Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH:6]=[CH:7][CH:8]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:34]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(CO)c2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(COC(=O)c3ccccc3)c2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-(3-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-(3-benzoyloxymethyl-phenyl)-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate as a colourless oil; MS: 569 (M+NH4)+.
Reaction SMILES: [I:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18]Br>>[F:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18][N:9]1[C:8](=[O:10])[C:7]([CH3:11])([CH3:12])[NH:6][C:5]2[N:13]=[CH:14][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: CC1(C)Nc2ncc(I)cc2NC1=O
Reactant: Fc1ccc(F)c(CBr)c1
Product: CC1(C)Nc2ncc(I)cc2N(Cc2cc(F)ccc2F)C1=O
Yield: 98 %

Procedure:
7-Iodo-3,3-dimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (237 mg) was reacted with 2,5-difluorobenzyl bromide as in General Procedure 1 to give the title compound as a white solid (98% yield). M.p. 198-201° C., LCMS: m/z=430.00 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.36 (s, 6H), 5.12 (s, 2H), 6.79-6.83 (m, 1H), 7.15-7.22 (m, 1H), 7.28-7.32 (m, 1H), 7.31 (s, 1H), 7.40 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Cl[C:30]1[N:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:39][O:38][C:36](=[O:37])[C:33]1[CH:32]=[CH:31][C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:35][CH:34]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)nc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 9.1 %

Procedure:
To a solution of 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (200 mg, 0.48 mmol, Example 56, step 4) in N′N-dimethylformamide (2.0 ml) were added methyl 6-chloropyridine-3-carboxylate (93 mg, 0.53 mmol) and potassium carbonate (199 mg, 1.44 mmol). The mixture was stirred for 4 h at 110° C. After cooling to r.t. water was added and the mixture was extracted twice with AcOEt. The organic phases were washed with water and brine, dried (MgSO4) and concentrated. The product was purified by column chromatography (silica gel, heptane/AcOEt 4:1) to give the title compound (24 mg) as light yellow solid. MS (m/e)=551.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[Na+].[CH3:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14]>CC(OC)(C)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:13](=[O:14])[C:12]([CH3:17])([CH3:16])[CH3:11]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC(C)(C)C(=O)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 2-chloroaniline 46 (200 mL, 1.9 mol) in MTBE (950 mL) in an ice-water bath was added 25 wt % NaOH (480 g, 3 mol). Trimethylacetyl chloride (248.5 mL, 2.02 mol) was then added dropwise and the reaction was stirred overnight at rt. The organic layer was separated, washed with brine (1.0 L) and water (1.0 L), dried over sodium sulfate, and concentrated in vacuo to give 47 (390 g, 97%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH:10](O)[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>CC#N>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(O)c1ccc(O)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CCCCc1oc2ccccc2c1Cc1ccc(O)cc1
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
At −10° C., to a stirred solution of 4-[(2-butyl-benzofuran-3-yl)-hydroxy-methyl]-phenol (2.78 g, 9.39 mmol) in CH3CN was added portionwise triethylsilane (two×1.50 mL, 18.78 mmol total, @ 0.5 h interval). To the reaction was added BF3.Et2O (1.19 mL, 9.39 mmol) and the reaction was stirred for 10 min. The reaction was quenched with sat. aq. KCO3 and extracted with CH2Cl2. The organic extracts were washed with brine (3×), dried (MgSO4) and concentrated. Purification on silica gel gave 2.35 g (89%) the title compound as a white solid, mp 67-70° C. (DMSO-d6) 8 0.87 (t, 3H), 1.31 (sextet, 2H), 1.62 (quintet, 2H), 2.78 (t, 2H), 3.84 (s, 2H), 6.64 (d, 2H), 7.02 (d, 2H), 7.09 (dt, 1H), 7.16 (dt, 1H), 7.31 (d, 1H), 7.42 (d, 1H), 9.16 (s, 1H). IR (KBr) 3300, 2950, 1610, 1510 and 1450 cm−1. mass spectrum (EI) m/z 280 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:31][C:32](=[O:34])[CH3:33]>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:31][C:32](=[O:34])[CH3:33])[C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(Nc2nccc(-c3ccc(NC(=O)OC(C)(C)C)s3)n2)c1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2ccnc(Nc3cccc(C)c3)n2)s1
Temperature: 60 °C
Reaction time: 0.13 h

Procedure:
[5-(2-m-Tolylamino-pyrimdin-4-yl)-thiophen-2-yl]-carbamic acid tert-butyl ester (30 mg, 0.078 mmol) was dissolved in DMF (0.8 mL) and 60% NaH (4.7 mg, 0.117 mmol) was added. After 8 min., KI (12.9 mg, 0.078 mmol) and chloroacetone (9.4 uL, 0.117 mmol) were added and the reaction was heated to 60° C. for 15 h. The reaction was ˜60% converted and an additional aliquot of 60% NaH (3.1 mg, 0.078 mmol) and chloroacetone (6.2 uL, 0.078 mmol) were added and reaction heated at 60° C. for another 18 h. The reaction was concentrated in vacuo and taken to the next step crude.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:6]=1)[CH3:2].N1C=CC=CC=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>ClCCl>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:28](=[O:29])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:16][CH:17]=2)[CH:6]=1)[CH3:20]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(OCC)c1cc(-c2ccc(N)cc2)nn1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(OCC)c1cc(-c2ccc(NC(=O)OCc3ccccc3)cc2)nn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109 %

Procedure:
4-[5-(Diethoxymethyl)-1-methyl-1H-pyrazol-3-yl]aniline (Intermediate 10, 5.9 g, 21.5 mmol), and pyridine (4 ml, 50 mmol) were dissolved in dichloromethane (25 ml) at 0° C. Benzyl chloroformate (3.8 ml, 26.7 mmol) was added slowly over 5 minutes and the resulting mixture was stirred at 0° C. for 30 min. The mixture was diluted with dichloromethane and washed with 1M HCl, saturated NaCl, then dried over sodium sulfate and evaporated give the title compound as a thick light orange oil (9.6 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][O:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:19](C#N)#[N:20].N1C=CC=CC=1.Cl>CN1CCCC1=O>[C:19]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][O:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:4][CH:3]=1)#[N:20]
Reactant: CCCCC[C@@H]1CO[C@@H](c2ccc(Br)cc2)CO1
Reactant: N#CC#N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CCCCC[C@@H]1CO[C@@H](c2ccc(C#N)cc2)CO1

Procedure:
A mixture of 31.3 g. trans-2-p-bromophenyl-5-pentyl-1,4-dioxane, 10 g. Cu2 (CN)2, 120 ml. pyridine and 60 ml. N-methylpyrrolidone is heated for 2 hours to 150°. One cools, adds thereto a solution of 120 g. FeCl3.6H2O in 600 ml. 20% hydrochloric acid, heats to 70° for 1.5 hours, while stirring. Works up as usu 1 and obtains trans-2-p-cyanophenyl-5-pentyl-1,4-dioxane.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([O:16][CH3:17])=[CH:8][C:9]=1[C:10]2=[O:15].CO.C[O-].[Na+].Cl[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>ClC1C=CC=CC=1>[CH2:25]([N:26]([CH2:29][CH3:30])[CH2:27][CH2:28][O:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([O:16][CH3:17])=[CH:8][C:9]=1[C:10]2=[O:15])[CH3:24]
Reactant: COc1ccc2c(c1)C(=O)c1cccc(O)c1-2
Reactant: CCN(CC)CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CO
Product: CCN(CC)CCOc1cccc2c1-c1ccc(OC)cc1C2=O

Procedure:
In a manner analogous to Example 3D1, combine 5-hydroxy-2-methoxy-fluoren-9-one (0.35 g, 1.5 mmole), 3 mL methanol and sodium methoxide (0.12 g, 2.1 mole) in 10 mL chlorobenzene. After cooling, add the specially prepared free base 2-chloroethyldiethyl amine to obtain the hydrochloride salt of the title compound as a yellow-orange powder. m.p. 196°-199° C. (dec.). Yield 0.387 g, 72%.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].FC(C(O)=O)(F)F.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[C:38]1([NH:44][C:45]([NH:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)CC(C)C
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)Nc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of Leu-DTrp-βAla-OEt.TFA (40.6 mg) obtained in Example 51-(1) in chloroform (2 ml) were added TEA (20 μl) and phenyl isocyanate (15 μl) at room temperature under nitrogen. The reaction mixture was stirred for 1 h, and concentrated under reduced pressure. The residue was purified by dry column flash chromatography (Merck, Kieselgel 60) with chloroform/methanol=10/1 for elution to give the product (39.6 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)([F:4])[F:3].[OH:13]O.[OH-].[Na+]>>[F:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH2:12])=[O:13])=[CH:7][CH:6]=1)([F:3])[CH3:1]
Reactant: CC(F)(F)c1ccc(C#N)cc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Product: CC(F)(F)c1ccc(C(N)=O)cc1

Procedure:
5 gm of p-CH3CF2C6H4CN, 200 ml of an aqueous solution of H2O2 at 3% and 10 ml of an aqueous solution of NaOH at 25% were reacted at 60° C. during 4 hours. A white precipitate was progressively formed. The reaction medium was then cooled, filtered, washed with water and dried under vacuum. 5.5 gm of ##STR45## were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=1.[CH3:13][C:14]1([CH3:21])[CH2:19][C:18](=O)[O:17][C:15]1=[O:16].C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:12]2[C:18](=[O:17])[CH2:19][C:14]([CH3:21])([CH3:13])[C:15]2=[O:16])[CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=1
Reactant: COCOc1cc(N)cc(Br)c1
Reactant: CC1(C)CC(=O)OC1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COCOc1cc(Br)cc(N2C(=O)CC(C)(C)C2=O)c1
Temperature: 50 °C
Yield: 2352.9 %

Procedure:
To a solution of 3-bromo-5-methoxymethoxy-phenylamine (1.0 g, 4.31 mmol) in methylene chloride (25 ml) was added 2,2-dimethylsuccinic anhydride (580 mg, 0.195 mmol). The mixture was heated to 50° C. (oil bath) for 1 hour and then stirred over night at ambient at which point a large amount of precipitate had formed. Carbonyldiimidazole (839 mg, 5.17 mmol) was added and within 2 minutes a homogeneous solution was obtained. The material was stirred over night and then the crude was adsorbed onto silica gel (12 g). Purification by silica gel chromatography eluting with 6%-45% EtOAc in hexanes afforded 1.57 g of 1-(3-bromo-5-methoxymethoxy-phenyl)-3,3-dimethyl-pyrrolidine-2,5-dione as a viscous yellow-white oil.
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[NH2:14])=[CH:10][CH:9]=[CH:8][CH:7]=3.Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[N:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[NH:14][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc2ccc3ccccc3n2n1
Agent: Cl
Product: O=C(Nc1nc2ccc3ccccc3n2n1)c1cccnc1
Yield: 25.2 %

Procedure:
The title compound was prepared following procedure described for example 2, but starting from [1,2,4]triazolo[1,5-a]quinolin-2-amine ((A13), 67 mg; 0.37 mmol; 1.5 eq.) and nicotinoyl chloride hydrochloride (80 mg; 0.44 mmol; 1.2 eq.). Purification by flash chromatography on silica (DCM/MeOH, gradient from 98:2 to 95:5) gave the title compound as an orange oil (27 mg, 38%). HPLC, Rt: 1.83 min. (purity 97.9%). LC/MS, M+(ESI): 290.0, M−(ESI): 288.0.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][C:11]#[C:12][CH3:13].C(N(CC)CC)C>C(O)C>[CH2:9]([NH:8][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:10][CH2:11][C:12]#[CH:13]
Reactant: CC#CCCN
Reactant: Clc1ncccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: C#CCCCNc1ncccn1
Temperature: 90 °C

Procedure:
A mixture of 2-chloropyrimidine (4.0 g, 35 mmol), 5-aminopent-2-yne (10.5 g, 88 mmol), triethylamine (12.3 mL, 88 mmol) in ethanol (50 mL) was heated in a sealed tube at 90° C. for 16 h. The mixture was cooled and evaporated in vaciio. The residue was taken up in ethyl acetate and was filtered through a plug of silica gel, eluting with ethyl acetate, and evaporated in vacuo to give the title compound:
Reaction SMILES: [OH-:1].[Li+].OO.C([C@@H]1COC(=O)N1[C:18](=[O:38])[C@@H:19]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[CH2:20][N:21]([CH:29]([CH3:31])[CH3:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])C1C=CC=CC=1>O.C1COCC1>[C:24]([O:23][C:22]([N:21]([CH:29]([CH3:30])[CH3:31])[CH2:20][C@H:19]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C:18]([OH:38])=[O:1])=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: [OH-]
Reactant: CC(C)N(C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A mixture solution of lithium hydroxide (374 mg, 15.6 mmol) in H2O (60 mL) and 30% hydrogen peroxide (1.60 mL, 15.6 mmol) was added dropwise to a solution of tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(5-chlorothiophen-2-yl)-3-oxopropyl(isopropyl)carbamate (7.54 g, 14.9 mmol) in THF (150 mL) at −5° C. The mixture was stirred at −5° C. After 10 minutes, the reaction was quenched with 10% Na2SO3 (16 mL) at −5° C. and stirred at room temperature for 30 minutes. The THF was removed in vacuo. The aqueous layer was acidified with 1M NaH2PO4 and extracted with DCM (3×100 mL). The combined organics were dried (Na2SO4), filtered and concentrated to give (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(5-chlorothiophen-2-yl)propanoic acid which was used in the next step without purification. MS (APCI+) [M+H]+ 348.2.
Reaction SMILES: O=[C:2]1[C:15]2[CH:14]=[C:13]([CH:16]([CH3:19])[CH2:17][OH:18])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O.Cl>[Zn].C1(C)C=CC=CC=1>[CH:14]1[C:15]2[CH2:2][C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:9][C:10]=2[CH:11]=[CH:12][C:13]=1[CH:16]([CH3:19])[CH2:17][OH:18]
Reactant: CC(CO)c1ccc2oc3ccccc3c(=O)c2c1
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CO)c1ccc2c(c1)Cc1ccccc1O2
Reaction time: 8 h

Procedure:
A mixture of 10 g. of 2-(9-oxo-2-xanthenyl)-propanol, 12 g. of amalgamized zinc, 15 ml. of water, 40 ml. of concentrated hydrochloric acid, and 20 ml. of toluene is refluxed for 48 hours. At 8 hour intervals, another 10 ml. of concentrated hydrochloric acid is added. After filtration over active carbon and removal of the solvent mixture by evaporation, 2-(2-xanthenyl)-propanol is obtained, m.p. 86°-89°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[C:50]([CH3:51])=[CH:49][CH:48]=[CH:47][C:46]=1[O:52][CH3:53]>>[CH3:53][O:52][C:46]1[CH:47]=[CH:48][CH:49]=[C:50]([CH3:51])[C:45]=1[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: COc1cccc(C)c1OCCCCBr
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4c(C)cccc4OC)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.081 g of 2-(4-bromobutoxy)-1-methoxy-3-methylbenzene are used to prepare the title compound. Rf=0.28 (2:1 EtOAc-heptane); Rt=6.15.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C@@H:5]1[CH2:7][C@H:6]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:10][CH:9]=1.[NH:24]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C@@H:6]3[CH2:7][C@H:5]3[NH:4][CH2:3][CH2:2][N:24]3[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:25]3)=[CH:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cccc(-c2ccc([C@@H]3C[C@H]3NCCCl)cc2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CCN[C@@H]2C[C@H]2c2ccc(-c3cccc(C(F)(F)F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37 %

Procedure:
To a solution of (trans)-N-(2-chloroethyl)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine (750 mg, 2.21 mmol) in dry DMF (7.5 mL), (S)-tert-butyl pyrrolidin-3-ylcarbamate (864 mg g, 4.64 mmol) was added and stirred at RT for 48 h. After completion, the reaction mixture was poured into ice water (25 mL), extracted with EtOAc (2×20 mL). The combined extracts were washed with water (25 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography (SiO2) using MeOH: CHCl3(4:96) to get tert-butyl (S)-1-(2-((trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-ylcarbamate (400 mg, 37%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([N:14](CC2C=CC=CC=2)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)C1CCC(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC1CCC(C(=O)OC(C)(C)C)CC1
Yield: 104.3 %

Procedure:
To a solution of 4-(benzyl-tert-butoxycarbonylmethyl-amino)-cyclohexanecarboxylic acid tert-butyl ester (300 mg, 0.7433 mmol) in EtOH (10 mL) is added 10% Pd/C (wet) (40 mg). The mixture stirs under a blanket of hydrogen gas at atmospheric pressure for 12 h. The mixture is then filtered though celite. The celite is washed with MeOH (50 mL). The filtrated is concentrated to afford 243 mg of 4-(tert-butoxycarbonylmethyl-amino)-cyclohexanecarboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.98 (m, 2H), 1.25 (m, 2H), 1.36 (m, 9H), 1.41 (m, 9H), 1.81 (m, 4H), 2.05 (m, 1H), 2.28 (m, 1H), 3.20 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N:15]1[CH:16]=[CH:17][C:12]([NH:11][S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])=[CH:13][CH:14]=1
Reactant: Nc1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccncc1)c1ccc(Br)s1
Temperature: 50 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
A mixture of 5-bromo-thiophene-2sulphonyl chloride (1.31 g, 5.0 mmol), 4-dimethylamino-pyridine (0.61 g, 5.0 mmol) and 4-amino-pyridine (0.71 g, 7.5 mmol) in pyridine (20 ml) was stirred at 50° C. for 16 h. THE reaction mixture was evaporated and diluted with dichloromethane/MeOH/NH4OH 80:10:1. The formed precipitate was collected by filtration to yield the title compound (1.53 g, 96%) as an off-white solid, which was used without further purification. MS (ISN) 317.0 [(M−H)−], mp 310° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:36]3[CH2:37][CH2:38][CH2:39][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CN1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of the product of step i) (0.45 g) in dichloromethane (50 mL) was treated with 1-methyl-1,4-diazepane (0.61 g) and sodium triacetoxyborohydride (0.68 g) and then stirred at room temperature overnight. Methanol (5 mL) was added and the solution purified directly by SiO2 chromatography (eluting with 0 to 20% methanol in dichloromethane) followed by HPLC to give the title compound as a solid (150 mg).