Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[N:11]2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:21]([C:17]2[S:16][C:15]([C:12]3[CH:13]=[CH:14][N:10]([CH2:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])=[CH:27][CH:26]=1
Reactant: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (0.1 g, 0.30 mmol) in methylene chloride (5 mL) was added 4-fluoro benzyl amine (0.04 g, 0.33 mmol), benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.146 g, 0.33 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.60 mmol) and the mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (50 mL), washed with water (50 mL) and brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (hexanes:ethyl acetate, 1:1) to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (83 mg, 62% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 2H), 7.14 (d, J=4.0 Hz, 1H), 6.92-7.07 (m, 6H), 6.72 (d, J=4.0 Hz, 1H), 6.06 (bs, 1H), 4.58 (d, J=4.0 Hz, 2H), 4.34 (t, J=8.0 Hz, 2H), 3.16 (t, J=8.0 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=439.1; Rt=1.55 min; HRMS (M+H)+=439.14.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH:4]=[N:3]1.C([Li])CCC.[CH2:15]([Sn:19]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])Cl)[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([Sn:19]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][CH2:16][CH2:17][CH3:18])[S:9][C:5]=2[CH:4]=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1ncc2sccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2c(cnn2C)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a cold (−78° C.) mixture of 1-methyl-1H-thieno[3,2-c]pyrazole (200 mg, 1.447 mmol) in THF (10 mL) was added n-butyllithium (0.637 mL, 1.592 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 60 minutes. Tributylchlorostannane (0.471 mL, 1.737 mmol) was added, and the reaction mixture was stirred at −78° C. for 60 minutes and then warmed to room temperature over a period of 2 hours. The reaction was quenched with brine (20 mL) and extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified via flash chromatography, eluting with 20% EtOAc and hexane to give the title compound as a clear oil (420 mg, 68%). 1H NMR (400 MHz, CDCl3) δ ppm 0.76-0.99 (m, 9H), 0.99-1.22 (m, 6H), 1.22-1.51 (m, 6H), 1.51-1.72 (m, 6H), 4.02 (s, 3H), 6.87 (d, J=0.51 Hz, 1H), 7.58 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[NH2:17].[Br-].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:14]([C:4]1[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[C:3]=1[NH2:17])([O-:16])=[O:15]
Reactant: Nc1c(Br)cc(-c2cccnc2)cc1[N+](=O)[O-]
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Nc1c(-c2ccccn2)cc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 2-bromo-6-nitro-4-pyridin-3-yl-phenylamine (100 mg, 1 eq), 2-pyridylzinc bromide (6 eq) and tetrakis(triphenylphosphine)palladium (0.1 eq) in THF (10 mL) was heated at 100° C. for 18 hours. The reaction was quenched with water (2 mL). The product was extracted with EtOAc (20×3). The combined organic layer was then concentrated in vacuo and the residue was purified by chromatography (Silica Gel, EtOAC) to afford the title compound (75 mg) as a yellow solid. (M+1) 293.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]2[C:19](Cl)=[N:20][C:21]([NH2:25])=[N:22][C:23]=2[CH3:24])[CH:12]=1)[CH3:8]>CN1C(=O)CCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]2[C:23]([CH3:24])=[N:22][C:21]([NH2:25])=[N:20][C:19]=2[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:12]=1)[CH3:8]
Reactant: CCOC(=O)c1cccc(Cc2c(C)nc(N)nc2Cl)c1
Reactant: CCCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1cccc(C(=O)OCC)c1
Temperature: 150 °C

Procedure:
Pentylamine (2.5 mL) was added to a stirred solution of the product from step (ii) (1.65 g) in NMP (3 mL). The mixture was heated at 150° C. for 15 h and allowed to cool. The solution was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL) added. The aqueous phase was separated and the organic phase washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography eluting with 2% to 5% MeOH in DCM to give the subtitle compound as an orange solid. 0.7 g.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.FC(F)(F)S(O[C:25]1[CH2:26][O:27][C:28](=[O:31])[C:29]=1[CH3:30])(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][C:29]1[C:28](=[O:31])[O:27][CH2:26][C:25]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)COC1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (I-11, 80.0 g, 315 mmol) and 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (I-9, 85.2 g, 346 mmol), Xantphos (13.6 g, 23.6 mmol), Cs2CO3 (153.7 g, 471.8 mmol) in toluene (1200 mL), was added Pd2(dba)3 (7.20 g, 7.86 mmol) under N2. The resulting reaction mixture was heated to 90° C. and stirred under N2 for 18 h. The mixture was filtered through a pad of CELITE® and the filtrate was concentrated. The residue was purified by precipitation to give tert-butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate. 1H NMR (400 MHz, CDCl3) δ 5.23 (s, 2H), 4.02-3.99 (m, 4H), 3.06-3.05 (m, 2H), 2.15-2.11 (m, 2H), 2.02 (s, 3H), 1.87-1.81 (m, 2H), 1.51-1.41 (m, 11H)
Reaction SMILES: C1C2C(COC(=O)N[C@H](C([N:25]3[C:29]4=[N:30][CH:31]=[C:32]([Br:34])[CH:33]=[C:28]4[C:27]([C@H:35]([C:37]4[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=4[Cl:45])[CH3:36])=[CH:26]3)=O)CC(C)C)C3C(=CC=CC=3)C=2C=CC=1.CO.C(Cl)Cl>C(#N)C.O>[Br:34][C:32]1[CH:33]=[C:28]2[C:27]([C@H:35]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=3[Cl:45])[CH3:36])=[CH:26][NH:25][C:29]2=[N:30][CH:31]=1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)n1cc([C@@H](C)c2c(Cl)ccc(F)c2Cl)c2cc(Br)cnc21
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: C[C@@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12

Procedure:
The procedure described above for the (S) enantiomer was followed, starting with ((S)-1-{5-Bromo-3-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methylbutyl)-carbamic acid 9H-fluoren-9-ylmethyl ester. 1H NMR and LCMS data match with the data for the racemic compound. Optical rotation: [α]25D=+ 115.7° (c=1.0, MeOH); [α]25D=+ 151.7° (c=1.0, CH2Cl2). HPLC (Chiralcel OD-RH, solvent 60:40 acetonitrile/water isocratic, flow rate 0.5 mL/min, column temperature 30° C., UV detection at 220 nm): tR=32.1 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14](O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.S(Cl)([Cl:23])=O>>[Cl:23][CH:14]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)c1ccc(C2CCCCC2)c(Cl)c1
Product: CCOC(=O)C(Cl)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 221.75 g. (0.747 mole) of ethyl 3-chloro-4-cyclohexylphenylglycolate prepared as described in U.S. Pat. No. 3,852,323 is stirred with 106.67 g. (0.895 mole) of thionyl chloride at room temperature for 24 hours and then heated to reflux for 6 hours. The cold reaction mixture is poured into 1125 ml. of ice-cold water with stirring. The mixture is extracted with 800 ml. of ether. The ethereal solution is washed with 450 ml. of cold saturated sodium hydrocarbonate solution followed by washing twice, each time with 250 ml. of cold water. The ethereal solution is dried over anhydrous sodium sulfate and filtered. The solvent is removed in vacuo to obtain ethyl α,3-dichloro-4-cyclohexylphenylacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:28])([F:29])[F:30])[CH:21]=2)[C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OC(F)(F)F)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with commercially available 1-(bromomethyl)-3-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 410.18 g/mol.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:16])=[CH:5][C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].[C:17](=O)([O:19]CC)[NH2:18]>[Cl-].[Zn+2].[Cl-]>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:6]2[CH:5]=[C:4]([CH3:16])[S:3][C:2]=2[NH:1][C:17](=[O:19])[N:18]=1
Reactant: Cc1cc(C(=O)c2ccccc2F)c(N)s1
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1cc2c(-c3ccccc3F)nc(=O)[nH]c2s1
Temperature: 200 °C

Procedure:
A mixture of 17.85 g of 2-amino-3-(o-fluorobenzoyl)-5-methylthiophene, 25.69 g of ethyl carbamate and 1.55 g of zinc chloride is heated at 200°C for 30 minutes. After cooling, the reaction mixture is washed with chloroform, then with water, and filtered to give 4-(o-fluorophenyl)-6-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystalline solids. Recrystallization from chloroform-ethanol gives crystals having a melting point of 282° - 284°C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][C@@H:20]2[CH3:19])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: C[C@H]1COCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1SCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (200.0 mg, 0.96 mmol) and Et3N (195.5 mg, 1.93 mmol) in DMF (2.0 mL) at 0° C. was added (S)-3-methylmorpholine (97.7 mg) dropwise. The mixture was stirred overnight at rt then was partitioned between H2O and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous Na2SO4, filtered, evaporated and then the crude product which was purified by column chromatography on silica gel (eluent: PE/EA=20:1-2/1) to provide (S)-2-chloro-4-(3-methylmorpholino)-6,7-dihydrothieno[3,2-d]pyrimidine as a light yellow solid (120 mg, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:17][O:11][C:5]1[C:6](=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N)cc1C(=O)O

Procedure:
A solution of 10 g of 5-aminosalicyclic acid, 100 ml of methanol and 5 ml of sulfuric acid are refluxed overnight. The reaction mixture is cooled, basified with sodium carbonate and the methanol is evaporated. The resulting solid is washed with water and dried giving 4.0 g of methyl-5-aminosalicylic acid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][C:12]1[C:13]([CH:19]=O)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1.C([O-])([O-])=O.[K+].[K+].[BH4-].[Na+]>CO.O>[CH3:11][C:12]1[C:13]([CH2:19][NH:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: NCCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cnc(CNCCCCN2CCCC2)c(C)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 33.1 %

Procedure:
A mixture of 4-pyrrolidin-1-yl-butylamine (0.180 g, 1.27 mmol) (Seguin, H. et al. Synth. Commun. 1998, 28, 4257-4272), 3,5-dimethyl-pyridine-2-carbaldehyde (0.171 g, 1.27 mmol) and K2CO3 (0.175 g, 1.27) in MeOH (5 mL) was stirred for 20 h. The mixture was filtered through a celite cake and the filtrate was cooled at 0° C. NaBH4 (0.048 g, 1.3 mmol) was added to the filtrate, and the mixture was stirred at for 1 h. Water (20 mL) was added and MeOH was removed. The aqueous residue was extracted with CH2Cl2 (3×20 mL). The organic extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (100:5:3 CH2Cl2/1MeOH/NH4OH), affording (3,5-dimethyl-pyridin-2-ylmethyl)-(4-pyrrolidin-1-yl-butyl)-amine as a colorless oil (0.110 g, 33%). 1H NMR (CDCl3) δ 1.54-1.58 (m, 4H), 1.72-1.76 (m, 4H), 2.24 (s, 3H), 2.25 (s, 3H), 2.39-2.46 (m, 6H), 2.66-2.71 (m, 2H), 3.81 (s, 2H), 7.21 (s, 1H), 8.18 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:14][N:15]=[C:16]=[S:17]>>[CH3:14][NH:15][C:16]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:17]
Reactant: COc1cccnc1CSCCN
Reactant: CN=C=S
Product: CNC(=S)NCCSCc1ncccc1OC

Procedure:
By reaction of 2-[2-aminoethylthiomethyl]-3-methoxypyridine with methyl isothiocyanate there may be produced N-methyl-N'-[2-((3-methoxy-2-pyridyl)methylthio)ethyl]thiourea.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:24][CH2:23][C:16]3[N:17]=[CH:18][N:19]=[C:20](OC)[C:15]=3[CH2:14]2)=[N:11][CH:12]=1.C1(OC)C=CC=CC=1.[OH-].[K+]>C(#N)C>[Br:3][C:20]1[C:15]2[CH2:14][N:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][N:11]=3)[CH2:24][CH2:23][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: COc1ncnc2c1CN(c1ccc(Cl)cn1)CC2
Reactant: O=P(Br)(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: CC#N
Product: Clc1ccc(N2CCc3ncnc(Br)c3C2)nc1
Temperature: 0 °C
Yield: 37.6 %

Procedure:
Phosphorus oxybromide (14 g, 49 mmol) was added portionwise over 2 min to a stirred suspension of 6-(5-chloropyridin-2-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.36 g, 12.1 mmol), anisole (50 mL), and acetonitrile (50 mL) in a 250 mL flask. The stirred mixture clarified briefly and was then heated at reflux. The mixture was removed from the heat after 4.5 h. The cooled mixture was diluted with CH2Cl2 (100 mL), and poured onto a mixture of crushed ice (250 g) and 50% aqueous KOH (20 mL; 0.18 mol). The pH of the mixture was then adjusted to 12 with 2M aq. KOH, and extracted with CH2Cl2 (300 mL). The aqueous phase was diluted with brine (200 mL) and extracted with CH2Cl2 (2×100 mL). The combined CH2Cl2 layers were washed with saturated NaHCO3 (200 mL), dried (Na2SO4), filtered and concentrated to a brown oil which was purified by silica gel column (0-50% ethyl acetate/hexane) to give a yellow solid (1.48 g).
Reaction SMILES: [CH3:1][Mg]I.[Cl:4][C:5]1[CH:16]=[C:15]([C:17]([C:19]2[N:20]=[CH:21][N:22]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])[C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1>>[Cl:4][C:5]1[CH:16]=[C:15]([C:17]([CH3:1])([C:19]2[N:20]=[CH:21][N:22]([C:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=2)[OH:18])[C:8]2[O:9][C:10]([CH3:13])([CH3:14])[O:11][CH2:12][C:7]=2[CH:6]=1
Reactant: CC1(C)OCc2cc(Cl)cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2O1
Reactant: C[Mg]I
Product: CC1(C)OCc2cc(Cl)cc(C(C)(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2O1
Yield: 80 %

Procedure:
This compound is prepared like the preceding compound starting from methyl magnesium iodide and (6-chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl)(1-triphenylmethyl-1H-imidazol-4-yl)ketone. The residue obtained after evaporation of the dichloromethane crystallizes when stirred in diethyl ether. Yield: 80% of theory; M.P.: 182°-184° C. (recrystallized from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[C:14]([C:19]([OH:21])=O)=[N:15][CH:16]=[CH:17][N:18]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[C:14]([C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[N:15][CH:16]=[CH:17][N:18]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1nccnc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: C1COCCN1
Product: O=C(c1nccnc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1)N1CCOCC1

Procedure:
This title compound was prepared following procedure described in example 42 step 3 wherein 3-(3,4-dichloro-benzenesulfonylamino)-pyrazine-2-carboxylic acid was coupled with morpholine. The crude was purified by flash column (65% ethyl acetate in hexane) to afford the above title product as a white powder. MS: (M+Na)/z=451.0.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:48])[C:19]([C:23]3[N:24]=[C:25]([NH:28]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:49])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].O>C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:48])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:49])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
A mixture of 0.975 g of the product of Example 3 in 4 ml of 50% aqueous formic acid was stirred at 55° C. for 10 minutes and 4 ml of water were added thereto. The mixture was vacuum filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was effloresced with 2 ml of ethanol and was vacuum filtered. The product was washed with ethanol and then with ether to obtain 0.428 g of pure 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-ceph-3-eme-4-carboxylic acid with a syn configuration.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.Cl[C:34]([NH:37][NH2:38])(Cl)[CH3:35].NN>CO>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([N:1]2[CH:35]=[CH:34][N:37]=[N:38]2)=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: CC(Cl)(Cl)NN
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: CO
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-n1ccnn1
Temperature: 50 °C
Yield: 30.3 %

Procedure:
Following the procedure of Harada et al., Heterocycles 1998, 48, 695-702, to a solution of 5-(5-amino-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.400 g, 1.8 mmol) in 5 ml methanol at 0° C. was added trimethylamime (0.308 g, 3.0 mmol) and hydrazine 1,1-dichloroethyl hydrazine tosylate (0.388 g, 1.4 mmol). The solution was warmed to 50° C. After 4 h the mixture was concentrated in vacuo and extracted with CH2Cl2. The combined organics were washed with H2O, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification via flash chromatography (94:6 CH2Cl2/MeOH) afforded 5-(2-isopropyl-4-methoxy-5-[1,2,3]triazol-1-yl-phenoxy)-pyrimidine-2,4-diamine (0.145 g, 31%) as a white solid; [MH]+=342.
Reaction SMILES: [Si](OC1C=CC2CC(C3C=CC(OC)=CC=3CCN)CCCC=2C=1)(C(C)(C)C)(C)C.Cl.N1(CCOC2C=CC(C(O)=O)=CC=2)CCCC1.[Si]([O:56][C:57]1[CH:58]=[CH:59][C:60]2[CH2:66][CH:65]([C:67]3[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][C:68]=3[N:75]([CH2:91][CH3:92])[CH2:76][C:77]3[CH:82]=[CH:81][C:80]([O:83][CH2:84][CH2:85][N:86]4[CH2:90][CH2:89][CH2:88][CH2:87]4)=[CH:79][CH:78]=3)[CH2:64][CH2:63][CH2:62][C:61]=2[CH:93]=1)(C(C)(C)C)(C)C>>[CH2:91]([N:75]([CH2:76][C:77]1[CH:82]=[CH:81][C:80]([O:83][CH2:84][CH2:85][N:86]2[CH2:87][CH2:88][CH2:89][CH2:90]2)=[CH:79][CH:78]=1)[C:68]1[CH:69]=[C:70]([O:73][CH3:74])[CH:71]=[CH:72][C:67]=1[CH:65]1[CH2:64][CH2:63][CH2:62][C:61]2[CH:93]=[C:57]([OH:56])[CH:58]=[CH:59][C:60]=2[CH2:66]1)[CH3:92]
Reactant: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)ccc1C1CCCc2cc(O[Si](C)(C)C(C)(C)C)ccc2C1
Agent: COc1ccc(C2CCCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(CCN)c1
Agent: Cl
Agent: O=C(O)c1ccc(OCCN2CCCC2)cc1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)ccc1C1CCCc2cc(O)ccc2C1
Yield: 87.1 %

Procedure:
Synthesized from {2-[2-(tert-butyldimethylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-5-methoxyphenyl}ethylamine and 4-(2-pyrrolidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, {2-[2-(tert-butyldimethylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-5-methoxyphenyl}ethyl[4-(2-pyrrolidin-1-ylethoxy)benzyl]amine (484 mg) was used according to an analogous synthetic method to Example 325 described below to provide the title compound (345 mg).