Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:3]=1
Reactant: Cc1cc(-n2cncn2)ncc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cc(-n2cncn2)ncc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 99.9 %

Procedure:
To a suspension of 4-methyl-5-nitro-2-(1,2,4-triazol-1-yl)pyridine (4.1 g, 20 mmol) in dry DMF (30 mL) was added dimethylformamide dimethyl acetal (5.9 mL, 44 mmol) and the mixture heated at 90° C. for 20 min. The solvent was evaporated in vacuo using toluene as an azeotrope to give the title compound (5.2 g, 100%) as a dark red solid. mp 225°-228° C. 1H NMR (360 MHz, CDCl3) δ 3.10 (6H, s) 6.13 (1H, d, J=13.1Hz), 7.54 (1H, d, J=13.1Hz), 7.81 (1H, s), 8.04 (1H, s), 8.92 (1H, s) and 9.17 (1H, s).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[O:20][CH:21]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:15][CH2:16][C:17]1[CH:18]=[C:19]([Si:22]([CH2:25][CH3:26])([CH2:27][CH3:28])[CH2:23][CH3:24])[O:20][CH:21]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC[Si](CC)(CC)c1cc(CN)co1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NCc1coc([Si](CC)(CC)CC)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Dodecanoyl chloride (109 mg, 0.49 mmol) was added to a solution of 4-aminomethyl-2-triethylsilylfuran (Compound 29, 70 mg, 0.33 mmol) and triethylamine (69 microliter, 0.49 mmol) in tetrahydrofuran (3 ml) at room temperature. After stirring at room temperature overnight (ca. 15 hours), most of the solvent was evaporated and the residue was purified by chromatography on preparative silica thin layer plates (developed with 50% ethyl ether/hexane) to give the title amide as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2N)[CH2:8][CH2:7][CH2:6]1.O>CCOCC>[NH:1]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:4]3[C:2]1=[O:3]
Reactant: Nc1cccc2c1NCCC2
Reactant: NC(N)=O
Solvent: O
Solvent: CCOCC
Product: O=c1[nH]c2cccc3c2n1CCC3
Temperature: 180 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
13 g (0.216 mol) of urea are added to 32 g (0.216 mol) of 1,2,3,4-tetrahydroquinolin-8-amine and the mixture is heated for 3 hours at 180° C. Boiling water is added, the reaction mixture is allowed to cool, ether is added and the mixture is stirred for 2 hours. The reaction mixture is then filtered, the precipitate is sucked dry, washed successively with water and ether and dried under vacuum. There are obtained 19 g of product which is recrystallized from isopropanol. The residue is purified by chromatography on a column of silica gel, the eluent being a dichloromethane/methanol (95/5) mixture. There are obtained 7 g of product which is used as is in the following stage.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:8]=[C:7]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)[N:6]=1)([CH3:3])[CH3:2].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)([O:26][CH3:27])=[O:25]>C(N(CC)CC)C>[CH:1]([O:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:8]=[C:7]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([C:24]([O:26][CH3:27])=[O:25])=[CH:29][CH:30]=3)=[O:36])=[CH:19][CH:18]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(N=C=O)cc1
Reactant: CC(C)Oc1nc(-c2ccc(N)cc2)nc(N2CCOCC2)n1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(OC(C)C)nc(N4CCOCC4)n3)cc2)cc1
Reaction time: 48 h

Procedure:
A mixture of 4-(4-isopropoxy-6-morpholino-1,3,5-triazin-2-yl)aniline (1.3 g, 4.1 mmol), triethylamine (2 ml) and 4-carbomethoxy-phenylisocyanate (1451 mg, 8.2 mmol) was stirred for 48 hours and quenched with water and washed well. The organic layer was dried and filtered. It was concentrated and purified by column chromatography by eluting it initially with 10% ethyl acetate:hexane and latter with 40% ethyl acetate:hexane. White solid; 600 mg, 30%; MS (ESI) m/z 492.5.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1>[C:1]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of Boc-isonipecotic acid (40 g, 0.17 mol) and N-methylmorpholine (19 mL, 0.17 mol) in tetrahydrofuran (900 mL) stirring at −10° C., ethyl chloroformate was slowly added (17 mL, 0.17 mol) via addition funnel. After 30 min, sodium borohydride was added (19.8 g, 0.5 mol) in one portion. The reaction mixture was stirred at −10° C. for 1 h; then it was slowly quenched with methanol. The solvent was removed in vacuo; the resulting residue was diluted with 10% aqueous acetic acid and partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with additional ethyl acetate (2×500 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo to a solid residue which was chromatographed on silica gel. Elution with ethyl acetate-hexanes (1:9 to 1:1) provided the title compound (33.8 g, 90%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15][NH2:16].N1C=CN=C1>ClC(Cl)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][CH2:15][CH2:14][CH:13]([CH3:17])[CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)CCN
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: c1c[nH]cn1
Solvent: CC(Cl)Cl
Product: CC(C)CCNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
To a stirred solution of 2,4-dichloro-5-nitropyrimidine (13.8 g, 99.28 mmol) and 3-methylbutan-1-amine (7.0 g, 80.45 mmol) in dichloroethane (150 mL) was added imidazole (3.78 g, 55.58 mmol) at 0° C., the resulting mixture was stirred at 0° C. for 30 minutes then stirred at rt for 16 h. The solvent was removed under reduced pressure to give a crude residue was purified by silica gel column chromatography (eluent: 2% ethyl acetate in hexane) to yield 5.5 g of the desired compound. 1H NMR (CDCl3, 300 MHz) δ 0.98 (d, J=6.8 Hz, 6H), 1.56-1.81 (m, 3H), 3.60-3.75 (m, 2H), 8.40 (br s, 1H), 9.01 (s, 1H); MS m/z 245[M+H+].
Reaction SMILES: C([O:5][P:6]([O:37]C(C)(C)C)([O:8][CH2:9][O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)[C@@:15]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])([F:26])[C:14]1=[O:36])=[O:12])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[P:6]([O:8][CH2:9][O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=2)[C@@:15]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])([F:26])[C:14]1=[O:36])=[O:12])([OH:7])([OH:37])=[O:5]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCOP(=O)(OC(C)(C)C)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCOP(=O)(O)O)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
To a 25 mL flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid di-tert-butoxy-phosphoryloxymethyl ester ((S)-XV) (0.110 g, 0.176 mmol) was added 2 mL anhydrous dichloromethane, and trifluoroacetic acid (0.060 g, 0.527 mmol). The reaction was allowed to stir at room temperature for 4 hours. The dichloromethane was evaporated in vacuo, and the crude foam was purified by reverse phase chromatography (C18 2:1CH3CN:H2O) producing the title compound (0.070 g, 78%) as a white powder. 1H NMR (CDCl3 400 MHz): δ=8.26 (s, 1H), 7.68 (s, 1H), 7.45 (d, 1H, J=7 Hz), 7.28-7.24 (m, 2H), 6.72 (d, 1H, J=7 Hz), 5.90-5.81 (m, 2H), 3.48 (s, 3H); 31P NMR (CDCl3 162 MHz) δ=−0.233; 19F NMR (CDCl3 376 MHz) δ=−63.3, −153.8; LRMS [M−H]−511.4, [M+NH4]+530.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[C:15]([C:16](Cl)=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:21]([N:24]1[C:28]2=[CH:29][C:30]([CH3:32])=[N:31][N:27]2[C:26]([C:33]2[CH:38]=[C:37]([NH2:39])[CH:36]=[CH:35][C:34]=2[O:40][CH3:41])=[N:25]1)(=[O:23])[CH3:22]>>[C:21]([N:24]1[C:28]2=[CH:29][C:30]([CH3:32])=[N:31][N:27]2[C:26]([C:33]2[CH:38]=[C:37]([NH:39][C:16](=[O:17])[C:15]3[CH:19]=[C:11]([N:10]=[N:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH:12]=[CH:13][C:14]=3[OH:20])[CH:36]=[CH:35][C:34]=2[O:40][CH3:41])=[N:25]1)(=[O:23])[CH3:22]
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Reactant: COc1ccc(N)cc1-c1nn(C(C)=O)c2cc(C)nn12
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)Nc3ccc(OC)c(-c4nn(C(C)=O)c5cc(C)nn45)c3)c2)cc1

Procedure:
5-(4-Methoxyphenylazo)salicoyl chloride and 1-acetyl-3-(5-amino-2-methoxyphenyl)-6-methyl-1H-pyrazolo[3,2-c]-s-triazole were reacted together as described for the preparation of Dye 7. The product crystallized as the monohydrate from aqueous pyridine, m.p. 282°-3°, λmax (methanol) = 350 nm.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:54][C:55]([C:57]1[C:65]2[N:64]=[C:63]([NH2:66])[NH:62][C:61]=2[CH:60]=[C:59]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:58]=1)=[O:56])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH2:47]([O:54][C:55]([C:57]1[C:65]2[NH:64][C:63]([NH:66][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:62][C:61]=2[CH:60]=[C:59]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:58]=1)=[O:56])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: Nc1nc2c(C(=O)OCc3ccccc3)cc(OCc3ccccc3)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2cc(OCc3ccccc3)cc(C(=O)OCc3ccccc3)c2[nH]1)c1cc2ccccc2cn1

Procedure:
600 mg (3.0 mmol) of isoquinoline-3-carboxylic acid and 1200 mg (3.1 mmol) of HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and reacted with 1.1 g (3.0 mmol) of 2-amino-6-benzyloxy-1H-benzoimidazole-4-carboxylic acid benzyl ester as described in general procedure A to produce 6-benzyloxy-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid benzyl ester. LCMS: 530 (M+1)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][OH:9].C(N(CC)CC)C.[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:20]([O:9][CH2:8][CH:7]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:21])[CH2:19][C:18]([CH3:17])=[O:22]
Reactant: OCC=Cc1cccs1
Reactant: C=C1CC(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC=Cc1cccs1

Procedure:
1.50 g (10.7 mmol) of 3-(thiophene-2-yl)-2-propene-1-ol, 0.5 ml (3.59 mmol) of triethylamine and 1.0 ml (13.0 mmol) of diketene were heated to 70° C. under stirring in 30 ml of toluene for 1.5 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture at room temperature. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:40]=[CH:39][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:36](O)=[O:37])[CH2:34][OH:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.C([O:46][C:47](=[O:57])[C@@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH2:49])(C)(C)C.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:40]=[CH:39][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:36]([NH:49][C@@H:48]([C:47]([OH:57])=[O:46])[CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:37])[CH2:34][OH:35])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Reactant: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@H](CO)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@H](CO)C(=O)N[C@H](Cc1ccccc1)C(=O)O
Reaction time: 25 h
Yield: 49.6 %

Procedure:
A solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-([2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-serine (diastereomeric mixture) (0.008 g, 0.014 mmol), D-phenylalanine tert-butyl ester hydrochloride (0.005 g, 0.018 mmol) and N-Methylmorpholine (0.006 ml, 0.055 mmol) in DCM (3 ml) was stirred at RT for 5 min. TBTU (0.008 g, 0.025 mmol) was added. After 3 days the conversion to the ester (M/z: 776.1) was complete and the mixture was concentrated under reduced pressure. The residue was dissolved in formic acid (3 ml) and the solution was stirred for 25 h. The mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (4 ml) and TEA (1 ml). The solution was stirred at 40° C. for 6 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-50% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.005 g (53% yield) of the title product was obtained as a white solid. M/z: 720.1. 1H NMR (DMSO, 400 MHz): δ 2.78-2.96 (m, 3H), 3.03-3.11 (m, 1H), 3.44-3.60 (m, 2H), 4.20-4.36 (m, 3H), 4.51 (s, 2H), 4.67-4.76 (m, 1H), 5.01-5.06 (m, 1H), 5.70 (bs, 1H), 6.90-6.98 (m, 2H), 7.05-7.25 (m, 1H), 7.29-7.37 (m, 4H), 7.84-8.00 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: ClCCN1CCOCC1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Temperature: 140 °C

Procedure:
A mixture of 2-methoxy-4-nitrophenol Compound 42a1 (1.0 g, 5.4 mmol), potassium carbonate (1.5 g, 10.9 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride Compound 42a2 (1.05 g, 5.64 mmol) in DMF (10 mL) was heated under microwave conditions to 140° C. for 30 minutes. The reaction mixture was filtered, diluted with EtOAc and subsequently washed with water, then brine. The organic layer was dried over sodium sulfate and concentrated to yield 4-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-morpholine Compound 42a3 (1.4 g). MS 283 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([F:23])([F:14])[F:24])=[CH:21][N:20]=1)=[O:8])=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(C(F)(F)F)cn1

Procedure:
2,6-Dichlorobenzoyl isocyanate (1.1 grams; 0.005 mole) and 5-(trifluoromethyl)-2-aminopyridine (800 mg; 0.005 mole) were mixed in 50 ml. of ethyl acetate at room temperature and stirred overnight (about 18 hours) at room temperature. Solvent was then evaporated and the product recrystallized from ethanol, m.p. 228°-230° C., yield 200 mg. Elemental analysis showed:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:24]=C[C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])=[CH:9][C:8]=1O)=[O:5].ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:64](CC)CC)C>C(#N)C.O>[Cl:1][C:2]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)[CH:27]=[CH:26][C:3]=1[C:4]1[O:5][C:8]2[CH:9]=[C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH3:14])[N:64]=[CH:24][C:7]=2[N:6]=1
Reactant: CCN(CC)CC
Reactant: C[C@@H](COc1ccc(NC(=O)c2ccc(OCC3CC3)cc2Cl)c(O)c1)NC(=O)OC(C)(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCC4CC4)cc3Cl)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl ((2S)-1-(4-((2-chloro-4-(cyclopropylmethoxy)benzoyl)amino)-3-hydroxyphenoxy)propan-2-yl)carbamate (200 mg), hexachloroethane (241 mg) and triphenylphosphine (321 mg) in acetonitrile (3 mL) was added triethylamine (0.454 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (65 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]3)[CH:13]=[CH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26].CO>O1CCOCC1>[C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:17][C:18](=[O:21])[C:19](=[CH:24][N:25]([CH3:27])[CH3:26])[CH2:20]3)[CH:13]=[CH:12][N:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCN(c2ccnc(C(=O)Nc3ccccc3)c2)C1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C=C1CN(c2ccnc(C(=O)Nc3ccccc3)c2)CC1=O
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A suspension of 4-(3-oxopyrrolidin-1-yl)-pyridine-2-carboxylic acid phenylamide (130 mg, 0.46 mmol) and dimethylformamide dimethylacetal (0.12 mL, 0.90 mmol) in 1,4-dioxane (2 ml) was heated under nitrogen at 100° C. for 4.5 h. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (25 g) eluted with dichlromethane:methanol 19:1 and gave the title compound (95 mg, 0.28 mmol, yield 61%).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].CN1C(=O)N(C)CCC1.P(OCC)(OCC)OCC.[Si:24]([O:31][C@H:32]([CH2:39]I)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C1COCC1.[Cu]I>[Si:24]([O:31][C@H:32]([CH2:39][CH:1]=[CH2:2])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CCOC(=O)C[C@@H](CI)O[Si](C)(C)C(C)(C)C
Reactant: C=C[Mg]Cl
Agent: [Cu]I
Agent: CCOP(OCC)OCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: C=CC[C@H](CC(=O)OCC)O[Si](C)(C)C(C)(C)C
Temperature: 11 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a suspension of CuI (83.64 g, 437.0 mmol) in dry THF (875 mL), vinylmagnesium chloride (1.9 M in THF, 460.0 mL, 874.0 mmol) is added under argon atmosphere at 44 to −31° C. in 15 minutes under vigorous stirring. The resulting dark slurry is stirred for 15 minutes, and DMPU (112 g, 874.0 mmol) is added at 42° C. in one portion followed by the dropwise addition (5 minutes) of P(OEt)3 (160.1 mL, 874.0 mmol) at 40° C. The resulting mixture is stirred for 30 minutes and a THF (220 mL) solution of (S)-ethyl 3-(tert-butyldimethylsilyloxy)-4-iodobutyrate (3) (162.7 g, 437.0 mmol) is added at −40 to −36° C. in 15 minutes. The stirring is continued for 1 hour at −40 to −35° C. before allowing the mixture to warm to 11° C. over a period of 3.5 hours. The reaction is quenched at −2° C. (saturated NH4Cl, 1.0 L) and stirred at 10° C. for 30 minutes. The product is extracted with i-Pr2O or t-BuMeO. Partial evaporation of the solvent under reduced pressure gives a yellow solution which is washed with 0.1 M H2SO4, water and dried (MgSO4). Ether is removed completely under reduced pressure (15 mbar) at 80° C. to produce a yellow oily residue. This residue is purified further by vacuum distillation (64-72° C. at 0.10-0.44 mbar) to give 80.8 g (67.8%) of ethyl 3(R)-(tert-butyldimethylsilyloxy)-5-hexenoate (4) as a colorless oil (GC purity 96%). 1H NMR (300 MHz, CDCl3): δ 5.81 (ddt, J=17.8, 9.6 and 7.2 Hz, 1H), 5.11-5.03 (m, 2H), 4.21 (quint., J=6.8 Hz, 1H), 4.12 (qt, J=7.1 and 1.5 Hz, 2H), 2.43 (d, J=7.1 Hz, 1H), 2.43 (d, J=5.4 Hz, 1H), 2.31−2.25 (m, 2H), 1.26 (t, J=7.2 Hz, 3H), 0.87 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 171.7, 134.1, 117.6, 68.9, 60.2, 42.1, 42.1, 25.7, 17.9, 14.1, −4.6, −5.0.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:15]=1[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:14]=1[O:13][CH3:12])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: COc1ccc(OC)c(N)c1
Product: COc1ccc(OC)c(NC(=O)c2cc(Br)ccc2O)c1
Yield: 39.7 %

Procedure:
Using 5-bromosalicylic acid and 2,5-dimethoxyaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.O(S(C)(=O)=O)S(C)(=O)=O.[CH3:49][C:50]1[C:54]2[CH:55]=[C:56]([NH2:60])[CH:57]=[C:58]([CH3:59])[C:53]=2[O:52][N:51]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:60][C:56]2[CH:57]=[C:58]([CH3:59])[C:53]3[O:52][N:51]=[C:50]([CH3:49])[C:54]=3[CH:55]=2)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1noc2c(C)cc(N)cc12
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(Nc1cc(C)c2onc(C)c2c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a stirred solution of ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (Step 46.11) (500 mg, 1.085 mmol) and triethylamine (0.756 mL, 5.42 mmol) in CH2Cl2 (10 mL) cooled down to 0° C. was added Ms2O (378 mg, 2.170 mmol) and the reaction was stirred for 1 hr at this temperature. 3,7-dimethylbenzo[d]isoxazol-5-amine (Step 46.6) (194 mg, 1.193 mmol) was added and the reaction mixture was allowed to warm up to RT and stir for 1 hr. The reaction was quenched with aq. NaH2PO4 solution and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 10-100%) to afford the title product (460 mg, 0.684 mmol, 63% yield) as yellow amorphous solid. tR: 1.38 min (LC-MS 2); ESI-MS: 605 [M+H]+ (LC-MS 2); Rf=0.25 (hexane/EtOAc 1:1).