Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[N+:6]1([O-])[CH:11]=[CH:10][CH:9]=[C:8]2[CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:7]=12>>[Cl:3][C:9]1[CH:10]=[CH:11][N:6]=[C:7]2[CH2:14][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][C:8]=12
Reactant: CCOC(=O)N1Cc2ccc[n+]([O-])c2C1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)N1Cc2nccc(Cl)c2C1
Temperature: 50 °C
Yield: 46 %

Procedure:
POCl3 (20 mL, 218 mmol) was added into ethyl 5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate N-oxide (1 g, 4.80 mmol) and heated to 35° C. for 12 hours and 50° C. for another 5 hours. The solvent was evaporated and poured into water. The material was extracted with CH2Cl2, washed with NaHCO3 and brine, dried with Na2SO4, filtered and concentrated. The residue was purified on silica gel to afford the title compound (0.5 g, 45.9% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:60]=[C:61]([CH:64]=[CH:65][CH:66]=2)[C:62]#[N:63])[CH2:54][CH2:53]1>CN(C=O)C.O>[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19]([N:52]2[CH2:53][CH2:54][CH:55]([O:58][C:59]3[CH:66]=[CH:65][CH:64]=[C:61]([C:62]#[N:63])[CH:60]=3)[CH2:56][CH2:57]2)=[O:21])=[CH:14][CH:15]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: N#Cc1cccc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(OC2CCN(C(=O)CC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1
Reaction time: 0.03 h
Yield: 20.5 %

Procedure:
DIPEA (135 mg, 11.0 mmol) was added to a stirred solution of N-biphenyl-4-yl-malonamic acid (64 mg, 0.3 mmol) in DMF (2.0 mL) followed by HOBt (61 mg, 0.45 mmol) and EDCI.HCl (85 mg, 0.45 mmol). After 2 minutes of stirring, 3-(piperidin-4-yloxy)-benzonitrile hydrochloride (60 mg, 0.3 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethylacetate, washed with brine and concentrated The residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) to afford 27 mg (19.7% Yield) of N-biphenyl-4-yl-3-[4-(3-cyano-phenoxy)-piperidin-1-yl]-3-oxo-propionamide. LC/MS [M+H]+: 440.2, 98.14%, 1H NMR (300 MHz, DMSO-d6): δ10.2 (s, 1H), 7.7 (m, 5H), 7.5 (m, 5H), 7.3 (m, 2H), 4.8 (m, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.6 (m, 2H), 3.3 (m, 2H), 2.0 (m, 2H), 1.7 (m, 1H), 1.6 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][N:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>C1COCC1.[Pd](Cl)Cl.[Cu](I)I>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ncc(I)c(Cl)n1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(Cl)nc1Cl

Procedure:
66.55 g of 2,4-dichloro-5-iodo-pyrimidine is stirred for three hours in 1.2 litres of absolute THF with 70 ml of triethylamine, 4.9 g of palladium chloride, 13.3 g of triphenylphosphine, 4 g of copper iodide and 39.3 ml of trimethylsilylacetylene at 40° C. After the reaction has ended the solvent is eliminated in vacuo and the dark red oil remaining is subjected to fractional distillation. The product is distilled over at 0.01 Torr and 100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([CH:29]=O)=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2ccccc2C=O)cc1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccc(-c2ccccc2CN2CCN(c3ccccc3OC)CC2)cc1

Procedure:
149 mg of the target compound (0.38 mmol, 81.6%) was obtained using 1-(2-methoxyphenyl)piperazine (181 mg, 0.94 mmol), 4′-methoxybiphenyl-2-carbaldehyde (100 mg, 0.47 mmol) and NaBH(OAc)3 (303 mg, 1.41 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[CH:18][C:13]=3[C:12]([CH2:19][C:20]3[CH:21]=[N:22][C:23](S(C)(=O)=O)=[N:24][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.CN1CCCC1=O.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][NH2:44].[OH-].[K+]>C(O)(=O)C>[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][NH:44][C:23]1[N:24]=[CH:25][C:20]([CH2:19][C:12]2[C:13]3[CH:18]=[N:17][CH:16]=[N:15][C:14]=3[NH:10][CH:11]=2)=[CH:21][N:22]=1
Reactant: NCc1ccccn1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncncc23)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: c1ccc(CNc2ncc(Cc3c[nH]c4ncncc34)cn2)nc1

Procedure:
In a microwave vial, 7-benzenesulfonyl-5-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (58, 12 mg, 0.028 mmol) was mixed with 600 μL of N-methylpyrrolidone and C-pyridin-2-yl-methylamine (59, 19.5 mg, 0.18 mmol). The reaction was irradiated at 160° C. for 40 minutes in microwave, then potassium hydroxide (500 μL, 4.00 M in water) was added and the reaction irradiated at 90° C. for 10 minutes in microwave. The reaction was neutralized with the addition of 120 μL of acetic acid, solvents were removed under vacuum, and the resulting material was dissolved in 400 μL of dimethylsulfoxide for purification by HPLC. Samples were purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H+]+=317.9.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:10][C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([F:11])=[C:17]([O:18][CH3:19])[CH:16]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: COc1cc(B(O)O)ccc1F
Product: COc1cc(-c2cc(F)c(N)c(F)c2)ccc1F
Yield: 197.5 %

Procedure:
The title compound (480 mg) was prepared from 4-bromo-2,6-difluoroaniline (200 mg, 0.96 mmol) and 4-fluoro-5-methoxyphenylboronic acid (210 mg, 1.24 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.39-7.29 (m, 3H), 7.21-7.12 (m, 2H), 5.33 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:11]/[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc3ccccc3c2)cc1OC
Yield: 86.4 %

Procedure:
2-Naphthaldehyde (500 mg) was condensed with 3,4-dimethoxybenzyl cyanide (567 mg) through Method A (production step 2), to thereby yield the target product (yield: 872 mg, 86%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[CH3:27])=[CH:14][CH:13]=2)[C:9](=[O:28])[CH2:8]1.C(N(CC)CC)C>ClCCl>[Cl:3][CH2:6][CH:7]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[CH3:27])=[CH:14][CH:13]=2)[C:9](=[O:28])[CH2:8]1
Reactant: CC1CCCN1CCCOc1ccc(N2CC(CO)CC2=O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCN1CCCOc1ccc(N2CC(CCl)CC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
Thionyl chloride (0.24 ml, 3.25 mmol, 1.5 eq) is added into a cold solution of 4-(hydroxymethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 72 (0.78 g, 2.16 mmol, 1 eq) and triethylamine (0.3 ml, 2.16 mmol, 1 eq) in dichloromethane (30 ml). The mixture is warmed to room temperature and stirred overnight. The solution is washed once with water and once with a saturated solution of aqueous sodium chloride. The organic layer is dried over magnesium sulfate and concentrated under vacuum to give 0.54 g of 4-(chloromethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one a56 as a dark-red oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>COCCOCCOC>[ClH:1].[N:21]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: ClCCCCOc1ccccc1/C=C/c1ccccc1
Reactant: c1c[nH]cn1
Solvent: COCCOCCOC
Product: C(=C/c1ccccc1OCCCCn1ccnc1)\c1ccccc1
Product: Cl
Yield: 108.7 %

Procedure:
A solution of the (E)-4-chlorobutoxystilbene (2.0 g, 7.0 mmol) and imidazole (1.0 g, 14 mmol) in 20 mL of 2-methoxyethyl ether was heated to 120° C. for 24 hours. The solvent was removed by distillation and the resulting residue was chromatographed (flash, SiGel, 9:1 CH2Cl2 -MeOH). The hydrochloride salt was made in HCl/MeOH and recrystallized from acetone to give 2.7 g (95%) of the title compound as an off-white solid. m.p. 208°-210° C. IR(KBr): 3400,1590cm-1. MS: 319(MH)+. 1H NMR(CD3OD): δ9.21(s,1H), 7.65-6.82(m,13H), 4.35(t,2H), 4.02 (t,2H), 2.01(m,4H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[PH4+].C(CCCC(OC)=O)=O.[CH:16]1[C:25]2[C:20](=[CH:21]C=CC=2)[CH:19]=[CH:18][C:17]=1/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CCCCCC.O1CCCC1>[CH3:4][C:3]1[CH:21]=[C:20]2[C:25](=[CH:1][CH:2]=1)[CH:16]=[C:17](/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:18]=[CH:19]2
Reactant: [Li]CCCC
Reactant: COC(=O)CCC/C=C/c1ccc2ccccc2c1
Agent: COC(=O)CCCC=O
Agent: [PH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CCC/C=C/c1ccc2cc(C)ccc2c1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
1.6M Butyl lithium solution in hexane (6.7 ml) was added to a stirred suspension of the phosphonium salt (5.0 g) in dry tetrahydrofuran (50 ml) at 5° C. under nitrogen. The dark solution was cooled to -50° C. and methyl 4-formylbutyrate (1.5 g) was added dropwise. The pale solution was stirred for 30 minutes at about -60° C., allowed to warm to -10° C., poured on to ice-sodium chloride solution and extracted with ether. The extract was washed with dilute hydrochloric acid, dried and evaporated and the residue was extracted with petroleum spirit to give a mixture of (Z) and (E) esters as an oil (2.8 g). Isomerisation by the method described in (b) above gave the title compound (2.1 g), m.p. 50° C.
Reaction SMILES: CC(O)C.C(N(CC)CC)C.[CH2:12]([O:14][C:15]([CH:17]([NH2:27])[C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[CH:19]=1)=[O:16])[CH3:13].Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Cl:39])[CH:37]=2)[N:32]=[CH:31][N:30]=1>O>[CH2:12]([O:14][C:15]([CH:17]([NH:27][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Cl:39])[CH:37]=2)[N:32]=[CH:31][N:30]=1)[C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[CH:19]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C(N)c1ccc2c(c1)OCO2
Reactant: Clc1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Yield: 85.5 %

Procedure:
30 ml of 2-propanol, 1.07 g of triethylamine and 1.01 g of α-ethoxycarbonyl-3,4-methylenedioxybenzylamine were added to 704 mg of 4,6-dichloroquinazoline. The obtained mixture was refluxed for 4 hours, followed by the addition of water. The obtained mixture was extracted with chloroform thrice. The chloroform layers were combined, dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The residue was recrystallized (from ethanol/ethyl acetate/hexane) to give 1.167 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([C:10]=1[OH:11])[C:7]([OH:9])=[O:8].[CH3:13][C:14]([CH3:16])=O.S(Cl)(Cl)=O>COCCOC.CN(C1C=CN=CC=1)C.O.C([O-])([O-])=O.[K+].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:14]([CH3:16])([CH3:13])[O:8][C:7](=[O:9])[C:6]=2[C:10]=1[OH:11]
Reactant: O=C(O)c1c(O)ccc(Cl)c1O
Reactant: CC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC1(C)OC(=O)c2c(ccc(Cl)c2O)O1
Temperature: 10 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
To a solution of 5-chloro-2,6-dihydroxybenzoic acid (Doyle, F. P. J. Chem. Soc., 1963, p. 497-506) (500 mg, 2.65 mmol) in DME (2 mL) was added DMAP (16.2 mg, 0.13 mmol) and acetone (200.2 mg, 3.45 mmol). The solution was cooled to 10° C. and thionyl chloride (448 mg, 3.77 mmol) was added over 10 min. The solution was allowed to overnight. The solution was diluted with water and neutralized with solid K2CO3 and the aqueous phase was extracted w/EtOAc. The combined organic layers were washed with water, brine and dried (Na2SO4). The crude residue was purified by column chromatography on silica gel to afford the product as yellow solid (162 mg, 27% yield). 1H NMR: 1.74 (s, 6H), 6.44 (d, 1H, J=8.0 Hz), 7.48 (d, 1H, J=8.0 Hz), 10.83 (s, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH2:36])=[N+:2]=[N-:3].[Cl:37][C:38]1[CH:39]=[C:40]2[C:45](=[C:46]([Cl:48])[CH:47]=1)[CH2:44][N:43]([CH3:49])[CH2:42][CH:41]2[C:50]1[CH:51]=[C:52]([S:56](Cl)(=[O:58])=[O:57])[CH:53]=[CH:54][CH:55]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH:36][S:56]([C:52]1[CH:53]=[CH:54][CH:55]=[C:50]([CH:41]2[C:40]3[C:45](=[C:46]([Cl:48])[CH:47]=[C:38]([Cl:37])[CH:39]=3)[CH2:44][N:43]([CH3:49])[CH2:42]2)[CH:51]=1)(=[O:58])=[O:57])=[N+:2]=[N-:3]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN=[N+]=[N-])c2)C1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of 32-azido-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontan-1-amine (436.9 mg, 0.777 mmol) in dry DMF (3.5 mL) under N2 was cooled to 0° C. A solution of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (300 mg, 0.706 mmol) and DIEA (273.2 mg, 2.118 mmol) in DMF (3 mL) was added dropwise. After 60 minutes LCMS indicated complete conversion and the solvent was removed to give N-(32-azido-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (620 mg) as a yellow oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][C:3]=1C(OCC)=O.S(=O)(=O)(O)O>O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(-c2c(F)c(F)c(C(F)(F)F)c(F)c2F)c1N
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 130 °C
Yield: 2.5 %

Procedure:
A stirred mixture of 18.6 grams (0.500 mole) of ethyl 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)pyrazole-4-ylcarboxylate, 23 mL of water, and 23 mL of sulfuric acid was heated at 130° C. for six hours. After the reaction mixture was cooled, 75 mL of crushed ice was added. A solid had formed and was collected by filtration; the filtrate was saved. This solid was washed with water and diethyl ether, allowed to dry, and set aside for further purification. To the filtrate was added an aqueous sodium hydroxide solution until a pH of 9.0 was obtained. A solid formed and was collected by filtration. This solid was washed with water and dried to yield 3.8 grams of 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)pyrazole, m.p. 102.5°-104.5° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]1([C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)Cl)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>N1C=CC=CC=1>[C:5]1([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:3][CH2:2][CH2:1][OH:4])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: OCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: OCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 2.4 %

Procedure:
Ethylene glycol (3.10 g, 49.9 mmol) (Wako Pure Chemical Industries, Ltd.) and triphenylchloromethane (1.39 g, 49.9 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in pyridine (6 mL) (Wako Pure Chemical Industries, Ltd.), and the solution was heated to 45° C. and stirred for 2 hours. Water (50 mL) was poured into the reaction solution, and mixture was extracted with toluene (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with an hydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled of funder reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):methanol (Wako Pure Chemical Industries, Ltd.)=9:1), to thereby obtain the title compound (0.37 g, 24% yield).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccccc1Sc1ccccc1F
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1Sc1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine (1 ml) was added to a solution of 2-(2-fluorophenylthio)phenol (9.4 g) in acetic anhydride (10 ml), and the mixture was stirred at room temperature for 30 minutes. The excess of acetic anhydride was distilled off under reduced pressure, and the resultant oily residue was dissolved in diethyl ether. The ether solution was washed with 10% hydrochloric acid and water in turn, dried and evaporated under reduced pressure to give oily 2-fluorophenyl 2-acetoxyphenyl thioether (11.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:25]12[CH2:31][CH:29]([O:30]1)[CH2:28][NH:27][CH2:26]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:27]4[CH2:26][C@@H:25]5[CH2:31][C@@H:29]([O:30]5)[CH2:28]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C1NCC2CC1O2
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2C[C@H]3C[C@@H](C2)O3)cn1
Yield: 22 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (36 mg, 0.11 mmol) was converted, using rac-6-oxa-3-aza-bicyclo[3.1.1]heptane instead of 2,2,2-trifluoroethylamine, to the title compound (10 mg, 22%) which was obtained as a colourless gum. MS: m/e=410.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.C(N(CC)CC)C.[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34](Cl)=[O:35].O>ClCCl>[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)=[O:35]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1Cc1ccccc1F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2n1Cc1ccccc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
23.2 g (74.28 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-indole-2-carboxylate from Example XXXVI and 15.03 g (20.71 ml, 148.56 mmol) of triethylamine are added to 300 ml of dichloromethane. The mixture is cooled to 0° C., and a solution of 11 g (11.35 ml, 81.71 mmol) of 3,3-dimethylbutyryl chloride in 300 ml of dichloromethane is added. The mixture is stirred at RT overnight and, for work-up, poured into water. The pH is adjusted to 7 and the mixture is extracted 3 times with ethyl acetate. The combined organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].BrC1C=[CH:23][C:22]([OH:25])=C(F)C=1.BrC(CC)[C:29]([O-])=[O:30]>>[CH3:29][O:30][C:22](=[O:25])[CH2:23][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:3][C:2]=1[Cl:1]
Reactant: Oc1ccc(Br)cc1F
Reactant: O=C(CCc1ccc(O)c(Cl)c1)C1CCCC1
Reactant: CCC(Br)C(=O)[O-]
Product: COC(=O)COc1ccc(CCC(=O)C2CCCC2)cc1Cl
Yield: 78 %

Procedure:
The title compound was prepared analogously to Step 1 from Example A(52), where 3-(3-Chloro-4-hydroxy-phenyl)-1-cyclopentyl-propan-1-one was substituted for 4-Bromo-2-fluorophenol and methyl bromo acetate was substituted for methyl □-bromobutyrate in Step 1 of that example. Yield 78%.
Reaction SMILES: C(OC([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][CH:15]=[CH:16][C:17]([O:19][CH2:20][CH:21]=[C:22]([CH2:24][CH2:25][CH:26]=[C:27]([CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH3:28])[CH3:23])=[O:18])=[CH:9][C:8]=1[O:35][CH3:36])=O)C.O.C(=O)([O-])[O-].[Na+].[Na+].Cl>CO>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][CH:15]=[CH:16][C:17]([O:19][CH2:20][CH:21]=[C:22]([CH2:24][CH2:25][CH:26]=[C:27]([CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH3:28])[CH3:23])=[O:18])=[CH:9][C:8]=1[O:35][CH3:36]
Reactant: CCOC(=O)Oc1ccc(C=CC=CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)C)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C=CC=CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)C)ccc1O
Reaction time: 3 h
Yield: 67.7 %

Procedure:
To a solution of 0.38 g of farnesyl 5-(4-ethoxycarbonyloxy-3-methoxyphenyl)-2,4-pentadienoate in 10 ml of methanol are added 2 ml of water and 0.08 g of sodium carbonate followed by stirring for 3 hours. To the reaction mixture is added 10 ml of water. The mixture is acidified with 1N hydrochloric acid and then extracted with chloroform. The organic layer is washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel. From the fraction eluted with chloroform is obtained 0.22 g of farnesyl 5-(4-hydroxy-3-methoxyphenyl)-2,4-pentadienoate (10). Spectroscopic data of the product support the structure of the formula (10) below.