Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:10]([OH:12])=[O:11])[NH2:9])=[CH:5][CH:4]=1.[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>O>[C:17]([NH:9][CH:8]([C:10]([OH:12])=[O:11])[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CC(N)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CC(NC(C)=O)C(=O)O)cc1

Procedure:
O-Methyl-DL-tyrosine, 114 g., is dissolved in 500 ml. of a solution of 46 g. of sodium hydroxide in water with cooling. Acetic anhydride, 80 ml., and 50% sodium hydroxide to maintain pH 9-11 are added with continued cooling. The reaction is stirred for twenty minutes at pH 11 and is then acidified to pH 1 with continued cooling. The precipitated solid is collected by filtration, washed with a small amount of water and dried to give the above named compound, mp. 144°-146° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:17](OC)=[O:18].Cl>O1CCCC1.COCCOC>[F:13][C:14]1[CH:15]=[C:16]([C:17](=[O:18])[CH2:3][S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH:21]=[CH:22][C:23]=1[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CS(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)CS(=O)(=O)c2ccccc2)cc1F

Procedure:
A solution of 864 mg. of sodium hydride and 5.3 g. of methylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 60° C. for one hour under an atmosphere of argon. To this solution is then added a solution of 5.0 g. of methyl 3-fluoro-4-(hexadecylamino)benzoate and 50 ml. of tetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5 hours. The mixture is cooled, poured onto ice, acidified with dilute hydrochloric acid to pH 3 and then extracted with chloroform. The organic layer is separated, washed three times with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated to dryness. The crude solid is chromatographed on silica gel, eluting with methylene chloride to yield 3'-fluoro-4'-(hexadecylamino)-2-(phenylsulfonyl)acetophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:31]=[CH:30][C:25]([C:26](OC)=[O:27])=[CH:24][N:23]=1.[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:31]=[CH:30][C:25]([CH2:26][OH:27])=[CH:24][N:23]=1
Reactant: COC(=O)c1ccc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(CO)cn2)c1

Procedure:
To 110 mg of methyl 6-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinate at 0° C. in 5 mL of EtOH was slowly added 148 mg of Sodium Borohydride. The reaction was subsquently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(5-(hydroxymethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 422.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[OH2:11].OO>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:11])=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(Cl)ccnc1C
Reactant: O
Agent: OO
Solvent: CC(=O)O
Product: COc1c(Cl)cc[n+]([O-])c1C
Temperature: 90 °C

Procedure:
36.98 g of 4-chloro-3-methoxy-2-methylpyridine (V) was dissolved in 685 ml of acetic acid and 92 ml of hydrogen peroxide water was added thereto and the resulting mixture was heated at 90° C. for 24 hours, and thereafter, the reaction solution was distilled off under reduced pressure. The resulting residue was dissolved in chloroform and washed with saturated sodium bicarbonate solution, and saturated salt water, and thereafter, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 37.64 g of 4-chloro-3-methoxy-2-methylpyridine N-oxide (VI).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]=O.[BH4-].[Na+]>C(O)(=O)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:26][C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=Cc1ccco1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4ccco4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.4 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in acetic acid (20 ml) was added furan-2-carbaldehyde (0.20 g, 2.05 mmol). The mixture was heated to reflux for 5 hours and allowed to cool at room temperature. Sodium borohydride (80 mg, 2 mmol) was added to the reaction mixture. The reaction mixture was stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml), washed with H2O (3×100 ml), saturated aqueous NaHCO3 (2×100 ml), brine (1×100 ml), and dried. The solvent was evaporated and the residue was purified by chromatography (ethyl acetate/hexane, 1:1) to give 0.25 g (35%) of product as a yellow solid: mp 171–173° C.; 1H NMR (DMSO-d6) δ 11.10 (s, 1H), 7.58 (t, J=7.1 Hz, 2H), 7.18 (d, J=8.6 Hz, 1H), 7.08–6.97 (m, 2H), 6.39–6.36 (m, 2H), 5.06 (dd, J=5.2 and 12.4 Hz, 1H), 4.57 (d, J=6.0 Hz, 2H), 2.96–2.82 (m, 1H), 2.63–2.46 (m, 2H), 2.06–2.02 (m, 1H; 13C NMR (DMSO-d6) δ 172.76, 170.01, 168.75, 167.21, 151.97, 145.81, 142.42, 136.05, 132.09, 117.60, 111.04, 110.42, 109.73, 107.38, 48.57,30.95,22.10; Anal. Calcd. For C18H15N3O5: C, 61.19; H, 4.28; N, 11.89. Found: C, 61.02; H, 4.24; N, 11.81.
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl.Cl[CH2:48][C:49]1[N:50]=[C:51]([CH3:54])[S:52][CH:53]=1>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:48][C:49]1[N:50]=[C:51]([CH3:54])[S:52][CH:53]=1)[CH2:23][CH2:22]2
Reactant: Cc1nc(CCl)cs1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCc3csc(C)n3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(chloromethyl)-2-methylthiazole hydrochloride as the alkylating agent in Step 1. MS: m/e 641.5 (M+H)+, 1.56 min (method 12). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (s, 3H) 0.97 (s, 3H) 1.02 (s, 3H) 1.10 (s, 3H) 1.26 (s, 3H) 1.71 (s, 3H) 0.88-1.83 (m, 16H) 1.89-2.04 (m, 3H) 2.08-2.21 (m, 1H) 2.14 (dd, J=17.19, 6.15 Hz, 1H) 2.22-2.30 (m, 1H) 2.33-2.45 (m, 1H) 2.68 (s, 3H) 4.09 (d, J=13.05 Hz, 1H) 4.64 (d, J=12.80 Hz, 1H) 4.69 (s, 1H) 4.80 (s, 1H) 5.32 (d, J=4.52 Hz, 1H) 7.24 (d, J=8.28 Hz, 2H) 7.28 (s, 1H) 8.00 (d, J=8.28 Hz, 2H).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].OS(O)(=O)=O.[Br:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15]2=[O:20].[OH-].[Na+]>O.C(Cl)(Cl)Cl>[Br:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:20])[NH:1]2
Reactant: O=C1CCc2c(Br)cccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CCc2c(Br)cccc2N1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a stirred mixture of sodium azide (862 mg, 13.3 mmol) in H2O (1.7 mL) and CHCl3 (6.5 mL) was added conc. H2SO4 (0.23 mL, 4.14 mmol). The reaction mixture was stirred vigorously at 0° C. for 2.5 h. The CHCl3 layer was separated, dried over Na2SO4, and added to a solution of 4-bromo-1-indanone (1.12 g, 5.31 mmol) in CHCl3 (20 mL). To this mixture was added conc. H2SO4 (1.75 mL, 31.5 mmol) dropwise over 10 min. The reaction mixture was heated at 45 C for 1 h then poured into ice-water, neutralized with 20% aqueous NaOH, and extracted with CH2Cl2 (100 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=226 (M+1).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.C(N(CC)C(C)C)(C)C.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:42]2C(=O)[CH2:46][CH2:45][CH2:44][C:43]=2[OH:49])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]>>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:42]2[C:43](=[O:49])[CH2:44][CH2:45][CH2:46][C:6]=2[O:7][CH3:9])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([C:38]([F:39])([F:41])[F:40])[CH:35]=[CH:34][N:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]
Reactant: C[O+](C)C
Reactant: N#Cc1ccc(C(NC(=O)Nc2cc(C(F)(F)F)ccn2)C2=C(O)CCCC2=O)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC1=C(C(NC(=O)Nc2cc(C(F)(F)F)ccn2)c2ccc(C#N)cc2)C(=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethyloxonium tetrafluoroborate (185 mg, 1.25 mmol) is added to a solution of N,N-diisopropylethylamine (210 μL, 1.21 mmol) and 1-((4-cyanophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(4-(trifluoromethyl)pyridin-2-yl)urea (intermediate 24, 264 mg, 0.613 mmol). The mixture is stirred at room temperature for 1 h and extracted with water. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. Yield: 200 mg; ESI mass spectrum [M+H]+=445, Retention time HPLC: 1.08 min (V011_S01).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15].C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CN2C(=O)c3ccccc3C2=O)CC1
Yield: 66.5 %

Procedure:
Phthalimide (33 mg, 0.23 mmol) was treated with tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (80.5 mg, 0.32 mmol), tetrabutylammonium iodide (TBAI, 84 mg, 2.3 mmol), diisopropylethylamine (DIEA, 0.20 mg, 1.14 mmol) in anhydrous CH2Cl2 (10 mL) for 24 h at 40° C. The mixture was partitioned between CH2Cl2 and water. The organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column with elution of EtOAc/hexane (1:1) to give the title compound (57.1 mg, 67% yield). C19H23N3O5; white solid; TLC (EtOAc/hexane=1:1) Rf=0.2; 1H NMR (400 MHz, CDCl3) δ 7.85-7.87 (2H, m), 7.70-7.72 (2H, m), 4.49 (2H, s), 3.51-3.57 (6H, m), 3.44 (2H, d, J=5.2 Hz), 1.46 (9H, d, J=4.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:14]([OH:35])[C@H:15]1[O:34][C@:16]1([CH3:33])[CH2:17][CH2:18][CH2:19][C@H:20]([CH3:32])[CH2:21][CH2:22][CH2:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>COC(C)(C)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:14]([OH:35])[CH2:15][C@:16]([CH3:33])([OH:34])[CH2:17][CH2:18][CH2:19][C@H:20]([CH3:32])[CH2:21][CH2:22][CH2:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30]
Reactant: COc1c(C)c(C)c(OC)c(C(O)[C@H]2O[C@]2(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C(O)C[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A solution of 342 mg (0.70 mmol) of (1RS,2R,3R,7R,11R)-1-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-3,7,11,15-tetramethylhexadecanol in 1 ml of tert.butyl methyl ether was added dropwise at room temperature while stirring to a suspension of 51 mg (2 mmol) of lithium aluminium hydride in 10 ml of tert.butyl methyl ether and the mixture was subsequently stirred at room temperature for a further 1 hour. Then, 0.5 ml of water was added dropwise, the mixture was filtered through sodium sulphate, rinsed with ether and the filtrate was concentrated on a rotary evaporator. The thus-obtained crude produce (341 mg) was chromatographed on silica gel with toluene/ethyl acetate (2:1 parts by volume) and there were obtained 284 mg (84%) of (1RS,3R,7R,11R)-1-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-3,7,11,15-tetramethylhexadecane-1,3-diol, [α]D20 =+0.2° (c=2.16% in chloroform).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][C:26]1([CH3:32])[O:30][C:29](=[O:31])[NH:28][CH2:27]1>>[CH3:25][C:26]1([CH3:32])[O:30][C:29](=[O:31])[N:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[CH2:27]1
Reactant: CC1(C)CNC(=O)O1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3)CC2)nc1C
Yield: 25.5 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (579 mg) described in Preparation Example 176 and 5,5-dimethyloxazolidin-2-one (153 mg) described in Preparation Example 43, the title compound (143 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12](O)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:22])=O.CN(C=O)C>C(Cl)Cl>[C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([Cl:22])=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (500 mg, 1.90 mmol) in methylene chloride (15 mL) was added oxalyl chloride (0.34 mL, 3.80 mmol) dropwise at 0° C. This was followed by a drop of DMF. The reaction was warmed to room temperature and stirred at room temperature for 1.5 hr. The mixture was concentrated to dryness to afford 2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl chloride as a light yellow solid which was used in the next step without further purification.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:34]=[CH:33][C:27]([CH2:28][NH:29][C:30](=O)[CH3:31])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:34]=[CH:33][C:27]([CH2:28][NH:29][C:30](=[S:10])[CH3:31])=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NCc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CC(=S)NCc1ccc(F)cc1
Temperature: 80 °C
Yield: 106.1 %

Procedure:
Step c) Add Lawesson reagent (1.8 g, 3.6 mmol) to N-(4-fluorobenzyl)acetamide (0.9 g, 5.4 mmol) in 50 mL of toluene and heat to 80° C. for 12 hours. Remove solvent under reduced pressure. Purify the residue by column chromatography (silica gel, Acetone: Hexane=20:80) to give a mixture. Wash with ether and discard insoluble solid impurities by filtration. Remove solvent under reduced pressure to give N-(4-fluorobenzyl)-thioacetamide (0.7 gm) in 71% as a yellow solid: MS 184 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[C:9]([C:11]1[CH:25]=[CH:24][C:14]([CH2:15][N:16]2[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17]2)=[CH:13][C:12]=1[F:26])#[CH:10]>C(N(CC)CC)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]#[C:9][C:11]2[CH:25]=[CH:24][C:14]([CH2:15][N:16]3[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17]3)=[CH:13][C:12]=2[F:26])=[N:6][CH:7]=1
Reactant: Brc1ccc(I)nc1
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(Cc2ccc(C#Cc3ccc(Br)cn3)c(F)c2)C1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 5-bromo-2-iodopyridine (800 mg, 2818 μmol), methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (704 mg, 2846 μmol), and copper(I) iodide (21.5 mg, 113 μmol) in triethylamine (9.4 mL) was sparged with argon (30 sec), and PdCl2(PPh3)2 (79.1 mg, 113 μmol) was then added in one portion at 25° C. The reaction mixture was cooled to 0° C. and stirred for 40 min, and then allowed to stir at 25° C. for 1.5 h. The mixture was subsequently diluted with EtOAc (120 mL) and sequentially washed with water (4×30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc/Hexanes) furnished methyl 1-(4-(2-(5-bromopyridin-2-yl)ethynyl)-3-fluorobenzyl)azetidine-3-carboxylate as a light yellow oil. MS (ESI) m/z: Calculated: 402.0/404.0; Observed: 402.8/404.8 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH:19]1([CH2:22][O:23][C:24]2[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)[CH2:21][CH2:20]1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[N:25][C:24]([O:23][CH2:22][CH:19]4[CH2:21][CH2:20]4)=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1cnc(OCC2CC2)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCC4CC4)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 36) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=436.2 [M+H]+.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)([Cl:13])=O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([Cl:13])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccc1O

Procedure:
Into a clean, dry three necked round bottomed flask were charged one equivalent of salicylic acid, 50 mls is of anhydrous toluene and a few drops of pyridine catalyst. The flask was equipped with a stir bar, thermometer and an addition funnel. Into the addition funnel was charged one equivalent of thionyl chloride in a few mls of toluene. The contents of the reaction flask were heated to 40° C. under a nitrogen blanket before the thionyl chloride solution was added slowly. Once the addition was complete, the reaction proceeded at 40-45° C. for several hours or until the reaction mixture was homogeneous. Upon completion of the reaction, any unreacted thionyl chloride was removed under vacuum.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]([C:11]1[CH:35]=[CH:34][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][C:24]3=[O:25])[CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:12]=1)=O.Cl.[O:37]1C[CH2:40][CH2:39][CH2:38]1>>[OH:37][CH2:38][CH2:39][CH:40]=[CH:9][C:11]1[CH:35]=[CH:34][C:14]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][C:24]3=[O:25])[CH2:21][CH2:22]2)=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Product: O=C(c1ccc(C=CCCO)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Hydroxypropyltriphenylphosphonium bromide (2.4 g) is dispersed into tetrahydrofuran (50 ml) and thereto is added dropwise lithium diisopropylamide (a solution in 1.99 N tetrahydrofuran) (6.1 ml) at 0°-5° C. After adding, the mixture is stirred at 0°-5° C. for 1 hour and thereto is added 1-[1-(4-formylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (2 g). The mixture is stirred at room temperature overnight. The reaction mixture is poured into ice-water and adjusted to pH 4-5 by adding conc. hydrochloric acid. The mixture is extracted with ethyl acetate and dried with magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate-1:1→ ethyl acetate:methanol=20:1) to give 1-{1-[4-(4-hydroxy-1-butenyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1 g).