Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]Cl.[Mg].Cl[Si:5]([CH:13]=C)([CH3:12])[O:6][Si:7](Cl)([CH:9]=[CH2:10])[CH3:8].[CH3:15][Mg:16][Cl:17].Cl.O1[CH2:23][CH2:22]CC1>O>[CH3:15][Mg:16][Cl:17].[CH:9]([Si:7]([CH3:1])([CH3:8])[O:6][Si:5]([CH:22]=[CH2:23])([CH3:13])[CH3:12])=[CH2:10]
Reactant: C=C[Si](C)(Cl)O[Si](C)(Cl)C=C
Reactant: C1CCOC1
Reactant: CCl
Agent: C[Mg]Cl
Agent: Cl
Agent: [Mg]
Solvent: O
Product: C=C[Si](C)(C)O[Si](C)(C)C=C

Procedure:
A methyl magnesium chloride solution is prepared by adding methylchloride to a mixture consisting of 1000 milliliters of tetrahydrofuran and 97.2 grams (4 mol) of magnesium in the form of magnesium shavings until the shavings have dissolved. About 400 grams (1.76 mol) of 1,3-dichloro-1,3-divinyl-1,3-dimethyldisiloxane is added dropwise to the methyl magnesium chloride solution with constant agitation and at a temperature between 25° and 75° C. About 1000 milliliters of paraffin oil having a boiling point of about 190° C. at 760 mm Hg (abs), is added, then about 700 milliliters of anhydrous tetrahydrofuran is distilled off until a bath temperature of 150° C. is obtained. The residue obtained from this distillation is mixed with 70 milliliters of water. About 280 milliliters of tetrahydrofuran having a water content of less than 0.5 percent by weight is recovered. After cooling, the residue obtained from the second distillation is mixed with 600 milliliters of water and 100 milliliters of 20 percent aqueous hydrochloric acid and from the organic phase is obtained 317 grams i.e. 94 percent of theoretical, of 1,3-divinyl-1,1,3,3-tetramethyldisiloxane having a boiling point of from 138° to 139° C. and a purity in excess of 98 percent by weight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16](=[O:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:26][Mg]Br.O1CCCC1.[Cl-].[NH4+]>[Na].CCOCC.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([CH3:26])([OH:24])[C:17]([F:22])([F:23])[C:18]([F:19])([F:21])[F:20])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[Mg]Br
Reactant: O=C(C(O)(Cn1cncn1)c1ccc(F)cc1F)C(F)(F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)(C(O)(Cn1cncn1)c1ccc(F)cc1F)C(F)(F)C(F)(F)F

Procedure:
2-(2,4-Difluorophenyl)-2-hydroxy-4,4,5,5,5-pentafluoro-1-(1H-1,2,4-triazol-1-yl)pentan-3-one (0.5 g; 0.00135 moles) was dissolved in sodium-dried diethyl ether (50 cm3) and methylmagnesium bromide (1.35 cm3 of a 3M solution in ether; 0.00405 moles) was added. Dry tetrahydrofuran (15 cm3) was then added. The mixture was heated at reflux for 2 hours, cooled and 5% aqueous ammonium chloride (50 cm3) was added, followed by ethyl acetate (100 cm3). The phases were separated and the organic phase was dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on 230-400 mesh silica, eluting with ethyl acetate:diethylamine (95:5, 500 cm3). Two diastereomers were recovered by collection and evaporation of appropriate fractions. The first diastereomer to be eluted was called diastereomer I.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[Na+].[Na+].O>CN1C(=O)N(C)CCC1.C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][NH:11][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCCNC[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (1R)-N1 -(tert-butoxycarbonyl)-1-(1H-indol-3-ylmethyl)-1,2-ethanediamine (1.00 g) in N,N'-dimethylpropyleneurea (10 ml) were added successively ethyl 4-bromobutyrate (0.49 ml) and sodium carbonate (0.73 g) at room temperature in a stream of nitrogen. The mixture was stirred at the same temperature for 45 minutes and then at 110° C. for 3 hours. After cooling to room temperature, water (100 ml) and diethyl ether (50 ml) were added into the mixture. The organic layer was separated and washed with brine, and dried over magnesium sulfate. After evaporation in vacuo, the residue was purified by column chromatography on silica gel (35 g) eluting with a mixture of dichloromethane-methanol (from 0% to 6% gradient solution) to give (1R)-N1 -(tert-butoxycarbonyl)-N2 -[3-(ethoxycarbonyl)-propyl]-1-(1H-indol-3-ylmethyl)-1,2-ethanediamine (0.78 g) as an oil.
Reaction SMILES: [CH:1]1[CH:2]=[N:3][C:4]([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[N:5][CH:6]=1.Cl[CH2:19][C:20]1[NH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(O)(=O)C>[OH-].[Na+]>[NH:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[CH2:19][NH:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([NH:7][C:4]2[N:5]=[CH:6][CH:1]=[CH:2][N:3]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=S(=O)(Nc1ncccn1)c1ccc(NCc2nc3ccccc3[nH]2)cc1
Yield: 38 %

Procedure:
628 mg (3.8 mmol) sulfadiazine and 728 mg (3.0 mmol) 2-chloromethylbenzimidazole were dissolved in 10 ml 1 M NaOH. Solution was stirred and refluxed for four hours. Reaction mixture was neutralised with addition of 1 M acetic acid until product precipitated. Crystals were filtered and purified on silica using gradient elution (chloroform to 5% methanol in chloroform) to obtain the title compound as white crystals with 38% yield. 1H NMR (DMSO-d6, 500 MHz): 8.46 (2H, m), 7.70 (2H, m) 7.49 (2H, br, m), 7.14 (1H, t, 5.7 Hz) 7.13 (2H, m), 6.98 (1H, m), 6.72 (2H, m), 4.53 (2H, 5.7 Hz); MS (ESI+): m/z 381 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH2:39])=[S:38])([CH3:29])[CH3:28].[C:40]([O-])(=[O:42])C.[Na+]>>[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH:39][C:40]([NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:42])=[S:38])([CH3:29])[CH3:28]
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1ccccc1NC(N)=S
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: CC(C)c1ccccc1NC(=S)NC(=O)NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 63 using 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (C60) and 1-(2-isopropylphenyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.161 g, 31%): 1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.08 (s, 1H), 9.39 (s, 1H), 8.13-7.99 (m, 4H), 7.68-7.58 (m, 2H), 7.49-7.31 (m, 4H), 7.24 (dtd, J=24.9, 7.4, 1.6 Hz, 2H), 7.09 (t, J=5.4 Hz, 1H), 3.17 (q, J=6.5 Hz, 2H), 3.01 (p, J=6.8 Hz, 1H), 2.70 (t, J=7.7 Hz, 2H), 1.82 (p, J=7.3 Hz, 2H), 1.17 (d, J=6.9 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 583 ([M+H]+), 581 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[C:26]([O:28]C(C)(C)C)=[O:27])=[CH:4][N:3]=1.C1(C)C=CC=CC=1>ClCCl.FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(/C=C/C(=O)O)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Yield: 128.7 %

Procedure:
A solution of Example 221B (1.5 g, 3.4 mmol) in dichloromethane and trifluoroacetic acid (10 mL) was stirred for 2 hours at ambient temperature, treated with toluene (200 mL), and concentrated to provide 1.7 g (100%) of the desired product as the trifluoroacetate salt. 1H NMR (DMSO-d6, 400 MHz) δ 8.42 (s, 1H), 7.95 (s, 1H), 7.76 (d, 1H), 7.54 (dd, 2H), 7.46 (dt, 2H), 7.21 (t, 1H), 7.16 (dd, 4H), 6.61 (d, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 167.0, 159.0, 158.6, 157.6, 156.0, 148.8, 137.7, 137.5, 131.0, 130.1, 128.2, 127.6, 124.0, 120.3, 119.4, 119.2, 118.7, 115.7.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[C:25]([CH:26]=O)=[CH:24][CH:23]=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[N:20]1[C:25]([CH2:26][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])=[CH:24][CH:23]=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: O=Cc1cccc(-c2ccccn2)n1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccn2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with [2,2′-bipyridine]-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.58 min.; [M+H]+: 403.99 g/mol.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:12]2[CH:23]=[CH:24][N:25]=[C:11]2[NH:10][C:9]=1[CH3:26])(=O)[NH2:6].C(Cl)(Cl)Cl>CN(C)C=O>[C:5]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:12]2[CH:23]=[CH:24][N:25]=[C:11]2[NH:10][C:9]=1[CH3:26])#[N:6]
Reactant: CC1=C(C(N)=O)C(c2cccc([N+](=O)[O-])c2)n2ccnc2N1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)n2ccnc2N1
Yield: 39 %

Procedure:
1.5 ml of thionyl chloride is added dropwise to a solution of 3 g of 6-carbamoyl-7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine in 30 ml of dimethylformamide. After stirring for an hour, the mixture is poured into chloroform and washed with sodium bicarbonate solution followed by passing the mixture through a column containing 50 g of silica gel with a mixture of dichloromethane and ethanol as an eluent. Upon allowing the eluates to stand, crystals are precipitated and collected by filtration to give 1.1 g of 6-cyano-7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 278°-280° C. with decomposition.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=23)[S:7]1(=[O:19])=[O:18].C(N(CC)CC)C.[C:27]1([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:27]1([C:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=45)[S:7]3(=[O:19])=[O:18])[CH2:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCCl
Reactant: C1=C(c2ccccc2)CCNC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCCN1CC=C(c2ccccc2)CC1
Temperature: 20 °C
Yield: 18.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (10 g), triethylamine (4.8 cc) and 4-phenyl-1,2,3,6-tetrahydropyridine (5.4 g) in toluene (300 cc). The mixture is heated for 9 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystalline from boiling acetonitrile (10 cc), 2-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (2.6 g) is obtained, m.p. 101° C.
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[CH3:24][NH2:25].O>>[CH3:22][N:21]([CH3:23])[CH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:12]2[C:11]3[C:10]4[CH2:9][CH2:8][CH2:7][C:6]=4[S:5][C:4]=3[N:3]=[C:2]([NH:25][CH3:24])[N:13]=2)[CH2:16][CH2:17]1
Reactant: CN
Reactant: CN(C)C1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Solvent: O
Product: CNc1nc(NC2CCC(N(C)C)CC2)c2c3c(sc2n1)CCC3
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a 10-mL sealed tube placed 4-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (120 mg, 0.34 mmol, 1.00 equiv) and CH3NH2—H2O solution (40%, 3 mL) was stirred overnight at 70° C. in an oil bath. After completion of the reaction, the resulting mixture was concentrated under vacuum and the crude product (140 mg) was purified by Prep-HPLC with the following conditions (Waters): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, mobile phase, water with 0.05% NH4HCO3 and CH3CN (25% CH3CN up to 100% in 15 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the corresponding 12-N-[4-(dimethylamino)cyclohexyl]-10-N-methyl-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene-10,12-diamine (50 mg) as a white solid. MS (ES, m/z): 346 [M+H]+; NMR (300 MHz, CD3OD): δ 4.75-4.70 (1H, m), 4.64 (1H, d), 4.05-3.94 (1H, m), 3.00 (3H, d), 2.89-2.87 (4H, m), 2.54-2.38 (2H, m), 2.32 (6H, s), 2.25-2.21 (3H, m), 1.96 (2H, d), 1.50-1.35 (2H, m), 1.29-1.19 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH2:18]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH2:18]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:17])[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Temperature: 85 °C
Yield: 71.3 %

Procedure:
To a solution of Ethyl-4,6-dichloroquinoline-3-carboxylate (1.0 g, 3.7 mmol) in 1,4-dioxane (10 mL) was added a solution of 4-benzylbenzenamine (733 mg, 4.0 mmol) in 1,4-dioxane (10 mL) at room temperature. After stirred at 85° C. 1 hour, the reaction mixture was then cooled down to room temperature and then treated with 20 mL of water. The resulting suspension treated with 10 N NaOH solutions to reach the pH about 9. It was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 9:1 v/v hexane:ethyl acetate as solvent to afford title compound (1.1 g, 65% yield) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:39]=[CH:38][C:6]([CH:7]=[CH:8][C:9]([NH:11][CH2:12][C:13]([N:15]([C:17]2[C:18]([Cl:37])=[C:19]([C:33]([Cl:36])=[CH:34][CH:35]=2)[CH2:20][O:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[C:29]([CH3:32])[CH:28]=[CH:27]3)[CH3:16])=[O:14])=[O:10])=[CH:5][CH:4]=1)#[N:2].C[Sn]([N:44]=[N+:45]=[N-:46])(C)C.ClC1C(N(C)C(=O)CNC(=O)C=CC2C=CC(C(=O)N(CC(=O)NC)C)=CC=2)=CC=C(Cl)C=1COC1C=CC=C2C=1N=C(C)C=C2>C1(C)C(C)=CC=CC=1>[Cl:37][C:18]1[C:17]([N:15]([CH3:16])[C:13](=[O:14])[CH2:12][NH:11][C:9](=[O:10])[CH:8]=[CH:7][C:6]2[CH:38]=[CH:39][C:3]([C:1]3[NH:46][N:45]=[N:44][N:2]=3)=[CH:4][CH:5]=2)=[CH:35][CH:34]=[C:33]([Cl:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29]([CH3:32])[CH:28]=[CH:27]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C#N)cc4)c3Cl)c2n1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: CNC(=O)CN(C)C(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(-c5nnn[nH]5)cc4)c3Cl)c2n1
Temperature: 125 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A mixture of 8-[3-[N-(4-cyanocinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (76 mg) and trimethyltin azide (109 mg) in xylene (1 ml) was heated at 125° C. for 20 hours. After cooled, methanol-chloroform (1:4 V/V, 10 ml) and silica gel (296 mg) was added to the reaction mixture. The resulting suspension was stirred at ambient temperature for one hour. The silica gel was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by preparative thin-layer chromatography eluting with methanol-chloroform (1:6) to afford 8-[2,6-dichloro-3-[N-methyl-N-[4-(5-tetrazolyl)cinnamoylglycyl]amino]-benzyloxy]-2-methylquinoline (40 mg) as a pale yellow glass.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.CN(C=O)C.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CCOCC.CC(C)=O>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:4]2[CH:5]=[C:6]([C:7]#[N:8])[C:2]([NH2:1])=[N:3]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: N#Cc1c[nH]nc1N
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cc(C#N)c(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.5 %

Procedure:
To a solution of 3-amino-1H-pyrazole-4-carbonitrile (1.211 g, 11.21 mmol) in anhydrous DMF (20 ml) K2CO3 (5.414 g, 39.24 mmol) was added. The suspension was stirred 5 min at room temperature and treated with p-bromomethylbenzoic acid methyl ester (2.568 g, 11.21 mmol), stirred for 2.5 hrs at 100° C., cooled and filtered. Filtrate was evaporated to form an oily residue, which was dissolved in a mixture Et2O-acetone and kept overnight at −10° C. A crystalline material was formed which was triturated with hot EtOAc, again kept overnight at −10° C. and was collected by filtration to form the title compound 95 (675 mg, 24% yield). LRMS: 256.3 (calc.), 257.3 (found).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([F:28])[CH2:10][O:9][CH2:8][C@:6]2([C:11]2[CH:12]=[C:13]([NH:18][C:19]([C:21]3[CH:26]=[N:25][C:24]([Cl:27])=[CH:23][N:22]=3)=[O:20])[CH:14]=[CH:15][C:16]=2[F:17])[N:7]=1.[F:29][C:30]1([CH2:33][OH:34])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C>[ClH:27].[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([F:28])[CH2:10][O:9][CH2:8][C@:6]2([C:11]2[CH:12]=[C:13]([NH:18][C:19]([C:21]3[CH:26]=[N:25][C:24]([O:34][CH2:33][C:30]4([F:29])[CH2:32][CH2:31]4)=[CH:23][N:22]=3)=[O:20])[CH:14]=[CH:15][C:16]=2[F:17])[N:7]=1
Reactant: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(Cl)cn4)ccc3F)COC[C@@]2(F)CO1
Reactant: OCC1(F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cl
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(OCC5(F)CC5)cn4)ccc3F)COC[C@@]2(F)CO1
Temperature: 150 °C
Yield: 27.6 %

Procedure:
N-[3-[(4aR,7aS)-2-Amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]oxazin-7a-yl]-4-fluoro-phenyl]-5-chloro-pyrazine-2-carboxamide (110 mg, 268. μmol), (1-fluorocyclopropyl)methanol (73 mg, 805 μmol) and potassium carbonate (111 mg, 805.31 μmol) are combined in a microwave vial. Acetonitrile (3 mL) is added and the reaction mixture is heated at 150° C. for 1.5 hours in a microwave reactor. The reaction mixture is diluted with ethyl acetate and the organic layer is washed with saturated aqueous NaHCO3 and water. The combined aqueous layers are extracted twice with ethyl acetate dried with MgSO4 and the solvent removed in vacuo to give the crude product. The crude product is purified by silica gel flash chromatography, eluting with 0-3% (7 N NH3-methanol) in dichloromethane to give the free base of the title product (37 mg, 30%). The free base is dissolved in dichloromethane (2 mL) and treated with hydrochloric acid (1 M in diethyl ether, 80 μL, 80 μmol), and concentrated under reduced pressure to give the title product (39 mg, 29%). ES/MS (m/e): 464 (M+1)
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:9])[CH:7]=O)[CH2:2][CH2:3][CH3:4].[CH:10](=[O:13])[CH2:11][CH3:12].C(NCCCC)CCC>CCOCC>[CH2:1]([O:5][C:6](=[O:9])/[CH:7]=[C:11](\[CH:10]=[O:13])/[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCC=O
Reactant: CCCCOC(=O)C=O
Solvent: CCCCNCCCC
Solvent: CCOCC
Product: CCCCOC(=O)/C=C(/C)C=O
Reaction time: 2 h

Procedure:
836 G. of the obtained glyoxalic acid butyl ester are introduced into 376 g. of propionaldehyde. The mixture is treated dropwise at 60° C. with 40.8 g of di-n-butylamine. In so doing, the reaction temperature should not rise higher than 105° C. The reaction mixture is then stirred for 2 hours at 116°-111° C., cooled and taken up in ether. The diethyl ether extract is washed successively with 500 ml. of 1 N sulphuric acid, 700 ml. of water, 1000 ml. of 5% by weight aqueous sodium bicarbonate solution and subsequently with 1000 ml. of water, dried over sodium sulphate and evaporated under reduced pressure. The remaining 3-formylcrotonic acid butyl ester boils, after rectification, at 93°-105° C./14 mm. Hg; nD25 = 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)[CH:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1.COC(OC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[S:28])[CH:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)C(OC)C(=O)Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: COC(C)OC
Product: COC(=O)C(OC)C(=S)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 116.7 %

Procedure:
A mixture of 3.50 grams (0.01 mole) of methyl 3-[(3,5-dichlorophenyl)amino]-2-methoxy-3-oxopropanoate (Compound 233, Example LXX), 2.42 grams (0.006 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide and 35 milliliters of anhydrous 1,1-dimethoxyethane was stirred at room temperature for a period of about 20 hours after which stirring was continued with testing at 55° C. for a 168-hour interval. Solvent was removed from the reaction mixture under reduced pressure and the residue worked up by flash column chromatography to give 2.31 grams (0.007 mole) of methyl 3-[(3,5-dichloro-phenyl)amino]-2-methoxy-3-thioxopropanoate having a melting point of 144° C.-147° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9].[CH3:37][NH2:38]>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[N:11]=[C:12]([NH:38][CH3:37])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: CN
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(Cl)c2ccccc2c1-c1ccccc1
Product: CNc1nc(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2)c2ccccc12

Procedure:
The compound obtained in Example 275 was reacted with methylamine by a method similar to Example 271 to yield the title compound as colorless crystals.