Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([N:17]3[CH2:21][C@H:20]([CH2:22][O:23][CH3:24])[O:19][C:18]3=[O:25])[CH:14]=[CH:13][C:11]=2[N:12]=1)[CH2:3][CH2:4][C:5](=O)[NH2:6].O1CCOCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[OH:1][C@H:2]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([N:17]3[CH2:21][C@H:20]([CH2:22][O:23][CH3:24])[O:19][C:18]3=[O:25])[CH:14]=[CH:13][C:11]=2[N:12]=1)[CH2:3][CH2:4][C:5]#[N:6]
Reactant: COC[C@H]1CN(c2ccc3nc([C@@H](O)CCC(N)=O)sc3c2)C(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC[C@H]1CN(c2ccc3nc([C@@H](O)CCC#N)sc3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
2.0 g of 3-[2-(1(S)-hydroxy-3-carbamoylpropyl)benzothiazol-6-yl]-5(R)-methoxymethyl-2-oxazolidinone was suspended in a liquid mixture of 20 ml of 1,4-dioxane and 3.6 ml of pyridine. 2.0 ml of trifluoroacetic anhydride was added dropwise thereto under cooling with ice for 20 min. The resulting mixture was stirred at room temperature for 2 h and the reaction liquid was added to a saturated aqueous sodium hydrogencarbonate solution. After extraction with ethyl acetate, the organic layer was washed with dilute hydrochloric acid and then with a saturated aqueous common salt solution, and dried. The solvent was distilled off and the resulting residue was crystallized from acetone/water to give 1.6 g of the titled compound.
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH2:13]>>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:12][NH:13][CH:3]=[CH:4][C:5](=[O:7])[CH3:6])[CH:14]=[CH:15][CH:16]=1
Reactant: NCc1cccc(Cl)c1
Reactant: COC=CC(C)=O
Product: CC(=O)C=CNCc1cccc(Cl)c1

Procedure:
The title compound 64 is prepared according to the procedure reported in step A of Example 18 with 4-methoxy-3-buten-2-one (0.1 g, 1 mmol) and 3-chlorobenzylamine (0.138 g, 1 mmol) as reactants. Yellow oil. (Yield 0.21 g, 100%).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[Br:13][CH2:14][C:15](Br)=[O:16]>>[Br:13][CH2:14][C:15]([O:3][C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:11][CH3:12])=[O:10])=[O:16]
Reactant: COC(=O)[C@H](O)c1ccccc1
Reactant: O=C(Br)CBr
Product: COC(=O)[C@H](OC(=O)CBr)c1ccccc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To methyl (R)-mandelate (8.3 g, 150 mmol), and neutral alumina [e.g. Aldrich type WN-3] (17 g, 167 mmol) cooled with an ice-bath was added bromoacetyl bromide (44 mL, 500 mmol). The ice bath was removed and after 1 h standing at RT, the reaction mixture was poured onto solid NaHCO3 (117 g) in a glass filter funnel, with a cotton wool plug (effervescence). After standing overnight, the solid was washed with toluene until 200 ml of filtrate had been collected. The volatiles were removed via rotary evaporation to yield a crude product in 88% yield. This crude product was sufficiently pure to carry through to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=3)[NH:9][C:8]=2[CH3:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=3)[N:9]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:8]=2[CH3:20])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: Cc1[nH]c2ccc(C(F)(F)F)cc2c1Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(C(F)(F)F)ccc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of the product from step (i) (0.60 g), potassium carbonate (0.516 g) and methyl bromoacetate (0.26 ml) in DMF (4 ml) was stirred at 50° C. for 4 h. The reaction was partitioned between ethylacetate/water. The organics were washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10-20% ethylacetate/iso-hexane. Yield 0.44 g
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[N+:14]([O-])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.O>[Ni].CO>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[NH2:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1C2CN(Cc3ccccc3)CC21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: NC1C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.3 %

Procedure:
To a mixture of 3-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane (4.00 g) and a catalytic amount of Raney nickel in MeOH was added slowly a solution of 98% H2NNH2—H2O (70 mL) at rt. The mixture was stirred for 5 h at room temperature and filtered. The filtrate was concentrated in vacuo to give the title compound as brown oil (3.60 g) and the crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 204.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1CC#N.[C:14]([OH:17])(=[O:16])[CH3:15].S(=O)(=O)(O)O>O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:15][C:14]([OH:17])=[O:16]
Reactant: CC(=O)O
Reactant: Cc1c(CC#N)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(CC(=O)O)cccc1[N+](=O)[O-]
Reaction time: 0.62 h

Procedure:
150 g of 2-Methyl-3-nitro phenylacetonitrile is added to 750 ml pure water and 600 ml acetic acid. 675 ml sulfuric acid is added drop wise to the reaction mixture and refluxed for 6-7 hours. After completion of reaction, 2000 ml water is added to it and stirred for 30-45 minutes, filtered and dried to give 2-Methyl-3-nitro phenylaceticacid (130-135 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.[OH-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Oc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4ccccc4n3)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 11 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67 mmol), (prepared as described for the starting material in Example 1), potassium carbonate (106 mg, 0.77 mmol) and 2-hydroxyquinoline (111 mg, 0.76 mmol) in DMF (7.5 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The reaction mixture was treated with 1.0 N aqueous sodium hydroxide solution (40 ml) and allowed to stir at ambient temperature for a few minutes. The reaction mixture was extracted 3 times with ethyl acetate and the extracts washed with water and brine. The organic extracts were dried over magnesium sulphate, filtered and the solvent removed by evaporation. The residue was purified by silica column chromatography eluting with dichloromethane/methanol (95/5) to give a solid which was triturated with ether, filtered and dried to give 6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-2-yloxy)-quinazoiine (33 mg, 11%).
Reaction SMILES: NC[C@@H](C1C=CC(O)=C2C=1C=CC(=O)N2)O[Si](C(C)(C)C)(C)C.C([O:31][C:32]1[CH:37]=[CH:36][C:35]([C@@H:38]([OH:75])[CH2:39][NH:40][C:41]([CH3:74])([CH3:73])[CH2:42][C:43]2[CH:44]=[C:45]([CH:70]=[CH:71][CH:72]=2)[C:46]([NH:48][CH2:49][C:50]2[C:51]([NH:63][CH:64]3[CH2:69][CH2:68][O:67][CH2:66][CH2:65]3)=[C:52]3[CH:60]=[N:59][N:58]([CH2:61][CH3:62])[C:53]3=[N:54][C:55]=2[CH2:56][CH3:57])=[O:47])=[CH:34][C:33]=1[CH2:76][OH:77])C1C=CC=CC=1>>[CH2:61]([N:58]1[C:53]2=[N:54][C:55]([CH2:56][CH3:57])=[C:50]([CH2:49][NH:48][C:46](=[O:47])[C:45]3[CH:70]=[CH:71][CH:72]=[C:43]([CH2:42][C:41]([NH:40][CH2:39][C@H:38]([OH:75])[C:35]4[CH:36]=[CH:37][C:32]([OH:31])=[C:33]([CH2:76][OH:77])[CH:34]=4)([CH3:74])[CH3:73])[CH:44]=3)[C:51]([NH:63][CH:64]3[CH2:65][CH2:66][O:67][CH2:68][CH2:69]3)=[C:52]2[CH:60]=[N:59]1)[CH3:62]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)(C)NC[C@H](O)c2ccc(OCc3ccccc3)c(CO)c2)c1
Agent: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)(C)NC[C@H](O)c2ccc(O)c(CO)c2)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 2, using Intermediate 53 as substrate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37](=[O:46])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:46])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][O:22][C:20]2[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=[C:16]([C:15](=[O:32])[NH:14][CH:11]3[CH2:12][CH2:13][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:33])[CH2:9][CH2:10]3)[CH:21]=2)=[CH:40][CH:39]=1)[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Product: CCOC(=O)c1ccc(COc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Yield: 81.2 %

Procedure:
Using 1.2 g (2.65 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester and 4-bromomethyl-benzoic acid ethyl ester (0.644 g, 2.65 mmol) and following the procedure of Example 42(b) afforded 1.32 g of the required product. Percentage purity (LCMS): 84.4%, (M+1)=613.2+1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])O1.C([O-])([O-])=O.[K+].[K+].CC#N>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.O>[OH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: CC(C)COC(=O)N1CCN(c2cc(Cl)ncn2)CC1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)COC(=O)N1CCN(c2cc(-c3ccccc3O)ncn2)CC1
Temperature: 130 °C

Procedure:
A mixture of isobutyl 4-(6-chloropyrimidin-4-yl)piperazine-1-carboxylate (0.10 g, 0.33 mmol), 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (87 mg, 0.11 mmol), Pd(PPh3)4 (3.8 mg, 3.3 μmol), K2CO3 (91 mg, 0.66 mmol), CH3CN (1 mL), and H2O (0.1 mL) was sealed in a microwave reactor vial. The reaction mixture was heated by microwave irradiation at 130° C. for two minutes. The reaction was filtered and purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give isobutyl 4-(6-(2-hydroxyphenyl)pyrimidin-4-yl)piperazine-1-carboxylate. LC/MS: m/z 357.3 (M+H)+ at 2.72 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[CH:3]1.[CH3:12][N:13](CCN(C)C)[CH3:14].C([Li])CCC.CN(C=O)C.[NH4+].[Cl-]>C(OCC)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[C:3]1[CH2:12][NH:13][CH3:14]
Reactant: Cc1cccc2ccn(C)c12
Reactant: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CNCc1cc2cccc(C)c2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a solution of 1,7-dimethylindole (2.85 g, 19.6 mmol) and TMEDA (3.3 mL, 21.6 mmol) in diethyl ether (30 mL) at −30° C. under N2 was added n-butyllithium (13.5 mL of a 1.6 M solution in hexanes, 21.6 mmol) dropwise. The resulting orange solution was heated to reflux for 1 h and then DMF (4.6 mL, 58.8 mmol) was added in one portion. The solution was stirred at room temperature overnight. Saturated aqueous NH4Cl solution was added and the mixture was then extracted with ethyl acetate (3×150 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide an orange oil. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 95:5) gave the title compound (1.57 g, 46%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 7.09-7.02 (m, 2H), 4.39 (s, 3H), 2.79 (s, 3H).
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)=[O:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]([C@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][C@@H:33]([CH3:41])[CH2:32]2)[C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:17][O:16][C:14](=[O:15])[C:13]([CH3:19])([CH3:18])[CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([N:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:31]([N:27]([C:28](=[O:30])[CH3:29])[C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][C@@H:33]2[CH3:41])=[O:3])=[CH:5][CH:6]=1
Reactant: COC(=O)C(C)(C)CCCc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)Nc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.1 %

Procedure:
To the prepared methyl 5-[4-(chlorocarbonyl)phenyl]-2,2-dimethylpentanoate (2.9 mmol, 1.0 eq.) was added a solution of N-(4-chlorophenyl)-N-((2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)acetamide (754 mg, 2.4 mmol, 0.83 eq.) in methylene chloride (8 ml) followed by diisopropylethylamine (505 ul, 2.9 mmol, 1.0 eq.) and reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate/hexane: ⅓ to ½ gradient) to afford 5-(4-{(2S,4R)-4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-2,2-dimethyl-pentanoic acid methyl ester (675 mg, 50%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:10][CH:9]1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[F:54][C:55]([F:69])([F:68])[C:56]1[CH:57]=[C:58]([N:62]2[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]2)[CH:59]=[CH:60][CH:61]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]([C:25]([F:28])([F:26])[F:27])[CH:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:20]=2)[CH2:10][C@H:9]1[C:29]([N:65]1[CH2:64][CH2:63][N:62]([C:58]2[CH:59]=[CH:60][CH:61]=[C:56]([C:55]([F:68])([F:69])[F:54])[CH:57]=2)[CH2:67][CH2:66]1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C([C@@H]1C[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 8 h
Yield: 10.6 %

Procedure:
The mixture of 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid (65 mg, 0.146 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (54.5.0 mg, 0.292 mmol), N-hydroxybenzotriazole (20.7 mg, 0.146 mmol), and 1-(3-trifluoromethyl-phenyl)-piperazine (29.67 mg, 0.219 mmol), triethylamine (0.08 ml) in dry dichloromethane (2 mL) was stirred overnight, and then concentrated. The residue was purified by preparative HPLC on reversed phase eluting with an acetonitrile/water [0.1% aq NH3 (25%)] gradient to afford the title compound (10.2 mg, 10.6%) as a light yellow oil. MS m/e=659.4 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH:24](=[O:28])/[CH:25]=[CH:26]/[CH3:27]>CN(C=O)C.O.CCOCC>[C:1]1([C@@:7]23[O:8][C@@:9]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)([C@@H:25]([CH:24]=[O:28])[C@@H:26]2[CH3:27])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]3=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2oc(-c3ccccc3)c3ccccc23)cc1
Reactant: C/C=C/C=O
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: C[C@H]1[C@H](C=O)[C@]2(c3ccccc3)O[C@@]1(c1ccccc1)c1ccccc12
Temperature: 10 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a 10° C. solution of 5(13 mg, 0.058 mmol), 1,3-diphenylisobenzofuran (162 mg, 0.60 mmol), and MeOH (12 μL, 0.30 mmol) in DMF/H2O (95/5 v/v, 1.0 M) was added (E)-crotonaldehyde (25 μL, 0.30 mmol). The solution was stirred at 10° C. for 24 h. The reaction mixture was then diluted with Et2O (10 mL) and washed with H2O (10 mL). The aqueous layer was extracted with Et2O (10 mL×2) and the combined organics were dried (Na2SO4), and concentrated. Purification by silica gel chromatography (7% EtOAc/hex) afforded the title compound as a yellow solid in 75% yield (76 mg, 0.22 mmol); 35:1 exo:endo; 96% ee. Product ratios were determined, after reduction to the corresponding alcohol (4 eq NaBH4, EtOH (0.1 M)), by HPLC (Chiralcel OD-H column, 3% EtOAc/hex, 1.0 mL/min) exo isomers tr=14.1 min and 15.3 min, endo isomers tr=16.5 min and 20.8. IR (CH2Cl2) 3066, 3041, 2828, 2729, 1722, 1603, 1499, 1457, 1448, 1381, 1355, 1309 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.36(d, J=5.8 Hz, 1H, CHO), 7.73-7.78(m, 2H, ArH), 7.43-7.57(m, 7H, ArH), 7.35-7.40(m, 1H, ArH), 7.16-7.26(m, 3H, ArH), 7.04-7.08(m, 1H, ArH), 3.08(dq, J=6.9, 4.1 Hz, 1H, CHCH3), 2.56(dd, J=5.8, 4.2 Hz, 1H, CHCHO), 0.96(d, J=6.9 Hz, 3H, CH3); 13C NMR (125 MHz) δ 201.9, 147.4, 145.0, 145.0, 136.6, 135.7, 135.5, 128.8, 128.6, 128.0, 127.4, 127.3, 127.0, 126.0, 125.5, 121.7, 118.5, 91.4, 89.2, 66.0, 43.0, 34.2, 30.3, 16.5; HRMS exact mass calcd for (C24H20O2) requires m/z 341.1541, found m/z 341.1542; [α]D=−82.4(c=1.0, CHCl3).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:15])[CH2:11][CH2:12][O:13][CH3:14])[CH:6]=[CH:7][CH:8]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:15])[CH2:11][CH2:12][O:13][CH3:14])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: COCCC(=O)Nc1cccc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: COCCC(=O)Nc1cccc(C=O)c1
Temperature: 25 °C

Procedure:
The above 1.26 g N-(3-Hydroxymethyl-phenyl)-3-methoxy-propionamide were dissolved in 50 ml acetone, 12.60 g manganese dioxide were added and the mixture stirred at room temperature over night. The mixture was filtered and the filtrate evaporated and further purified by chromatography on silica in ethyl acetate/heptane mixtures.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([Cl:13])[N:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+]>CC(C)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([N:14]=[N+:15]=[N-:16])[CH:9]=[C:8]([Cl:13])[N:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1cc(Cl)nc(-c2ccco2)n1
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=Nc1cc(Cl)nc(-c2ccco2)n1

Procedure:
2-(2-Furyl)-4,6-dichloropyrimidine (m.p. 68° - 70°C.) was reacted with sodium azide in aqueous acetone to give 2-(2-furyl)-4-azido-6-chloropyrimidine (m.p. 117° - 119°C.) and this was then nitrated to give 2-(5-nitro-2-furyl)-4-azido-6-chloropyrimidine (m.p. 114° - 116°C.) which was, in turn, reacted with hydrazine hydrate in isopropanol.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)[N:19]=2)=[C:9]1[CH3:42])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:40][C:38]([F:39])([F:41])[O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:20]2[N:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:43])=[O:5])[C:9]=3[CH3:42])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:28])=[O:29])=[CH:32][CH:33]=1
Reactant: Cc1c(C2=NN(Cc3ccc(OC(F)(F)F)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(Cc3ccc(OC(F)(F)F)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(4-Trifluoromethoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.17 (d, 1H), 7.93 (t, 1H), 7.85 (t, 1H), 7.50 (m, 3H), 7.38 (m, 3H), 6.89 (dt, 1H), 6.59 (dd, 1H), 5.11 (bs, 2H), 4.52 (s, 2H), 2.08 (s, 3H) ppm. MS calculated for C26H19F4N3O5S—H: 560, observed: 560.
Reaction SMILES: [OH-].[Li+].O.C([O:6][P:7]([CH2:15][C@@H:16]([OH:19])[CH2:17][NH2:18])([CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)=[O:8])C>C(O)C>[NH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][P:7]([CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)(=[O:6])[OH:8]
Reactant: CCOP(=O)(C[C@@H](O)CN)C1CC=CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC[C@H](O)CP(=O)(O)C1CC=CCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.2 g of lithium hydroxide and 4 ml of water are added to a solution of 1.1 g of 3-amino-2(S)-hydroxy-propyl-(cyclohex-3-enyl)-phosphinic acid ethyl ester in 4 ml of ethanol. The mixture is heated to 60° and stirred for 20 hours. The mixture is then allowed to cool to room temperature, adjusted to pH 7 with aqueous phsophoric acid, concentrated to dryness by evaporation, taken up with methanol/water and filtered. After removal of the solvent there remains behind a foam which, after crystallisation from ethanol/methanol, yields 3-amino-2(S)-hydroxy-propyl-(cyclohex-3-enyl)-phosphinic acid in the form of white crystals having a melting point of 221°-225°.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH2:1][CH2:2][CH2:3][CH2:4]2)=[O:12]
Reactant: c1ccc2c(c1)CCCC2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)CCCC2

Procedure:
Compound 12 was prepared by an alternate procedure as follows: Tetralin was formylated with dichloromethyl methyl ether and titanium tetrachloride catalyst to give 6-formyltetralin. Reaction of the aldehyde with malonic acid in the presence of an amine catalyst gave the substituted acrylic acid. Catalytic hydrogenation of the double bond gave the corresponding substituted propionic acid, 3-(6-tetralyl)propionic acid. Conversion of the acid to the acid chloride with phosphorus pentachloride followed by cyclization with aluminum chloride gave the desired 2,3,5,6,7,8-hexahydro-1H-benz[f]inden-1-one.