Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC1C=CC(C(Cl)=O)=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[NH2:15].[I:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[I:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:44]([NH:43][C:41](=[O:42])[C:38]2[CH:39]=[CH:40][C:35]([I:34])=[CH:36][CH:37]=2)=[S:45])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(I)cc1
Agent: O=C(N=C=S)c1ccc(I)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(I)cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4-Iodo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-iodo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-iodo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (94 mg, yield 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)/[CH:5]=[N:6]\[OH:7].[Cl:11]N1C(=O)CCC1=O>CN(C=O)C>[OH:7]/[N:6]=[C:5](\[Cl:11])/[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C\c1cccc(F)c1
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of (E)- and/or (Z)-3-fluoro-benzaldehyde oxime (6.9 g, 50 mmol) in DMF (50 mL) was added N-chlorosuccinimide (6.6 g, 50 mmol) portionwise over 1 h, keeping the temperature below 35° C. The reaction mixture was stirred at room temperature for 1 h. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (6.3 g, 73%) which was obtained as an off white solid. MS m/e (EI): 173.1 [M].
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)(Cl)=O.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH2:23]>O1CCCC1>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: Nc1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(F)cc1F)c1ccccc1O

Procedure:
To a solution of salicylic acid (1.38 g, 10 mmole) in tetrahydrofuran (40 mL) was added thionyl chloride (2.5 mL, 35 mmole) and refluxed 3 hr. The mixture was steamed (110° C.) by Dean-Stark. The residue was directly reacted with 2,4-difluorobenzenamine (1 mL, 10 mmole) in THF (40 mL) for 3 hr. The reaction mixture was concentrated and extracted with ethyl acetate, dried over anhydrous magnesium sulfate. Recrystallization of desired products from hot dichloromethane afforded the compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[C:5]([OH:16])[CH:4]=1.[CH2:17](O)[CH3:18]>>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:17][CH3:18])=[O:12])=[O:8])=[C:5]([OH:16])[CH:4]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCC(=O)c1ccc(Cl)cc1O
Yield: 98 %

Procedure:
Hydrogen chloride was bubbled into a gently boiling solution of 3-(4-chloro-2-hydroxybenzoyl)propionic acid (12.0 g, 0.053 mole) in dry ethanol (21.2 cc) until esterification was complete. The product crystallised from ether to give ethyl 3-(4-chloro-2-hydroxybenzoyl)propionate (13.29g, 98%, m.p. 68°-69°).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:15]2[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncc(Br)cn2)C1

Procedure:
According to the same method as in Example 1-1) but using 1-t-butoxycarbonyl-3-hydroxypyrrolidine and 2-chloro-5-bromopyrimidine, the entitled compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:16])[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[O:13][CH:14]=[CH:15][C:8]=3[C:6]=2[N:7]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][C:4]2[C:5]3[CH2:12][CH2:11][CH2:10][C:9]4[O:13][CH:14]=[CH:15][C:8]=4[C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Nc1nc(O)c2c(n1)-c1ccoc1CCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2occc2-3)cc1

Procedure:
The product from Example 4B (0.06 g, 0.27 mmol) was treated with p-toluenesulfonyl chloride as described in Example 1C to yield the title product: 1H NMR (300 MHz, CDCl3) δ 7.94 (dt, J=8.48, 2.04 Hz, 2H), 7.35 (dd, J=8.48, 0.68 Hz, 2H), 7.31 (d, J=1.7 Hz, 1H), 6.93 (d, J=2.03 Hz, 1H), 4.78 (br s, 2H), 3.01 (t, J=6.61 Hz, 2H), 2.7 (m, 2H), 2.47 (s, 3H), 1.91 (m, 2H); MS (ESI+) m/z 372 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH:13]([N:16]([CH:19]([CH3:21])C)CC)([CH3:15])C.N1CCCC1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:16]2[CH2:13][CH2:15][CH2:21][CH2:19]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (0.83 g, 2.73 mmol) in tetrahydrofuran (10 mL) under argon was added diisopropylethylamine (0.525 mL, 3.00 mmol) followed by pyrrolidine (0.183 mL, 2.73 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between diethyl ether and aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was triturated with diethyl ether/heptane at −20° C. to provide the title compound (0.56 g, 67% yield).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH:8]=[N:7]1)C.O[Li].O.Cl>C1COCC1.O>[N:6]1([CH2:5][C:4]([OH:15])=[O:3])[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH:8]=[N:7]1
Reactant: CCOC(=O)Cn1ncc2cccnc21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1ncc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a stirred solution of pyrazolo[3,4-b]pyridin-1-yl-acetic acid ethyl ester (210 mg, 1.02 mmol) (Preparation 133) in THF (4 mL) and water (1 mL) at 0° C. was added LiOH.H2O (129 mg, 3.06 mmol). The reaction mixture was stirred at room temperature for 2 hours. The pH was of the mixture was adjusted to pH 4 with 2 N aqueous hydrochoric acid and extracted with 20% isopropanol in dichloromethane (8×5 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid in 40% yield, 70 mg.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[C:14]#N.Cl.[O:22]1CCCC1>O>[Cl:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:22]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Product: O=Cc1ccc(O)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Diisobutylaluminium hydride (1M in hexane, 240 mL, 240 mmol) was added to a solution of 2-chloro-4-hydroxybenzonitrile (15 g, 97.7 mmol) in tetrahydrofuran (200 mL), cooled to −78° C., and the mixture was stirred at this temperature for 1 hour then at room temperature for 18 hours. The mixture was then cooled to 0° C. and 1M hydrochloric acid (80 mL) was added dropwise. The reaction mixture was diluted with water (200 mL) and filtered, washing through with ethyl acetate (×2). The layers of the filtrate were separated and the organic solution was dried over magnesium sulfate and concentrated in vacuo, Trituration of the residue with dichloromethane afforded the title compound as a solid in 84% yield, 12.92 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[F:23])=[O:4].[OH-].[Na+]>CO.O1CCCC1>[F:23][C:6]1[CH:7]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH3:18])=[CH:15][CH:16]=2)[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc(N(C)S(C)(=O)=O)cc2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Procedure UU: To a stirring solution of 3-Fluoro-4′-(methanesulfonyl-methyl-amino)-biphenyl-4-carboxylic acid methyl ester (see Intermediate Preparation 33) (1.0 mmol) in 1:1 methanol/tetrahydrofuran, add 2N sodium hydroxide (3.0 mmol) and stir at room temperature for 4 hours. After this time wash the reaction with 1N hydrochloric acid while extracting with dichloromethane. Dry the organics with sodium sulfate, decant, and concentrate in vacuo. MS (m/e): 322.1 (M−1)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH3:16])=[N:4][C:3]=1[O:17][C:18](=[O:24])[N:19]([CH2:22][CH3:23])[CH2:20][CH3:21].[O-:25][C:26]#[N:27].[Na+]>C(O)(=O)C>[CH2:20]([N:19]([CH2:22][CH3:23])[C:18]([O:17][C:3]1[N:4]=[C:5]([CH3:16])[C:6]2[C:11]([C:2]=1[NH:1][C:26]([NH2:27])=[O:25])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:24])[CH3:21]
Reactant: N#C[O-]
Reactant: CCN(CC)C(=O)Oc1nc(C)c2cc(OC)c(OC)cc2c1N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN(CC)C(=O)Oc1nc(C)c2cc(OC)c(OC)cc2c1NC(N)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.3 %

Procedure:
To a solution of 4-amino-3-(diethylcarbamyloxy)-6,7-dimethoxy-1-methylisoquinoline (1.0 g, 3 mmol) in acetic acid (10 mL) was added sodium cyanate (0.23 g, 3.6 mmol) and the mixture was stirred under nitrogen at room temperature for 72 hours. Then the mixture was evaporated to dryness in vacuo and the residue triturated with water to give a gelatinous precipitate which was collected (0.69 g). The filtrate gave additional solids (0.50 g). The combined solids were dissolved in chloroform and purified by low pressure column chromatography on a silica gel column. Elution with 1.8% methanol/chloroform gave purified title compound which was collected from methylene chloride/ether as a colorless crystalline solid (0.865 g, 68.7%), mp 215°-216° C. IR (KBr): 3323, 3316, 3313, 3199, 1712, 1697, 1667, 1428 cm-1 ; NMR (CDCl3): δ 1.23 and 1.28 [each t, J=7 Hz, total 6H, N(CH2CH3)2 ], 2.80 (s, 3H, 1-CH3), 3.20-3.70 [br m, 4H, N(CH2CH3)2 ], 4.98 (s, 2H, NHCONH2), 6.78 and 7.01 (two s, each 1H, 5,8-H), 6.876 (br s, 1H, 4-NH). MS (DCI): 377 (MH)+ ; UV (EtOH) nm: 247 (ε51600), 275 (ε4800), 287 (ε5050), 297 (ε5000).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:21])[C@@H:4]2[CH2:19][C:18](=[O:20])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8].O1CCCC1.C(O)(=O)C>[Ni].C1(C)C=CC=CC=1.C(Cl)Cl.[Zn]>[CH3:1][CH:2]1[CH:6]([C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:16])[CH3:14])=[O:8])[N:5]2[C:18](=[O:20])[CH2:19][C@H:4]2[C:3]1=[O:21]
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C[C@H]2C1=O
Agent: [Ni]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1C(=O)[C@@H]2CC(=O)N2C1C(=O)OCOC(=O)C(C)(C)C
Reaction time: 1 h

Procedure:
Pivaloyloxymethyl 2-methyl-1-oxocarbapen-2-em-3-carboxylate, freshly prepared from 50 mg. of pivaloyloxymethyl 1-beta-oxo-2-diazo-3-methylceph-3-em-4-carboxylate by the method of Example 1 (employing the alternative Raney nickel step), was taken up in approximately 0.25 ml. of tetrahydrofuran and added to a slurry of 500 mg. of zinc powder, specially activated by the method of Rieke and Uhm [Synthesis, 452 (1975)], in 15 ml. of acetic acid-30% tetrahydrofuran at 0° C. After stirring for 1 hour at this temperature, the reaction mixture was diluted with toluene, stripped in vacuo and the residue chased several times with toluene. The vacuum pumped residue was taken up in excess methylene chloride, the zinc removed by filtration, and the filtrate reevaporated in vacuo to yield essentially homogeneous pivaloyloxymethyl 2-methyl-1-oxocarbapenam-3-carboxylate (tlc: Rf 0.45 with 18:1 chloroform:ethyl acetate as eluant; ir 1780, 1760 cm-1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1)[CH3:2].C1C(=O)N([Br:20])C(=O)C1>C(Cl)Cl>[Br:20][C:8]1[C:9]([NH2:12])=[N:10][CH:11]=[C:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOCCc1cnc(N)cn1
Solvent: ClCCl
Product: CCOCCc1cnc(N)c(Br)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(2-ethoxyethyl)pyrazin-2-amine (45 mg, 0.269 mmol) in DCM (897 μL) was added NBS (43.1 mg, 0.242 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min. After quenched with sat. NaHCO3, the reaction mixture was extracted with EtOAc 3 times. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was used in next step reaction without purification. LCMS (m/z): 246.0 (MH+), 0.59 min.
Reaction SMILES: [F:1][C:2]1[C:3]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])=[C:7]2[OH:26]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:3]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: CC(C)COc1ccc2c(c1F)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COc1ccc2c(c1F)C(C)(C)C(=O)C(C(=O)NCC(=O)O)=C2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A mixture of 1,1-dimethylethyl N-((8-fluoro-4-hydroxy-1,1-dimethyl-7-((2-methylpropyl)oxy)-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.22 g, 0.51 mmol) in 2 mL TFA was stirred at room temperature for 30 minutes, M+1=380. The mixture was concentrated and triturated in DCM/hexane (5:10). The solid was filtered, washed with 10 mL DCM/hexane (5:10), and dried under high vacuum to give 0.18 g of the product as a pale yellow solid. MS (m/z)=380 (M+H)+. Calculated for C19H22FNO6 379.14.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1>N1C=CC=CC=1>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)[CH:19]=1
Reactant: Nc1cccnc1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: c1cncc(N=C2SC[C@@H]3Cc4ccccc4CN23)c1
Reaction time: 24 h
Yield: 79.7 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (36.3 g.) is added, a little at a time, to a solution of 3-aminopyridine (15 g.) in pyridine (1 liter). The suspension gradually passes into solution. After 24 hours at a temperature of about 20° C., the solution is concentrated to dryness under reduced pressure (25 mm. Hg.). The residue is dissolved in a mixture of methylene chloride (250 cc.), 2N sodium hydroxide solution (200 cc.) and water (200 cc.). The organic phase is decanted, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (30 mm. Hg) at 40° C. The residue is recrystallised from acetonitrile (150 cc.) to give (S)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (22.4 g.) in the form of white crystals which melt at 111° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1>>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:24]2[CH2:25][CH2:26][CH:21]([CH:19]3[O:18][C:15]4=[CH:16][N:17]=[C:12]([C:9]5[CH:10]=[CH:11][C:6]([CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=5)[CH:13]=[C:14]4[CH2:20]3)[CH2:22][CH2:23]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from 5-(4-methanesulfonylmethyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.55 min; Mass spectrum (ESI+): m/z=479 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][OH:23])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=[O:23])=[CH:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CO)cc2-c2ccccc2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution (10 mL) of {1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanol (1.50 g) in acetonitrile were added tetra-n-propylammonium perruthenate (150 mg), N-methylmorpholine N-oxide (932 mg) and molecular sieves 4A powder (1.5 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→1:1) to give the title compound as a brown oil (yield 1.23 g, 82%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([N:34]5C(=O)C6=CC(C)=CC=C6C5=O)[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:46])[C:14]2=[O:15])[N:3]=1.C1(C)C=CC=CC=1.C(CN)O>O>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:28]2[CH2:29][C@H:30]([NH2:34])[CH2:31][CH2:32][CH2:33]2)=[N:18][C:17]2[N:16]([CH3:46])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccc(C)cc4C3=O)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Solvent: Cc1ccccc1
Solvent: NCCO
Solvent: O
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 77.5 °C

Procedure:
In a clean round bottom flask, 10 gm of 1-[(4-Methylquinazolin-2yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3(R)-4-methyl phthalimidopiperidine-yl)-xanthine and 100 ml of toluene were charged. 10 ml of ethanolamine was added to the reaction mass and heated to 75-80° C. to complete the reaction. The reaction mass was cooled to 50-55° C. Water was added to reaction mass & layers were separated. Organic phase was distilled under vacuum to get Linagliptin crude. Dry wt: 7.50 gm
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([C:8]1[S:12][C:11]([NH2:13])=[N:10][N:9]=1)[CH:6]=[CH2:7]>C(OCC)(=O)C>[CH2:5]([C:8]1[S:12][C:11]([N:13]=[C:1]=[O:2])=[N:10][N:9]=1)[CH:6]=[CH2:7]
Reactant: O=C(Cl)Cl
Reactant: C=CCc1nnc(N)s1
Solvent: CCOC(C)=O
Product: C=CCc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-allyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-allyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:16])[CH2:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][CH:5]=1.Br[CH2:18][O:19][CH3:20]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.ClCCl>[CH3:18][O:19][CH2:20][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:16])[CH2:9][C:10]([CH3:14])([CH3:15])[O:11]2)=[CH:6][CH:5]=1
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Reactant: COCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1ccc2c(c1)OC(C)(C)CC2=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
A mixture of 20 ml of 10% sodium hydroxide solution, 50 ml of dichloro methane, 0.5 g (2 millimoles) of triethyl benzyl ammonium chloride and 0.9 g (10 millimoles) of 7-hydroxy-2,2-dimethyl-4-chromanone is intensively stirred at 20° C. for 30 minutes. To the mixture 3.1 g (2 ml, 25 millimoles) of bromomethyl-methyl-ether are added. The reaction mixture is stirred for a further 30 minutes, the organic phase is separated, washed twice with 50 ml. of water each, dried and the solvent is removed. The residue is crystallized from 70% ethanol. Thus 2.1 g of the desired compound are obtained, yield 90%. Mp.: 77°-79° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:21]1[C:30]([N:31]([CH:33]([CH3:35])[CH3:34])[CH3:32])=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:36]([O:38][CH3:39])=[O:37])[CH:27]=2)[N:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:21]3[C:30]([N:31]([CH:33]([CH3:35])[CH3:34])[CH3:32])=[N:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:36]([O:38][CH3:39])=[O:37])[CH:27]=4)[N:22]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4c(c3)CCCO4)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 54.4 %

Procedure:
To a solution of 2-(chroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (320 mg, 1.23 mmol) in dioxane (5.0 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 180 mg, 0.61 mmol), K3PO4 (392 mg, 1.86 mmol), Pd(PPh3)4 (35.8 mg, 0.03 mmol) and water (3 drops) with stirring for 4 h at 95° C. maintained with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was applied onto a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl 2-(chroman-6-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (130 mg, 51%).