Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.O.NN>CO>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:20][CH3:21])[CH:12]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: COc1cc(N2CCN(CC3CC3)CC2)ccc1[N+](=O)[O-]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(N2CCN(CC3CC3)CC2)ccc1N
Yield: 90 %

Procedure:
A solution of 1-(cyclopropylmethyl)-4-[3-(methyloxy)-4-nitrophenyl]piperazine (1.05 g, 3.41 mmol), FeCl3 (0.165 g, 1.02 mmol), activated carbon (1.0 g), and hydrazine hydrate (1.3 mL, 41 mmol) was heated in methanol (50 mL) for 3 hours. Once the starting material was judged consumed by thin layer chromatography (10% MeOH/CH2CL2) the mixture was filtered over celite and concentrated to give 4-[4-(cyclopropylmethyl)-1-piperazinyl]-2-(methyloxy)aniline as a yellow solid (0.800 g, 3.07 mmol, 90% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.15 (q, J=4.89 Hz, 2 H), 0.52-0.60 (m, 2 H), 0.94 (d, J=6.23 Hz, 1 H), 2.35 (d, J=6.59 Hz, 2 H), 2.74 (s, 4 H), 3.07-3.15 (m, 4 H), 3.53 (s, 2 H), 3.83 (s, 3 H), 6.43 (dd, J=8.43, 2.20 Hz, 1 H), 6.53 (d, J=2.20 Hz, 1 H), 6.65 (d, J=8.06 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:13][C:14]1[N:15]=[C:16]([Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[S:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li][CH2:30][CH2:31][CH2:32][CH3:33]>C1COCC1>[CH2:1]([O:13][C:14]1[N:15]=[C:16]([Si:19]([CH:26]([CH3:27])[CH3:28])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:21])[CH3:22])[S:17][C:18]=1[C:18]1[S:17][C:16]([Si:19]([CH:23]([CH3:24])[CH3:25])([CH:26]([CH3:27])[CH3:28])[CH:20]([CH3:22])[CH3:21])=[N:15][C:14]=1[O:13][CH2:30][CH2:31][CH2:32][CH2:33][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1csc([Si](C(C)C)(C(C)C)C(C)C)n1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1nc([Si](C(C)C)(C(C)C)C(C)C)sc1-c1sc([Si](C(C)C)(C(C)C)C(C)C)nc1OCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 96.1 %

Procedure:
A solution of 6.24 g (14.7 mmol) of compound 11 in 150 mL of THF was cooled to −78° C. and treated dropwise with 6.45 mL (16.1 mmol) of n-BuLi (2.5 M in hexanes). The mixture was stirred for 45 minutes, then the dry ice bath was removed and the mixture was stirred at ambient temperature for 1 hour. The mixture was cooled to 0° C. and treated with 5.69 g (16.1 mmol) of Fe(acac)3 (Strem Chemicals, Inc.). The mixture was heated in an 80° C. oil bath for 2 h, cooled to room temperature, and filtered. The filter cake was washed with 3×25 mL of THF. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, 5.5×35 cm, chloroform) to give 6.0 g (96% yield) of compound 12 as a yellow oil. 1H NMR (500 MHz) δ 4.51 (t, 4H, J=6.3 Hz), 1.86-0.88 (m, 88H).
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].CCN(CC)CC.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:5][C@H:2]([CH3:1])[CH2:3][CH3:4])(=[O:16])=[O:15]
Reactant: CC[C@@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C)OS(C)(=O)=O
Temperature: 0 °C

Procedure:
An ice cold solution of (R)-2-butanol (888 mg) in DCM (15 ml) was treated with Et3N (1.26 ml) and followed by dropwise addition of methanesulfonyl chloride (0.52 ml). After 1 h the solution was washed with saturated sodium hydrogen carbonate solution (5 ml), water (2×5 ml), brine (5 ml), dried (MgSO4) and evaporated to give the title compound (D33)(0.9 g). 1H NMR δ (CDCl3): 4.74 (1H, m), 3.00 (3H, s), 1.67 (2H, m), 1.41 (1H, d, J=6.5 Hz), 0.99 (3H, t, J=7.5 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[OH:33])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=2)=[CH:40][CH:41]=1)[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(CCc2ccc(CCl)cc2)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1OCc1ccc(CCc2ccc(F)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
10 g (21.81 mmol) of rac-ethyl 5-{(tert-butoxycarbonyl)[2-(5-fluoro-2-hydroxyphenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 106A), 5.98 g (23.99 mmol) of 1-(chloromethyl)-4-[2-(4-fluorophenyl)ethyl]benzene and 4.52 g (32.71 mmol) of potassium carbonate in 240 ml of acetonitrile were heated to 110° C. and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). This gave 14.11 g (21.03 mmol, 96% of theory) of the target compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].O.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1C=CC=CC=1.O>[C:8]1([CH3:18])[CH:9]=[CH:10][C:11]([S:14]([OH:17])(=[O:15])=[O:16])=[CH:12][CH:13]=1.[CH2:32]([O:5][C:4](=[O:6])[C@H:2]([CH3:3])[NH2:1])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)[C@H](C)N
Reaction time: 11 h
Yield: 95 %

Procedure:
4.46 g (0.05 mole) of L-alanine was used, 11.4 g (0.06 mole) of p-toluenesulfonic acid hydrate was used, and 11.79 g (0.055 mole) of myristyl alcohol was used as an alcohol. After 200 ml of benzene was added thereto as a solvent, these materials were stirred and mixed well. The resulting mixture was heated at the reflux temperature of benzene to carry out the esterification reaction. In this case, water was formed with the progress of the esterification reaction and released in the form of an azeotropic mixture with benzene, which was continuously removed from the reaction system. Thus, the reaction was completed in about 7-15 hours. Then, the reaction mixture was concentrated under reduced pressure to remove the benzene used as solvent. After the addition of ether and petroleum ether, the precipitated crystals were collected by filtration. These crude crystals were recrystallized from acetone, ether, petroleum ether and the like to obtain 21.74 g (95% yield) of L-alanine myristyl ester p-toluenesulfonate. An infrared absorption spectrum of the L-alanine myristyl ester p-toluenesulfonate thus obtained is shown in FIG. 3. In this figure, the peak 5 indicates the absorption of light by a parasubstituted phenyl group, the peaks 6 and 7 by the ester linkage, the peak 8 by sulfonic acid, the peaks 9 and 10 by a primary amine salt, and the peak 11 by the C=O stretching vibration originating from the ester linkage.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:26]I>CN(C)C=O.O>[CH3:26][N:19]1[C:20]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:17][C:18]1=[O:23]
Reactant: O=C1CCc2cc(OCCCCSc3ccccc3)ccc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(OCCCCSc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16.2 gm of 6-(4-phenylmercapto-butoxy)-3,4-dihydro-carbostyril were dissolved in 100 ml of dimethylformamide, and 4.8 gm of a 50% sodium hydride suspension in paraffin oil were added to this solution. After addition of 12.5 ml of methyl iodide, the mixture was stirred for 3 hours at room temperature, diluted with water and extracted with chloroform. The evaporation residue of the chloroform extract was recrystallized with methanol in the presence of activated charcoal.
Reaction SMILES: [C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[C:20](O)=[O:21])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:32]([O:36][C:37](=[O:49])[NH:38][CH2:39][C@@H:40]([NH2:48])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:35])([CH3:34])[CH3:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:32]([O:36][C:37](=[O:49])[NH:38][CH2:39][C@@H:40]([NH:48][C:20]([C:8]1[C:9]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][CH:13]=[CH:12]3)[NH:19][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:21])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1)NC(=O)c1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a suspension of 2-phenyl-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid G2 (0.087 mmol) in DMF (1 mL), DIEA (0.26 mmol) and ((S)-2-amino-3-phenyl-propyl) -carbamic acid tert-butyl ester (0.13 mmol) were added. The mixture was cooled to 0° C., EDCI hydrochloride (0.13 mmol) and HOBT (0.13 mmol) were added and stirring was kept overnight at rt. The suspension was filtered and the solid was washed with aq saturated NaHCO3 and with water. After drying, the title compound was isolated in 43% yield. ESI (+) MS: m/z 521 (MH+). 1H NMR: 1.40 (s, 9H) 2.80-2.89 (m, 1H) 3.00-3.11 (m, 2H) 3.12-3.21 (m, 1H) 4.18-4.30 (m, 1H) 6.91-6.97 (m, 1H) 7.00-7.06 (m, 1H) 7.16-7.23 (m, 1H) 7.25-7.34 (m, 4H) 7.37-7.43 (m, 1H) 7.49-7.56 (m, 2H) 7.88 (d, J=7.62, 2H) 8.00 (d, J=9.00, 1H) 8.31 (d, J=9.00, 1H) 8.72 (s, 2H) 9.51 (s, 1H) 11.72 (bs, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:13][C:14]([F:32])([F:31])[C:15]1[N:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.N>ClCCl>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:32])([F:13])[F:31])[N:20]=2)=[CH:27][CH:26]=1
Reactant: NCCc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Reactant: Fc1cccc2c(Cl)ccnc12
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cccc2c(NCCc3ccc(Oc4cccc(C(F)(F)F)n4)cc3)ccnc12
Yield: 58.5 %

Procedure:
A mixture of 4-chloro-8-fluoroquinoline (1.81 g, 0.01 mol), and 2-(4-(6-trifluoromethyl-2-pyridinyloxy)-phenyl)ethylamine (2.82 g, 0.01 mol), triethylamine (1.1 g, 0.011 mol) was heated at 180°-190° C. for two hours and allowed to cool to a glass. Dichloromethane (50 mL) and concentrated ammonia solution (50 mL) were added, and the mixture was stirred until the glass dissolved. The organic phase was washed with 0.5M sodium hydroxide solution and water, and was dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and recrystallization from ethyl acetate:hexane gave 2.5 g of product. MP 157° C.
Reaction SMILES: O1CCCCC1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C4CCCCO4)[CH:18]=3)[CH:12]=[C:13]2[NH2:16])=[N:8]1.CCN(C(C)C)C(C)C.[CH:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.[OH-].[Na+]>C(Cl)Cl>[OH:23][C:19]1[CH:18]=[C:17]([C:11]2[CH:12]=[C:13]3[C:14]([CH:15]=[N:7][NH:16]3)=[C:9]([NH:8][C:45]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:46])[CH:10]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1cc(-c2cccc(OC3CCCCO3)c2)cc2nn(C3CCCCO3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(-c2cccc(O)c2)cc2[nH]ncc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Tetrahydro-2H-pyran-2-yl)-6-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-indazol-4-amine (50 mg, 0.127 mmol) was dissolved in DCM (1 ml) and DIPEA (0.111 ml, 0.635 mmol) and cyclohexanecarbonyl chloride (45 mg, 0.254 mmol) were added. The reaction was stirred at RT for 1 h. 2 M Sodium hydroxide (aq) (2 ml) was added and the reaction stirred at RT for 1 h, before the organic layer was passed through a hydrophobic frit. The aqueous layer was washed several times with DCM, which was passed through a hydrophobic frit. The combined organic layers were evaporated under a stream of nitrogen. The residue was dissolved in MeOH (2 ml) and 4 M HCl in dioxane was added (2 ml). The reaction was stirred at RT for 1 h. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO:MeOH (1:1, v/v) and purified by MDAP (Method B). The residue was dissolved in 1,4-dioxane:water and freeze dried to produce the title compound.
Reaction SMILES: C(OC([NH:11][CH:12]([C:14]1[C:15]([O:33][CH3:34])=[C:16]([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[C:17]([Cl:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13])=O)C1C=CC=CC=1.O.[H][H]>CO.Cl.[Pt]>[NH2:11][CH:12]([C:14]1[C:15]([O:33][CH3:34])=[C:16]([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:23]2)[C:17]([Cl:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13]
Reactant: [H][H]
Reactant: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [Pt]
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1c(C(C)N)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Yield: 98.2 %

Procedure:
A solution of tert-butyl 3-[3-(1-{[(benzyloxy)carbonyl]amino}ethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate [peak 2 isomer from step 6] (0.29 g, 0.57 mmol) in methanol (17 mL) and 0.25 M HCl in water (5.7 mL, 1.4 mmol) was degassed with nitrogen, treated with 5% Pt/C (Degussa type) (73 mg, 25 wt %), and stirred under a balloon of hydrogen for 1 hour. The reaction mixture was treated with additional 5% Pt/C (Degussa type) (100 mg) and stirred under a balloon of hydrogen for an additional 1 hour. The reaction mixture was filtered over Celite and neutralized with saturated sodium bicarbonate solution. The reaction mixture was concentrated to remove the methanol, extracted with dichloromethane, and concentrated to give the desired product (0.21 g, 99%) as a colorless foam that was used without further purification. LCMS for C13H14C12NO3 (M−[NH2]−[t-Bu]+H)+: m/z=302.0, 304.0. Found: 301.9, 304.0.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>N1C=CC=CC=1>[Si:21]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
To a stirred solution of 2′-deoxycytidine 47 (1.00 g; 4.40 mmol) in dry pyridine (37 mL), TBDMSCl (814 mg; 5.39 mmol) was added. The mixture was stirred at room temperature for 20 h. After evaporation, the residue was purified by flash column chromatography using CH3OH—CH2Cl2 (1:10) as the eluent to afford 48 as white solid (1.26 g; 84% yield): 1H NMR (400 MHz, CH3OD) δ 8.03 (d, J=7.5 Hz, 1H, 6-H), 6.23 (t, J=6.3 Hz, 1H, 1′-H), 5.86 (d, J=7.5 Hz, 1H, 5-H), 4.35 (m, 1H, 3′-H), 3.91-3.98 (m, 2H, 4′-H and one of 5′-H), 3.85 (dd. J=2.5, 11.3 Hz, 1H, one of 5′-H), 2.36-2.43 (ddd, J=4.1, 6.1, 13.5 Hz, 1H, one of 2′-H), 2.05-2.13 (m, 1H, one of 2′-H), 0.94 (s, 9H, C(CH3)3), 0.14 (s, 3H, one of SiCH3), 0.13 (s, 3H, one of SiCH3); 13C NMR (100 MHz, CD3OD) δ 167.1, 157.6, 142.1, 95.6, 88.7, 87.4, 71.7, 64.1, 42.7, 26.5, 19.3, −5.2, −5.3; HRMS (FAB+) calcd for C15H28O4N3Si (M+H+): 342.1849. found: 342.1844.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[CH:4][C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:12][CH2:13][CH2:14][CH3:15])[O:7][C:6]=2[CH:16]=1.[CH3:18][S:19]([O-:21])=[O:20].[Na+].N1CCC[C@H]1C(O)=O>[Cu](I)I.CS(C)=O>[F:17][C:3]1[C:2]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:16][C:6]2[O:7][CH:8]([CH2:11][NH:12][CH2:13][CH2:14][CH3:15])[O:9][CH2:10][C:5]=2[CH:4]=1
Reactant: CCCNCC1OCc2cc(F)c(Br)cc2O1
Reactant: CS(=O)[O-]
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCNCC1OCc2cc(F)c(S(C)(=O)=O)cc2O1
Yield: 45 %

Procedure:
Preparation according to Example 18. N-[(7-bromo-6-fluoro-4H-1,3-benzodioxin-2-yl)methyl]propan-1-amine (0.30 g, 0.99 mmol), sodium methanesulfinate (0.15 g, 1.23 mmol, 85%), copperiodide (19 mg, 0.10 mmol), L-proline (56 mg, 0.49 mmol) and DMSO (6 ml) was heated at 140° C. for 1 h. Purification was made twice by flash column chromatography (ETOAc/MeOH 10:1) and afforded the title compound (135 mg, 45%). The amine was converted into the hydrochloric acid salt and crystallized from EtOH/DEE. M.p. 225° C. 1H-NMR (400 MHz, MeOH): δ 7.34 (1H, d, J 6.0 Hz), δ 7.13 (1H, d, J 9.6 Hz), δ 5.21 (1H, t, J 4.8 Hz), δ 5.02 (2H, dd, J1 45.2 Hz, J2 15.6 Hz), δ 3.23 (3H, s), δ 2.96 (2H, m), δ 2.64 (2H, t, J 7.6 Hz), δ 1.56 (2H, m), δ 0.95 (3H, t, J 7.2 Hz).
Reaction SMILES: [O:1]1CCC[CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[CH3:14][O:15][CH:16]([O:21][CH3:22])[CH2:17][CH2:18][C:19]#[N:20].C(OC)=O>C1COCC1>[CH:2]([CH:18]([CH2:17][CH:16]([O:21][CH3:22])[O:15][CH3:14])[C:19]#[N:20])=[O:1]
Reactant: COC(CCC#N)OC
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: COC=O
Product: COC(CC(C#N)C=O)OC
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (1.5 M in cyclohexane, 22.0 mL, 33.00 mmol) was added to THF (100 mL) at −30° C. and the resulting solution was stirred for 10 min before 3-cyanopropionaldehyde dimethyl acetal (3.90 mL, 29.90 mmol) was added dropwise over 5 min. After 15 min, methyl formate (2.80 mmol, 45.42 mmol) was added and the resulting solution was stirred at −20° C. to −15° C. for 2 h. The reaction mixture was quenched with water (100 mL) and washed with ether (2×50 mL, discarded). The aqueous layer was acidified with 10% HCl and extracted with ether (3×50 mL). The combined ether extracts were washed with brine (3×50 mL), dried (MgSO4), and concentrated. The residue was dissolved in dichloromethane and concentrated to remove traces of THF and provide 2.28 g (49%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[O:21][N:20]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=3)[O:21][N:20]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: FC(F)(F)c1cccc(-c2cc(CCl)no2)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(-c2cccc(C(F)(F)F)c2)on1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]isoxazole (Example 324C): 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.57 (m, 3H), 6.66 (s, 1H), 6.17 (s, 1H), 5.44 (s, 2H), 2.58 (s, 3H); MS (ES) m/z 450 (M+1).
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:18]1[O:20][C@@H:19]1[CH2:21][OH:22]>C(O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH2:18][CH:19]([OH:20])[CH2:21][OH:22])=[CH:16][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC[C@@H]1CO1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Solvent: CO
Solvent: CCO
Product: OCC(O)CNc1ccc(OCc2ccccc2)cc1

Procedure:
The product is obtained with a 90% yield; m.p.: 102° C.; [α]D20 =+12,7° (c=1, CH3OH). This same product can be obtained by heating 4-benzyloxyaniline in ethanol in the presence of (R)-glycidol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN1CCOCC1.[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH2:59]>ClCCl>[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH:59][C:18]([C:17]1[CH:16]=[C:15]([CH:10]2[C:9]([CH3:24])([CH3:25])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[NH:11]2)[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: CN(C)CCN
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NCCN(C)C)c1)N2
Reaction time: 0.67 h
Yield: 106 %

Procedure:
To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (150 mg, 0.44 mmol, 1.0 eq.) in dichloromethane (10.0 ml) was added N-hydroxy benzotriazole (89.2 mg, 0.66 mmol, 1.5 eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (253.0 mg, 1.32 mmol, 3.0 eq.), followed by 4-methylmorpholine (133.5 mg, 1.32 mmol) and the resultant mixture was stirred at room temperature for 40 min. Then N1,N1-dimethylethane-1,2-diamine (42.7 mg, 0.48 mmol, 1.1 eq.) was added to the flask and the reaction mixture was stirred for an additional 40 min, LC-MS showed the reaction was complete. The reaction was quenched with water, separated, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and brine (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 191 mg of methyl 2-(3-(2-(dimethylamino)ethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a off-white solid, which was washed with hexane and collected by filtration to afford 162 mg product as a white solid. Yield: 89.5%.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1.C([Li])CCC.CN(C)[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1.CCCCC>[F:11][C:4]1[CH:3]=[C:2]([CH:19]=[O:20])[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c2occc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=Cc1cc(F)cc2ccoc12
Temperature: -97.5 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
7-Bromo-5-fluoro-benzofuran (7 g, 32 mmol, Step B) was dissolved in a mixture of tetrahydrofuran (350 mL) and pentane (100 mL), cooled to −95 to −100° C., and treated with n-butyl lithium (14 mL, 35 mmol, 2.5M in hexane, Aldrich). After stirring for 5 minutes, a solution of dimethylformamide (5 mL) in tetrahydrofuran (15 mL) was added dropwise and the reaction temperature raised to −20° C. This was treated with aqueous ammonium chloride (50 mL) and stirred for 0.5 hour at ambient temperature. The reaction mixture was concentrated in vacuo and diluted with hexane. The organic fraction was washed with water and dried (Na2SO4). Removal of solvent afforded crude 5-fluoro-benzofuran-7-carbaldehyde (˜30%) as an oil. Purification was by silica gel chromatography (5-10% ethyl ether/hexane). HRMS, observed: 163.0201; Calcd for (M+H)+: 163.0195