Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:10]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)([O-:13])(=[O:12])=[S:11].[K+]>C(O)C>[C:3]1([CH2:2][CH2:1][O:13][S:10]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[S:11])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Reactant: BrCCc1ccccc1
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=S)OCCc2ccccc2)cc1

Procedure:
The title compound was prepared according to General Method 2 using phenethyl bromide (0.088 mmol), potassium thiotosylate(0.088 mol), and absolute ethanol (250 mL). A clear liquid was obtained which was used without purification. 1H NMR (CDCl3) δ 2.47 (s, 3 H), 2.92 (t, 2 H), 3.24 (t, 2 H), 7.1-7.4 (m, 7 H), 7.84 (d, 2 H).
Reaction SMILES: N#N.[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[CH3:29][C:30]1[NH:31][C:32]([CH3:41])=[CH:33][C:34]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>CCCCCC.CCOCC>[CH3:29][C:30]1[NH:31][C:32]([CH3:41])=[CH:33][C:34]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:20]2[CH:21]=[CH:22][C:17]([CH2:16][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][N:10]3[CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:18][CH:19]=2)[N:36]=1
Reactant: Brc1ccc(CC2CCCCN2Cc2ccccc2)cc1
Reactant: Cc1cc(-c2ccccn2)c(C)[nH]1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(-c2cccc(-c3ccc(CC4CCCCN4Cc4ccccc4)cc3)n2)c(C)[nH]1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
To a 100 mL 3N round-bottomed flask equipped with septum and N2 inlet were added 175 mg (0.509 mmol) N-benzyl-2-(4-bromobenzyl)-piperidine and 7 mL dry ether. The solution was cooled to −70° C., and 0.38 mL (0.610 mmol) of a 1.6 M solution of butyl lithium in hexane added dropwise over 1 minutes. The reaction was stirred at −70° C. for 5 min, then warmed to room temperature over 20 minutes. To the stirring reaction was then added a solution of 105 mg (0.610 mmol) 2-(2,5-dimethylpyrrolyl)-pyridine in 5 mL dry ether, and the reaction, turning dark orange, was stirred at room temperature for 4 hours then quenched with aqueous ammonium chloride solution. After extraction into ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate for 16 hours to effect air-oxidation to the pyridine, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford 36 mg (16%) of an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(=O)O[CH2:10][CH2:9][O:8]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:10][CH2:9][OH:8])=[C:16]([O:21][CH3:22])[CH:15]=1
Reactant: COc1cc(Br)ccc1O
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(Br)ccc1OCCO
Temperature: 115 °C
Yield: 82.6 %

Procedure:
Potassium carbonate (1.4 g, 10 mmol) was added to a solution of ethylene carbonate (1.8 g, 20 mmol) and 4-bromo-2-methoxyphenol (1.05 g, 5 mmol) in 5 mL of toluene under an inert atmosphere. The reaction was heated at 115° C. for 12 h. Water (50 mL) and ethyl acetate (2×100 mL) were added to the reaction mixture to stir. The organic layers were combined, dried, filtered, and evaporated to get a yellow oil residue. The residue was purified by flash chromatography (eluting with 40→45% EtOAc in hexanes) to give compound 8a as a light brown yellow oil (1 g; 4.13 mmol; 82.6% yield); MS (APCI) (M+H)+ 246. 1H NMR (400 MHz, chloroform-D) δ ppm 2.83 (t, J=6.3 Hz, 1H) 3.84 (s, 3H) 3.89-4.01 (m, 2H) 4.03-4.13 (m, 2H) 6.78 (d, J=8.3 Hz, 1H) 6.99 (d, 1H) 7.02 (d, 1H).
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:16][CH:17]1[CH2:22][NH:21][CH:20]([CH3:23])[CH2:19][NH:18]1.C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>CC(O)C.ClCCl>[CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:18]2[CH2:19][CH:20]([CH3:23])[N:21]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[C:32]([F:31])([F:42])[F:43])[CH2:22][CH:17]2[CH3:16])=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC1CNC(C)CN1
Reactant: CCCCCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCNC(=O)c1ccc(N2CC(C)N(C(=O)c3ccccc3C(F)(F)F)CC2C)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.8 %

Procedure:
To a mixture of 6-chloropyridazine-3-carboxylic acid pentylamide (304 mg, 1.00 mmol) in 2-propanol (12 mL) was added 2,5-dimethylpiperazine (1.37 g, 12.0 mmol). The reaction mixture was refluxed for 2 days. Another 0.25 g of 2,5-dimethylpiperazine and 1.0 mL of triethylamine were added to the reaction mixture and heating was continued for another 24 hours. After the reaction mixture was cooled to ambient temperature and the solvent was removed by rotary evaporator. To the dichloromethane solution of the crude material (20 mL) was added the solution of 2-trifluoromethylbenzoyl chloride (0.63 g, 3.00 mmol) in dichloromethane (20 mL) and the reaction mixture was stirred at ambient temperature for 16 hours. The organic layer was diluted with dichloromethane (50 mL) and then washed with 10% HCl, dried over MgSO4. After filtration, the filtrate was concentrated in vacuo. The crude material was purified by column chromatography eluting with ethyl acetate (100%) to afford 300 mg (31% yield) of the product as a colourless solid. 1H NMR (300 MHz, CDCl3) δ 7.74-7.43, 7.36-7.24, 5.17-5.04, 4.91-4.79, 4.52, 4.52, 3.68-3.57, 3.54-3.44, 3.39-3.11, 2.93, 2.85-2.71, 1.36-1.31, 1.27-1.15, 1.23-1.05.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5]([SH:8])=[N:6][CH:7]=1.Br[CH:12]([CH3:14])[CH3:13]>>[CH:12]([S:8][C:5]1[C:4]([C:9]#[N:10])=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)([CH3:14])[CH3:13]
Reactant: CC(C)Br
Reactant: Cc1cnc(S)c(C#N)c1
Product: Cc1cnc(SC(C)C)c(C#N)c1
Yield: 70 %

Procedure:
5-Methyl-2-sulfanyl-pyridine-3-carbonitrile (0.2 g, 1.3 mmol) and 2-bromopropane were reacted in the same manner as in Step A of Preparation Example 5 to obtain the title compound (0.18 g, 70%).
Reaction SMILES: [C:1]([C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(C(C)=O)C(C)C.[CH2:31]([Cl:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1CCCCC1>[CH3:6][C:5]([CH2:4][C:1]([C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N+:19]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:21])[CH3:20])=[CH:11][CH:10]=1)([CH3:2])[CH3:3])([CH3:8])[CH3:7].[Cl-:38]
Reactant: CN(C)CCOCCOc1ccc(C(C)(C)CC(C)(C)C)cc1
Reactant: ClCc1ccccc1
Solvent: C1CCCCC1
Solvent: CC(=O)CC(C)C
Product: CC(C)(C)CC(C)(C)c1ccc(OCCOCC[N+](C)(C)Cc2ccccc2)cc1
Product: [Cl-]
Reaction time: 2 h

Procedure:
170.0 g of p-tert-octyl phenoxy ethoxy ethyl dimethylamine was added to a 1 L four-necked reaction flask, to which were sequentially added 100.2 g of methyl isobutyl ketone and 126.6 g of benzyl chloride. The reaction mixture was heated to reflux. The reaction was carried out for 2 hours. Then, 168.2 g of cyclohexane was added slowly. The flask was cooled to carry out crystallization. 156.8 g of a white solid was collected. The content of benzethonium chloride was 99.2% determined by titration according to the method described on page 247 of the United States Pharmacopeia USP29. The measured melting point was from 159.0 to 162.0° C. As calculated with reference to p-tert-octyl phenol, an overall yield of the three steps was less than 15%, which is remarkably far from that obtained by using a phase transfer catalyst. Thus, it does not have a practical application value.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1.C[O:14][C:15]1C=CC=C[C:16]=1C1CC(=O)CC(=O)C1>>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([CH:7]2[CH2:8][C:9](=[O:11])[CH2:10][C:15](=[O:14])[CH2:16]2)=[CH:5][CH:6]=1
Reactant: CC(=O)C=Cc1ccc(C)cc1
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Product: Cc1ccc(C2CC(=O)CC(=O)C2)cc1

Procedure:
The title compound was prepared from 4-p-tolyl-but-3-en-2-one stage 1 (4.8 g, 30.0 mmol), following the procedure describing the synthesis of 5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (example 1/a stage 2).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:6]([F:10])([F:9])[CH2:7][CH3:8])=[CH:4][F:5].[FH:13]>>[F:1][C:2]([F:11])([F:12])[CH:3]([C:6]([F:9])([F:10])[CH2:7][CH3:8])[CH:4]([F:13])[F:5]
Reactant: F
Reactant: CCC(F)(F)C(=CF)C(F)(F)F
Product: CCC(F)(F)C(C(F)F)C(F)(F)F

Procedure:
As another example, 4-trifluoromethyl-3,5,5,5-tetrafluoro-1-pentene may be prepared by fluorinating 3-pentanone to form 3,3-difluoropentane which may then be dehydrogenated to form 3,3-difluoro-1-pentene. CF3 may then be reacted with the 3,3-difluoro-1-pentene to form 2-trifluoromethyl-1,3,3-trifluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3-trifluoro-1-pentene. The 2-trifluoromethyl-1,3,3-trifluoro-1-pentene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3-tetrafluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,1,3,3-tetrafluoro-1-pentene which may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,1,3,3-pentafluoropentane. The 2-trifluoromethyl-1,1,1,3,3-pentafluoropentane may then be dehydrohalogenated to form 4-trifluoromethyl-3,5,5,5-tetrafluoro-1-pentene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:11][O:10][C:4]1[N:3]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])(=[O:21])=[O:20])=[O:24])[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(N)nc(OC)n1
Solvent: ClCCl
Product: COc1cc(NC(=O)NS(=O)(=O)c2ccccc2C)nc(OC)n1
Reaction time: 0.67 h

Procedure:
To a stirred mixture of 2.40 g of 4-amino-2,6-dimethoxypyrimidine in 40 ml methylene chloride at ambient temperature and pressure was slowly added 3.0 g of 2-methylbenzenesulfonylisocyanate. The reaction was stirred 40 minutes, filtered, and the solid thereby obtained was washed with a small amount of acetonitrile; yield 4.0 g, m.p. 174°-175°, NMR (DMSO-d6) relative to tetramethylsilane: δ 2.77, S, area 30; δ 4.05, S, area 60; δ 6.85, S, area 89; δ 7.7-8.6, multiplets, area 45; δ 10.00, S, area 9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH:9]([C:12]1[C:13]([CH2:32][OH:33])=[C:14]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:15]([CH2:21]C(O)=O)=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=1)([CH3:11])[CH3:10].[CH2:34](Cl)Cl.CCCCCC>>[CH:18]([C:16]1[C:15]([CH2:21][S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[C:14]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:13]([CH:32]([OH:33])[CH3:34])=[C:12]([CH:9]([CH3:11])[CH3:10])[CH:17]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(-c2ccc(F)cc2)c1CO
Reactant: ClCCl
Reactant: Cc1ccc(S)cc1
Solvent: CCCCCC
Product: Cc1ccc(SCc2c(C(C)C)cc(C(C)C)c(C(C)O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from p-thiocresol and 3,5-diisopropyl-2-hydroxymethyl-6-carboxymethyl-4′-fluoro-1,1′-biphenyl (Example 244, Step D), according to the procedures described in Example 47, Steps B and C, followed by the procedures described in Example 244, Steps I-K. Rf=0.36 (70% CH2Cl2/hexane); 1H NMR (300 MHz, CDCl3): δ 7.40 (s, 1H), 7.28 (m, 2H), 7.11 (m, 6H), 4.76 (dq, J=1.8, 7 Hz, 1H), 3.92 (septet, J=6.6 Hz, 1H), 3.78 (s, 2H), 3.26 (septet, J=6.6 Hz, 1H), 2.36 (s, 3H), 1.66 (s, 1H), 1.40 (d, J=6.6 Hz, 3H), 1.28 (m, 12H); FAB-MS calcd for (C28H33FOS) 436, found 436 (M+); Anal. Calcd for C29H35FOS: C, 77.02; H, 7.62; S, 7.34; F, 4.35. Found: C, 76.90; H, 7.77; S, 7.30; F, 4.37; [α]22=+32.2.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12]C(C2C=NC3C(C=2Cl)=CC(F)=CC=3F)=O)[CH2:8][CH2:7]1>C(N(CC)CC)C>[ClH:3].[CH3:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1
Reactant: C[C@H]1CC[C@H](NC(=O)c2cnc3c(F)cc(F)cc3c2Cl)CC1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@H]1CC[C@H](N)CC1
Product: Cl

Procedure:
Hydrolysis of ethyl 4-chloro-6,8-difluoroquinoline-3-carboxylate afforded 10.5 g of crude 4-hydroxy-6,8-difluoroquinoline-3-carboxylic acid hydrochloride. The crude acid (2 g,), thionyl chloride, trans-4-methylcyclohexylamine hydrochloride (748 mg, 5 mmol), and triethylamine (0.3 mLs) afforded crude N-(trans-4-methylcyclohexyl)-4-chloro-6,8-difluoroquinoline-3-carboxamide.
Reaction SMILES: O.[NH2:2][NH2:3].[N-:4]=[C:5]=[S:6].[Cl:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14]>C(O)C>[Cl:7][C:8]1[CH:9]=[C:10]([NH:2][NH:3][NH:4][CH:5]=[S:6])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: [N-]=C=S
Reactant: Clc1ccccc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: S=CNNNc1ccc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
The hydrazine hydrate (7.12 mL; 147 mmol) is dissolved in 220 mL of ethanol. This solution is stirred at 0° C. and 3,4-dichlorobenzenisothiocyanate (20.00 g; 98 mmol) is added dropwise, and the reaction mixture is warmed to RT and stirred for two hours. After being cooled to 0° C., the mixture is filtered and the solid washed by cold ethanol (40 mL). The solid is crystallized from ethanol to yield ([(3,4-dichlorophenyl)-amino]hydrazinomethane-1-thione) (12.702 g; 55%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:20]([NH2:21])[C:19](=[O:22])[N:6]2[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9].[ClH:23].F[C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.Cl>CN(C=O)C.C(#N)C.CO>[ClH:23].[NH:26]1[CH:27]=[CH:28][N:29]=[C:25]1[NH:21][CH:20]1[C:19](=[O:22])[N:6]2[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17])=[O:9])=[C:2]([CH3:1])[CH2:3][S:4][C@H:5]12
Reactant: Fc1ncc[nH]1
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1

Procedure:
A solution of 0.18 g. of pivaloyloxymethyl 3-methyl-7-aminoceph-3-em-4-carboxylate (0.18 g.) and 2-fluoroimidazole hydrochloride (0.14 g.) in DMF (1 ml.) and acetonitrile (1 ml.) was heated at 50° for 7 hours. After evaporation the residue was chromatographed on silica gel using CH2Cl2 /MeOH 95:5 v/v as eluant. The oily product was treated with one equivalent of HCl in MeOH. The solution was evaporated and the residue was triturated with ether and filtered to give pivaloyloxymethyl 7-(imidazol-2-yl)amino-3-methylceph-3-em-4-carboxylate hydrochloride having the following n.m.r. in d6DMSO+CD3COOD: 1.2 (s, 9H); 2.1 (s, 3H); 3.6 (m, 2H); 5.25 (d, 1H); 5.7 (d, 1H); 5.85 (m, 2H); 7.05 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]12[CH2:23][CH2:22][CH2:21][CH2:20][C:7]1([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1)[NH:8][C:9](=[O:19])[N:10]2[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1)C.[Li+].[OH-].Cl>CO.O>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:7]23[CH2:20][CH2:21][CH2:22][CH2:23][C:6]2([CH2:5][C:4]([OH:33])=[O:3])[N:10]([C:11]2[CH:12]=[C:13]([Cl:18])[CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:9](=[O:19])[NH:8]3)=[CH:26][CH:27]=1)#[N:32]
Reactant: CCOC(=O)CC12CCCCC1(Cc1ccc(C#N)cc1)NC(=O)N2c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(CC23CCCCC2(CC(=O)O)N(c2cc(Cl)cc(Cl)c2)C(=O)N3)cc1
Reaction time: 96 h
Yield: 12.2 %

Procedure:
[7a-(4-Cyano-benzyl)-3-(3,5-Dichlorophenyl)-2-oxo-2,3,5,6,7,7a-hexahydro-benzimidazol-3a-yl]-acetic acid ethyl ester (34 mg) (0.07 mmol) and LiOH (3.0 mg) (1.1 eq) in a 1:1 mixture of MeOH/H2O (4 ml) (5 ml) were stirred 4 days. The reaction mixture was acidified with an aqueous solution of HCl 1N, then concentrated. The residue was purified on HPLC to give [7a-(4-Cyano-benzyl)-3-(3,5-Dichlorophenyl)-2-oxo-2,3,5,6,7,7a-hexahydro-benzimidazol-3a-yl]-acetic acid (3.9 mg) as a white solid. 1H NMR (CDCl3): 7.55 (2H, d), 7.25 (2H, d), 7.15 (1H, m), 6.75 (2H, m), 5.0 (1H, m), 4.45 (1H, d), 3.83 (1H, d), 3.05 (1H, d), 2.9 (1H, d), 2.5-2.1 (2H, m), 2.1-1.8 (4H, m).
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: NCCO
Solvent: O
Solvent: Cc1ccccc1
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(=O)([O-])[O-].[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:29]3[CH:30]=[C:31](OS(C(F)(F)F)(=O)=O)[CH:32]=[CH:33][C:28]=3[N:27]3[C:42]([CH3:45])=[N:43][N:44]=[C:26]3[C@H:25]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[N:24]=2)=[CH:19][CH:18]=1.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:29]3[CH:30]=[C:31]([C:10]4[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=4)[CH:32]=[CH:33][C:28]=3[N:27]3[C:42]([CH3:45])=[N:43][N:44]=[C:26]3[C@H:25]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[N:24]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccncc3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
Sodium carbonate (66.3 mg), 4-pyridinylboronic acid (22.5 mg) and bis(triphenylphosphine)palladium(II) chloride (19.1 mg) were added to a 2-5 ml microwave vial. A solution of ethyl ((4S)-6-(4-chlorophenyl)-1-methyl-8-{[(trifluoromethyl)sulfonyl]oxy}-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)acetate (for a preparation see intermediate 2) (147.5 mg) in DME (3 ml) and water (1 ml) was added to the microwave vial. The reaction mixture was heated at 120° C. for 90 min (microwave). Ethyl acetate (2 ml) was added and the water layer was separated and acidified with glacial acetic acid. The aqueous was extracted with ethyl acetate (3×5 ml), the organic fractions dried and the solvent evaporated. The residue was chromatographed (0-10% methanol:DCM) and then further purified by MDAP (formate modifier) to give ethyl [(4S)-6-(4-chlorophenyl)-1-methyl-8-(4-pyridinyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate as a white solid (5.5 mg).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=O)[CH2:3]1)[CH2:9]2.CO.[CH2:15](B1OC(C)(C)C(C)(C)O1)[CH:16]=[CH2:17].[NH3:27]>>[CH2:15]([C:5]1([NH2:27])[CH:6]2[CH2:11][C:2]3([OH:1])[CH2:9][CH:8]([CH2:10][CH:4]1[CH2:3]3)[CH2:7]2)[CH:16]=[CH2:17]
Reactant: N
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Solvent: CO
Product: C=CCC1(N)C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Hydroxy-2-adamantanone (3.0 g, 18.1 mmol) was dissolved in a solution of ammonia in methanol (7N, 26 mL, 180 mmol, 10 eq.) and stirred for 15 min at room temperature. Then, 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (5.4 mL, 28.9 mmol, 1.6 eq.) was added dropwise. The reaction mixture was stirred for 16 h at room temperature before the volatiles were removed in vacuo. The residue was taken up in methanol twice and evaporated, then lyophilized from water to give 4-allyl-4-amino-adamantan-1-ol (3) as a mixture of diastereomers. Rt=1.05 min, 1.79 min (Method 2). Detected mass: 270.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:4]2[C:13]3[CH:12]=[C:11]([O:14][CH3:15])[C:10]([C:16]4[C:17]([CH3:22])=[N:18][O:19][C:20]=4[CH3:21])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:23]=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>CN1C(=O)CCC1.CS(C)=O>[CH3:22][C:17]1[C:16]([C:10]2[C:11]([O:14][CH3:15])=[CH:12][C:13]3[C:4]4[N:3]([CH2:24][CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:2]([NH:34][CH2:33][CH2:31][OH:32])=[N:23][C:5]=4[CH:6]=[N:7][C:8]=3[CH:9]=2)=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: NCCO
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n(CC3CCOCC3)c12
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(NCCO)n(CC3CCOCC3)c12
Temperature: 180 °C
Yield: 5.4 %

Procedure:
2-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (for a preparation see Intermediate 15) (14 mg, 0.033 mmol) and ethanolamine (0.020 ml, 0.327 mmol) were dissolved in NMP (2 ml) and heated at 180° C. in the microwave for 1 h, then cooled and loaded onto a 10 g SCX-2 cartridge, washing with methanol (30 ml). The cartridge was then eluted with 2M methanolic ammonia (30 ml) and the eluant evaporated in vacuo to give a sparingly soluble brown gum. This was dissolved in DMSO (1 ml) and purified by MDAP (formate) to give 2-{[7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]amino}ethanol (0.80 mg, 1.772 μmol, 5.40% yield) as a pale yellow glass. LCMS (formate) Rt 0.62 min, MH+ 452
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[N:22][N:21]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:25]([C:23]1[S:24][C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:21][N:22]=1)(=[O:26])=[O:27])[CH3:4]
Reactant: O=S(=O)(Cl)c1nnc(-c2ccc(Cl)cc2)s1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of N-(2-aminoethyl)-glycine ethyl ester 2HCl (1.4 g, 6.4 mmol), prepared as described by Will (D. W. Will et al., Tetrahedron, 1995, 51, 12069.), in dichloromethane (50 mL) was added 5-(4-chlorophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride (1.5 g, 5.1 mmol) at 0° C. Then triethylamine (2.7 mL) was slowly added. The resulting reaction mixture was stirred for additional 2 h. at room temperature and washed with water (30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated, followed by column chromatography to give the title compound (1.1 g, 2.7 mmol, 53%) as a solid. 1H NMR (500 MHz; DMSO-d6) δ 8.08 (d, 2H), 7.66 (d, 2H), 4.03 (q, 2H), 3.26 (s, 2H), 3.15 (t, 2H), 2.64 (t, 2H), 1.14 (t, 3H).