Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+].O1CCCC1>CO.C(#N)C>[NH2:30][CH:12]([C:10]1[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(CCO)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(CCO)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(2-hydroxyethyl)piperidin-1-yl]quinolin-7-yl}ethanone (0.0948 g, 0.285 mmol) and ammonium acetate (0.220 g, 2.85 mmol) in methanol (1 mL) and acetonitrile (1 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.71 mL, 0.71 mmol). The reaction was heated at 65° C. overnight. The resulting mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C18H25ClN3O (M+H)±: m/z=334.2; Found: 334.2.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:16][CH2:15][CH2:14][C@@:13]2([CH3:17])[C@H:8]1[CH2:9][CH2:10][CH2:11][C@@H:12]2[C@H:18]([CH3:21])[CH2:19][NH2:20])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:34])([F:33])[C:26](O)([CH3:31])[CH2:27][C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]1[CH2:16][CH2:15][CH2:14][C:13]2([CH3:17])[CH:8]1[CH2:9][CH2:10][CH2:11][CH:12]2[CH:18]([CH3:21])[CH2:19][NH:20][C:28](=[O:29])[CH:27]=[C:26]([CH3:31])[C:25]([F:34])([F:33])[F:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](CN)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reactant: CC(O)(CC(=O)O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=CC(=O)NCC(C)C1CCCC2C(O[Si](C)(C)C(C)(C)C)CCCC12C)C(F)(F)F
Yield: 15.2 %

Procedure:
701 mg (2.06 mmol) of (S)-2-[(1R,4aR,5S,8aR)-5-(tert-Butyl-dimethyl-silanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-propylamine, 532 mg (1.5 eq.) of rac-3-trifluoromethyl-3-hydroxy-butyric acid, and 50 mg (0.2 eq.) of DMAP (N,N-dimethylaminopyridine) were dissolved in 20 ml of CH2Cl2. At 0° 680 mg (1.6 eq.) of DCC (dicyclohexylcarbodiimide) was added and the mixture allowed to react for 4 h at ambient temperature. The precipitated urea was filtered off and the filtrate evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=85/15) yielded in the less polar fractions 149 mg of unwanted 4,4,4-trifluoro-3-methyl-but-2-enoic acid {2-[5-(tert-butyl-dimethyl-silanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-propyl}-amide and in the more polar ones 811 mg of the title compound as colorless oil. Medium pressure chromatography of the latter (SiO2, hexane/AcOEt=90/10) gave in the less polar fractions 367 mg of the (R)-butyramide and in the more polar ones 314 mg of the (S)-isomer, both as white foam. For determination of abs. configuration see d] below.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:9]1[C:17]([OH:19])=[O:18])(OC(C)(C)C)=O>Cl.O1CCOCC1>[CH:9]1([C:17]([OH:19])=[O:18])[CH:10]2[CH:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:16][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CC2CCCCC2C1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C1NCC2CCCCC21
Reaction time: 1 h
Yield: 131.2 %

Procedure:
N-BOC-octahydroisoindole-1-carboxylic acid (18.6 mmol) was dissolved in 4 M HCl in dioxane (46.5 mL) at rt. After stirring for 1 hr, the reaction was determined to be complete by TLC. The reaction mixture was concentrated in vacuo, triturated with Et2O (2×70 mL) and then dried in vacuo to afford octahydroisoindole-1-carboxylic acid (4.13 g) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C:10]1=[O:26])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:10]1=[O:26])[CH3:2]
Reactant: CCC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-ethyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.34 g, 0.93 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (2.16 mL, 28 mmol) and the resulting solution was stirred at rt for 1 h. After removing the volatiles, the residue was dissolved in dichloromethane (2 mL) and treated with hydrogen chloride (2 mL, 4 N in dioxane) and the mixture was concentrated to give 2-(4-ethyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one. LC/MS: (M+1)+: 265.16.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C:15]([C@@H:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]2)=[CH:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([CH:15]([C@@H:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]2)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COCCCC=C(c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COCCCCC(c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1

Procedure:
(S)-tert-butyl 2-(1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxypent-1-enyl)morpholine-4-carboxylate (133 mg, 0.28 mmol) was dissolved in methanol and hydrogenated under 50 psi of hydrogen in the presence of 10% Pd(OH)2/C as catalyst for 48 h. The reaction mixture was filtered and evaporated to give (2S)-tert-butyl 2-(1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxypentyl)morpholine-4-carboxylate in nearly quantitative yield. MS m/z 470 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([NH:9][C:10]1[C:17]([CH2:18][CH2:19]Br)=[CH:16][C:15]([Br:21])=[CH:14][C:11]=1CBr)(=[O:8])[CH3:7]>C(Cl)(Cl)(Cl)Cl>[C:6]([NH:9][C:10]1[C:11]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:14][C:15]([Br:21])=[CH:16][C:17]=1[CH:18]([CH3:19])[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1c(CBr)cc(Br)cc1CCBr
Reactant: CCNCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCN(CC)c1cc(Br)cc(C(C)N(CC)CC)c1NC(C)=O

Procedure:
24 gm of diethylamine were added to a solution of 16.5 gm of 2-acetylamino-5-bromo-3-bromoethyl-benzyl bromide in 1.6 liters of carbon tetrachloride, and the mixture was refluxed for 1 hour. Subsequently, the reaction solution was evaporated, the residue was dissolved in 0.7 liter of 2 N hydrochloric acid, and the solution was extracted twice with chloroform. The hydrochloric acid phase was made alkaline with concentrated ammonia and extracted three times with chloroform. The organic phase was dried with sodium sulfate, and the solvent was distilled off. The residue was purified by column-chromatography on silicagel with ethylacetate/methanol (1:1), the corresponding fractions were united, and 2-acetylamino-5-bromo-N,N-diethyl-3-diethylamino-methyl-benzylamine, m.p. 91.5°-93°C, was obtained by recrystallization from petroleum ether.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH3:33])[C:6]([C:8]1[S:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11](=[O:30])[C:10]=2[C:9]=1[O:31][CH3:32])=[O:7].C(N(CC)CC)C.[CH3:41][O:42][CH2:43][C:44](Cl)=[O:45]>C1COCC1.C(=O)([O-])O.[Na+]>[CH3:32][O:31][C:9]1[C:10]2[C:11](=[O:30])[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[S:20][C:8]=1[C:6]([N:5]([CH2:4][CH2:3][NH:2][C:44](=[O:45])[CH2:43][O:42][CH3:41])[CH3:33])=[O:7]
Reactant: COc1c(C(=O)N(C)CCN)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: COCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NCCN(C)C(=O)c1sc2c(c1OC)c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a solution of the compound of Example 103 (100 mg, 0.21 mmol) and triethylamine (46 mg, 0.45 mmol) in THF (10 mL) was added methoxyacetyl chloride (25 mg, 0.23 mmol) under ice-cooling. After stirring at room temperature for 2 hr, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate; ethyl acetate to ethyl acetate/methanol=50/1) to give a white solid. Recrystallization of the white solid from ethyl acetate-hexane gave the title compound (61 mg, 56%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23](Br)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:33][O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23]([C:39]4[CH:38]=[CH:37][CH:36]=[C:35]([O:34][CH3:33])[CH:40]=4)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3cc(Br)cnc3N)o2)CC1
Reactant: COc1cccc(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-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2cnc(N)c(-c3nnc(C4CCN(C(=O)OC(C)(C)C)CC4)o3)c2)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-(2-amino-5-bromo-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.35 mmol) in dioxane (20 mL) and water (20 mL) were added K2CO3 (0.95 g, 7.05 mmol), 3-methoxyphenyl boronic acid (0.39 g, 2.59 mmol) in a sealed tube. The reaction mixture was degassed with argon for 20 min, then Pd(PPh3)4 (0.13 g, 0.11 mmol) was added to the reaction mixture. The reaction mixture was stirred for 18 h at 100° C. The reaction mixture was diluted with water (100 mL) extracted with ethyl acetate (2×150 mL) and organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude product. The crude compound was purified by column chromatography using 100-200 mesh silica gel and compound was eluted with 40% ethyl acetate in petroleum ether to afford 500 mg, which was further purified by washing with diethyl ether and hexane to afford the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:10])[C:3]=1[C:20]([O:22]C)=O.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][NH2:32]>>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:10])[C:3]=1[C:20](=[O:22])[NH:32][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[Cl:24]
Reactant: NCc1ccccc1Cl
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)NCc1ccccc1Cl
Yield: 64.8 %

Procedure:
The title compound was prepared from (S)-Methyl 3-bromo-1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (310 mg, 0.8 mmol) and (2-chlorophenyl)methanamine (385 μL, 3.2 mmol) following the experimental procedure described in Preparation 44a. 259 mg (65% yield) of the desired compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C@H:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6]([O:8]C(C)(C)C)=[O:7])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C@H:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)O

Procedure:
200 mg (0.395 mMol) of tert.butyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate (melting point: 122-123° C.; [α]D20 =+8.7°; c=1 in methanol) are stirred into 2 ml of methylene chloride together with 0.45 g (3.95 mMol) of trifluoroacetic acid overnight at ambient temperature. The mixture is evaporated down in vacuo and the evaporation residue is distributed between aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic extract is dried, filtered and evaporated down in vacuo. The evaporation residue is crystallised from ethanol/water (2/1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]
Reactant: OCCc1ccccn1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OCCc2ccccn2)cccc1[N+](=O)[O-]
Yield: 82 %

Procedure:
Prepared as in Example 172172c from 2-(pyridin-2-yl)ethanol and 2,6-dinitrobenzonitrile in 82% yield as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.27 (t, J=6.4 Hz, 2H), 4.64 (t, J=6.4 Hz, 2H), 7.23-7.27 (m, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.71-7.79 (m, 2H), 7.86-7.91 (m, 2H), 8.50-8.52 (m, 1H). MS 270 (MH+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[C:46]([CH3:47])=[CH:45][CH:44]=[CH:43][N:42]=5)=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[C:46]([CH3:47])=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:58])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ncccc4C)cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4c(C)ccc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-N-[4-[hydroxy(3-methylpyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (291 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 128 mg) at 0° C. and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added sodium thiosulfate solution and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9) and further recrystallized from ethyl acetate-diisopropylether, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 100) (210.9 mg) as pale yellow crystals.
Reaction SMILES: [NH2:1][C@@H:2]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]3[N:23]=[C:24]4[C:29](=[C:30]5[C:35]=3[CH:34]=[CH:33][CH:32]=[CH:31]5)[CH:28]=[CH:27][CH:26]=[CH:25]4)[CH2:20][C@H:14]2[C:13](=[O:36])[NH:12][C@:11]2([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:37][C@H:10]2[CH:9]=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH3:44][C:45]1[O:49][N:48]=[C:47]([C:50](O)=[O:51])[CH:46]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:44][C:45]1[O:49][N:48]=[C:47]([C:50]([NH:1][C@@H:2]2[C:16](=[O:17])[N:15]3[CH2:18][C@H:19]([O:21][C:22]4[N:23]=[C:24]5[C:29](=[C:30]6[C:35]=4[CH:34]=[CH:33][CH:32]=[CH:31]6)[CH:28]=[CH:27][CH:26]=[CH:25]5)[CH2:20][C@H:14]3[C:13](=[O:36])[NH:12][C@:11]3([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:37][C@H:10]3[CH:9]=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[O:51])[CH:46]=1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](N)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Reactant: Cc1cc(C(=O)O)no1
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](N)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-amino-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate, Hydrochloric Acid (Example 18b, 5.00 g, 8.24 mmol), 5-methylisoxazole-3-carboxylic acid (1.15 g, 9.06 mmol) and 2-(3H41,2,31triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (3.44 g, 9.06 mmol) in dichloromethane (82 ml) was added N-ethyl-N-isopropylpropan-2-amine (5.03 ml, 28.8 mmol). The mixture was stirred at rt for 2 h, and then quenched with saturated aqueous sodium carbonate solution. The organic layer was washed with 1N HCl, separated, filtered, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to provide a white foam. This material was purified flash chromatography on silica gel (4:1 dichloromethane/ethyl acetate) to give (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (4.5 g, 80% yield).
Reaction SMILES: Cl.C([O:6][C:7]1[C:8](=[O:23])[C:9]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(O)[C:10]=1[O:11]CCCC)CCC.O>C1COCC1>[CH2:17]([C:9]1[C:10](=[O:11])[C:7](=[O:6])[C:8]=1[OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCC1(O)C(=O)C(OCCCC)=C1OCCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCc1c(O)c(=O)c1=O
Yield: 33 %

Procedure:
6N Hydrochloric acid (150 mL) was added in one portion to a stirred solution of crude 2,3-dibutoxy-4-hexyl-4-hydroxycyclobut-2-en-1-one (15.1 g, prepared in Part A above) in THF (150 mL), and the resultant solution was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure to give a yellow solid. To this solid was added water (100 mL), which was then removed under reduced pressure. Toluene (100 mL) was similarly added and removed under reduced pressure, and then dichloromethane (200 mL) was added to the residue and the resultant solution was filtered and concentrated to produce a yellow oil. Hexanes (200 mL) were added and the resultant solution was cooled to induce crystallization. After recrystallization from hexanes, the desired compound was isolated as tan crystals (4.28 g, 33% yield over Parts A and B). The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: S1C=CC=C1.C(O)C.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([NH:17][CH2:18][CH2:19][OH:20])=[C:12]([N+:21]([O-])=O)[CH:11]=1.[H][H]>[Pt].CO>[NH2:21][C:12]1[CH:11]=[C:10]([Cl:9])[C:15]([Cl:16])=[CH:14][C:13]=1[NH:17][CH2:18][CH2:19][OH:20]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCO
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Solvent: CCO
Product: Nc1cc(Cl)c(Cl)cc1NCCO
Yield: 81 %

Procedure:
To 2 parts of a solution of 2 parts of thiophene in 40 parts of ethanol are added 71 parts of 2-[(4,5-dichloro-2-nitrophenyl)-amino]-ethanol and 400 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in methylbenzene and the latter is evaporated again. The solid residue is stirred in 2,2' -oxybispropane. The product is filtered off and dried, yielding 50 parts (81%) of 2-[(2-amino-4,5-dichlorophenyl)amino]ethanol; mp. 120° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][CH:9]2[C:4](=[C:5]([N+:13]([O-])=O)[CH:6]=[CH:7][CH:8]2[Br:12])[CH2:3]1.C1C[O:19][CH2:18][CH2:17]1>>[Br:12][C:8]1[CH:7]=[CH:6][C:5]([NH:13][C:18](=[O:19])[CH3:17])=[C:4]2[C:9]=1[CH2:10][CH2:11][N:2]([CH3:1])[CH2:3]2
Reactant: CN1CCC2C(=C([N+](=O)[O-])C=CC2Br)C1
Reactant: C1CCOC1
Product: CC(=O)Nc1ccc(Br)c2c1CN(C)CC2
Reaction time: 3 h
Yield: 80 %

Procedure:
A solution of the product of Example 30 (6 g, 22.1 mmol) was dissolved in 100 mL THF. Raney nickel washed with acetone (2×5 mL) and THF (3×5 mL) was added and the reaction vessel purged with hydrogen. The reaction was stirred for 3 hours and freshly rinsed catalyst added. After 90 minutes, the reaction was complete. The catalyst was removed by filtration, washed with THF, and the filtrate evaporated. The residue was dissolved in 100 mL acetic anhydride and stirred for 72 hours. Excess acetic anhydride was removed in vacuo and the solid residue washed with ether. The solid was dissolved in chloroform and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The solid was washed with ether and dried to give 5.03 g (80%) of the desired product, mp 192-194° C. (dec).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:10]=2)=[CH:4][CH:3]=1.[CH:28]([Mg]Cl)([CH3:30])[CH3:29].O>O1CCCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:28]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])[CH:10]=2)=[CH:4][CH:3]=1)([CH3:30])[CH3:29]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Cl)nc2)c2cccnc21
Reactant: CC(C)[Mg]Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)cn1
Temperature: 20 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To 3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6, 54.0 mg, 0.000135 mol, prepared as described in Example 2) in Tetrahydrofuran (4.0 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (23.0 mg) and Isopropylmagnesium Chloride (0.15 mL, 2.0M in Tetrahydrofuran). The reaction was stirred at 20° C. under an atmosphere of Nitrogen for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound 39 (38 mg, 70.4%).