Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:13]([C:20]#[N:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2-].[Na+]>C1(C)C=CC=CC=1>[C:14]1([CH:13]([C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[N:6]=2)[C:20]#[N:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CCc1ccccc1
Reactant: Clc1nc(-c2ccncc2)cs1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC(c1ccccc1)c1nc(-c2ccncc2)cs1
Temperature: 100 °C
Yield: 8.3 %

Procedure:
To a solution of 2-chloro-4-(4-pyridyl)thiazole (1.00 g, 0.005 mol) and benzylcyanide (1.18 g, 0.010 mol) in dry toluene (10 mL) at 5° C. was added sodamide (400 mg, 0.010 mol) and the mixture heated to 100° C. for 20 minutes. After cooling, the mixture was quenched with water, the layers separated, and the aqueous phase washed with methylene chloride (2×50 mL). The combined extracts were dried over sodium sulfate, concentrated, and chromatographed through silica gel (3:1 ethyl acetate/methylene chloride as eluant). After decolorizing with charcoal, recrystallization from hexane/ethyl acetate afforded 2-phenyl-2-[4-(4-pyridyl)-2-thiazolyl]acetonitrile (115 mg, 8%). mp. 110°-111° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:28])[CH2:23][O:24]C(=O)C)[CH3:21])[C:14]=3[Cl:29])[C:5]2=[N:4][C:3]=1[CH3:30].C(=O)([O-])[O-].[K+].[K+].CO>O1CCCC1>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:28])[CH2:23][OH:24])[CH3:21])[C:14]=3[Cl:29])[C:5]2=[N:4][C:3]=1[CH3:30]
Reactant: CC(=O)OCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CO)c3Cl)cccn2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A mixture of 3-bromo-8-[3-(N-acetoxyacetyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (1.42 g), potassium carbonate (761 mg), methanol (7 ml) and tetrahydrofuran (7 ml) was stirred at ambient temperature for 1 hour. The mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane twice. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol to give 3-bromo-8-[2,6-dichloro-3-(N-glycoloyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (1.16 g) as crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][C:9]([OH:11])=O)=[CH:3][CH:2]=1.[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1>>[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:9](=[O:11])[CH2:8][S:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: O=C(O)CSc1ccncc1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)CSc1ccncc1
Yield: 33.7 %

Procedure:
Using the general method of Example 105 (4-pyridylthio)acetic acid (0.11 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.2 g, 0.64 mmol) to provide 0.1 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(4-pyridylsulfanyl)acetamide as a solid, m.p. 127.5-129° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([C:17]#[N:18])[CH:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:25]NC(=O)CCC(N)=O.O.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([C:17]#[N:18])[C:16]([I:25])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2c(cc(C#N)c2-c2ccccc2)C1
Reactant: NC(=O)CCC(=O)NI
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCn2c(c(I)c(C#N)c2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
A solution of 7-cyano-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (8.6 g, Reference Example 4(b)) in dry dimethylformamide (80 mL) was treated with N-iodosuccinamide (6.07 g) over 10 minutes. After stirring at room temperature for a further 4 hours the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, further washed with water, then dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give the title compound (7.50 g) as a buff solid, m.p. 174–178° C. 1H NMR [(CD3)2SO]: δ 7.58–7.48 (m, 5H), 4.43 (s, 2H), 3.97 (t, 2H), 3.65 (t, 2H) and 1.46 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][C:3]=1[Cl:15].CO.[OH-].[Na+]>O>[NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:15]
Reactant: CON=Cc1cc(C(=O)[O-])cc(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CON=Cc1cc(C(=O)O)cc(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
In a 5-liter three-necked round-bottomed flask was placed 210 g (0.86 moles) of the previously prepared 4-amino-3-chloro-5-methoxyiminomethylbenzoate, 1.7 l of methanol and 462 g (1.73 moles) of 15% aqueous sodium hydroxide. The resulting mixture was refluxed for 3 hours, after which the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated using a rotary evaporator. The crude reaction mixture was dissolved in 2 l of water. The resulting aqueous solution was washed once with 500 mL of ethyl acetate, cooled in an ice bath and acidified to pH=2 with concentrated hydrochloric acid. The expected 4-amino-3-chloro-5-methoxyiminomethylbenzoic acid precipitated as a light yellow solid which was separated by suction filtration. The filter cake was washed with a 1:2 mixture of ethyl ether and hexane yielding after drying 185.2 g (94% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2[C:36](=[O:37])[N:35]([CH2:38][CH3:39])[C:27]3[N:28]=[C:29](S(C)=O)[N:30]=[CH:31][C:26]=3[CH:25]=2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(OCC)(=O)C.O>C1COCC1>[CH3:23][O:22][C:20]1[CH:19]=[C:18]([C:24]2[C:36](=[O:37])[N:35]([CH2:38][CH3:39])[C:27]3[N:28]=[C:29]([NH:1][C:2]4[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=4)[N:30]=[CH:31][C:26]=3[CH:25]=2)[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(S(C)=O)nc21
Reactant: Nc1ccnc(Cl)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccnc(Cl)c3)nc21
Temperature: -10 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a −78° C. solution of 4.1 g (32.1 mmol) of 4-amino-2-chloropyridine in 120 mL of THF was added dropwise 17.5 mL (30.5 mmol) of 1.6 M n-butyllithium in hexanes. The reaction solution was stirred for 15 minutes at which time 3.0 g (8.0 mmol) of the product of Example 7, 6-(3,5-dimethoxy-phenyl)-8-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one, was added in small portions as a solid. The reaction mixture was allowed to warm slowly to −10° C. then remain at −10° C. overnight. The reaction mixture was poured into ethyl acetate/water/5 mL 6N HCl. The mixture was shaken and separated. The organic phase was washed with a saturated solution of sodium bicarbonate, twice with water, and brine, then dried over magnesium sulfate, filtered, and concentrated to a volume of about 200 mL. The suspension was stirred overnight and filtered to give a yellow solid. The solid was triturated under 20 mL of 1:9 methanol/chloroform, filtered, and dried to give 1.89 g (54%) of the titled compound.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC.[C:44]([C:48]1[O:49][C:50]([CH3:68])=[C:51]([CH2:53][CH2:54][O:55][C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:59]([CH:66]=[O:67])=[CH:58][CH:57]=2)[N:52]=1)([CH3:47])([CH3:46])[CH3:45]>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:66]([C:59]1[C:60]2[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:56]([O:55][CH2:54][CH2:53][C:51]2[N:52]=[C:48]([C:44]([CH3:47])([CH3:46])[CH3:45])[O:49][C:50]=2[CH3:68])=[CH:57][CH:58]=1)[OH:67])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: Cc1oc(C(C)(C)C)nc1CCOc1ccc(C=O)c2ccccc12
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(C(C)(C)C)oc2C)c2ccccc12

Procedure:
0.234 g of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (0.889 mmol) was dissolved under an argon atmosphere in 3 ml of abs. CH2Cl2 and treated with 0.149 ml of triethylamine (1.2 eq.). After cooling to −78°, nBu2BOTf was added slowly (0.980 ml of 1M solution in CH2Cl2) and enolborinate formation allowed to proceed for 15 Min. at −78° and for 50 Min. at 0°. After recooling, a solution of 0.300 g of the above prepared 4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalene-1-carbaldehyde (0.889 mmol) in 5 ml of abs. CH2Cl2 was slowly added via dropping funnel and the mixture kept for 30 Min. at −78° and for additional 30 Min. at 0°. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=1/1) left finally 0.268 g of the title compound as white foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[O:3]1.[Cl:13][CH:14]([Cl:18])[C:15](Cl)=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[N:6]([C:15](=[O:16])[CH:14]([Cl:18])[Cl:13])[CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:10])[CH3:11])[O:3]1
Reactant: CC(C)OCC1CNC(C)(C)O1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)OCC1CN(C(=O)C(Cl)Cl)C(C)(C)O1

Procedure:
In a similar manner as Example I, 27.7 milliliters of 25 percent w/v, 2,2-dimethyl-5-isopropoxymethyl oxazolidine solution in 50 milliliters of benzene and 4.9 grams of dichloroacetyl chloride was added 4.1 grams of triethylamine. After the appropriate work up procedure, there was obtained a yield of 8.9 grams, nD30 1.4564. Analytical data supports the structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[NH:19][C:18](=[O:20])[NH:17][C:16](=[O:21])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Li+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.[I-].[Na+]>O.CN(C)C=O>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:17]2[C:18](=[O:20])[N:19]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[NH:15][C:16]2=[O:21])=[CH:27][CH:26]=1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)[nH]c(=O)[nH]1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)[nH]c(=O)n1Cc1ccc(Cl)cc1
Yield: 16.3 %

Procedure:
To an N,N-dimethylformamide solution of 6-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazine-2,4(1H,3H)-dione (1.20 g, 4.12 mmol) synthesized in Reference Synthesis Example 18, lithium hydride (75 mg, 4.94 mmol), 4-chlorobenzyl chloride (0.70 g, 4.12 mmol), and sodium iodide (catalytic amount) were added at room temperature and the resultant solution was stirred at 50° C. for 8 hours. After completion of the reaction, the reaction solution was poured into water and the resultant mixture was washed with ethyl acetate. Diluted hydrochloric acid was added to the water phase to adjust pH to 3 and the obtained solid was collected by filtration. Extraction with a mixed solution of ethyl acetate and tetrahydrofuran from the filtrate was performed and the organic layer was concentrated under reduced pressure. The residue and the solid collected by filtration were combined to obtain the title compound (280 mg, yield 15%).
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=1[C:13]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[CH2:18][CH2:17]1)=[O:14])=[O:9])C1C=CC=CC=1.[CH2:35]([NH2:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C1(C)C=CC=CC=1>[CH2:35]([NH:42][C:8](=[O:9])[NH:10][C:11]1[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=1[C:13]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[CH2:18][CH2:17]1)=[O:14])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCN
Reactant: O=C(Nc1ccccc1C(=O)NC1CCN(C(=O)Oc2ccccc2)CC1)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCN(C(=O)Oc2ccccc2)CC1
Yield: 95 %

Procedure:
A solution of 2-phenoxycarbonylamino-N-(1-phenoxylcarbonylpiperidin-4-yl)benzamide (1.6 g, 3.5 mmol) and n-heptylamine (0.45 g, 3.9 mmol) in toluene (20 ml) was refluxed for 4 hours and then concentrated. The residue was purified by column chromatography on silica gel (50% ethyl acetate in petroleum ether) to give 2-(N'-n-heptylureido)-N-(1-phenoxy carbonylpiperidin-4-yl)benzamide: yield 95.0%: mp 142°-144° C.; 1H NMR (CDCl3)ppm: 0.88 (3H, t) 1.28-1.33 (7H, m), 19-1.62 (4H, m), 2.05-2.17 (2H, m), 3.04-3.19 (2H, m), 3.25 (2H, q), 4.10-4.15 (1H, m), 4.24-4.40 (2H, m), 4.59 (1H, t), 6.35 (1H, d), 6.92 (1H, t), 6.97-7.44 (8H, m), 8.40 (1H,d), 10.20 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1.C1COCC1>[C:17]([O:1][C:2]1[CH:11]=[C:10]([O:12][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCc1cc(=O)oc2cc(OC(=O)C(C)(C)C)cc(OC(=O)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 177.9 %

Procedure:
To a solution of 5,7-dihydroxy-4-propylcoumarin (2) (1.10 g, 5 mmol) in pyridine (12 mL) and THF (6 mL) was added pivaloyl chloride (0.673 mL, 5.5 mmol) and the reaction mixture was allowed to stir at room temperature for 24 h. TLC revealed formation of a new less polar spot and unreacted starting material. In an effort to drive the reaction to completion, pivaloyl chloride (0.50 mL) was added and the reaction continued to stir at room temperature for another 72 h. The pyridinium hydrochloride was removed by filtration and washed a few times with ethyl acetate. The organic solutions were combined and washed, successively, with 1 M HCl (2×25 mL), water (25 mL), aqueous saturated sodium bicarbonate (25 mL). After being dried over sodium sulfate and concentrated under vacuum, the crude product was purified by silica gel chromatography (2:1 hexane/ethyl acetate) to obtain 8b as a white solid (1.90 g, 98% yield). mp 110-112° C.; Rf=0.49 (4:1 hexane/ethyl acetate); 1H-NMR (CDCl3),: 1.03 (3H, t, J=7.8 Hz), 1.36 (9H, s), 1.41 (9H, s), 1.69 (2H, sextet, J=7.4 Hz), 2.81 (2H, t, J=7.8 Hz), 6.22 (1H, s), 6.60 (1H, d, J=2.4 Hz), 7.03 (1H, d, J=2.1 Hz); 13C-NMR (CDCl3): 13.5, 20.7, 26.4, 26.8, 26.9, 36.4, 39.2, 39.4, 108.6, 111.5, 113.4, 114.2, 149.4, 152.7, 154.9, 155.4, 159.9, 177.1; IR (film): 3090, 2971, 2941, 2876, 1757, 1615, 1481, 1422, 1273 cm−1; MS m/e 389 (M+1); Anal. Calcd. for C22H28O6: C, 68.02; H, 7.26. Found: C, 67.77; H, 7.18.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:19][CH2:18][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CO)cc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (0.689 g, 2.48 mmol) in THF (6 mL) at 0° C. was added LAH (4.97 mL of 1.0 M in THF, 4.97 mmol) dropwise under nitrogen. The reaction mixture was allowed to stir for 2 hours at 0° C., and then quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide tert-butyl 7-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH2:6][NH:7][CH3:8].C(N(CC)CC)C.[Cl:25][C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH2:6][N:7]([CH3:8])[C:26]([Cl:25])=[O:28]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)Cl
Reaction time: 0.17 h

Procedure:
In 3.0 ml of dichloromethane was dissolved 831 ml of triphosgene, and added dropwise thereto were a solution of 1.08 g of N-(3,5-bistrifluoromethylbenzyl)-N-methylamine and 1.76 ml of triethylamine in 5.0 ml of dichloromethane, spending 10 minutes, under nitrogen atmosphere under ice-cooling. The reaction mixture was stirred at 0° C. to 5° C. for 30 minutes. The solvent was removed by distillation, and the residue was dried. To the residue were added water and dichloromethane and the mixture was extracted twice with dichloromethane. The organic layers were combined and washed with saturated brine, and dried. Then, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (hexane→hexane:ethyl acetate=10:1), to give 760 mg of N-(3,5-bistrifluoromethylbenzyl)-N-methylaminocarbonyl chloride as shown in Table 134 below.
Reaction SMILES: I[CH:2]=[C:3]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[O:23][C:22]([CH3:28])([CH3:27])[CH:21]=[CH:20]2)[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1.[CH2:29]([Sn:33]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37][CH2:38][CH3:39])C=C)[CH2:30][CH2:31][CH3:32].[Li+].[Cl-].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[F-].[NH+]1C=CC=CC=1>O1CCOCC1.C(OCC)C.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.N1C=CC=CC=1>[CH2:40]([Sn:33]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:36][CH2:37][CH2:38][CH3:39])[CH:2]=[C:3]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[O:23][C:22]([CH3:28])([CH3:27])[CH:21]=[CH:20]2)[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)[CH2:41][CH2:42][CH3:43]
Reactant: COc1cc(CC(=CI)c2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCC[Sn](C=C(Cc1cc(OC)c(OC)c(OC)c1)c1ccc2c(c1)C=CC(C)(C)O2)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-[2-iodo-1-(3,4,5-trimethoxy-benzyl)-vinyl]-2,2-dimethyl-2H-chromene (974 mg, 1.98 mmol) in 1,4-dioxane (9 mL) is added tri-n-butylethenyl-stannane (650 mg, 2.05 mmol), LiCl (252 mg, 594 mmol), Pd(PPh3)4 (46 mg, 0.04 mmol), and a few crystals of 2,6-di-tert-butyl-4-methyl phenol. The resulting suspension is heated to reflux for 4 hours, cooled to room temperature and treated with pyridine (1 mL) and pyridinium fluoride (2 mL, 1.4 M solution in THF, 2.8 mmol). The resulting mixture is stirred at room temperature for 16 hours and then diluted with diethyl ether and filtered through a small pad of diatomaceous earth (Celite®). The filtrate is washed with water, 10% HCl, water, brine, and dried over sodium sulfate, filtered, and concentrated. Crude material is used in the next step without further purification.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][C:10]([CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])([NH:12]CC3C=CC=CC=3)[CH2:9]2)C=CC=CC=1.[ClH:31].O1CCOCC1>CO.[OH-].[Pd+2].[OH-]>[ClH:31].[CH3:23][CH:22]([NH:21][CH2:20][C:10]1([NH2:12])[CH2:11][NH:8][CH2:9]1)[CH3:24]
Reactant: CC(C)NCC1(NCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)NCC1(N)CNC1
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of the 1-(diphenylmethyl)-3-{[(1-methylethyl)amino]methyl}-N-(phenylmethyl)azetidin-3-amine (0.35 g, 0.88 mmol) in methanol was added a solution of hydrogen chloride in dioxane (4 molar solution, 0.96 mL, 4.40 mmol) and the resulting mixture was concentrated to give a white solid which was taken back into methanol. To this solution were added palladium hydroxide (20% on carbon, 0.50 g, 0.19 mmol) and the resulting mixture shaken at 50 psi in a Parr apparatus for 3 h. The reaction mixture was filtered and concentrated to give a solid, which was washed with ether and dried in vacuo to give 3-{[(1-methylethyl)amino]methyl}azetidin-3-amine hydrochloride as a white solid (0.18 g, 81% yield). MS (EI) for CH17N3: 144 (MH+).
Reaction SMILES: B(O)(O)O.[NH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:15].[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](O)=O.O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19]1[O:15][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=2[N:5]=1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C(O)c1c(F)cccc1F
Agent: OB(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cccc2oc(-c3c(F)cccc3F)nc12

Procedure:
2 g (32.4 mmol; 1 eq.) of boric acid is added to a solution of 5 g (32.4 mmol) of 2-amino-3-nitrophenol and 5.12 g (32.4 mmol; 1 eq.) of 2,6-difluorobenzoic acid in 50 ml of xylene. The mixture is heated under reflux of the xylene for 8 hours with elimination of the water formed by a Dean-Stark apparatus. After returning to ambient temperature, the reaction medium is diluted by 100 ml of ethyl acetate and neutralized by a 10% aqueous solution of soda. The organic phase is washed 3 times with 50 ml of water then with a saturated solution of NaCl before being dried over sodium sulphate, filtered and concentrated under reduced pressure. The 2-(2,6-difluorophenyl)-4-nitro-1,3-benzoxazole is used without other purification in the following stage.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[S:11]([Cl:14])([Cl:13])=[O:12].ClC1C=C(C=CC=1)C(Cl)=O.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][CH2:27][C:26]([CH3:30])([CH3:29])[N:25]=2)[CH:8]=[CH:9][CH:10]=1.[S:11]([Cl:14])([Cl:13])=[O:12]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CC(C)(N)CO
Agent: O=C(Cl)c1cccc(Cl)c1
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2cccc(Cl)c2)=N1

Procedure:
2-(3-Chlorophenyl)-4,4-dimethyl-2-oxazoline was prepared from 3-chlorobenzoic acid by reaction with thionyl chloride to give 3-chlorobenzoylchloride, reaction of this acid chloride with 2-amino-2-methylpropanol to give the amide and cyclization of the amide with thionyl chloride followed by neutralization with dilute sodium hydroxide to give 2-(3-chlorophenyl)-4,4-dimethyl-2-oxazoline.