Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][CH:25]=1)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[C:14]([CH:23]=[CH:24][CH:25]=2)[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(=O)c2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
With agitation, 4.9 g 4-chlorobenzoyl chloride are added bit by bit to a solution, cooled to 5° C., of 5 g 3-amino-benzophenone in 60 ml dimethylacetamide, in the presence of 4.9 g triethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1F.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31]>CS(C)=O.CCOCC>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC2(CC1)CNc1cc(Cl)ccc12
Reactant: Fc1ccccc1Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CN1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A mixture of 2.4 g of 6-chloro-1'-methylspiro[indoline-3,4'-piperidine], Example 23b, 0.5 g of sodium hydride (99% ) and 6 g of 2-chlorofluorobenzene in 25 ml of dimethylsulfoxide is stirred at 45° C. under nitrogen for 1 hour. Thereafter, the mixture is quenched with ice-water before being extracted thrice with ether. The combined ether extracts are successively washed with water, dried and concentrated under vacuum leaving a reddish oil. The oil is passed through an alumina column, ether eluant, and the purified oil, in ether, is converted to its maleic acid salt. The salt is recrystallized from an acetone-ether mixture to provide off-white platelets, mp 172°-173° C. of 6-chloro-1-(2-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine] maleate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[C:19](=[O:24])[NH:20][CH:21]=[CH:22][N:23]=2)[CH2:13][CH2:12]1)=[O:10].[BH4-].[Na+].O.ClCCl>CO>[OH:10][CH:9]([CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C:18]2[C:19](=[O:24])[NH:20][CH:21]=[CH:22][N:23]=2)[CH2:15][CH2:16]1)[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C(Cc1ccccc1F)C1CCN(Cc2ncc[nH]c2=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]ccnc1CN1CCC(C(O)Cc2ccccc2F)CC1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
After suspending 200 mg of 3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one in 6 ml of methanol, an excess of sodium borohydride was added while stirring at room temperature until completion of the reaction. Water was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added and the insoluble portion was filtered out to obtain the title compound (112 mg, 56% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1>O.[OH-].[Na+].[Ni]>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH2:6][CH2:7]1
Reactant: CC(C)(C(=O)O)c1ccc(O)cc1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C(=O)O)[C@H]1CC[C@@H](O)CC1
Reaction time: 24 h

Procedure:
2.690 g of 2-(4-hydroxy-phenyl)-2-methyl-propionic acid [29913-51-7] are dissolved in 20 ml of water and 30 ml of 1M NaOH solution. 0.200 g of Raney-Nickel are added and the reaction mixture is hydrogenated at 50 bar and 150° C. for 24 hours. The catalyst is removed by filtration over Hyflo and the filtrate is concentrated by evaporation. The residue is taken up in 200 ml of water and the solution neutralized with 1M HCl to pH 6. The reaction mixture is then extracted with dichloromethane (2×200 ml) and ethyl acetate (2×20 ml) and the combined organic phases are dried over sodium sulphate and concentrated by evaporation to provide the title compounds as a ca. 1:4 mixture of cis/trans-isomers. The white solid is used for the next step without further purification.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][N:6]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]([CH3:25])[CH3:24])[CH:17]=2)=[N:9][C:8](N)=[N:7]1>O.S(=O)(=O)(O)O.C(O)C.[Cl-].[Na+].O>[CH3:5][N:6]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]([CH3:24])[CH3:25])[CH:17]=2)=[N:9][CH:8]=[N:7]1
Reactant: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1cccc(OCCCNc2ncnn2C)c1
Yield: 37.9 %

Procedure:
A solution of sodium nitrite (1.74 g) in water (15 ml) was added dropwise to a solution of 1-methyl-N5 -[3-[3-(N,N-dimethylaminomethyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (5 g) in concentrated sulphuric acid (3.68 g) and ethanol (200 ml). The reaction mixture was heated at 65° for 4 h, cooled, treated with saturated brine (100 ml) and extracted with ethyl acetate. Evaporation of the organic extract gave a red oil which was extracted with ether. Distillation of the ether extracts gave the title compound as a pale yellow oil (1.8 g) b.p. 190° (0.04 mm). tlc System A,Rg 0.6.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1.[NH:14]([CH2:18][CH2:19]O)[CH2:15][CH2:16]O>>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[C:5]([B:9]2[O:10][CH2:19][CH2:18][NH:14][CH2:15][CH2:16][O:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: OCCNCCO
Product: FC(F)(F)c1cccc(B2OCCNCCO2)c1
Yield: 79 %

Procedure:
The title compound (79%, crystals) was prepared from 3-trifluoromethylphenylboronic acid and diethanolamin.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8]2[O:13][C:11](=[O:12])[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.CN(C)CCN(C)C>C(Cl)Cl>[C:4]1([N:7]2[C:11](=[O:12])[CH:10]=[CH:9][C:8]2=[O:13])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C1C=CC(=Nc2ccccc2)O1
Agent: CN(C)CCN(C)C
Solvent: ClCCl
Product: O=C1C=CC(=O)N1c1ccccc1
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
To 2.6 g (0.015 mole) of N-phenyl isomaleimide in 50 ml of methylene chloride are added 0.00045 mole of the compounds of the formula III which are given below and 0.069 g (0.0006 mole) of N,N,N',N'-tetramethylethylenediamine. The reaction mixture is stirred for two hours at 20-25° C. and is subsequently extracted by being shaken twice with 100 ml of water each time and the solvent is then removed. The yields of N-phenyl maleimide are given in the following Table.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([CH2:12][CH2:13][CH2:14][C@H:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26]([OH:36])[CH2:27][CH2:28]2)=[CH:23][CH2:22]3)[CH2:19][CH2:18]1)[CH3:16])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCCCC1=O.O>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10]([CH2:12][CH2:13][CH2:14][C@H:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH2:27][CH2:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1)[CH3:16])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CO[Si](C)(C)C(C)(C)C
Agent: CN1CCCCC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)CO[Si](C)(C)C(C)(C)C
Yield: 85 %

Procedure:
A mixture of (25R)-26-(tert-butyldimethylsilyloxy)cholest-5-en-3β-ol (7.4g, 14.3mmol) and 1-methylpiperidone (55 mL) in toluene (550 mL) was heated to reflux temperature and 100ml toluene was distilled off. Aluminium triisopropyl oxide (15 g, 1377 mmol) was then added portionwise over 10 minutes and the whole heated at refux for 4 hours. After cooling, water (300 mL) was added and the aqueous layer separated and extracted with diethyl ether (5×100 mL). The combined organic layers were washed with water (2×60 mL), dried over magnesium sulphate and concentrated to give residue which was purified by flash chromatography to give 6.26 g (25R)-26-(tert-Butyldimethylsilyloxy)-cholest-4-en-3-one (6.26 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Br)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=1)[CH2:39][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:30])[CH:10]2[CH2:19][CH2:20][CH:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[OH:22])=[CH:17][CH:16]=1
Reactant: BrCc1cccc(CBr)c1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3cccc(CBr)c3)cc2)N1c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl )-3-hydroxypropyl]4-(4-hydroxyphenyl)azetidin-2-one (11) was reacted with 1,3-bisbromomethylbenzene and potassium carbonate analogously to Example IV, giving a colorless solid (18) of molecular weight 592.49 (C32H28BrF2NO3); MS (ESI): 592.2 (MH+).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1/[C:15](/[CH3:19])=[CH:16]/[CH2:17]O>C(Cl)Cl>[Cl:3][CH2:17]/[CH:16]=[C:15](/[C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1)\[CH3:19]
Reactant: C/C(=C\CO)c1ccc2ccccc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C/C(=C\CCl)c1ccc2ccccc2c1

Procedure:
Thionyl chloride (5.0 ml) was added to a solution of (E)-3-(2-naphthyl)-2-buten-1-ol (4.59 g) in CH2Cl2 (30 ml)at 0° C. and the mixture was refluxed for 4 hours. The mixture was washed with water, saturated NaHCO3 solution and brine, dried and concentrated. The residue was washed with hexane to give the titled compound (1.22 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1B(O)O.C(C1C=CC(B(O)O)=CC=1)(O)=O.Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32]>>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([CH:34]=2)[C:31]([OH:33])=[O:32])[CH:5]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: O=C(O)c1cncc(Br)c1
Agent: O=C(O)c1ccc(B(O)O)cc1
Product: COc1ccc(Cl)cc1-c1cncc(C(=O)O)c1

Procedure:
Following the procedure of Example 1b), except substituting 2-methoxy-5-chlorophenylboronic acid; for 4-carboxyphenylboronic acid; and substituting 5-bromonicotinic acid; for the compound of 1a), the title compound was prepared. MS (ES) m/z 264 [M+H].
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C:44]2([CH2:51][CH2:50][CH:49]([C:52]([OH:54])=O)[CH2:48][CH2:47]2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[CH3:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[CH3:55][N:56]1[CH2:61][CH2:60][N:59]([C:52]([CH:49]2[CH2:48][CH2:47][C:44]3([CH2:43][CH2:42][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:40])[CH2:46][CH2:45]3)[CH2:51][CH2:50]2)=[O:54])[CH2:58][CH2:57]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(C(=O)O)CC2)CC1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)C2CCC3(CC2)CCN(C(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.32 g, 1 eq.) and 1-hydroxybenzotriazole hydrate (0.14 g, 1 eq.) were added to a solution of 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid (commercially obtainable from Anthem, Order No. A1106) (0.3 g, 1 eq.) in tetrahydrofuran (20 ml) and the reaction mixture was stirred at room temperature for 0.5 h. 1-Methylpiperazine (0.11 ml, 1 eq.) and N-ethyl-diisopropylamine (0.17 ml, 1 eq.) were then added and the mixture was stirred at room temperature overnight. For working up, the reaction mixture was concentrated, methylene chloride and sat. NaHCO3 solution were added to the residue and the aqueous phase was extracted with methylene chloride a further 2×. The combined organic phases were washed 1× with sat. NaCl solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica; ethyl acetate/ethanol/ammonia (25% aq.) 10:1:0.05) in order to obtain the desired product (AMN-10). Yield: 0.22 g (101%)
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O>Br>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1F
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3ccccc3F)C2)o[nH]1
Yield: 49.4 %

Procedure:
(2R,4R)-Methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (185 mg, 0.55 mmol) (from example 102, step 2) was stirred in hydrogen bromide (33% in AcOH) overnight (17 h). Evaporation of solvents and purification by preparative HPLC (Instrument: FractionLynx I, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) yielded 5-((2R,4R)-2-(2-fluorobenzyl)-piperidin-4-yl)isoxazol-3(2H)-one (75 mg, 49%). 1H NMR (600 MHz, DMSO) δ 1.48-1.55 (m, 1H), 1.68-1.80 (m, 3H), 2.58-2.64 (m, 1H), 2.72 (d, 2H), 2.81-2.87 (m, 1H), 2.87-2.94 (m, 1H), 3.12-3.17 (m, 1H), 5.70 (s, 1H), 7.11-7.17 (m, 2H), 7.24-7.31 (m, 2H). HRMS Calcd for [C15H17FN2O2+H]+: 277.1352. Found: 277.1357.
Reaction SMILES: CC([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])C=C>CCOCC>[CH3:8][CH:7]([C:11]1[C:10]([CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:6]=1[OH:5])[CH:6]=[CH2:11]
Reactant: C=CC(C)Oc1cc(C)ccc1[N+](=O)[O-]
Solvent: CCOCC
Product: C=CC(C)c1c(C)ccc([N+](=O)[O-])c1O

Procedure:
197 g of 1A was placed in a flask, which then was purged with nitrogen, and a slow stream of nitrogen was passed through the system while the 1A was heated gradually. At about 160° C., an exothermic reaction began, and the temperature rose to 220° C. The mixture was contained with cooling, then heated at 185°-200° C. for 1.5 hours, diluted with ether, and filtered. The solvent was evaporated from the filtrate to give crude 2-(1-methyl-2-propenyl)-3-methyl-6-nitrophenol (1B), as a dark syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1.C(N(CC)CC)C.[C:20]([CH2:24][C:25](Cl)=[O:26])([CH3:23])([CH3:22])[CH3:21]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([NH:10][C:25](=[O:26])[CH2:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: COc1cc(Br)cc(OC)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Br)cc(OC)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of the crude 5-bromo-1,3-dimethoxy-2-amino-benzene from above and triethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane (50 mL) was added dropwise tert-butyl acetyl chloride (1.6 g, 12 mmol) with stirring at room temperature. The reaction mixture was stirred for 3 hours at room temperature. Then the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) to give a white solid (3.0 g, 91%). 1H-NMR (DMSO-d6, 400 MHz): δ 8.69 (brs, 1H, exchangeable with D2O), 6.87 (s, 2H), 3.73 (s, 6H), 2.11 (s, 2H), 1.02 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1.[Sn](Cl)Cl.[OH-].[NH4+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2cnccn2)c1
Agent: Cl[Sn]Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(F)c(-c2cnccn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-fluoro-5-nitrophenyl)pyrazine (0.72 g, 3.3 mmol) in ethanol (20 ml) was added tin(II) chloride (2.8 g) and the mixture stirred for 3 h at ambient temperature. 25% Ammonium hydroxide (25 ml) was added and the mixture evaporated to dryness. The residual solid was boiled with ethyl acetate, and filtered whilst hot. The filtrate was evaporated at reduced pressure to give 4-fluoro-3-(pyrazin-2-yl)phenylamine: δH (400 MHz, CDCl3) 9.09 (1H, dd, J 2 and 1.5), 8.66 (1H, m), 8.51 (1H, d, J 2), 7.31 (1H, dd, J 6 and 3), 7.02 (1H, dd, J 11 and 9), 6.74 (1H, m), 3.60 (2H, br).
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl-].[CH3:12][NH2+]C.C=O>>[CH:2]([C:3](=[CH2:12])[CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:1]
Reactant: C[NH2+]C
Reactant: CCOC(=O)CCCC=O
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCC(=O)OCC

Procedure:
With stirring, 14.4 g (100 mmol) of ethyl 5-oxopentanoate, 9.2 g (112.6 mmol) of dimethylammonium chloride and 10.8 ml (117 mmol) of 37% formaldehyde solution are heated to 100° C. The mixture is cooled and extracted with 3×30 ml of diethyl ether. The batch is cooled and the organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness, giving ethyl 4-formylpent-4-enoate as a colorless oil which can be further reacted without additional purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]2[CH:38]=[CH:37][CH:36]=[CH:35][C:10]=2[S:11][C:12]=1[N:13]([S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=1)(C)(C)C>Cl.O1CCOCC1.C(OCC)C>[NH2:7][C:8]1[C:9]2[CH:38]=[CH:37][CH:36]=[CH:35][C:10]=2[S:11][C:12]=1[N:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=1)[S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:27])=[O:28]
Reactant: CC(C)(C)OC(=O)Nc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)S(=O)(=O)c2ccccc2)sc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)S(=O)(=O)c2ccccc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.6 %

Procedure:
Compound 509-A (1.0 g, 1.72 mmol) was dissolved in 4N HCl in dioxane (20 mL) and stirred at ambient temperature for 18 h. The resultant suspension was diluted with diethyl ether, filtered, washed with diethyl ether and dried under vacuo to afford 0.65 g of compound 509-B. MS: m/z 481.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=2)[N:3]=1.CO.[OH-].[Na+]>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=2)[N:3]=1
Reactant: CCOC(=O)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a 100 mL flask, ethyl 3-bromo-1-(3,5-dichloropyridin-2-yl)-1H-pyrazole-5-carboxylate (2.0 g, 5.5 mmol), methanol (10 mL), water (10 mL) and sodium hydroxide (0.3 g, 5.5 mmol) were added. After being stirred at room temperature for 1 hour, the mixture reacted completely. The reaction mixture was concentrated by rotary evaporator to about 10 mL as a dark brown solution. Then water (40 mL) was added into the dark brown solution. The aqueous solution was extracted with ethyl ether (50 mL) and acidified with concentrated hydrochloric acid to pH of 4. The precipitate was isolated by filtration, washed with water (2×50 mL) and dried to give the product (0.97 g) as white solid in 48% yield.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([N:17]3[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[OH:25][C:26]1([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:35][N:34]=2)[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl>[N:40]1[CH:41]=[CH:42][CH:43]=[N:44][C:39]=1[C:36]1[CH:37]=[CH:38][C:33]([C:26]2([OH:25])[CH2:31][CH2:30][CH:29]([NH:22][C@H:19]3[CH2:20][CH2:21][N:17]([C:15]([CH:12]4[CH2:11][CH2:10][N:9]([C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[N:8]=5)[CH2:14][CH2:13]4)=[O:16])[CH2:18]3)[CH2:28][CH2:27]2)=[N:34][CH:35]=1
Reactant: N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)n3)CC2)C1
Reactant: O=C1CCC(O)(c2ccc(-c3ncccn3)cn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2cccc(C(F)(F)F)n2)CC1)N1CC[C@H](NC2CCC(O)(c3ccc(-c4ncccn4)cn3)CC2)C1

Procedure:
A solution of (3S)-1-({1-[6-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}carbonyl)pyrrolidin-3-amine (40 mg, 0.1 mmol), 4-hydroxy-4-(5-pyrimidin-2-ylpyridin-2-yl)cyclohexanone (47 mg, 0.18 mmol), sodium triacetoxyborohydride (50 mg, 0.23 mmol), and triethylamine (35 mg, 0.35 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight. The reaction mixture was passed through a silica gel pad. The filtrate was concentrated and purified by HPLC to give the cis- and trans-isomers. MS (M+H) 596.2 for both isomers.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]2[O:11][C@@H:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:9]3[C@@H:8]2[OH:17])[CH2:4][O:3]1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>CN(C)C=O>[CH3:1][C:2]1([CH3:18])[O:6][CH:5]([CH:7]2[O:11][CH:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][CH:9]3[CH:8]2[O:17][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][O:3]1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@@H](O)[C@H]2O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(C)OCC(C2OC3OC(C)(C)OC3C2OCc2ccccc2)O1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 1,2:5,6-Di-O-isopropylidene-α-D-allofuranose (30A) (obtained from Pfanstiehl Laboratories Inc.) (40 g) in dimethylformamide at 0° C. was added sodium hydride in smaller portions. The reaction mixture was stirred for 1 h, benzyl bromide was added drop wise over a period of 1 h. The reaction mixture was stirred at room temperature for 16 h. Methanol was added to quench the reaction and dimethylformamide was removed under pressure. The syrup was extracted with ethyl acetate and washed with brine. Evaporation of the ethyl acetate layer yielded a semisolid (93%). Homogeneous by TLC.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24].CN(C)P(N(C)C)(N(C)C)=O>O>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][CH2:14][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: COc1ccccc1CCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCCc2ccccc2OC)cc1

Procedure:
A mixture of 14.5 g. of ethyl p-aminobenzoate, 10 g. of 1-bromo-3-(o-methoxyphenyl)propane and 50 ml. of hexamethylphosphoramide is heated at 130° C. for 15 hours, cooled and diluted with 20 ml. of water. The mixture is chilled, diluted with 50 ml. of cold ethanol:H2O (1:1) and filtered. The solid is washed with three 50 ml. portions of cold ethanol-water (1:1) and with water to give crystals, m.p. 106°-109° C. Recrystallization from ethanol (100 ml.) gives yellow crystals, m.p. 111°-113° C.