Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.C([O:8][CH:9]([CH2:22][Cl:23])[C:10]1[CH:15]=[C:14]([S:16](=[O:19])(=[O:18])[NH2:17])[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])(=O)C>CO>[Cl:23][CH2:22][CH:9]([C:10]1[CH:15]=[C:14]([S:16](=[O:19])(=[O:18])[NH2:17])[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])[OH:8]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(CCl)OC(C)=O
Solvent: CC(=O)Cl
Solvent: CO
Product: COc1ccc(S(N)(=O)=O)cc1C(O)CCl
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
61 μl of acetyl chloride are added to 100 ml of methanol and the mixture is stirred for 15 minutes. 1.32 g (−)-α-chloromethyl-2-methoxy-5-sulphamoylbenzyl acetate are then added and the mixture is heated to reflux for 1 hour (degree of conversion of 97% shown by HPLC). The mixture is thereafter evaporated, the residue is then taken up in 100 ml of ethyl acetate and the medium is neutralized with 5 ml of 2% ethyl hydrogen carbonate. The carbonate phase is extracted with 2 times 5 ml of ethyl acetate, the organic phases are then combined, dried and concentrated to 30 ml and cyclohexane is added. After one night at room temperature, the product which has crystallized is filtered off. 1 g of (−)-α-chloromethyl-2-methoxy-5-sulphamoylbenzenemethanol is obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[CH2:23][CH2:22][C:21]([CH3:26])([CH3:25])[CH2:20][C:19]=4[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[CH2:23][CH2:22][C:21]([CH3:25])([CH3:26])[CH2:20][C:19]=4[N:18]([CH3:27])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CCC(C)(C)C4)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4c3CCC(C)(C)C4)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
To a solution of N-isopropyl-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 181 μmol) in dichloromethane (3 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol). The reaction mixture was stirred at 25° C. for 18 h then concentrated. The residue was re-dissolved in 5 mL of a solution of dichloromethane/MeOH/ammonium hydroxide (60:10:1) and stirred at 25° C. for 3 h, then evaporated and purified by chromatography (40 g, 50 μm particle size, Analogix, 0 to 5% MeOH containing 10% ammonium hydroxide in dichloromethane, 15 min gradient). The pure product was suspended in dichloromethane and cyclohexane added to promote solid formation. The solid was separated by decanting the mother liquors and then dried to give N-isopropyl-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (54 mg, 147 μmol, 81.3%) as a white solid. MS (M+H)+=367; 1H NMR (300 MHz, DMSO-d6) δ ppm 12.68 (m, 1H), 8.91 (s, 1H), 8.31 (s, 1H), 8.04 (d, J=8.31 Hz, 1H), 4.17-4.26 (m, 1H), 3.75 (s, 3H), 2.92 (t, J=6.42 Hz, 2H), 1.52 (t, J=6.42 Hz, 2H), 1.37 (s, 2H), 1.22 (d, J=6.42 Hz, 6H), 1.01 (s, 6H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.[NH2:32][C:33]1[CH:41]=[CH:40][C:39]([I:42])=[CH:38][C:34]=1[C:35](O)=[O:36].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:32][C:33]1[CH:41]=[CH:40][C:39]([I:42])=[CH:38][C:34]=1[C:35]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)=[O:36]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(CNC(=O)c2cc(I)ccc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a stirred solution of 15 g (74.4 mmol) of methyl 4-(aminomethyl)benzoate hydrochloride, 300 ml of dimethylformamide and 10.3 ml (7.53 g, 74.4 mmol) of triethylamine were added, at room temperature, followed by 10.06 g (74.4 mmol) of 1-hydroxybenzotriazole hydrate, 19.6 g (74.4 mmol) of 2-amino-5-iodobenzoic acid and 14.3 g (74.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride. After stirring at room temperature overnight, the mixture was concentrated and the residue was dissolved in 300 ml of dichloromethane. The organic phase was washed with 150 ml H2O, 150 ml HCl 1N, and 150 ml H2O, dried over sodium sulfate and concentrated. The residue was recrystallized from 170 ml acetonitrile to afford after filtration 19.6 g of the desired product (yield: 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(O)c(Cl)c1

Procedure:
46.2 g (0.273 mol) of 3-chloro-4-hydroxy-benzaldehyde, 104 g (1 mol) of malonic acid, 140 ml of pyridine and 4 ml of piperidine are heated to 100° C for 2 hours, whilst stirring. The volatile constituents are distilled off under reduced pressure at 80° C and the residue is stirred with 800 ml of water. The resulting crystals are filtered off and recrystallised from methanol-water. 3-Chloro-4-hydroxy-cinnamic acid of melting point 180°-182° C is obtained.
Reaction SMILES: Cl.[S:2]([CH2:5][C:6]([CH2:8][S:9][C:10]#[N:11])=O)[C:3]#[N:4].C[OH:13]>>[S:2]([CH2:5][C:6]1[NH:11][C:10](=[O:13])[S:9][CH:8]=1)[C:3]#[N:4]
Reactant: N#CSCC(=O)CSC#N
Reactant: CO
Agent: Cl
Product: N#CSCc1csc(=O)[nH]1
Reaction time: 4 h
Yield: 48.3 %

Procedure:
After absorbing 7.3 g (0.20 mol) of gaseous hydrogen chloride in 100 ml of anhydrous methanol, 17.22 g (0.10 mol) of 1,3-bis(thiocyanato)-acetone are added and the mixture is stirred at 45° to 50° C. for 4 hours. Then, the reaction mixture is evaporated under reduced pressure until a crystalline precipitate begins to separate. After cooling down the residue, the precipitate is filtered off. After washing with methanol and drying, 8.3 g (48.3%) of the named compound are obtained with the same quality characteristics as described in Example (1a). The active ingredient content of the substance obtained is 99.0%.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:19][CH:18]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][N:31]([CH3:33])[CH3:32])([OH:34])[C:5]2[C:4]([C:3]([NH:2][CH3:1])=[O:10])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:19][CH:18]=1
Reactant: CN(C)Cc1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: CNC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1ccccc1C(O)(c1ccc(Cl)cc1)c1ccccc1CN(C)C
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 19.7 g (0.146 mole) of N-methyl benzamide and 400 ml. dry tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5°C. Stirring is initiated and 204 ml. of 1.6 M. n-butyl lithium (~0.321 mole) in hexane is added dropwise over about 1 hour maintaining the temperature below 8°C. The resulting dilithio salt is stirred at 5°C. for an additional hour and then a solution of 40 g. (0.146 mole) of 4'-chloro-2-dimethylaminomethyl benzophenone in 500 ml. tetrahydrofuran is added dropwise over about 1 hour maintaining the temperature between -10 to 10°C. The resulting mixture is stirred at 5°C. for 1 hour longer and 150 ml. of saturated ammonium chloride is added maintaining the temperature at about 10°C. The layers are separated and the organic phase dried over ahydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is crystallized from ether to give α-(4-chlorophenyl)-α-(2-dimethylaminomethyl phenyl)-α-hydroxy-N-methyl-o-toluamide; m.p. 154°-156°C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([O-:21])=[O:20])=[C:6]([CH2:9][N+:10]3[N:11]([CH3:18])[CH:12]=[C:13]([NH:15][CH:16]=[O:17])[CH:14]=3)[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(=O)C.[NH2:32][C:33]1[S:37][N:36]=[C:35](/[C:38](=[N:46]/[O:47][CH2:48][C:49]([OH:51])=[O:50])/[C:39](OS(C)(=O)=O)=[O:40])[N:34]=1.C(OC(C)C)(C)C>O1CCCC1>[NH2:32][C:33]1[S:37][N:36]=[C:35]([C:38](=[N:46][O:47][CH2:48][C:49]([OH:51])=[O:50])[C:39]([NH:1][C@@H:2]2[C:22](=[O:23])[N:4]3[C:5]([C:19]([O-:21])=[O:20])=[C:6]([CH2:9][N+:10]4[N:11]([CH3:18])[CH:12]=[C:13]([NH:15][CH:16]=[O:17])[CH:14]=4)[CH2:7][S:8][C@H:3]23)=[O:40])[N:34]=1
Reactant: CS(=O)(=O)OC(=O)/C(=N\OCC(=O)O)c1nsc(N)n1
Reactant: Cn1cc(NC=O)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)N[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: Cn1cc(NC=O)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a solution of di(trifluoroacetic acid) salt of 7β-amino-3-(4-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (4.0 g) and N-(trimethylsilyl)acetamide (9.29 g) in tetrahydrofuran (60 ml) was added methanesulfonyl (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetate (2.07 g) under ice-cooling. The mixture was stirred for 1 hour at ambient temperature and then the resulting mixture was added dropwise to diisopropyl ether. Thus produced precipitate was collected by filtration, dissolved in water and then subjected to column chromatography on macroporous non-ionic adsorption resin, Diaion HP-20 (Trademark: manufactured by Mitsubishi Chemical Industries). The desired product was eluted with 10% aqueous isopropyl alcohol solution, and then lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3- (4-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer 0.714 g).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N:14]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:21][CH2:20][CH2:19][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[S:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: NCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Product: O=[N+]([O-])c1ccc2nc(NCCN3CCCC3)sc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
A mixture of 2-chloro-6-nitrobenzothiazole (250 mg, 1.16 mmol) and 2-pyrrolidin-1-yl-ethylamine (0.59 mL, 4.66 mmol) was heated at 100° C. for 4 hours then at 60° C. for 16 hours. After this time, the reaction mixture was filtered and the precipitate was washed with 2×5 mL of H2O. The solid was subjected to silica gel column chromatography (7.5% MeOH:92.5% CH2Cl2) to give the title compound as a yellow residue. Yield: 20.6%, 1H-NMR (DMSO-d6): δ 8.80 (br s, 1H); 8.70 (d, 1H, J=2.4 Hz); 8.11 (dd, 1H, J=6.8, 2.4 Hz); 7.47 (d, 1H, J=8.8 Hz); 3.58 (m, 2H); 2.60 (m, 6H); 1.73 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:15]2[O:14][C:13]3[CH:16]=[CH:17][C:18]([C:22](=[CH2:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[C:19]([O:20][CH3:21])[C:12]=3[C:11](=[O:28])[O:10][CH2:9][C:8]=2[CH:7]=[C:6]([CH3:29])[CH:5]=1)[CH3:2].[OH-:30].[Na+].OO>CCCCCC.O1CCCC1.C(O)C>[CH2:1]([O:3][C:4]1[C:15]2[O:14][C:13]3[CH:16]=[CH:17][C:18]([CH:22]([CH2:27][OH:30])[CH2:23][CH:24]([CH3:25])[CH3:26])=[C:19]([O:20][CH3:21])[C:12]=3[C:11](=[O:28])[O:10][CH2:9][C:8]=2[CH:7]=[C:6]([CH3:29])[CH:5]=1)[CH3:2]
Reactant: [OH-]
Reactant: C=C(CC(C)C)c1ccc2c(c1OC)C(=O)OCc1cc(C)cc(OCC)c1O2
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1cc(C)cc2c1Oc1ccc(C(CO)CC(C)C)c(OC)c1C(=O)OC2
Reaction time: 14 h

Procedure:
2 ml (1 mmol) of a 0.5 M 9-borabicyclo-3.3.1-nonane solution in hexane are added dropwise under argon to a solution of 130 mg (0.33 mmol) of the compound from Example 148 in 4 ml of absolute tetrahydrofuran. After 14 h at room temperature, a few drops of ethanol, 2 ml of 2 N sodium hydroxide solution and 0.5 ml of 30% strength hydrogen peroxide solution are added. The mixture is stirred vigorously for 3 h and then concentrated carefully and the residue is taken up in dichloromethane. The solution is washed with water, and the organic phase is dried over magnesium sulphate and concentrated, and the residue is purified by column chromatography on silica gel using petroleum ether/ethyl acetate 6:1.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:22])=[CH:17][C:3]=1[NH:4][C:5](=[O:16])[CH:6](Cl)[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[K].[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:22])=[CH:17][C:3]=1[NH:4][C:5](=[O:16])[CH:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:43]1[C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]2[C:39]1=[O:49]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)C(Cl)C(=O)c2ccccc2)c1
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)C(C(=O)c2ccccc2)N2C(=O)c3ccccc3C2=O)c1

Procedure:
A mixture of 16.3 g of 2'-chloro-5'-tetradecyloxycarbonylchloro-benzoylacetanilide and 18.5 g of phthalimide potassium was stirred in 300 ml of dimethylformamide for 3 hours at room temperature. The reaction product thus obtained was treated as in Synthesis example 1. Upon recrystallizing the product from methanol, 12 g of Coupler 6 having a melting point of 81°-82° C. was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][N:3]=1.[OH:15][C:16]1[CH:17]=[C:18]2[C:22](=[N:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[NH:21]1[C:22]2[C:18](=[CH:17][C:16]([O:15][C:2]3[C:11]4[C:6](=[CH:7][C:8]5[O:14][CH2:13][O:12][C:9]=5[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:24][N:23]=2)[CH:19]=[CH:20]1
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: Clc1ncnc2cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: c1nc(Oc2cnc3[nH]ccc3c2)c2cc3c(cc2n1)OCO3
Temperature: 85 °C
Yield: 62.6 %

Procedure:
8-Chloro[1,3]dioxolo[4,5-g]quinazoline (100 mg, 0.48 mmol), (WO 9749688), was dissolved in dimethylacetamide (2.5 ml). 5-Hydroxy-7-azaindole (71 mg, 0.53 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (73 mg, 0.53 mmol) were added and the mixture heated to 85° C. for 3 hours. The reaction mixture was cooled, filtered and concentrated. The resulting residue was purified by column chromatography eluting with methylene chloride/methanol (91/9) to yield 4-(7-azaindol-5-yloxy)-6,7-methylenedioxyquinazoline (92 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17]C)=[O:16])=[C:12]([CH3:22])[N:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:9]=2)=[C:4]([O:29]C)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([OH:17])=[O:16])=[C:12]([CH3:22])[N:11]=[C:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:9]=2)=[C:4]([OH:29])[CH:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 1.5 %

Procedure:
To a cooled (−78° C.) stirred solution of methyl 2-(4-(4-chloro-2-methoxyphenyl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.125 mg; 0.294 mmol) in dichloromethane (1.5 mL) was added a solution of boron tribromide (1M in dichloromethane) (0.340 mL; 0.340 mmol) dropwise. After 1 h the mixture was allowed to warm up to room temperature and the reaction was stirred for 16 h. The reaction was quenched by adding water and the mixture was extracted with ethyl acetate, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purifications by flash-chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane and by preparative TLC on silica gel using a mixture methanol-dichloromethane (5:95) as eluent furnished 0.0018 g (1.5%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cccc(C=O)c1OCc1ccccc1
Reactant: Br[Mg]c1ccccc1
Product: CC(C)(C)c1cccc(C(O)c2ccccc2)c1OCc1ccccc1
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of 2-(benzyloxy)-3-tert-butylbenzaldehyde (5.4 g, 20 mmol) was stirred under nitrogen on an ice bath and 1M phenyl magnesium bromide (30 mL, 1.5 equiv) was added at such a rate that temperature did not exceed 7° C. Stirring was continued at room temperature for 2 hr. The reaction mixture was cooled on an ice bath and quenched with saturated ammonium chloride (50 mL). The resulting mixture was partitioned between water (25 mL) and 1:1 ethyl acetate/heptane (150 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate and the solvent was removed in a rotary evaporator. The crude product (7.3 g) was purified by chromatography on silica (75 g) with heptane (0.5 L) and 2.5% ethyl acetate in heptane (2 L) to produce 13 (5.4 g, 78%) as a pale yellow oil.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]=2[CH2:24][CH3:25])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:28])=O.C(=O)([O-])O.[Na+].O>C1(C)C=CC=CC=1>[Cl:28][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[O:11][C:10]=1[CH2:24][CH3:25]
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Cl)C1CCCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl {2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (705 mg) in toluene (10 mL) was added thionyl chloride (290 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled, neutralized with saturated aqueous sodium hydrogen carbonate, and poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (742 mg, 100%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[NH2:8].[C:20]1(C)[CH:25]=CC=[CH:22][CH:21]=1>O>[CH2:16]([NH:15][C:3]1[C:2]2[C:7](=[N:8][C:20]([CH3:25])=[C:21]([CH3:22])[N:1]=2)[N:6]=[C:5]([CH3:9])[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNc1c(N)c(N)nc(C)c1C(=O)OCC
Reactant: Cc1ccccc1
Solvent: O
Product: CCCCNc1c(C(=O)OCC)c(C)nc2nc(C)c(C)nc12
Reaction time: 5 h

Procedure:
26.6 g. of 5,6-Diamino-4-butylamino-2-methylpyridine-3-carboxylic acid, ethyl ester (0.1 Mol) are dissolved in 150 ml. of toluene. 9 g. of diacetyl are added and the mixture is refluxed while the water formed is removed by a water separator. After about 5 hours, the theoretical amount of water is separated and the solution is evaporated to dryness. The dark oily residue is extracted twice with 100 ml. portions of gasoline and addition of activated charcoal. The gasoline extracts are combined and concentrated to about 100 ml. 8-Butylamino-2,3,6-trimethylprido[2,3-b]pyrazine-7-carboxylic acid, ethyl ester crystallizes on cooling, yield 21 g. (66%); m.p. 97°-99°.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:51][OH:52])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:51]=[O:52])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Yield: 86.4 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol 19a (3.48 g, 4.8 mmol, purchased from Shanghai Caerulum Pharma Discovery Co., Ltd.) in dichloromethane (100 mL) was added 2-iodoxybenzoic acid (2.68 g, 9.6 mmol) at room temperature. The mixture was refluxed for 16 hours and filtered. The filtrate was partitioned and the organic layer was adjusted with saturated aqueous sodium bicarbonate to pH 7. The mixture was extracted with dichloromethane (250 mL×2). The combined organic layers were washed with water (100 mL×2) and saturated brine (100 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 19b as yellow oil (3 g, 86.4%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ(ppm): 9.79 (s, 1H), 7.50 (m, 3H), 7.25 (m, 13H), 7.02 (d, 1H), 6.95 (m, 1H), 6.87 (d, 1H), 6.81 (m, 2H), 4.71 (m, 4H), 4.29 (m, 1H), 4.17 (m, 1H), 4.00 (m, 5H), 3.75 (m, 3H), 3.41 (m, 1H), 1.29 (t, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[CH:19](=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:19]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: CCCCCCC=O
Solvent: CCO
Product: CCCCCCCNCCc1ccc(OC(C)(C)C(=O)OCC)cc1
Yield: 100.7 %

Procedure:
The product from step (c) (1.5 g) and heptaldehyde (0.7 g) were mixed together in a observably exothermic reaction and the product dissolved in absolute ethanol (100 ml). Paar hydrogenation for 1.0 hour resulted in a drop in bottle pressure from 49.0 to 42.7 psi. The Pd/C was removed by filtration and the filtrate evaporated in vacuo to give the desired product as a colourless oil (2.1 g).