Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[C:7]=2[CH:21]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[C:29]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[C:7]=2[CH:21]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2ccc(CN)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccc2c(c1)[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2
Reaction time: 2 h

Procedure:
To the compound of example 10 (0.57 g) and triethylamine (0.55 ml) stirred in dichloromethane (50 ml) was added acetyl chloride (0.154 ml) dropwise, at 0° C. After 2 h at 0° C., more acetyl chloride (0.154 ml) was added and the reaction mixture stirred for a further 16 h and allowed to attain room temperature. The organic phase was washed with water and brine and dried over anhydrous magnesium sulphate. Filtration and evaporation gave the crude product (0.33 g) which was recrystallised from ethyl acetate-dichloromethane to give the title compound (0.24 g) as colorless crystals of mp 206°-208° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CCc5ccccc54)CC3)nn2)n1

Procedure:
The object product (175 mg, 76%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (130 mg) obtained in Example 43(2), 2,3-dihydrospiro[indene-1,4′-piperidine] hydrochloride (180 mg) and potassium carbonate (110 mg).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:39][CH2:40][CH2:41]Cl)=[CH:34][CH:33]=1>CN(C=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:41][CH2:40][CH2:39][CH:38]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=3)[C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
N-Cyclopropyl-N-{1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide (34) was prepared by dissolving N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide (110.6 mg, 0.318 mmol) in 10 mL of DMF and followed by the addition of triethylamine (48.3 mg, 0.477 mmol) and bis(4-fluorophenyl)butyl chloride (98.2 mg, 0.350 mmol). The reaction mixture was stirred overnight at 85° C. The crude compound was purified by column chromatography on silica gel (hexane/EtOAc, 7:3) to give the title compound 34 as a yellow sticky solid. 1H NMR (CDCl3): δ 8.12 (s, 1H), 8.04 (d, 1H), 7.84 (d, 1H), 7.61 (t, 1H), 7.13 (dd, 4H), 6.94 t, 4H), 3.84 t, 2H), 2.85 (d, 2H), 2.30 (t, 2H), 1.92 (m, 7H), 1.48 (m, 2H), 1.37 (m, 2H), 0.96 (m, 2H), 0.75 (m, 2H). LC: 100%. MS (M+H+): 593.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:25]C(=O)C2C=CC=CC=2)[CH:6]=[C:7]([CH2:23][CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:2].[OH-].[K+].Cl>CO.O>[CH2:23]([C:7]1[CH:6]=[C:5]([OH:25])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:24]
Reactant: CCOC(COCCCCOc1c(CC)cc(OC(=O)c2ccccc2)cc1CC)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(COCCCCOc1c(CC)cc(O)cc1CC)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.5 %

Procedure:
To a solution of 31.0 g of 3,5-diethyl-1-benzoyloxy-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene dissolved in 100 ml of methanol was added a solution of 5.1 g of potassium hydroxide dissolved in 25 g of water. After stirring at room temperature for 1 hour, the reaction mixture was acidified by the addition of diluted hydrochloric acid, and concentrated. The residue was poured into water, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.60 g (yield, 94%) of 3,5-diethyl-4-(4-(2,2-diethoxyethoxy)butyloxy)phenol, nD25.0 1.4890.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=1>>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: COc1cc(Cl)ccc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Chloro-2-methoxy-benzoic acid. LC-MS (basic): tR=0.96 min; [M+H]+=496.0.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[C:16](=[S:18])=[S:17].Cl>CN(C=O)C.O>[CH3:9][C:6]1[CH:7]=[CH:8][C:2]2[S:17][C:16]([SH:18])=[N:4][C:3]=2[CH:5]=1
Reactant: S=C=S
Reactant: Cc1ccc(Cl)c(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2sc(S)nc2c1
Temperature: 150 °C
Yield: 27.3 %

Procedure:
To a suspension of 2-chloro-5-methyl aniline (9, 1.00 g, 7.06 mmol) and K2CO3 (2.80 g, 28.2 mmol) in DMF (20 mL) was added CS2 (0.50 mL, 8.50 mmol) under N2 at room temperature. The reaction mixture was heated at 150° C. for 16 h. After cooling, the reaction mixture was diluted with water (30 mL) and acidified with 1N HCl. The precipitate was collected by filtration, washed with water, and dried over P2O5 under vacuum to yield compound 10 (0.35 g, 27%).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[F:9][C:10]([F:23])([F:22])[C:11]([F:21])([F:20])[C:12]([F:19])([F:18])[C:13](OCC)=[O:14]>>[F:18][C:12]([F:19])([C:11]([F:20])([F:21])[C:10]([F:9])([F:22])[F:23])[C:13](=[O:14])[CH2:2][C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CCOC(=O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(=O)c1ccco1
Product: O=C(CC(=O)C(F)(F)C(F)(F)C(F)(F)F)c1ccco1

Procedure:
The compound was synthesized according to example 1 using 2-acetylfuran and ethyl heptafluorobutyrate as starting materials. 1H NMR (CDCl3): 6.54 (s, 1 H); 6.65 (dd, 1 H, J=1.6 & 3.6 Hz); 7.37 (dd, 1 H, J=0.6 & 3.6 Hz); 7.70 (dd, 1 H, J=0.6 & 1.6 Hz). IR (film): 1616 (C═O); 1231 (C—F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH:11]1([Mg]Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH:7]([C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[OH:8])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(C=O)cc1
Reactant: Br[Mg]C1CCCCC1
Product: COc1ccc(C(O)C2CCCCC2)cc1

Procedure:
Referring now to FIG. 2, this alternative synthesis starts from 4-methoxy-benzaldehyde (VI) which is subjected to treatment with cyclohexyl magnesium bromide to yield cyclohexyl-(4-methoxy-phenyl)-methanol (V). This in turn is then oxidised so as to yield cyclohexyl-(4-methoxy-phenyl)-methanone (III).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[H-].[Na+].[CH2:12]([N:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[C:21](Cl)[C:20]1=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([N:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([NH:1][C:2]2[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=2)[C:20]1=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1c(Cl)nc(Cl)cn1Cc1ccccc1
Reactant: Cc1cnc(N)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(Nc2nc(Cl)cn(Cc3ccccc3)c2=O)c(Br)c1
Temperature: 72 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
2-Amino-3-bromo-5-methyl-pyridine (1.0 g, 5.35 mmol) was added to a solution of sodium hydride (60%, 321 mg, 8.0 mmol) in dry THF (20 mL) at r.t. under nitrogen. After 30 minutes, 1-benzyl-3,5-dichloro-2(1H)-pyrazinone (see Vekemans, et. al., J. Heterocyclic Chem., 20, (1983), 919-923) (1.36 g, 5.35 mmol) was added, and the reaction stirred at 72° C. for 4 h. The solution was concentrated in vacuo and the residue was dissolved in CH2Cl2. Organics were washed with H2O and brine, dried (MgSO4), and concentrated. Purification by silica gel chromatography (2:1:1 hexanes/EtOAc/CH2Cl2) provided the title compound as a pale yellow solid (860 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.43 (s, 1H), 7.29-7.39 (m, 5H), 5.07 (s, 2H), 2.29 (s, 3H). MS (ES) [m+H] calc'd for C17H14BrClN4O, 405, 407; found 405, 407.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:26][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCCO3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCCC3CCCO3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a solution of N2-butyl-8-(methyloxy)-9-[4-(tetrahydro-2-furanyl)butyl]-9H-purine-2,6-diamine (75 mg, 0.207 mmol) in methanol (10 ml) at room temperature was added 4M HCl in 1,4-dioxane (1.324 ml, 5.30 mmol) to give a pale straw coloured solution. The reaction mixture was stirred at ambient temperature overnight (16 hours) when LCMS showed the reaction had not proceeded to completion. The solvent was removed overnight (16 hours) using a nitrogen blowdown unit when LCMS confirmed the presence of the desired product. This crude product was loaded in methanol onto a 5 g aminopropyl SPE cartridge and eluted with methanol over 20 mins. The appropriate fractions were combined and evaporated under a stream of nitrogen to give the title compound as a white powder (49 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: OC1CCCCC1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OC2CCCCC2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, cyclohexanol and DBU in DME. ES-MS m/e (%): 285 (M+H+, 75), 203 ([M—C6H10]+, 100).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=2)=[CH:3]1.[CH3:22][N:23]([CH3:29])[C@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:22][N:23]([CH3:29])[C@H:24]1[CH2:28][CH2:27][N:26]([C:16](=[O:17])[C:15]2[CH:20]=[CH:21][C:12]([CH2:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[CH:13][CH:14]=2)[CH2:25]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccccc23)cc1
Product: CN(C)[C@H]1CCN(C(=O)c2ccc(Cc3cn(C)c4ccccc34)cc2)C1

Procedure:
Using essentially the same procedure described in Example 228 and employing methyl 4-((1-methyl-1H-indol-3-yl)methyl)benzoate and (S)—N,N-dimethylpyrrolidin-3-amine as starting materials, the title compound is obtained as a white solid, mp 101-105° C., identified by H1 NMR and mass spectral analyses. MS (ES) m/z 362.2; MS (ES) m/z 723.4.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([CH2:15][CH2:16][CH3:17])[C:11](=[O:14])[CH2:12][CH3:13].C(O)(=O)C.[Br:22]Br>ClCCl>[Br:22][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH:2]([N:10]([CH2:15][CH2:16][CH3:17])[C:11](=[O:14])[CH2:12][CH3:13])[CH2:1]2)=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: CCCN(C(=O)CC)C1Cc2ccccc2C1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCN(C(=O)CC)C1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
N-Indan-2-yl-N-propyl-propionamide (Preparation 13, 1 g, 4.32 mmol) was dissolved in dichloromethane (100 mL). Glacial acetic acid was added to adjust the pH to 4. This was followed by the addition of bromine (0.4 ml, 7.78 mmol). The solution was stirred at room temperature for 8 h. Additional bromine (0.2 ml, 3.89 mmol) was added and the solution was refluxed for 18 h. Since the reaction was not complete another portion of bromine (0.2 ml, 3.89 mmol) was added and the reaction mixture was refluxed for another 4 h. The organic layer was extracted with aqueous Na2CO3 (10%) and the layers were separated. The organic layer was dried (MgSO4). The solvent was evaporated and the remaining crude product was chromatographed (SiO2) with n-hexane:ethyl acetate (4:1) as eluant. The pure fractions were pooled yielding 0.45 g (34%) of N-(6-Bromo-indan-2-yl)-N-propyl-propionamide. 1H NMR (300 MHz, CDCl3) δ 0.85 (t, 3H), 1.15 (t, 3H), 1.50-1.65 (m, 2H), 2.30-2.50 (m, 2H), 2.90-3.25 (m, 6H), 4.70-5.10 (m, 1H), 7.00-7.10 (t, 1H), 7.25-7.40 (m, 2); MS m/e 309 (1, M+), 116 (100), 115 (92), 194 (57), 196 (55).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH:6]([C:15](OC)=[O:16])[O:7][CH2:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH:6]([CH2:15][OH:16])[O:7][CH2:8]2
Reactant: COC(=O)C1Cc2c(OC)ccc(OC)c2CO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c1COC(CO)C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5,8-dimethoxy-3-methoxycarbonyl-isochroman (310 mg; 1.23 mmol) in 5 ml of tetrahydrofuran at 0° C. was added lithium aluminum hydride (47 mg; 1.23 mmol). The mixture was stirred at 0° C. for 15 minutes and was quenched with 1N HCl. The product was extracted with ether and the combined organic layers were washed with brine and dried over MgSO4 affording crude title alcohol (246 mg; 90%) used as such for subsequent steps:
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[NH:9])[CH2:3][CH3:4].[Na].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.Cl>C(O)C>[O:18]=[C:19]1[NH:10][C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:2][CH2:3][CH3:4])=[N:9][CH:26]=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCCOc1ccccc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Temperature: 0 °C
Yield: 96 %

Procedure:
2-n-Propoxybenzamidine hydrochloride (12.0 g., 0.0558 mole) was added to a stirred, cooled (ice-water) solution of sodium (2.57 g., 0.112 g-atom) in ethanol (50 ml.). To this cooled, stirred solution was added a solution of diethyl ethoxymethylenemalonate (12.1 g., 0.0558 mole) in ethanol (50 ml.) during 10 minutes. The mixture was heated under reflux for 2.5 hours. The cooled solution was poured onto ice and acidified with 6N hydrochloric acid. The precipitated ethyl 1,6-dihydro-6-oxo-2-(2-n-propoxyphenyl)pyrimidine-5-carboxylate (16.2 g., 96% yield) had m.p. 111°-113°. Two recrystallizations from cyclohexane gave title product with m.p. 112°-113°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][C:4]2[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([CH3:1])[CH:3]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CSc1ccc(O)cc1C
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CSc1ccc(Oc2ccnc(Cl)c2)cc1C
Reaction time: 3 h

Procedure:
A solution of 17 gm (0.1 mol) of 3-methyl-4-methylmercaptophenol and 15.9 gm (0.1 mol) of 2-chloro-4-nitropyridine in 150 ml of acetonitrile was mixed with 13.8 gm (0.1 mol) of K2CO3 and stirred for 3 hours under reflux. It was then cooled and poured into 300 ml of water. The oil which separated out was separated off and taken up in methylene chloride, and the solution was washed with dilute sodium hydroxide solution and with water. The organic solution was then dried over Na2SO4 and concentrated by evaporation. The oil which remained was crystallized from hexane.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:14][NH2:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1cnc2ccc(Br)cc2n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1cnc2ccc(Br)cc2n1
Temperature: 78 °C
Yield: 87 %

Procedure:
To the solution of 7-bromo-2-chloroquinoxaline (2 g, 8.2 mmol) in ethanol (20 mL) was added hydrazine hydrate (85%, 4.5 mL, 32.8 mmol). The mixture was heated to 78° C. for 2 h. After cooling to r.t., the precipitate was collected by filtration to afford 7-bromo-2-hydrazinylquinoxaline as white solid in 87% yield (1.7 g).
Reaction SMILES: C[O:2][C:3]([C:5]1([OH:28])[CH2:10][C@@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:8](=[CH2:19])[C@H:7]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:6]1)=O.C1COCC1>>[Si:12]([O:11][C@H:9]1[C:8](=[CH2:19])[C@H:7]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:6][C:5]([CH2:3][OH:2])([OH:28])[CH2:10]1)([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(C(=O)OC)C[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(CO)C[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 6 h

Procedure:
(i) To a stirred solution of the ester 3 (90 mg, 0.21 mmol) in anhydrous THF (8 mL) lithium aluminum hydride (60 mg, 1.6 mmol) was added at 0° C. under argon. The cooling bath was removed after 1 h and the stirring was continued at 6° C. for 12 h and at room temperature for 6 h. The excess of the reagent was decomposed with saturated aq. Na2SO4, and the mixture was extracted with ethyl acetate and ether, dried (MgSO4) and evaporated. Flash chromatography of the residue with hexane/ethyl acetate (9:1) afforded unreacted substrate (12 mg) and a pure, crystalline diol 4 (35 mg, 48% based on recovered ester 3): 1H NMR (CDCl3 +D2O) δ 0.079, 0.091, 0.100, and 0.121 (each 3H, each s, 4× SiCH3), 0.895 and 0.927 (9H and 9H, each s, 2× Si-t-Bu), 1.339 (1H, t, J~12 Hz), 1.510 (1H, dd, J=14.3, 2.7 Hz), 2.10 (2H, m), 3.29 and 3.40 (1H and 1H, each d, J=11.0 Hz), 4.66 (1H, t, J~2.8 Hz), 4.78 (1H, m), 4.92 (1H, t, J=1.7 Hz), 5.13 (1H, t, J=2.0 Hz); MS m/z (relative intensity) no M+, 345 (M+-t-Bu, 8), 327 (M+-t-Bu-H2O, 22), 213 (28), 195 (11), 73 (100).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH:19]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH:19]([N:32]1[CH2:37][CH2:36][N:35]([CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:34][CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)cc2)nc1
Yield: 24.1 %

Procedure:
Using a method similar to Example 334, using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.300 g, 1.24 mmol), 1-benzhydryl-piperazine (0.470 g, 1.86 mmol), and sodium borohydride (0.111 g, 2.93 mmol) in methanol (12 mL) after additional purification by reverse-phase HPLC, provides 0.143 g (24%) of the title compound as a yellow foam: high resolution mass spectrum (electrospray): m/z calc for C30H31N4O2 479.2447, found 479.2462; 1H NMR (methanol-d4): 8.65 (d, 1H, J=2.0 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.49-7.42 (m, 6H), 7.30 (t, 4H, J=7.8 Hz), 7.23-7.17 (m, 2H), 7.14 (d, 2H, J=8.8 Hz), 7.03 (d, 1H, J=8.8 Hz), 4.28 (s, 1H), 3.63 (s, 2H), 2.72-2.30 (m, 8H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=1)=[O:7].[CH2:28]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:28]([C:32]1[CH:33]=[CH:34][C:35]([NH:36][CH2:2][C:3]2[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=2)[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:37][CH:38]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc(CCl)c2)c2ccccc21
Reactant: CC(C)Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc(CNc3ccc(CC(C)C)cc3)c2)c2ccccc21
Temperature: 100 °C
Yield: 42.2 %

Procedure:
A mixture of ethyl 4-[3-[3-(chloromethyl)benzoyl]-indol-1-yl]butyrate (42.1 mg), 4-isobutylaniline (18.0 mg) and potassium carbonate (30.3 mg) in N,N-dimethylformamide (5 ml) was heated at 50° C. for 20 hours and at 100° C. for 2.5 hours. The mixture was worked up in an usual manner and purified by this layer silica gel chromatography eluting with a mixture of chloroform, hexane and ethyl acetate (6:2:1) to give ethyl 4-[3-[3-[(4-isobutylphenyl)aminomethyl]benzoyl]indol-1-yl]butyrate (23 mg) as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6]([P:8](=[O:11])([OH:10])[OH:9])=O>>[CH2:2]([NH:1][CH2:6][P:8]([OH:11])([OH:10])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: O=CP(=O)(O)O
Reactant: NCC(=O)O
Product: O=C(O)CNCP(=O)(O)O
Yield: 27 %

Procedure:
Reaction of glycine and formylphosphonic acid was carried out under the conditions described in Example 6 except that the initial pH was 4.0. A 27% yield of glyphosate was obtained.