Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13].[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:15]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:12]([CH3:13])[CH3:14])[N:6]1[C:7]2[C:3](=[C:2]([N:31]3[CH2:32][CH2:33][N:28]([CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:29][CH2:30]3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1)([CH3:17])[CH3:16]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)cccc21
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(N3CCN(Cc4ccccc4)CC3)cccc21

Procedure:
A mixture of 1.0 g (2.8 mmole) 4-bromo-triisopropylsilanyl-1H-indole, 0.54 mL (3.1 mmole) N-benzylpiperazine, 31 mg (0.14 mmole) palladium(II)acetate, 28 mg (0.14 mmole) tri-t-butylphosphine and 403 mg sodium t-butoxide in 5 mL xylene was heated at 120° for 15 hours. The reaction mixture was diluted with 100 mL 50% ether-hexane and filtered through a pad of silica gel 230-400 mesh. The filtrate was concentrated under reduced pressure to afford 1-triisopropylsilanyl-4-(4-benzyl-piperazin-1-yl)-1H-indole as a semi-solid, 1.2 g, M+H=448.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[C:16]([O:20][C:21]([NH:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27]([OH:29])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CCCCCCC.CCOC(C)=O>[C:16]([O:20][C:21](=[O:22])[NH:23][C:24]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:26]([C:27](=[O:29])[N:2]([CH3:1])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:25]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-tert-butoxycarbonylamino-5-trifluoromethyl-benzoic acid and using a gradient of n-heptane:EtOAc (100:0 to 0:60) for the chromatographic purification. Light brown solid (4%). MS (ESI): m/z=486.20 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>C(O)C>[CH2:28]([O:27][C:25]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:26])[CH3:29]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(C2=NNC(=O)CC2)cc1)C(=O)OCC

Procedure:
A solution containing 0.38 g of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one and 0.45 g of diethyl ethoxymethylenemalonate in 5 ml of dry ethanol was refluxed for 1.5 h. After cooling the product was filtered and washed with ethanol. Yield 0.3 g, mp 164° C.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH2:30][C:31]#[N:32]>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][C:31]#[N:32])[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: N#CCBr
Agent: Cl
Product: N#CCN1CN(c2ccccc2)C2(CCN(C3CCCCCCCCC3)CC2)C1=O

Procedure:
The title compound, white solid, m. p. 240° C. and MS: m/e=409.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and bromoacetonitrile.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:24]=[CH:23][C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:25])[CH:19]=3)[C:14](=[O:26])[C:13]=2[CH:12]=1>O1CCCC1>[Cl:25][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)([OH:26])[C:13]1[CH:12]=[C:11]([F:10])[CH:24]=[CH:23][C:22]=1[S:21]2
Reactant: CN1CCC(Cl)CC1
Reactant: O=c1c2ccc(Cl)cc2sc2ccc(F)cc12
Agent: [Mg]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccc(Cl)cc3Sc3ccc(F)cc32)CC1

Procedure:
The Grignard reagent prepared from 5.9 g. (0.044 mol) of 4-chloro-N-methylpiperidine and 1.1 g. (0.044 mol) of magnesium turnings of tetrahydrofuran is treated with 5.8 g. (0.022 mol) and the above-prepared thioxanthone. The mixture is refluxed for four hours and worked up by the usual procedure to yield 6-chloro-2-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 133°-142° C.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:43])[C@H:35]([NH2:42])[CH2:36][C:37]1[CH:41]=[CH:40][S:39][CH:38]=1>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26]([NH:42][C@H:35]([CH2:36][C:37]4[CH:41]=[CH:40][S:39][CH:38]=4)[C:34]([OH:33])=[O:43])=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Reactant: COC(=O)[C@H](N)Cc1ccsc1
Agent: Cl
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@H](Cc4ccsc4)C(=O)O)nc(CC4CCCC4)c3c2)cc1
Yield: 94.9 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2R)-amino-3-thiophen-3-yl-propionic acid methyl ester HCl (28.1 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 63.4 mg of the title compound as a white solid.
Reaction SMILES: [Si]([O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([CH:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH3:17])=[CH:11][C:10]=1[Cl:26])(C(C)(C)C)(C)C.CCOCC>CN(C=O)C.O>[Si:19]([O:18][CH:16]([C:12]1[CH:13]=[C:14]([Cl:15])[C:9]([OH:8])=[C:10]([Cl:26])[CH:11]=1)[CH3:17])([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(O[Si](C)(C)C(C)(C)C)c1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A sol. of (rac.)-2-(tert-butyldimethylsilanyloxy)-5-[1-(tert-butyldimethylsilanyloxy)ethyl]-1,3-dichlorobenzene (188 mg, 0.432 mmol) and CS2CO3 (76.2 mg, 0.126 mmol) in a mixture of DMF (0.50 mL) and water (50 μL) was stirred at rt overnight. Et2O (75 mL) was added. The sol. was washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification by FC(CH2Cl2) yielded the title compound (122 mg, 88%). LC-MS: tR=1.15 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1>C1COCC1>[OH:2][CH:1]([C:22]1[CH:23]=[CH:24][C:19]([S:18][CH3:17])=[CH:20][CH:21]=1)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: CSc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2cnccc2-c2cccc(C#N)c2)cc1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 4-methylsulfanylphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(4-methylsulfanyl-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]=[O:12])=[CH:5][C:4]=1[CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17]C)=[O:16]>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]=[O:12])=[CH:5][C:4]=1[CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCCCCC(CC(=O)OC)c1cc(C=O)c(OC)cc1OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)O)c1cc(C=O)c(OC)cc1OC

Procedure:
Methyl 3-(2,4-dimethoxy-5-formylphenyl)octanoate [prepared as described in step (ii) above] was hydrolyzed in a similar manner to that described in Preparation 7 to give the title compound as crystals, melting at 110-111.5° C. (from ethyl acetate-hexane).
Reaction SMILES: C(O)C.[BH4-].[Na+].C([O:8][C:9]([CH:11]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)=O)C>O>[OH:8][CH2:9][CH:11]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1
Reactant: CCOC(=O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCC(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Yield: 16.8 %

Procedure:
10 ml of ethanol and 197 mg of sodium borohydride were added to 200 mg of 4-(α-ethoxycarbonyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was refluxed for 30 minutes, followed by the addition of 5 ml of water. The obtained mixture was concentrated under a reduced pressure, followed by the addition of 10 ml of water. The crystal thus precipitated was recovered by filtration. Thus, 30 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[NH:10].Br[CH:23]([CH3:31])[C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])(O)=O.[Na+]>CC(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[C:23]([CH3:31])=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:10]=1
Reactant: CCOC(=O)C(=O)C(C)Br
Reactant: N=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(C(F)(F)F)cc2)c1C
Yield: 52.4 %

Procedure:
Part C: 2,4-Dichloro-N-(4-(trifluoromethyl)phenyl)benzenecarboxamidine (15.0 g, 0.0450 mol) is dissolved in 2-propanol and ethyl 3-bromo-2-oxobutanoate (20.8 g, 2 molar equivalent) and NaHCO3 are successively added. The resulting mixture is heated at reflux temperature for 40 hours and allowed to attain room temperature. The 2-propanol is removed in vacuo, ethyl acetate is added to the residue and the resulting organic layer is washed with NaHCO3 (5% aqueous solution). The ethylacetate layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is purified by column chromatography (diethyl ether/petroleum ether=1/3 (v/v), silicagel) and further purified by crystallisation from cyclohexane to give ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxylate (10.45 g, 52% yield) as a yellow solid. Melting point: 160-162° C.
Reaction SMILES: [CH3:1][C:2]1[N:3](COCC[Si](C)(C)C)[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH2:15][O:16][CH2:17][C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH2:15][O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)[CH:7]=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1c2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c2nn1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2c(COCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)cc12

Procedure:
tert-Butyl 4-(((3-methyl-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (100 mg, 0.16 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 3 mL) for 4 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated and the compound purified by reverse phase HPLC to afford 24 mg (38%) as a clear oil. 1H-NMR (CD3OD, 500 MHz) δ 8.02 (s, 1H), 7.39-7.45 (m, 5H), 7.29-7.45 (m, 1H), 4.76 (s, 2H), 3.56 (s, 2H), 3.27-3.31 (m, 2H), 2.89-2.96 (m, 2H), 2.60 (s, 3H), 2.49-2.52 (m, 2H), 2.16-2.22 (m, 2H). Mass spec.: 404.14 (MH)+. Accurate mass spec.: m/z 404.1930 [MH]+, Δ=4.9 ppm.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: COc1ccc(CNc2nc(Cl)nc3nc[nH]c23)cc1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
The 2,6-dichloropurine (4.06 g, 21.5 mmol) was suspended in n-butanol (150 ml) and the 4-methoxybenzylamine was added (3.4 ml, 26 mmol). The solution turned clear and then cloudy a few minutes later. The solution was heated at 120° C. for 2 hr and then cooled. The n-butanol was evaporated followed by suspension of the residue in water and diethyl ether mixture. A solution of 2N NaOH (1.3 ml, 26 mmol) was added and the solution stirred for 10 min before filtration. The filtered precipitate was washed with water and a small portion of ether and then dried under vacuum. The residual liquor was left overnight and more crystals were collected the next day and washed with diethyl ether.
Reaction SMILES: O(C)S(C(F)(F)F)(=O)=O.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[CH3:26][O:27][C:28](=[O:60])[CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][C@H:35]1[C:39](=[O:40])[CH2:38][C@@H:37]([O:41][CH3:42])[C@@H:36]1/[CH:43]=[CH:44]/[CH2:45][CH:46]([C:49]1([CH2:53][C:54]2[S:55][C:56]([Cl:59])=[CH:57][CH:58]=2)[CH2:52][CH2:51][CH2:50]1)[O:47]C>C1(C)C=CC=CC=1>[CH3:26][O:27][C:28](=[O:60])[CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][C@H:35]1[C:39](=[O:40])[CH2:38][C@@H:37]([O:41][CH3:42])[C@@H:36]1/[CH:43]=[CH:44]/[CH2:45][CH:46]([C:49]1([CH2:53][C:54]2[S:55][C:56]([Cl:59])=[CH:57][CH:58]=2)[CH2:50][CH2:51][CH2:52]1)[OH:47]
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](OC)[C@@H]1/C=C/CC(OC)C1(Cc2ccc(Cl)s2)CCC1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: COS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](OC)[C@@H]1/C=C/CC(O)C1(Cc2ccc(Cl)s2)CCC1
Reaction time: 72 h

Procedure:
Methyl triflate (145 mg, 09 mmol) was added to a mixture of alcohol 26-H (26 mg, 0.054 mmol) and proton sponge (200 mg, 0.933 mmol) in toluene (5 ml). After 3 days, the mixture was quenched with NaHCO3 (sat) and extracted with CH2Cl2 (3×). The combined organics were washed with 1N HCl, NaHCO3 (sat), brine, dried (Na2SO4) and concentrated in vacuo. FCC (silica gel, 4:1, hexane/EtOAc followed by 2:1, haxane/EtOAc) gave the above named compounds 28 and 29-H.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:18]=[CH:19][C:20]2[O:24][CH:23]=[C:22]([CH3:25])[C:21]=2[CH:26]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:18]=[CH:19][C:20]4[O:24][CH:23]=[C:22]([CH3:25])[C:21]=4[CH:26]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Cc1coc2ccc(Br)cc12
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1coc2ccc(N3CCN(c4cnccc4C4CC4)C3=O)cc12
Yield: 42.1 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 5-bromo-3-methylbenzofuran (125 mg, 0.5904 mmol), 1,4-dioxane (4 mL), copper iodide (10 mg, 0.0492 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (7.0 mg, 0.0492 mmol) and potassium phosphate (313 mg, 1.476 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.0% methanol in CHCl3) afforded 69 mg of the product (42% yield).
Reaction SMILES: [Br:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]([CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)[CH3:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]([CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)[CH3:15])=[CH:9][CH:8]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(CN2CCC[C@@H]2CN(C)Cc2ccc(Oc3ccc(Br)cc3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1ccc(Oc2ccc(Br)cc2)cc1)C[C@H]1CCCN1Cc1ccc(C(=O)O)cc1
Reaction time: 72 h

Procedure:
A solution of methyl 4-[[(R)-2-[[[[4-(4-bromophenoxy)phenyl]methyl]methylamino]methyl]-1-pyrrolidinyl]methyl]benzoate in a mixture of THF and methanol and treated with an aqueous solution of lithium hydroxide (400 mg). The reaction was stirred for 3 days. After acidification with 1 N hydrochloric acid, purification by reverse phase preparative HPLC using a gradient of acetonitrile in water containing 0.1% TFA give 270 mg of 4-[[(R)-2-[[[[4-(4-bromophenoxy)phenyl]methyl]methylamino]methyl]-1-pyrrolidinyl]methyl]benzoic acid; 1NMR (400 MHz, DMSO-d6) δ 7.98 (d, 2H), 7.61 (d, 2H), 7.54 (d, 2H), 7.40 (d, 2H), 7.07 (d, 2H), 6.96 (d, 2H), 4.46 (m, 1H), 4.17 (dbr, 1H), 3.18 (m, 4H), 3.02 (m, 2H), 2.37 (sbr, 3H), 2.25 (m, 1H), 1.82 (m, 4H), 1.21 (m, 2H) ppm.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH:15]1[CH2:19][O:18]C(=O)[O:16]1)[CH2:5][CH2:6][CH2:7][CH:8]1[CH:12](C)[CH2:11][C:10](=[NH:14])[NH:9]1.[OH-].[Ba+2].[OH-]>>[NH2:3][CH:4]([CH2:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][C:10](=[NH:14])[NH:9]1)[CH:15]([OH:16])[CH2:19][OH:18]
Reactant: CC1CC(=N)NC1CCCC(N)C1COC(=O)O1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Product: N=C1CCC(CCCC(N)C(O)CO)N1

Procedure:
The product of EXAMPLE 263 is treated with aqueous barium hydroxide at 70° C. to yield the title material.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][C@@H:6]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:14]([CH3:20])[O:13][C@H:8](OC(=O)C)[C@@H:7]1[O:21][C:22](=[O:24])[CH3:23])=[O:4].[BrH:27].C(O)(=O)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:26])([F:25])[C:3]([NH:5][C@@H:6]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:14]([CH3:20])[O:13][C@H:8]([Br:27])[C@@H:7]1[O:21][C:22](=[O:24])[CH3:23])=[O:4]
Reactant: Br
Reactant: CC(=O)O[C@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](NC(=O)C(F)(F)F)[C@H]1OC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1[C@H](NC(=O)C(F)(F)F)[C@H](OC(C)=O)[C@H](C)O[C@@H]1Br
Reaction time: 2 h
Yield: 92 %

Procedure:
The residue obtained from the reaction mixture by evaporation in vacuo, which consists of 3-trifluoroacetamido-1,2,4-tri-O-acetyl-3,6-dideoxy-β-L-talopyranose, is dissolved in 20 ml. of a 30% hydrogen bromide-acetic acid solution. After being kept for 2 hours at room temperature, 200 ml. of chloroform is added to the reaction mixture and the chloroform solution is washed with ice and water, a cold saturated sodium hydrogen carbonate solution, and water. The solution is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to heavy syrup. The syrup is crystallized by adding ether, and recrystallization from a mixture of chloroform-ether gives 16 g. (92% yield) of 3-trifluoroacetamido-2,4-di-O-acetyl-3,6-dideoxy-β-L-talopyranosyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)(Cl)Cl>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C:33]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[F:23])=[O:34]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(F)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoro-aniline (50 mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl isocyanate (29 μl) was then added to the solution. The mixture was stirred at 60° C. overnight. The precipitated crystal was collected by filtration and was washed to give. 50 mg (yield 67%) of the title compound.
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].[P:5]([OH:8])([OH:7])[OH:6]>C(O)C>[NH2:4][C:1]([P:5]([OH:8])([OH:7])=[O:6])([P:5]([OH:8])([OH:7])=[O:6])[CH2:2][CH3:3]
Reactant: OP(O)O
Reactant: CCC#N
Solvent: CCO
Product: CCC(N)(P(=O)(O)O)P(=O)(O)O
Temperature: 150 °C
Yield: 52 %

Procedure:
A mixture of propionitrile (5.5 g, 0.1 mole), phosphorous acid (16.4 g, 0.2 mole), ISOPAR-M (22 g), and wetting agents (0.5 g each) was heated under nitrogen at ambient pressure for 2 hours at 150° C. The product was worked up with ethanol. Colorless crystals of 1-amino-1,1-diphosphono propane (52% yield), m.p. 282° C was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:15][C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]2)[CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:3][C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:5]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(=O)C2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(CC(O)C2)C1

Procedure:
The process is performed according to the procedure described in Example 6, step 6.1. Starting with 1.40 g (6.63 mmol) of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, obtained in step 11.2., dissolved in 17 mL of methanol and 0.376 g (9.94 mmol) of sodium borohydride. After evaporating off the solvent and crystallizing from a 70/30 mixture of petroleum ether and diisopropyl ether, 1.18 g of the expected product are obtained in the form of a white powder.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:12]([O:14][CH2:15][CH2:16]Br)[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OC(=O)C)C>[CH2:12]([O:14][CH2:15][CH2:16][O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:13]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCCON=C(C(C)=O)C(=O)OCC
Yield: 97.7 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer 40 g.), ethoxyethyl bromide (41.1 g.), potassium carbonate (54.1 g.), N,N-dimethylformamide (65 ml.) and ethylacetate (65 ml.) were treated in a similar manner to that of Example A-(1) to give ethyl 2-(2-ethoxyethoxyimino)-3-oxobutyrate (syn isomer, 56.8 g.).