Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH2:19]([O:26][C:27](=[O:31])[C@H:28](O)[CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:19]([O:26][C:27](=[O:31])[C@@H:28]([O:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][N:7]=2)=[CH:15][CH:14]=1)[CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: C[C@@H](O)C(=O)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol (2.90 g, 11.4 mmol) and (R)-2-hydroxypropionic acid benzyl ester (2.25 g, 12.5 mmol) in dry THF (100 mls) at 0° C. under nitrogen is added triphenylphosphine followed by dropwise addition of diisopropylazodicarboxylate (3.36 mls, 17 mmol). The resulting yellow mixture is stirred for 1 hr then left the stand for 16 hours. The reaction mixture is partitioned between water and ethyl acetate and the layers separated. The aqueous is further extracted with ethyl acetate and the combined organic layers dried over magnesium sulphate, filtered and the solvent removed under reduced pressure. Column chromatography on silica gel using 10% ethyl acetate/hexane as eluent yielded (S)-2-[4-(5-Trifluoromethyl-pyridin-2-yloxy)-phenoxy]-propionic acid benzyl ester as a colourless oil. In one example 3.25 g are made representing 69% yield and in >99% ee (as determined by nmr).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[F:13][C:14]([F:19])([F:18])C(O)=O>ClC1C=CC=CC=1Cl>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([C:14]([F:19])([F:18])[F:13])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc2sc(N)nc12
Solvent: Clc1ccccc1Cl
Product: COc1cccc2sc(C(F)(F)F)nc12

Procedure:
Starting from 2-amino-4-methoxybenzothiazole (1.5 g) and trifluoroacetic acid (5.5 ml), without 1,2 dichlorobenzene. Purification by flash chromatography (eluent 20% ethyl acetate/hexane) yielded the title compound as a light brown oil (0.74 g). TLC Rf 0.70 (50% ethyl acetate in hexane)
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:13]1([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)CCl>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:23]2[CH:24]=[CH:25][C:20]([O:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][CH:22]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
By following the manipulative procedure described above in Example 4(a), 32.0 g of 1-acetylisonipecotoyl chloride, [Example 1(b)] are added to a stirring solution of 30.6 g of diphenylether and 45.3 g of aluminum chloride in 100 ml of ethylene dichloride to produce a yellow oil of 1-acetyl-4-(4-phenoxybenzoyl)piperidine.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17](O)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.Cl.[C:56]([NH:60][CH2:61][CH2:62][NH2:63])([CH3:59])([CH3:58])[CH3:57]>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[C:56]([NH:60][CH2:61][CH2:62][NH:63][C:17]([C:13]1[N:8]2[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:2]=3[F:1])[C:7]2=[N:15][C:14]=1[CH3:16])=[O:18])([CH3:59])([CH3:58])[CH3:57]
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(C)(C)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCCNC(C)(C)C)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mg (0.21 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid Example 21A, 71 mg (0.22 mmol) of TBTU and 128 mg (1.26 mmol) of 4-methylmorpholine were initially charged in DMF (0.74 ml), 44 mg (0.23 mmol) of N-tert-butylethane-1,2-diamine dihydrochloride were added and the reaction mixture was stirred at RT overnight. Another 22 mg (0.12 mmol) of N-tert-butylethane-1,2-diamine dihydrochloride and 21 mg (0.21 mmol) of 4-methylmorpholine were added, and the mixture was stirred at RT for 1.5 h. The mixture was diluted with a few drops of water/TFA and purified by preparative RP-HPLC (acetonitrile/water with addition of 0.1% TFA), and the product fractions were concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off and concentrated. This gave 78 mg (86% of theory, purity 96%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 96 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 96%). 1H NMR (300 MHz, CDCl3): δ 3.18-3.26 (m, 4H), 3.76 (s, 3H), 4.11-4.14 (m, 4H), 6.84-6.87 (d, J=8.7 Hz, 2H), 7.22-7.34 (m, 3H), 7.41-7.53 (m, 1H), 7.65-7.66 (m, 1H), 7.79 (s, 1H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH:12]=[CH:11][C:10]=1[OH:30].C([O:34][CH:35]1[CH:40]([CH2:41][CH:42]([OH:44])[CH3:43])[C:39]2[CH:45]=[CH:46][C:47]([C:49]([CH3:57])([CH3:56])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:48][C:38]=2[O:37][C:36]1([CH3:59])[CH3:58])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH:12]=[CH:11][C:10]=1[OH:30].[OH:34][CH:35]1[CH:40]([CH2:41][C:42](=[O:44])[CH3:43])[C:39]2[CH:45]=[CH:46][C:47]([C:49]([CH3:57])([CH3:56])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:48][C:38]=2[O:37][C:36]1([CH3:58])[CH3:59]
Reactant: CCCCCCC(C)(C)c1ccc2c(c1)OC(C)(C)C(OC(C)=O)C2CC(C)O
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCC(C)(C)c1ccc2c(c1)OC(C)(C)C(O)C2CC(C)=O

Procedure:
A solution of 5.0 g (0.02 mole) chromic anhydride in 5.0 ml water is added with stirring and ice cooling to 50 ml pyridine. To this is added at 10° C. 4.04 g (0.01 mole) dl-5-acetoxy-4-(2-hydroxypropyl)-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran and the resulting mixture stirred at room temperature for three hours. The reaction mixture is poured into water, made alkaline (pH 8.5-9.0) with sodium carbonate, stirred for 20 minutes then acidified with dilute hydrochloric acid and extracted with methylene chloride. The organic layer is washed with sodium bicarbonate solution, water, brine, dried over magnesium sulfate and the solvent evaporated, the last of the solvent being removed in vacuo. The residue is purified by column chromatography on silica gel to obtain the desired ketone.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([O:22][CH3:23])[CH2:20][C@@:19]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:25])[CH2:16][C@@:15]2([CH3:26])[C@H:8]3[CH2:9][C:10]([CH3:27])=[C:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C@@H:2]1[C@@H:21]([O:22][CH3:23])[CH2:20][C@@:19]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:25])[CH2:16][C@@:15]2([CH3:26])[C@H:8]3[CH2:9][C@H:10]([CH3:27])[C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1
Reactant: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=C(C)C[C@@H]32)C[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4C[C@H](C)[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Yield: 36.2 %

Procedure:
3α-Hydroxy-2β-methoxy-16-methyl-5α-pregn-16-ene-11,20-dione (187 mg.) in ethyl acetate (50 ml.) was hydrogenated over 10% palladium-on-carbon catalyst (60 mg.) at atmospheric pressure for 20 minutes, during which time 11 ml. of hydrogen was taken up. The catalyst was filtered off and the filtrate evaporated to a white foam (190 mg.) which was purified by preparative T.L.C. in ethyl acetate/petrol 3/2, run 3 times, to give 88 mg. of impure product which was purified by preparative T.L.C. in ethyl acetate/benzene (1/1) and recrystallisation from ether/petrol to give title compound (68 mg.) as fine white crystals, m.p. 180°-182°, [α]D + 69.5° (c 0.2).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][NH:7]1)=[O:5].[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1(Cl)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[NH:24][C:23]1=[O:32].C1COCC1.CCN(C(C)C)C(C)C>ClCCl.O>[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:22]1([C:14]2[S:13][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[NH:24][C:23]1=[O:32])=[O:5]
Reactant: O=C1Nc2ccc(Cl)cc2C1(Cl)c1nc2ccccc2s1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C1(c2nc3ccccc3s2)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid dimethylamide hydrochloride (0.78 g, 4.0 mmol) was added to a solution of the intermediate from step B in a mixture of dichloromethane (9 ml), THF (2 ml) and DIPEA (2 ml). The reaction mixture was stirred at room temperature for 48 h. After addition of water, the mixture was extracted four times with ethyl acetate. The combined organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The less polar diastereomer, as judged by thin-layer-chromatography using 5% MeOH in dichloromethane, precipitated on concentration and was filtered off. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) resulted in 0.28 g of the less polar diastereomer. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) of the mother liquor resulted in 0.36 g of the more polar diastereomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](OC(F)(F)F)[CH:5]=[CH:4][C:3]=1[NH2:13].C[Al](C)C.C[O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][N:23]=1)=O.Cl>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:13][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][N:23]=1)=[O:19]
Reactant: COC(=O)c1ccc(OCC(F)(F)F)cn1
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1Cl)c1ccc(OCC(F)(F)F)cn1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-4-trifluoromethoxy-phenylamine (2.0 g, 9.29 mmol) in toluene (50 mL) was added to trimethylaluminum (2.0 M 4.65 mL) then 5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester 3 (1.1 g, 4.65 mol) was added and the mixture was heated to 80-90° C. for 2 h. The reaction was cooled down and 1N HCl solution (10 mL) was added to be acidic. Dichloromethane (100 mL) was then added and the organic phase was further washed with water (100 mL) and dried over sodium sulfate. The solvent was removed and the residue was mixed with ether (50 mL) and stirred for 0.5 h. The solid was filtered and dried to give 5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid (2-chloro-phenyl)-amide 4 as a solid. Yield: 1.0 g, 71%.
Reaction SMILES: [CH2:1]([N:5]([CH2:37][CH2:38][CH2:39][CH3:40])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[C:8]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CN(C)[CH:48]=[O:49].O>O1CCCC1.C(OCC)(=O)C>[CH2:37]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:15][C:16]([CH:48]=[O:49])=[CH:17][CH:18]=2)=[C:8]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CN(C)C=O
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: -71.5 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
In a stream of argon, in 25 ml of tetrahydrofuran was dissolved 2.32 g (4.09 mmol) of dibutyl[3-(tert-butyldiphenylsiloxy)-4-[2-(thiophene-2-yl)vinyl]phenyl]amine, and 3.8 ml of n-butyllithium (1.6 mol solution in hexane) (6.08 mmol) was added dropwise thereto under cooling at −70 to −73° C. After the mixture was stirred for 1 hour, 0.4 ml (5.77 mmol) of N,N-dimethylformamide was added dropwise. The reaction mixture was stirred for 1 hour and the temperature was allowed to rise. To this mixture, 10 ml of water was added dropwise. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was dissolved in 200 ml of ether and 100 mg of iodine pieces were added thereto. After stirred at room temperature, the mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution. Drying over anhydrous sodium sulfate and concentration were performed. The residue was purified by silica gel column chromatography to give 1.99 g of a dark red oily matter (yield: 81.9%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](C(F)(F)F)=[CH:18][C:17]([CH2:24][OH:25])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH3:26])=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:34]CCl>C1(C)C=CC=CC=1>[Cl:34][C:19]1[CH:18]=[C:17]([CH2:24][OH:25])[CH:16]=[N:15][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][C@H:9]([CH3:26])[CH2:10]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-(5-hydroxymethyl-3-trifluoromethyl-pyridin-2-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester from step (f) above (3.75 g, 10 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL, Aldrich) dropwise at 0° C. over a period of 10 min. The mixture was stirred at room temperature for 16 h and diluted with toluene (20 mL). The solvents were removed in vacuo and the residue was dissolved in EtOAc (100 mL), washed with saturated aqueous solution of NaHCO3 (2×30 mL) and brine (20 mL), dried over Na2SO4, and filtered. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 90:10:1 mixture of MeOH/CH2Cl2/ammonium hydroxide to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 276 (M+1).
Reaction SMILES: C([O:4][C@H:5]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@:7]([OH:33])([CH2:8][CH2:9][C@@H:10]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:23])[CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])[CH2:6]1)(=O)C.[OH-].[Na+].Cl>CO.O1CCOCC1>[OH:4][C@H:5]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@:7]([OH:33])([CH2:8][CH2:9][C@@H:10]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:23])[CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@H]4[C@@H]3CC[C@@]2(O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of 3β-acetoxy-5α,25-dihydroxy-cholestane (IV) in 40 cc of methanol and 10 cc of dioxane was treated with 6 cc of a 10% solution of sodium hydroxide and refluxed for 3 hours. The reaction mixture was neutralized with a solution of 5% aqueous hydrochloric acid, extracted with ether and washed with water. The ether solution was evaporated in vacuo and the residue was recrystallized from ether to give 850 mg of the 3β, 5α,25-tri-hydroxy-cholestane (VI) m.p. 202°-204° Nmr δ 0.67 (s, 3H), 0.9 (d, J=5 cps, 3H), 1.22 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][C:18]([C:23]([N:25]6[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]6)=[O:24])=[CH:19][CH:20]=5)[NH:15][C:14]=4[C:13]([C:32]([NH2:34])=[O:33])=[CH:12][CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([N:1]2[C:9]3[C:4](=[C:5]([C:10]4[C:22]5[C:21]6[C:16](=[CH:17][C:18]([C:23]([N:25]7[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]7)=[O:24])=[CH:19][CH:20]=6)[NH:15][C:14]=5[C:13]([C:32]([NH2:34])=[O:33])=[CH:12][CH:11]=4)[CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:41])=[CH:38][CH:37]=1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc5[nH]ccc45)c23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc5c4ccn5C(=O)c4ccc(F)cc4)c23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 34 %

Procedure:
A solution of 4-(1H-indol-4-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-47, 50 mg, 0.100 mmol) in DCM (1 mL) was treated sequentially with DMAP (3.7 mg, 0.030 mmol), TEA (0.028 mL, 0.199 mmol) and 4-fluorobenzoyl chloride (0.013 mL, 0.110 mmol). The mixture was stirred at rt for 17 h, then was treated with additional 4-fluorobenzoyl chloride (0.013 mL, 0.110 mmol) and TEA (0.028 mL, 0.199 mmol) and stirring was continued for 111 h. The mixture was concentrated and the residue was dissolved in methanol and purified by preparative HPLC. The appropriate effluent fractions were partitioned between NaHCO3 (aq) and EtOAc, and the aqueous phase was extracted twice more with EtOAc. The combined organic phases were dried and concentrated to provide 4-(1-(4-fluorobenzoyl)-1H-indol-4-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a yellow solid (19.5 mg, 31%). 1H NMR (400 MHz, methanol-d4) δ 8.51 (1H, d, J=8.3 Hz), 8.03 (1H, d, J=7.9 Hz), 7.84 (2H, dd, J=8.8, 5.3 Hz), 7.68 (1H, s), 7.57 (1H, t, J=7.7 Hz), 7.46 (1H, d, J=7.5 Hz), 7.26-7.36 (3H, m), 7.20 (1H, d, J=7.9 Hz), 6.96 (1H, d, J=7.9 Hz), 6.86 (1H, dd, J=8.3, 1.3 Hz), 6.19 (1H, d, J=4.0 Hz), 3.77 (2H, br. s.), 3.46 (2H, br. s.), 2.51 (2H, br. s.), 2.38 (2H, br. s.), 2.30 (3H, s). Mass spectrum m/z 574.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][C:19]([C:21]4[CH:35]=[CH:34][C:24]([CH2:25][N:26](C)[C:27](=O)C(F)(F)F)=[CH:23][CH:22]=4)=[O:20])[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CO.O1CCCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][C:19]([C:21]4[CH:22]=[CH:23][C:24]([CH2:25][NH:26][CH3:27])=[CH:34][CH:35]=4)=[O:20])[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(Cc1ccc(C(=O)Cn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CNCc1ccc(C(=O)Cn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 19.8 %

Procedure:
A mixture of the compound (0.49 g) obtained in Example 12, potassium carbonate (0.39 g), water (4 ml), methanol (8 ml) and tetrahydrofuran (8 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (79 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([N+:20]([O-:22])=[O:21])([CH3:19])[CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12](C=O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)(Cl)Cl>[CH3:1][C:2]([N+:20]([O-:22])=[O:21])([CH3:19])[CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([OH:28])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(Cc1ccc(Oc2ccc(C=O)cc2)cc1)[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: CC(C)(Cc1ccc(Oc2ccc(O)cc2)cc1)[N+](=O)[O-]
Reaction time: 1 h

Procedure:
4-(4-(2-Methyl-2-nitropropyl)phenoxy)benzaldehyde (6.00 g, 20 mmol) was dissolved in chloroform (500 mL). m-Chloroperoxy-benzoic acid (10.0 g, 58 mmol) was added in small portions at RT. After stirring for 1 hour, the mixture was concentrated in vacuo and MeOH (300 mL) added followed by the dropwise addition of conc. HCl (5 mL). This mixture was stirred for 3 hours at RT and then concentrated in vacuo. Chromatography over silica gel (MeOH/CHCl3) allowed for the isolation of 3.20 g (55%) of the desired product. MS(FD+): 287.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7](=[O:23])[C:8]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[CH3:24]I.[H-].[Na+]>CN(C)C(=O)C.O.C(OCC)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:24])[C:7](=[O:23])[C:8]3([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:9][N:10]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:11]=2[N:12]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC12CCCCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOCC
Product: CN1C(=O)C2(CCCCC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
2′-chloro-9′-cyclopentyl-8′,9′-dihydrospiro[cyclohexane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 256; 300 mg, 0.94 mmol) was dissolved in N,N-dimethylacetamide (10 mL) and methyl iodide (65 mL, 1.03 mmol) added followed by sodium hydride (41 mg of a 60% dispersion in mineral oil, 1.00 mmol). The reaction mixture was stirred for 30 minutes. A drop of water added was added and then the reaction mixture was diluted with water and extracted with ethyl acetate (×2). The combined organic extracts were dried (MgSO4) and concentrated and the residue purified by column chromatography (1% MeOH/DCM) to give a sticky white solid (Note 4) that was suspended in diethyl ether and filtered off to yield the title compound as a white crystalline solid (242 mg, 77%).