Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]>[Ni]>[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O
Agent: [Ni]
Product: C[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO

Procedure:
D-Fucose (6-deoxy D-galactose) was reduced [a composition in total of 500 ml containing D-fucose at 1% and 20 ml of the Raney-nickel catalyst] to produce D-fucitol (6-deoxy D-galactitol). FIG. 57(a) shows HPLC analysis results of D-fucose before reduction and FIG. 57(b) shows HPLC analysis results of 6-deoxy L-galactitol after the reduction. The optical rotation of 6-deoxy L-galactitol was +1.7, and FIG. 58 shows 13C NMR spectrum of 6-deoxy L-galactitol.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.CO>O>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: CN1CCNCC1
Solvent: O
Solvent: CO
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 75 °C
Yield: 74 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (5 g, 0.02 mol), N-methylpiperazine (12.5 mL, 2.5 vol) and methanol (15 mL, 3 vol) were charged into a three-necked round bottom flask equipped with a reflux condenser, overhead stirrer, and thermometer. The reaction mixture was slowly heated under nitrogen to reflux (75° C.) and kept at this temperature overnight. The reaction mixture was allowed to cool to below 50° C. and water (15 mL, 3 vol) was added. The precipitated light yellow solid was isolated by filtration, then was washed twice with water (5 mL) and dried to provide olanzapine in 74% yield (4.35 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.[C:23](O)(=[O:27])[C:24]([CH3:26])=[CH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>C(Cl)(Cl)Cl>[C:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1)(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: O=C(O)c1ccc(OCCCCCCCCCCCO)cc1
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 79.2 %

Procedure:
In 200 ml of chloroform were dissolved 15.0 g (48.6 mmol) of the compound (2), 60.0 g (697 mmol) of methacrylic acid, 2.0 g of p-toluenesulfonic acid, and 3.0 g of hydroquinone as polymerization inhibitor. The whole was refluxed for 13 hours under removing water formed. Then, after removal of solvent, the reaction mixture was poured into a plenty of ice-water, and the resulting precipitate was collected by filtration and dried after washing with water. The obtained white solid was recrystallized from acetone to obtain 14.5 g of p-(11-methacryloxyundecyloxy)benzoic acid (3) (yield: 78.9%).
Reaction SMILES: [Na].CS([C:5]1[N:20]=[C:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=[C:12]([NH2:13])[N:7]2[N:6]=1)=O.[C:21]1([CH2:27][CH2:28][OH:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:28]([O:29][C:5]1[N:20]=[C:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=[C:12]([NH2:13])[N:7]2[N:6]=1)[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCc1ccccc1
Reactant: CS(=O)c1nc2cc(-c3ccccn3)cc(N)n2n1
Agent: [Na]
Product: Nc1cc(-c2ccccn2)cc2nc(OCCc3ccccc3)nn12
Reaction time: 16 h
Yield: 83 %

Procedure:
0.06 g (0.003 mol) sodium in 50 ml 2-phenylethanol were stirred overnight at 60° C. 0.2 g (0.0007 mol) 2-methanesulfinyl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine added and stirring was continued at 160° C. for 16 hours. Evaporation of the solvent and chromatography on silicagel with ethylacetate gave 0.2 g (83%) 2-phenethyloxy-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, MS m/e (%):332 (M+H+,100).
Reaction SMILES: [CH:1]1(NC(C)C)CCCCC1.C([Li])CCC.[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:45][CH2:44][C@@:43]2([CH3:46])[C@H:23]([CH2:24][C@H:25]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C@@H:26]3[C@@H:42]2[CH2:41][C@H:40]([OH:47])[C@@:39]2([CH3:48])[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@H:31]([CH3:38])[CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:22]1)=[O:20])[CH3:17].CI.Cl>C1COCC1>[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:45][CH2:44][C@@:43]2([CH3:46])[C@H:23]([CH2:24][C@H:25]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C@@H:26]3[C@@H:42]2[CH2:41][C@H:40]([OH:47])[C@@:39]2([CH3:48])[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@H:31]([CH3:38])[CH2:32][CH:33]([CH3:1])[C:34]([O:36][CH3:37])=[O:35])[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)[C@@H]1CC[C@@]2(C)[C@@H](C1)C[C@H](C(=O)OCC)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]12
Reactant: CC(C)NC1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)[C@@H]1CC[C@@]2(C)[C@@H](C1)C[C@H](C(=O)OCC)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CC(C)C(=O)OC)CC[C@@H]12
Temperature: -78 °C
Reaction time: 5 h

Procedure:
To a solution of N-cyclohexyl-isopropyl-amine (2.8 ml: 0.017 mol) in anhydrous THF (120 ml), 11.4 ml (0.016 mol) of a butyllithium solution were added in 30'; the stirred mixture was then cooled (under nitrogen) to -78° C., and 3α,7β-diethoxycarbonyl-12α-hydroxy-5β-cholan-24-oic acid, methyl ester (2.5 g; 0.0045 mol), dissolved in 22 ml of anhydrous THF was added very slowly (45'). Fifteen minutes after the addition, CH3I (10.2 g; 0.072 mol) was added, and the mixture was brought to room temperature. After 5 hours the reaction was complete; the solution was acidified with a 10% aqueous solution of HCl and extracted with CHCl3 (3×80 ml). The chloroform solution was washed with water, dried on Na2SO4, and evaporated to dryness. The yield is almost quantitative.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>CCO.[Pt]>[NH2:11][C:9]1[C:8]([O:14][CH3:15])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Cl:1])[CH:10]=1
Reactant: COc1cc(C(=O)O)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: COc1cc(C(=O)O)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-chloro-5-methoxy-4-nitro-benzoic acid (Intermediate 218; 762 mg, 3.8 mmol) was dissolved in EtOH (20 mL) and a catalytic amount of 5% Pt on carbon added under an inert atmosphere. The solution was de-gassed and stirred under an atmosphere of hydrogen at room temperature overnight. The catalyst was filtered off and washed with EtOH and solvent evaporated and the resultant material dried under vacuum to yield the title compound as an off-white solid. (617 mg, 98%)
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]([O:12]C)=O.C([O-])=O.[NH4+].[CH:18]([NH2:20])=O>O>[CH:7]([CH:4]1[C:3]2[C:10]([OH:12])=[N:20][CH:18]=[N:1][C:2]=2[CH2:6][CH2:5]1)([CH3:9])[CH3:8]
Reactant: COC(=O)C1=C(N)CCC1C(C)C
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: CC(C)C1CCc2ncnc(O)c21
Temperature: 150 °C
Yield: 134.8 %

Procedure:
A mixture of methyl 2-amino-5-isopropylcyclopent-1-enecarboxylate (3.272 g, 17.86 mmol), ammonium formate (5.630 g, 89.28 mmol), and formamide (7.092 mL, 178.6 mmol) was heated at 150° C. for 20 hours. The reaction was diluted with water, and extracted with 1:5 IPA:DCM, until no more product in aqueous by TLC. The combined organics were concentrated under reduced pressure, dissolved in DCM and dried Na2SO4. The reaction was filtered and concentrated to give 5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (4.29 g, 100%), which was used without further purification. LCMS (APCI+) m/z 179.0 [M+H]+; Rt=2.33 min.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:8]([OH:13])[C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 61.5 %

Procedure:
28.45 g (0.1 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one and 43.25 g (0.1 mol) of formic acid/triethylamine (5:2 addition compound) were heated to 145° to 150° C. for 4.5 to 5 hours. The reaction mixture was allowed to cool and was concentrated in vacuo. The residue was taken up in dilute sodium hydroxide solution and the mixture was extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulphate and concentrated in vacuo. The residue was suspended in hot cyclohexane, the suspension was filtered hot and the solid was dried. 18.2 g (63.6% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 114°-116° C. were obtained.
Reaction SMILES: CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[NH:25][C:24]=1[CH3:32].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])=[CH:38][CH:37]=1>CN(C=O)C>[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])=[CH:40][CH:41]=2)[C:24]=1[CH3:32]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CCS(=O)(=O)c1ccc(CBr)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)cc1
Reaction time: 1.33 h

Procedure:
BEMP (182 μl, 0.64 mmol) is added to a stirring solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (prepared as described in U.S. Pat. No. 3,320,268, 82 mg, 0.40 mmol) in DMF (2.6 ml). After 80 minutes, 1-bromomethyl-4-ethanesulfonyl-benzene (75 μl, 0.63 mmol) is added and the reaction stirred for 2 hours before partitioning between water and 1:1 EtOAc/diethyl ether. The organic layer is washed with brine then reduced in vacuo. The residue is purified by flash column chromatography (1:1 iso-hexane/EtOAc elution) to furnish [1-(4-ethanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C@@H:9]([C:13]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[O:30])[C:20]2[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=2)[N:14]=1)[CH:10]([CH3:12])[CH3:11])[C:5](=[O:8])[CH:6]=[CH2:7].C(OC(=O)NCCN(C(=O)C=C)[C@@H](C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:23]([N:22]1[C:21](=[O:30])[C:20]2[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=2)[N:14]=[C:13]1[C@H:9]([N:4]1[C:5](=[O:8])[CH2:6][CH2:7][NH:1][CH2:2][CH2:3]1)[CH:10]([CH3:12])[CH3:11])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=CC(=O)N(CCN)[C@@H](c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Agent: C=CC(=O)N(CCNC(=O)OC(C)(C)C)[C@@H](c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O

Procedure:
N-(2-Amino-ethyl)-N-[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-acrylamide: According to the procedure of Example 1d above, (2-{acryloyl-[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-amino}-ethyl)-carbamic acid tert-butyl ester was treated with 50% TFA in CH2Cl2 (3 mL) to give the title compound: MS (ES) m/e 439.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[S:7])[N:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[C:14]([O:18][C:19]([NH:21][C@@:22]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[C@H:26](OS(C)(=O)=O)[C@@H:25]2[C@H:23]1[C@H:24]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.[Cl-].[Na+].O>[C:14]([O:18][C:19]([NH:21][C@@:22]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[C@@H:26]([S:7][C:6]2[N:2]([CH3:1])[N:3]=[CH:4][N:5]=2)[C@@H:25]2[C@H:23]1[C@H:24]2[C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cn1[nH]cnc1=S
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](OS(C)(=O)=O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1S[C@H]1[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 100 %

Procedure:
Add 2-methyl-1H-1,2,4-triazole-3-thione (0.126 g, 1.09 mmol) and potassium carbonate (0.35 g, 2.52 mmol) to a solution of di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-[(methylsulfonyl)oxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.80 g, 0.84 mmol) in dimethylformamide (1.68 mL. After heating for 2 days at 80° C., pour the solution into brine and extract with ethyl acetate three times, dry the combined organic phases with sodium sulfate, filter and concentrate under reduced pressure. Purify by flash chromatography eluting with 10% ethyl acetate/CH2Cl2 to yield the title compound as an oil (0.576 g, 0.84 mmol, 100%). MS (m/z): 685/687/689 (M+1).
Reaction SMILES: [CH3:1][O:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:6]=1[S:13](Cl)(=[O:15])=[O:14].[OH-].[Na+]>CCOCC.O.O1CCCC1>[CH3:1][O:2][NH:3][S:13]([C:6]1[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:5]=1[Cl:4])(=[O:15])=[O:14]
Reactant: CON
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CONS(=O)(=O)c1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.0 g. of methoxy amine was dissolved in 100 ml. of H2O. Then, 14.0 g. of 2,4,5-trichlorobenzene sulfonyl chloride dissolved in 25 ml. of tetrahydrofuran was added under high speed mechanical stirring. Then, 8.8 g. of sodium hydroxide in a 50% solution + 10 ml. of water was dropped in at room temperature. An exothermic reaction took place and the temperature went up to 37.5° C. When the reaction subsided, it was stirred at room temperature for two hours and the solid was then filtered off and stirred into 150 ml. of ether for 1 hour. The solid was removed by filtration to yield 11.3 g. of product. The product was redissolved in ether. The ether was evaporated to yield 7.4 g. of product, m.p. 163°-166° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=O.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:13][C:4]1[S:3][C:2]2[N:1]=[C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][N:20]3[C:7](=[O:9])[C:6]=2[C:5]=1[CH3:12]
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Reactant: O=C(O)c1ccc(Cl)nc1
Product: Cc1sc2nc3ccc(C(=O)O)cn3c(=O)c2c1C
Yield: 1.8 %

Procedure:
From 8.0 g (0.04 mol) of 2-amino-4,5-dimethyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol 99, pages 94-100, 1966) and 6.3 g (0.04 mol) of 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company) following the procedure of Example 3, there is obtained 0.2 g of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid; mp 364°-368° C. after recrystallization from pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]=[N+]=[N-])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4].C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4]
Reactant: COC(=O)C1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C

Procedure:
A solution of 4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, THF and PPh3 and water is refluxed for about 6 hours and then concentrated. The residue is dissolved in Et2O and treated with HCl. The aqueous layer is extracted, washed, dried and concentrated to afford 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (32).
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].BrCCC#[N:36]>C(OC(=O)C)C>[C:19]([CH2:18][CH2:17][N:16]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:14](=[O:15])[NH:13][C:11]1[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=1)#[N:36]
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: N#CCCBr
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@H](N(CCC#N)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 3-bromopropionitrile and 2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[C:7]([OH:13])=[C:6]([O:14][CH3:15])[CH:5]=1.[CH3:17]I>>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[C:7]([O:13][CH3:17])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: CI
Reactant: CCCc1cc(C(=O)OC)cc(OC)c1O
Product: CCCc1cc(C(=O)OC)cc(OC)c1OC
Reaction time: 4 h
Yield: 99 %

Procedure:
3,4-Dimethoxy-5-propylbenzoic acid methyl ester was prepared from 4-hydroxy-3-methoxy-5-propylbenzoic acid methyl ester using methyl iodide as an alkylating agent in 99% yield by following Method C. The reaction was conducted at room temperature for 4 h, for complete conversion of starting material. The resulting product was used without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.S(Cl)(Cl)=O.[CH3:23]O>>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:23])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
3,5-Bis(trifluoromethyl)phenylacetic acid (10.0 g, 36.7 mmol), was dissolved in methanol (150 ml). The solution was cooled to 4° C. under an atmosphere of dry nitrogen, and thionyl chloride (10 ml) was added dropwise with vigorous stirring over 30 minutes. The mixture was warmed to room temperature, and then stirred for 1 hour. The solvents were evaporated at reduced pressure, the residue dissolved in ether (150 ml), washed with saturated aqueous NaHCO3, dried (Na2SO4), and evaporated to afford the title compound (10.5 g, 100%), as a colourless oil, used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-])=O.S.[Na]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH2:9]
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: S
Agent: [Na]
Solvent: O
Product: Cc1ccc(Cl)c(N)c1
Yield: 60 %

Procedure:
514 Parts of 4-chloro-3-nitro-toluene and 300 parts of water were reacted in the same manner as described in Example 1 at from 90° to 95°C with 1446 parts of a 36% aqueous sodium hydrogen sulfide solution while stirring. Then, the 4-chloro-3-amino-toluene which had formed as by-product was eliminated by steam distillation. After cooling to 20° - 30°C, 1,210 parts of sodium sulfite (Na2SO3 . 7 H2O) and 430 parts of xylene were successively added and the pH was adjusted at 6 at a temperature within the range of from 10° to 12°C within from 2 to 3 hours with 565 parts of a 30% hydrochloric acid while stirring. For better separation of the phases, the mixture was heated at 25°C and the mother liquor was stirred with 174 parts of xylene. The 4-methyl-2-amino-thiophenol was isolated from the organic phase by vacuum distillation.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[CH:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].CO>CN(C=O)C>[C:3]1([C:9]2[N:10]=[CH:11][N:12]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[C:29](=[O:30])[C:28]4[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]3=[O:35])[C:13]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1cnc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.7 g (70.8 mmol) sodium hydride are placed in 130 ml DMF and 1.0 g (54.5 mmol) 4,5-diphenylimidazole are added under cooling. The suspension is stirred for four hours at RT and, subsequently, 15.4 g (54.5 mmol) N-(4-bromobutyl)-phthalimide dissolved in DMF is added dropwise under cooling. After complete addition, the reaction mixture is stirred for 12 hours at RT, 18 ml methanol are carefully added dropwise and the suspension is filtered. The filtrate is concentrated under vacuum and the residue is distributed between 500 ml chloroform and 170 ml water. The organic phase is dried over sodium sulfate and evaporated under vacuum until dry dried. The residue is purified by chromatography on silica gel with CHCl3/CH3OH (95/5) and subsequently crystallized from methanol: Yield 16.5 g (72%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>>[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[S:25][C:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:27][CH:28]=1
Reactant: COCCOc1cccs1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: COCCOc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-(2-methoxy-ethoxy)-thiophene (prepared by cupric oxide-mediated coupling of 2-methoxy-ethanol and 2-iodo-thiophene, J. Am. Chem. Soc. 1953, 3697).
Reaction SMILES: [Na+].[I-:2].CN[C@@H]1CCCC[C@H]1NC.[Br:13][C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH2:15].CCCCCCCCCCCC>C(OCC)(=O)C.[Cu]I.ClCCl.C1COCC1>[Br:13][C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH2:15].[I:2][C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH2:15]
Reactant: [I-]
Agent: [Cu]I
Agent: C=C(Br)[Si](C)(C)C
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: CCCCCCCCCCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C(I)[Si](C)(C)C
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), NaI (300 mg, 2.00 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %), 1-bromo-1-(trimethylsilyl)ethylene (155 μL, 1.00 mmol), and THF (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 70° C. for 15 h. The resulting suspension was allowed to reach room temperature. Dichloromethane (2 mL) and dodecane (internal GC standard, 230 μL) were added to the reaction mixture. A 50 μL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC to provide 95% conversion of 1-bromo-1-(trimethylsilyl)ethylene and clean formation of 1-iodo-1-(trimethylsilyl)ethylene.