Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[N:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:12](O)=[O:13].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.[Cl-].[Na+].O>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:12]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][N:6]=1)=[O:13]
Reactant: O=C(O)c1cnccn1
Reactant: NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(NCCCO)c1cnccn1
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 68.2 %

Procedure:
To a solution of 3-amino-1-propanol (1.20 mL, 15.7 mmol) in CH2Cl2 (80 mL) was added 2-pyrazinecarboxylic acid (1.99 g, 16.0 mmol), DIPEA (5.6 mL, 32.1 mmol), HOBT (2.61 g, 19.3 mmol) and EDC.HCl (3.70 g, 19.3 mmol). The solution was stirred at room temperature under nitrogen for 14.5 hours, then was diluted with brine (25 mL). The layers were separated and the aqueous solution was extracted with EtOAc (50 mL×3) and CHCl3 (50 mL×3). The combined organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH2Cl2/MeOH/NH4OH, 19:1:0.1) gave the amide as a white solid (1.94 g, 10.7 mmol, 68%). 1H NMR (CDCl3) δ 1.83 (quint, 2H, J=5.9 Hz), 3.03 (br. s, 1H), 3.61-3.74 (m, 4H), 8.12 (br. s, 1H), 8.53 (dd, 1H, J=2.4, 1.5 Hz), 8.75 (d, 1H, J=2.4 Hz), 9.40 (d, 1H, J=1.5 Hz).
Reaction SMILES: COC1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2SC=C(C(OC)=O)N=2)CC1)=O.[Br:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][N:37]=[C:36]2[C:42]([OH:44])=O.[NH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1>>[Br:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][N:37]=[C:36]2[C:42]([NH:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1)=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)c1n[nH]c2ccc(Br)cc12
Agent: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2n[nH]c3ccc(Br)cc23)CC1

Procedure:
Tert-butyl 4-({[(5-bromo-1H-indazol-3-yl)carbonyl]amino}methyl)piperidine-1-carboxylate 11a was prepared, according to the procedure described for compound 7, from 5-bromo-1H-indazole-3-carboxylic acid and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate. Yield: 40.6 g, 87%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[BH4-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[C:5]=1[N:12]([S:21]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCN(c1c(C=O)cccc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCN(c1c(CO)cccc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 2 h

Procedure:
To a solution of 0.547 g (1.187 mmol) of the product of Example 322 in 10 mL of methanol and 3 mL of THF was added 0.045 g (1.187 mmol) of sodium borohydride. The reaction was stired for 2 h at room temperature and then concentrated in vacuo. The residue was diluted with ether and washed with 5% HCl and water, dried over MgSO4, filtered and concentrated in vacuo to provide 0.549 g (100%) as a colorless oil. Electrospray Mass Spec: 464.2 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][CH2:11]I)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1C=CC=CC=1.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:5]([O:8][CH2:9][CH2:10][CH2:11][C:20]([C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1)=[O:21])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
A mixture of Zn—Cu couple (2.68 g, 41.3 mmol) and tert-butyl(3-iodopropoxy)dimethylsilane (8.26 g, 27.5 mmol) in benzene (55 mL) and DMF (3.6 mL) was stirred vigorously at room temperature for 1 hour, heated to 60° C. for 4 hours, cooled to room temperature, and treated with a solution of 4-nitrobenzoyl chloride (3.4 g, 18.3 mmol) and (Ph3P)4Pd (0.847 g, 0.73 mmol) in benzene (36 mL) by cannula. The mixture was stirred for 1 hour, filtered through diatomaceous earth (Celite™), and partitioned between saturated NH4Cl and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% ethyl acetate/hexanes to provide 2.81 g of the desired product. MS(ESI(−)) m/e 322 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:22][C:23]1[C:27](B(O)O)=[C:26]([CH3:31])[O:25][N:24]=1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:27]3[C:23]([CH3:22])=[N:24][O:25][C:26]=3[CH3:31])=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Reactant: Cc1noc(C)c1B(O)O
Product: Cc1noc(C)c1-c1cnc2c(c1)N(Cc1c(F)ccc(F)c1Cl)CCN2
Yield: 45 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (75 mg) was reacted with 3,5-dimethylisoxazole-4 boronic acid as in General Procedure 4A to give the title compound as a pale yellow solid (45% yield). M.p. 215-216° C., LCMS: m/z=393.42 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.22 (s, 3H), 2.36 (s, 3H), 3.31 (t, J=5.0 Hz, 2H), 3.52-3.58 (m, 2H), 4.47 (s, 2H), 4.98 (bs, 1H), 6.71 (s, 1H), 6.98-7.05 (m, 1H), 7.09-7.17 (m, 1H), 7.36 (d, J=1.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[C:10]([I:11])[C:5]2=[C:4]([Cl:12])[N:3]=1.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(I)cnc-2[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
2,4-dichloro-5-iodo-1H-pyrrolo[2,3-d]pyrimidine (660 mg, 2.103 mmol) and tosyl-chloride (441 mg, 2.31 mmol) were combined in dry dichloromethane (20 ml). Diisopropylethylamine (0.734 mL, 4.21 mmol) was added and the reaction mixture was let stir at rt for 18 h. The reaction was then diluted with dichloromethane and the organic layer was washed with a saturated solution of sodium bicarbonate, water and a saturated solution of brine, then dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2,4-dichloro-5-iodo-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (901 mg, 1.94 mmol) as a yellow solid. ESIMS (M+H)+=469.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[C:6]1([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)C>[CH2:2]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13][CH2:14]1)[CH2:3][CH:4]=[CH2:5]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C=CCCBr
Solvent: CCOCC
Product: C=CCCN1CCN(c2ccccc2)CC1
Yield: 74.8 %

Procedure:
A mixture of 4-bromobut-1-ene (8.68 g) and 1-phenylpiperazine (35.7 g) is heated to reflux in diethyl ether (100 mL) for 2 hours. The mixture is filtered and the filtrate is extracted with 2N hydrochloric acid (150 mL). The extracts are washed with diethyl ether (150 mL) and basified with 25% sodium hydroxide. The aqueous layer is extracted with diethyl ether (3×100 mL), the extracts dried over MgSO4, filtered and evaporated to leave a brown oil. This oil is purified by MPLC on silica gel eluting with 5% methanol in dichloromethane to give 10.4 g of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([N:3](C(OC(C)(C)C)=O)[NH2:4])[CH3:2].O[CH:13]=[C:14]1[C:23]2([CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:25][CH2:24]2)[O:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=O.C(O)(C(F)(F)F)=O.NN>ClC(Cl)C.ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([N:3]1[C:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3([CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH2:25][CH2:24]3)[C:14]=2[CH:13]=[N:4]1)[CH3:2]
Reactant: CCN(N)C(=O)OC(C)(C)C
Reactant: O=C1C(=CO)C2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1ncc2c1-c1ccccc1OC21CCN(C(=O)OCc2ccccc2)CC1
Yield: 65.7 %

Procedure:
A mixture of tert-butyl 1-ethylhydrazinecarboxylate (320 mg, 2.0 mmol) and benzyl 3-(hydroxymethylene)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (770 mg, 2.0 mmol) in dichloroethane (5 mL) was allowed to stir at 25° C. with TFA (78 μL, 1.0 mmol) for 2 h. Once LC/MS analysis showed complete imine formation, more TFA was added to deprotect the hydrazine and cyclize the product. The reaction was diluted with dichloromethane, and aqueous sodium bicarbonate was added with stirring. The layers were separated and the organics were further washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over sodium sulfate and evaporated to dryness. The crude material was purified by column chromatography (0-100% ethyl acetate in hexanes) to afford benzyl 1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (530 mg, 65%). ESI-MS m/z calc. 403.2. found 404.7 (M+1)+; Retention time: 1.94 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=7.6 Hz, 1H), 7.40-7.29 (m, 4H), 7.29-7.19 (m, 2H), 7.10-6.99 (m, 2H), 5.16 (s, 2H), 4.47 (q, J=7.3 Hz, 2H), 4.15-3.95 (m, 2H), 3.45-3.26 (m, 2H), 2.15-2.03 (m, 2H), 1.88-1.78 (m 2H), 1.54 (t, J=7.3 Hz, 4H).
Reaction SMILES: O.[O:2]=[C:3]1[CH2:8][CH2:7][CH2:6][C:5](=O)[CH:4]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].S(Cl)([Cl:18])=O>C(Cl)Cl>[Cl:18][C:5]1[CH2:6][CH2:7][CH2:8][C:3](=[O:2])[C:4]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)CC1C(=O)CCCC1=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC1=C(Cl)CCCC1=O

Procedure:
A slurry of ethyl α-(2,6-dioxocyclohexyl)acetate hydrate (1.53 kg) in methylene chloride (7.7L) is brought to reflux and then thionyl chloride (1.80 kg) is added dropwise over a period of 1.75 hours. The solution is refluxed for 3 hours and then evaporated in vacuo to yield an oil which is distilled to give ethyl α-(2-chloro-6-oxocyclohex-1-enyl)acetate as a yellow oil, bp 115°-125°/0.2 mm.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([NH:13][CH:14]([B:27]3[O:35][CH:34]4[C:29]([CH3:39])([CH:30]5[CH2:36][CH:32]([CH2:33]4)[C:31]5([CH3:38])[CH3:37])[O:28]3)[CH2:15][C:16]3[C:17]([O:25][CH3:26])=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])=[O:12])=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[C:40]([NH:47][CH2:48][CH:49]=O)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CO>[C:43]([O:42][C:40]([NH:47][CH2:48][CH2:49][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:13][CH:14]([B:27]3[O:35][CH:34]4[C:29]([CH3:39])([CH:30]5[CH2:36][CH:32]([CH2:33]4)[C:31]5([CH3:38])[CH3:37])[O:28]3)[CH2:15][C:16]3[C:17]([O:25][CH3:26])=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])=[O:12])[CH:5]=2)[CH2:1]1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: COc1c(CC(NC(=O)Cc2ccc3c(c2)CNC3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Solvent: CO
Product: COc1c(CC(NC(=O)Cc2ccc3c(c2)CN(CCNC(=O)OC(C)(C)C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Reaction time: 91 h

Procedure:
A solution of 3-[2-(2-2,3-Dihydro-1H-isoindol-5-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid (0.110 g, 0.207 mmol) (prepared following the procedures in Steps 1-4 in Example 48), N-Boc-2-aminoacetaldehyde (0.06 g, 0.427 mmol), and methanol (2.5 mL) was purged with argon. Palladium on carbon (10%, 0.051 g) was added, the flask evacuated, and the reaction placed under hydrogen for 91 hr. The reaction mixture was filtered through a Celite-plugged filter frit, washed with CH3OH and CH2Cl2, and concentrated. The crude product was carried forward without purification. ESI-MS m/z 676 (MH)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.Cl.CCOC(C)=O>C1COCC1>[C:17]([C:11]1([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:18]
Reactant: N#Cc1ccc(F)cc1
Reactant: N#CC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(C#N)CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Solid KHMDS (4.36 g, 22.0 mmol) is dissolved in THF (80.0 mL) and cooled to 0° C. Cyclohexanecarbonitrile (2.38 g, 22.0 mmol) is added, and the resulting solution is stirred for 40 minutes. A solution of 4-fluorobenzonitrile (1.33 g, 10.95 mmol) in THF (10.0 mL) is added, and the mixture is stirred for 2 hours at 0° C. and 10 hours at room temperature. 1N HCl (50.0 mL) is added, and the aqueous phase is extracted with EtOAc (4×50.0 mL). The combined organic phases are dried over MgSO4, filtered and concentrated on the rotovaporator. The product is purified by flash chromatography (CombiFlash), eluting with mixtures of heptanes and EtOAc (0% EtOAc to 30% EtOAc) (1.55 g, 7.38 mmol, 67%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.23-1.38 (m, 1H) 1.52-1.68 (m, 2H) 1.68-1.78 (m, 1H) 1.78-1.93 (m, 4H) 2.00-2.11 (m, 2H) 7.75 (d, J=8.79 Hz, 2H) 7.91 (d, J=8.79 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[CH:5][C:4]=1[O:30][CH2:31][CH2:32][CH3:33].Cl.Cl.[CH3:36]OC(=O)C1C(C(F)(F)F)=CC(NC2CCNCC2)=NC=1.C(OC1C=C(C=CC=1OC)C=O)C(C)C>>[CH2:31]([O:30][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:3]=1[O:2][CH3:1])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=2)[CH2:12][CH2:13]1)[CH:32]([CH3:36])[CH3:33]
Reactant: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F
Reactant: CCCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(N)=O)cn3)CC2)ccc1OC
Agent: COc1ccc(C=O)cc1OCC(C)C
Agent: Cl
Product: COc1ccc(CN2CCC(Nc3cc(C(F)(F)F)c(C(N)=O)cn3)CC2)cc1OCC(C)C

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide (example 197) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (intermediate B7) and 3-isobutoxy-4-methoxy-benzaldehyde (intermediate E12) in a yield of 15.1 mg (21%). MS (ISP): 482.4 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@H:5]([NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)[C@H](CN=[N+]=[N-])NC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](CN)NC(=O)c1ccccc1
Reaction time: 2 h
Yield: 79.3 %

Procedure:
A mixture of ethyl 3-azido-2(S)-(benzoylamino)propionate (0.35 g) and 10% Pd—C (0.07 g) in ethanol (4 ml) was hydrogenated at an atmospheric pressure for 2 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo to give ethyl 3-amino-2(S)-(benzoylamino)propionate (0.25 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][C:12]=2[C:13]([O:15]CC2C=CC(F)=C(F)C=2)=[O:14])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Li+].CO.O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][C:12]=2[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)OCc2ccc(F)c(F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3,4-difluorophenyl)methyl 2-{[(3,4-difluorophenyl)methyl]oxy}-5-formylbenzoate (may be prepared by Description 100; 7 g, 16.73 mmol) in tetrahydrofuran (50 ml) was added lithium hydroxide (1.202 g, 50.2 mmol) followed by methanol (12.50 ml) and water (12.5 ml). The mixture was stirred at room temperature overnight. The mixture was then evaporated under reduced pressure to one third volume. The mixture was diluted with water (50 ml) and acidified to pH=1 using 2M aqueous HCl. The solid formed was filtered off, washed with water and air dried under vacuum to give a white solid. 4.85 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5](Cl)=[O:6].Cl.[FH:17]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([F:17])=[O:6]
Reactant: F
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)c(Br)c1
Agent: Cl
Product: O=C(F)c1ccc(OC(F)(F)F)c(Br)c1
Yield: 88.7 %

Procedure:
100 ml of anhydrous hydrofluoric acid were cooled to -10° C. 420 g of 3-bromo-4-trifluoromethoxy-benzoyl chloride were added dropwise in the course of two hours at -5° to 0° C., with vigorous evolution of hydrogen chloride. After the evolution of hydrogen chloride had ceased, the temperature was allowed to increase and the reaction allowed to go to completion at 20° C. The excess hydrofluoric acid was distilled off. The residue was purified by distillation. 352.8 g (88.7% of theory) of 3-bromo-4-trifluoromethoxybenzoyl fluoride of refractive index nD20 : 1.4760 were obtained. ##STR21##
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:4].O.[OH-].[Li+]>O1CCOCC1.O.Cl>[C:19]1([S:16]([NH:15][C:6]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]=2[C:3]([OH:4])=[O:2])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1CCCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1CCCC2
Temperature: 160 °C

Procedure:
2-Benzenesulfonylamino-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate 4, 0.68 g) was dissolved in dioxane (12 mL) and a solution of lithium hydroxide monohydrate (0.6 g) in water (6 mL) was added. The mixture was heated by microwave irradiation at 160° C. for 15 minutes then diluted with 1N hydrochloric acid. The product was extracted into DCM and the organic solution was separated, dried with magnesium sulfate, filtered and the filtrate was concentrated under vacuum to give the title compound as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[F:27])([CH3:20])[C:18](=[O:28])[CH2:17][CH2:16]4)[C@H:13]([CH2:29][CH2:30][CH2:31][CH2:32]Cl)[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[CH2:36]([NH2:41])[CH2:37][CH2:38][CH2:39][CH3:40]>CN(C)C=O>[CH2:29]([C@@H:13]1[CH2:12][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:26]=[CH:25][C:24]=2[C@@H:23]2[C@@H:14]1[C@H:15]1[C@@:19]([CH2:21][C@@H:22]2[F:27])([CH3:20])[C:18](=[O:28])[CH2:17][CH2:16]1)[CH2:30][CH2:31][CH2:32][NH:41][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCN
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCl)[C@H]3[C@@H]1CCC2=O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCNCCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 0 °C

Procedure:
A solution of 273 mg of 3-benzyloxy-7α-(4-chlorobutyl)-11β-fluor-estra-1,3,5(10)-trien-17-one in 7 ml of dimethylformamide is stirred with 262 mg of sodium iodide and 0.5 ml of n-pentylamine for 24 hours at 80° C. Then, the reaction mixture is added to ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a methylene chloride-methanol gradient, 275 mg of 7α-(5-azadecyl)-3-benzyloxy-11β-fluor-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH2:17][C:18](=[O:49])[CH:19]([CH2:25][CH2:26][NH:27][C:28](C3C=CC(OC)=CC=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:20][C:21]([O:23]C)=[O:22])[C:3]=12.[OH-].[Na+].OS([O-])(=O)=O.[K+].O1[CH2:63][CH2:62][O:61][CH2:60]C1>>[OH:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:11])[CH3:12])[N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH2:17][C:18](=[O:49])[CH:19]([CH2:25][CH2:26][N:27]=[C:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:3]3[CH:2]=[CH:63][C:62]([O:61][CH3:60])=[CH:17][CH:16]=3)[CH2:20][C:21]([OH:23])=[O:22])[C:3]=12
Reactant: C1COCCO1
Reactant: COC(=O)CC(CCNC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1)C(=O)Cc1n[nH]c2nc(NC(=O)C(C)C)nc(O)c12
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Product: COc1ccc(-c2ccccc2C(=NCCC(CC(=O)O)C(=O)Cc2n[nH]c3nc(NC(=O)C(C)C)nc(O)c23)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
Compound 19 (1.33 g; 2 mmole) is dissolved in 10 ml dioxane. This solution is cooled to 0° C. and 1 M aqueous NaOH (8.66 ml) is added drop-wise in 5 aliquots over 2.5 hours. After an additional 2 hours at room temperature the solution is adjusted to pH 5 by drop-wise addition of 2 M KHSO4. Precipitated salts are filtered off and washed with dioxane, and the combined filtrates are evaporated. The residue is co-evaporated with ethanol and methanol/CH2Cl2, then purified by silica gel chromatography to yield (20).