Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][N:13]([CH3:28])[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:28])[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cn2cc(N(C)C)ccc2n1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CN(C)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.46 ml of a 2M solution of trimethylaluminum in toluene is added dropwise to a solution, cooled to 0° C., of 60.8 μl of aniline in 3 ml of toluene, followed, at 20° C., by the addition of 76 mg of ethyl 6-dimethylaminoimidazo[1,2-a]pyridine-2-carboxylate. The reaction mixture is stirred at ambient temperature for 15 minutes. It is cooled to 0° C. and then 20 ml of a saturated ammonium chloride solution are added. The organic phase is dried over magnesium sulfate, filtered through Celite and evaporated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, elution being carried out with a mixture of dichloromethane and ethyl acetate. The fractions comprising the product are combined and concentrated to dryness under reduced pressure. The residue obtained is crystallized from methanol to give 36 mg of 6-(dimethylamino)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a gray powder.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[CH:5]=[CH:4]1.N1C=CC=CC=1.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[CH:5]=[CH:4]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1C=C[C@H](CO)O1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1C=C[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Reaction time: 6 h
Yield: 90.3 %

Procedure:
(R)-(+)-5-Hydroxymethyl-2 (5H)-furanone (1.94 g, 17.0 mmol) was dissolved in anhydrous pyridine (60 mol), triphenylmethyl chloride (14.3 g, 51.2 mmol) was added to the solution at room temperature, and the mixture was stirred for 6 hr. Ethanol was added to the reaction solution at 0° C., and the mixture was stirred for one hr. The reaction solution was concentrated under reduced pressure, and the concentrate was subjected to azeotropic distillation twice with toluene and purified by column chromatographic separation on silica gel (hexane:ethyl acetate=3:1 to 2:1) to give (R)-(+)-5-triphenylmethyloxymethyl-2 (5H)-furanone (5.47 g, 90%).
Reaction SMILES: C(Cl)(=O)[C:2]([Cl:4])=O.[CH3:7][O:8][C:9]([CH:11]1[O:15][CH:14]([C:16]([OH:18])=O)[CH2:13][CH2:12]1)=[O:10]>ClCCl.CN(C)C=O>[Cl:4][CH2:2][C:16]([CH:14]1[O:15][CH:11]([C:9]([O:8][CH3:7])=[O:10])[CH2:12][CH2:13]1)=[O:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)C1CCC(C(=O)O)O1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(C(=O)CCl)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.55 ml) was added to a stirred solution of (2RS, 5SR) -5-methoxycarbonyltetrahydrofuran-2-ylcarboxylic acid (2.00 g) in dichloromethane (30 ml). Dimethylformamide (1 drop) was added and the mixture stirred at room temperature for 1 h, and then heated to reflux for 10 min. The mixture was cooled and the solvent removed on a rotary evaporator. Chloroform was then evaporated from the residue twice. The residue was dissolved in dichloromethane (100 ml) and the solution cooled in an ice bath, then excess diazomethane was passed into the solution. The mixture was stirred at 0° C. for 15min and then excess hydrogen chloride was passed into the solution. The solution was washed with brine, dried over magnesium sulphate and evaporated. The title compound (2.02 g) was isolated by column chromatography of the residue using gradient elution (silica gel, 4:1 going to 1:1 hexane:ethyl acetate); νmax (CHCl3) 1740 cm-1 ; δH (CDCl3) 1.9-2.5 (4 H, m), 3.71 (3 H, s), 4.45-4.8 (2 H, m), 4.54 (1 H, d, J 18 Hz) and 4.89 (1 H, d, J 18 Hz).
Reaction SMILES: [CH:1]12[CH2:12][CH2:11][CH:8]([CH:9]=[CH:10]1)[C:7]1[C:2]2=[CH:3][CH:4]=[CH:5][CH:6]=1.C1C[O:16]CC1>>[C@@H:8]12[CH2:11][CH2:12][C@H:1]([CH:10]([OH:16])[CH2:9]1)[C:2]1[C:7]2=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CC2CCC1c1ccccc12
Reactant: C1CCOC1
Product: OC1C[C@H]2CC[C@H]1c1ccccc12
Reaction time: 8 h

Procedure:
A solution of 15.8 g of tricyclo[6.2.2.02,7]dodeca-2,4,6,9-tetraene in 42 mL of THF was added to 82 mL of 1M BH3 in THF at 0° C. The reaction mixture was stirred overnight while the temperature reached rt. The reaction was quenched by addition of 40 mL of 0.3N NaOH solution followed by 134 mL of a 35% H2O2 solution. The mixture was extracted with Et2O, washed with H2O, dried over MgSO4 and concentrated in vacuo to obtain 17.7 g of the desired compound as yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Cl[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[NH:10][CH:11]=[N:12]2.[N-:17]=[N+:18]=[N-:19].[Li+]>CS(C)=O>[NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[N:17]([C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[NH:10][CH:11]=[N:12]2)=[N+:18]=[N-:19]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: [N-]=[N+]=[N-]
Agent: O=C1CCCN1
Agent: [Li+]
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1ncnc2nc[nH]c12

Procedure:
The 6-chloropurine pyrrolidone (1 mmol) is treated with lithium azide (2 mmol) in dimethyl sulfoxide (2 ml) at 30°-100° C. for several h. At the end of this time the mixture is evaporated under reduced pressure, dissolved in chloroform, washed with 10% sodium bicarbonate, and the organic layer dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica using a gradient of methanol in chloroform (0-25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:11][C:12]#[C:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)=[CH:5][CH:4]=1.C(Cl)(Cl)Cl.[OH-:26].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[S:9][CH2:11][CH:12]([C:13](=[O:26])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(S(=O)CC#CCOc2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(C(=O)COc1ccccc1)CS2
Reaction time: 18 h

Procedure:
NMR analysis of both gums indicated the second to be of higher purity, so this was used in the subsequent stages. A mixture of the crude 1-(4-methoxyphenylsulphinyl)-4-phenoxybut-2-yne (2.1 g) and chloroform (25 ml) was heated under nitrogen at an external temperature of 80°-85° C. for 1 hour, allowed to stand at ambient temperature for 18 hours, and heated at an external temperature of 90°-95° C. for 6 hours. The solvent was removed by distillation to leave crude 5-methoxy-3-methylene-2-phenoxymethyl-2,3-dihydrobenzo[b]thiophen-2-ol as an orange gum. The orange gum was dissolved in dichloromethane (30 ml) and the solution was shaken vigorously for a few seconds with 5M aqueous sodium hydroxide solution (25 ml), then the organic solution was separated, washed with water (25 ml), dried (MgSO4), and the solvent removed in vacuo to leave crude 1-(5-methoxy-2,3-dihydrobenzo[b]thiophen-3-yl)-2-phenoxyethanone as a red gum (1.94 g) which was used without purification.
Reaction SMILES: [Si]([O:18][C:19]1[CH:67]=[CH:66][C:22]([O:23][CH2:24][C@@H:25]([OH:65])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:64]=[CH:63][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([N:43]4[CH2:48][CH2:47][CH:46]([C:49]5[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[C:51]([O:57][CH:58]6[CH2:62][CH2:61][CH2:60][CH2:59]6)[CH:50]=5)[CH2:45][CH2:44]4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH:58]1([O:57][C:51]2[CH:50]=[C:49]([CH:46]3[CH2:45][CH2:44][N:43]([C:41]([N:38]4[CH2:39][CH2:40][CH:35]([NH:34][C:33]5[CH:63]=[CH:64][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:65])[CH2:24][O:23][C:22]6[CH:66]=[CH:67][C:19]([OH:18])=[CH:20][CH:21]=6)=[CH:31][CH:32]=5)[CH2:36][CH2:37]4)=[O:42])[CH2:48][CH2:47]3)[CH:54]=[CH:53][C:52]=2[O:55][CH3:56])[CH2:62][CH2:61][CH2:60][CH2:59]1
Reactant: COc1ccc(C2CCN(C(=O)N3CCC(Nc4ccc(CCNC[C@H](O)COc5ccc(O[Si](c6ccccc6)(c6ccccc6)C(C)(C)C)cc5)cc4)CC3)CC2)cc1OC1CCCC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2CCN(C(=O)N3CCC(Nc4ccc(CCNC[C@H](O)COc5ccc(O)cc5)cc4)CC3)CC2)cc1OC1CCCC1
Yield: 68 %

Procedure:
{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-1-piperidinyl}{4-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-piperidinyl}methanone (0.168 g, 0.181 mmol) was reacted according to Procedure H to yield (eluant: 5:1 chloroform-methanol) the title compound (0.085 g, 0.123 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:23]([F:40])=[C:24](/[CH:28]=[C:29](/[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])\[C:30]#[N:31])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[C:23]=2[F:40])[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])([C:30]#[N:31])[CH:9]([CH2:10][C:11]([CH3:12])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:19])[NH:8]1)=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)C/N=C/CC(C)(C)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1NC(CC(C)(C)c2ccccc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 22.2 %

Procedure:
In a manner similar to the method described in Example 1c, [[3-methyl-3-phenyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 82a (2.3 g, 8.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.4 g, 7.7 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.1 g, 21 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1 g, 22%).
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:5]([CH3:9])[N:6]=[CH:7][N:8]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[N:5]([CH3:9])[N:6]=[CH:7][N:8]=1
Reactant: [I-]
Reactant: Cn1ncnc1SCCl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1ncnc1SCI
Temperature: 50 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 3-chloromethylthio-2-methyl-1,2,4-triazole (981 mg: 6.0 mMol.) in acetone (10 ml) is added sodium iodide (1.78 g: 12.0 mMol.), and the mixture is stirred at 50° C. for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated to give 3-iodomethylthio-2-methyl-1,2,4-triazole (1.47 g) as yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(O)(C)(C)C>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=3)[N:5]=[CH:4][C:3]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CCOC(=O)c1cnc2ccc(Cl)nc2c1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.7 %

Procedure:
Ethyl 4,6-dichloro-1,5-naphthyridine-3-carboxylate (0.5 g, 1.85 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (0.45 g, 2.22 mmol) were dissolved in the mixture of DCM (5 mL) and tert-butyl alcohol (5 mL). Potassium carbonate (0.612 g, 4.43 mmol) was added to the solution. The reaction mixture was stirred at ambient temperature for 24 h and filtrated under reduced pressure. The solid was washed by DCM. The filtrate was concentrated under reduced pressure. The residue was recrystallized in diethyl ether to give a faint yellow solid (0.73 g, 90.9% yield).
Reaction SMILES: Cl.[OH:2][NH2:3].C[O-].[Na+].[C:7]([C:11]1[N:12]=[C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=4[O:29][CH:30]([CH2:33][CH2:34][CH3:35])[C:31]#[N:32])=[CH:21][C:19]=3[CH:20]=2)[S:14][CH:15]=1)([CH3:10])([CH3:9])[CH3:8]>CS(C)=O.CO>[C:7]([C:11]1[N:12]=[C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=4[O:29][CH:30]([CH2:33][CH2:34][CH3:35])[C:31](=[N:3][OH:2])[NH2:32])=[CH:21][C:19]=3[CH:20]=2)[S:14][CH:15]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: NO
Reactant: CCCC(C#N)Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(N)=NO
Temperature: 25 °C
Yield: 110.8 %

Procedure:
Hydroxyamine hydrochloride (174 mg) was dissolved in dimethylsulfoxide (2 ml) and 28% solution of sodium methoxide in methanol (0.125 g) was added into it. The mixture was stirred for ten minutes at room temperature. 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}-pentanenitrile (224 mg) was added into the solution and the resulting mixture was stirred at 80° C. for an hour. The reaction mixture was collected and diluted with water and was extracted with ethyl acetate. The organic layer was washed with brine and was dried over magnesium sulfate. Concentration gave 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanamide oxime as an amorphous solid (266 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:47]([C:49]1[N:50]=[C:51]([C:62]([O-])=[O:63])[N:52]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=1)#[N:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:15]1([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[N:2]([CH3:1])[CH3:21])[CH:13]=[CH:12][C:11]=2[NH:14][C:62]([C:51]2[N:52]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=[C:49]([C:47]#[N:48])[N:50]=2)=[O:63])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)S(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Yield: 100.3 %

Procedure:
A solution of 365 mg (1.18 mmol) of 2-(4-amino-3-cyclohex-1-enyl-phenyl)-ethanesulfonic acid dimethylamide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 827 mg (1.78 mmol) of PyBroP, 398 mg (1.30 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 618 μL, (3.55 mmol) of DIEA at RT for 16.5 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with water (1×20 mL). The aqueous layer was extracted with CH2Cl2 (1×20 mL) and the combined organic layers dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25-40% EtOAc-hexane afforded 660 mg (100%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C27H39N5O4SSi, 558.2 (M+H). found 557.9.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[CH3:19]C(C)([O-])C.[K+].CI>C1COCC1>[CH3:19][O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1,1-dimethylethyl 3-hydroxy-4,4-bis(methyloxy)-1-piperidinecarboxylate D16 (11 g) in THF (150 ml) was added Potassium t-Butoxide (23.5 g, 210 mmol) at 0° C. The reaction mixture was stirred for 20 mins and the methyliodide (5.2 ml, 84 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The resulting mixture was concentrated and dissolved in EtOAc and washed with water. The organic layer was concentrated in vacuo to obtain crude product. Product was purified on silica gel eluting with DCM/MeOH 50/1 to obtain the desired product D17 as a yellow oil in 5 g. LCMS [MH+] 298@1.385 min (5 min run)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(Cl)(=O)C(Cl)=O.[CH2:30](O)[CH2:31][CH2:32][CH2:33][CH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Reactant: CCCCCO
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Product: CCCCCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Yield: 52.8 %

Procedure:
2 g of 2-[2-(4-fluorophenyl)-5-(3-thienyl)-4-oxazolyl]acetic acid, 0.5 g of potassium hydroxide, 4.2 g of oxalyl chloride and 20 ml of n-pentanol are treated in the same manner as described in Example 17. 1.3 g of n-pentyl 2-[2-(4-fluorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate are thereby obtained. Yield: 52.8%
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][C:20]3([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:35]([O:34][C:32]([C:20]1([CH2:19][O:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:33])[CH3:36]
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)CCN(c2ccncc2)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(COc2ccc3c(c2)CNCC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 7-[4-ethoxycarbonyl-1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (10.87 g) in chloroform (50 ml) was dropwise added trifluoroacetic acid (30 ml) with ice-cooling, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated and to the obtained residue was added aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (8.29 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(=O)([O-])O.[Na+].O.[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([C:24](=O)[CH2:25]Br)=[CH:16]1>C(O)CC>[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([C:24]2[N:8]=[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]3[CH:25]=2)=[CH:16]1
Reactant: O=C(CBr)c1coc2ccccc12
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: Brc1ccc2nc(-c3coc4ccccc34)cn2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
In a glass tube, 250 mg of 1-(benzofuran-3-yl)-2-bromoethanone, 181 mg of 5-bromopyridin-2-ylamine and 105 mg of sodium hydrogencarbonate are dissolved in 15 ml of n-propanol. The tube is closed and heated at 80° C. for 20 h. After cooling, 20 ml of water are added and the reaction mixture is stirred for 1 hour at ambient temperature. A precipitate forms, and is recovered by filtration, washed with water and then with diisopropyl ether, and dried in a desiccator under reduced pressure. 250 mg of compound are obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[C:10]([O:14][CH3:15])[C:11](Br)=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:22][CH3:23])[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:35]([O:39]CC)(=[O:38])[CH2:36][SH:37]>CN(C=O)C.O>[O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[C:10]([O:14][CH3:15])[C:11]([S:37][CH2:36][C:35]([OH:39])=[O:38])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:22][CH3:23])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC)cc2S(=O)(=O)C1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(SCC(=O)O)c(OC)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 50.6 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (113 mg, 0.24 mmol), Cs2CO3 (170 mg, 0.52 mmol) and ethyl thioglycolate (0.060 ml, 0.54 mmol) in DMF (4.0 ml) were subjected to microwave irradiation in a Smith Synthesiser at 80° C. for 3 min and then at 90° C. for 8 min. The reaction mixture was diluted with water (250 ml) and extracted with DCM (5×10 ml) and collected organic layers were dried (MgSO4), concentrated and purified on a short column (petroleum ether: EtOAc 4:1→2:1). The resulting product was dissolved in THF (2 ml) and water (2 ml) and NaOH (aq., 0.5 ml, 1 M) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with HCl (1 M) and the reaction mixture was diluted with water (10 ml) and extracted with DCM (3×3 ml). Purification with preparative HPLC yielded the title compound (58 mg, 59%). NMR (300 MHz, CD3OD) 0.81 (m, 6H), 1.00–1.70 (m, 8H), 3.21 (m, 2H), 3.42 (m, 2H), 3.71 (m, 2H), 3.92 (s, 3H), 6.88 (m, 2H), 7.02 (m, 2H), 7.23 (t, 2H), 7.40 (s, 1H).
Reaction SMILES: [O:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH:3]=[C:2]1[C:13]([OH:15])=O.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[O:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH:3]=[C:2]1[C:13]([Cl:18])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2[nH]c3ccccc3c2o1
Solvent: c1ccccc1
Product: O=C(Cl)c1cc2[nH]c3ccccc3c2o1

Procedure:
To ethyl furo[3,2-b]indole-2-carboxylate (10 g), 10% aqueous sodium hydroxide solution (100 ml) was added, then the mixture was stirred for an hour at 60° C. The resulting solution was acidified with hydrochloric acid, and the precipitate formed was collected by filtration to give furo[3,2-b]indole-2-carboxylic acid (8.5 g). To furo[3,2-b]-indole-2-carboxylic acid (8.5 g), thionyl chloride (40 ml) and benzene (50 ml) were added, the resulting solution was refluxed for 5 hours, and the excess amounts of thionyl chloride and the benzene were evaporated to give furo[3,2-b]indole-2-carbonyl chloride (7.1 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[N:30]=[CH:31][S:32][C:33]=1[CH3:34]>>[CH3:28][C:29]1[N:30]=[C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:24])[CH3:25])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:4][CH:3]=2)[S:32][C:33]=1[CH3:34]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1ncsc1C
Product: Cc1nc(-c2ccc(C(C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)sc1C

Procedure:
The title compound was prepared from 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 4,5-dimethyl-thiazole following a procedure analogous to that described in Example 180. Mass spectrum (ESI+): m/z=465 [M+H]+.