Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.C([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)C1C=CC=CC=1.[CH2:27]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)[CH3:28].Cl>C1COCC1.[OH-].[Pd+2].[OH-].O>[CH2:27]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[OH:19])=[CH:32][CH:31]=1)[CH3:28]
Reactant: CCOc1ccc(C=O)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(Cc2ccccc2O)cc1
Reaction time: 0.5 h
Yield: 195 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.71 M, 3.8 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.5 g, 9.5 mmol) in THF (90 mL) at −78° C. and the mixture solution was stirred at the same temperature for 30 minutes. To this mixture, a solution of 4-ethoxybenzaldehyde (1.29 mL, 1.86 mmol) in THF (30 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for two hours, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure and the obtained residue was treated by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)]. To a methanol solution (26.8 mL) of the obtained crude product, a 20% palladium hydroxide catalyst (147 mg) was added and furthermore 36% HCl (0.4 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (828.1 mg, 38%).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1)#[CH:55].[Na]>CN(C)C=O.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)I>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:55]#[C:54][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: C#Cc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3ccccn3)ccc12
Temperature: 120 °C
Yield: 64.1 %

Procedure:
A solution of 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (150 mg, 0.35 mmol), trans-dichlorobis(triphenylphosphine)palladium (22 mg, 0.035 mmol), copper iodide (13 mg, 0.071 mmol), triphenylphosphine (19 mg, 0.071 mmol) in dimethylformamide (3 ml) was degassed with argon for 10 min and then treated with triethylamine (74 μl, 0.53 mmol) and 2-ethynylpyridine (45 μl, 0.45 mmol). The solution was warmed to 120° C. under microwave irradiation (power max=80 W) for 1 hour and then poured onto a saturated aqueous solution of sodium hydrogenocarbonate, extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate and purified by flash chromatography over silica gel (cyclohexane/ethyl acetate: 20-40%) to yield 2-isoquinolin-3-yl-7-(pyridin-2-yl-ethynyl)-chromen-4-one O-tert-butyl oxime (100 mg, 63%) as a yellow solid.
Reaction SMILES: C(S[C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:12](=[O:51])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)C.[O-:52][CH2:53][CH3:54].[Na+]>C(O)C>[CH2:53]([O:52][C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:12](=[O:51])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:54]
Reactant: CC[O-]
Reactant: CCSc1nc2ccccc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2ccccc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14.7 %

Procedure:
A mixture of 2-ethylthio-3-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-4(3H)-quinazolinone (0.5 g) and sodium ethoxide (182 mg) in ethanol (20 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated to dryness. The residue was extracted using methylene chloride and an aqueous solution of ammonium chloride. The organic layer was washed with water, dried and evaporated to dryness. The resulting syrup was purified by column chromatography on silica gel to give a colorless oil (72 mg, 21%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Cl[C:7]1[C:16]2[C:11](=[CH:12]C=C[CH:15]=2)[N:10]=[CH:9][CH:8]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C(COC)OC.C1COCC1>[CH2:3]([C:2]1[C:1]2[C:9](=[CH:8][CH:7]=[CH:16][CH:15]=2)[N:10]=[CH:11][CH:12]=1)[CH3:4]
Reactant: [Li]CCCC
Reactant: Clc1ccnc2ccccc12
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Ethyltriphenylphosphonium bromide (45.0 g, 0.122 m) was suspended in anhydrous dimethoxyethane under a nitrogen atmosphere and cooled to -30° C. n-Butyllithium (12.2 mL of a 1 molar solution in THF) was added and the reaction mixture was stirred at -30° to -40° C. for 1 hour. 4-Chloroquinoline (9.0 g, 0.055 m) was added and the suspension was slowly warmed to room temperature and allowed to stir overnight. After heating under reflux for 2-3 hours, 50-100 mL of solvent was distilled out and replaced by a solution of sodium carbonate (12.9 g) in water (60-80 mL). After refluxing for another 2-3 hours, the solvents were evaporated and the residue was partitioned between methylene chloride and aqueous HCl. The organic phase was extracted twice with HCl, and the combined aqueous phases were basified with sodium hydroxide (50:50) to pH 9-10, extracted with ether, dried, and evaporated to give an oil which was purified by HPLC on silica gel eluting with 1:1 ethyl acetate:hexane to give 5.54 g (64%) of 4-ethylquinoline.
Reaction SMILES: C(N(CC)CC)C.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]1>O1CCCC1.C(OCC)(=O)C>[CH2:8]([O:23][C:21]([CH:19]1[CH2:20][C:17](=[O:16])[CH2:18]1)=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC(C(=O)O)C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CC(C(=O)OCc2ccccc2)C1

Procedure:
Triethylamine (2.0 mL) and benzyl bromide (1.2 mL) were added to a solution of 3-oxocyclobutanecarboxylic acid (J. Org. Chem., vol. 53, pp. 3841-3843 (1981)) (995 mg) in tetrahydrofuran (5.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and was sequentially washed with 1N aqueous HCl, saturated aqueous sodium hydrogencarbonate, and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:6), to thereby give the title compound (886 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.[NH2:14][C@H:15]([C:19]([NH:21][CH:22]([CH:31]([OH:34])[CH2:32][F:33])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:20])[CH:16]([CH3:18])[CH3:17].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([CH:31]([OH:34])[CH2:32][F:33])[CH2:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13]
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 1-methylindole-2-carboxylic acid (130 mg, 0.74 mmol) and N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, tert-butyl ester in methylene chloride (5 mL) and cooled to 0° C. Solid 4-dimethylaminopyridine (DMAP) (95 mg, 0.78 mmol) and 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (200 mg, 1.04 mmol) were added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm slowly to room temperature. After 4 h the reaction was partitioned between ethyl acetate (EtOAc) and 5% KHSO4 aqueous solution. The organic layer was washed with 5% KHSO4 solution, saturated sodium bicarbonate solution, brine, dried (Na2SO4) and concentrated to a foam. The crude residue was triturated with diethyl ether and the solid filtered to afford the title compound as a light brown solid (224 mg, 65% yield). TLC(MeOH:CH2Cl2, 1:9): Rf=0.46.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+]>CO>[NH2:13][C:9]1[C:10]([CH3:12])=[N:11][CH:2]=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)nc1Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cnc(C)c(N)c1
Temperature: 25 °C

Procedure:
Methyl 2-chloro-6-methyl-5-nitronicotinate (step 1) (6.9 g, 29.9 mmol) was added to a suspension of ammonium formate (18.87 g, 299 mmol) and 10% Pd(Carbon) (0.522 g, 0.491 mmol) in MeOH (330 ml) and the mixture was heated at reflux for 3 hrs. After cooling to RT, the mixture was filtered through Celite® (filter material) and washed through with MeOH. The solvent was removed in vacuo and the crude product was triturated with EtOAc to give an orange solid. Purification by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the title product.
Reaction SMILES: ClC1C(C(=O)N(CCCC)CCCC)=NN(C2C=CC(C(NS(C3C=C4C(C=CC(C(O)=O)=C4)=CC=3)(=O)=O)=O)=CC=2C(N2CCC3C(=CC=CC=3)C2)=O)C=1C.[Cl:56][C:57]1[C:58]([C:109](=[O:119])[N:110]([CH2:115][CH2:116][CH2:117][CH3:118])[CH2:111][CH2:112][CH2:113][CH3:114])=[N:59][N:60]([C:63]2[CH:96]=[CH:95][C:66]([C:67]([NH:69][S:70]([C:73]3[CH:82]=[C:81]4[C:76]([CH:77]=[CH:78][CH:79]=[C:80]4[O:83][CH2:84][C:85]4[CH:94]=[CH:93][C:88]([C:89]([O:91]C)=[O:90])=[CH:87][CH:86]=4)=[CH:75][CH:74]=3)(=[O:72])=[O:71])=[O:68])=[CH:65][C:64]=2[C:97]([N:99]2[CH2:108][CH2:107][C:106]3[C:101](=[CH:102][CH:103]=[CH:104][CH:105]=3)[CH2:100]2)=[O:98])[C:61]=1[CH3:62]>>[Cl:56][C:57]1[C:58]([C:109](=[O:119])[N:110]([CH2:115][CH2:116][CH2:117][CH3:118])[CH2:111][CH2:112][CH2:113][CH3:114])=[N:59][N:60]([C:63]2[CH:96]=[CH:95][C:66]([C:67]([NH:69][S:70]([C:73]3[CH:82]=[C:81]4[C:76]([CH:77]=[CH:78][CH:79]=[C:80]4[O:83][CH2:84][C:85]4[CH:86]=[CH:87][C:88]([C:89]([OH:91])=[O:90])=[CH:93][CH:94]=4)=[CH:75][CH:74]=3)(=[O:71])=[O:72])=[O:68])=[CH:65][C:64]=2[C:97]([N:99]2[CH2:108][CH2:107][C:106]3[C:101](=[CH:102][CH:103]=[CH:104][CH:105]=3)[CH2:100]2)=[O:98])[C:61]=1[CH3:62]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCc5ccc(C(=O)OC)cc5)c4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(C(=O)O)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCc5ccc(C(=O)O)cc5)c4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 51 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 46A, methyl 4-((7-(N-(4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoyl)sulfamoyl)naphthalen-1-yloxy) methyl)benzoate (Example 26, 10 mg, 0.011 mmol) was converted to the title compound (5 mg, 49%). 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 9.17 (d, J=1.8 Hz, 1H), 8.24-8.00 (m, 6H), 7.81-7.56 (m, 5H), 7.35-7.03 (m, 4.5H), 6.89-6.87 (m, 0.5H), 5.48 (s, 2H), 4.56 (br s, 2H), 3.77-3.42 (m, 4H), 3.24-3.14 (m, 1H), 3.06 (br s, 1H), 2.89 (br s, 2H), 2.37 (s, 2H), 2.32 (s, 1H), 1.63-1.20 (m, 6H), 1.21-1.03 (m, 2H), 1.01-0.88 (m, 3H), 0.86-0.63 (m, 3H); MS(ESI+) m/z 890.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:35])[N:4]([C:8]2[C:9]([CH3:34])=[C:10]([C:14]3[C:26]4[C:25]5[C:20](=[CH:21][C:22]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][CH:24]=5)[NH:19][C:18]=4[C:17]([C:31]([NH2:33])=[O:32])=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:5][C:6]=1[CH3:7].C([O-])=O.[NH4+]>CO.[Pd].C(Cl)Cl>[CH3:1][CH:2]1[CH:6]([CH3:7])[CH2:5][N:4]([C:8]2[C:9]([CH3:34])=[C:10]([C:14]3[C:26]4[C:25]5[C:20](=[CH:21][C:22]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][CH:24]=5)[NH:19][C:18]=4[C:17]([C:31]([NH2:33])=[O:32])=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)[C:3]1=[O:35]
Reactant: CC1=C(C)C(=O)N(c2cccc(-c3ccc(C(N)=O)c4[nH]c5cc(C(C)(C)O)ccc5c34)c2C)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1N1CC(C)C(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A mixture of 4-(3-(3,4-dimethyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Example 81-21, 20 mg, 0.043 mmol) and ammonium formate (27.0 mg, 0.428 mmol) in methanol (5 mL) was treated with 10% palladium on charcoal (20 mg, 0.019 mmol). The mixture was stirred under nitrogen at rt for 2 h. Additional ammonium formate (27.0 mg, 0.428 mmol) was added and the mixture was stirred at rt overnight. More ammonium formate (57 mg) and 10% palladium on charcoal (40 mg) were added, and after 6 h more additional ammonium formate (57 mg) was added. The mixture was again stirred overnight, then was diluted with DCM and filtered through Celite. The filtrate was washed with water, dried and concentrated. The residue was purified by preparative HPLC and the appropriate effluent fractions were made basic with 1 M aqueous sodium hydroxide and extracted twice with DCM. The combined organic phases were washed with water, dried and concentrated to provide 4-(3-(3,4-dimethyl-2-oxopyrrolidin-1-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a white solid (11 mg, 55%), which was a mixture of diastereomers. Mass spectrum m/z 452.1 (M+H—H2O)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[CH:4][N:3]=1.N[C:9](N)=N.[CH3:12][O:13][C:14](=[NH:16])[NH2:15]>>[NH2:1][C:2]1[N:7]=[C:6]([O:13][CH3:12])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:12][O:13][C:14](=[NH:15])[NH2:16]
Reactant: N=C(N)N
Reactant: Nc1ncncn1
Agent: COC(=N)N
Product: COc1nc(C)nc(N)n1

Procedure:
According to U.S. Pat. No. 3,754,547, 2-amino-s-triazine derivatives can be prepared by reaction of N-cyanimido-esters with guanidine, O-methylisourea or amides. This process is also unsuitable on an industrial scale, since the yields produced are only about one-half of the desired yield (a maximum yield of 45% results in the case of the important compound 2-amino-4-methoxy-6-methyl-s-triazine), and the free O-methylisourea base, which is relatively unstable, must be used as the starting substance in this process.
Reaction SMILES: [C:1]([C:14]1[CH:18]=[CH:17][O:16][C:15]=1[CH:19]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(O)(=O)[CH2:22][C:23]([OH:25])=[O:24]>CO>[C:1]([C:14]1[CH:18]=[CH:17][O:16][C:15]=1[CH:19]=[CH:22][C:23]([OH:25])=[O:24])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCCCCCCC#Cc1ccoc1C=O
Solvent: CO
Product: CCCCCCCCCCCC#Cc1ccoc1C=CC(=O)O
Yield: 96 %

Procedure:
Reaction of 3-(1-tridecynyl)furan-2-carboxaldehyde (700 mg, 2.56 mmole from Example 6) with malonic acid (535 mg, 5.12 mmole) as described in Example 2 gave 0.778 g (98%) of the title compound, mp (methanol) 71°-72° C. νmax (mull) 3140, 2600 (broad), 1680, 1630, 1465 cm-1 ; δ(DMSO) 0.80 (3H, distorted t, terminal CH3), 1.09-1.60 (18H, m, alkylene chain), 2.42 (2H, t, CH2C≡C), 6.25 (1H, d, J 15.3 Hz, C=CH--CO2H), 6.62 (1H, d, J 2 Hz, C-4H), 7.33 (1H, d, J 15.3 Hz, Ar CH=C), 7.79 (1H, d, J 2 Hz, C-5H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[NH:18][CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@@:8]3([O:21][CH3:22])[C@H:9]([CH3:20])[CH2:10][C:11](=[O:19])[CH2:12]4.[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26]Br.[ClH:29]>C(O)C>[ClH:29].[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26][N:18]1[CH2:17][CH2:16][C@@:13]23[C:14]4[CH:15]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=4[CH2:6][C@@H:7]1[C@:8]2([O:21][CH3:22])[C@H:9]([CH3:20])[CH2:10][C:11](=[O:19])[CH2:12]3
Reactant: CO[C@@]12[C@H](C)CC(=O)C[C@@]13CCN[C@@H]2Cc1ccc(O)cc13
Reactant: CC(C)=CCBr
Agent: Cl
Solvent: CCO
Product: CO[C@@]12[C@H](C)CC(=O)C[C@@]13CCN(CC=C(C)C)[C@@H]2Cc1ccc(O)cc13

Procedure:
A mixture of 3-hydroxy-14-methoxy-8α methylmorphinan-6-one (27) (0.13 g, 0.43 mmol), dimethylallyl bromide (0.125 g, 0.84 mmol) and ethanol (10 ml) was refluxed under a nitrogen atmosphere for 16 hours (oil bath temperature 105°-110° C). The mixture was filtered and the residue washed with ethanol. The filtrate upon concentration gave a solid product which was chromatographed over silica gel using graded methanol/chroloform mixtures as the eluant. Fractions containing the desired product were collected and evaporated to give total of 0.02 g (12.6% theory) of pure product. An additional 0.026 g of less pure 28 was also obtained. The pure material was converted into the HCl salt by treatment with ethereal HCl.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][C:23]1[S:24][C:25]([CH3:30])=[C:26]([CH2:28]Br)[N:27]=1>CC#N>[Br:22][C:23]1[S:24][C:25]([CH3:30])=[C:26]([CH2:28][O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:27]=1
Reactant: Cn1nnnc1C(=NO)c1ccccc1
Reactant: Cc1sc(Br)nc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1sc(Br)nc1CON=C(c1ccccc1)c1nnnn1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.4 %

Procedure:
To a stirred solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (1.47 g, 7.25 mmol, 1.0 eq.) in 25 ml of MeCN was added Cs2CO3 (2.59 g, 7.97 mmol, 1.1 eq.) followed by KI (0.120 g, 0.725 mmol, 0.1 eq.) in one portion. The resulting suspension was stirred for 5 mins before addition of 2-bromo-4-(bromomethyl)-5-methyl-1,3-thiazole (1.96 g, 7.25 mmol, 1 eq.) in one portion. The reaction was stirred for 24 hrs at room temperature. The solvent was evaporated and the residue was dissolved in EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give N-[(2-bromo-5-methyl-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (2.92 g, 97% yield, 93:7 mixture of stereoisomers) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.C(O)(=O)C.[NH2:29][CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:34][N:33]([CH3:35])[C:31]([CH2:30][NH:29][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21])=[O:32]
Reactant: CN(C)C(=O)CN
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CN(C)C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Yield: 74.3 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (33 mg) was prepared by following General Procedure F using 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (36 mg), 2-amino-N,N-dimethyl-acetamide acetic acid salt (48 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 444. 1H NMR (DMSO-d6, 400 MHz): δ 11.70 (br, 1H), 8.44 (t, 1H), 8.11 (s, 1H), 7.94 (m, 1H), 7.80 (m, 1H), 7.66 (br, 1H), 7.50 (d, 1H), 7.38 (d, 1H), 4.12 (d, 2H), 3.61 (s, 3H), 3.03 (s, 3H), and 2.87 (s, 3H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2([CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:14][CH:15]=3)[C:10]2=[O:24])[CH2:6][CH2:5]1)(=O)C.[ClH:25]>C(O)C>[ClH:25].[CH3:23][S:20]([NH:19][C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH2:18][C:7]3([C:10]2=[O:24])[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=1)(=[O:21])=[O:22]
Reactant: CC(=O)N1CCC2(CCc3ccc(NS(C)(=O)=O)cc3C2=O)CC1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C1(CCNCC1)CC2
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 0.53 g (1.5 mmoles) 1'-acetyl-3,4-dihydro-7-methanesulfonamido-1-oxospiro[naphthalene-2(1H),4'-piperidine] in 15 ml ethanol and 5 ml 3N hydrochloric acid was heated at reflux for 18 hours. An additional 10 ml 3N hydrochloric acid was added and the solution was heated at reflux for 5 hours, then cooled to room temperature. The solvents were removed in vacuo and the residue was stirred with 3 ml ethanol to give a solid which was filtered off and dried to give 0.35 g (67%) product, m.p. 277°-279° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].N1C=CN=C1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].O>CN(C=O)C>[C:11]([Si:14]([CH3:16])([CH3:15])[O:4][CH2:1][C:2]#[CH:3])([CH3:13])([CH3:12])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of propargyl alcohol (15 g, 267 mmol) in DMF (60 mL), imidazole (21.85 g, 321 mmol) was added at 0° C. followed by the slow addition of a solution of TBDMS-Cl (47.2 mL, 272 mmol) in DMF (70 mL). Resulting reaction mixture was stirred at 0° C. for 30 min and then at room temperature for overnight. On completion, water was added to the reaction mixture and the aqueous layer extracted with 20% ethyl acetate/hexane. The combined organic layers were dried over sodium sulfate and concentrated to obtain crude material which was purified by column chromatography over silica gel affording tert-butyldimethyl(prop-2-yn-1-yloxy)silane (45.5 g, 32.9%).
Reaction SMILES: C([C:3]1[C:7]2[CH:8]=[C:9]([O:12]C)[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:14]([OH:16])=[O:15])C.B(Br)(Br)Br>ClCCl>[OH:12][C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([C:14]([OH:16])=[O:15])=[CH:3][C:7]=2[CH:8]=1
Reactant: CCc1c(C(=O)O)oc2ccc(OC)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1cc2cc(O)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a stirred solution of ethyl 5-methoxybenzofuran-2-carboxylic acid (5.0 g, 26 mmol) in dichloromethane (CH2Cl2) (100 ml) at 0° C. was added boron tribromide (8.6 mL, 91 mmol) and the resulting dark solution was allowed to stir at room temperature for 2 hours. The reaction solution was poured over ice, stirred for 30 minutes and extracted with ethyl acetate (EtOAc). The organic phase was washed with water, saturated aqueous brine, dried over sodium sulfate, (Na2SO4), and concentrated in vacuo to afford 5-hydroxybenzofuran-2-carboxylic acid (4.0 g; m.p. 223°-228° C.).