Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@@H:32]([C:39]([NH2:41])=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:25][C:26](=[O:28])[OH:27])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O1CCOCC1.Cl.SC(O)C>CCOCC>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@@H:32]([C:39]([NH2:41])=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:25][C:26](=[O:27])[OH:28])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Agent: CC(O)S
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CSCC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 7.7 %

Procedure:
6.0 g (88.8 mmoles) of BOC-Trp-Met-Asp-D-Phg-NH2, prepared as described in Example 1, Step 7, are treated with 60 ml of a dioxane solution of hydrochloric acid in the presence of 3.1 ml (44 mmoles) of mercaptoethanol. After 15 minutes the reaction mixture is diluted with dry ether, and the separated solids are filtered off. The resulting 6.23 g. of hydrochloride, containing a large excess of hydrochloric acid, is suspended in 150 ml of water, the suspension is neutralized (pH=7) with triethylamine, stirred, and the precipitate is filtered off and washed with water. 4.0 g (78%) of H-Trp-Met-Asp-D-Phg-NH2 are obtained; m.p.: 230°-232° C. (decomposition); Rf7 =0.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]3[C:22](=[O:25])[NH:23][N:24]=[C:14]3[C:13]3[CH:26]=[CH:27][CH:28]=[N:29][C:12]2=3)=[O:10])[CH2:4][CH2:3]1.[H-].[Na+].[N:32]1([CH2:37][CH2:38][CH2:39]Cl)[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O.C1(C)C(C)=CC=CC=1>[N:32]1([CH2:37][CH2:38][CH2:39][N:23]2[C:22](=[O:25])[N:15]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:11]([C:9](=[O:10])[CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[C:12]4[N:29]=[CH:28][CH:27]=[CH:26][C:13]=4[C:14]3=[N:24]2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: ClCCCN1CCCC1
Reactant: CN1CCN(CC(=O)N2c3ccccc3-n3c(n[nH]c3=O)-c3cccnc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)N2c3ccccc3-n3c(nn(CCCN4CCCC4)c3=O)-c3cccnc32)CC1
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 2,9-dihydro-9-[(4-methylpiperazino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling (3-pyrrolidinopropyl)chloride in xylene is added. The mixture is kept at 95°-100°C. for a period of 22 hours, evaporated and worked up as in example 25 to give 2,9-dihydro-2-(3-pyrrolidinopropyl)-9-[(4-methylpiperazino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].P([O-])(O)(O)=O.[K+].P([O-])([O-])(O)=O.[K+].[K+].P([O-])([O-])([O-])=O.C1C=[N+]([C@H]2O[C@@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)([O-])=O)[C@H](O)[C@@H]2O)C=C(C(N)=O)C=1.[Na][Na].[C:77]([O:81][C:82](=[O:90])[NH:83][C@H:84]([C:86](=[O:89])[CH2:87][Cl:88])[CH3:85])([CH3:80])([CH3:79])[CH3:78]>[Cl-].[Mg+2].[Cl-].O.CC(O)C.O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].C(OCC)(=O)C.COC(C)(C)C>[C:77]([O:81][C:82](=[O:90])[NH:83][C@H:84]([C@@H:86]([OH:89])[CH2:87][Cl:88])[CH3:85])([CH3:78])([CH3:79])[CH3:80]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)CCl
Agent: NC(=O)c1ccc[n+]([C@H]2O[C@@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@H](O)[C@@H]2O)c1
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: COC(C)(C)C
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CCl
Temperature: 22 °C
Reaction time: 0.75 h
Yield: 28 %

Procedure:
A 0.1 M potassium phosphate buffer, 2.0 mM in magnesium chloride, was prepared by combining potassium dihydrogenphosphate (9.86 g, 72.4 mmol), potassium hydrogenphosphate (22.2 g, 127 mmol) and magnesium chloride hexahydrate (0.812 g, 4.0 mmol) in water (2 L); the pH of the resulting solution was 7.05. To this phosphate buffer (1.8 L) was added nicotinamide adenine dinucleotide phosphate, disodium salt trihydrate (1.9 g, 2.4 mmol) and ketoreductase enzyme (Codexis, KRED-P1-E05) (8 g), and the mixture was stirred for 45 minutes at 22° C. to dissolve the ketoreductase. A solution of tert-butyl[(2S)-4-chloro-3-oxobutan-2-yl]carbamate (C43) (50.0 g, 226 mmol) in 2-propanol (200 mL) was added, and the resulting suspension was stirred for 46 hours at 30° C., under a nitrogen flow (10 mL/minute) from a sparge inlet containing 2-propanol and water (1:1, 300 mL). At this point, tert-butyl methyl ether (1 L) was added to the reaction mixture, which was swirled for 20 minutes. The resulting emulsion was filtered through diatomaceous earth (200 g), and the filter cake was broken and washed with tert-butyl methyl ether (3×400 mL). The combined organic layers from the filtrates were dried with sodium sulfate (625 g), filtered, and concentrated in vacuo to afford the crude product as a red oil (50 g). This material was mixed with ethyl acetate (80 mL) and treated with decolorizing carbon (5 g) over 10 minutes with gentle heating. After filtration through Celite, the solution was concentrated in vacuo and mixed with warm hexanes (40 mL) under stirring. After 18 hours, the resulting solid was collected via filtration and rinsed with pentane, providing the product as a white powder (14.14 g). The mother liquor was concentrated under reduced pressure to yield an oil (32 g), which was crystallized in the same way using warm hexanes (30 mL) to obtain additional product as a white powder (13.65 g). Total yield: 27.79 g, 124 mmol, 55%. 1H NMR (400 MHz, CDCl3) δ 4.77 (br s, 1H), 3.77-3.87 (m, 1H), 3.69-3.76 (m, 1H), 3.65 (dd, half of ABX pattern, J=11.1, 3.9 Hz, 1H), 3.53 (dd, half of ABX pattern, J=11.3, 8.0 Hz, 1H), 3.00 (br s, 1H), 1.45 (s, 9H), 1.26 (d, J=6.8 Hz, 3H).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:32]([C:29]1[CH:30]=[N:31][C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:34])=[O:5])[S:12][CH:13]=2)=[N:27][CH:28]=1)[CH3:33]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(CC)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (6.20 g) obtained in Example 265-2 was dissolved in dichloromethane (60 mL), trifluoroacetic acid (12 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (4.50 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][O:10][N:9]=2)=[CH:4][C:3]=1[F:18].S(=O)(=O)(O)O.[CH3:24]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:24])=[O:16])=[CH:11][O:10][N:9]=2)=[CH:4][C:3]=1[F:18]
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1conc1-c1ccc(Cl)c(F)c1
Yield: 96 %

Procedure:
A mixture of 3-[3-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionic acid (5.00 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[3-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionate (5.01 g, yield 96%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 57–58° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:17]3[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OCC1CCNCC1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=S(=O)(c1ccc(N2CCC(CO)CC2)cc1)N1CCCCC1

Procedure:
1-[(4-fluorophenyl)sulfonyl]piperidine (0.437 g, 1.8 mmol), 4-piperidinylmethanol (0.230 g, 2 mmol), and ;potassium carbonate (0.262 g, 2 mmol) were heated to 120° C. for 4 hours. The reaction was cooled, and partitioned between ethyl acetate and water. The organic layer was washed with aqueous HCl, and brine. It was dried with sodium sulfate, filtered, and removal of the solvent gave 0.040 g (0.12 mmol).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:7]([C:20]([OH:22])=O)=[CH:6]2.[OH:25][CH:26]1[CH2:29][N:28]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=2)[CH2:27]1>>[OH:25][CH:26]1[CH2:29][N:28]([C:30]2[N:31]=[CH:32][C:33]([NH:36][C:20]([C:7]3[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)[C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:11][CH:10]=4)=[O:22])=[CH:34][CH:35]=2)[CH2:27]1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(N2CC(O)C2)nc1
Product: O=C(Nc1ccc(N2CC(O)C2)nc1)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1

Procedure:
The process is carried out according to the method described in example 2, using 5-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO 2006/072736) and 2-(3-hydroxyazetidin-1-yl)-5-aminopyridine, prepared in step 10.2 of example 10 (Compound Ve).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Cl[CH2:14][C:15]1[S:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:30][C:16]1[N:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[S:19][C:15]=1[CH2:14][S:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(S)ccc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc2c(c1)CCCC2=O
Reaction time: 16 h

Procedure:
To a solution of 6-mercapto-3,4-dihydro-2H-naphthalen-1-one (3.5 g, 20 mmol) in acetonitrile (100 mL), under nitrogen atmosphere, was added %-chloromethyl-4-methyl-2-(4-trifluoromethylphenyl)thiazole (5.7 g, 20 mmol) followed by cesium carbonate (6.4 g, 20 mmol). The resulting mixture was stirred 16 h, diluted with water (100 mL). The precipitate was collected by filtration, dried, dissolved in EtOAc, and filtered through a plug of silica gel. The filtrate was concentrated under vacuum and the residue purified by recrystallization in iso-propanol to give 5.21 g (61%) of cream colored crystals. (mp 123–124° C.) Analyzed for C22H18F3NOS2: Calcd: C, 60.95%; H, 4.19%; N, 3.23%; Found: C, 60.79%; H, 4.09%; N, 3.09%.
Reaction SMILES: CO[C:3]([C:5]1[S:12][C:11]2[CH:10]=[N:9][N:8]([C:13](=[O:15])[CH3:14])[C:7]=2[CH:6]=1)=O.[CH3:16][C:17]1S[C:20](C(O)=O)=[CH:19][CH:18]=1>>[C:3]1([C:5]2[S:12][C:11]3[CH:10]=[N:9][N:8]([C:13](=[O:15])[CH3:14])[C:7]=3[CH:6]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: COC(=O)c1cc2c(cnn2C(C)=O)s1
Product: CC(=O)n1ncc2sc(-c3ccccc3)cc21

Procedure:
1-(5-phenyl-thieno[3,2-c]pyrazol-1-yl)-ethanone [Intermediate (44), LC/MS: 243.1 (M+H), RT=3.45 minutes; 1H NMR (300 Mhz, CDCl3): δ 7.84 (s, 1H), 7.78 (s, 1H), 7.64 (m, 2H), 7.43-7.31 (m, 3H), 2.75 (s, 3H)] is prepared using procedures similar to those described hereinabove for Intermediate (25) substituting 2-phenyl-5-methyl-thiophene for 5-methylthiophene-2-carboxylic acid in step 1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][N:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].[CH2:32]([CH:34]1[O:36][CH2:35]1)Br.O>CN(C)C=O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:32][CH:34]1[CH2:35][O:36]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][N:19]=[CH:18][CH:17]=2
Reactant: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (126 mg) was dissolved in N,N-dimethylformamide (8 ml) to prepare a solution. Potassium carbonate (156 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 3-(6-methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (48 mg, yield 33%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:56])([CH3:55])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:54])([C@@:17]4([CH3:53])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([NH:38][CH2:39][CH2:40][C:41]([N:43]2[CH2:48][CH2:47][CH:46]([C:49]([O:51]C)=[O:50])[CH2:45][CH2:44]2)=[O:42])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1.Cl>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:56])([CH3:55])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:54])([C@@:17]4([CH3:53])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([NH:38][CH2:39][CH2:40][C:41]([N:43]2[CH2:44][CH2:45][CH:46]([C:49]([OH:51])=[O:50])[CH2:47][CH2:48]2)=[O:42])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)N3CCC(C(=O)OC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)N3CCC(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 74.7 %

Procedure:
To a solution of methyl 1-(3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxamido)propanoyl)piperidine-4-carboxylate (0.058 g, 0.075 mmol) in 1,4-dioxane (2 mL) was added NaOH (1N) (0.377 mL, 0.377 mmol). The mixture was heated to 85° C. for 15 h then was cooled to rt. The mixture was diluted with 5 mL of 1N HCl and was extracted with dichloromethane (4×5 mL). The combined organic layers were dried with Na2SO4, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage flash chromatography using a 0-10% MeOH in dichloromethane gradient with 0.1% HOAc added to the mixture. The compound was further purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give the title compound (41.5 mg, 0.056 mmol, 74.3% yield) as a white solid. LCMS: m/e 739.4 (M−H)−, 2.37 min (method 4). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=6.10 Hz, 1H), 4.79 (s, 1H), 4.64 (s, 1H), 4.43-4.53 (m, 1H), 3.95-4.02 (m, 1H), 3.46-3.70 (m, 2H), 3.18-3.27 (m, 1H), 3.13 (qd, J=11.04, 4.12 Hz, 1H), 2.65-2.97 (m, 4H), 2.47-2.57 (m, 1H), 1.74 (s, 3H), 1.07 (s, 3H), 1.06 (s, 3H), 1.05 (s, 3H), 1.03-2.24 (m, 25H), 1.00 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2]1.C1C(=O)N(Br)C(=O)C1.[C:18]([O:26]OC(=O)C1C=CC=CC=1)(=[O:25])C1C=CC=CC=1.C1C2C(=CC=CC=2)C=CC=1>CN(C=O)C>[CH2:4]([CH:3]1[CH2:2][O:26][C:18](=[O:25])[O:1]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: CCCCCCC1CO1
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: c1ccc2ccccc2c1
Product: CCCCCCC1COC(=O)O1
Yield: 87 %

Procedure:
A 5 mL volumetric flask was charged with 1.5 mL of 1,2-epoxyoctane (1a, 10 mmol), 89 mg of NBS (0.5 mmol), 0.12 g of benzoyl peroxide (0.5 mmol), and 0.13 g of naphthalene (1.0 mmol). The volumetric flask was filled to the mark with anhydrous DMF (2 M). An 8 mL, stainless steel Harvard Apparatus syringe was filled with the solution and then attached to the flow apparatus (syringe pump). The flow apparatus itself was set up as described above. After approximately 4 tR's (˜2 h), a sample was taken using the 6-way valve. The sample was analyzed by GC and 1H NMR. GC analysis indicated 96% conversion whereas 1H NMR analysis indicated a yield of 87% of the title compound 2a. IR (neat): 2928, 2859, 1788, 1384, 1165, 1059, 774 cm−1. 1H NMR (400 MHz, CDCl3): δ 4.67 (qd, J=7.5, 5.5 Hz, 1H), 4.50 (t, J=8.1 Hz, 1H), 4.04 (dd, J=8.3, 7.3 Hz, 1H), 1.79-1.73 (m, 1H), 1.68-1.61 (m, 1H), 1.45-1.27 (m, 10H), 0.86 (t, J=6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 155.1, 77.1, 69.4, 33.9, 31.5, 28.8, 24.3, 22.5. HRMS (DART) m/z calcd for C9H20NO3 [M+NH4]+: 190.1438. Found: 190.1438.
Reaction SMILES: S1C2C=CC=CC=2C=C1.[CH3:10][O:11][C:12]1[C:13]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:14]=2[S:15][C:16]=1[C:17]([O:19]C)=[O:18]>>[CH3:10][O:11][C:12]1[C:13]2[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][C:14]=2[S:15][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: COC(=O)c1sc2ccc(C(F)(F)F)cc2c1OC
Agent: c1ccc2sccc2c1
Product: COc1c(C(=O)O)sc2ccc(C(F)(F)F)cc12

Procedure:
When the starting benzothiophene of the above example was replaced by methyl 3-methoxy-5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, there was obtained 3-methoxy-5-(trifluoromethyl)-benzo[b]thiophene-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:22]=[C:23]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=4)[C:24]4[S:29](=[O:30])[CH2:28][CH2:27][C:25]=4[N:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C:64]1[CH:72]=[CH:71][C:67]([C:68](O)=[O:69])=[CH:66][N:65]=1.FC(F)(F)C(O)=O>CS(C)=O.C(N(C(C)C)CC)(C)C.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:63][C:64]1[CH:72]=[CH:71][C:67]([C:68]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[N:22]=[C:23]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=5)[C:24]5[S:29](=[O:30])[CH2:28][CH2:27][C:25]=5[N:26]=4)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[O:69])=[CH:66][N:65]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: Nc1ccc(N2CCN(c3nc4c(c(Nc5cccc(Cl)c5)n3)S(=O)CC4)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(C(=O)Nc2ccc(N3CCN(c4nc5c(c(Nc6cccc(Cl)c6)n4)S(=O)CC5)CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
200 mg of {2-[4-(4-amino-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-(3-chloro-phenyl)-amine trifluoroacetate are placed in 2.50 ml dimethylsulphoxide and combined with 100 μl diisopropylethylamine and 150 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU). The mixture is stirred for 0.25 hours at ambient temperature, then 50 mg 6-aminonicotinic acid in 100 μl diisopropylethylamine are added. The reaction mixture is stirred for 16 hours at ambient temperature, then acidified with trifluoroacetic acid and 2 ml of water are added. The resulting salt is purified by preparative HPLC (method A). 140 mg of the product are obtained as the trifluoroacetate. Analytical HPLC (method B): RT=2.74 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH:10]1([CH:16]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH:5][CH2:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(N)cc1Cl
Reactant: O=CC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(NCC2CCCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 3-chloro-4-methylaniline (7.08 g) in methanol (35 ml) were added cyclohexanecarbaldehyde (5.33 g) and sodium cyanoborohydride (3.78 g) under ice-cooling and the mixture was stirred at room temperature. After one hour, the reaction mixture was concentrated and water and saturated brine were added. The mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=15/1) to give 3-chloro-N-cyclohexylmethyl-4-methylaniline as a pale-yellow oil (9.64 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14]2)([O-:3])=[O:2].OC1C=C2C(=CC=1)OC(C1C=CC=CC=1)CC2.[OH-].[K+].ClC1C=CC([C:53]([F:56])([F:55])[F:54])=CC=1[N+]([O-])=O>CS(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([C:53]([F:56])([F:55])[F:54])[CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2

Procedure:
2-Nitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene was prepared as described for 2-nitro-1-(2-phenylchroman-6-yloxy)-benzene in Example 29(a) except that 6-hydroxyflavane (0.339 g) was used in 7 ml of dry DMSO under nitrogen. Also KI (0.374 g) and KOH (0.168 g) and 4-chloro-3-nitro-1-trifluoromethylbenzene (0.24 ml) were added in similar manner. Product was purified by column chromatography (CH2Cl2:n-heptane/60:40). 1H-NMR (300 MHz; d6-DMSO): δ 8.44 (d, 1H, J=2.1 Hz), 7.99 (dd, 1H, J=9.0 Hz; J=2.2 Hz), 7.51-7.29 (m, 5H), 7.15 (d, 1H, J=8.7 Hz), 7.09-6.91 (m, 3H), 5.15 (dd, 1H, J=10.1 Hz; J=2.3 Hz), 3.08-2.90 (m, 1H), 2.83-2.68 (m, 1H), 2.25-2.11 (m, 1H), 2.09-1.91 (m, 1H).