Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:15]([CH3:17])[CH3:16])[CH2:5][CH2:6][NH:7][C:8](N1C=CN=C1)=[O:9])([CH3:3])[CH3:2].[NH2:18][CH2:19][C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[C@H:29]2[C@H:33]([OH:34])[C@H:32]([OH:35])[C@@H:31]([CH2:36][OH:37])[O:30]2)=[C:22]([NH:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:21]=1.C1(C)C=CC=CC=1.C(O)(C)C>ClCCl>[OH:34][C@@H:33]1[C@H:32]([OH:35])[C@@H:31]([CH2:36][OH:37])[O:30][C@H:29]1[N:26]1[CH:25]=[N:24][C:23]2[C:27]1=[N:28][C:20]([CH2:19][NH:18][C:8]([NH:7][CH2:6][CH2:5][N:4]([CH:15]([CH3:17])[CH3:16])[CH:1]([CH3:2])[CH3:3])=[O:9])=[N:21][C:22]=2[NH:38][CH2:39][CH:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)N(CCNC(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)C(C)C
Temperature: 25 °C
Yield: 26.5 %

Procedure:
N-[2-(Diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (84 mg, 0.35 mmol) (Preparation 27) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydro-3,4-furandiol (150 mg, 0.35 mmol) (Preparation 2) in dichloromethane (5 ml) at room temperature. The reaction was heated under reflux for 1 hour and then toluene (5 ml) and isopropanol (2 ml) were added. The dichloromethane was boiled off and the reaction was then heated under reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume increasing to 80:20:2 by volume). This gave the title compound as a foam (60 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[C:20]3[N:21]([CH2:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]4)[C:22]([N:24]4[CH2:29][CH2:28][O:27][C@@H:26]5[CH2:30][CH2:31][CH2:32][C@@H:25]45)=[N:23][C:19]=3[CH:18]=[C:17](Cl)[N:16]=2)=[CH:13][C:12]([Cl:42])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:44]([N:46](C)C)=O>[C-]#N.[Zn+2].[C-]#N.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.O>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[C:20]3[N:21]([CH2:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]4)[C:22]([N:24]4[CH2:29][CH2:28][O:27][C@@H:26]5[CH2:30][CH2:31][CH2:32][C@@H:25]45)=[N:23][C:19]=3[CH:18]=[C:17]([C:44]#[N:46])[N:16]=2)=[CH:13][C:12]([Cl:42])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cc(Cl)cnc4OCc4ccccc4)c32)CC1
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cc(Cl)cnc4OCc4ccccc4)c32)CC1
Temperature: 90 °C

Procedure:
4-[2-(benzyloxy)-5-chloropyridin-3-yl]-6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic, 450 mg, 0.74 mmol), zinc cyanide (43 mg, 0.37 mmol) and Pd(PPh3)4 (128 mg, 0.11 mmol) were placed in a dry vial. Degassed DMA (4 mL) was added to the reaction, and the reaction was placed under an atmosphere of Ar, sealed, and heated at 90° C. for 12 hours. The reaction was then cooled to room temperature, and cold water was added slowly. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue on a silica gel column (0 to 50% EtOAc/hexanes) afforded 4-[2-(benzyloxy)-5-chloropyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile as a racemic mixture. The enantiomers were separated on a chiral OD column using 2% IPA/98% heptanes. MS ES calc'd. for C34H37ClN6O2 [M+H]+ 597. found 597.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N+:15]([O-])=O>C1(C)C=CC=CC=1.[C].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH2:15]
Reactant: O=[N+]([O-])c1cc(OC2CCCC2)c(Cl)cc1F
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F

Procedure:
The resulting 2-fluoro-4-chloro-5-cyclopentyloxynitrobenzene (13.0 g, 50.1 mmol) was dissolved in toluene (100 ml), a catalytic amount of 10% palladium-carbon (0.5 g) was added thereto, and the mixture was reacted at room temperature to 70° C. under a hydrogen pressure of 3 to 5 arms. in a glass autoclave. After absorption of hydrogen gas ceased, the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure from the filtrate to obtain substantially quantitatively oily 2-fluoro-4-chloro-5-cyclopentyloxyaniline. The spectral data and the like are as described in Reference Example 1.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]3[O:10][C:11]4[C:12](=[C:14]([C:18]([O:20]C)=[O:19])[CH:15]=[CH:16][CH:17]=4)[N:13]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.O.[OH-].[Li+]>C1COCC1.O>[N:1]12[CH2:2][CH2:3][C:4]([C:9]3[O:10][C:11]4[C:12](=[C:14]([C:18]([OH:20])=[O:19])[CH:15]=[CH:16][CH:17]=4)[N:13]=3)([CH2:7][CH2:8]1)[CH2:5][CH2:6]2
Reactant: COC(=O)c1cccc2oc(C34CCN(CC3)CC4)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc2oc(C34CCN(CC3)CC4)nc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 108.8 %

Procedure:
A mixture of methyl 2-(quinuclidin-4-yl)benzoxazole-4-carboxylate (233 mg, 0.81 mmol), lithium hydroxide monohydrate (51 mg, 1.22 mmol) and THF/water (2:1, 15 mL) was stirred at room temperature for 6 h. The reaction mixture was concentrated, and washed with brine (10 mL), the precipitate which formed was filtered, washed with hexanes and dried to afford 2-(quinuclidin-4-yl)benzoxazole-4-carboxylic acid (240 mg, 108%) as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 7.80 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 2.83-2.81 (m, 6H), 1.89-1.84 (m, 6H); MS (ESI+) m/z 273 (M+H).
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[OH:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>C(O)C.[OH-].[Na+]>[OH:15][C:16]1[C:7](=[O:8])[C:4]2[C:3](=[CH:2][CH:1]=[CH:6][CH:5]=2)[O:18][C:17]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(CO)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1c(O)c(-c2ccccc2)oc2ccccc12

Procedure:
180 mg of 4'-vinyl, 4-biphenyl aldehyde was mixed with 0.3 ml of 2-hydroxyacetophenone in 30 ml of ethanol. In a separate flask, 2.0 gms of NaOH was dissolved in 10 ml of aq. ethyl alcohol (50%). An NaOH solution was slowly added to the aldehyde solution. The resulting solution slowly changed its color from green to yellow to dark red. The rest of the reaction was carried out according to the method described in Example 1(b) above, producing 4'styryl, 3-hydroxyflavone.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23]Cl)[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4].[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>CN(C)C=O>[CH2:27]([N:30]([CH2:31][CH2:32][CH3:33])[CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4])[CH2:28][CH3:29]
Reactant: O=C(CCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCl)cccc1C2=O
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)CC(=O)Nc1cccc2c1C(=O)c1c(NC(=O)CN(CCC)CCC)cccc1C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Add 0.4 g, 1.0 mmol 1,8-bis(chloroacetamido)anthraquinone (compound 3) with 0.5 ml TEA, and 0.7 ml, 6 mmole Dipropylamine, dissolved in 20 ml dehydrated dimethylformamide (DMF). The mixture is reacted in a mini-reactor. The reaction temperature is 120° C. in the oil bath and the reaction time is 30 minutes. The reacted mixture is poured into 50 ml ice water and is filtered to collect precipitate. The precipitate is recrystallized from ethanol to get yellow compound 3n.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11]([NH2:13])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[C:11]([CH2:10][N:9]([CH2:14][C:15]([F:16])([F:18])[F:17])[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:19]([F:21])([F:22])[F:20])[CH:5]=1)#[N:13]
Reactant: N#Cc1ccc(N(CC(N)=O)CC(F)(F)F)cc1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: N#CCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 87 °C
Yield: 54.3 %

Procedure:
A mixture of N2-[4-cyano-3-(trifluoromethyl)phenyl]-N2-(2,2,2-trifluoroethyl)glycinamide (0.060 g, 0.18 mmol), CCl4 (0.5 mL), DCE (4.5 mL) and polymer-supported triphenyl phosphine (3 mmol/g, 0.123 g, 0.36 mmol) was heated at 87° C. for 3 h. Upon cooling, the resin was filtered off, washed thoroughly with CHCl3 and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography (5-40% EtOAc-hexane gradient) and the product was crystallized from CH2Cl2-hexanes to give the title compound as a white solid (0.030 g, 55% yield): 1HNMR (400 MHz, CDCl3) δ 7.90 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.6 Hz, 1H), 7.09 (dd, J=8.6, 2.6 Hz, 1H), 4.38 (s, 2H), 4.06 (q, J=8.2 Hz, 2H); MS (ES) m/z 308 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C3CCCCC3)CC2)nc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 61.7 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 ml of 95:5 methanol-acetic acid was treated with excess cyclohexanone (1.30 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 48 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol afforded 0.34 g (62%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:15].[CH3:16]O>>[ClH:15].[C:1]1([C:7]2[CH:11]=[C:10]([C:12]([O:14][CH3:16])=[O:13])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]1
Agent: Cl
Product: COC(=O)c1cc(-c2ccccc2)n[nH]1

Procedure:
3-Phenyl-1H-pyrazole-5-carboxylic acid (4.96 g) was suspended in methanol (80 mL) and concentrated hydrochloric acid (22.0 mL) and the reaction mixture heated at reflux overnight. Upon cooling the title compound (3.00 g) precipitated from the reaction mixture, was filtered and dried under vacuum. The material was used without further purification having the following physical data.
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl[CH2:47][C:48]([N:50]([CH2:53][CH3:54])[CH2:51][CH3:52])=[O:49]>>[CH2:51]([N:50]([CH2:53][CH3:54])[C:48](=[O:49])[CH2:47][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:52]
Reactant: CCN(CC)C(=O)CCl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(CC)CC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 2-chloro-N,N-diethylacetamide as alkylating reagent in Step 1. The product was isolated as a white solid (20 mg, 39%). LCMS: m/e 643.50 (M+H)+, 2.35 min (method 11). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.99 (d, J=8.28 Hz, 2H), 7.24 (d, J=8.28 Hz, 2H), 5.31 (d, J=4.52 Hz, 1H), 4.74 (d, J=1.76 Hz, 1H), 4.60 (s, 1H), 3.58-3.21 (m, 6H), 2.82-2.69 (m, 1H), 2.22-1.02 (m, 28H), 1.72 (s, 3H), 1.18 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.95 (s, 6H).
Reaction SMILES: [O:1]1[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:19])[CH2:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=1>>[OH:19][CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][CH2:2][C:3]2([OH:1])[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:10]=1)[CH2:16][C:17]#[N:18]
Reactant: N#CCC(O)c1cccc(N)c1
Reactant: C1CCC2(C1)CO2
Product: N#CCC(O)c1cccc(NCC2(O)CCCC2)c1

Procedure:
Reaction between 1-oxaspiro[2.4]heptane and aniline 12 gives 3-hydroxy-3-(3-((1-hydroxycyclopentyl)methylamino)phenyl)propanenitrile.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[O:20][CH2:19][CH2:18][O:17]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][C:22](C)([O-])[CH3:23].[K+].C(I)C=C.OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH:1]1([CH:7]([CH2:23][CH:22]=[CH2:21])[C:8]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]3[O:17][CH2:18][CH2:19][O:20]3)=[CH:14][CH:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC1CCCCC1)c1ccc(C2OCCO2)cc1
Reactant: CC(C)(C)[O-]
Agent: C=CCI
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCC(C(=O)c1ccc(C2OCCO2)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
The product of Example J (1.6 g, 0.006 mole) was dissolved in 30 mls of dry DMF at room temperature under a nitrogen atmosphere and potassium t-butoxide (1.4 g) was added. After stirring for 5 minutes, 1 g of allyl iodide was added and the reaction was warmed to +50° C. for 1 hour. Another half equivalent of allyl iodide was added and the stirring was continued for 2 hours at +50° C. After cooling to room temperature the mixture was poured into 50 mls of 0.5N KHSO4 and extracted with ethyl acetate. After drying the organic layer over Na2SO4, the solvent was removed and the residue was chromatographed on silica gel using 10% ethyl acetate/hexane to give 1 g of the title compound (54% yield).
Reaction SMILES: [CH3:1][PH:2]([O-:17])([O-:16])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1.[CH2:24](P(C)([O-])([O-])[O-])CCCCCCCCCCC>>[O:22]=[C:21]1[CH2:20][CH:19]([CH2:1][P:2](=[O:16])([O:17][CH3:24])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:23]1
Reactant: CCCCCCCCCCCCP(C)([O-])([O-])[O-]
Reactant: C=C1CC(=O)O1
Reactant: CCCCCCCCCCCCO[PH](C)([O-])[O-]
Product: CCCCCCCCCCCCOP(=O)(CC1CC(=O)O1)OC
Temperature: 85 °C

Procedure:
A mixture of 13.2 parts of dodecyl methylphosphite, 4.2 parts of diketene and 0.6 parts of bis-(t-butylcyclohexyl)-perdicarbonate was added dropwise over 30 minutes to 39.6 parts of dodecylmethylphosphite which was vigorously stirred at 85° C. in a nitrogen atmosphere. On completion of the addition the reaction mixture was heated for a further 30 minutes at 85° C., then the excess of dodecylmethylphosphite was removed on a wiped wall still at a wall temperature of 80° C. and pressure 0.013 mb. The residue was distilled on a wiped wall still at a wall temperature of 150° C. and pressure 0.013 mb, and gave dodecyl methyl 2-oxo-4-oxetanylmethylphosphonate as a colourless oil which had the following analysis by weight:
Reaction SMILES: [I:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]([CH3:18])[CH:10](O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>ClC1C=CC=CC=1Cl>[I:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH3:18])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(NC(=O)c1ccc(I)cc1)C(O)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1cc2ccccc2c(-c2ccc(I)cc2)n1
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of amide 3c, 8.54 g, 22.4 mmol) and P2O5 (40 g) in o-dichlorobenzene (140 mL) was refluxed for overnight, then cooled to room temperature. It was cooled to 0° C. by application of an external ice-water bath. To this cooled mixture was cautiously added 200 mL of H2O. After the vigorous reaction had subsided, the dark solution was washed with toluene (2×40 mL). The aqueous layer was cooled to 0° C. and made to pH >11 with 50% aqueous NaOH. The resulting mixture was extracted with toluene (4×50 mL). The organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from benzene, thereby affording a white solid (6.1 g, 79%). mp 146.5-147.4° C. 1H NMR (CDCl3) d 2.72 (s, 3 H, CH3), 7.38-7.51 (m, 4 H, aromatic) 7.61 (t, J=6.9 Hz, 1 H, aromatic), 7.75 (d, J=8.1 Hz, 1 H, aromatic), 7.84 (d, J=8.1 Hz, 1 H, aromatic), 7.94 (d, J=8.7 Hz, 1 H, aromatic). 13C NMR (CDCl3) d 24.34 (q, CH3), 94.58 (s, =CI--, aromatic), 118.20 (d, aromatic), 124.56 (s, aromatic), 126.31 (d, aromatic), 126.42 (d, aromatic), 126.94 (d, aromatic), 129.96 (d, aromatic), 131.68 (d, aromatic), 137.41 (d, aromatic), 137.51 (s, aromatic), 139.12 (s, aromatic), 150.88 (s, aromatic), 158.97 (s, =CCH3 --, aromatic). Anal. Calcd for C16H12IN: C, 55.67; H, 3.50; N, 4.06. Found: C, 55.63; H, 3.55; N, 4.07.
Reaction SMILES: C[O-].[Na+].C(OP([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(OCC)=O)C.[CH2:18](/[C:20](=[CH:23]\[CH3:24])/[CH:21]=O)[CH3:19].O>CO.C1(C)C=CC=CC=1>[CH2:23](/[C:20](=[CH:18]\[CH3:19])/[CH:21]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:24]
Reactant: C/C=C(/C=O)CC
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: C/C=C(/C=C/C(=O)OCC)CC
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 12.7 kg (235 mol) of sodium methoxide and 48.0 kg (214 mol) of ethyl diethylphosphonoacetate in 40 l of methanol is added dropwise 20 kg (204 mol) of 2-ethylcrotonaldehyde at 20°-30° C. during 0.5 hour. After stirring for 2 hours at same temperature, the reaction mixture is poured into the solution of 180 l of water and 120 l of toluene. The toluene layer is separated and combined with 50 l toluene extract of aqueous phase, and washed with two 120 l portions of saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent is removed and the residue is distilled under reduced pressure to give ethyl (E,E)-4-ethyl-2,4-hexadienoate (Yield 28.5 kg) (83.1%), b.p. 41°-75° C./5-8 mmHg.
Reaction SMILES: CC1C=CC=CC=1O[CH:5]([C:12]([OH:14])=O)[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:38]1[CH:42]=[N:41][N:40]=[N:39]1.N(C(OCC)=O)=N[C:45](OCC)=O>O1CCCC1.C(Cl)(Cl)Cl>[N:38]1[N:39]([CH:5]2[CH2:6][CH:7]([C:9]([O:11][CH3:45])=[O:10])[NH:8][C:12]2=[O:14])[N:40]=[N:41][CH:42]=1
Reactant: Cc1ccccc1OC(C[C@H](N)C(=O)O)C(=O)O
Reactant: c1nnn[nH]1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)C1CC(n2ncnn2)C(=O)N1
Temperature: 25 °C

Procedure:
A mixture of the compound prepared as described in Example 4 (318 mg), triphenylphosphine (577 mg), and tetrazole (155 mg) in dry tetrahydrofuran (4.5 ml) was cooled in an ice/water bath, and treated with diethyl azodicarboxylate (383 mg) over a ten minute period. After the addition was complete, the reaction was allowed to warm to room temperature. After about 171/2 hours, the reaction solution was concentrated in vacuo to give a greasy crystalline mass. This material was diluted with chloroform (10 ml) and concentrated in vacuo. This procedure was repeated to remove traces of tetrahydrofuran. The residue was dissolved in chloroform (10 ml) and purified by centrifugal thin-layer chromatography, eluting with ethyl acetate/hexane (1:1) followed by ethyl acetate/hexane (9:1), ethyl acetate, ethyl acetate/methanol (9:1), and ethyl acetate/methanol (4:1). The first isomer to elute was the tetrazol-2-yl compound, and the second isomer to elute was the tetrazol-1-yl compound. Fractions containing each of these isomers in pure form were pooled and concentrated in vacuo. The residue was triturated in methylene chloride (3 ml), and the title compounds isolated by filtration to give 46 mg of the tetrazol-2-yl compound and 227 mg of the tetrazol-1-yl compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][S:10]([CH3:9])(=[O:12])=[O:11])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(O)c1
Temperature: 10 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
2 g (18.33 mmol) of 3-aminophenol were dissolved in 6 ml of pyridine with magnetic stirring, the mixture was cooled to 10° C. and then 1.8 ml (23.26 mmol) of methanesulfonyl chloride were added. The cold bath was withdrawn and the mixture was stirred at r.t. for 18 h before being diluted with 100 ml of a saturated NaCl aqueous solution. The aqueous phase was extracted with 100 ml of ethyl acetate. The organic phase was washed with 50 ml of a saturated NaHCO3 aqueous solution, extracted with 50 ml of an aqueous solution of NaOH (0.5 N). The basic aqueous phase was washed with 2×100 ml of ethyl acetate and then acidified down to pH 2-3 by adding a 1N HCl aqueous solution. The acidified aqueous phase was extracted with 2×100 ml of ethyl acetate. The combined organic phases were washed with 100 ml of a saturated NaCl aqueous solution and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. 3.3 g (yield=80%) of N-(3-hydroxyphenyl)methanesulfonamide were obtained as an oil. LC-MS: m/z=186 (M-H+); UV purity at 254 nm=81%.