Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([C:5]1([CH2:25][CH:26]=[CH2:27])[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:24])=O.[Br-].[Li+]>CN(C)C=O.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:11]2[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[NH:7][C:6](=[O:24])[C@H:5]2[CH2:25][CH:26]=[CH2:27])=[CH:13][CH:14]=1
Reactant: C=CCC1(C(=O)OC)C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC[C@@H]1C(=O)Nc2ccccc2C[C@@H]1c1ccc(OC)cc1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-3-(2-propenyl)-2H-1-benzazepin-2-one (4.56 g, 12.48 mmol), lithium bromide (6.18 g, 71.13 mmol) and α-aminothiophenol (3.12 g, 24.96 mmol) in 38 ml of dry dimethylformamide was heated to 137° C. (oil bath temperature) under argon for 51/2 hours. The reaction mixture was cooled to room temperature and diluted with water (250 ml total volume). The precipitate was collected by filtration, rinsed with 1M hydrochloric acid, saturated aqueous potassium carbonate solution, water, and dried in vacuo with phosphorous pentoxide to give 3.5 g of a white solid. Recrystallization from methanol (3 crops) yielded 3.03 g of white needles, melting point 169°-171° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:33][CH2:34][CH2:35][N:36]2[CH:40]=[N:39][CH:38]=[N:37]2)[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C(#N)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:33]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:34][CH2:35][N:36]2[CH:40]=[N:39][CH:38]=[N:37]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: c1ncn(CCNC2CCCC2)n1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCn2cncn2)C2CCCC2)c1)c1ccncc1
Yield: 38.9 %

Procedure:
A solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.040 g), cyclopentyl-(2-[1,2,4]triazol-1-yl-ethyl)-amine (0.05 g) and EEDQ (0.040 g) in acetonitrile (2 ml) was stirred at reflux, under nitrogen, for 2 h. The solvent was evaporated and the residue was purified by flash chromatography eluting with dichloromethane:methanol (95:5 v/v) to give the title compound as a yellow oil (0.022 g).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].C(N(CC)CC)C.[CH:20]#[C:21][CH3:22]>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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:20]([C:12]1[CH:2]=[C:3]2[C:4](=[CH:10][CH:11]=1)[C:5](=[O:6])[O:7][C:8]2=[O:9])#[C:21][CH3:22]
Reactant: O=C1OC(=O)c2c(Br)cccc21
Reactant: C#CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC#Cc1ccc2c(c1)C(=O)OC2=O
Temperature: 50 °C
Yield: 97.9 %

Procedure:
Bromophtalic anhydride (50.0 g, 0.22 mol), triethylamine (33.8 mL, 0.24 mol) and toluene (220 mL) were mixed in a glass reactor over nitrogen (g) atmosphere at room temperature. Bis(triphenylphosphine)palladiumchloride (0.77 g, 0.001 mol), CuI (0.42 g, 0.002 mol) and triphenylphosphine (0.87 g, 0.003 mol) were added and the temperature was raised to 50° C. Propyne (18.0 g, 0.45 mol) was slowly added through a gas inlet during 3 hours. The reaction mixture was filtered through a glass filter funnel and the solution was concentrated to dryness to give crude solid product (40.1 g, 98%). The product was re-crystallized from toluene to give a light yellow solid (24.7 g, 60%).
Reaction SMILES: [I:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([I:10])[CH:9]=1)[CH:5]=O.[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>>[I:1][C:2]1[C:3]([OH:11])=[C:4]([CH:5]=[N+:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[O-:17])[CH:7]=[C:8]([I:10])[CH:9]=1
Reactant: CC(C)(C)NO
Reactant: O=Cc1cc(I)cc(I)c1O
Product: CC(C)(C)[N+]([O-])=Cc1cc(I)cc(I)c1O

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 3,5-diiodo-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 73.8% yield as a yellow crystalline solid, m.p. 164.1° C. (Rf=0.38 on a silica gel plate using 7:3 hexanes/EtOAc as an eluant)
Reaction SMILES: COC1C=CC=C(OC)C=1C(N[C@H]1CCC[C@@H]1[NH:13][C:14]1C=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=O.Cl.[NH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[NH:37][C:38](=[O:50])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N:45]1[N:49]=[CH:48][CH:47]=[N:46]1.ClC1N=CC(C(F)(F)F)=CN=1>>[N:49]1[N:45]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:38]([NH:37][C@H:33]2[CH2:34][CH2:35][CH2:36][C@@H:32]2[NH:31][C:14]2[N:13]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)=[O:50])[N:46]=[CH:47][CH:48]=1
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Agent: Cl
Agent: FC(F)(F)c1cnc(Cl)nc1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cn1)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2,6-dimethoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 1) from N-[(1S,2S)-2-amino cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 100 mg, 0.325 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 59.3 mg, 0.325 mmol). The crude reaction was filtered through cotton wool before being purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([CH3:21])[C:15]([CH3:23])([CH3:22])[CH2:14]2)[CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([N:24]([CH:29]2[CH2:34][C:33]([CH3:36])([CH3:35])[N:32]([CH3:37])[C:31]([CH3:39])([CH3:38])[CH2:30]2)[CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH2:47].[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:2]1[N:7]=[C:6]([N:8]([CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([CH3:21])[C:15]([CH3:22])([CH3:23])[CH2:14]2)[CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([N:24]([CH:29]2[CH2:30][C:31]([CH3:38])([CH3:39])[N:32]([CH3:37])[C:33]([CH3:35])([CH3:36])[CH2:34]2)[CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1
Reactant: CCCCN(c1nc(Cl)nc(N(CCCC)C2CC(C)(C)N(C)C(C)(C)C2)n1)C1CC(C)(C)N(C)C(C)(C)C1
Reactant: NCCCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCN(c1nc(NCCCCCCN)nc(N(CCCC)C2CC(C)(C)N(C)C(C)(C)C2)n1)C1CC(C)(C)N(C)C(C)(C)C1
Reaction time: 8 h
Yield: 89.9 %

Procedure:
56.4 g of 2-chloro-4,6-bis-(1,2,2,6,6-pentamethyl-4-piperidyl-butylamino)-1,3,5-triazine are introduced into a melt of 120 g of hexamethylenediamine at 80°. The reaction mixture is then stirred for 8 hours at 100° and after adding 50 ml of xylene is then stirred for 16 hours at 140°. The reaction mixture is diluted with 200 ml of xylene, a solution of 4.4 g of sodium hydroxide in 50 ml of water is added and the resulting mixture is stirred vigorously for 4 hours at room temperature. The xylene solution is separated off from the aqueous phase in a separating funnel, dried over sodium sulphate and evaporated in vacuo. 57.9 g of the 2-(6-aminohexylamino)-4,6-bis-(1,2,2,6,6-pentamethyl-4-piperidyl-butylamino)-1,3,5-triazine thus obtained are dissolved in 200 ml of xylene and the resulting solution is cooled to 5°. 5.5 g of cyanuric chloride are introduced at this temperature and the reaction mixture is stirred at 5°-10° for 1 hour. After adding 1.2 g of finely powdered sodium hydroxide, the temperature is raised to 35°-40° and the mixture is stirred for 2 hours at this temperature. After adding a further portion of 1.2 g of sodium hydroxide, the reaction mixture is slowly heated to the reflux temperature. After 3 hours under reflux, a final portion of 1.4 g of sodium hydroxide is added and the reaction mixture is then stirred under reflux for 16 hours. After cooling, 200 ml of water are added, the mixture is stirred well for 15 minutes, the aqueous solution is separated off and the xylene solution is washed with 3 times 100 ml of water. The xylene solution is evaporated in vacuo and the residue is then dried under a high vacuum (130°/0.001 mm Hg). The resulting, pale yellowish mass can be comminuted to a virtually colourless powder. The light stabiliser having the above structural formula melts at about 125°.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[CH3:6][C:7]1[CH:8]=[C:9]([CH:11]=[C:12]([CH3:21])[C:13]=1[S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:16])=[O:15])[NH2:10].[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>O1CCCC1>[CH3:21][C:12]1[CH:11]=[C:9]([NH:10][S:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH:8]=[C:7]([CH3:6])[C:13]=1[S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:15])=[O:16]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2ccc(F)cc2)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Yield: 36.4 %

Procedure:
1.65 g (16.5 mmol) of calcium carbonate are added to a solution of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 40 ml of anhydrous tetrahydrofuran, followed by portionwise addition of 2.4 g (12.3 mmol) of 4-fluorobenzenesulphonyl chloride. The reaction medium is refluxed for 50 hours. After cooling, it is poured into 200 ml of water and extracted with 3 times 100 ml of methylene chloride. The combined organic extracts are washed with 100 ml of water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The oily residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) and recrystallization from a mixture of hexane and ethyl acetate, to give 1.2 g (36%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-4-fluorobenzenesulphonamide.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][CH2:12][CH2:13][OH:14])([CH3:10])([CH3:9])[CH3:8].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:24][O:23]2)[CH:19]=[CH:20][CH:21]=1>C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]([OH:23])[CH2:24][O:14][CH2:13][CH2:12][O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:19]=[CH:20][CH:21]=1
Reactant: Clc1cccc(C2CO2)c1
Reactant: CC(C)(C)OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OCCOCC(O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5.1 g of potassium tert-butoxide was added to 105 ml of ethylene glycol mono-tert-butyl ether. The mixture was heated to 80° C. Thereto was dropwise added 35.0 g of 2-(3-chlorophenyl)oxirane over 1 hour. The mixture was stirred for 2 hours at the same temperature. The reaction mixture was added to a mixture of 100 ml of ice water and 100 ml of ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to further distillation under reduced pressure to obtain 37.7 g of colorless oily 1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethanol having a boiling point of 140°-146° C./0.9 mmHg.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[CH2:8](Cl)[CH:9]=[CH2:10]>>[CH2:10]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[CH:9]=[CH2:8]
Reactant: C=CCCl
Reactant: COC(CN)OC
Product: C=CCNCC(OC)OC

Procedure:
Aminoacetaldehyde dimethyl acetal was reacted with allyl chloride to give N-allyl-N-dimethoxyethyl amine, which was then acetylated with acetyl chloride to give N-allyl-N-dimethoxyethylacetamide, according to the following reactions: ##STR3##
Reaction SMILES: [F:1][C:2]([F:16])([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:2]([F:1])([F:16])[C:3]([F:4])([F:5])[F:6])=[CH:15][CH:14]=2)=[CH:20][CH:19]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCc1ccc(F)cc1)c1ccc(C(F)(F)C(F)(F)F)cc1
Yield: 99.3 %

Procedure:
A solution of 4-pentafluoroethyl-benzoic acid (500 mg, 2.08 mmol), 2-(4-fluorophenyl)ethylamine (319 mg, 2.29 mmol), 4-methylmorpholine (632 mg, 6.24 mmol), and HBTU (1.19 g, 3.12 mmol) in DMF (38 mL) was stirred at RT for 16 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (746 mg, 99%). White solid, MS (ISP) 362.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].O>CN(C=O)C>[C:13]([NH:17][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc2c(NC(C)(C)C)nc(Cl)nc12
Reaction time: 3 h
Yield: 91.3 %

Procedure:
In 3 ml of DMF was dissolved 300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and after 150 mg (2.1 mmol) of t-butylamine was added to the resulting solution, the mixture was stirred for 3 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered to give 327 mg (yield: 93.4%) of the title compound.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[F:13][C:14]([F:24])([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](OCC)=[O:16].OS(O)(=O)=O>O1CCCC1.CCCCC>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:16])[C:14]([F:24])([F:13])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(F)(F)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A solution of dimethyl methylphosphonoate (6.5 g, 80 mmol, 2.2 equiv) in tetrahydrofuran (100 mL) was cooled to −78° C. and n-butyllithium (2.5 M in hexanes, 14 mL, 36 mmol, 1 equiv) was added dropwise. The solution was stirred at −78° C. for 30 min and ethyl 2,2-difluorohexanoate (6.5 g, 36 mmol, 1 equiv) was added dropwise. The solution was stirred at −78° C. for 1 h and warmed to 0° C. over 1 h. Pentane (100 mL) was added followed by the dropwise addition of 2M H2SO4 to pH=6. The aqueous layer was separated and extracted with pentane (3×15 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated to dryness under vacuum on a rotary evaporator. The crude oil was purified by column chromatography using methyl tert-butyl ether as eluant to afford 4.1 g of 26 as a yellow oil (44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]([CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH2:26])[C:7]([C@H:9]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10]C=C)=[O:8]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:26][CH2:10][C@@H:9]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]1=[O:8]
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=C)c1ccccc1)Cc1ccc(OC)cc1OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COc1ccc(CN2CC(c3ccccc3)=CC[C@@H](NC(=O)OCc3ccccc3)C2=O)c(OC)c1
Temperature: 40 °C
Reaction time: 40 h
Yield: 52.3 %

Procedure:
[1,3-bis-(2,4,6-trimethylphenyl-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium] (Grubbs second generation catalyst) (0.68 g, 0.79 mmol) was added to a solution of benzyl (1R)-1-{[(2,4-dimethoxybenzyl)(2-phenylprop-2-enyl)amino]carbonyl}but-3-enylcarbamate (2.02 g, 3.93 mmol) in dichloromethane (395 mL) and heated to 40° C. After 40 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (1.00 g). MS 487 (M+1). 1HNMR (500 MHz, CDCl3) δ 7.39-7.31 (m, 5H), 7.26-7.19 (m, 3H), 7.17 (d, J=8.3 Hz, 1H), 6.99 (d, J=7.1 Hz, 2H), 6.41 (dd, J=8.3, 2.0 Hz, 1H), 6.33 (s, 1H), 6.22 (d, J=6.4 Hz, 1H), 5.77-5.76 (m, 1H), 5.16-5.09 (m, 3H), 4.82 (d, J=14.7 Hz, 1H), 4.65 (dd, J=17.6, 2.7 Hz, 1H), 4.54 (d, J=14.4 Hz, 1H), 3.93 (d, J=17.6 Hz, 1H), 3.77 (s, 3H), 3.64 (s, 3H), 2.91-2.86 (m, 1H), 2.42-2.36 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>C1C=CC=CC=1.C(OCC)C>[C:4]([O:11][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12])([CH3:9])([CH3:5])[CH3:3]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1

Procedure:
0.50 g (3.10 mmol) indole-5-carboxylic acid is suspended in 20 ml absolute benzene and heated under reflux. A solution of 2.80 g (12.39 mmol) 90% N,N-dimethylformamidedi-tert-butylacetal in 20 ml absolute benzene is added drop-wise within 30 min. Following another heating under reflux for 30 minutes and subsequent cooling, the reaction mixture is diluted with diethyl ether, washed with 5% sodium carbonate solution and with saturated NaCl solution. Drying on sodium sulfate, filtration and concentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C@H:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:8])([CH3:4])[CH3:3].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[C:25](O)[CH:26]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[C:23]([CH:22]=1)[O:18][C@@H:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:10][CH2:9][N:7]([CH3:8])[C:6](=[O:19])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1O
Reactant: CN(CC[C@H](O)c1ccccc1)C(=O)OC(C)(C)C
Product: CN(CC[C@@H](Oc1cc(Cl)ccc1[N+](=O)[O-])c1ccccc1)C(=O)OC(C)(C)C

Procedure:
This was prepared by the method of Example 20(a) using [(3S)-3-hydroxy-3-phenylpropyl]methylcarbamic acid 1,1-dimethylethyl ester and 5-chloro-2-nitrophenol.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([CH:15]=[O:16])[CH2:9][CH2:8]2.[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(O)(C)C>[CH:15]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:17][NH:21][CH:18]([CH3:20])[CH3:19])[CH:6]=2)[CH2:11]1)=[O:16]
Reactant: O=CN1CCc2cc(OCC3CO3)ccc2C1
Reactant: CC(C)N
Solvent: CC(C)O
Product: CC(C)NCC(O)COc1ccc2c(c1)CCN(C=O)C2

Procedure:
23.3 g. of 6-(2,3-epoxy-propoxy)-2-formyl-1,2,3,4-tetrahydroisoquinoline are held at the boiling point under reflux with 59.1 g of isopropylamine in 100 ml of isopropanol for 5 hours. The mixture is evaporated and the residue is rubbed with 150 ml of diethyl ether. 27.5 g of 2-formyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylamino-propoxy)-isoquinoline are obtained. m.p. = 56.6° - 58° C.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][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][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([N+:35]([O-])=O)[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[H][H]>[Pd].C1COCC1.CN(C=O)C>[C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][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][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([NH2:35])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N(CC(=O)O)CC(=O)O)cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 4 h
Yield: 44.2 %

Procedure:
A mixture of 0.6 g of N-(carboxymethyl)-N-[3-nitro-5-(octadecyloxy)phenyl]glycine and 0.2 g of 10% palladium on carbon in 170 ml of THF and 10 ml of DMF was stirred in a hydrogen atmosphere at room temperature until uptake ceased after 4 hours. The reaction mixture was heated to dissolve the precipitated product and the catalyst was removed by filtration. The filtrate was concentrated at reduced pressure and the solid residue was dissolved in THF and the solution was passed through a SEP-PAK silica cartridge (Waters Associates). The eluent was concentrated at reduced pressure to a solid which was triturated with ethyl acetate and filtered to give 0.25 g (44% yield, mp 185°-195°) of N-(carboxymethyl)-N-[3-amino-5-(octadecyloxy)phenyl]glycine. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:44])[NH:10][C@H:11]([C:16](=[O:43])[NH:17][C@@:18]1([C:33](=[O:42])[NH:34][C@H:35]([C:40]#[N:41])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:30][C:29]2[C:28]3[C:23](=[C:24]([Cl:32])[CH:25]=[C:26]([Cl:31])[CH:27]=3)[NH:22][C:21]=2[CH2:20][CH2:19]1)[CH:12]([CH3:15])[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:45]=[N+:46]=[N-:47].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:44])[NH:10][C@H:11]([C:16](=[O:43])[NH:17][C@@:18]1([C:33](=[O:42])[NH:34][C@H:35]([C:40]2[NH:47][N:46]=[N:45][N:41]=2)[CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:30][C:29]2[C:28]3[C:23](=[C:24]([Cl:32])[CH:25]=[C:26]([Cl:31])[CH:27]=3)[NH:22][C:21]=2[CH2:20][CH2:19]1)[CH:12]([CH3:15])[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@]1(C(=O)N[C@H](C#N)CC(C)C)CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@]1(C(=O)N[C@@H](CC(C)C)c2nnn[nH]2)CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Reaction time: 6 h

Procedure:
0.122 g (0.19 mmol) of {(S)-1-[(R)-6,8-Dichloro-3-((S)-1-cyano-3-methyl-butylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methyl-butyl}-carbamic acid benzyl ester synthesized according to 84 (see below), 0.028 g (0.44 mmol) of sodium azide and 0.026 (0.48 mmol) of ammonium chloride were heated in 2 mL of DMF in a microwave at 110° C. and 100 watt for 6 h. The reaction solution was separated on a preparative HPLC column.