Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1.[NH2:22][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:13]([NH:12][C:4]2[N:3]=[C:2]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH3:14])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)nc1N[C@@H](C)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Nc2cnccn2)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
2.83 g of methyl (S)-6-chloro-2-[1-(4-fluorophenyl)ethylamino]nicotinate, 870 mg of 2-aminopyrazine, 1.06 g of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 4.09 g of tripotassium phosphate and 475 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 15 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 3.14 g of the objective compound as orange powder.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CI.[C:18]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:18][O:13][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=1
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)phenol (47, 1.0 g, 4.35 mmol), methyl iodide (0.7 mL, 10.8 mmol) and K2CO3 (3 g, 21.75 mmol) in acetone (10 mL) was heated to reflux while stirring overnight. Solid residue was filtered off and the filtrate was concentrated on warm water bath at atmospheric pressure (Caution: product was volatile) to afford 1-methoxy-3,5-bis(trifluoromethyl)benzene (48, 0.6 g, 56%) as clear oil: 1H NMR (300 MHz, CDCl3) δ 7.46 (s, 1H), 7.30 (s, 1H), 3.90 (s, 1H).
Reaction SMILES: [C:1]1([P:7]2(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]=[O:14].C1(C)C=CC=CC=1>C1COCC1>[C:1]1([P:7]2(=[O:12])[CH2:8][CH2:9][CH2:10][CH:11]2[CH2:13][OH:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: O=P1(c2ccccc2)CCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=P1(c2ccccc2)CCCC1CO
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
In a 1 l round bottom 2-neck flask charged a with a magnetic stirring bar, 23.4 g 1-phenylphospholane-1-oxide (0.11 mol) was dissolved in 300 ml freshly distilled THF, and 10.4 g dry paraformaldehyde was added. The reaction flask was flushed with argon and cooled to −20° C. Subsequently 100 ml phenyllithium solution in cyclohexane/diethylether 7:3 (1.8M) was added in one portion. The resulting mixture was stirred until the temperature reached +10° C. and additionally 5 minutes at that temperature. Then 10 g NH4Cl was added. The mixture was filtered, concentrated, and the residue purified by flash chromatography (EtOAc, followed by EtOAc/methanol 10:1). Yields: 2.5 g substrate (1-phenylphospholane-1-oxide) (11%), 11.7 g (43%) trans-1-phenyl-2-phospholanemethanol-1-oxide as white crystals, m.p. 109-110° C. (toluene); 1H NMR (500 MHz) δ: 1.70-1.85 (m, 1H), 1.95-2.30 (m, 6H), 3.90-4.00 (m, 2H), 4.19 (t, 1H, J=6.1), 7.45-7.55 (m, 3H), 7.70-7.76 (m, 2H); 31P NMR (200 MHz) δ: 63.3; and 2.2 g (8%) cis-1-phenyl-2-phospholanemethanol-1-oxide, white crystals, m.p. 149-151° C. (toluene); 1H NMR (500 MHz) δ: 1.46-1.57 (m, 1H), 2.02-2.22 (m, 4H), 2.28-2.42 (m, 1H), 2.44-2.58 (m, 1H), 3.32-3.49 (m, 2H), 3.76 (t, 1H, J=5.7), 7.46-7.51 (m, 2H.), 7.52-7.57 (m, 1H), 7.67-7.73 (m, 2H); 31P NMR (200 MHz) δ: 62.7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1CO
Yield: 86.8 %

Procedure:
(S)-1-(tert-butoxycarbonyl)-2-azetidinecarboxylic acid (10.42 g, 49.4 mmol) was introduced into a 500-mL pear-shaped flask, and tetrahydrofuran (200 mL) was added to dissolve the compound. Then, a tetrahydrofuran solution of 10 M borane-dimethyl sulfide complex salt (9.87 mL, 98.7 mmol) was slowly added at 0° C., and the mixture was heated to reflux for 2 hours while stirring. The reaction solution was left to cool, and then was concentrated under reduced pressure. Ice water (100 mL) was poured thereto, and the mixture was extracted with ethyl acetate (200 mL×2). The extract was washed with saturated brine (200 mL), and then dried over anhydrous sodium sulfate. After filtering the extract, the filtrate was concentrated under reduced pressure to obtain the title compound (8.03 g, 42.9 mmol, 87%) as an oily matter.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].[NH:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:12])=[N:4][N:5]([CH2:8][C:9]([N:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)=[O:11])[C:6]=1[CH3:7]
Reactant: Cc1nn(CC(=O)O)c(C)c1Br
Reactant: OC1CNC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nn(CC(=O)N2CC(O)C2)c(C)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)acetic acid (0.4 g, 1.716 mmol) in DMF (6 mL) were added azetidin-3-ol (0.151 g, 2.060 mmol), HOBt (0.301 g, 2.231 mmol), and EDC (0.461 g, 2.403 mmol), followed by N-ethyl-N-isopropylpropan-2-amine (1.495 mL, 8.58 mmol). The reaction mixture was stirred for 18 hours at room temperature. The crude reaction mixture was subsequently diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26]Cl)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[I-:30].[Na+]>C(#N)C>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][I:30])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(C)(C)C(=O)OCI
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
To a solution of chloromethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate (3.85 g, 9 mmol) in acetonitrile (50 mL), was added sodium iodide (5.40 g, 36 mmol). The solution was stirred for 4 h at 60° C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH2Cl2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1% MeOH in CH2Cl2), to give 4.26 g of iodomethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([NH2:24])=[CH:16][N:15]=1)(=O)[CH3:12].CC([O-])(C)C.[K+]>C1COCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[C:3]=1[CH:4]=[CH:12][C:11]([C:14]1[N:15]=[CH:16][C:17]([NH2:24])=[CH:18][C:19]=1[C:20]([F:23])([F:21])[F:22])=[N:1]2
Reactant: CC(=O)c1ncc(N)cc1C(F)(F)F
Reactant: Nc1nccc(Cl)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1cnc(-c2ccc3c(Cl)ccnc3n2)c(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
Dissolve 2-amino-4-chloronicotinaldehyde (78 mg, 0.5 mmol) and 2-acetyl-5-amino-3-trifluoromethylpyridine (102 mg, 0.5 mmol) in anhydrous THF (5.0 mL) and cool it to −40° C. under N2 atmosphere. Add in portion t-BuOK (112 mg, 1.0 mmol) to the reaction mixture and stir the mixture at −110° C. for 2 hours. Concentrate the reaction mixture under vacuum, dilute the residue with water (20 mL), extract with CH2Cl2 (3×30 mL) and dry (MgSO4). Filter, concentrate under vacuum and purify the crude by column chromatography to afford the title compound product as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:19]=3)[C:8]=2[F:13])[C:3]=1[OH:27].[F:28][C@@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:30]O>>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[C:3]=3[O:27][CH2:30][CH:29]([F:28])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:8]=2[F:13])=[CH:15][N:16]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCOc1ccc(-c2ccc3c(O)c(F)c(F)cc3c2F)cn1
Reactant: CCCCCCCC[C@H](F)CO
Product: CCCCCCCCC(F)COc1c(F)c(F)cc2c(F)c(-c3ccc(OCCCCCC)nc3)ccc12

Procedure:
From 2,3,5-trifluoro-6-(6-hexyloxypyridin-3-yl)naphthalen-1-ol and 2-(S)-fluorodecan-1-ol by means of the Mitsunobu reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[NH2:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:35]3[CH2:36][CH2:37][C@H:33]([NH2:32])[CH2:34]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: N[C@H]1CCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](N)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
2.92 g of N,N'-carbonyldiimidazole were added to a solution of 6.70 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 50 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 1 hour. A solution of 1.55 g of (3S)-3-aminopyrrolidine in 10 ml of dry acetonitrile was then added to the mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with water and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 4.10 g of the title compound, as a powder.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.Cl[CH2:33][C:34]1[CH:35]=[CH:36][C:37]2[O:42][CH2:41][C:40](=[O:43])[N:39]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[C:38]=2[CH:49]=1>>[CH3:48][O:47][CH2:46][CH2:45][CH2:44][N:39]1[C:38]2[CH:49]=[C:34]([CH2:33][O:1][CH:2]3[CH:7]([C:8]4[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:12][CH:13]=4)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]3)[CH:35]=[CH:36][C:37]=2[O:42][CH2:41][C:40]1=[O:43]
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccccc3)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccccc4)cc3)cc21

Procedure:
Analogously to Method D, 1.05 g of tert-butyl 3-hydroxy-4-[4-(3-phenoxypropoxy)phenyl]piperidine-1-carboxylate and 0.735 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a colourless oil. Rf=0.36 (1:1 EtOAc-heptane); Rt=5.84.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=4[CH:26]=3)=[CH:4][C:3]=2[O:2]1.Cl>COCCOC>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]=4[CH:26]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: O=C(O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2S(=O)(=O)CC1
Yield: 86.4 %

Procedure:
To a solution of methyl 7-(3,4-methylenedioxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (500 mg) in 1,2-dimethoxyethane (50 ml) was added 6N hydrochloric acid (30 ml), and the mixture was refluxed for 5 hours and concentrated under reduced pressure. Precipitates were collected by filtration and washed with 2-propanol and diethylether to give pale yellow crystals of 7-(3,4-methylenedioxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (415.7 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=[O:9])(C)([CH3:3])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.CC(C)=O>[CH3:2][C:1]1([CH3:3])[O:9][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=2)=[CH:7][C:6](=[O:18])[O:5]1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)C=C(c2ccnc(C#N)c2)O1

Procedure:
Prepared from 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H10) by stirring in TFA/acetone with TFAA according to general procedure J (method b). Obtained as a brown solid (3.30 g).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[N:5]=[C:4]([C:10]([O:12]C)=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22].[CH:23]1([CH2:26][O:27][NH2:28])[CH2:25][CH2:24]1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[N:5]=[C:4]([C:10]([NH:28][O:27][CH2:26][CH:23]2[CH2:25][CH2:24]2)=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22]
Reactant: COC(=O)c1nn(C)c(=O)c(Br)c1Nc1ccc(Br)cc1F
Reactant: NOCC1CC1
Product: Cn1nc(C(=O)NOCC2CC2)c(Nc2ccc(Br)cc2F)c(Br)c1=O
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield by the procedure described in Example 166 (step I) using methyl 5-bromo-4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (31 mg, 0.071 mmol) and O-cyclopropylmethyl-hydroxylamine (20 mg, 0.23 mmol). MS APCI (−) m/z 487, 489, 491 (M−1, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 7.38 (dd, 1H), 7.31 (dd, 1H), 7.05 (t, 1H), 3.82 (s, 3H), 3.65 (d, 2H), 1.13 (m, 1H), 0.58 (q, 2H), 0.31 (q, 2H).
Reaction SMILES: [C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[N:8]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH:30][NH2:31])=[O:29])=[CH:26][CH:25]=2)[C:7]=1[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:4])([CH3:3])[CH3:2].C1N=C[N:41](C(N2C=NC=C2)=N)[CH:40]=1>CN(C=O)C>[C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[N:8]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]3[O:29][C:40]([NH2:41])=[N:31][N:30]=3)=[CH:32][CH:33]=2)[C:7]=1[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(C(=O)NN)cc1
Reactant: N=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(-c2nnc(N)o2)cc1
Temperature: 85 °C

Procedure:
To 4-[3-tert-Butylsulfanyl-2-(2,2-dimethyl-propyl)-5-(pyridin-2-ylmethoxy)-indol-1-ylmethyl]-benzoic acid hydrazide (0.05 g, 0.10 mmol) in DMF (1 mL) was added C-(Di-imidazol-1-yl)-methyleneamine (0.08 g, 0.50 mmol), and the reaction was heated at 85° C. for 3 hours. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (EtOAc:hexane gradient) to give the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]2[N:43]=[C:42](Cl)[N:41]=[C:40]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]3[CH2:55][C:54]([CH3:57])([CH3:56])[N:53]([O:58][CH:59]4[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]4)[C:52]([CH3:66])([CH3:65])[CH2:51]3)[N:39]=2)[N:3]=1.[CH2:67]([CH2:69][NH2:70])[OH:68]>>[OH:68][CH2:67][CH2:69][NH:70][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][C:15]([CH3:29])([CH3:28])[N:16]([O:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[C:17]([CH3:19])([CH3:20])[CH2:18]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]2[N:43]=[C:42]([NH:70][CH2:69][CH2:67][OH:68])[N:41]=[C:40]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]3[CH2:55][C:54]([CH3:56])([CH3:57])[N:53]([O:58][CH:59]4[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]4)[C:52]([CH3:65])([CH3:66])[CH2:51]3)[N:39]=2)[N:3]=1
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCCCNc3nc(Cl)nc(NCCCCC4CC(C)(C)N(OC5CCCCC5)C(C)(C)C4)n3)n2)CC(C)(C)N1OC1CCCCC1
Reactant: NCCO
Product: CC1(C)CC(CCCCNc2nc(NCCO)nc(NCCCCCCNc3nc(NCCO)nc(NCCCCC4CC(C)(C)N(OC5CCCCC5)C(C)(C)C4)n3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of N,N'-bis{2-chloro-4-[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and ethanolamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:22])[C:16](=[O:21])[CH2:17][CH2:18][C:19]#[CH:20])[CH:12]=[CH:13][CH:14]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:22])[C:16](=[O:21])[CH2:17][CH2:18][C:19]#[C:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Brc1ccccn1
Reactant: C#CCCC(=O)N(C)c1cccc(Cl)c1
Product: CN(C(=O)CCC#Cc1ccccn1)c1cccc(Cl)c1
Yield: 33.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (80 mg, 0.51 mmol) and pent-4-ynoic acid (3-chloro-phenyl)-methyl-amide (113 mg, 0.51 mmol). The crude residue was purified by C18 flash chromatography to yield 51 mg (0.17 mmol, 33%) of N-(3-chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide as a brown liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[N:4][N:3]=1.[C:30]1([C@H:36]([NH2:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([C@H:36]([NH:38][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][C:13]=3[O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[N:4][N:3]=2)[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(Oc1ccc2ccccc2c1-c1nnc(Cl)c2ccccc12)C(F)(F)F
Reactant: C[C@@H](N)c1ccccc1
Product: C[C@@H](Nc1nnc(-c2c(OS(=O)(=O)C(F)(F)F)ccc3ccccc23)c2ccccc12)c1ccccc1
Temperature: 23 °C
Yield: 93.8 %

Procedure:
A solution of trifluoromethanesulfonic acid 1-(4-chlorophthalazin-1-yl)-naphthalen-2-yl ester (4.9 g, 11 mmol) in (R)-1-phenylethylamine (7.2 ml, 56 mmol) was stirred for 4 hrs at 120° C., then cooled to 23° C. The resulting viscous mixture was purified by flash chromatography on silica gel (toluene/EtOAc 7:1) to give 5.4 g of the title compound as a light brown solid as a 1:1 mixture of diastereomers. (yield: 93%)
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[O:7]1)=[N+]=[N-]>C(OCC)(=O)C.O=[Pt]=O>[CH3:11][C:8]1([CH3:12])[O:7][C@@H:6]([CH2:5][CH2:4][NH2:1])[CH2:10][O:9]1
Reactant: CC1(C)OC[C@H](CCN=[N+]=[N-])O1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](CCN)O1
Reaction time: 18 h
Yield: 87.7 %

Procedure:
A suspension of (S)-4-(2-azido-ethyl)-2,2-dimethyl-[1,3]dioxolane as a yellow oil (18.7 g, 0.11 mol) and PtO2 (2.5 g) in ethyl acetate (100 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 18 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine as a colorless oil (14 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]2[C:24]([O:26]CC)=[O:25])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Ethyl (RS)-1-(4-Methoxyphenyl)-3-phenylindene-2-carboxylate. To a solution of ethyl (1RS) [1-hydroxy-1-(4-methoxyphenyl)]-3-phenylindene-2-carboxylate (4.65 g, 12.0 mmol) in CH2Cl2 (40 ml) at 0° C. under an argon atmosphere was added triethylsilane (2.34 ml, 14.6 mmol), followed by boron trifluoride etherate (8.8 ml, 71 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 min, at which time was added slowly 3 M HCl (50 ml). The mixture was extracted with EtOAc (150 ml). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/hexanes to provide the title compound (4.2 g, 95%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:4]([C@H:5]2[CH3:8])[C:3]=1[CH:9]=O.[CH2:11]([O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15])[CH3:12]>>[Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:4]([C@H:5]2[CH3:8])[C:3]=1/[CH:9]=[CH:16]/[C:14]([O:13][CH2:11][CH3:12])=[O:15]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H]1[C@H]2CC(Cl)=C(C=O)[C@@H]12
Product: CCOC(=O)/C=C/C1=C(Cl)C[C@@H]2[C@H](C)[C@H]12

Procedure:
±(1S,5R,6S)-3-Chloro-6-methylbicyclo[3.1.0]hex-2-ene-2-carbaldehyde was olefinated with ethoxycarbonylmethylene triphenylphosphorane according to General Procedure 1.1.B to afford the title compound.