Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:52][CH:53]([CH:55]1[CH2:63][C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:56]1)[CH3:54]>C(OCC)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:52][CH:53]([CH:55]3[CH2:63][C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[CH2:56]3)[CH3:54])=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: CC(N)C1Cc2ccccc2C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(NC(=O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The following was added sequentially to DCM (5 mL): 1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (109 mg, 0.275 mmol), DIPEA (0.144 mL, 0.825 mmol), EDC (63 mg, 0.330 mmol), HOBT (51 mg, 0.330 mmol), and crude 2-(1-aminoethyl)indane (˜44 mg, 0.275 mmol). The mixture was stirred for 16 h at rt, at which time the solution diluted with a 1:1 solution of ethyl acetate:diethyl ether and washed with 1M HCl (1×), 10% aq. sodium carbonate (1×) and brine (1×). The organic phase was dried with magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in EtOAc and precipitated out hexanes, and then collected over a filter and washed with diethyl ether to give the title compound as a white solid. (Yield: 59 mg, 0.109 mmol, 40%) 1H NMR (400 MHz, CDCl3) 7.64, 7.31, 7.27-7.09, 7.02, 6.63, 5.45, 5.24, 4.33, 4.17, 3.00, 2.90-2.58, 2.49, 2.29-2.11, 1.83-1.34, 1.18
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C1(C(C2C=CC=CC=2)=[NH:26])C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH2:26])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Nc1nccc2nc(-c3c(Cl)cccc3Cl)sc12
Temperature: 25 °C
Yield: 38.6 %

Procedure:
To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (1.00 g, 2.80 mmol), diphenylmethanimine (607 mg., 3.40 mmol), Pd2(dba)3 (128 mg, 0.140 mmol), BINAP (174 mg, 0.280 mmol), sodium tert-butoxide (403 mg, 4.20 mmol), and toluene (15.0 mL). The mixture was degassed with nitrogen for 10 min. The resulting mixture was irradiated in a microwave reactor at 130° C. for 1 hour and then cooled to room temperature. The mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:2) to give the desired product as a solid (320 mg, 38.7% yield). LCMS (ESI) m/z: 296 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:2].CN1C=CN=C1.[C:33](Cl)(=[O:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].C(N(CCCC)CCCC)CCC>[Ti](Cl)(Cl)(Cl)Cl.O.C(Cl)Cl>[C:7]([NH:6][CH:5]([C:33](=[O:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:4]([O:3][CH2:1][CH3:2])=[O:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCC(=O)OCC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCCCCCCCCCCC(=O)NC(C(=O)CCCCCCCCCCCCCCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0.1 %

Procedure:
A methylene chloride solution (100 ml) of N-octadecanoylglycine ethyl ester (3.70 g, 10 mmol) and N-methylimidazole (985.4 mg, 12 mmol) was cooled to −45° C., and a methylene chloride solution (10 ml) of palmitoyl chloride (2.76 mg, 9.74 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 20 minutes at the same temperature, a methylene chloride solution (10 ml) of titanium tetrachloride (6.81 mg, 35 mmol) and a methylene chloride solution (10 ml) of tributylamine (7.42 g, 40 mmol) were added thereto. The resulting mixture was stirred for 2 hours at −45° C. After 100 ml of water was added thereto and the mixture was heated to room temperature, the organic layer was separated. Further, the water layer was extracted twice with methylene chloride (100 ml), and the organic layers were combined and dried with magnesium sulfate. After the solvent was removed in reduced pressure, the obtained crude product was purified by silica gel chromatography (Kieselgel 60 manufactured by Merck, hexane:ethyl acetate=4:1) to obtain the title compound (3.20 mg, yield: 54%).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.C(N(CC)CC)C>C1COCC1.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.[Cu](I)I>[C:9]1([CH3:12])[CH:10]=[CH:11][C:6]([C:3]#[C:2][CH2:1][OH:4])=[CH:7][CH:8]=1
Reactant: C#CCO
Reactant: Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C#CCO)cc1
Temperature: 35 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (120 mg; 0.171 mmol) was added to a stirred solution of propargyl alcohol (5.38 g; 95.88 mmol, 1.02 eq), 1-iodo-4-methylbenzene (20.50 g; 94.0 mmol, 1 eq), triethylamine (18.99 g; 188 mmol, 2 eq), and copper iodide (60 mg; 0.32 mmol) in THF (50 mL). The mixture was stirred at 35° C. for 12 h under a nitrogen atmosphere. The mixture was then filtered through a bed of celite and the filtrate was washed with ethyl acetate. The filtrate was then concentrated at 35° C. (vac.=28 in Hg) using a rotary evaporator. The residue was purified using a silica gel column (4:1 heptane/ethyl acetate→2:1 heptane/ethyl acetate) to give the desired product as a light yellow oil (9.62 g; 65.8 mmol; 70%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.34 (s, 3 H) 4.48 (s, 2H) 7.11 (d, 2H) 7.33 (d, 2H).
Reaction SMILES: N1CCCCC1.C1C2C(COC([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:41][C:42]3[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=3)[CH2:34][C:35]3[N:36]([CH3:40])[CH:37]=[CH:38][N:39]=3)[C:26]([OH:28])=[O:27])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C=O)C>[NH2:24][C@@H:25]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:41][C:42]1[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=1)[CH2:34][C:35]1[N:36]([CH3:40])[CH:37]=[CH:38][N:39]=1)[C:26]([OH:28])=[O:27]
Reactant: Cn1ccnc1CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccn1C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Piperidine (0.80 mL) was added to a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino)hexanoic acid (556 mg, 1.00 mmol) in DMF (4.0 mL). The mixture was stirred at room temperature for 2 hrs. Solvent was evaporated under reduce pressure to afford a residue, which was purified by Amberchrom to afford (S)-2-amino-6-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino) hexanoic acid (330 mg, 99%). 1H NMR (400 MHz, DMSO-d6) 7.94 (s, 1H), 7.04 (d, J=3=1.2 Hz, 2H), 6.74 (d, J=1.2 Hz, 2H), 3.54 (s, 4H), 3.98 (brs, 1H), 2.88 (s, 3H), 2.72 (s, 3H), 2.35 (t, J=6.8 Hz, 2H), 1.60-1.54 (m, 1H), 1.43-1.29 (m, 3H), 1.16-1.11 (m, 2H); MS (ESI), 335 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[OH-:35].[Na+].Cl>O1CCOCC1>[OH:35][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][CH:15]([NH:18][S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccnc(Cl)c5c4)C3=O)cc2c1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2ccc(S(=O)(=O)NC3CCN(Cc4ccc5ccnc(O)c5c4)C3=O)cc2c1

Procedure:
7-Methoxynaphthalene-2-sulfonic acid [1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.07 g, 0.14 mmol), prepared as described in EXAMPLE 1, Part K, is treated with dioxane (1 mL) and 10% aq. NaOH (3 mL) and heated to reflux for 48 hours. The reaction was cooled, acidified with 1 N HCl and extracted with CH2Cl2. The organic layer is separated, dried and concentrated. The residue is purified by column chromatography eluting with 2.5% MeOH/CH2Cl2. The product fractions are collected, concentrated and precipitated with dilute HCl/ether to yield the title compound (0.041 g, 0.086 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.[F:51][P-](F)(F)(F)(F)F.CN1CCOCC1.FC1C=CC(N)=CC=1>CN(C)C=O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([F:51])=[CH:28][CH:29]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ncnn3cccc23)c(F)c1)Nc1ccccc1
Reactant: F[P-](F)(F)(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Nc1ccc(F)cc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CC(=O)Nc1ccc(Oc2ncnn3cccc23)c(F)c1)Nc1ccc(F)cc1

Procedure:
A solution of 3-(3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenylamino)-3-oxopropanoic acid (18 mg, 0.55 mmol, Compound B of Example 23), BOP reagent (36 mg, 0.082 mmol), 4-methylmorpholine (30 μL, 0.27 mmol), and 4-fluoroaniline (5.2 μL, 0.055 mmol) in dimethylformamide (0.5 mL) was stirred at room temperature for 16 h. The reaction was diluted with EtOAc (4 mL) and washed with water, 10% aq LiCl solution, and brine (1×3 mL each). The organic solution was dried over anhydrous Na2SO4 and then concentrated in vacuo. Purification by flash chromatography on silica gel (SiO2, EtOAc/Hexane 7:3) gave the desired compound as a white solid. The product was lyophilized with acetonitrile/water to give the title compound (14 mg, 61%) as a white powder. 1H NMR (CDCl3) δ 9.28 (br s, 1H), 8.64 (br s, 1H), 7.89 (s, 1H), 7.73 (dd, 1H, J=2.5, 1.5 Hz), 7.69 (dd, 1H, J=11.6, 1.9 Hz), 7.42 (m, 3H), 7.21 (m, 1H), 6.97 (m, 3H), 6.80 (dd, 1H, J=4.5, 2.6 Hz), 3.49 (s, 2H); MS(ESI+) m/z 424.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1.C[CH2:18][O:19]CC>C(O)=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][O:15][CH:18]=[O:19])=[C:4]([NH2:16])[N:3]=1
Reactant: CCOCC
Reactant: Nc1nc(N)c2ncn(COCCO)c2n1
Solvent: O=CO
Product: Nc1nc(N)c2ncn(COCCOC=O)c2n1

Procedure:
A solution of 2-amino-9-(2-hydroxyethoxymethyl)adenine (0.5 g) in 97% formic acid (2.5 ml) was stirred in an ice bath for 3 hours, and then at room temperature overnight. Dry ether (80 ml) was added and the mixture chilled. The solid was removed by filtration and dissolved in hot acetonitrile (125 ml); residual solids were removed by filtration. The filtrate was applied to a column containing silica gel (14 g) in acetonitrile. The column was eluted with dry acetone. The eluate was evaporated and the residual solid recrystallized from acetonitrile to give 2-amino-9-(2-formyloxyethoxymethyl)adenine (93 mg, m.p. 238°-240° C.).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH:6]([CH2:11][N:12]3[C:17]4=[N:18][C:19]([C:23]5[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=5)=[CH:20][C:21](=[O:22])[N:16]4[CH2:15][C:14]([CH3:30])([CH3:29])[CH2:13]3)[CH2:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.O>C1(C)C=CC=CC=1.C(O)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>[CH3:29][C:14]1([CH3:30])[CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:18]=[C:17]2[N:12]([CH2:11][CH:6]2[CH2:5][C:4]3[N:3]=[C:2]([C:40]4[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=4)[CH:10]=[CH:9][C:8]=3[CH2:7]2)[CH2:13]1
Reactant: CC1(C)CN(CC2Cc3ccc(Cl)nc3C2)c2nc(-c3ccncc3)cc(=O)n2C1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)CN(CC2Cc3ccc(-c4ccncc4)nc3C2)c2nc(-c3ccncc3)cc(=O)n2C1
Temperature: 140 °C
Reaction time: 24 h
Yield: 20.2 %

Procedure:
To a solution of 0.22 g (0.521 mmol) of (+/−)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one in 3 ml of anhydrous toluene and 0.5 ml of ethanol was treated with 0.625 ml (2M solution in water) of sodium carbonate, 36 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium and 0.096 g (0.781 mmol) of pyridine-4-boronic acid. After being stirred for 24 h at 140° C., water was added, the mixture was extracted with dichloromethane. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with dichloromethane/methanol/ammonia in the proportions 99/1/0.1 to give 0.049 g of pure product obtained in the form of free base. Mp: 170–171° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N+:21]([O-])=O>[Pd].CO>[NH2:21][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
N-(4-Methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide (10.6 g, 32.7 mmol) obtained in Step (1) was stirred in a solvent of methanol. The reaction solution was mixed with Pd/C (1 g, 9.40 mmol), followed by stirring under hydrogen conditions for about 2 hours at room temperature. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with methanol. The filtrate was concentrated under reduced pressure to obtain the title compound (8.9 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15](O)C>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([CH3:15])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCO
Reactant: CCOC(=O)C=Cc1ccc(F)cc1
Agent: [Pd]
Product: CCOC(=O)CC(C)c1ccc(F)cc1
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of ethyl 4-fluorocinnamate (47.5 g, 0.228 mol) and 10% palladium on carbon (0.85 g, Aldrich) in 95% ethanol was shaken in a Parr hydrogenator under 2-3 atm of H2 pressure for 1 h. The mixture was filtered and concentrated by spin evaporation in vacuo. Fractional distillation gave 46.5 g (97%) of ethyl 3-(4-fluorophenyl)butyrate as a clear oil, b.p., 122°-128° C.: c) Preparation of 3-(4-Fluorophenyl)butanoic Acid.
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:23][O:22][C:8]2=[C:9]3[C:14](=[CH:15][CH:16]=[C:7]2[N:6]1[CH2:24][C:25]([F:28])([F:27])[F:26])[NH:13][C:12](=[O:17])[CH:11]=[C:10]3[C:18]([F:21])([F:20])[F:19])[CH:2]([CH3:4])[CH3:3].NC1C=CC2N(CC(F)(F)F)[C@H](CC(C)C)COC=2C=1.C(OC(=O)CC(C(F)(F)F)=O)C>C1(C)C=CC=CC=1>[CH2:1]([C@@H:5]1[CH2:23][O:22][C:16]2[C:7](=[CH:8][C:9]3[C:10]([C:18]([F:20])([F:21])[F:19])=[CH:11][C:12](=[O:17])[NH:13][C:14]=3[CH:15]=2)[N:6]1[CH2:24][C:25]([F:28])([F:26])[F:27])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H]1COc2c(ccc3[nH]c(=O)cc(C(F)(F)F)c23)N1CC(F)(F)F
Agent: CC(C)C[C@@H]1COc2cc(N)ccc2N1CC(F)(F)F
Agent: CCOC(=O)CC(=O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H]1COc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2N1CC(F)(F)F
Temperature: 95 °C
Yield: 9 %

Procedure:
(3R)-2,3,4,7-Tetrahydro-3-isobutyl-4-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-8H-[1,4]oxazino[2,3-f]quinolin-8-one (Compound 155, Structure 17 of Scheme III, where R1, R3, R4, R5, R7, R8=H, R2=trifluoromethyl, R6=isobutyl, R=CH2CF2), and (2R)-1,2,3,6-tetrahydro-2-isobutyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-f]quinolin-7-one (Structure 18 of Scheme III, where R1, R3, R4, R5, R7=H, R=trifluoromethyl, R6=isobutyl, R13=CH2CF3): This compound was prepared by treatment of (3R)-7-amino-3,4-dihydro-3-isobutyl-4-trifluoroethyl-2H-1,4-benzoxazine (0.13 g, 0.45 mmol) and ethyl-4,4,4-trifluoroacetoacetate (0.25 g, 1.4 mmol) in 6 mL toluene heated at reflux for 3 h, followed by removal of solvent and treatment with 3 mL concentrated H2SO4 heated to 95° C. for 1 h. The mixture was poured into water (100 mL), neutralized with 6N NaOH, and extracted with chloroform (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The baseline impurities and were removed and partial purification achieved by flash chromatography (95:5 CH2Cl2:MeOH). Further purification by HPLC (Kromasil, 0.5″ semi-prep column, 70% MeOH/water at 3 mL/min) afforded 5.0 mg (3%) of Compound 155, and recrystallization of the other impure fractions (ethyl acetate:hexanes) afforded 17 mg (9%) of (2R)-1,2,3,6-tetrahydro-2-isobutyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, the regioisomer of Compound 155. Data for Compound 155: 1H NMR (500 MHz, CDCl3) δ 12.0–12.4 (v broad s, 1H), 7.15 (s, 1H), 7.13 (d, J=9.0, 1H), 7.01 (d, J=9.0, 1H), 4.34 (d, J=11, 1H), 3.99 (broad d, J=10, 1H), 3.75–3.85 (m, 1H), 3.65–3.75 (m, 1H), 3.35–3.40 (m, 1H), 1.70–1.80 (m, 1H), 1.40–1.50 (m, 1H), 1.30–1.40 (m, 1H), 0.95 (d, J=6.5, 3H), 0.93 (d, J=7.0, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1c(O)cccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1c(O)cccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of 2-bromo-6-hydroxybenzaldehyde (3.8 g, 18.91 mmol, 1 eq.) in a mixture of THF and MeOH (4/1, 25 mL) was added NaBH4 (1.4 g, 37.81 mmol, 1.5 eq.) at rt portion-wise. Upon the completion of addition, the mixture was continued to stir at rt for 30 min. The mixture was quenched with HCl (4 N) and extracted with EtOAC twice. The combined organic layer was dried over Na2SO4, concentrated, and purified on silica gel using 25% EtOAc/hexanes as eluent to give 3-bromo-2-(hydroxymethyl)phenol (2.3 g, 60%) as a colorless oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][NH2:25]>CO.[Pt]=O>[CH2:1]([NH:25][CH2:24][CH2:23][O:22][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:20][C:21]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCOc1ccc2c(c1)[nH]c1ccccc12
Reactant: O=Cc1ccccc1
Agent: O=[Pt]
Solvent: CO
Product: c1ccc(CNCCOc2ccc3c(c2)[nH]c2ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzaldehyde (9.38 g) was added to a solution of N-[2-(9H-carbazol-2-yloxy)]ethylamine (20 g; synthesized according to the process indicated in JP-A-9-249623) in methanol (500 mL). The mixture was then stirred at room temperature for 1 hour. Under an argon atmosphere, platinum oxide (1.00 g; mfd. by Wako Pure Chemical Industries) was added to the mixture, which was then stirred under a hydrogen atmosphere at atmospheric pressure for 3 hours. After replacing the atmosphere in the reaction system with argon, benzaldehyde (1.88 g) was added to the mixture, which was then further stirred under a hydrogen atmosphere at atmospheric pressure for 3 hours. After replacing the atmosphere with argon, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol and dried under reduced pressure to give the title compound (25.2 g) as a pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](O)=[O:12])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(CCCO)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of the 3-(4-methoxyphenyl)propionic acid in 100 ml of anhydrous ether was added dropwise to a suspension of 1.10 g of lithium aluminum hydride in 50 ml of anhydrous ether with stirring at room temperature over 20 minutes. After stirring at room temperature for 30 minutes, the mixture was refluxed for 1 hours. After cooling, water was added with ice cooling, and the mixture was made acidic by further addition of 10% hydrochloric acid and then extracted with ether. The organic layer was washed with saturated aqueous solution of sodium chloride, driven over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5.06 g of 3-(4-methoxyphenyl)propanol.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.Br[CH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([O:16][CH3:17])=[O:15].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([O:1][CH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([O:16][CH3:17])=[O:15])[N:7]=1
Reactant: CCCCC(Br)C(=O)OC
Reactant: COc1cc(OC)nc(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(Oc1nc(OC)cc(OC)n1)C(=O)OC
Temperature: 25 °C
Yield: 73.7 %

Procedure:
3.5 g of 2-hydroxy-4,6-dimethoxypyrimidine, 4.7 g of methyl 2-bromohexanoate, 50 ml of N,N-dimethylformamide and 3.3 g of anhydrous potassium carbonate were stirred at a temperature of from 85° to 90° C. for 3 hours. The reaction mixture was cooled to room temperature and then diluted with water. This aqueous mixture was extracted with ethyl ether. The ethyl ether extract was washed with water and dried. Then, ethyl ether was removed by distillation under reduced pressure to obtain a slightly yellow oily substance. The slightly yellow oily substance was purified by silica gel column chromatography (eluent: hexane/ethyl acetate =6/1) to obtain 4.7 g of the desired product.