Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][OH:8].[H-].[Na+].[Br:11][C:12]1[C:13](Cl)=[N:14][C:15]([Cl:18])=[N:16][CH:17]=1>C1COCC1>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:13]1[C:12]([Br:11])=[CH:17][N:16]=[C:15]([Cl:18])[N:14]=1
Reactant: OC[C@H]1COCCO1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ncc(Br)c(OC[C@H]2COCCO2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17.7 %

Procedure:
To a solution of (S)-(1,4-dioxan-2-yl)methanol (185 mg, 1.6 mmol) in anhydrous THF (2 mL), was added NaH (60% oil dispersion, 42 mg, 1.04 mmol). The mixture was stirred at room temperature for 2.5 h. The reaction mixture was cooled to −20° C. and 5-bromo-2,4-dichloropyrimidine (252 mg, 1.04 mmol) was added at once. The resulting mixture was stirred between −15° C. and 15° C. for 6 h and quenched with water. The aqueous solution was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified on ISCO (hexane/ethyl acetate gradient, 5-20%) to give the title compound (57 mg, 17.7%) as colorless oil. 1HNMR (CDCl3, 400 MHz): 8.44 (s, 1H), 4.47 (dd, J1=5.5 Hz, J2=11.7 Hz, 1H), 4.43 (dd, J1=4.5 Hz, J2=11.7 Hz, 1H), 3.98-4.04 (m, 1H), 3.72-3.91 (m, 4H), 3.61-3.69 (m, 1H), 3.55 (dd, J1=10.0 Hz, J2=11.5 Hz, 1H). MS (ESI) m/z: Found: 309.0 (M1+1); Calc. 308.0 (M+)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH:15]1([N:18]2[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[C:19]2=[O:26])[CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:23]([CH:20]1[CH2:21][CH2:22][N:18]([CH:15]2[CH2:17][CH2:16]2)[C:19]1=[O:26])=[O:24]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(C2CC2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(C2CC2)C1=O
Yield: 67.9 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-cyclopropyl-2-oxopyrrolidine-3-carboxylic acid (0.075 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 7 to 60% of ethyl acetate in dichloromethane) to give 0.0995 g (68%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-cyclopropyl-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][CH2:9][CH2:10][C:11]1[N:15]([CH2:16][CH2:17][C:18]#[N:19])[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O.O>[O:7]=[CH:8][CH2:9][CH2:10][C:11]1[N:15]([CH2:16][CH2:17][C:18]#[N:19])[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1
Reactant: N#CCCn1c(CCCO)nc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#CCCn1c(CCC=O)nc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 0.5 g of oxalyl chloride in 15 mL of methylene chloride cooled to −78° C. was added 1 mL of anhydrous DMSO. After 15 min, a solution of 1 g of 3-[2-(3-hydroxy-propyl)-benzimidazol-1-yl]-propionitrile in 50 mL of methylene chloride and 10 mL of anhydrous DMSO was added while keeping the temperature below −50° C. There was considerable precipitate which redissolved on warming to 0° C. over 20 min. After cooling back down to −50° C., 5 mL of triethyl amine was added and the mixture allowed to warm to room temperature. After 15 min, the mixture was diluted with 250 mL of water, shaken and separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude 3-[2-(3-oxo-propyl)-Benzimidazol-1-yl]-propionitrile was an amber resin (1 g), and contained only traces of the starting alcohol by TLC (90:10 methylene chloride:methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])=[C:6](B(O)O)[CH:7]=1.[CH2:17]([O:20][C:21]1([CH3:54])[CH2:26][CH2:25][N:24]([C:27]2[N:32]3[CH:33]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38](Br)[CH:37]=4)[N:35]=[C:31]3[CH:30]=[C:29]([CH3:43])[C:28]=2[C@H:44]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C:45]([O:47][CH3:48])=[O:46])[CH2:23][CH2:22]1)[CH:18]=[CH2:19].C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=CC(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:17]([O:20][C:21]1([CH3:54])[CH2:22][CH2:23][N:24]([C:27]2[N:32]3[CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([C:6]5[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=5[O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH:39]=[CH:40][CH:41]=4)[N:35]=[C:31]3[CH:30]=[C:29]([CH3:43])[C:28]=2[C@H:44]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C:45]([O:47][CH3:48])=[O:46])[CH2:25][CH2:26]1)[CH:18]=[CH2:19]
Reactant: C=CC[C@H](C)Oc1ccc(F)cc1B(O)O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(F)ccc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 82 %

Procedure:
Prepared in 82% yield from (S)-(5-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid and (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 684.4.
Reaction SMILES: [H][H].[CH:3]([OH:11])=[CH:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Ni].C(O)CCCCCCC>[CH2:3]([OH:11])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: CCCCC=CC=CO
Reactant: [H][H]
Agent: [Ni]
Solvent: CCCCCCCCO
Product: C=CCCCC=CCO
Temperature: 130 °C

Procedure:
A one-liter stainless steel autoclave equipped with thermometer, magnetic stirrer, liquid metering and feeding pump, hydrogen gas inlet, off gas flow meter, and liquid outlet was charged with 1.5 g of nickel-on-diatomaceous earth catalyst (Nissan-Girdler's G-69; Ni content 52 percent by weight) and 100 g of n-octanol. After sufficiently replacing the atmosphere with hydrogen gas, the system was heated to 160° C. with stirring. Then, the octadienol mixture obtained by the procedure mentioned above under (iii) was continuously fed to the system at the rate of 70 g per hour at the temperature of 160° C., hydrogen pressure of 10 kg/cm2 (gauge), rate of stirring of 500 rpm and off gas flow rate of 30 liters per hour, with stirring for 7 hours. After effecting the hydrogenation reaction in this manner, octadienol mixture feeding, hydrogen gas introduction and stirring were discontinued, and the reaction mixture was immediately removed from the system via the liquid outlet. After removing the catalyst by filtration, the mixture was analyzed by gas chromatography, whereupon it was revealed that the average conversion of octadienols to octanols was 98.5 percent and that the hydrogenation product contained small amounts of intermediary hydrogenation products, namely octenols. The filtrate obtained upon separation of the catalyst by filtration was charged into the above-mentioned autoclave. The autoclave was connected via the liquid feeding pump to a column hydrogenation reactor (50 mm in inside diameter and 250 mm in column length) packed with a nickel-on-diatomaceous earth (Nissan-Girdler's G-49B; Ni content 55 percent by weight) in the form of cylinders (3/16"×1/8"), containing 123 g of n-octanol, and fitted with a jacket. The autoclave and packed column were heated to 130° C., and hydrogen was introduced to the pressure of 5 kg/cm2 (gauge). The autoclave contents were saturated with hydrogen gas by stirring at the rate of 400 rpm. After the internal temperature and hydrogen pressure respectively became constant, the mixture was continuously fed from the autoclave to the bottom of the packed column hydrogenation reactor at the rate of 450 ml/hr (corresponding to the liquid space velocity of 3 hr-1). The hydrogenated mixture was continuously taken out from the top of the packed column into a one-liter reservoir autoclave by the overflow method. The finishing hydrogenation was carried out under said conditions continuously for 90 minutes. Gas chromatography and ultraviolet absorption spectrometry of the mixture taken out did not reveal the presence of octenols and octanals within the limits of analytical error.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[C:4]([C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:3]1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:12]3[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:5]=12
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(=O)[nH]cnc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Temperature: 0 °C

Procedure:
To a mixture of 5.0 grams of 1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 100 milliliters of phosphorus oxychloride were slowly added 48 grams of N,N-dimethylaniline. The mixture was heated under reflux for 2 hours, cooled and carefully added to 1 kilogram of crushed ice. The crystalline product was collected, washed with ether and dried. Recrystallisation from ethyl acetate gave 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine having melting point 195°C.
Reaction SMILES: CC([N:5]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:5][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:13][CH2:14]1
Reactant: COc1ccc(CN2CCC(N(C(=O)[O-])C(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN2CCC(N)CC2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 1,1-dimethylethyl1-[(4-methoxyphenyl)methyl]-4-piperidinylcarbamate (0.02 mole) and trifluoroacetic acid (0.01 mole) in 50 ml. of methylene chloride was refluxed for a 3 hr. period. Additional trifluoroacetic acid (0.08 mole) was added and reflux continued for an additional 30 minutes. The crude solution was evaporated in vacuo, residual material dissolved in water and the aqueous phase washed with ether and then made basic with 50% sodium hydroxide. Extraction of the basified solution with chloroform, drying of the chloroform extracts, and removal of the solvent afforded 4-amino-1-[(4-methoxyphenyl)methyl]piperidine in nearly quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.BrC1C=CC(N)=CC=1.[NH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]
Reactant: NCCCN1CCCC1=O
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Agent: Nc1ccc(Br)cc1
Product: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Yield: 87.8 %

Procedure:
6-Bromo-4-chloro-3-nitroquinoline (50.62 g, 177.8 mmol), prepared from 4-bromoaniline according to the methods described in Parts A–D of Example 1, was treated with 1-(3-aminopropyl)pyrrolidin-2-one (27.5 mL, 196 mmol) according to the method described in Part E of Example 1 to provide 61.41 g of 1-[3-(6-bromo-3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one as a solid.
Reaction SMILES: [CH2:1]([N:3]([C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][N:32]=1)=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=O>>[CH3:43][N:42]([CH3:44])[CH2:40][CH2:39][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][N:3]([CH2:1][CH3:2])[C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[N:32][CH:33]=1
Reactant: CN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cn1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C)cn1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 101.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(5-hydroxypyridine-2-carbonyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N,N-dimethylacetamide (12 mg) following the synthetic method of Example 404 described below and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[CH:8])(C)(=O)=O.[CH2:9]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:5]([N:19]1[CH2:20][CH2:21][CH:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:17][CH2:18]1)[CH2:6][C:7]#[CH:8]
Reactant: C#CCCS(C)(=O)=O
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCC(Cc2ccccc2)CC1
Yield: 94.6 %

Procedure:
A mixture of 1-mesylbut-3-yne (3.03 g, 20.0 mmol), 4-benzylpiperidine (4.21 g, 24.0 mmol) and K2CO3 (8.28 g, 60.0 mmol) in 50 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×30 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as pale yellow oil (4.30 g, 95%): 1H NMR (CDCl3) 1.32 (m, 2 H), 1.51 (m, 1 H), 1.65 (m, 2 H), 1.94 (m, 3 H), 2.36 (m, 2 H), 2.54 (m, 4 H), 2.86 (d, J=11.4 Hz, 2 H), 7.12-7.27 (m, 5 H).
Reaction SMILES: COC(C1(NC(=O)C2C=CC(OC)=C(Br)C=2)CC2C(=CC=CC=2)C1)=O.C(C1C=C(B(O)O)C=CC=1)(C)C.[F-].[Cs+].C[O:41][C:42]([C:44]1([NH:53][C:54]([C:56]2[CH:57]=[C:58]([C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([CH:70]([CH3:72])[CH3:71])[CH:65]=3)[C:59]([O:62][CH3:63])=[CH:60][CH:61]=2)=[O:55])[CH2:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45]1)=[O:43].[OH-].[Li+]>CN(C=O)C.C1COCC1.O.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.C1(C)C=CC=CC=1>[CH:70]([C:66]1[CH:65]=[C:64]([C:58]2[C:59]([O:62][CH3:63])=[CH:60][CH:61]=[C:56]([C:54]([NH:53][C:44]3([C:42]([OH:43])=[O:41])[CH2:52][C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45]3)=[O:55])[CH:57]=2)[CH:69]=[CH:68][CH:67]=1)([CH3:72])[CH3:71]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(-c3cccc(C(C)C)c3)c2)Cc2ccccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)c1cccc(B(O)O)c1
Agent: COC(=O)C1(NC(=O)c2ccc(OC)c(Br)c2)Cc2ccccc2C1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1-c1cccc(C(C)C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
250 mg (0.62 mmol) of the compound of example 194, step 1, and 152.1 mg (0.93 mmol) of 3-isopropylphenylboronic acid were dissolved in 5 ml of DMF and 5 ml of toluene under an argon atmosphere. 187.9 mg (1.24 mmol) of cesium fluoride and 35.73 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium(0) were added, and the mixture was stirred overnight at 100° C. After cooling, the mixture was filtered and the solvent was evaporated. The obtained 2-[(3′-isopropyl-6-methoxy-biphenyl-3-carbonyl)-amino]-indane-2-carboxylic acid methyl ester was dissolved in 10 ml of a mixture of THF and water (9:1), 42.2 mg (1.80 mmol) of lithium hydroxide were added and the mixture was stirred overnight. The solvent was evaporated and the residue was purified by preparative RP HPLC (water/ACN gradient). 71 mg of the title compound were obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([CH3:26])([CH3:25])[C@H:9]([NH:17][C:18](=O)OC(C)(C)C)[C:10](=O)[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O.[OH-].[Na+]>C1COCC1>[CH3:18][NH:17][C@@H:9]([C:8]([CH3:26])([CH3:25])[CH3:7])[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCCC1)C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@H](CN1CCCC1)C(C)(C)C
Temperature: 55 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a 1M solution of LAH in THF (28.1 mL, 28.1 mmol) was (S)-tert-butyl 3,3-dimethyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-ylcarbamate (Compound F1) (2.0 g, 7.03 mmol) dropwise added (over approximately 60 min) as a solution in THF (40 mL) under a nitrogen atmosphere. The resultant mixture was stirred at rt for 30 min and heated at 55° C. over night. The reaction mixture was cooled to 0° C. Water (1.5 mL) was slowly added, followed by THF (10 mL), 15% aq. NaOH (1.5 mL) and additional water (4 mL). The reaction mixture was warmed to rt and stirred for 1 h. The mixture was filtered and the solid was washed with THF. The filtrate was dried (Na2SO4) and concentrated under reduced pressure to give the title compound (1.24 g, 96%). The obtained crude product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 0.90, 1.72-1.81, 2.08, 2.26, 2.32-2.48, 2.50, 2.53-2.68. Total no of protons: 23. LCMS (M+H)+: 185.
Reaction SMILES: [F-:1].[K+].CC(CC(O)CO)C.Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.C1(C)C(C)=CC=CC=1>[F:1][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1
Reactant: [F-]
Reactant: N#Cc1ccc(Cl)cc1
Agent: CC(C)CC(O)CO
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1C
Product: N#Cc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
In a 250 ml flange flask and fitted with an impeller stirrer, 69.6 g (1.2 mol) of potassium fluoride, 6.9 g (0.02 mol) of tetrabutyl-phosphonium bromide, 13.8 g (0.02 mol) of dimethyldi(ethoxypolyoxypropyl)ammonium chloride, 13.8 g (0.028 mol) of polyethylene glycol dimethyl ether 500 and 20 g of xylene were metered at 120° C. into the melt of 137.6 g (1.0 mol) of 4-chlorobenzonitrile. After stirring for 30 minutes, the reaction suspension was azeotropically dried by distilling off the xylene under vacuum. The reaction suspension was stirred for 30 hours at 190° C. Amount of 4-fluorobenzonitrile formed: after 9 hours: 12 GC area-% after 30 hours: 48 GC area-%, besides 45 GC area-% of unreacted 4-chlorobenzonitrile.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.O1CCCC1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:36]([CH:37]([OH:49])[C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)=[C:35]([CH:50]([CH3:52])[CH3:51])[CH:34]=[C:33]3[C:25]=2[C:26](=[O:53])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:20][CH:19]=1>CO>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:36]([C@H:37]([OH:49])[C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:47])([F:48])[F:46])=[CH:40][CH:39]=3)=[C:35]([CH:50]([CH3:51])[CH3:52])[CH:34]=[C:33]3[C:25]=2[C@@H:26]([OH:53])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:23]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](O)c1ccc(OC(F)(F)F)cc1)[C@@H](O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1.5 mg (0.01 mmol) of (1R,2S)-1-aminoindan-2-ol are dissolved in 1.5 ml of abs. tetrahydrofuran, 69 μl (0.39 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 50 mg (0.10 mmol) of 5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 58A), dissolved in 2 ml of abs. tetrahydrofuran, are added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature overnight. 2 ml of methanol are added, and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product is purified by preparative thick-layer chromatography (mobile phase: cyclohexane/ethyl acetate 5:1). This gives 13.5 mg (27% of theory, 78% ee) of Example 38 and 16.5 mg (33% of theory) of Example 39.
Reaction SMILES: C([O:3][C:4]([CH:6]([O:11][C:12](=[O:18])[C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[CH:7]1[CH2:10][O:9][CH2:8]1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].CO.Cl>O1CCCC1.O>[C:4]([CH:6]([O:11][C:12](=[O:18])[C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[CH:7]1[CH2:10][O:9][CH2:8]1)([OH:5])=[O:3]
Reactant: C=CC(C)(C)C(=O)OC(C(=O)OCC)C1COC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CC(C)(C)C(=O)OC(C(=O)O)C1COC1
Yield: 66.7 %

Procedure:
To a stirred solution of 2,2-dimethyl-but-3-enoic acid ethoxycarbonyl-oxetan-3-yl-methyl ester (207 mg, 0.808 mmol) in tetrahydrofuran (81 mL) was added a solution of potassium carbonate (123 mg, 0.888 mmol) in water (20.25 mL) followed by methanol (4.05 mL). The reaction mixture was heated to reflux for 7 h and then allowed to cool. Hydrochloric acid (2 M, 400 μL) was added (pH 7) and the solvents were evaporated. The residue was extracted with dichloromethane (2×) and the washes discarded. The aqueous was acidified with hydrochloric acid (2 M) to pH 5, extracted with dichloromethane (2×) and the combined organic extracts passed through a hydrophobic frit and evaporated. To the aqueous layer was added hydrochloric acid (about 5 drops) and the mixture was extracted with dichloromethane (2×) and the combined organic extracts passed through a hydrophobic frit, evaporated and combined with previous material to give the title compound (123 mg, 67%) as a yellow/green oil. 1H NMR (300 MHz, CDCl3) δ 1.39 (s, 3H), 1.40 (s, 3H), 3.54-3.67 (m, 1H), 4.67-4.75 (m, 2H), 4.81-4.92 (m, 2H), 5.14 (d, J=10.9 Hz, 1H), 5.15-5.32 (m, 2H), 6.08 (dd, J=17.5, 10.5 Hz, 1H), 9.30 (br s, 1H). LCMS (m/z) 229.1 [M+H] Tr=1.67 min.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2.[Cl:20][C:21]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[C:25]([Cl:32])[C:22]=1[CH2:23]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:20][C:21]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[C:25]([Cl:32])[C:22]=1[CH2:23][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CCl)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a mixture of sodium hydride (40% in oil, 2.64 g) and N,N-dimethylformamide (100 ml) was added 8-hydroxy-2-methylquinoline (10 g) in an ice-water bath. The mixture was stirred for 30 minutes at the same temperature and then 2,6-dichloro-3-nitrobenzyl chloride (15.1 g) and tetrabutylammonium iodide (100 mg) were added therein. The reaction mixture was stirred at ambient temperature for 1 hour. To this mixture was added water (100 ml) in an ice-water bath. The precipitates were collected by vacuum filtration and washed with water (60 ml) to give 8-(2,6-dichloro-3-nitrobenzyloxy)-2-methylquinoline (20.36 g) as a powder.