Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([C:23]#[N:24])[CH2:18]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].C[Al](C)C.[Si]([N:33]=[N+:34]=[N-:35])(C)(C)C>C1(C)C=CC=CC=1>[NH:33]1[C:23]([CH:19]2[CH2:20][CH2:21][CH2:22][N:17]([CH2:16][C:12]3[CH:13]=[CH:14][C:15]4[N:3]([CH2:1][CH3:2])[C:4]5[C:9]([C:10]=4[CH:11]=3)=[CH:8][CH:7]=[CH:6][CH:5]=5)[CH2:18]2)=[N:24][N:35]=[N:34]1
Reactant: CCn1c2ccccc2c2cc(CN3CCCC(C#N)C3)ccc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCn1c2ccccc2c2cc(CN3CCCC(c4nnn[nH]4)C3)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
A 100-mL 3-necked round-bottomed flask was charged with a solution of 1-((9-Ethyl-9H-carbazol-3-yl)methyl)piperidine-3-carbonitrile (700 mg, 2.17 mmol, 1.00 equiv, 98%) in toluene (30 mL). To this solution was add AlMe3 (960 mg, 13.07 mmol, 6.02 equiv, 98%) and TMSN3 (1.52 g, 12.95 mmol, 5.97 equiv, 98%). The resulting mixture was stirred at 80° C. overnight. Upon completion, it was cooled down to room temperature and transferred into a reparatory funnel and extracted with ethyl acetate (3×50 mL). Combined organic layers were with brine and aqueous NaHCO3 (10%). The mixture was dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude that was purified by preparative HPLC eluted with 1-10% MeOH in DCM affording 3-((3-(1H-tetrazol-5-yl)piperidin-1-yl)methyl)-9-ethyl-9H-carbazole as white solid (85 mg, 16%). LCMS: [M+H]+: 361. 1H NMR (DMSO-d63, 300 MHz) δ 8.15-8.10 (m, 2H), 7.62-7.57 (m, 2H), 7.47-7.43 (m, 2H), 7.22-7.18 (m, 1H), 4.47-4.40 (m, 2H), 3.92-3.82 (m, 2H), 3.26-3.16 (m, 2H), 2.98-2.94 (m, 1H), 2.37-2.31 (m, 1H), 2.04-2.00 (m, 1H), 1.74-1.57 (m, 3H), 1.32 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1)(=[O:3])[NH2:2].[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=2)[CH:6]=1
Reactant: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(4,6-dimethylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (75 mg, 165 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.88 g, 1.27 mL, 16.5 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated and then the residue was diluted with dichloromethane and neutralized with NH4OH. Purification by chromatography (silica, 0-100% of a 10:0.5:89.5 methanol:NH4OH:dichloromethane in dichloromethane) followed by further purification by HPLC (C-18, 10-100% water in acetonitrile gradient) gave 6-((1R,2S)-2-aminocyclohexylamino)-4-(4,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide 2,2,2-trifluoroacetate (33 mg, 70.3 μmol, 43%) as a fluffy off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 7.86 (br. s, 1H), 7.40 (br. s, 2H), 6.76 (s, 1H), 6.65 (s, 1H), 4.40 (s., 1H), 3.63 (s, 1H), 2.48 (s, 3H), 1.58-1.86 (m, 8H), 1.46 (m, 2H); MS (EI/CI) m/z: 356.1 [M+H].
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[C:7]([O:11][C:12]([NH:14][CH2:15][C@H:16]([NH:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:49])[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)=[O:23])[C:17]([O:19]C)=O)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CO.C1COCC1.C(Cl)(Cl)Cl.CC(O)C>[OH:3][NH:2][C:17]([C@@H:16]([NH:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]2[CH:33]=[CH:34][C:35]([NH:38][C:39](=[O:49])[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])=[CH:36][CH:37]=2)=[CH:26][CH:25]=1)=[O:23])[CH2:15][NH:14][C:12]([O:11][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:13])=[O:19]
Reactant: NO
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1ccc(C#Cc2ccc(NC(=O)CNC(=O)OC(C)(C)C)cc2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(C#Cc2ccc(C(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)NO)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
To a solution of hydroxylamine hydrochloride (98 mg, 1.41 mmol) in MeOH (1.3 mL) at 0° C. was added 25 wt % NaOMe (460 mg, 2.13 mmol). The solution was stirred at 0° C. for 15 min and then charged with a solution of methyl (2S)-3-[(tert-butoxy)carbonylamino]-2-({4-[2-(4-{2-[(tert-butoxy)carbonylamino]acetylamino}phenyl)ethynyl]phenyl}carbonylamino)propanoate (4) (279 mg, 0.469 mmol) in THF (1.5 mL) and MeOH (0.6 mL). The reaction was stirred at 0° C. for 30 min and at room temperature for 2.5 h. The reaction mixture was diluted with 4:1 CHCl3/iPrOH (50 ml) and washed with 0.1 M HCl (30 mL). The layers were separated and the aqueous layer extracted once more with 4:1 CHCl3/iPrOH (30 ml). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The crude residue was suspended in 10:1 CH2Cl2/MeOH (4 mL), filtered, and washed with 50:1 CH2Cl2/MeOH (2 mL) and Et2O (10 mL) to afford 180 mg (64%) of N-(4-{2-[4-(N-{1-(N-hydoxycarbamoyl)(1S)-2-[(tert-butoxy)carbonylamino]ethyl}carbamoyl) phenyl]ethynyl}phenyl)-2-[(tert-butoxy)carbonylamino]acetamide (6) as a white powder.
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=O)[CH2:19][CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].O.NN.C(O)CO>O>[NH:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH2:18][CH2:19][CH2:20][CH:11]([C:12]=23)[CH2:10]1
Reactant: O=C1CCC2CN(C(=O)c3ccccc3)c3cccc1c32
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: c1cc2c3c(c1)NCC3CCC2
Temperature: 120 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A mixture of 5.0 g of 1-benzoyl-1,2,2a,3,4,5-hexahydrobenz[cd]indol-5-one, 2.7 g of potassium hydroxide, 2 ml of hydrazine hydrate and 20 ml of ethylene glycol was heated at 120° C. for 2 hours and then at 190° C. for 3 hours. After mixture cooling, water was added, and the reaction product was extracted with dichloromethane. After the extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: dichloromethane-ethyl acetate=10:1 (v/v)) to yield 1.9 g of 1,2,2a,3,4,5-hexahydrobenz[cd]indole as a colorless crystal having a melting point of 58° to 59° C.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:10]([C@H:18]([CH3:22])[CH2:19][CH:20]=[O:21])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].O>C(OC(C)C)(C)C>[O:10]([C@H:18]([CH3:22])[CH2:19][CH:20]([C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1)[OH:21])[Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: C[C@H](CC=O)O[Si](C)(C)C(C)(C)C
Reactant: Clc1cnc(Cl)c(Br)c1
Solvent: CC(C)OC(C)C
Solvent: O
Product: C[C@H](CC(O)c1cc(Cl)cnc1Cl)O[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a cooled (-70° C.) solution of n-butylithium (129.3 mL of 1.18 M hexanes solution, 0.153 mol) in isopropyl ether was added a solution of 3-bromo-2,5-dichloropyridine (36.45 g, 0.161 mol) in isopropyl ether (225 mL) over a period of 30 minutes. The resulting white suspension was then treated with a solution of 3(R)-t-butyldimethylsiloxybutyraldehyde (34.14 g, 0.169 mol) in isopropyl ether (106 mL) and allowed to stir for an additional 30 minutes at -70° C. followed by warming to room temperature. After the addition of 480 mL of water, the biphasic mixture was separated and the organic layer was extracted with isopropyl ether (2×200 mL). The combined organic layers were washed once with water, heated with decolorizing carbon [G-60 DARCO (trademark)] filtered through diatomateous earth [Celite (trademark)] and condensed on a rotary evaporator. The resulting hazy yellow liquid was heated at 80° C. under high vacuum overnight to yield the desired product (mixture of diastereomers) as an amber oil (40.52 g, 72%): Rf 0.36 (25% Et2O in hexanes); 1H NMR (60 MHz, CDCl3) δ 0.1 (s, 6H), 0.82 (s, 9H), 1.18 (m, 3H), 1.72 (m, 2H), 4.16 (m, 1H), 4.42 (m, 1H), 5.10 (m, 1H), 7.92 (d, 1H, J=2.6 Hz), 8.13 (d, 1H, J=2.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN1CCCC1=O>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:7]([C:3]5[N:4]=[CH:5][S:6][C:2]=5[CH3:1])=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1scnc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: Cc1scnc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 47.3 %

Procedure:
Using 5-methyl-1,3-thiazole-4-carboxylic acid (143 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (107 mg, yield 47%) was obtained.
Reaction SMILES: [C:1]([N:18]([CH3:33])[C@H:19]([C:23](ON1C(=O)CCC1=O)=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[NH2:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40]([NH2:42])=[O:41].C([O-])(O)=O.[Na+]>COCCOC.C1COCC1.O>[C:1]([N:18]([CH3:33])[C@H:19]([C:23]([NH:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40]([NH2:42])=[O:41])=[O:24])[CH:20]([CH3:21])[CH3:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CC(C)[C@@H](C(=O)ON1C(=O)CCC1=O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: O
Product: CC(C)[C@@H](C(=O)N[C@@H](CCCNC(N)=O)C(=O)O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To a room temperature suspension of Fmoc-MeVal-OSu (2.18 g, 4.84 mmol) in DME (13 mL) and THF (6.5 mL) is added a solution of L-citrulline (0.85 g, 4.84 mmol) and NaHCO3 (0.41 g, 4.84 mmol) in H2O (13 mL). The suspension is allowed to stir at room temperature for 16 hr, then it is extracted into tert-BuOH/CHCl3/H2O and acidified to pH=2-3 with 1 M HCl. The organic phase is separated, dried and concentrated under reduced pressure. The residue is triturated with diethyl ether resulting Fmoc-MeVal-Cit-COOH (e.g., 2.01 g) which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12]CC)=[O:11])=[C:7]([CH3:15])[C:6]=2[C:16]=1[O:17][CH:18]([CH3:20])[CH3:19]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([CH3:15])[C:6]=2[C:16]=1[O:17][CH:18]([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1oc2ccc(Br)c(OC(C)C)c2c1C
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)oc2ccc(Br)c(OC(C)C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To 0.58 g (1.7 mmole) of ethyl 5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-carboxylate in 15 mL of THF and 15 mL MeOH was added 8.5 mL of 1NaOH and the reaction was stirred at room temperature for 1 hour. The solvent was concentrated in vacuo, the residue was neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to provide 0.46 g of 5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-carboxylic acid. Yield 86.8%; m.p. 182-184° C.; MS 311.0 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:12].[NH2:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].Cl>C(#N)C.O1CCOCC1>[ClH:12].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[NH:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Nc1cc(O)ccc1Cl
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Oc1ccc(Cl)c(Nc2ccnc3ccc(Br)cc23)c1
Yield: 88 %

Procedure:
500 mg (2.06 mmol) of 6-bromo-4-chloroquinoline in 20 ml acetonitrile are mixed with 325 mg (2.27 mmol) of 3-amino-4-chlorophenol and 0.5 ml of 1 M HCl solution in dioxane and heated under reflux for 3 days. The crystals which have separated out are filtered off with suction and dried under high vacuum. 700 mg (70%) of the title compound are obtained as hydrochloride.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].C(N(C(C)C)CCC(C1C=C(COC(=O)CCC=C)C=CC=1OC(=O)CCC=C)C1C=CC=CC=1)(C)C>ClCCl>[C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)CCCCCCC(=O)O
Agent: C=CCCC(=O)OCc1ccc(OC(=O)CCC=C)c(C(CCN(C(C)C)C(C)C)c2ccccc2)c1
Solvent: ClCCl
Product: O=C(O)CCC=CCCC(=O)O
Yield: 71 %

Procedure:
Intramolecular cyclic diester of octane-1,8-dioic acid and 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol Grubbs catalyst (benzylidene-bis-(tricyclohexylphosphine)-dichlororuthenium, 16 mg, 0.002 mmol, 2 mol-%) was added to a solution of (±)-pent-4-enoic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-(pent-4-enoyloxymethyl)-phenyl ester (483 mg, 0.96 mmol) in dichloromethane (150 ml) and the mixture was refluxed for 96 hrs. under an atmosphere of nitrogen gas, after which all of the starting material was consumed as indicated by tlc. The mixture was filtered through a short pad of basic alumina, and the solvent was removed in vacuum. Flash chromatography (solvent system (4)) afforded the intermediate intramolecular cyclic diester of oct-4-ene-1,8-dioic acid and 2-(3-diisopropylamino)-1-(phenylpropyl)-4-hydroxymethyl-phenol (324 mg) as a colourless syrup (tlc: (4) Rf 0.68) in 71% yield, mixture of two geometrical isomers.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(COCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCc1ccc(C#N)cc1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 93.8 %

Procedure:
4-[(2-Hydroxyethoxy)methyl]benzonitrile (5.5 g, 30.5 mmol; see step (i) above) was dissolved in DCM (61 mL) and cooled to −10° C. Triethylamine (5 mL, 36.5 mmol) and methanesulfonyl chloride (3.84 g, 33.5 mmol) were added and the resulting mixture was stirred at below −5° C. for 1.5 h and then at RT overnight. Dichloromethane (200 mL) was added and the mixture was washed with water (2×100 mL) and then dried over Na2SO4. Evaporation of solvents gave 7.3 g (94%) of the title compound, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].[C:14]([C:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])([CH3:18])[CH3:17])#[N:15]>O1CCCC1>[C:14]([C:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1)=[O:23])([CH3:18])[CH3:17])#[N:15]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(O)c2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (10 g, 52.8 mmol) in tetrahydrofuran (100 mL) were added N,N-dimethylformamide (80 μL) and oxalyl chloride (6.28 mL, 72.0 mmol), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give 3-(cyano-1-methylethyl)benzoyl chloride as a pale-brown oil. To a solution of 3-aminophenol (5.24 g, 48.0 mmol) in tetrahydrofuran (40 mL) was added an aqueous suspension (60 mL) of sodium hydrogen carbonate (6.05 g, 72.0 mmol), and the mixture was vigorously stirred at room temperature. To this mixture was added dropwise a solution of 3-(cyano-1-methylethyl)benzoyl chloride in tetrahydrofuran (60 mL) synthesized above under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate (200 mL) and washed with saturated brine (200 mL). The extract was dried over anhydrous magnesium sulfate and decolored with activated carbon. The insoluble material was filtered off through a pad packed with silica gel and celite in two layers. The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate-hexane mixture to give the title compound (13.03 g, 96%) as a colorless powder.
Reaction SMILES: OC[C:3]1[CH:4]=[C:5]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:39](OCC)(=[O:41])C.[OH-].[Na+]>O1CCCC1.CCOCC>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH:9][C:5]2[CH:4]=[CH:3][CH:8]=[CH:7][C:6]=2[CH2:39][OH:41])=[CH:16][CH:15]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2cccc(CO)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCOc1ccc(CNc2ccccc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the N-[3-(hydroxymethyl)phenyl]-4-(tetradecyloxy)benzamide in 80 ml of tetrahydrofuran at 0° C. under argon is added 36.39 ml of 1M lithium aluminum hydride. Stirred at room temperature for 1 hour and refluxed for 7 hours. After stirring overnight and cooling to 0° C., ethyl acetate is added followed by sodium hydroxide solution until a solid forms. The mixture is diluted with ether, filtered and evaporated to a residue which is crystallized from hexane to give 6.7 g of the desired product as a white solid, m.p. 72°-75° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[C:3]([CH:2]=[P:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCC(=O)CCl
Solvent: ClC(Cl)Cl
Product: CCCCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 20.4 %

Procedure:
A solution of 1-chloro-2-heptanone (33 g.) and triphenylphosphine (60 g.) in chloroform (50 ml.) was saturated with nitrogen and refluxed under nitrogen overnight. The chloroform was removed in vacuo and the residue was dissolved in methylene chloride (150 ml.). Dry diethyl ether (600 ml.) was added to precipitate 2-oxoheptyltriphenylphosphonium chloride (60 g.), m.p. 165°-168°C. This compound (23 g.) was added portionwise to a solution of sodium carbonate (25 g.) in water (250 ml.), and the mixture was stirred vigorously for 24 hours. The solution was extracted with diethyl ether, and the ethereal extracts were dried over magnesium sulphate. The solvent was removed by evaporation and the residue was cooled and triturated with petrol (b.p. 40°-60°C.). The solid thus obtained was recrystallised from petrol (b.p. 60°-80°C.) to give hexanoylmethylene triphenylphosphorane (17 g.), m.p. 73°-74°C.
Reaction SMILES: CO[C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][N:12]([CH3:11])[C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: CNCCO
Product: CC(C)C(=O)CC(=O)N(C)CCO
Yield: 97.4 %

Procedure:
0.351 mol (50 ml) of 4-methyl-3-oxovaleric acid methyl ester and 0.369 mol (29.5 ml) 2-(methylamino)ethanol were stirred for 15 h at 120° C. in a Dean-Stark apparatus. 12 ml of methanol were collected. Subsequently, the excess starting materials 2 h were distilled off on a rotary evaporator (80° C. water bath, 1 mbar). There were obtained 64 g of the title compound.
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[CH2:6]([O:8][CH:9]=[CH2:10])[CH3:7].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+]>O>[CH2:1]([P:3]([CH2:7][CH2:6][O:8][CH2:9][CH3:10])(=[O:5])[OH:4])[CH3:2]
Reactant: CCP(O)O
Reactant: C=COCC
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOCCP(=O)(O)CC
Temperature: 100 °C
Yield: 95.6 %

Procedure:
564 g (6 mol) of ethylphosphonous acid are dissolved in 860 g of water and initially charged to a 5 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. After heating the reaction mixture to 100° C., 504 g (7 mol) of vinyl ethyl ether and 500 g of a 5% strength sodium peroxodisulfate solution (1.5 mol % based on vinyl ethyl ether) are added dropwise at atmospheric pressure over 1 h. The water is then distilled off in vacuo. The residue is taken up in tetrahydrofuran and the insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo. Chromatographic purification leaves 953 g (82% of theory) of ethyl(2-ethoxyethyl)phosphinic acid being obtained as oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:4]1.[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Br.[I-].[Na+]>CN(C=O)C.C1COCC1.O>[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4]1
Reactant: CCOC(=O)CCc1c[nH]c2ccccc12
Reactant: Clc1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(Cl)cc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.38 g) was added to the mixed solution of ethyl 3-(indol-3-yl)propionate (1.8 g) in DMF (20 ml) and THF (20 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 10 minutes, to which were added 2,4-dichlorobenzyl bromide (1.8 g) and sodium iodide (0.3 g). The reaction mixture was stirred at room temperature for 3 hours and then poured into water, and the mixture was extracted with IPE. The organic layer was washed with water, then dried and concentrated. The residue was dissolved in ethanol (30 ml), which was stirred at 50° C. for 2 hours in the presence of water (10 ml) and sodium hydroxide (1 g). The reaction mixture was concentrated, made acidic, and then extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-IPE to obtain the entitled compound (2.4 g).