Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH2:27][CH2:28][CH3:29]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:21])[F:22])[CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:27][CH2:28][CH3:29])[N:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)c2n[nH]c3c(C(F)(F)F)cccc23)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc(C(=O)c2cccc(OC)c2)c2cccc(C(F)(F)F)c21
Temperature: 50 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
To a solution of [3-(methoxy)phenyl](7-trifluoromethyl-1H-indazol-3-yl)methanone (0.27 g, 0.85 mmol) in 5 mL DMF was added in one portion sodium hydride (0.034 g, 0.85 mmol, 60% in oil). After the gas evolution ceased, 1-iodopropane (0.097 mL, 1.0 mmol) was added and the reaction was stirred at ambient to 50° C. for 24 hours. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). Removal of the solvent in vacuo afforded the crude product which was purified by flash chromatography (silica gel, hexane/EtOAC, 9:1) to give the title compound (0.262 g) as an oil. MS (ESI) m/z 363 ([M+H]+);
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([Br:24])[C:21]=1[O:22][CH3:23])[C:16](Cl)=[O:17].C(N(CC)CC)C.Cl>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([C:16]([N:9]2[CH2:8][CH2:7][O:6][C:5]3[N:10]=[CH:11][C:2]([CH3:1])=[CH:3][C:4]2=3)=[O:17])[CH:19]=[C:20]([Br:24])[C:21]=1[O:22][CH3:23]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: Cc1cnc2c(c1)NCCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(C)cc32)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
In a 10 ml flask, 7-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (79 mg, 0.52 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (259 mg, 0.79 mmol) were dissolved in dichloromethane (2 ml). Triethylamine (0.22 ml, 1.58 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of methanol:dichloromethane=1:30. The fractions containing the product were collected and evaporated to obtain white solid (210 mg, 90%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([S:12](Cl)=[O:13])([CH3:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1.O>O1CCCC1>[CH3:8][C:9]([S:12]([NH:26][C@H:27]1[CH2:28][CH2:29][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:31][CH2:32]1)=[O:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)S(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](NS(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Triethylamine (1658 mL, 2.7 eq) was added dropwise to a solution of 2-methylpropane-2-sulfinyl chloride (3) (900 g, 1.3 eq) and methyl trans-4-amino-1-cyclohexane carboxylate p-toluenesulfonate (10) (1452 g, 4.407 mol) in tetrahydrofuran (9.5 L) with ice-cooling. The mixture was stirred for 1.5 hours at room temperature, poured into water (9.5 L) and extracted with ethyl acetate (9.5 L, 5 L). Each of organic layer was washed with brine twice, dried over sodium sulfate, and concentrated under reduced pressure to obtain (11) (1.26 kg).
Reaction SMILES: [C:1]([N:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:7][C:8]([NH2:10])=[S:9])(=O)[CH2:2][CH2:3][CH3:4].Cl>C(=O)([O-])[O-].[Na+].[Na+]>[SH:9][C:8]1[N:10]=[C:1]([CH2:2][CH2:3][CH3:4])[N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: CCCC(=O)N(NC(N)=S)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCc1nc(S)nn1-c1ccccc1
Yield: 89.3 %

Procedure:
A suspension of the product of stage (a) (40 g) in aqueous 10% sodium carbonate solution (200 ml) was heated under reflux for 2 hours. The clear yellow solution obtained was cooled and acidified with concentrated hydrochloric acid to afford an off-white precipitate. This was filtered off and recrystallised from ethanol to give the desired product (33 g), as white needles, mp 142°-143° C.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][CH:35]=[C:36]([C:42](=[O:46])[CH:43]([CH3:45])[CH3:44])[C:37]([O:39]CC)=O)=[CH:30][CH:29]=1>>[OH:39][C:37]1[C:32]2[C:31](=[CH:30][CH:29]=[C:28]([O:27][CH3:26])[N:33]=2)[N:34]=[CH:35][C:36]=1[C:42](=[O:46])[CH:43]([CH3:44])[CH3:45]
Reactant: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)C(C)C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COc1ccc2ncc(C(=O)C(C)C)c(O)c2n1
Temperature: 25 °C
Reaction time: 0.62 h
Yield: 141.6 %

Procedure:
To a flask containing Dowtherm™ A (400 mL) at 250° C. was added ethyl 2-(((6-methoxypyridin-3-yl)amino)methylene)-4-methyl-3-oxopentanoate (11.5 g, 39.3 mmol) portion wise over 3 to 5 min and the reaction mixture was stirred for an additional 30 to 45 min. The reaction mixture was removed from the heat source, cooled to room temperature and diluted with hexanes to facilitate precipitation. The solids were filtered, washed with hexanes and dried under vacuum to afford the desired product (13.7 g, crude) as a yellow-brown solid: ESI MS m/z 247 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:31](=[O:32])[NH:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: O=C=NC1CCCCC1
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)OCC1(CO)CCSc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (424 mg, 1.78 mmol) in 22 ml of tetrahydrofuran were added, at 0° C., triethylamine (0.27 ml, 1.96 mmol) and cyclohexyl isocyanate (1.0 ml, 7.84 mmol). The mixture was stirred at 80° C. for 18 hours, concentrated and purified by column chromatography on silica (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 366 mg (57%).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH:8]([CH3:31])[CH:9]([NH:14][C:15]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[N:21]=1)=[O:16])[C:10]([O:12][CH3:13])=[O:11].[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:21]=[C:17]([C:15]([NH:14][CH:9]([CH:8]([CH3:31])[CH3:7])[C:10]([O:12][CH3:13])=[O:11])=[O:16])[S:18][CH:19]=2)=[CH:23][CH:24]=1)(=[O:42])=[O:41]
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NS(=O)(=O)c3ccc(Cl)cc3Cl)cc2)cs1)C(C)C
Reaction time: 0.08 h

Procedure:
Pyridine (1.5 ml) was added to a solution of methyl-2-(4-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 3, 160 mg) in DCM (4 ml), and reaction mixture was stirred for 5 minutes. 2,4 dichloro benzenesulfonyl chloride (130 mg) was added and reaction mixture was stirred for 16 hours at RT. Organic solvent was concentrated to obtain sticky solid, was purified by column chromatography (silica gel, EtOAc-petroleum ether) to obtain title compound as solid. Yield: 215 mg (82%); 1H NMR (CDCl3, 300 MHz): δ 7.97 (d, 1H), 7.81 (d, 2H), 7.75 (d, 1H), 7.63 (s, 1H), 7.51 (d, 1H), 7.33 (dd, 1H), 7.21 (d, 2H), 7.13 (bs, 1H), 4.73 (m, 1H), 3.78 (s, 3H), 2.32 (m, 1H), 1.04 (dd, 6H); MS (ESI) m/z 542.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:3].[I-].[CH3:13][C:14]1[CH:19]=[CH:18][N+:17]([CH3:20])=[CH:16][CH:15]=1.[C:21]1([B-:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na+]>>[C:40]1([B-:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1.[CH3:1][N:2]([C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:13]/[C:14]2[CH:19]=[CH:18][N+:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: Cc1cc[n+](C)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [I-]
Agent: [Na+]
Agent: c1ccc([B-](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CN(C)c1ccc(/C=C/c2cc[n+](C)cc2)cc1

Procedure:
14.9 g (0.1 mol) of 4-(N,N-dimethylamino)benzaldehyde were reacted with 23.6 g (0.1 mol) of 4-methyl-N-methylpyridinium iodide, prepared according to Example 3, and the resulting solution was treated with 34.6 g (0.1 mol) of sodium tetraphenyborate, under the conditions described in Example 6, to form dye2 as a red solid in a yield of 70%. 1H-NMR (DMSO-d6) δ3.00 (s, 6H), 4.1 (s, 3H), 6.70 (t, 4H), 6.8 (t, d, 2H), 6.9 (t, 8H), 7.02 (d, 1H), 7.10 (d, 8H) 7.50 d, 2H), 7.9 (d, 1H), 8.0 (d, 2H), 8.62 (d, 2H) ppm. Td 266° C.
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH2:16][CH:15]3[CH2:17][CH:11]([CH2:12][NH:13][CH2:14]3)[CH:10]=2)[CH:4]=1.[H][H]>CO.[Pd]>[ClH:1].[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[CH2:16][CH:15]3[CH2:17][CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[CH:4]=1
Reactant: [H][H]
Reactant: C1=C(c2cccnc2)CC2CNCC1C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1cncc(C2CC3CNCC(C3)C2)c1
Reaction time: 3 h

Procedure:
7-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene dihydrochloride (17.2 mg, 0.0629 mmol) was dissolved in methanol (10 ml), and 10% Pd/C (5 mg) was added. The mixture was hydrogenated for 3 h using a hydrogen-filled balloon. When the reaction was complete, the reaction was filtered through Celite, washed with methanol and concentrated by rotary evaporation to a light brown solid. This was dissolved in ethanol (10 ml) and treated with concentrated HCl (5 drops). The excess HCl and residual water were removed by repeated azeotropic rotary evaporation with ethanol. 7-(3-Pyridinyl)-3-azabicyclo[3.3.1]nonane dihydrochloride was isolated as a white solid (18.2 mg, 100%). GC-MS shows a 85:15 ratio of diastereomers.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:43][CH:44]1[CH2:49][CH2:48][O:47][C:45]1=[O:46]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([NH:43][CH:44]2[CH2:49][CH2:48][O:47][C:45]2=[O:46])=[O:35])=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCOC1=O
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1
Agent: Br
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)NC3CCOC3=O)c2)cc1

Procedure:
The product from Example 116B (57 mg, 0.10 mmole) and (α-Amino-γ-butyrolactone hydrobromide (36 mg, 0.20 mmole) were processed as in Example 279A to provide the titled compound. 1H NMR (500 M/z, DMSO-d6) δ8.95 (s, 1 H), 8.36 (d, 1 H), 7.23 (m, 8 H), 7.04 (m, 1 H), 6.94 (m, 4 H), 6.69 (dd, 1 H), 6.50 (m, 2 H), 4.53 (d, 1 H), 4.33 (d, 1 H), 4.19 (ddd, 1 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.94 (t, 2 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 2.35 (m, 1 H), 2.27 (m, 2 H), 2.13 (m, 1 H), 1.91 (m, 2 H); MS (APCI+) m/z 702.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.C([O-])(O)=O.[Na+].CO>O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][N:7]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=[C:6]2[CH:5]=1)=[O:11]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1ccnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccn2cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-amino-isonicotinic acid methyl ester (5 g, 32 mmol), ω-bromoacetophenone (6.47 g, 32 mmol), NaHCO3 (2.95 g, 35 mmol) and methanol (30 ml) was heated under an atmosphere of argon to reflux (3 h). After cooling, water (20 ml) was added, the mixture was stirred at r.t. (15 min), and filtered. The obtained solid was washed (water, methanol, diethyl ether) and dried under vacuum. The product (6.8 g, 85%) was used in the next step without further purification. MS (m/e)=253.2 [M+H+].
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]([C:9]1[CH:24]=[C:23]2[C:12]([CH2:13][C:14]3[CH:18]=[CH:17][N:16]([CH2:19][C@H:20](O)[CH3:21])[C:15]=32)=[CH:11][CH:10]=1)([CH3:8])[CH3:7].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.CN(C)C=O.O>[N:32]([C@@H:20]([CH3:21])[CH2:19][N:16]1[CH:17]=[CH:18][C:14]2[CH2:13][C:12]3[C:23]([C:15]1=2)=[CH:24][C:9]([CH:6]([CH3:8])[CH3:7])=[CH:10][CH:11]=3)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc2c(c1)-c1c(ccn1C[C@H](C)N=[N+]=[N-])C2
Yield: 57.3 %

Procedure:
1.08 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.78 g of (R)-1-(7-isopropyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.86 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 70 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.91 g of sodium azide and the reaction mixture was heated to 60° for 16 hours while stirring. After cooling, the solution was poured into 150 ml of water and extracted twice with 200 ml of ethyl acetate each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.12 g (57%) of (S)-1-(2-azido-propyl)-7-isopropyl-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>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.O>[Cl:12][C:4]1[CH:3]=[C:2]([CH:13]2[CH2:15][CH2:14]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C2CC2)cc1Cl
Temperature: 110 °C
Yield: 63.2 %

Procedure:
Charged methyl 4-bromo-2-chlorobenzoate (1.50 g, 6.01 mmol), cyclopropylboronic acid (931 mg, 10.82 mmol), Pd(PPh3)4 (347 mg, 0.30 mmol), K3PO4 (1.82 g, 18.04 mmol), toluene (15 mL) and water (15 mL) to a flask, the mixture was then purged with nitrogen, and heated to 110° C. overnight. It was then cooled to room temperature and filtered, the filtrate was extracted with ethylacetate twice, concentrated the organic phase and purified by flash column chromatograph to give 800 mg of the title compound (63%). 1H NMR (400 MHz, CDCl3): δ 0.73-0.77 (2H, m), 0.98-1.07 (2H, m), 1.85-1.90 (1H, m), 3.90 (3H, s), 6.96 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.11 (1H, d, J=1.6 Hz), 7.74 (1H, d, J=8.0 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH2:13][CH3:14])[CH2:9][C:8]([NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:15])[CH2:7]2)(=O)[CH3:2].C(C1C=C2C(=CC=1)CC(NC(=O)C1C=CC=CC=1)(C)C2)C>>[CH2:13]([C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[CH2:1][CH3:2])[CH2:7][C:8]([NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:15])[CH2:9]2)[CH3:14]
Reactant: CCc1cc2c(cc1C(C)=O)CC(C)(NC(=O)c1ccccc1)C2
Agent: CCc1ccc2c(c1)CC(C)(NC(=O)c1ccccc1)C2
Product: CCc1cc2c(cc1CC)CC(C)(NC(=O)c1ccccc1)C2

Procedure:
N-(5,6-Diethyl-2-methyl-indan-2-yl)-benzamide is prepared from N-(5-acetyl-6-ethyl-2-methyl-indan-2-yl)-benzamide (1.1 g) following the procedure used to prepare N-(5-ethyl-2-methyl-indan-2-yl)-benzamide. ES+ MS m/e 308 (MH+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:36]=[CH:35][C:10]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([N:30]3[CH:34]=[CH:33][CH:32]=[CH:31]3)[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)=[O:12])=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([N:30]3[CH:31]=[CH:32][CH:33]=[CH:34]3)[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:12])=[CH:35][CH:36]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)n1cccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCCOc1ccc(CC(C(=O)O)n2cccc2)cc1)c1ccc(-c2ccccn2)cc1

Procedure:
Ethyl 3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]-2-(pyrrole-1-yl)propionate, which is the product of Example 191, is hydrolyzed by sodium hydroxide in methanol to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:26])[CH:17]2[CH2:22][CH2:21][N:20](C(C)C)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:26])[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CCC(C(O)c2ccc([C@H](C)NC(=O)OC(C)(C)C)cc2)CC1
Solvent: CC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C2CCNCC2)cc1
Yield: 121 %

Procedure:
2.14 g of tert-butyl((1S)-1-{4-[hydroxy(1-isopropylpiperidin-4-yl) methyl]phenyl}ethyl)carbamate [334] (hereinafter, referred to as the compound [334]) was obtained from 2.3 g of the compound [33-3] and 15 mL of acetone according to the method of Example 1 7-(3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8](O)[CH2:9][CH3:10])[CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:13][CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[CH2:9][CH3:10]
Reactant: BrC(Br)(Br)Br
Reactant: CCC(O)c1cccc(Cl)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(Br)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(6-chloropyridin-2-yl)propan-1-ol (0.497 g, 2.90 mmol), CBr4 (1.2 g, 3.62 mmol) and triphenylphosphine (0.987 g, 3.76 mmol) in 25 mL of THF was stirred at room temperature for 2 h. The solid was filtered off and washed with THF. The filtrate was concentrated and residue was purified by chromatography on silica gel, eluting with 10 to 50% EtOAc/hexane to provide the title compound. Mass Spectrum (ESI) m/z=236 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[NH:43][N:42]=[N:41][N:40]=3)=[CH:29][CH:28]=2)[C:6]2[C:12]([C:13]([NH:15][CH:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:17][S:18]C(=O)C)=[O:14])=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2]>CO.[OH-].[Na+]>[SH:18][CH2:17][CH:16]([NH:15][C:13]([C:12]1[C:6]2[N:5]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:43][N:42]=[N:41][N:40]=4)=[CH:29][CH:28]=3)[C:4]([O:3][CH2:1][CH3:2])=[N:8][C:7]=2[CH:9]=[CH:10][CH:11]=1)=[O:14])[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CCOc1nc2cccc(C(=O)NC(CSC(C)=O)CC(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1nc2cccc(C(=O)NC(CS)CC(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 1 h
Yield: 1 %

Procedure:
Thioacetic acid S-[2-({2-ethoxy-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazole-4-carbonyl}amino)-4-methylpentyl]ester (80 mg, 0.1 mmol) was dissolved in MeOH (5 mL) and 1M NaOH (5 mL). The mixture was stirred for 1 hour with nitrogen gas bubbling through the solution. The reaction was quenched with acetic acid (5 mL) and the mixture evaporated to dryness. The residue was purified using reverse phase preparative HPLC to afford the title compound (540 μg). ESMS [M+H]+ calcd for C30H33N7O2S, 555.3. found 556.4.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:4][CH2:3]1>CCOC(C)=O.CO>[CH3:20][O:19][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:15]=[CH:14][C:13]=1[NH2:16]
Reactant: COc1cc(CCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(CCN2CCN(C)CC2)ccc1N
Reaction time: 8 h
Yield: 85.6 %

Procedure:
1-Methyl-4-{2-[3-(methyloxy)-4-nitrophenyl]ethyl}piperazine (0.6 g, 2.15 mmol) was placed in a 100 mL high pressure vessel and dissolved in 30 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.42 g, 0.107 mmol) was added followed quickly by a rubber septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (50 psi). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step D (0.460 g, 1.84 mmol, 86%). 1H NMR (400 MHz, CDCl3) δ ppm 6.60-6.64 (m, 3H), 3.82 (s, 3H), 3.64 (bs, 2H), 2.64-2.73 (m, 2H), 2.38-2.63 (m, 10H), 2.29 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40]>>[OH:40][CH2:39][CH:38]([NH:37][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH2:41][OH:42]
Reactant: NC(CO)CO
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: O=C(NC(CO)CO)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 52.5 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl} benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol, 1.0M in DMF) were combined (reaction time 3 days at room temperature) to give 30 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 572 [M+H]+.