Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C@@H:17]([C@@H:23]([O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[C@@H:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:25])[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.O.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C@@H:17]([C@@H:23]([O:36][Si:37]([CH:38]([CH3:40])[CH3:39])([CH:41]([CH3:43])[CH3:42])[CH:44]([CH3:46])[CH3:45])[C@@H:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[CH3:25])[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](CCC[C@H](CCC(C)C)[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](C)OCc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CO[C@@H](C)[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)CCC(C)C)cc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 99.3 %

Procedure:
To a solution of (2S,6R)-methyl 2-((tert-butoxycarbonyl)amino)-6-((1R,2S)-2-((4-methoxybenzyl)oxy)-1-((triisopropylsilyl)oxy)propyl)-9-methyldecanoate (8.76 g, 13.2 mmol) in a mixture of THF and H2O (125 mL/62.5 mL) was added LiOH (2.047 g, 85.0 mmol) and the resulting mixture was stirred for 24 h at 40° C. and then for another 24 h at room temperature. The reaction mixture was diluted with EtOAc and washed with 1.0 M aqueous HCl. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, and concentrated to furnish the title compound as a pale yellow oil (8.55 g, 100%): IR (neat) 2943, 2866, 1715, 1513, 1392, 1247, 1162, 1038 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.26-7.20 (m, 2H), 6.88-6.82 (m, 2H), 4.96-4.83 (m, 1H), 4.51-4.31 (m, 2H), 4.31-4.20 (m, 1H), 3.88 (t, J=3.8 Hz, 1H), 3.80 (s, 3H), 3.52-3.43 (m, 1H), 1.91-1.72 (m, 2H), 1.68-1.46 (m, 5H), 1.45 (s, 9H), 1.44-1.19 (m, 2H), 1.18 (d, J=6.2 Hz, 3H), 1.18-0.98 (m, 24H), 0.86-0.80 (m, 6H); ESIMS m/z 674.6 ([M+Na]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:25])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[F:24])=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>COCCOC.C(O)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)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>[C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:25])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[F:24])=[CH:12][C:11]=1[C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:28])[CH:34]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2F)cc1Br
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2F)cc1-c1cccc(N)c1
Temperature: 130 °C

Procedure:
To a solution of {1-[2-bromo-4-(3-fluoro-pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1094 μmol) and 3-aminophenylboronic acid (2 eq) in a mixture of DME/ethanol/1N Na2CO3: 1/1/1 (10 ml) was added Pd tetrakis (0.05 eq). The reaction mixture was heated in the microwave at 130° C. for 1.5 hours. The reaction mixture was cooled to RT and diluted with water and citric acid and extracted with EtOAc. The combined organic layers were washed with water and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C)C=O.[NH2:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([CH3:24])[C:16]=1[C:17]#[N:18]>O>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH3:24])[C:20]([Br:1])=[C:21]([F:23])[CH:22]=1
Reactant: Cc1cc(F)cc(N)c1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)c(F)cc(N)c1C#N
Temperature: 0 °C
Reaction time: 6 h
Yield: 94.5 %

Procedure:
N-Bromosuccinimide (16.6 g, 93.3 mmol) was gradually added to an N,N-dimethylformamide (250 ml) solution of 2-amino-4-fluoro-6-methylbenzonitrile (I-264) (14.0 g, 93.3 mmol). After stirring for 6 hours, the reaction liquid was poured into water with ice (750 ml), the precipitated solid was collected by filtration. The solid was washed with water, then dried to obtain the entitled compound (20.2 g, 95%) as a gray solid.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]([O:27][C:28]([N:30]1[CH2:37][C@H:36]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][C@H:31]1[C:32]([OH:34])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].[N:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[C:48]([NH:56][C:57](=[O:76])[C@@H:58]2[CH2:62][C@@H:61]([NH:63][C:64](=[O:75])[C@H:65]([OH:74])[CH2:66][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:60][NH:59]2)[CH:47]=1>ClCCl.C(N(CC)CC)C>[N:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[C:48]([NH:56][C:57](=[O:76])[C@@H:58]2[CH2:62][C@@H:61]([NH:63][C:64](=[O:75])[C@H:65]([OH:74])[CH2:66][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:60][N:59]2[C:32](=[O:34])[C@@H:31]2[CH2:35][C@@H:36]([NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:37][N:30]2[C:28]([O:27][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:29])[CH:47]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
Triethylamine (30 μL), 1-hydroxybenzotriazole (28 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg) were added to a cold (0° C.) stirred solution of N-tert-butoxycarbonyl-trans-4-(N-tert-butoxycarbonylamino)-L-proline (O, 76 mg) and trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide(H, 76 mg) in dichloromethane (10 mL). The mixture was stirred at room temperature for 16.5 hr and evaporated in vacuo. The residue was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (Whatman, PLK5F Silica Gel 50, 20 cm×20 cm×2 mm, methanol:chloroform=1:20, v/v) to give the title compound (90 mg) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 1.45 (s, 9H), 1.69-1.84 (m, 5H), 1.90-2.03 (m, 1H), 2.09-2.28 (m, 3H), 2.68-2.83 (m, 3H). 3.39-3.46 (m, 1H), 3.50-3.56 (m, 1H), 3.74-3.81 (m, 1H), 3.93-3.99 (m, 1H), 4.01-4.08 (m, 1H), 4.29-4.37 (m, 1H), 4.45-4.53 (m, 2H), 4.57-4.76 (m, 2H), 4.91-4.98 (m, 1H), 7.15-7.30 (m, 5H), 7.38-7.53 (m, 2H), 7.63-7.70 (m, 1H), 7.81-7.87 (m, 1H), 8.57-8.60 (m, 1H), 8.66-8.70 (br s, 1H), and 9.93 (br s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]([N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:17]=[CH:16][C:6]([N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])=[CH:5][CH:4]=1
Reactant: CCCCN(CCCC)c1ccc(OC)cc1
Agent: Br
Product: CCCCN(CCCC)c1ccc(O)cc1

Procedure:
4-Methoxy-N,N-dibutylaniline (9.2 g) in 48% hydrobromic acid (50 mL) was heated under reflux for 2.5 hours and the acid then removed under reduced pressure. Addition of water and neutralization with solid sodium bicarbonate gave a precipitate which was filtered off, washed with water and recrystallized from methanol-ether to give 4-hydroxy-N,N-dibutylaniline.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2.N1C=CC=CC=1>CO>[N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12][S:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)(=[O:10])=[O:9])[CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1cccc2cccnc12
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccnc1
Yield: 17.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, pyridine-3-sulfonyl chloride hydrochloride (0.30 g, 1.39 mmol), 8-aminoquinoline (0.20 g, 1.39 mmol) in pyridine (0.56 ml, 6.94 mmol) gave the title compound (70 mg, 18%) after trituration from MeOH.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C@H:3]([NH:12][C:13](=[O:31])[C@@H:14]([CH2:19][N:20]([O:23]CC1C=CC=CC=1)[CH:21]=[O:22])[CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1)=[O:5]>CO.C(OCC)(=O)C.[Pd]>[CH3:32][C:2]([CH3:1])([CH3:33])[C@H:3]([NH:12][C:13](=[O:31])[C@@H:14]([CH2:19][N:20]([CH:21]=[O:22])[OH:23])[CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1)=[O:5]
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N[C@H](C(=O)c1nccn1C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCC[C@H](CN(O)C=O)C(=O)N[C@H](C(=O)c1nccn1C)C(C)(C)C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 2(R)-[(N-benzyloxy-N-formylamino)-methyl]-hexanoic acid-[2,2-dimethyl-1(S)-(1-methyl-1H-imidazole-2-carbonyl)-propyl]-amide. (76 mg, 0.17 mmol) in methanol (2 mL) was added a slurry of 10% Pd/C (10 mg) in ethyl acetate (1 mL). Hydrogen gas was bubbled through the reaction for 15 minutes after which time the reaction was allowed to stir under one atmosphere of hydrogen for 2 hours. The reaction was flushed with argon and filtered through glass wool. The solvents were removed in vacuo to afford the title compound as a hygroscopic white crystalline solid (43 mg, 70%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:13]=[C:10]3[CH:9]=[CH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][N:11]3[CH:15]=2)=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Nc1ccc(-c2ccccc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2cn3cc(-c4ccccc4)ccc3n2)cc1
Yield: 31 %

Procedure:
Dissolving crude 5-phenyl-2-amino-pyridine obtained and 6.5 g (23 mmol) of 2,4′-dibromo acetophenone into 50 milliliter of ethanol, adding 3.7 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining 3.1 g of 2-(4-bromo-phenyl)-6-phenyl-imidazo [1,2-a] pyridine (yield: 31%).
Reaction SMILES: [CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]2)=[CH:13][CH2:12]4)[CH2:3][CH2:2]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:2][CH2:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Yield: 57.2 %

Procedure:
A solution of 17β-cyclopropyloxy-androst-5-en-3β-ol (19.36 g, 58.9 mM) in acetone (1.9 L) is cooled to -3° C. and then treated with Jones reagent (20 ml). The excess reagent is decomposed with methanol. The solids are removed by filtration. The filtrate is concentrated to a green oil which is purified by flash chromatography on silica gel to give 17β-cyclopropyloxy-androst-4-en-3-one (11.0 g, 57%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CC(O)C>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[N:34]1[CH2:33][CH2:32][N:31]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:36][CH2:35]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3ccc([N+](=O)[O-])cc23)CC1
Temperature: 60 °C
Reaction time: 13 h
Yield: 89 %

Procedure:
To a solution of 4-chloro-6-nitroquinazoline (prepared according to the literature: Alexander J. Bridges et al. J. Med. Chem. 1996, 39, 267-276, and references therein; 12 g, 57.5 mmol) and DIEA (10 mL, 57.5 mmol) in 230 mL IPA was added Boc-piperazine (10.7 g, 57.5 mmol). The reaction mixture was heated to 60° C. and stirred for 13 hours, after which it was cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in dichloromethane (DCM) and washed with 1N NaOH. The organic layer was dried (Na2SO4), filtered, and concentrated by rotary evaporation. The resulting oil was purified on silica gel (1:1 to 1:4 DCM:EtOAc gradient) to furnish 4-(6-nitro-quinazolin-4-yl)-1-Boc-piperazine as a pale yellow oil (18.3 g, 89%). LCMS (APCI+) m/z 360 [M+H]+. HPLC Rt 3.06 min.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[N:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[N:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CCOC(=O)Cc1ccc(-n2cnnn2)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-n2cnnn2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture ethyl [5-(1H-tetrazol-1-yl)pyridin-2-yl]acetate (0.19 g, 0.81 mmol) in THF (4 mL) was added 1.4 M LiOH (aq.) (2.9 mL) at room temperature. The mixture was stirred 3 hours at room temperature. The reaction was acidified with citric acid until pH about 3-4. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give [5-(1H-tetrazol-1-yl)pyridin-2-yl]acetic acid. 1H-NMR (400 MHz, MeOD) δ 9.83 (s, 1H), 9.02 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 3.95 (s, 2H).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4]C[CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:54])CC2)CC1>>[OH:54][CH:5]1[CH2:4][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6]1
Reactant: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)cc1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCC(O)CC5)CC4)cc23)cc1

Procedure:
This compound is synthesized analogously to Example 1 from 4-p-tolyloxy-1H-indole-2-carboxylic acid 137 (see example 115) and amine 21.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.[CH2:45]1[N:50]([CH2:51][CH2:52][NH2:53])[CH2:49][CH2:48][O:47][CH2:46]1>>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:53][CH2:52][CH2:51][N:50]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[CH2:19][CH2:20]3)[N:12]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:26][CH:27]=3)[N:10]=1)[CH2:2]2
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: NCCN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCC(NCCN4CCOCC4)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) and 1-(2-aminoethyl)morpholine (0.031 mL) and following the procedure as outlined in example 118, the titled compound was isolated as its tri-TFA salt after HPLC purification; MS (ES+) 615.9 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:31])([F:30])[C:17]1[CH:29]=[CH:28][C:20]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:25]2[CH2:24][CH2:23][CH:22]([O:21][C:20]3[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:30])[F:31])=[CH:29][CH:28]=3)[CH2:27][CH2:26]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: FC(F)(F)c1ccc(OC2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCC(Oc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 99.6 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (500 mg, 2.30 mmol) and 4-(4-trifluoromethylphenoxy)piperidine (730 mg, 3.0 mmol) in DMF (10 ml) were stirred at 70-75° C. for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water, and extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylphenoxy)piperidin-1-yl]propan-2-ol (1.06 g, yield 99%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([OH:12])[C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.C(OCC)C>[CH2:16]([NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([OH:12])[C:3]=1[N+:13]([O-:15])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(C(F)(F)F)nc1O
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1O
Temperature: 25 °C
Yield: 115 %

Procedure:
4-Chloro-3-nitro-6-trifluoromethyl-pyridin-2-ol (65.1 gm 268 mmol) was dissolved in tetrahydrofuran (350 mL) and stirred at room temperature under N2. Benzylamine (86.3 gm 805 mmol) in tetrahydrofuran (50 mL) was added drop wise over 30 minutes to give a bright yellow solution. The reaction was heated in an oil bath at 50° C. for 18 hours, (a solid formed during the reaction). Cooled to ambient temperature, diluted the reaction mixture with diethyl ether (200 mL) and filtered off the solid (benzylamine hydrochloride). The filtrate was evaporated to low bulk under reduced pressure to give a thick yellow slurry. Added diethyl ether (300 mL) and filtered off the yellow solid, dried on the filter pad to give the benzylamine salt (96.5 gm). The desired product was liberated by partition of the solid between aqueous 2N HCl and dichloromethane and crystallization from ethyl acetate/n-pentane gave 4-benzylamino-3-nitro-6-trifluoromethyl-pyridin-2-ol as a pale yellow solid (61.7 gm 73.4% yield).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][N:16]=[C:17]([C:20]3[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:28][CH3:29])[CH:18]=2)[N:13]([C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH:12]=1)([CH2:8][CH3:9])[CH2:6][CH3:7])C.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH2:26]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:28][CH3:29])[C:20]=1[C:17]1[CH:18]=[C:19]2[C:11]([CH2:10][C:5]([CH2:6][CH3:7])([CH2:8][CH3:9])[CH2:4][OH:3])=[CH:12][N:13]([C:30]3[CH:31]=[CH:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=3)[C:14]2=[CH:15][N:16]=1)[CH3:27]
Reactant: CCOC(=O)C(CC)(CC)Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1cc2c(CC(CC)(CC)CO)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-2-ethyl-butyric acid ethyl ester (100 mg, 0.19 mmol) in DCM (10 mL) at −78° C., DIBAL (1M solution in toluene, 0.95 mL, 0.9 mmol) is added and the mixture is allowed to gradually warm up room temperature, at which stirring is continued for 2 h. To the mixture, a saturated aqueous Rochelle's salt solution (10 mL) is added and stirring is continued for 1 h. The organic layer is separated and the aqueous is extracted with DCM. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (Hexane/EtOAc, 2:1) to afford 2-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-2-ethyl-butan-1-ol as colorless oil: LCMS m/z 483.21 (2.64 min)
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C.[CH:17]1([C:23]2[NH:27][C:26](=[O:28])[C:25]3([CH2:33][CH2:32][N:31]([S:34]([CH2:37][C:38](=O)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[CH3:45])(=[O:36])=[O:35])[CH2:30][CH2:29]3)[N:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>C(Cl)Cl>[CH:17]1([C:23]2[NH:27][C:26](=[O:28])[C:25]3([CH2:33][CH2:32][N:31]([S:34]([C:37]#[C:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[CH3:45])(=[O:36])=[O:35])[CH2:30][CH2:29]3)[N:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1ccccc1C(=O)CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C#CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 78.9 %

Procedure:
2-Chloro-1-methyl-pyridinium iodide (18 mg, 0.070 mmol) and triethylamine (0.28 mL, 1.98 mmol) were added to a solution of 2-cyclohexyl-8-(2-oxo-2-o-tolyl-ethanesulfonyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (20 mg, 0.046 mmol) in methylene chloride (1.0 mL), and the mixture was stirred at room temperature for 19 hours. 2-Chloro-1-methylpyridinium iodide (18 mg, 0.070 mmol) and triethylamine (0.28 mL, 1.98 mmol) were further added, and the mixture was stirred at room temperature for five hours. A 1 M aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The aqueous layer was extracted with methylene chloride, and the organic layer was washed with a 1 M aqueous sodium hydroxide solution, water and saturated brine and dried over sodium sulfate. The organic layer was concentrated, and the residue was then silica gel column chromatography to give 2-cyclohexyl-8-(2-o-tolyl-ethynesulfonyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (15 mg, 79%) as a white solid.