Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:16][O:15][C:14]2[C:5](=[CH:6][C:7]3[C:8]([C:21]([F:24])([F:23])[F:22])=[CH:9][C:10]([O:17][CH:18]([CH3:20])[CH3:19])=[N:11][C:12]=3[CH:13]=2)[N:4]1[CH2:25][C:26]([F:29])([F:28])[F:27].[H-].[Na+].I[CH3:33]>C1COCC1>[CH:18]([O:17][C:10]1[CH:9]=[C:8]([C:21]([F:22])([F:23])[F:24])[C:7]2[CH:6]=[C:5]3[N:4]([CH2:25][C:26]([F:28])([F:29])[F:27])[CH:3]([CH2:2][O:1][CH3:33])[CH2:16][O:15][C:14]3=[CH:13][C:12]=2[N:11]=1)([CH3:20])[CH3:19]
Reactant: CI
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)OCC(CO)N3CC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1COc2cc3nc(OC(C)C)cc(C(F)(F)F)c3cc2N1CC(F)(F)F
Yield: 78.9 %

Procedure:
This compound was prepared by General Method 16 from (±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (EXAMPLE 28) (10 mg, 0.024 mmol), NaH (4.7 mg, 0.12 mmol) and iodomethane (17 mg, 0.12 mmol) in 0.6 mL THF to afford 8.3 mg (81%) of (±)-2,3-dihydro-7-isopropoxy-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a yellow solid, after flash chromatography (5:1 hexanes:EtOAc). Data for (±)-2,3-dihydro-7-isopropoxy-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: Rf 0.21 (3:1 hexanes: EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.14 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J =6.2), 4.43 (dd, 1H, J=11.0, 1.6), 4.16 (dd, J=11.0, 2.6), 3.98-4.21 (m, 2H), 3.67-3.73 (m, 1H), 3.50-3.60 (m, 2H), 3.37 (s, 3H), 1.38 (d, 6H, J=6.2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[N:6][CH:7]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:18][N:17]=2)=[N:6][CH:7]=1
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)nnn2C)nc1
Yield: 41 %

Procedure:
As described for example 35b, 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (82 mg, 0.25 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (38 mg, 41%) which was obtained as a white solid. MS: m/e=371.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[C:14]([C:12]1[CH:13]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:35]3[CH:34]=[CH:33][C:32]([CH2:31][N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[CH:37][CH:36]=3)[CH:3]=2)[N:9]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:11]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CN1CCN(Cc2ccc(B(O)O)cc2)CC1
Reactant: CC(C)(C)c1cc(-c2cncc(Br)c2)nc(-c2ccccn2)n1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CN1CCN(Cc2ccc(-c3cncc(-c4cc(C(C)(C)C)nc(-c5ccccn5)n4)c3)cc2)CC1

Procedure:
To a solution of 4-(5-bromo-pyridin-3-yl)-6-tert-butyl-2-pyridin-2-yl-pyrimidine (1 eq, 200 mg, 0.542 mmol) in EtOH/DME (2 ml, 1:1) is added 4-(4-methyl-piperazin-1-ylmethyl)-phenyl-boronic acid (1.1 eq, 174 mg, 0.596 mmol), aqueous Na2CO3 solution (2 M, 3 eq, 0.812 ml, 1.63 mmol) and Pd(PPh3)4 (0.05 eq, 31 mg, 0.027 mmol). The resulting mixture is heated using microwave radiation for 20 min at 140° C. The mixture is filtered, washed with DCM and concentrated in vacuo. The residue is partitioned between sat. aqueous NaHCO3 solution and DCM and the organic layer is washed with brine, dried (MgSO4) concentrated under reduced pressure. The resulting residue is purified by reverse phase chromatography yielding the title compound; [M+H]+=479. 1H NMR (CDCl3, 400 MHz): 9.26 (d, 1H), 8.95 (d, 1H), 8.87 (m, 1H), 8.66 (t, 1H), 8.62 (m, 1H), 7.88 (td, 1H), 7.77 (s, 1H), 7.64 (d, 2H), 7.47 (d, 2H), 7.41 (ddd, 1H), 3.58 (s, 2H), 2.60-2.43 (m, 8H), 2.32 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]([F:26])([F:25])[O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)=[O:19])[CH:14]=[CH:15][CH:16]=1.[C:27]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][C:40](O)=[O:41])=[CH:31]1)(=[O:29])[NH2:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[F:26][C:9]([F:25])([F:8])[O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:40](=[O:41])[CH2:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]([C:27]([NH2:28])=[O:29])[CH:31]=2)=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CCCN1
Reactant: NC(=O)n1cc(CC(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)n1cc(CC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(S)-Pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl)-amide TFA salt (59.3 mg, 0.153 mmol, prepared as described in Sheme D5 steps A and B), (1-carbamoyl-1H-indol-3-yl)-acetic acid (40 mg, 0.183 mmol, prepared as described in Scheme A8) and HBTU (86.9 mg, 0.229 mmol) were dissolved in CH2Cl2 (4 mL) under nitrogen, DIPEA (52.3 μl, 0.306 mmol) was added and the reaction mixture was stirred at RT for 5 h. After completion of the reaction aqueous 1N HCl and EtOAc were added, the layers were separated and the aqueous one back-extracted twice with EtOAc. The combined organic extracts were washed with an aqueous saturated solution of NaHCO3, dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19×50 mm, 20% CH3CN/H2O 2.5 min, 20-100% CH3CN/H2O in 10 min, CH3CN/H2O containing 0.1% HCOOH flow: 20 mL/min) to give after extraction of the pure fractions the desired compound. MS (LC/MS): 475 [M+H]+, 497 [M+Na]+; tR (HPLC conditions a) 3.47 min. DMF can also be used instead of Dichloromethane.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[N:4]([C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH:3]=1.Cl.[CH3:27][NH2:28]>>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[N:4]([C:19]2[N:20]=[CH:21][N:22]=[C:23]([NH:28][CH3:27])[CH:24]=2)[CH:3]=1
Reactant: CN
Reactant: COc1ccc(-c2ccc3c(Br)cn(-c4cc(Cl)ncn4)c3c2)cc1
Agent: Cl
Product: CNc1cc(-n2cc(Br)c3ccc(-c4ccc(OC)cc4)cc32)ncn1

Procedure:
The target compound was prepared as in Example 10 using 3-bromo-1-(6-chloropyrimidin-4-yl)-6-(4-methoxyphenyl)-1H-indole (400 mg, 0.96 mmol) and methylamine hydrochloride (326 mg, 4.8 mmol).
Reaction SMILES: C(OC1C=CC(C(C2CCN(CC(O)=O)CC2)=O)=CC=1)C.FC1C=CC(C(C2CCN(CC(O)=O)CC2)=O)=CC=1.[CH3:41][O:42][CH2:43][CH2:44][O:45][C:46]1[CH:63]=[CH:62][C:49]([C:50]([CH:52]2[CH2:57][CH2:56][N:55]([CH2:58][C:59]([OH:61])=[O:60])[CH2:54][CH2:53]2)=[O:51])=[CH:48][CH:47]=1.[NH2:64][CH2:65][C:66]1[NH:67][C:68](=[O:76])[C:69]2[CH2:75][O:74][CH2:73][CH2:72][C:70]=2[N:71]=1.C(O)(C(F)(F)F)=O>C(#N)C.O.COCCO>[CH3:41][O:42][CH2:43][CH2:44][O:45][C:46]1[CH:47]=[CH:48][C:49]([C:50]([CH:52]2[CH2:57][CH2:56][N:55]([CH2:58][C:59]([OH:61])=[O:60])[CH2:54][CH2:53]2)=[O:51])=[CH:62][CH:63]=1.[CH3:41][O:42][CH2:43][CH2:44][O:45][C:46]1[CH:47]=[CH:48][C:49]([C:50]([CH:52]2[CH2:53][CH2:54][N:55]([CH2:58][C:59]([NH:64][CH2:65][C:66]3[NH:67][C:68](=[O:76])[C:69]4[CH2:75][O:74][CH2:73][CH2:72][C:70]=4[N:71]=3)=[O:61])[CH2:56][CH2:57]2)=[O:51])=[CH:62][CH:63]=1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Agent: COCCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Agent: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: CC#N
Solvent: COCCO
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)COCC4)CC2)cc1

Procedure:
{4-[4-(2-Methoxy-ethoxy)-benzoyl]-piperidin-1-yl}-acetic acid was prepared following the general procedures for the synthesis of 2-(4-(4-ethoxybenzoyl)piperidin-1-yl)acetic acid from 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid and 2-methoxy-ethanol. The title compound (190 mg, 0.373 mmol) was prepared following the general procedure of Example 1 from {4-[4-(2-methoxy-ethoxy)-benzoyl]-piperidin-1-yl}-acetic acid and 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one. MS (ESI) m/z 484.8 (M+H+); HPLC (Insertsil ODS3 100×3 mm C-18 column: mobile phase: 5-95% acetonitrile/water with 0.1% TFA, at 1 mL/min over 7.75 min.) t=1.46 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.83 (m, 6H), 2.20-2.33 (m, 2H), 2.51 (br. s., 2H), 2.92-3.03 (m, 4H), 3.24-3.41 (m, 4H), 3.65-3.71 (m, 2H), 3.82 (t, J=5.31 Hz, 2H), 4.16-4.24 (m, 2H), 4.34 (s, 2H), 7.05 (d, J=8.59 Hz, 2H), 7.95 (d, J=8.59 Hz, 2H), 8.24 (br. s., 1H), 12.38 (br. s., 1H). HRMS calculated for C25H33N4O6: 485.2400 (M+H). found (ESI, [M+H]+): 485.2394.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([CH3:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[CH3:37][C:30]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:35])=[O:34]
Reactant: Cc1ccc(Br)cc1S(N)(=O)=O
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(N)(=O)=O

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (156 mg, 0.4 mmol) and 5-Bromo-2-methyl-benzenesulfonamide (example B.18) (124 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (22 mg, 10%). MS (ISP) 525.3 [(M+H)+]; mp 255-267° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[CH2:10]([O:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(O)cc(Br)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Br)cc(OCc2ccccc2)c1

Procedure:
A mixture of 3-bromo-5-methylphenol [(40.7 g, 218 mmol) J. Amer. Chem. Soc., 2003, 125, 7792)], benzyl bromide (28.6 mL, 239 mmol) and potassium carbonate (90.2 g, 653 mmol) in acetone (1 L) was heated under reflux for 2 hours. The cooled reaction mixture was then acidified with 2M hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic solution was washed with brine (×3), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a red oil in quantitative yield.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[CH2:12][NH2:13].C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[CH2:12][NH:13][C:1](=[O:3])[CH3:2]
Reactant: NCc1cc(Br)ccc1F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)NCc1cc(Br)ccc1F
Reaction time: 3 h
Yield: 95.7 %

Procedure:
Add acetyl chloride (0.18 mL, 2.49 mmol) to a mixture of 5-bromo-2-fluorobenzylamine hydrochloride (500 mg, 2.08 mmol) in dichloromethane (8 mL) and diisopropylethylamine (0.90 mL, 5.20 mmol) and stir 3 h. Dilute with diethyl ether and separate the layers. Wash the organic layer twice with 1 N hydrochloric acid and once with an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate to give the title compound as a white crystalline solid (490 mg, 96%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].[OH:11]S(O)(=O)=O>[O-2].[O-2].[Mn+4]>[CH2:1]([C:4]1[C:5](=[O:10])[CH:6]=[CH:7][C:8](=[O:11])[CH:9]=1)[CH2:2][CH3:3]
Reactant: O=S(=O)(O)O
Reactant: CCCc1ccccc1O
Agent: [Mn+4]
Agent: [O-2]
Product: CCCC1=CC(=O)C=CC1=O

Procedure:
Manganese dioxide (45 g) was stirred in 25% H2SO4 (1300 ml) at room temperature. 2-propylphenol (90 g) was added followed by managanese dioxide (270 g), added over 1 hr to maintain a reaction temperature below 50° C. After a further 11/2 hours the reaction mixture was steam distilled, the distillates extracted with chloroform and the chloroform evaporated to yield propyl-p-benzoquinone (7 g), delta H(CDCl3) 1.00 (3H, t, J8.0Hz), CH3), 1.57(2H, tq, J 8.0,8.0Hz, CH2), 2.42(2H,t,J 8.0Hz, CH2), 6.58-6.82 (3H, m, CH).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>O>[CH3:15][C:14]([NH:18][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:17])[CH3:16]
Reactant: CC(=O)c1ccc(OCCCl)cc1
Reactant: CC(C)(C)N
Solvent: O
Product: CC(=O)c1ccc(OCCNC(C)(C)C)cc1
Temperature: 120 °C

Procedure:
A mixture of 6.5 g of the product of Step A in 30 ml of tert.-butylamine was heated at 120° C. for 30 hours and was then diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over a deshydrant, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 7.264 g of 1-[4-{-2-(1,1-dimethylethylamino)-ethoxy}-phenyl]-ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=[O:13])[CH2:11][CH3:12].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=[O:13])[C:11](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12]
Reactant: O=Cc1ccccc1
Reactant: CCC(=O)c1cc(C)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C)cc1C(=O)C(C)=Cc1ccccc1
Yield: 101.3 %

Procedure:
To a mixture of 140 g of 2'-methoxy-5'-methylpropiophenone, 83.4 g of benzaldehyde and 1.5 lilers of ethanol was added 154 ml of 20%-sodium hydroxide aqueous solution under stirring. The reaction mixture was stirred overnight at room temperature, then 10%-hydrochloric acid was added to make the reaction mixture acidic, and extracted with benzene. The benzene extract was washed with water and an aqueous solution saturated with sodium chloride in this order, then dried to obtain 212 g of 2'-methoxy-5'-methyl-2-benzylidenepropiophenone. Yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([CH:8]1[CH2:10][CH2:9]1)=[O:7])[CH3:2].[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[CH2:23][C:24](Cl)=[O:25]>>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([C:6]([CH:8]1[CH2:10][CH2:9]1)=[O:7])[C:24](=[O:25])[CH2:23][N:14]1[C:15](=[O:22])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]1=[O:12])[CH3:2]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)CC(=O)C1CC1
Product: CCOC(=O)C(C(=O)CN1C(=O)c2ccccc2C1=O)C(=O)C1CC1
Yield: 60 %

Procedure:
In analogy to the procedure described in Example 160A], 3-cyclopropyl-3-oxo-propionic acid ethyl ester and (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetyl chloride gave the title compound as a white solid (60%). MS: 342.1 (M−H−).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH:10](=O)[CH2:11][CH:12]([CH3:14])[CH3:13].[OH-].[Na+]>[Pd].C(O)C>[CH3:13][CH:12]([CH2:11][CH3:10])[CH2:14][NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)CC=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C)CN[C@@H](CC(C)C)C(=O)O
Yield: 32.6 %

Procedure:
A vessel containing 100 g of L-Leucine, 1600 mL of ethanol, 8 g of 2% Pd/C, and 131.5 g of isovaleraldehyde was shaken under hydrogen. After the reaction was finished, the ethanol solution was collected by filtration. Then 300 mL of concentrated HCl was added to the Pd/C-compound mixture, and the mixture was filtered again to give the second filtrate. The second filtration provided the product in concentrated HCl, and it was added NaOH to pH 6.5. The product precipitated out as a white solid, and it was collected by filtration. The crude product was washed with water (200 mL) and acetone (300 mL), then it was dried under vacuum to yield N-(2-methylbutyl)-leucine (50 g); mp 275° C. (dec.).
Reaction SMILES: [F:1][C:2]([CH3:18])([CH3:17])[C@@H:3]([CH:13]1[CH2:16][NH:15][CH2:14]1)[C:4]1[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[C:6]([F:12])[CH:5]=1.Br[CH:20]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C@H:20]([N:15]2[CH2:16][CH:13]([C@@H:3]([C:4]3[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[C:6]([F:12])[CH:5]=3)[C:2]([F:1])([CH3:18])[CH3:17])[CH2:14]2)[C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[CH:34][CH:33]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CSc1cc(F)cc([C@H](C2CNC2)C(C)(C)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CSc1cc(F)cc([C@H](C2CN([C@@H](c3ccc(Cl)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1

Procedure:
A sample of 0.233 mg (0.86 mmole) of 3-{(1S)-2-fluoro-1-[3-fluoro-5-(methylthio)phenyl]-2-methylpropyl}azetidine was alkylated with 263 mg (0.86 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile and 0.975 mg (3 mmole) of Cs2CO3 as described in Step 2 of Example 79 to afford the title compound; Mass Spectrum: m/e=497 (M+1, 35Cl); 499 (M+1, 37Cl)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17][C:18]([CH3:25])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Sc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Sc1ccc2c(-c3ccc(Cl)cc3)noc2c1)C(=O)O

Procedure:
A solution of 3.7 g of ethyl 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionate, 30 ml of 15% sodium hydroxide solution and 30 ml of methanol, is stirred under reflux for 3 hr. The methanol is evaporated and the aqueous solution poured into ice/dilute hydrochloric acid. The precipitate is collected, dried and recrystallized from toluene to afford 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6yl]thio}-2-methylpropionic acid, mp 176°-7° C.
Reaction SMILES: Cl.F[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2.[NH2:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1>>[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([O:20][C@@H:17]3[CH2:18][CH2:19][C@H:14]([NH2:13])[CH2:15][CH2:16]3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Fc1ccc2cnccc2c1
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: Cl
Product: N[C@H]1CC[C@@H](Oc2ccc3cnccc3c2)CC1

Procedure:
Starting from 6-fluoro-isoquinoline hydrochloride and cis-4-amino-cyclohexanol the title compound was prepared following the protocol described for compound (15). Rt=0.64 min (Method B). Detected mass: 243.2 (M+H+).
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[O:20][C:19](=[O:21])[C:18]([CH2:28][CH3:29])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>[Pd].C(O)C.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH2:28][CH3:29])[C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCC1(c2ccccc2)OC(c2ccc(-c3ccc(Cl)cc3)cc2)OC1=O
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)c1ccccc1
Reaction time: 4 h

Procedure:
Hydrogen gas was allowed to react with a stirred suspension of 2-[4-(4-chlorophenyl)phenyl]-5-ethyl-5-phenyl-1,3-dioxolan-4-one (3.8 g.) and 5% w/w palladium on carbon (0.2 g.) in ethanol (160 ml.) at 55° to 60° C. and atmospheric pressure for four hours. The mixture was diluted with toluene (50 ml.). The solid material was separated by filtration and the filtrate was evaporated. The resultant solid may be purified by high pressure liquid chromatography on "Spherisorb"* 5μ ODS solid phase using an eluant containing acetonitrile (62% v/v), water (37.9% v/v) and phosphoric acid (0.1% v/v) using ultraviolet absorbance at 262 μm for detection to give 2-[4-(4-chlorophenyl)benzyloxy]-2-phenylbutyric acid identical to that obtained in previous examples.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C:18]5=[O:22])=[CH:13][CH:12]=4)([CH2:5][CH:6]1[CH2:7]3)[CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]#[N:39])=[O:32]>CS(C)=O.CCOC(C)=O>[O:22]=[C:18]1[CH2:19][CH2:20][CH2:21][N:17]1[C:14]1[CH:15]=[CH:16][C:11]([C:4]23[CH2:10][CH:8]4[CH2:9][C:2]([NH:1][CH2:30][C:31]([N:33]5[CH2:37][CH2:36][CH2:35][C@H:34]5[C:38]#[N:39])=[O:32])([CH2:3]2)[CH:6]([CH2:7]4)[CH2:5]3)=[CH:12][CH:13]=1
Reactant: NC12CC3CC1CC(c1ccc(N4CCCC4=O)cc1)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCCC4=O)cc1)(C3)C2
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To a stirred solution of 1-[4-(3-aminotricyclo[3.3.1.03,7]non-1-yl)phenyl]pyrrolidin-2-one obtained in step II (0.36 g, 1.2 mmol) in DMSO (4.8 mL) at an ice bath temperature under nitrogen atmosphere was added K2CO3 (0.48 g, 3.6 mmol) followed by addition of (2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.21 g, 1.2 mmol). After stirring the reaction mixture at r.t for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain the title compound (2S)-1-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a white solid (0.26 g) in 50% yield. M.R: 254-256° C.; m/z (M+1) 433; 1H NMR (300 MHz, CDCl3) δ: 7.54 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.30-4.20 (m, 1H), 4.06-4.18 (m, 2H), 3.87 (t, J=7.0 Hz, 1H), 3.80-3.50 (m, 4H), 2.64 (t, J=7.8 Hz, 2H), 2.58-1.60 (m, 18H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH:15]([O:18][C:19]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:20]=1[C:21](O)=[O:22])([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[CH2:9][N:8]([C:21]([C:20]1[CH:24]=[C:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=[CH:27][C:19]=1[O:18][CH:15]([CH3:17])[CH3:16])=[O:22])[CH2:7][CH2:6]2
Reactant: COc1cc2c(c(OC)c1)CNCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: COc1cc2c(c(OC)c1)CN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)CC2

Procedure:
Prepared in analogy to example 1.1 from 6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (CA [88207-92-5]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).