Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1.Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1)[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25]
Reactant: O=C(CCl)N1CCOCC1
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCOCC1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
Note: For the preparation of the starting material compound 1, see Example 147. To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]cyclohexane-1,4-diamine (90 mg, 0.30 mmol, 1.00 equiv) in DMF (10 mL) was added 2-chloro-1-(morpholin-4-yl)ethan-1-one (73.35 mg, 0.45 mmol, 1.50 equiv) and potassium carbonate (83 mg, 0.60 mmol, 2.00 equiv) at room temperature under nitrogen. The resulting solution was stirred overnight at ambient temperature. After completion of the reaction, the solids were removed by filtration and the filtrate was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 50.0% in 19 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino)cyclohexyl]amino]-1-(morpholin-4-yl)ethan-1-one (30.8 mg) as a white solid. MS (ES, m/z): 430 (M+H+). NMR (400 MHz, CD3OD-do): δ 8.23 (s, 1H), 4.05-4.08 (m, 1H), 3.67-3.68 (m, 6H), 3.59-3.60 (m, 2H), 3.40 (s, 2H), 3.08 (t, 2H), 3.01 (t, 2H), 2.52-2.59 (m, 3H), 2.34 (s, 3H), 2.16-2.19 (m, 2H), 1.93-1.96 (m, 2H), 1.45-1.57 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:17])=[C:8]3[C:15](=O)[CH2:14][CH2:13][CH2:12][N:9]32)=[CH:5][CH:4]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:17])=[C:8]3[C:15](=[N:19][OH:20])[CH2:14][CH2:13][CH2:12][N:9]32)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)c3n(c2c1)CCCC3=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(C)c3n(c2c1)CCCC3=NO
Yield: 98.2 %

Procedure:
A solution of 6,7,8,9-tetrahydro-3-methoxy-10-methylpyrido[1,2-a]indol-9-one (2.29 g, 10 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol) in dry pyridine (40 mL) was refluxed for 2 hours. The reaction mixture was concentrated to 10% of its original volume and distilled water (80 mL) was added. The organic product was extracted with ether (3×60 mL). The combined organic layers were washed with water (100 mL), 5% hydrochloric acid (50 mL), and 10% sodium bicarbonate (50 mL). The separated organic layer was dried over MgSO4, filtered, and evaporated. The residue was recrystallized from methanol/water to afford 2.4 g (98%) of the title compound as gray microcrystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH2:15][OH:16])=[N:12][C:11]=2[CH:17]([CH3:19])[CH3:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClS([N:24]=[C:25]=[O:26])(=O)=O.O.Cl>C(#N)C>[C:25](=[O:26])([O:16][CH2:15][C:13]1[NH:14][C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:17]([CH3:19])[CH3:18])[N:12]=1)[NH2:24]
Reactant: CC(C)c1nc(CO)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CC(C)c1nc(COC(N)=O)[nH]c1Sc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
The compound 2 40 g (126 mmol) obtained in the step 1 was suspended in acetonitrile 400 ml, and the suspension was cooled down under nitrogen atmosphere. To the suspension was added dropwise chlorosulfonyl isocyanate 24.3 g (171 mmol) at -20 to -25° C. for 1 hour. To the mixture was added water 400 ml under 10° C. To the mixture was added concentrated hydrochloric acid 40 ml, and the mixture was stirred at 50° C. for 2 hours. The mixture was cooled down to -10° C. and crystallized at the same temperature for 1 hour. The obtained slurry was filtered, washed with cooled acetonitrile, and dried to yield the compound 3 43.2 g. Yield 83%
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([S:21][CH3:22])[N:15]=1.CON(C)[C:26](=[O:28])[CH3:27]>C1COCC1>[CH3:20][C:18]1[N:17]=[C:16]([S:21][CH3:22])[N:15]=[C:14]([CH2:13][C:26](=[O:28])[CH3:27])[CH:19]=1
Reactant: CON(C)C(C)=O
Reactant: CSc1nc(C)cc(C)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1nc(C)cc(CC(C)=O)n1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
n-Butyllithium (1.6 M in hexanes, 67 ml, 107 mmol) is added dropwise to a stirred solution of diisopropylamine (15 ml, 107 mmol) in dry THF (90 ml) under argon at −78° C. After 15 minutes at −78° C. to 50° C. the mixture is cooled to −78° C. and a solution of 4,6-dimethyl-2-methylsulfanyl-pyrimidine (15 g, 97.4 mmol) in dry THF (45 ml) is added dropwise. The reaction is stirred for 2.5 hours at −78° C. then N-methoxy-N-methylacetamide (10.4 ml, 97.4 mmol) is added dropwise. The reaction is allowed to warm to room temperature over 1 hour followed by quenching with saturated aqueous ammonium chloride solution (10 ml). The mixture is concentrated to remove most of the THF then partitioned between water (200 ml) and DCM (200 ml). The organic extract is separated, dried (MgSO4), and the solvent is removed to afford the titled compound. The material is a mixture of keto and enol forms as observed by 1H nmr (CDCl3)
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.[NH2:32][C@H:33]([CH3:37])[C@H:34]([OH:36])[CH3:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:36][C@H:34]([CH3:35])[C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30])[CH3:37]
Reactant: C[C@@H](N)[C@@H](C)O
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](C)[C@@H](C)O)[nH]2)c1
Reaction time: 72 h
Yield: 57.4 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (2.00 g, 4.48 mmol) synthesized in Example (78k) and (2R,3R)-3-aminobutan-2-ol (0.94 g, 8.96 mmol) synthesized in Example (88a) were dissolved in methanol (30 mL), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (2.84 g, 8.96 mmol) was added at room temperature, followed by stirring for 3 days under nitrogen atmosphere. The solvent was distilled off under reduced pressure, water (30 mL) was added, and the solution was separated with ethyl acetate (70 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-90%) to afford the desired compound (1.33 g, 57%) as a white solid.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:19](=[O:20])[C:18]2[S:21][CH:22]=[CH:23][C:17]=2[N:16]=[C:15]1[CH:24]=CN(C)C>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:19](=[O:20])[C:18]2[S:21][CH:22]=[CH:23][C:17]=2[N:16]=[C:15]1[CH:24]=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)C=Cc1nc2ccsc2c(=O)n1-c1ccccc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1nc2ccsc2c(=O)n1-c1ccccc1Cl

Procedure:
To a well stirred mixture of sodium periodate (9.7 g, 45.3 mmol) in pH 7 buffer (115 mL) and tetrahydrofuran (115 mL) was added 3-(2-chloro-phenyl)-2-(dimethylamino-vinyl)-4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidine (5.0 g, 15.1 mmol) all at once. The mixture warmed slightly to the touch and was stirred for 1 hour at ambient temperature. The reaction was filtered through celite and the pad was washed with ethyl acetate. The phases were separated from the filtrate and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to a yellow oil. The oil was flash chromatographed on silica gel (70 g) with elution proceeding as follows: 50% methylene chloride/hexane (500 mL), unweighed forerun; 50% ethyl acetate/hexane (1000 mL), 4.6 g (100%) of 3-(2-chloro-phenyl)-4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidine-2-carboxaldehyde as a foam which was a 2:1 mixture of free aldehyde and hydrate and had: 1H NMR δ 9.56 (s) [CHO], 7.94 and 7.87 (pair of d, J=5.2, 5.4 Hz, respectively, 1 H), 7.60-7.30 (m, 5 H), 5.30 (dd, J=7, 9.5 Hz) [hydrate methine CH), 4.76 (d, J=9.5 Hz) [hydrate OH], 3.79 (d, J=7 Hz) [hydrate OH]. Note that the doublets at 4.76 and 3.79 ppm are washed out and the dd at 5.30 ppm is converted to a singlet when deuterium oxide is added to the NMR sample.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4].[CH3:15][C:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([CH3:18])[CH3:17].CN1CCOCC1>C(#N)C>[CH3:18][C:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][CH2:14][CH:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:26])=[O:27])=[CH:21][CH:20]=1)([CH3:15])[CH3:17]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1CCc2ccccc2N1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)C1CCc2ccccc2N1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 18 h

Procedure:
A solution is prepared of 300 mg (1.32 mmol) of 1,2,3,4-tetrahydro-2-quinolinylcarboxylic acid methyl ester in 20 ml of acetonitrile and, at ambient temperature, 309 mg (1.32 mmol) of 4-(1,1-dimethylethyl)-benzenesulfonyl chloride are added, then 0.29 ml (2.64 mmol) of N-methylmorpholine. The reaction mixture is agitated for 18 hours with solvent reflux and then concentrated under reduced pressure. The evaporation residue is collected in 50 ml of ethyl acetate and washed with a solution of hydrochloric acid 1 N then by a solution of saturated sodium bicarbonate. The organic phase is dried on magnesium sulfate and concentrated under reduced pressure. The raw product is purified by silica gel chromatography eluting with the help of a methylcyclohexane/ethyl acetate mixture (99/1 then 95/5; v/v). In this way the expected product is obtained in the form of a white solid (yield=22%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:17][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COC(c1cccc(N)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(3-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g), (S)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g), PPh3 (2.64 g) and molecular sieves 4 Å in THF (100 mL) was added DEAD (1.55 mL) slowly. The reaction was stirred at RT for 4 h and at reflux for overnight. After filtration to remove solids, the filtrate was concentrated and the residue was taken into Et2O. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a crude compound as very viscous brown oil, which was purified by chromatography through silica gel (500 g, 30% to 50% EtOAc in hexanes) to afford (S)-2-[1-(3-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown oil.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[C:4]([C:13]([OH:15])=O)[CH:3]=1.S(Cl)(Cl)=O.[NH2:20][CH2:21][C@@H:22]([OH:39])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[CH2:26][CH2:25]1>C(N(CC)CC)C>[Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([F:10])([F:11])[F:12])=[C:4]([C:13]([NH:20][CH2:21][C@@H:22]([OH:39])[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=3)[CH2:26][CH2:25]2)=[O:15])[CH:3]=1
Reactant: O=C(O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Yield: 46.8 %

Procedure:
Made by the method of Example 1 using 5-bromo-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid (0.10 g), thionyl chloride (2 mL), (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.112 g) and triethylamine (0.244 mL) to yield the title compound as a colourless solid (0.096 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([NH:17][CH3:18])=[O:16].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O.[I-].[K+]>[CH3:18][NH:17][C:15]([CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:16]
Reactant: CNC(=O)Cc1ccccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccccc1CC(=O)NC
Reaction time: 16 h
Yield: 103 %

Procedure:
Potassium carbonate (2.81 g, 20.34 mmol) was given to a solution of 2-(2-hydroxyphenyl)-N-methylacetamide (3.36 g, 20.34 mmol) in acetone (150 ml). Ethyl bromoacetate (2.13 ml, 19.32 mmol) and potassium iodide (166 mg, 1.02 mmol) were added successively. The reaction mixture was heated to reflux for 6 h. It was left at room temperature for 16 h. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/dichloromethane (1:1) as eluent, to give 5.00 g of ethyl 2-(2-((N-methylcarbamoyl)methyl)phenoxy)acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22]Br)=[CH:16][CH:15]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCCOc1ccc(Br)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCOc2ccc(Br)cc2)cc1

Procedure:
A mixture of 26.4 g of ethyl p-aminobenzoate, 22.4 g of 2-bromoethyl p-bromophenyl ether and 80 ml of hexamethylphosphoramide is heated at 100°-110° C. for 20 hours. The mixture is chilled, diluted with 25 ml of water, chilled and filtered. The solid is washed with 100 ml of ethanol-water (1:1), with 25 ml of ethanol and with water to give tan crystals, mp 128°-133° C. Recrystallization from ethanol gives yellow crystals, mp 135.5°-137° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[C:18]4[CH:39]=[CH:38][C:37]([CH2:40][NH2:41])=[CH:36][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:24][CH:23]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].CC[O:50]CC>C(OCC)(=O)C>[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[C:18]4[CH:39]=[CH:38][C:37]([C:40](=[O:50])[NH2:41])=[CH:36][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:24][CH:23]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reactant: CCOCC
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 99 %

Procedure:
3-[[4-[2-(1-Piperidinyl)ethoxy]phenyl]methyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene-6-methanamine (Part C) was dissolved in 50 mL of ethyl acetate and added to a solution of 100 mg of oxalic acid in 30 mL of ethyl acetate. After adding 10 mL of ether to the solution, the precipitate was filtered to give 1.05 g (99%) of a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15](/[CH:19]=[CH:20]/[CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([C@@H:19]2[O:9][C@H:20]2[CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=1
Reactant: OC/C=C/c1cccc(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: OC[C@@H]1O[C@H]1c1cccc(Br)c1
Reaction time: 16 h
Yield: 71.1 %

Procedure:
A magnetically stirred solution of m-chloroperbenzoic acid (3.57 g, 10.33 mmol) in dichloromethane (60.0 ml) at 25° C. was treated dropwise with a solution of trans-3-(3-bromophenyl)-2-propenol (2.0 g, 9.39 mmol) in dichloromethane (20.0 ml). After stirring for 16 h the mixture was diluted with dichloromethane (200 ml), washed with aqueous 1M NaOH (2×200 ml), brine (2×200 ml) and dried (Na2SO4). Evaporation of the solvent in vacuo returned the crude epoxide as a pale yellow oil (2.06 g). Column chromatography (ethyl acetate--light petroleum (b.p. 40°-60° C.), 3:7) provided the title compound (1.53 g, 71%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
Methyl 3-chloro-4-hydroxybenzoate (5 g, 26.8 mmol) in DMF (45 ml) was treated with potassium carbonate (7.41 g, 53.6 mmol), 2-iodopropane (3.85 ml, 40.2 mmol) and then stirred at 25° C. for 18 h. Work-up with ethyl acetate gave the title compound (6.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[CH:6]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=3)[C:14]=2[CH3:24])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Reactant: CCCn1cc(Br)cn1
Product: CCCn1cc(-n2c(C)c(Sc3cc(F)cc(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-5-fluoro-benzoic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[CH:22]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:30][C:20]2[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NC1CCCCCCC1
Product: O=[N+]([O-])c1ccc2c(c1)COC(NC1CCCCCCC1)=N2
Yield: 87.9 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (4.0 g, 12 mmol) and cyclooctylamine (1.6 g, 12 mmol) according to the procedure described for Example 1. Obtained the title compound as a yellow viscous oil (3.2 g, 83%), MS (ISP) m/e=304.1 [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]([C:15]1[O:19][C:18]([C:20]2[C:25]([NH:26]C(=O)OC(C)(C)C)=[CH:24][C:23]([C:34]([F:37])([F:36])[F:35])=[C:22]([O:38][CH3:39])[N:21]=2)=[N:17][N:16]=1)([CH3:14])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[CH2:1]([O:8][C:9]([C:15]1[O:19][C:18]([C:20]2[C:25]([NH2:26])=[CH:24][C:23]([C:34]([F:37])([F:36])[F:35])=[C:22]([O:38][CH3:39])[N:21]=2)=[N:17][N:16]=1)([CH3:14])[C:10]([F:11])([F:12])[F:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: COc1nc(-c2nnc(C(C)(OCc3ccccc3)C(F)(F)F)o2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(-c2nnc(C(C)(OCc3ccccc3)C(F)(F)F)o2)c(N)cc1C(F)(F)F
Reaction time: 0.75 h

Procedure:
To a stirring solution of the tert-butyl 2-(5-(2-(benzyloxy)-1,1,1-trifluoropropan-2-yl)-1,3,4-oxadiazol-2-yl)-6-methoxy-5-(trifluoromethyl)pyridin-3-ylcarbamate (707 mg, 1.257 mmol) in DCM (10 ml) was added TFA (3 ml) and stirring continued for 45 min. The resulting mixture was washed with 2M NaOH and the organic phase separated using a phase separator. The solvent was removed in vacuo to afford the title product as a TFA salt; LC-MS Rt=1.42 min [M+H]+ 463.2 Method High pH_v003.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:17]([N:19]([CH2:20][CH3:21])[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
To a stirred solution of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (5 g, 22.0 mmol) in DMF (100 mL) was added diethyl amine (4.6 mL, 44 mmol), triethylamine (9.1 mL, 66.0 mmol), HOAt (22.0 mL, 0.5 M in DMF, 22.0 mmol) and finally EDCI (8.4 g, 44 mmol). This was allowed to stir for 14 hours at room temperature. The solvent was then removed under reduced pressure. The mixture was taken up in DCM (100 mL). The organic layer was then washed with water (100 mL), 1N HCl (100 mL), NaCl (sat.) (100 mL), dried over MgSO4 and then filtered. To the organic layer was added TFA (33 mL). The reaction was allowed to stir at room temperature for 2 hours. The solvent was then removed under reduced pressure. The mixture was taken up in DCM (100 mL). The organic layer was then washed with 1N NaOH (100 mL), water (100 mL), NaCl (sat.) (100 mL), dried over MgSO4 and then filtered. The solvent was removed under reduced pressure. The crude material was sufficiently pure to use without further purification. The title compound was obtained in 86% yield (3.5 g, 19.0 mmol).