), 4-methylthiophenol (241 mg), triphenylphosphine (463 mg) and solution of diethylazodicarboxylate in toluene (40%, 0.31 ml) and the reaction mixture was treated to afford the desired compound (265 mg) as a colorless oil which contained some impurities.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:37]=[CH:36][C:24]2[CH2:25][CH2:26][N:27]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:28][CH2:29][C:23]=2[C:22]=1OS(C(F)(F)F)(=O)=O.COC(=O)C1C=CC(CN)=CC=1>C1(C)C=CC=CC=1.O>[Cl:20][C:21]1[CH:37]=[CH:36][C:24]2[CH2:25][CH2:26][N:27]([C:30](=[O:35])[C:31]([F:32])([F:34])[F:33])[CH2:28][CH2:29][C:23]=2[C:22]=1[NH:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH3:2])=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
Treat 4-aminomethyl-benzoic acid methyl ester hydrochloride (0.2 g, 0.71 mmol) with K2CO3 (1.0 g, 0.71 mmol) in a mixture of toluene/water (1:1, 2 mL). Separate the organic layer, dry over anhydrous Na2SO4 and use as a toluene solution for the next step. Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.1 g, 0.24 mmol) and 4-aminomethyl-benzoic acid methyl ester (0.2 g, 0.71 mmol) to give 7-chloro-6-(4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12](=[S:14])=[S:13]>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12](=[S:13])[SH:14]
Reactant: S=C=S
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CCO
Product: Cc1nc[nH]c1CSCCNC(=S)S
Reaction time: 8 h

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (10.2 g.) in ethanol (75 ml.) was added slowly, with stirring, to carbon disulphide (200 ml.). The mixture was set aside overnight at room temperature and the solid formed was collected and recrystallised from aqueous isopropyl alcohol to afford N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]dithiocarbamic acid (9.8 g.) m.p. 127°-129°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[N:18]2)([CH2:15][CH3:16])[CH2:9][CH2:10][C:11]([O:13]C)=O)=[CH:4][CH:3]=1.[CH3:31][Li]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[N:18]2)([CH2:9][CH2:10][C:11](=[O:13])[CH3:31])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCC(CCC(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Reactant: [Li]C
Solvent: C1CCOC1
Product: CCC(CCC(C)=O)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
A mixture of methyl 4-(4-chlorophenyl)-4-(4-(methylsulfonamido)-1H-indazol-1-yl)hexanoate (50 mg), as described in Example 44 Step E, in 2 mL of anhydrous THF was added CH3Li (1.5 M in ether, 0.2 mL) dropwise at 0° C. and stirred for 30 min. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified on revered—phase HPLC (0.05% TFA in H2O—MeCN) to give the title product as a white solid. LC/MS m/z=434.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:31])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C1CCNC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)N1CCCC1

Procedure:
Pyrrolidine-1-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-yl-methyl)-amide was prepared starting from intermediate M and pyrrolidine. MS calcd. for C21H21ClN3O2 [(M+H)+] 382.1, obsd. 381.9.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:21]1([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][NH2:31])=[N:28][CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH:21]1([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:2]3[C:3]4[CH2:11][N:10]([C:12]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=5[C:14]#[N:15])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[N:28][CH:29]=2)[CH2:23][CH2:22]1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: NCc1ccc(C2CC2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc(C5CC5)cn4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (150 mg, 0.53 mmol) and (5-cyclopropylpyridin-2-yl)methanamine (115 mg, 0.78 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (0.14 mL, 0.78 mmol) was subjected to microwave irradiation at 180° C. for 2 h. The mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 50-70% CH3CN-water [10 mM Et2NH]) to yield an off-white foam.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33](O)[CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:27][C:26]=1[NH:42][C:43](=[O:59])[CH2:44][CH:45]1[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[O:52][C:51]2[C:46]1=[CH:47][CH:48]=[CH:49][CH:50]=2)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33]([O:2][C:1](=[O:3])[C:4]2[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:8][CH:9]=2)[CH2:34][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)=[CH:27][C:26]=1[NH:42][C:43](=[O:59])[CH2:44][CH:45]1[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[O:52][C:51]2[C:46]1=[CH:47][CH:48]=[CH:49][CH:50]=2)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(Cc1ccc(C(=O)O)cc1)OCc1ccccc1
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(=O)c2ccc(CC(=O)OCc3ccccc3)cc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Preparation 25, but using benzyl 4-carboxyphenylacetate [prepared as described in step (iv) above] and N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12) as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained as a foam-like material.
Reaction SMILES: C[O:2][CH:3](Cl)Cl.[CH2:6]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH3:7]>[Ti](Cl)(Cl)(Cl)Cl>[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:10]=[O:14])=[C:3]([OH:2])[CH:9]=1)[CH3:7]
Reactant: COC(Cl)Cl
Reactant: CCc1cccc(O)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: CCc1ccc(C=O)c(O)c1
Reaction time: 0.75 h
Yield: 65.3 %

Procedure:
Titanium(IV) chloride (100 mL, 100 mmol, 1M in CH2Cl2) followed by dichloromethyl methyl ether (7.47 mL, 82.5 mmol) was added to a cooled 0° C. solution of 3-ethylphenol (6.11 g, 50 mmol). The reaction mixture was stirred for 45 mins. The mixture was poured into ice and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a bright pink oil. Purification by flash column chromatography (0% to 10% EtOAc in hexanes) gave 4-ethyl-2-hydroxy-benzaldehyde (4.9 g, 65%) followed by 2-ethyl-4-hydroxy-benzaldehyde (1.32 g, 18%). A: 1H NMR (400 MHz, CDCl3): δ 1.25 (t, J=7.6 Hz, 3 H), 2.67 (d, J=7.6 Hz, 2 H), 6.82 (s, 1 H), 6.85 (d, J=8.0 Hz, 1 H), 7.46 (t, J=8.0 Hz, 1 H), 9.83 (s, 1 H), 11.05 (s, 1 H). B: 1H NMR (400 MHz, CDCl3): δ 1.27 (t, J=7.6 Hz, 3 H), 3.03 (d, J=7.6 Hz, 2 H), 6.68 (s, 1 H), 6.78 (s, 1 H), 6.82 (d, J=8.3 Hz, 1 H), 7.77 (t, J=8.3 Hz, 1 H), 10.10 (s, 1 H).
Reaction SMILES: [CH2:1]1[N:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[N:12]=[CH:13][C:7]3=[C:8]2[C:3](=[CH:4][CH:5]=[CH:6]3)[CH2:2]1.[CH3:18][Mg]Br.[NH4+].[OH-]>O1CCCC1.CCOCC>[CH3:18][CH:13]1[NH:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]2[CH2:1][CH2:2][C:3]3=[CH:4][CH:5]=[CH:6][C:7]1=[C:8]23
Reactant: C[Mg]Br
Reactant: C1=Nc2ccccc2N2CCc3cccc1c32
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1Nc2ccccc2N2CCc3cccc1c32

Procedure:
To a stirred solution of 2.00 g of 1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine in 40 ml of tetrahydrofuran, cooled under N2 to 0° C., is added dropwise 10 ml of a 2.5 molar solution of methyl magnesium bromide in ether. The reaction mixture is refluxed for 3 hours, cooled, and treated cautiously with saturated aqueous NH4OH solution. The mixture is partitioned between CH2Cl2 and water. The organic phase is separated, washed once with brine, dried over Na2SO4 and concentrated to a solid of 6-methyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 134°-136° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]1[CH2:41][NH2:42].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]1[CH2:41][NH:42][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCc1cc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1cc2ccccc2[nH]1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 43.5 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), (1H-indol-2-yl)methanamine (10.17 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (YMC S5 ODS 5u 20×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=12.3 min) to provide (R/S)-N-((1H-indol-2-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (13 mg, 0.02 mmol, 43.7% yield): LCMS=560.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15-8.20 (2 H, m), 7.55-7.75 (9 H, m), 7.27-7.46 (2 H, m), 6.92-7.08 (2 H, m), 6.29 (1 H, s), 5.20 (1 H, s), 4.48-4.64 (2 H, m); HPLC peak RT=10.7 min (Method A).