Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:33][CH3:34])=[C:19]([S:21]([O:24][C:25]2[CH:26]=[C:27]([OH:32])[CH:28]=[C:29]([CH3:31])[CH:30]=2)(=[O:23])=[O:22])[CH:20]=1.[CH2:35](O)[CH2:36][CH2:37][OH:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C.ClCCl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:33][CH3:34])=[C:19]([S:21]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[C:29]([CH3:31])[CH:30]=2)[O:32][CH2:35][CH2:36][CH2:37][OH:38])(=[O:23])=[O:22])[CH:20]=1
Reactant: OCCCO
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Reaction time: 3 h
Yield: 69 %

Procedure:
Tri-n-butylphosphine (7.6 mL) 30.4 mmol) was added dropwise over 20 min to 3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenol (5.00 g, 15.2 mmol, prepared in step a of Example 2), 1,3-propanediol (3.3 mL, 45.6 mmol) and 1,1′-(azodicarbonyl)dipiperidine (7.68 g, 30.4 mmol) in anhydrous tetrahydrofuran (80 mL) at 0° C. under a nitrogen atmosphere. Dichloromethane (150 mL) was added mid-way through the tri-n-butylphosphine addition to aid stirring. The slurry was stirred for an additional 5 min at 0° C. then at ambient temperature for 3 h. Diethyl ether (400 mL) was added, and the mixture was stirred for 10 min then filtered. The filtrate was concentrated and the product was purified by flash column chromatography (25% to 60% ethyl acetate in hexane) to give the title compound (4.07 g, 69%) as a gold oil. 1H-NMR (300 MHz, CDCl3) (7.82 (d, 1H, J=2.8 Hz), 7.56 (dd, 1H, J=8.9, 2.6 Hz), 7.03 (d, 1H, J=8.9 Hz), 6.62 (br s, 1H), 6.52 (br s, 1H), 6.47 (t, 1H, J=2.3 Hz), 4.03 (t, 2H, J=6 Hz), 4.01 (s, 3H), 3.85-3.80 (m, 2H), 2.26 (s, 3H), 2.00 (pentet, 2H, J=6 Hz), 1.64 (t, 1H, J=5 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H19ClO6S: 409.0 (M+Na). Found: 409.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:8]#[N:9])[CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18]>>[C:8]([C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:18][CH2:17][C:16]#[N:19])#[N:9]
Reactant: N#CC(c1cccnc1)N1CCOCC1
Reactant: C=CC#N
Product: N#CCCC(C#N)(c1cccnc1)N1CCOCC1

Procedure:
Leete et al. [J. Org. Chem. 37, 4465-6 (1972)] shows the reaction of 2-(3-pyridinyl)-2-(4-morpholinyl)ethanenitrile with acrylonitrile to produce 4-cyano-4-(3-pyridinyl)-4-(4-morpholinyl)butanenitrile and its conversion by heating it with acetic acid, water and tetrahydrofuran to 4-oxo-4-(3-pyridinyl)butanenitrile.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([CH2:33][O:34][CH3:35])[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=1)[C:5]2=[O:36]>C1COCC1.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:35][O:34][CH2:33][N:32]1[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:15][N:6]3[C:5](=[O:36])[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([O:1][C:5](=[O:36])[NH:6][CH2:7][CH2:12][CH3:13])[CH:3]=4)[N:8]=[C:7]3[CH2:12][CH2:13][CH3:14])=[CH:21][CH:20]=2)=[N:29][N:30]=[N:31]1
Reactant: CCCc1nc2ccc(O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCNC(=O)Oc1ccc2nc(CCC)n(Cc3ccc(-c4ccccc4-c4nnnn4COC)cc3)c(=O)c2c1
Yield: 158.7 %

Procedure:
A mixture of 6-hydroxy-3-[[2'-(N-methoxymethyltetrazol-5-yl)biphenyl-4-yl]methyl]-2-propyl-4(3H)-quinazolinone (0.15 g) propyl isocyanate (0.9 ml) in a mixture of THF (5 ml) and pyridine (2 ml) was heated under reflux for 6 days. The reaction mixture was diluted with ethyl acetate and the solution was washed with 1N hydrochloric acid and water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give a pale yellow powder (0.14 g, 79%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>COCCOC>[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:24][CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C=C1CCN(C(=O)OCC)CC1
Reaction time: 1 h
Yield: 106.6 %

Procedure:
To a suspension of 4 g oily sodium hydride (60%) in 200 ml of anhydrous 1,2-dimethoxyethane, was added dropwise 23.6 g ethyl diethylphosphonoacetate at about 20° C., and the mixture was stirred at that temperature for about one hour. To the solution thus obtained, was added dropwise 17.1 g N-ethoxycarbonyl-4-piperidone at temperatures below 30° C., the mixture was stirred for an additional two hours, and the solvent was distilled off under reduced pressure. Ice water (100 ml) and ethyl acetate (100 ml) were added to the residue, the mixture was shaken, and the layers were separated. The aqueous layer was extracted twice with 100 ml ethyl acetate, and all the organic solutions were obtained, washed with water and dried over anhydrous magnesium sulfate. Distilling off the solvent from the dried solution gave 25.7 g of ethyl N-ethoxycarbonyl-4-piperidylideneacetate as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[NH:17][C:18]([C:20]1([CH3:34])[CH2:29][CH2:28][C:27]2[C:22](=[C:23]([CH3:33])[C:24]([CH3:32])=[C:25]([OH:31])[C:26]=2[CH3:30])[O:21]1)=[O:19].N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl>[C:41]([O:31][C:25]1[C:26]([CH3:30])=[C:27]2[C:22](=[C:23]([CH3:33])[C:24]=1[CH3:32])[O:21][C:20]([CH3:34])([C:18]([NH:17][C:3]1[C:4](=[O:16])[N:5]([CH3:15])[C:6](=[O:14])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]=1[NH2:1])=[O:19])[CH2:29][CH2:28]2)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)Nc1c(N)n(-c3ccccc3)c(=O)n(C)c1=O)O2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Nc1c(N)n(-c3ccccc3)c(=O)n(C)c1=O)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
The compound of Example 1 (1.77 g, 3.80 mmol) and pyridine (0.154 mL, 1.90 mmol) were dissolved in dichloromethane (30 mL). To the resultant solution was added dropwise acetic anhydride (0.714 mL, 7.60 mmol) under ice cooling. The resultant reaction mixture was stirred overnight at room temperature, washed with 1N hydrochloric acid and 10% aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in ethyl acetate and filtered to give the title compound (yield 87%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].[Li]C(C)(C)C.CCCCC.[B:22](OC)([O:25]C)[O:23]C.C1COCC1.Cl>C(OCC)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][C:10]=1[B:22]([OH:25])[OH:23]
Reactant: COCOc1ccccc1C
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: COCOc1c(C)cccc1B(O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(methoxymethoxy)-2-methylbenzene in diethyl ether (0.3M) cooled at −60° C. tBuLi in pentane (1.7M, 1.4 eq) was added dropwise and the mixture was stirred for 1 h while warming gradually to 0° C. then for further 2 h at 0° C. The mixture was cooled to −78° C. and a solution of B(OMe)3 in THF (3 eq, 3.0M) was added dropwise and the mixture was allowed to reach RT and stirred overnight. The mixture was cooled to 0° C. and 1N HCl was added, then the reaction mixture was stirred for 2 h. All volatiles were removed under reduced pressure and the residue was extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over Na2SO4, filtered and evaporated in vacuo to give a yellow solid which was triturated with PE to give a white solid which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]1([CH3:17])[CH:10]=[CH:9][C:8]([S:11](N=C=O)(=[O:13])=[O:12])=[CH:7][CH:6]=1>O1CCOCC1>[C:5]1([CH3:17])[CH:10]=[CH:9][C:8]([S:11]([NH:1][C:2]([NH2:4])=[S:3])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: NC(N)=S
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)NC(N)=S)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a 100 mL RBF equipped with a condenser, thermo-probe, sealed system nitrogen purge, pressure-equilibrated addition funnel and magnetic stirrer were placed thiourea (9.36 g, 0.12 mol) and dioxane (50 mL). The mixture was warmed to a temperature of 100° C. to encourage dissolution. The mixture was then cooled to a temperature of about 20° C., at which point para-toluenesulfonylisocyanate (25.0 g, 0.12 mol) was added slowly over a period of time of 1 hour. A milky-white suspension was observed to form. The temperature was maintained with an ice-water bath between 20° C. and 32° C. The reaction mixture was stirred overnight at room temperature before it was concentrated in vacuo at a temperature of 40° C. to yield a white solid that was further dried to constant weight in vacuo at a temperature of 50° C. and a pressure of <1 mTorr.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:7](Cl)=[O:8].[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13].CCCCCCC>C(Cl)CCl.ClCCl>[C:12]([O:16][C:7](=[O:8])[NH:5][C:3](=[O:4])[CH2:2][Br:1])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)O
Reactant: NC(=O)CBr
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC(=O)CBr
Temperature: 2.5 °C
Yield: 81.4 %

Procedure:
2-Bromoacetamide (11.1 g, 80 mmol) was suspended in ethylene dichloride (130 ml) in a 250-ml round-bottomed flask fitted with a magnetic stirrer, a thermometer, and a condenser with nitrogen flow. Oxalyl chloride (9.76 ml, 112 mmol, 1.4 eq) was added slowly to the solution at room temperature with stirring. The mixture was stirred at room temperature for 30 min, and then heated to reflux for 5 hours (the suspension became a clear solution). The condenser was replaced with a distillation system, and about 35-40 ml solvent was removed with stirring. The heating mantle was withdrawn and the reaction mixture was cooled with an ice bath to 0-5° C. A solution of tert-butanol (10.7 ml, 112 mmol, 1.4 eq) in 10 ml dichloromethane was added slowly to maintain temperature below 15° C. and the mixture was stirred at 0-15° C. for 15-30 min. The reaction mixture was diluted with dichloromethane (220 ml) and washed sequentially with aqueous saturated sodium bicarbonate solution (50 ml) and water (3×80 ml) (The amount of unreacted 2-bromoacetamide in organic layer should be controlled to <1% by 1H NMR or HPLC, otherwise, continue washing with water to meet this requirement). The combined organic layers were concentrated under reduced pressure to remove about 200-250 ml solvent (A slurry was formed). Heptane (110 ml) was added and the mixture was concentrated to remove about 50-70 ml solvent at reduced pressure. Heptane (110 ml) was added and the mixture was heated to 50° C. for 30 min, and then cooled to room temperature. The mixture was stirred at room temperature for 1 hour and filtered and washed with heptane (30 ml) to afford the desired product (15.5 g, 86%) as a white crystalline solid.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.[Cl:18][C:19]1[C:20]([O:42][CH3:43])=[CH:21][C:22]([O:40][CH3:41])=[C:23]([CH2:25][CH2:26][C:27]2([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[O:32][C:31](=[O:33])[CH2:30][C:29](=[O:34])[CH2:28]2)[CH:24]=1>>[Cl:18][C:19]1[C:20]([O:42][CH3:43])=[CH:21][C:22]([O:40][CH3:41])=[C:23]([CH2:25][CH2:26][C:27]2([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[O:32][C:31](=[O:33])[C:30]([CH2:2][C:3]3[NH:12][C:11](=[O:13])[C:10]4[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=4)[N:4]=3)=[C:29]([OH:34])[CH2:28]2)[CH:24]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: COc1cc2nc(CCl)[nH]c(=O)c2cc1OC
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc4cc(OC)c(OC)cc4c(=O)[nH]3)C(=O)O2)cc1Cl
Yield: 20 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-(chloromethyl)-6,7-dimethoxyquinazolin-4(3H)-one (Example B(57), Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 20%.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[N:10]=[CH:9][N:8](C(OC(C)(C)C)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:19][N:20]([CH:22](C(OCC)=O)C(OCC)=O)[CH3:21].C([N:36](C(C(OCC)=O)C(OCC)=O)CCC)CC>>[CH3:19][N:20]([CH3:22])[CH:21]1[CH2:2][C:3]2[C:11]3=[C:7]([N:8]=[N:36][N:10]3[CH2:9]1)[CH:6]=[CH:5][CH:4]=2
Reactant: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)C(C(=O)OCC)N(C)C
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Product: CN(C)C1Cc2cccc3nnn(c23)C1

Procedure:
This compound was prepared by following the procedure of Example 18, but substituting methyl 4-(bromomethyl)-1H-benzotriazole-1-carboxylate for t-butyl 4-(bromo-methyl)-1H-benzimidazole-1-carboxylate and diethyl (dimethylamino)-malonate for diethyl (dipropylamino)malonate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)#[N:17].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1(C)C(C)=CC=CC=1>[C:11]([C:7]1[CH:8]=[C:9]([CH:22]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:21]2[CH:24]=[CH:25][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1cc(C(c2ccc(C#N)cc2)N2CCCCC2)cc(C(C)(C)C)c1O

Procedure:
2,6-Di-tert-butylphenol (4.12 g, 0.02 mol), 2.62 g (0.02 mol) of 4-cyano-benzaldehyde and 1.7 g (0.02 mol) of piperidine are refluxed under nitrogen in 25 ml of xylene for 24 hours. The solution is then evaporated in vacuo and the residue chromatographed on silica gel with toluene/ethyl acetate (9:1) to give 6.2 g of a practically pure title compound. A 5 g portion of said compound is recrystallized twice from acetonitrile to give 1.0 g of a pure sample as colorless crystals, melting at 139°-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[C:4]([NH:6][C:7]1[CH:37]=[CH:36][C:10]([CH2:11][CH:12]([C:20]([NH:22][S:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)(=[O:25])=[O:24])=[O:21])[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)=[O:5].[CH2:42](O)C.C(O)(=O)C>C([O-])([O-])OCC>[CH2:16]([N:15]([CH2:18][CH3:19])[C:13](=[O:14])[CH:12]([CH2:11][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:1]=[CH:42]2)=[CH:37][CH:36]=1)[C:20]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=[O:25])=[O:24])=[O:21])[CH3:17]
Reactant: CCO
Reactant: CCN(CC)C(=O)C(Cc1ccc(NC(=O)c2ccccc2N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Agent: CCOC([O-])[O-]
Solvent: CC(=O)O
Product: CCN(CC)C(=O)C(Cc1ccc(-n2cnc3ccccc3c2=O)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1

Procedure:
The compound (429 mg) obtained in Example 43 was dissolve in a mixed solution (1.5 mL) of ethanol/acetic acid (10/1), ethyl ortho-formate (187 μL) was added, and the mixture was heated under reflux for 7 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (175 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C#C)[C:5]2[O:9][C:8]([CH2:10][C:11]3[CH:16]=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)=[N:7][C:6]=2[CH:26]=1.BrC1[S:31][CH:32]=[CH:33][N:34]=1>C(N(CC)CC)C.[Pd](Cl)Cl.[Cu]I>[S:31]1[CH:32]=[CH:33][N:34]=[C:16]1[C:11]#[C:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][CH:2]=[CH:26][C:6]=2[N:7]=1
Reactant: Brc1nccs1
Reactant: C#Cc1cc(Cl)cc2nc(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)oc12
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#Cc1nccs1)c1nc2ccccc2o1
Temperature: 90 °C
Yield: 100 %

Procedure:
A suspension of 5-chloro-2-(3,5-di-t-butyl-4-hydroxy-benzyl)-7-ethynyl-benzoxazole (2.38 g, 6.0 mM), 2-bromothiazole (1.13 ml, 95%, 12 mM), bistriphenylphosphine)palladium(II) dichloride (21.1 mg, 30 uM), copper (I) iodide (1.2 mg, 6 uM) in triethylamine (12 ml) was heated at 90° C., under argon, for 3 hours. The triethylamine was removed in-vacuo and the residue dissolved in ether (70 ml) and water (30 ml). The organics were washed with 1N HCl (30 ml) and saturated sodium hydrogen carbonate (30 ml), dried (Na2SO4) and evaporated in-vacuo to give 2.86 g (100%) of crude thiazolylethynylbenzoxazole, which was purified by flash chromatography (SiO2 ; dichloromethane). The product was crystallized and recrystallized from methanol to give 1.43 g (50.4%) of the title compound (mp 137°-41° C.).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH2:23])[CH:19]=2)[NH:14][C:13]=1[CH3:24])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26]1.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH2:2]([O:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:25][CH2:31]3)[CH:19]=2)[NH:14][C:13]=1[CH3:24])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1[nH]c2ccc(CCN)cc2c1C(=O)OCc1ccccc1
Reactant: O=C1CCCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: Cc1[nH]c2ccc(CCNC3CCCCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-(2-Amino-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester hydrochloride (0.331 g, 0.961 mmol) and cyclopentanone (99.6 μL, 0.961 mmol) were mixed together in dichloroethane and stirred at room temperature under N2 for 30 minutes. The mixture was then cooled to 0° C., whereupon sodium triacetoxyborohydride (0.209 g, 0.988 mmol) was added and stirred without warming for a further 30 minutes). The reaction was then permitted to warm to rt and stirred for 20 hours. 1N NaOH (10 ML) was then added and extracted with EtOAc. The combined organic layers was washed with brine, dried on Na2SO4 and chromatographed (10% MeOH/CH2Cl2) to give 0.200 g, (53%), of the desired product, mp 97-100° C. pure product. 1HNMR (400 MHz, DMSO): δ 0.86-1.73 (m, 10H), 2.31 (m, 1H), 2.59 (s, 3H, ArCH3), 2.69 (m, 4H), 5.29 (s, 2H), 6.93 (d, J=8.06 Hz, J=1.64 Hz, ArH), 7.21 (d, J=8.06 Hz, 1H), 7.28-7.45 (m, 5H, ArH), 7.70 (s, 1H, ArH), 11.74 (s, ArNH). MS (APCI+) m/z 391.2(MH+). Anal. Calcd for C25H30N2O2.0.20H2O: C, 76.19; H, 7.77; N, 7.11. Found: C, 75.84: H, 8.09: N, 6.73. IR (KBr): 3309, 2927, 2854,1662, 1450, 1076 cm−1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:10]([O-:12])=[O:11].[Na+].Cl>O.CCOCC>[N+:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)([O-:12])=[O:11]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])N1CCc2ccccc21
Yield: 111.1 %

Procedure:
Following the procedure of Example 1, step 1, indoline (20 g, 170 mmol), sodium nitrite (14 g, 200 mmol), concentrated hydrochloric acid (30 mL) in water (70 mL) and ether (120 mL) provided 1-nitroindoline (31 g), which was reduced with zinc dust (˜50 g) in acetic acid (500 mL) to provide 1-aminoindoline (29 g). A mixture of 1-aminoindoline (17 g, 130 mmol), cycloheptanone (15 mL, 130 mmol), and concentrated sulfuric acid (20 mL) in water (180 mL) provided 8.2 g of 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole. MS (ESI) m/z 212.
Reaction SMILES: Cl.[CH:2]1([C:7]2[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C:22]([F:25])([F:24])[F:23])[CH2:6][CH2:5][CH2:4][CH2:3]1.[N:26]([O-])=O.[Na+].[Sn](Cl)[Cl:31]>O.Cl>[ClH:31].[CH:2]1([C:7]2[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:17][NH2:26])=[CH:18][CH:19]=3)=[CH:9][C:8]=2[C:22]([F:23])([F:24])[F:25])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Reactant: Nc1ccc(OCc2ccc(C3CCCC3)c(C(F)(F)F)c2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(OCc2ccc(C3CCCC3)c(C(F)(F)F)c2)cc1
Temperature: -1 °C
Reaction time: 0.5 h
Yield: 129.6 %

Procedure:
4-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)aniline hydrochloride (30 g, 81 mmol) was suspended in water (285 mL), and concentrated HCl (18 mL) was added. The suspension was stirred efficiently and cooled in ice/IPA bath to −0° C. Sodium nitrite (5.57 g, 81 mmol) in water (12 mL) was added. After addition, the reaction was stirred at 2° C. for 40 minutes. Some solids on the side were washed with ACN (10 mL). The mixture was cooled to −1° C. and tin (II)chloride (45.9 g, 242 mmol) dissolved in concentrated HCl (30 mL) was added slowly. A thick precipitate was formed and stirring was continued for 30 minutes. The mixture was warmed to room temperature and stirred for 3 h. The mixture was filtered, washed with HCl (0.1 M) and the solid was dried under vacuum to give the title compound (40.6 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][CH:6]=1.CN(C=O)C.[CH:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OC)(C)(C)C>[C:17]([C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][CH:6]=1)#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)c1cc(Br)cs1
Reactant: C#CCCCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCCCCC#Cc1csc(C(=O)OCC)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A reaction mixture of compound 1015 (5.64 g, 24.0 mmol), DMF (50 mL), copper (I) iodide (1.37 g, 7.2 mmol), 1-heptyne (9.42 mL, 72.0 mmol), triethylamine (6.70 mL, 48.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.77 g, 2.4 mmol) was stirred at 65° C. for 2 hours and then cooled to room temperature. Methyl tert-butyl ether (300 mL) was added to the reaction mixture and the precipitation was removed by filtration. The clear organic solution was washed with saturated sodium chloride, dried over magnesium sulfate and concentrated under vacuum. The crude brown oil was purified with flash silica gel chromatogram (with 0%→5% EtOAc in hexane) to afford ethyl 4-(hept-1-ynyl)thiophene-2-carboxylate (1016, 5.89 g) as a brown oil. 1H NMR (300 MHz, δ, CDCl3) 0.89 (t, 3H). 1.28-1.45 (m, 7H), 1.52-1.62 (m, 2H), 2.36 (t, 12.4 Hz, 2H), 4.33 (q, 2H), 7.48 (s, 1H), 7.72 (s, 1H).