Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:41])[N:15]([C:17]1[N:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:26][C:25]=2[NH:36][C:37](=[O:40])[CH:38]=[CH2:39])[CH:18]=1)[CH3:16].CCN(C(C)C)C(C)C.[C:51](Cl)(=[O:53])[CH3:52]>C(Cl)Cl>[C:51]([N:33]1[CH2:32][CH2:31][N:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:19]3[CH:18]=[C:17]([N:15]([CH3:16])[C:14]([NH:13][C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])=[O:41])[N:22]=[CH:21][N:20]=3)=[C:25]([NH:36][C:37](=[O:40])[CH:38]=[CH2:39])[CH:26]=2)[CH2:35][CH2:34]1)(=[O:53])[CH3:52]
Reactant: C=CC(=O)Nc1cc(N2CCNCC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(piperazin-1-yl)phenyl)acrylamide (Procedure 2L, Example 157) (8.6 g, 0.014 mmol) and DIEA (7.5 μl, 0.043 mmol) were stirred in DCM (1.0 ml) at room temperature under nitrogen atmosphere. A solution of acetyl chloride (1.0 μl, 0.016 mmol) in DCM (11 ul) was added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the resulting material was dissolved in 400 ul of DMSO. The DMSO solution was diluted with 1.0 ml of MeOH and purified by prep-HPLC (water/ACN in formic acid condition) to afford the title compound (1.4 mg, yield: 15%). 1H-NMR (400 MHz, MeOH-d4) δ 2.16 (s, 3H) 3.65-3.80 (m, 4H) 3.94 (s, 6H) 5.76 (dd, 1H) 6.15 (s, 1H) 6.28-6.49 (m, 2H) 6.78-6.82 (m, 1H) 6.95 (dd, 2.89 Hz, 1H) 7.28-7.38 (m, 2H) 8.31 (d, 1H) 8.58 (br. s., 1H); ESI-MS: 643 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=2)[CH:3]=1.[F:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[C:2]1[C:10]([CH3:11])=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=2)[CH:3]=1
Reactant: COc1ccc(B(O)O)c(F)c1
Reactant: Cc1cc2nn(COCC[Si](C)(C)C)cc2cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3cn(COCC[Si](C)(C)C)nc3cc2C)c(F)c1
Yield: 97.1 %

Procedure:
A mixture of 5-bromo-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (600 mg, 1.75 mmol), 2-fluoro-4-methoxyphenylboronic acid (320 mg, 1.88 mmol) and 2 N aqueous potassium carbonate solution (1.8 mL, 3.6 mmol) in 1,4-dioxane (7.2 mL) was purged with N2 three times, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (66.0 mg, 0.090 mmol) and subjected to microwave irradiation at 90° C. for 40 minutes. The reaction mixture was filtered through Celite, rinsed with EtOAc and concentrated in vacuo. The residue was purified by flash chromatography (0-33% EtOAc/heptane) to provide the title compound (657 mg, 92% yield) as a yellow solid. MS (ES+) 387.3 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 8.09 (s, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 7.19 (t, J=8.54 Hz, 1H), 6.78 (dd, J=8.42, 2.56 Hz, 1H), 6.73 (dd, J=11.47, 2.44 Hz, 1H), 5.75 (s, 2H), 3.87 (s, 3H), 3.64-3.70 (m, 2H), 2.28 (s, 3H), 0.93-1.00 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:28])[CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:21]([N:18]1[CH2:19][CH2:20][NH:15][CH2:16][C:17]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CNCCN1Cc1ccccc1
Yield: 92.4 %

Procedure:
To a solution of 35 mL of TFA in dichloromethane was added 4-benzyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (10.39 g, 35.8 mmol) in portions. After 18 hours the solution was concentrated via rotary evaporator and H20 was added. The pH was adjusted to 12 with 4M NaOH. The mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-benzyl-piperazin-2-one (6.29 g, 92%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:15][CH2:16][CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)=O)=[CH:4][CH:3]=1.[O-][Si]([O-])=O.[Mg+2]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]2[N:15]([CH2:16][CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[OH:24])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccnc1NCC(O)c1ccccc1)c1ccc(Cl)cc1
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: OC(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)c1ccccc1
Yield: 6.4 %

Procedure:
4-Chloro-N-[2-[(2-hydroxy-2-phenylethyl)amino]-3-pyridinyl]benzamide (13.2 g, 0.036 mole) was heated at 180°-190° C. in a glass flask on a Wood's metal bath for 12 minutes. The residue was dissolved in ethyl acetate, treated with Florisil®, and filtered. The filtrate was diluted with hexanes to initiate crystallization. The solid was collected by filtration, washed with ethyl acetate/hexanes mixture and then hexane. The solid still contained 10-15% uncyclized material, and therefore a portion of the solid (1.25 g) was heated at 180°-190° C. for an additional 17 minutes. The solid residue was recrystallized from methylene chloride/hexane and dried under high vacuum at 70° C. overnight to give 0.8 g of solid, mp. 166°-168° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](O)=[O:12])=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O>>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([Cl:18])=[O:12])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Product: O=C(Cl)CCc1ccc(C(F)(F)F)cc1

Procedure:
A stirred solution of 3-(4-(trifluoromethyl)phenyl)propanoic acid (500 mg, 2.292 mmol) in thionyl chloride was allowed to reflux for 2 hours and concentrated under reduced pressure to afford the crude title product.
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@H:9]([OH:8])[CH2:10][CH:11]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1cccc(CCc2ccccc2OCC2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(CCc2ccccc2OCC2C[C@@H](O)CN2C(=O)OC(C)(C)C)c1
Yield: 82 %

Procedure:
Following a procedure similar to that described in Example 65(b), 550 mg of (4R)-4-benzyloxy-1-t-butoxycarbonyl-2-{2-[2-(3-methylphenyl)ethyl]phenoxymethyl}pyrrolidine [prepared as described in step (a) above] were dissolved in 20 ml of ethanol and hydrogenated in an atmosphere of hydrogen at atmospheric pressure and in the presence of 120 mg of 5% w/w palladium-on-charcoal as a catalyst. The mixture was then worked up as described in Example 65(b), and the crude product thus obtained was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 370 mg (yield 82%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(COC)OC>[C:18]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccc(N2CCOCC2)c(N)c1
Solvent: COCCOC
Product: CC(=O)Nc1cc(C(C)(C)C)ccc1N1CCOCC1
Temperature: 0 °C
Yield: 85 %

Procedure:
A mixture of 12.5 g. (53 mmoles) of 4-(2-amino-4-tert-butylphenyl)morpholine and 8.7 g. (85 mmoles) of acetic anhydride in 40 ml. of dimethoxyethane was heated at 70° C. for 15 hours. The cooled reaction mixture was then poured into an excess of ice-water and the water mixture extracted twice with 70 ml. of methylene chloride. The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized from a 10:1 mixture of n-hexane and chloroform to give 12.5 g. (85%) of the desired product, m.p. 112°-113° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].Cl[C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[C:20]([O:19][C:18]([NH:17][CH:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][NH:10][C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])([CH3:21])([CH3:23])[CH3:22]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCCC1CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)NCC1CCCC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
iPr2NEt (0.5 mL) was added into a solution of tert-butyl (2-(aminomethyl)cyclopentyl)carbamate (300 mg) and ethyl 2-chloro-2-oxoacetate (191 mg) in THF (10 mL). The reaction was stirred at room temperature for 16 hours before being quenched by water. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give the crude ethyl 2-(((2-((tert-butoxycarbonyl)amino)cyclopentyl)methyl)amino)-2-oxoacetate which was used as was.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([C:25](O)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:68][C:69]1[CH:81]=[CH:80][C:72]([CH2:73][C@@H:74]2[CH2:79][CH2:78][CH2:77][NH:76][CH2:75]2)=[CH:71][CH:70]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([C:25]([N:76]2[CH2:77][CH2:78][CH2:79][C@@H:74]([CH2:73][C:72]3[CH:71]=[CH:70][C:69]([F:68])=[CH:81][CH:80]=3)[CH2:75]2)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C[C@@H]2CCCNC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
In a flask (3R,4R)-4-benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (3.93 g, 10.4 mmol) was dissolved in dichloromethane (200 mL) and then benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (6.48 g, 12.5 mmol) and triethylamine (3.3 mL, 23.7 mmol) were added. After stirring for 5 minutes, (S)-3-(4-fluorobenzyl)-piperidine (2.21 g, 11.4 mmol) was added. The mixture was stirred for 16 hours. The reaction mixture was extracted with water (50 mL) and brine (50 mL). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude orange glass (10.49 g). Purification by flash column chromatography (50-70% ethyl acetate/hexanes) provided a colorless oil (4.79 g, 83%). 1H NMR (300 MHz, CDCl3), δ: 7.32 (m, 2H), 7.26 (m, 3H), 7.07 (m, 2H), 6.95 (m, 2H), 5.04 (m, 2H), 4.41 (d, 1H, J=13), 4.12 (bm, 2H), 3.83 (bm, 2H), 3.06 (bm, 1H), 2.76 (bs, 2H), 2.60 (dd, 2H, J=14, J′=6), 2.37 (m, 2H), 1.90 (bs, 1H), 1.63 (bm, 2H), 1.45 (m, 9H), 1.12 (m, 3H), 0.87 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:6][C:7]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=23)=[N:8][CH:9]=1)([O-])=O>[Pd].C(O)C>[N:12]1[N:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]2=[C:10]([C:7]2[N:6]=[C:5]([NH:19][CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:4]([NH2:1])=[CH:9][N:8]=2)[CH:11]=1
Reactant: O=[N+]([O-])c1cnc(-c2cnn3ccncc23)nc1NC1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnc(-c2cnn3ccncc23)nc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
10% Palladium on carbon (0.392 g, 0.37 mmol) was added to a suspension of 5-nitro-2-(pyrazolo[1,5-a]pyrazin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine (Preparation 25, 0.785 g, 2.31 mmol) in ethanol (50 mL) and the mixture was stirred under an hydrogen atmosphere at ambient temperature. After 4 hours, the mixture was filtered through Celite® and the filter cake was washed with ethanol. The combined filtrate and washings were evaporated to give the title compound (0.670 g, 94%) as a pale green solid.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH:10]([OH:12])[CH3:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.CC1(C)N([O])C(C)(C)CCC1.C1(N(Cl)C(=O)N(Cl)C(=O)N1Cl)=O>CC(C)=O>[O:1]1[C:5]2=[CH:6][N:7]=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CC(O)c1cc2ccoc2cn1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CC(C)=O
Product: CC(=O)c1cc2ccoc2cn1
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
1-(Furo[2,3-c]pyridin-5-yl)ethanol (356 mg, 2.19 mmol) was dissolved in acetone (11 mL), and added 2,2,6,6-tetramethylpiperidine 1-oxyl (34 mg, 220 μmol) at room temperature. Then, the reaction solution was added 1,3,5-trichloro-2,4,6-triazinetrione (560 mg, 2.41 mmol), and stirred at the same temperature for 30 minutes. The reaction solution was concentrated in vacuo, added water and a saturated aqueous solution of sodium hydrogen carbonate under ice-cold conditions, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (119 mg (yield 34%)) was obtained as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[CH:4]=1)#[N:2].N1(CC2C=CN=CC=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].OS(O)(=O)=O>O.CO>[OH:10][CH2:9][C:5]1[CH:4]=[C:3]([CH2:1][N:2]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: c1cc(CN2CCOCC2)ccn1
Reactant: N#Cc1ccnc(CO)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: OCc1cc(CN2CCOCC2)ccn1
Yield: 21 %

Procedure:
In a manner similar to the procedure described for the preparation of 4-cyano-2-hydroxymethylpyridine, 4-(4-morpholinyl)methylpyridine (9.15 g, 51.40 mmol), ammonium persulfate (23.44 g, 102.81 mmol, 2.0 equiv.), methanol (92 ml), water (46 ml) and concentrated H2SO4 (11.59 g, 118.2 mmol, 2.3 equiv.) provided 2.29 g (21%) of 2-hydroxymethyl-4-(4-morpholinyl)methylpyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[N+:21]([O-])=O)=[N:7]1)[CH3:2].[O:25]1[C:29]2([CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[NH:21][CH:32]2[CH2:33][CH2:34][C:29]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:30][CH2:31]2)=[N:7]1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CSC(c2cc3cc(C)cc([N+](=O)[O-])c3[nH]2)=N1
Reactant: O=C1CCC2(CC1)OCCO2
Product: CCOC(=O)C[C@@H]1CSC(c2cc3cc(C)cc(NC4CCC5(CC4)OCCO5)c3[nH]2)=N1

Procedure:
[(R)-2-(5-methyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid ethyl ester prepared in Preparation 54 and 1,4-dioxa-spiro[4,5]decan-8-one were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.N1C(C)=CC=CC=1C.[C:20]([O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])(=[O:22])[CH3:21]>O1CCCC1>[C:20]([O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)=[O:27])(=[O:22])[CH3:21]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Cc1nc2cc(N)ccc2o1
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc2oc(C)nc2c1
Temperature: 3 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
5-Amino-2-methylbenzoxazole (18.6 g, 0.126 mol) and 2,6-lutidine (14.8 g, 0.138 mol) were combined with 125 mL of tetrahydrofuran and the solution was cooled to 3° C. in an ice-bath under nitrogen. 2-Acetoxybenzoyl chloride (25.0 g, 0.126 mol) was added as a solid, portionwise, so as to keep the temperature below 10° C. An additional 150 mL of tetrahydrofuran was added. After addition of all the 2-acetoxybenzoyl chloride, the ice-bath was removed and after stirring for 2 hr the mixture was poured into 300 mL of water and then combined with an additional 300 mL of water. The solid was collected and washed with water and dried. This afforded 33.6 g (86% yield) of product; m.p. 169°-171° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br>C(O)C>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2([OH:12])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]3[CH2:21][CH2:22][CH2:23][CH2:24][N:2]=[C:3]23)[CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCCBr
Reactant: NC1=Nc2ccccc2C1(O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Product: OC1(c2cccc(Cl)c2)C2=NCCCCN2c2ccccc21

Procedure:
2-Amino-3-(m-chlorophenyl)-3H-indol-3-ol hydrochloride (8.66 g) was converted to its oily base then heated under reflux with 1,4-dibromobutane (6.35 g) in ethanol (20 ml) for 4 hours. On cooling the title compound was obtained as its hydrobromide salt (2.41 g) m.p. 270°-275° C (decomp.) after recrystallization from methanol/ethyl acetate.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O>[N:29]1([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:1])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@@H]6O[C@@H]6C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Reactant: C1CCNCC1
Solvent: O
Product: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](N6CCCCC6)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1

Procedure:
14.8 g (0.03 mole) of 2α,3α-epoxy-17β-hydroxy-16β-N-methyl-piperazino-5α-androstane (Example 10) are dissolved in 168 ml (1.65 moles) of piperidine and 24 ml of water, whereafter the reaction mixture is heated in a bomb tube of 72 hours at a temperature of 140° C. After the reaction is accomplished the reaction mixture is evaporated at reduced pressure. The residue is stirred in acetonitrile, filtered and the product above the filter is heated under reflux in acetonitrile. The crystallized product is filtered and dried. Yield: 12.4 g (69.0%) of 2β-piperidino-16β-N-methyl-piperazino-3α,17β-dihydroxy-5α-androstane; m.p. 154°-156° C; [α]D25 = +84.5° (c = 1 in chloroform).
Reaction SMILES: [CH3:1][N:2]([CH3:57])[CH2:3][CH2:4][N:5]([CH2:14][C@:15]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:16]1[C@@H:17]1[C@@:30]([CH3:33])([CH2:31][CH2:32]2)[C@@:29]2([CH3:34])[C@@H:20]([C@:21]3([CH3:50])[C@@H:26]([CH2:27][CH2:28]2)[C:25]([CH3:36])([CH3:35])[C:24]([C:37]2[CH:49]=[CH:48][C:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:39][CH:38]=2)=[CH:23][CH2:22]3)[CH2:19][CH2:18]1)[C:6](=[O:13])[CH2:7][CH2:8][C:9]([O:11]C)=[O:10].[OH-].[Na+]>O1CCOCC1>[C:44]([O:43][C:41]([C:40]1[CH:48]=[CH:49][C:37]([C:24]2[C:25]([CH3:36])([CH3:35])[C@H:26]3[C@:21]([CH3:50])([CH2:22][CH:23]=2)[C@@H:20]2[C@:29]([CH3:34])([C@@:30]4([CH3:33])[C@H:17]([CH2:18][CH2:19]2)[C@H:16]2[C@H:51]([C:54]([CH3:56])=[CH2:55])[CH2:52][CH2:53][C@:15]2([CH2:14][N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:57])[C:6](=[O:13])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:32][CH2:31]4)[CH2:28][CH2:27]3)=[CH:38][CH:39]=1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((N-(2-(dimethylamino)ethyl)-4-methoxy-4-oxobutanamido)methyl)-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]chrysen-9-yl)benzoate (53 mg, 0.068 mmol) in 1,4-dioxane (1 ml) was added NaOH (0.338 ml, 0.338 mmol). The mixture was heated to 75° C. for 3 h. The mixture was cooled to rt and was quenched with 1N HCl (3 ml) and extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4, were filtered, and concentrated under reduced pressure. The crude product was used in the next step with no additional purification. LCMS: m/e 771.6 (M+H)+, 2.70 min (method 6).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl[Sn]Cl>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[C:12]([F:15])([F:13])[F:14]
Reactant: Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(F)cc(C(F)(F)F)c1N
Temperature: 90 °C
Yield: 30.9 %

Procedure:
To a stirred mixture of 2-amino-5-fluoro-3-nitrobenzotrifluoride (554 mg, 2.47 mmol) in ethanol (10 mL) was added SnCl2 ·2 H2O (2.78 g, 12.36 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) for 1 h, cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 and extracted with ethyl acetate. The extract was dried over Mg2SO4 and evaporated to give 148 mg (30%) of 2,3-diamino-5-fluorobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ3.666 (s, 2H); 3.676 (s, 2H); 6.610 (dd, 1H, J1 =2.4 Hz, J2 =9.0 Hz), 6.703 (dd, 1H, J1 =2.4 Hz, J2 =9.0 Hz).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].Cl[C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([N+]([O-])=O)=[CH:29][N:28]=1>>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2cc(C)ccn2)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) and 2-chloro-4-methyl-5-nitropyridine as described in Example 113 Steps A-C to provide a white solid.