Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([CH3:12])=[CH:4][C:3]=1[CH3:13].[CH3:14][O-:15].[Na+]>CO.N1C=CC=CC=1>[N+:9]([C:6]1[C:7]([CH3:8])=[C:2]([O:15][CH3:14])[C:3]([CH3:13])=[CH:4][C:5]=1[CH3:12])([O-:11])=[O:10]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COc1c(C)cc(C)c([N+](=O)[O-])c1C
Temperature: 85 °C
Reaction time: 16 h
Yield: 53.8 %

Procedure:
To a solution of 2-bromo-4-nitro-1,3,5-trimethylbenzene (2.0 g, 8.19 mmol) in methanol (20 mL) and pyridine (1.0 mL) under nitrogen was added sodium methoxide (6.2 mL, 32.8 mmol, 30% in methanol), and cuprous chloride (1.62 g, 16.4 mmol). The reaction mixture was heated to 85° C. After 16 hours, it was allowed to cool to room temperature. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate (2×80 mL). The organic phases were combined and washed with saturated aqueous NaCl (2×) and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 3-nitro-2,4,6-trimethyl-1-methoxybenzene (0.86 g, 54%) was obtained as a light-yellow liquid.
Reaction SMILES: C(O)(=O)C.[CH:5]1([CH:8]=O)[CH2:7][CH2:6]1.[NH2:10][C:11]1[C:16]([NH2:17])=[CH:15][C:14]([Br:18])=[CH:13][N:12]=1.[BH4-].[Na+]>ClCCl>[Br:18][C:14]1[CH:15]=[C:16]([NH:17][CH2:8][CH:5]2[CH2:7][CH2:6]2)[C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: O=CC1CC1
Reactant: Nc1cc(Br)cnc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1NCC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic acid (304 μl) and cyclopropanecarbaldehyde (406 μl) were added to a solution of 2,3-diamino-5-bromopyridine (1000 mg) in dichloromethane (25 ml) at room temperature, followed by stirring for 1 hour. Sodium tetrahydroborate (604 mg) was added to the reaction solution under ice-cooling, and the mixture was stirred with warming to room temperature for 22 hours. The reaction solution was extracted by adding a saturated aqueous sodium bicarbonate solution and dichloromethane. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound (286 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][C@@H:16]4[CH:28](C(O)=O)[C:29]([OH:31])=[O:30])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>COCCOCCOC>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][C@@H:16]4[CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@@H](C(C(=O)O)C(=O)O)CC2=O
Solvent: O
Solvent: COCCOCCOC
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@@H](CC(=O)O)CC2=O
Temperature: 162 °C

Procedure:
A solution of 297 mg (0.642 mmol) of 62 crude in 10 mL of 2-methoxyethyl ether was stirred and heated at 162° C. for 15 min. The reaction mixture was allowed to cool to rt, poured into H2O (100 mL) and extracted with EtOAc (3×, 70 mL). Combined organic extracts were washed with 10% Na2S2O5 and concentrated in vacuo giving a yellow oil which was used without purification in the next step. Data for 63: TLC, T-3, Rf 0.58; 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 3H, H-18), 5.04 (s, 2H, benzylic-H), 6.72 (d, 1H, J=2.6 Hz, H-4), 6.81 (dd, 1H, J=8.5, 2.6 Hz, H-2), 7.22 (d, 1H, J=8.5 Hz, H-1), 7.30–7.45 (m, 5H, Ar—H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)C(O)=O.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1.C(O)(C)(C)C.Cl>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CSc1ccc(C=C(C(=O)O)c2ccccc2C)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1ccc(CC(=O)c2ccccc2C)cc1
Temperature: 0 °C
Yield: 273.1 %

Procedure:
A solution of the acid from Step 1 (8.29 g, 9.2 mmol) and triethylamine (3.46 g, 34.2 mmol) dissolved in 30 mL of anhydrous toluene, was cooled to 0° C. and treated with diphenylphosphoryl azide (8.23 g, 9.9 mmol). The solution was maintained at 0° C. for 45 minutes and warmed to room temperature for 3.75 hours. The reaction was poured into water, extracted with ether, dried over magnesium sulfate, and concentrated in vacuo to remove the ether. The remaining toluene solution was heated to 110° C. for 1 hour. Tert-Butyl alcohol (6 mL, 63 mmol) was added to the reaction mixture, after an additional twenty minutes, concentrated hydrochloric acid (2.6 mL) was cautiously added and the reaction maintained at 90° C. overnight (16 hours). After cooling the solution to room temperature, the mixture was concentrated in vacuo and the residue taken up in ethyl acetate, washed successively with water, sat. aq. NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a yellow solid (6.44 g, 86%): mp 54°-61° C. 1H NMR (CDCl3) 300 MHz 7.69 (d, J=7.7 Hz, 1H), 7.36 (m, 1H), 7.20-7.26 (m, 4H), 7.16 (d, J=8.5 Hz, 2H), 4.17 (s, 2H), 2.46 (s, 3H), 2.44 (s, 3H). Mass spectrum M+H=257.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:2].C[Si]([N:22]=[N+:23]=[N-:24])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:8][C:5]1([CH3:9])[N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([CH3:17])([C:1]2[N:22]=[N:23][NH:24][N:2]=2)[CH2:7][O:6]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C(C)(C#N)COC1(C)C
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(C)(C)OCC1(C)c1nn[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
A mixture of 317 mg of tert-butyl 4-cyano-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate, 307 mg of trimethylsilyl azide, 67 mg of dibutyltin oxide, and 10 ml of toluene was stirred for 8 hours under heating to reflux. The reaction mixture was left to be cooled to room temperature and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 168 mg of tert-butyl 2,2,4-trimethyl-4-(2H-tetrazol-5-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[N:25]1([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Fc1ccc2nnc(N3CCCCCC3)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCCCC4)n3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 55.2 %

Procedure:
To a solution of Intermediate A (137 mg, 0.84 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 68 mg, 1.7 mmol) and the mixture stirred at RT for 25 min. A solution of Intermediate 67a (197 mg, 0.84 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.25 h. The cooled mixture was diluted with water and extracted with DCM (5×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (175 mg, 55%). LCMS (Method 3): Rt 2.22 min, m/z 378 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.CC(C1C=CC=CC=1)=C.[OH-].[Na+]>[C].[Pd].O>[C:2]1([OH:1])[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2=CCC(O)CC2)cc1
Agent: [Pd]
Agent: C=C(C)c1ccccc1
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-c2ccc(O)cc2)cc1
Yield: 99.4 %

Procedure:
A 300-ml stainless steel autoclave was charged with 38.0 g (0.20 mole) of 4-(4-hydroxyphenyl)-3-cyclohexene-1-ol, 1.5 g of 5% palladium-carbon, 70.9 g (0.60 mole) of α-methylstyrene and 100 g of water, and the internal atmosphere was replaced with nitrogen. The mixture was heated and reacted at 200° C. for 3 hours. The reaction mass was poured into a large volume of an aqueous sodium hydroxide solution, and the insoluble catalyst was removed by filtration. The organic layer was removed from the filtrate. The rest of the filtrate was neutralized to pH 4 by adding an aqueous hydrochloric acid solution. The separated crystals were filtered, washed with water and dried to obtain 37.0 g of 4,4'-biphenol as white crystals. The product had a purity of 98.0% and the yield was 97.4% based on 4-(4-hydroxyphenyl)-3-cyclohexene-1-ol.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28]C)=[O:27])[CH2:15]1.CCN(C(C)C)C(C)C.[OH-].[K+].Cl>CO.C1COCC1>[CH2:5]([O:4][C:2]([NH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:16]([C:26]([OH:28])=[O:27])[CH2:15]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.1 %

Procedure:
Step (a) Benzyl chloroformate (1.40 mL, 9.79 mmol) was added to a flask charged with (2S,4R)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate hydrochloride salt (2.5 g, 8.9 mmol), DIEA (5.0 mL, 29 mmol), and THF (20 mL). The mixture was stirred for 5 minutes at ambient temperature and then quenched with saturated sodium bicarbonate (aq., 20 mL). The mixture was extracted with methylene chloride (40 mL) and the extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was diluted with methanol (30 mL) and 2N potassium hydroxide (10 mL, 20 mmol) and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture then was concentrated to approximately one-half the volume and quenched with cold 1N hydrochloric acid (30 mL, 30 mmol). The mixture was extracted with methylene chloride (30 mL) and the extract dried over anhydrous sodium sulfate, filtered and concentrated to give (2S,4R)-4-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2.51 g, 6.86 mmol) as a white solid.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CCCC.Cl[C:22]1[N:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=1>>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:22]2[N:23]=[N:24][C:25]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:13][CH:14]=3)=[CH:26][CH:27]=2)=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCOc1ccc(B(O)O)cn1
Reactant: Clc1ccc(Cl)nn1
Product: CCCCCCOc1ccc(-c2ccc(-c3ccc(OCCCCCC)nc3)nn2)cn1

Procedure:
Analogously to Example 5a from 2-decyloxypyridin-5-boronic acid and 3,6-dichloropyridazine.
Reaction SMILES: OS(O)(=O)=O.[CH:6]([O:11][CH3:12])([O:9]C)OC.[Cl:13][C:14]1[CH:30]=[CH:29][C:17]([C:18]([C:20]2C(=O)[O:22][C:23]([CH3:27])=[CH:24][C:25]=2[OH:26])=O)=[CH:16][CH:15]=1.C(OC)=O>CO>[CH3:12][O:11][C:6]([C:20]1[C:25](=[O:26])[CH:24]=[C:23]([CH3:27])[O:22][C:18]=1[C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:30][CH:29]=1)=[O:9]
Reactant: COC(OC)OC
Reactant: Cc1cc(O)c(C(=O)c2ccc(Cl)cc2)c(=O)o1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: COC=O
Product: COC(=O)c1c(-c2ccc(Cl)cc2)oc(C)cc1=O
Temperature: 25 °C
Yield: 84 %

Procedure:
A 5000 ml 3-neck flask is fitted with a N2 inlet, magnetic stirring bar, thermometer and a Dean-Stark trap with condenser. 2300 mls of dry methanol is added to the flask along with 244 gms of 96% H2SO4 and 352 gms of trimethyl orthoformate. 173 gms of 3-(4'-chlorobenzoyl)-4-hydroxy-6-methyl-2-pyrone is added and the reaction mixture is gently brought to reflux. The most volatile by-product of the reaction (methyl formate) is condensed and collected in the Dean-Stark trap. After 281/2 hours of reflux the reaction mixture is cooled to room temperature and poured into 6000 mls of brine. The resulting suspension is extracted with methylene chloride (6×250 mls). Evaporation of the solvent yields 153 gms of 3-methoxycarbonyl-6-methyl-2-(4'-chlorophenyl)-4-pyrone. mp (methylene chloride/ether)=131-2.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([OH:22])=O)[CH:4]=1.S(Cl)(Cl)=O.C([N:35](CC1C=CC=CC=1)[NH2:36])C1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O.C1C=CC=CC=1>[CH3:23][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=2)[N:6]=[C:5]([C:20]([NH:35][NH2:36])=[O:22])[CH:4]=1
Reactant: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reactant: NN(Cc1ccccc1)Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1

Procedure:
4-dimethylamino-6-[3-(trifluoromethyl)phenoxy] picolinic acid (0.64 g, 0.0020 mol) was mixed with thionyl chloride (0.50 g, 0.0020×2.1 mol) and benzene (about 10 ml), and further with a small amount of dimethyl formamide. Thereafter, the resultant mixture was refluxed for about 30 minutes. The obtained reaction solution was concentrated and then dissolved in dichloromethane (about 30 ml). The obtained solution was mixed with N,N-dibenzyl hydrazine (0.66 g, 0.0020×1.6 mol) and further with triethyl amine (0.53 g, 0.0020×2.6 mol). After the resultant mixture was stirred at room temperature for about one hour, the obtained reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and the organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated. The obtained concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([C:7]([NH2:9])=[NH:8])=[O:6])C.[Na].BrBr.[S-:13][C:14]#[N:15].[K+]>CO>[NH2:15][C:14]1[S:13][N:9]=[C:7]([C:5]([O:4][CH3:2])=[O:6])[N:8]=1
Reactant: N#C[S-]
Reactant: CCOC(=O)C(=N)N
Agent: Br
Agent: BrBr
Agent: [K+]
Solvent: CO
Product: COC(=O)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 6 h
Yield: 67.8 %

Procedure:
To a solution of 1-ethoxycarbonylformamidine. hydrobromide (16.6 g.) in absolute methanol (84 ml) was added a solution of sodium (1.93 g) in absolute methanol (42 ml) at 0° C. To the mixture were added alternately bromine (12.8 g) and a solution of sodium (1.93 g) in absolute methanol (42 ml) at 0° C. and then to the suspension was added potassium thiocyanate (8.1 g) in absolute methanol (100 ml). The reaction mixture was stirred for an hour at 0° C. and for an additional 6 hours at ambient temperature. The mixture was filtered through cellulose powder and the filtrate was evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and water, and then the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was triturated with diethyl ether to give the title compound (9.0 g), mp. 202° to 205° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1.C(O)(C(F)(F)F)=O>CS(C)=O>[NH2:16][C:12]1[CH:11]=[C:10]([NH:17][C:7]2[C:2]([Cl:1])=[C:3]([NH2:9])[N:4]=[CH:5][N:6]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ncnc(Cl)c1Cl
Reactant: Nc1cccc(N)c1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(Nc2ncnc(N)c2Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Into a 20 mL was placed 5,6-dichloropyrimidin-4-amine (500 mg, 3.05 mmol), benzene-1,3-diamine (329.72 mg, 3.05 mmol) and a pre-made mixture of TFA:TEA (1:1 mol) (347.64 mg: 308.52 mg) dissolved in DMSO (6 mL). The mixture was heated at 90° C. overnight. The reaction mixture was then cooled to rt and the crude mixture was purified using column chromatography eluting 0-40% MeOH in EtOAc. The fractions containing the desired product was concentrated and lyophilized overnight to afford the desired product N4-(3-aminophenyl)-5-chloropyrimidine-4,6-diamine (82% yield) as a brown syrup.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:16]=[CH:15][C:7]2[NH:8][C:9]([CH3:14])=[N:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1>>[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[NH:8][C:9]([CH3:14])=[N:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)N=C(C)N2
Agent: Cl
Product: CC1=NS(=O)(=O)c2cc(O)ccc2N1
Temperature: 0 °C
Yield: 74.6 %

Procedure:
HCl (20 g) is heated to 210° C. and 5 g of 7-methoxy-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide are added. This mixture was kept at about 210° C. for about 11/2 hours. The mixture was then cooled slightly and about 60 ml of ice cold water was added with stirring. This mixture was filtered and the solid washed with 25 ml. of cold water and dried yielding 3.5 g of 7-hydroxy-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide (A). An additional 0.63 g of A was recovered from the filtrate to allowing it to stand in the refrigerator for about one hour. Total yield of this product was 4.13 g (88%), m.p. 333°-336° C. (dec.). ##STR14##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[F:21])O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[F:21]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1F)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 c], (2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester was treated with triethylsilane in trifluoroacetic acid to yield (2S)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20](O)=[O:21])=[C:16]([Cl:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:21])=[C:16]([Cl:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)O)c(Cl)cc21
Reactant: Nc1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)Nc3ccncc3)c(Cl)cc21
Yield: 103.9 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)-6-chlorothiochromane-7-carboxylic acid (250 mg), 4-aminopyridine (68.4 mg) and 2-chloro-1-methylpyridinium iodide (222 mg), the objective (S)-4-(tert-butoxycarbonylamino)-6-chloro-N-(4-pyridyl)thiochromane-7-carboxamide (317 mg) was obtained as a colorless amorphous solid.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C@H:13]([CH3:22])[C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(C(C)C)C(C)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCOCC>[C:1]12([CH2:11][N:12]3[C@H:13]([CH3:22])[C@H:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:15][C:33]3=[O:35])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C[C@@H](NCC12CC3CC(CC(C3)C1)C2)[C@@H](O)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cold, stirred solution of (1S,2R)-2-(1-adamantylmethylamino)-1-phenylpropan-1-ol (715 mg, 2.4 mmol) and DIEA (1.3 mL, 7.2 mmol) in CH2Cl2 (50 mL) was added solid triphosgene (233 mg, 0.79 mmol). The ice bath was allowed to melt and the mixture was stirred at rt for 3 h. The mixture was diluted with ether (150 mL), washed with 5% aq HCl (50 mL) and satd aq NaHCO3 (50 mL), and dried over MgSO4. Removal of the solvent left (4R,5S)-3-((1-adamantyl)methyl)-4-methyl-5-phenyloxazolidin-2-one as a white solid. 1H NMR (CDCl3) 0.76 (d, 3H), 1.5-1.8 (12H), 2.01 (3H), 2.52 (d, 1H), 3.30 (d, 1H), 4.09 (m, 1H), 5.63 (d, 1H), 7.25-7.40 (5H); LC-MS (3 min) tR=2.26 min, m/z=326, 348.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl>[CH2:31]([N:10]([CH2:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:8][CH2:7]1)[S:11]([NH:14][C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1)(=[O:12])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Amine (22) (23.5mg, 40 μmole, 1.0 eq) was suspended in dichloromethane, then triethylamine (16.7 μL, 120 μmole, 3.0 eq) and benzoyl chloride (4.7 μL, 40 μmole, 1.0 eq) were added and the reaction stirred 30 minutes. Silica gel chromatography provided the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.32 (t, 1H), 8.18 (s, 1H), 7.77 (d, 2H), 7.47 (t, 1H), 7.37 (m, 4H), 7.25 (d, 2H), 7.18 (t, 1H), 4.40 (s, 2H), 3.30 (water), 2.98 (t, 4H), 2.48 (DMSO), 1.61 (m, 4H), 1.36 (m, 1H), 1.28 (m, 1H), 0.62 (m, 4H).