Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[CH:4]=1.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:10][C:5]1[CH:4]=[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:7]([Br:9])[CH:6]=1
Reactant: Ic1ccccc1
Reactant: [O-]B([O-])Oc1cc(Br)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Brc1cc(Br)cc(-c2ccccc2)c1
Yield: 72.8 %

Procedure:
Suspended in 32 ml of 1,2-dimethoxymethane were 3.0 g (11 mmol) of 3,5-dibromophenyl borate, 2.2 g (11 mmol) of iodobenzene and 0.25 g (0.21 mmol) of tetrakis(triphenylphosphine)palladium, and a solution prepared by dissolving 3.4 g (32 mmol) of sodium carbonate in 16 ml of water was added thereto and refluxed for 9 hours under argon atmosphere by heating. The reaction solution was separated into two layers, and then the organic layer separated was washed in order with 5% sodium carbonate, 5% hydrochloric acid, water and saturated brine and dried on anhydrous sodium sulfate. After the organic solvent was distilled off under reduced pressure, the residue was refined by silica gel chromatography (only hexane) to obtain 2.5 g (yield: 75%) of 3,5-dibromobiphenyl (5).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:17][O:18][C:19](=[O:44])[CH2:20][CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([N:36]3[CH2:41][CH2:40][CH:39]([CH:42]=O)[CH2:38][CH2:37]3)(=[O:35])=[O:34])=[CH:29][CH:28]=2)[N:23]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH3:17][O:18][C:19](=[O:44])[CH2:20][CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[CH:29][C:30]([S:33]([N:36]3[CH2:37][CH2:38][CH:39]([CH2:42][NH:1][CH2:2][C@H:3]([OH:4])[C:5]4[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=4)[CH2:40][CH2:41]3)(=[O:34])=[O:35])=[CH:31][CH:32]=2)[N:23]=1
Reactant: COC(=O)CCc1nc(-c2ccc(S(=O)(=O)N3CCC(C=O)CC3)cc2)no1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CCc1nc(-c2ccc(S(=O)(=O)N3CCC(CNC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)no1
Yield: 51.3 %

Procedure:
Prepared from N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methane-sulfonamide (0.136 g, 0.55 mmol), 3-[3-(4-{[4-formyl-1-piperidinyl]-sulfonyl}phenyl)-1,2,4-oxadiazol-5-yl]propanoic acid methyl ester (0.55 mmol), glacial acetic acid (0.040 g, 0.66 mmol) and sodium cyanoborohydride (0.0382 g, 0.061 mmol) according to the procedure used for example 67 (Step B) to give 0.180 g of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:6][C:5]=1[C:30]([F:33])([F:32])[F:31])([O-])=O.O.O.[Sn](Cl)Cl.CCCCCC.CCOC(C)=O>CCO>[NH2:1][C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:6][C:5]=1[C:30]([F:32])([F:33])[F:31]
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4ccc([N+](=O)[O-])c(C(F)(F)F)c4)cc3)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(N)c(C(F)(F)F)c4)cc3)sc2c1
Yield: 73.1 %

Procedure:
Prepared as described in the Nitro Reduction section using 4-nitro-3-trifluoromethyl-N-[4-(6-methoxybenzothiazol-2-yl)-phenyl]-benzamide (0.35 g, 0.74 mmol) and tin (II) chloride dihydrate (1.33 g, 5.91 mmol) in EtOH (7 ml) to give the title compound (0.24 g, 73%) as a pale yellow solid after work-up and flash chromatography (3:2 Hexane/EtOAc).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH:7]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[N:8]1[CH2:12][CH:11]([CH2:13][CH2:14][CH3:15])[CH2:10][C:9]1=[O:16])C>CCO>[OH:5][CH2:6][CH:7]([N:8]1[CH2:12][CH:11]([CH2:13][CH2:14][CH3:15])[CH2:10][C:9]1=[O:16])[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CCCC1CC(=O)N(C(C(=O)OCC)n2ccnc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCC1CC(=O)N(C(CO)n2ccnc2)C1
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 68 %

Procedure:
In a 500 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, NaBH4 (1.92 g, 0.05 mol) is added by portions into a solution of imidazol-1-yl-(2-oxo-4-propyl-pyrrolidin-1-yl)-acetic acid ethyl ester a20 (9.4 g, 0.034 mol. in dry EtOH (200 ml) at 0° C. After 2.5 h, the reaction mixture is quenched carefully with a saturated solution of NH4Cl and the temperature raised up to 10° C. The solvent is evaporated to dryness and the residue is purified by chromatography on silicagel (CH2Cl2/MeOH: 95/05 (v/v)) to give 1-(2-hydroxy-1-imidazol-1-yl-ethyl)-4-propyl-pyrrolidin-2-one 39 (5.47, 68%).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[F:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[F:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:27][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=1
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2cccc(F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 3-fluoro-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C18H19FO5 [M−H]−: 333.3.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[NH:60]1[CH2:63][CH:62]([OH:64])[CH2:61]1>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([N:60]4[CH2:63][CH:62]([OH:64])[CH2:61]4)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)nc1
Reactant: OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)N5CC(O)C5)S4)cc3c2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
A mixture of {2-[5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (190 mg), 1H-1,2,3-benzotriazol-1-ol (70 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (100 mg), azetidin-3-ol hydrochloride (80 mg), triethylamine (80 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with ethyl acetate-methanol (100/0 to 90/10, volume ratio) to give colorless crystals. The crystals were recrystallized from acetone-hexane to give the title compound (130 mg, yield 62%) as colorless prism crystals.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=3)[N:20]=2)=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][CH:25]=3)[N:20]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(-c2nc(-c3ccc(C=O)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Florosil (250 mg) and PCC (121.5 mg, 0.564 mmol) was added to a solution of {4-[5-(4-methylphenyl)-1,2,4-oxadiazol-3-yl]phenyl}methanol (75.1 mg, 0.282 mmol) and CH2Cl2 (1.5 mL) and stirred at room temperature for 3 hours. The reaction mixture was diluted with CH2Cl2 and filtered through a pad of silica gel. The pad was eluted with CH2Cl2 and 1:1 ethyl acetate:hexanes and the combined eluents were concentrated in vacuo to provide the title compound as a crude residue.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26](OC)=O)[CH:22]=[CH:23][CH:24]=1.[H-].[Na+].Cl>C(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[CH2:25][C:26]1[NH:17][C:15](=[O:16])[C:3]2[CH:4]=[N:5][N:6]([C:7]3[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:14])[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1cccc(Cl)c1
Reactant: Cc1cccc(C)c1-n1ncc(C(N)=O)c1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(C)c1-n1ncc2c(=O)[nH]c(Cc3cccc(Cl)c3)nc21
Temperature: 25 °C

Procedure:
0.1 g (0.43 mmol) of 5-amino-1-(2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (Example 16A) is dissolved under argon in 6 ml of absolute ethanol and 0.24 g (1.3 mmol) of methyl 3-chlorophenylacetate and 0.17 g (4.34 mmol) of 60% sodium hydride (suspension in mineral oil) are added. The reaction mixture is heated to reflux overnight. Cooling to room temperature is followed by acidification with concentrated hydrochloric acid. The sodium chloride precipitated thereby is filtered off. The filtrate is concentrated in vacuo, and the remaining residue is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 59 mg (37% of theory) of the product are obtained as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1Cl.SC1SC2C=C(C#N)C=CC=2N=1.[Cl:23][C:24]1[S:25]C2C=CC(Cl)=CC=2N=1>>[Cl:23][C:24]1[S:25][C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[N:1]=1
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: Clc1ccc2sc(Cl)nc2c1
Agent: N#Cc1ccc2nc(S)sc2c1
Product: N#Cc1ccc2nc(Cl)sc2c1
Temperature: 120 °C

Procedure:
The title compound was prepared from 4-amino-3-chlorobenzonitrile via 2-mercapto-1,3-benzothiazole-6-carbonitrile as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 120° C. for 12 h.
Reaction SMILES: I[C:2]1[N:14](S(C2C=CC(C)=CC=2)(=O)=O)[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[CH:31]=[C:30]2B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[CH:31]=[C:30]2[C:2]1[NH:14][C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1
Reactant: COc1ccc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2C
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)cnn4C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnn(C)c43)[nH]1)cn2C
Temperature: 87.5 °C
Yield: 10.2 %

Procedure:
A flask was charged with 7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.200 g, 0.442 mmol, Example #41, Step C), 5-methoxy-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.140 g, 0.486 mmol, Preparation #31), Pd(PPh3)4 (0.036 g, 0.031 mmol, Strem) and Na2CO3 (0.117 g, 1.11 mmol) in 1,4-dioxane:water (3:1, 10 mL). The reaction mixture was heated at about 85-90° C. for about 5 h. The reaction mixture was filtered, concentrated to dryness under reduced pressure to give a crude solid that was added to a microwave reaction vessel. MeOH (3 mL) and aqueous NaOH (5 N, 0.412 mL, 2.06 mmol) were added and the vessel was sealed and heated to about 120° C. in a microwave for about 20 min (250 psi maximum pressure, 2 min ramp time, 300 max watts). The reaction mixture was filtered and washed with MeOH. The filtrate was concentrated in vacuo, and purified by silica gel chromatography eluting with a gradient of 5-68% EtOAc in heptane to give 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.015 g, 22% over 2 steps): LC/MS (Table 2, Method d) Rt=1.30 min; MS m/z: 332 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[O:23][C:4]2([CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([CH3:22])[CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.[CH:32](O)([CH3:34])[CH3:33].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([N:7]2[CH2:6][CH2:5][C:4]3([O:23][C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:25][CH:2]([O:1][CH:32]([CH3:34])[CH3:33])[CH2:3]3)[CH2:9][CH2:8]2)=[O:11])=[CH:13][C:14]=1[CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)O
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CC(O)C=C(c2cccnc2)O3)ccc1OC(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Product: Cc1cc(C(=O)N2CCC3(CC2)CC(OC(C)C)C=C(c2cccnc2)O3)ccc1OC(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
[8-hydroxy-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-9-en-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (300 mg, 0.71 mmol) was dissolved in isopropanol (6.0 mL, 78 mmol). Pyridinium p-toluenesulfonate (178 mg, 0.71 mmol) was added, and the reaction mixture was allowed to stir at 50° C. for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (50-75% ethyl acetate/hexane) to provide (4-isopropoxy-3-methyl-phenyl)-[8-isopropoxy-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-9-en-3-yl]methanone (173 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J=1.5 Hz, 1H), 8.55 (d, J=3.6 Hz, 1H), 7.90 (dt, J=8.0, 1.9 Hz, 1H), 7.28 (dd, J=7.6, 4.5 Hz, 1H), 7.26-7.17 (m, 2H), 6.82 (d, J=8.2 Hz, 1H), 5.55 (d, J=3.9 Hz, 1H), 4.71-4.27 (m, 2H), 4.19 (dd, J=9.4, 5.3 Hz, 1H), 3.97-3.59 (m, 2H), 3.39 (br s, 2H), 2.40-2.10 (m, 1H), 2.21 (s, 3H), 2.05-1.84 (m, 3H), 1.83-1.49 (m, 2H), 1.33 (t, J=9.8 Hz, 6H), 1.19 (dd, J =6.1, 2.8 Hz, 6H). ESI-MS m/z calc. 464.27, found 465.5 (M+1)+; Retention time: 1.56 minutes (3 min run).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][N:35]5[CH2:3][CH2:2][CH2:41][CH2:36]5)[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC)c4)cc23)CC1
Reactant: CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN5CCCC5)c4)cc23)CC1
Yield: 41 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (20.4 mg, 0.42 mmol) for methanamine to afford 18 mg of the title compound (41%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[Br:15]N1C(=O)CCC1=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]([Br:15])=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C=NNc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Br)=NNc1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
A solution of [(4-chlorophenyl)hydrazono]acetic acid methyl ester (30, 13.0 g, 61.2 mmol) in anhydrous THF (100 mL) was treated with N-bromosuccinimide (NBS, 11.97 g, 67.3 mmol, 1.1 equiv) at 0–5° C. under N2, and the resulting reaction mixture was stirred at 0–5° C. for an additional 30 min. When HPLC and TLC showed the reaction was deemed complete, the solvent removed in vacuo. The residue was directly purified by column chromatography (SiO2, 0–15% EtOAc/hexane gradient elution) to afford the desired bromo[(4-chlorophenyl)hydrazono]acetic acid methyl ester (31, 15.0 g, 17.84 g theoretical, 84%) as pale-yellow solids, which was found to be essentially pure to do the following cycloaddition reaction without further purification. For 31, CIMS m/z 290/292 (M+−H, C9H8BrClN2O2).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH3:5].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[CH:2]([C@@H:3]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][CH3:5])=[O:1]
Reactant: CC[C@@H](CO)NC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC[C@@H](C=O)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
A solution of benzyl [(1S)-1-(hydroxymethyl)propyl]carbamate (30.0 g) in dimethyl sulfoxide (260 mL) was ice-cooled under a nitrogen atmosphere, and triethylamine (56.9 mL) and a solution of sulfur trioxide pyridine complex (71.3 g) in dimethyl sulfoxide (260 mL) was successively added. The mixture was stirred at the same temperature for 1 hr, and at room temperature for 4 hr. A 1 mol/L aqueous citric acid solution (450 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%) to give the title compound as a colorless oil (yield: 16.3 g, 55%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9]Cl)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClCCN1CCOCC1.[N:20]1[N:24]2[C:25]3[C:33]4[CH:34]=[N:35][NH:36][C:32]=4[N:31]=[CH:30][C:26]=3[C:27](=[O:29])[NH:28][C:23]2=[N:22][CH:21]=1>>[N:1]1([CH2:7][CH2:8][CH2:9][N:28]2[C:27](=[O:29])[C:26]3[CH:30]=[N:31][C:32]4[NH:36][N:35]=[CH:34][C:33]=4[C:25]=3[N:24]3[N:20]=[CH:21][N:22]=[C:23]23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: ClCCCN1CCNCC1
Reactant: O=c1[nH]c2ncnn2c2c1cnc1[nH]ncc12
Agent: ClCCN1CCOCC1
Product: O=c1c2cnc3[nH]ncc3c2n2ncnc2n1CCCN1CCNCC1

Procedure:
By substituting 3-piperazinopropyl chloride for the 1-chloro-2-morpholinoethane in the procedure of Example 8 and utilizing the 4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one product of Example 11, 4-(3-piperazino)propyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:50])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C@H:19]([C:47](O)=[O:48])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:46])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH:32][CH2:33][CH2:34][O:35][C@@H:36]1[O:44][C@@H:43]([CH3:45])[C@@H:41]([OH:42])[C@@H:39]([OH:40])[C@@H:37]1[OH:38])=[O:31])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([NH:73][CH2:74][CH2:75][O:76][C@@H:77]1[O:85][C@@H:84]([CH3:86])[C@@H:82]([OH:83])[C@@H:80]([OH:81])[C@@H:78]1[OH:79])=[O:72]>CN(C=O)C>[C@@H:77]1([O:76][CH2:75][CH2:74][NH:73][C:71](=[O:72])[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][NH:65][C:47](=[O:48])[C@@H:19]([NH:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:50])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:46])[CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:31])[NH:32][CH2:33][CH2:34][O:35][C@@H:36]2[O:44][C@@H:43]([CH3:45])[C@@H:41]([OH:42])[C@@H:39]([OH:40])[C@@H:37]2[OH:38])[O:85][C@@H:84]([CH3:86])[C@@H:82]([OH:83])[C@@H:80]([OH:81])[C@@H:78]1[OH:79]
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCCN)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](NC(=O)CCCCCCC(=O)OCc2ccccc2)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCCCNC(=O)[C@H](CCCCNC(=O)CCCCC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)NC(=O)CCCCCCC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 40 mL vial was added N2-{8-(benzyloxy)-8-oxooctanoyl}-N6-[6-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoyl]-L-lysine (100 mg, 0.141 mmol) and DMF (5 mL). To the above solution at 0° C. was added EDC (40.5 mg, 0.211 mmol) and HOBt (23.7 mg, 0.155 mmol). The reaction was warmed to rt and stirred at rt for 20 min. To the above mixture was added 6-amino-N-{2-[(α-L-fucopyranosyl)oxy]ethyl}hexanamide (45.1 mg, 0.141 mmol). After stirring at rt for 18 hr, the mixture was concentrated. The residue was purified by flash chromatography eluting with 0-40% AcCN in water to give the title compound. UPLC Method B: m/e=1012.6348 [M+1]; Rt=3.28 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:14][C:15]1([CH2:19][OH:20])[CH2:18][O:17][CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:14][C:15]1([CH2:19][OH:20])[CH2:18][O:17][CH2:16]1
Reactant: OCC1(CBr)COC1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: OCC1(COc2ccc(C(F)(F)F)cc2Cl)COC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
600 mg of 3-chloro-4-hydroxybenzotrifluoride and 829 mg of 3-bromomethyl-3-oxetanemethanol were dissolved in 20 ml of acetonitrile, and 1.49 g of cesium carbonate were added. The reaction mixture was heated to 110° C. and stirred at this temperature for three hours. 50 ml of water and 50 ml of ethyl acetate were added to the cooled reaction mixture. The organic phase was removed, dried over MgSO4 and then concentrated under reduced pressure. The residue was purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100% n-heptane=>100% ethyl acetate. This gave 990 mg of [3-(2-chloro-4-trifluoromethylphenoxymethyl)oxetan-3-yl]methanol.
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[CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:19]4[CH:23]=[CH:22][N:21]=[C:20]4[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CC1
Reactant: c1cc(-c2ncc[nH]2)ccn1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3ccncc3)nc2N1C1CC1

Procedure:
The title compound was prepared similarly to the methods described in Example 77, with Intermediate O instead of Intermediate C and with 4-(1H-imidazol-2-yl)pyridine instead of 2-phenyl-1H-imidazole. LCMS: 376.1 m/z (M+H)+; ret. Time: 3.90 min (Analytical Method C).