Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6](=[O:14])[CH2:7]P(=O)(OC)OC.[H-].[Na+].[H][H].[CH:19]([CH:21]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH:22]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])=O>O1CCCC1.C(O)(=O)C>[OH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:22]1[CH:21]([CH:19]=[CH:7][C:6](=[O:14])[CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:29][CH2:28][C:23]21[O:24][CH2:25][CH2:26][O:27]2
Reactant: COCCCC(=O)CP(=O)(OC)OC
Reactant: [H][H]
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCCCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of dimethyl 5-methoxy-2-oxopentylphosphonate (5.3 g.) in tetrahydrofuran (19 ml.) was added to a stirred suspension of sodium hydride (0.39 g.) in tetrahydrofuran (140 ml.). The mixture was stirred at room temperature until the evolution of hydrogen had ceased, then treated dropwise with a solution of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [4.8 g.; prepared as described in Example 1(iv)] in tetrahydrofuran (47 ml.) and stirred for a further 2 hours. The mixture was acidified to pH 4 by the addition of glacial acetic acid, the solvents were removed in vacuo and diethyl ether was added to the residue. The solid was filtered off and the filtrate was washed with aqueous sodium carbonate, dried over anhydrous sodium sulphate, and evaporated to dryness, to give 6-(7-hydroxyheptyl)-7-(6-methoxy-3-oxohex-1-enyl)-1,4-dioxaspiro[4,4]nonane (6.4 g.), νmax 1620 cm-1, 1660 cm-1.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]CCl>CS(C)=O.O>[CH2:7]([NH:15][CH2:29][CH2:28][CH:27]([O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH3:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCN
Reactant: ClCCCCOc1ccc2ccccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCNCCC(C)Oc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-octylamine (0.33 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-octyl)-(3-(napthalen-2-yloxy)butyl)amine, solid, m.p 114° C., (yield 0.65 gm, 93.4%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]([NH2:23])=[O:22])[CH:14]=2)[N:4]([CH:24]([CH3:26])[CH3:25])[N:3]=1.[CH3:27][N:28]([CH:30](OC)OC)[CH3:29]>O1CCOCC1>[CH3:27][N:28](/[CH:30]=[N:23]/[C:21]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9]1[N:19]([CH:20]=[C:7]([C:5]3[N:4]([CH:24]([CH3:26])[CH3:25])[N:3]=[C:2]([CH3:1])[N:6]=3)[N:8]=1)[CH2:18][CH2:17][O:16]2)=[O:22])[CH3:29]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C(N)=O)cc2OCC3)n(C(C)C)n1
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)/N=C/N(C)C)cc2OCC3)n(C(C)C)n1
Temperature: 100 °C
Yield: 77.8 %

Procedure:
To a solution of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-12-carboxamide (200 mg, 0.568 mmol) in dioxane (20 mL) was added DMF-DMA (0.2 mL, 1.7 mmol). The reaction mixture was heated at 100° C. for 1 h. The solvent was removed under reduce pressure and the resultant residue was triturated with hot diethyl ether. The solid was collected by filtration, washed with diethyl ether, and dried in vacuo to afford N-[(1E)-(dimethylamino)methylidene]-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-12-carboxamide (180 mg, 78% yield) as a brown solid. LCMS (ESI) m/z: 408.3 [M+H+].
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].CB(O)O.ClCCl.[CH:14]([O:17][C:18]([N:20]1[C:26]2[C:27]3[CH2:28][CH2:29][CH2:30][C:31]=3[C:32](Br)=[CH:33][C:25]=2[C@@H:24]([NH:35][CH2:36][C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)[CH2:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15]>O1CCOCC1>[CH:14]([O:17][C:18]([N:20]1[C:26]2[C:27]3[CH2:28][CH2:29][CH2:30][C:31]=3[C:32]([CH3:1])=[CH:33][C:25]=2[C@@H:24]([NH:35][CH2:36][C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)[CH2:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15]
Reactant: CC(C)OC(=O)N1CCC[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)c3c(c21)CCC3
Reactant: O=C([O-])[O-]
Agent: CB(O)O
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc2c(c3c1CCC3)N(C(=O)OC(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Add cesium carbonate (383 mg, 2.52 mmol), methyl boronic acid (76 mg, 1.26 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (69 mg, 0.084 mmol) to a solution of (S)-6-(3,5-bis-trifluoromethyl-benzylamino)-4-bromo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (500 mg, 0.84 mmol) in dioxane (7 mL). Stir the mixture under nitrogen at 110° C. for 2 h. Cool down the mixture to room temperature and filter over Celite® washing with dichloromethane. Evaporate the solvent and purify the crude by chromatography, eluting with hexane/ethyl acetate (90/10) to afford the title compound (355 mg, 0.67 mmol, 80%). MS (ES+): 529 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][C@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[CH3:9])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C[C@H]1CCCN1
Solvent: ClCCl
Product: C[C@H]1CCCN1c1ncc(Br)cn1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
Solid 5-bromo-2-chloropyrimidine (27.5 g, 142 mmol) was added in three portions to a 500 mL flask containing (S)-2-methylpyrrolidine (20.24 ml, 213 mmol) stirred at room temperature. After 1 hr the resulting solids were dissolved in warm DCM, washed with water, brine, dried over MgSO4 and concentrated onto silica in vacuo. Column purified by silica gel chromatography to afford white crystalline solids (30.7 g, 89%), ESI-MS (EI+, m/z): 241.02, 1H NMR (Chloroform-d) δ: 8.31 (d, J=5.0 Hz, 2H), 4.33-4.14 (m, 1H), 3.61 (tt, J=7.6, 3.0 Hz, 1H), 3.56-3.41 (m, 1H), 2.23-1.88 (m, 3H), 1.88-1.63 (m, 1H), 1.25 (t, J=5.5 Hz, 3H)
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[O:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])=[CH:11][N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cnc(-c3ccccc3)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cnc(-c2ccccc2)nc1)N1CCNCC1
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a mixture consisting of tert-butyl 4-(2-phenylpyrimidine-5-carbonyl)piperazine-1-carboxylate (587 mg) in dichloromethane (8 mL) at 0° C. was added trifluoroacetic acid (7 mL). The mixture was stirred cold for one hour and was subsequently concentrated under reduced pressure to provide a residue, which was purified by flash silica column chromatography. Elution with 95:5 dichloromethane-methanol with 0.5% concentrated ammonium hydroxide afforded the title compound (400 mg, 94% yield); MS (ESI+) m/z 269 (M+1); HPLC (Column: 2.1×150 mm, 3μGeminiC18; detection wavelength: 210 nm; mobile phase A: 90/10H2O/CH3CN 10 mM NH4OAc; mobile phase B: 10/90H2O/CH3CN 10 mM NH4OAc; gradient: 0-6 minutes 0-100% B, 6-10 minutes 100% B, 10.1-15 minutes 0% B; flow rate: 0.25 mL/min) purity: 98.5%, retention time: 9.7 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][C:10](=O)[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]=2)[CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][C:10](=[S:28])[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]=2)[CH:2]=1
Reactant: O=C1CC(c2cccnc2)=NN1c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1CC(c2cccnc2)=NN1c1ccccc1
Yield: 116.1 %

Procedure:
A mixture of 1.2 g (4.5 mmol) of 3-(3-pyridyl)-1-phenyl-4, 5-dihydropyrazol-5-one, 1.4 g (3.4 mmol) of Lawesson's reagent and 10 ml of toluene was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/2 (v/v)) and recrystallized from ethanol to give 1.0 g of 3-(3-pyridyl)-1-phenyl-4, 5-dihydropyrazole-5-thione.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([OH:16])[OH:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:19])=[N-]>CCOCC>[CH3:19][O:16][P:14]([CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:13])[OH:15]
Reactant: CC(NC(=O)OCc1ccccc1)P(O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COP(O)C(C)NC(=O)OCc1ccccc1

Procedure:
1-Benzyloxycarbonylaminoethylphosphonous acid, prepared by the method of E. K. Baylis et al. [J. Chem. Soc., Perkin Trans, 2845-2853 (1984)] was esterified with diazomethane in an ether solution prepared by a method of F. Arndt [Organic Syn. Coll. V. II 165-167 (1943)]. The compound was purified by standard chromatography on silica gel. TLC (silica, 9:1, ethyl acetate:acetonitrile) Rf =0.51 NMR (CDCl3, TMS) δ 1.2 and 1.5 (2d, 3H); 2.2 and 10.1 (d, 1H); 3.6 (d, 3H); 3.9 (m, 1H); 5.0 (s, 2H); 6.0-6.6 (overlapping doublets, 1H); 7.2 (s, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:24](OCCCCC)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:9][C:6]1[C:7]2[CH:8]=[N:24][NH:1][C:2]=2[C:3](=[O:11])[N:4]([CH3:10])[CH:5]=1
Reactant: CCCCCON=O
Reactant: Cc1c(Br)cn(C)c(=O)c1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Cn1cc(Br)c2cn[nH]c2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-amino-5-bromo-1,4-dimethylpyridin-2(1H)-one (12.1 g, 55.9 mmol) in toluene (300 mL) was treated with acetic anhydride (15.8 mL, 168 mmol) followed by potassium acetate (6.58 g, 67.1 mmol) and stirred at RT overnight. The reaction mixture was treated with amyl nitrite (11.3 mL, 83.8 mmol) and heated at 80° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to give a mixture of the desired product along with the acetylated desired product. This mixture was diluted with methanol (490 mL) and treated with 1.0 M sodium hydroxide in water (280 mL) and stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to give crude product. Purification by flash column chromatography (100% hexanes to 100% EtOAc) gave the desired product (8.4 g, 66%). LCMS calculated for C7H7BrN3O (M+H)+: m/z=228.0, 230.0. found: 227.9, 229.9.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]([OH:27])=[O:26])[C:19](=[O:28])[CH2:18]3)[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:4][CH2:3]1.[Cl:29][C:30]1[CH:31]=[N+:32]([O-:55])[CH:33]=[C:34]([Cl:54])[C:35]=1[CH2:36][C@@H:37]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH:46]([F:48])[F:47])=[C:41]([O:49][CH2:50][CH:51]2[CH2:53][CH2:52]2)[CH:40]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:29][C:30]1[CH:31]=[N+:32]([O-:55])[CH:33]=[C:34]([Cl:54])[C:35]=1[CH2:36][C@@H:37]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH:46]([F:48])[F:47])=[C:41]([O:49][CH2:50][CH:51]2[CH2:53][CH2:52]2)[CH:40]=1)[O:26][C:25](=[O:27])[CH2:24][N:20]1[C:21]2[C:17](=[CH:16][C:15]([N:10]([CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][O:2][CH2:3][CH2:4]3)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:23][CH:22]=2)[CH2:18][C:19]1=[O:28]
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)CC(=O)N2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)CC(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
A mixture of 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2-oxoindolin-1-yl)acetic acid hydrochloride (0.105 g, 0.242 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.092 g, 0.220 mmol), EDC (0.127 g, 0.660 mmol), and DMAP (0.054 g, 0.440 mmol) in DCM (15 ml) was stirred at room temperature for 24 hours. The mixture was diluted with DCM and washed with aqueous sat. NH4Cl and aqueous 5% NaHCO3; the organic phase was dried over sodium sulfate and the solvent was removed. The crude was purified by flash chromatography on silica gel column (DCM:MeOH=99:1 to 96:4) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-morpholinoethyl)-methylsulfonamido)-2-oxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.070 g, 0.088 mmol, 39.8% yield, MS/ESI+ 799.46 [MH]+, [αD]=−40.88, c=0.25, MeOH). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 7.32 (s, 1H), 7.26 (dd, 1H), 7.19 (d, 1H), 7.11 (d, 1H), 6.97 (dd, 1H), 6.83 (d, 1H), 7.07 (t, 1H), 6.03 (dd, 1H), 4.61 (d, 1H), 4.50 (d, 1H), 3.95 (d, 2H), 3.70 (t, 2H), 3.67 (s, 2H), 3.48-3.57 (m, 4H), 3.39 (dd, 1H), 3.22 (dd, 1H), 3.07 (s, 3H), 2.30-2.43 (m, 6H), 1.14-1.34 (m, 1H), 0.50-0.69 (m, 2H), 0.25-0.46 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5]C=O)[CH3:4].[CH3:8][C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[C:10](=[O:12])C.Cl>CCOCC.C1C=CC=CC=1>[CH3:13][C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:8])[C:10](=[O:12])[CH2:4][CH:3]=[O:5]
Reactant: CCOC=O
Reactant: CC(=O)C(C)(C)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)(C(=O)CC=O)c1ccccc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 8.8 g. of 50% NaH oil dispersion in 150 ml. of dry benzene was treated at 25° C. with 13.6 g. of ethylformate in 20 ml. of dry benzene under N2. Over a period of a half hour, 14.9 g. of 3-methyl-3-phenyl-2-butanone in 80 ml. of dry benzene was added at 0° C. After stirring at 40° C. for 4 hours, the mixture was diluted with 250 ml. of ether, treated with ice and acidified with hydrochloric acid. The acidic solution ws extracted with ether and the ether extract was washed with brine, sodiuim bicarbonate solution, washed again with brine and dried. The solvent was evaporated and the residue was distilled under reduced pressure to afford 14.8 g. of the title product as an oil, B. P. 83°-84°/0.2 mm., λmaxfilm 3.5 (broad) 5.75, 5.90, 6.12, 6.30, 6.70, 6.80, 6.95, 7.31, 7.94, 8.18, 9,38, 12,60, 13.05 and 14.28 μ.
Reaction SMILES: Br[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=O.[NH2:12][C:13]([NH2:15])=[O:14]>C(O)C>[CH2:5]([C:2]1[O:14][C:13]([NH2:15])=[N:12][CH:3]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(N)=O
Reactant: O=CC(Br)Cc1ccccc1
Solvent: CCO
Product: Nc1ncc(Cc2ccccc2)o1
Temperature: 90 °C

Procedure:
To a solution of 2-bromo-3-phenyl-propionaldehyde (26.0 g, purity 60%, 0.0732 mol) in ethanol (300 ml) was added urea (14.66 g, 0.244 mol) and the reaction mixture was heated to 90° C. for 12 h. The solvent was evaporated, the residue was diluted with dichloromethane and washed with aqueous sodium hydroxide solution (2 N) and water. The organic phase was extracted three times with aqueous hydrochloric acid solution (2 N). The combined aqueous phases were adjusted to pH 10 with aqueous sodium hydroxide solution (2 N) and then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a yellow solid (1.78 g, 14%). MS ISP (m/e): 175.2 (100) [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[C:19]([NH:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1ccc(N)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)o1
Reaction time: 48 h

Procedure:
To a solution of 28.7 g. of ethyl 5-amino-2-furancarboxylate, 50 ml. of triethylamine and 300 ml. of methylene chloride is added 51.7 g. of palmitoyl chloride dropwise. The reaction mixture is allowed to stir for 48 hours. The solvent is evaporated and the residue dissolved in a small amount of methylene chloride. The methylene chloride solution is filtered through Magnesol and concentrated to an oil. The product is obtained by cryytallization of the residual oil from hexane.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[CH2:27][C:26]3[C:21](=[C:22]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:34])[CH2:15][C:16](O)=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C(N1C=CN=C1)([N:38]1C=CN=C1)=O.[OH-].[NH4+].O>O1CCCC1>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[C:20](=[O:34])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:27]2)[CH2:15][C:16](=[O:17])[NH2:38])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid (400 mg, 0.81 mmol) in tetrahydrofurane was added carbonyldiimidazole (200 mg, 1.21 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added ammonium hydroxide (0.12 ml, 1.6 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give cyclopropanecarboxylic acid {2-[1-(3,4-bis-difluoromethoxy-phenyl)-2-carbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (230 mg, 46%): mp, 198-200° C.; 1HNMR (DMSO-d6): δ 0.87 (d, J=5 Hz, 4H, cyclopropyl ring CH2CH2), 1.74-1.79 (m, 1H, cyclopropyl ring CH), 2.99 (d, J=7.5 Hz, 2H, CH2CONH2), 4.29 (d, J=18 Hz, 1H, CHHN), 4.61 (d, J=18 Hz, 1H, CHHN), 5.69-5.75 (m, 1H, CHN), 6.97 (broad, 1H, NHH), 7.19 (t, JH-F=75 Hz, 1H, OCF2H), 7.22 (t, JH-F=75 Hz, 1H, OCF2H), 7.34-7.37 (m, 3H, Ar), 7.47-7.58 (m, 2H, NHH+1 Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.51 (s, 1H, NHCO); 13C NMR (CDCl3): 8.26, 15.95, 38.10, 47.37, 51.89, 112.77, 112.90, 116.90, 117.03, 117.40, 117.70, 117.99, 120.57, 121.03, 121.16, 121.74, 125.72, 133.38, 137.51, 138.81, 141.60, 141.65, 141.70, 142.15, 142.20, 142.25, 142.79, 168.74, 171.37, 172.24; Anal. Calcd. for C23H21F4N3O5: C, 55.76; H, 4.27; N, 8.48. Found: C, 55.98; H, 4.00; N, 8.46.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11](I)[CH3:12].C(=O)([O-])[O-:15].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:15][CH2:11][CH3:12])=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 40 °C

Procedure:
4-Chloro-3-nitrobenzene (5.0 g) was dissolved in acetone and ethyl iodide (2.5 ml) and potassium carbonate (4.4 g) were added. The reaction mixture was stirred at 40° C. for 4½ hours. After cooling to room temperature the mixture was filtered and the filtrate was evaporated to dryness. 1H NMR (400 MHz, d6-DMSO) δ: 7.64 (m, 2H), 7.27 (dd, 1H, J 9.0, 3.1 Hz), 4.12 (q, 2H, J 7.0 Hz), 1.34 (t, 3H, 7.0 Hz).
Reaction SMILES: Br[CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[OH:27]>CC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[O:27][CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: C[C@H](CBr)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C[C@H](COc1c(Cl)cccc1Cl)NC(=O)OC(C)(C)C
Yield: 32.2 %

Procedure:
Intermediate 7A (230 mg, 0.970 mmol), cesium carbonate (409 mg, 1.26 mmol) and 2,6-dichlorophenol (157 mg, 0.970 mmol) were heated in acetone (1 mL) under microwave irradiation at 100° C. for 30 min. The solvents were removed and CH2Cl2 was added. The organic phase was washed with H2O, dried over Na2SO4, filtered and concentrated. The colorless oil was purified by flash chromatography (hexanes/EtOAc) to give Intermediate 7B (100 mg, 0.312 mmol, 32.3% yield). LC-MS 219.9 (M-Boc+H), RT=2.23 min (Method B).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([NH2:7])=[O:6])#N.[OH-:8].[Na+].[C:10]([OH:14])(=[O:13])[CH:11]=O.[OH-]>CO.O>[C:10]([OH:14])(=[O:13])[C:11]1[NH:7][C:5](=[O:6])[NH:4][C:3](=[O:8])[CH:1]=1
Reactant: N#CCNC(N)=O
Reactant: O=CC(=O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Temperature: 30 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A suspension of 57 g of cyanomethylurea in 45 ml of methanol is heated to boiling under agitation, combined with 3 ml of 8N sodium hydroxide solution, and heated under reflux for 30 minutes. The reaction mixture is then allowed to cool down to 30° C., 550 ml of water and 90 g of 50% strength glyoxylic acid are added thereto, and the mixture is neutralized with 8N sddium hydroxide solution at a temperature of maximally 30° C. until a pH of 6.5 has been attained. The mixture is then heated to 55°-60° C., 225 ml of 8N sodium hydroxide solution is added dropwise thereto at this temperature within one hour, and the mixture is stirred for another 2 hours. Then about 150 ml of aqueous methanol is removed by distillation to 95° C.; the mixture is heated for one hour under reflux and gently acidified with concentrated nitric acid. The mixture is allowed to cool down to room temperature, the thus-separated crystallized product is filtered off, washed with water, and dried under vacuum, thus obtaining 72 g of orotic acid (=71.8% of theory).