Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:27])[CH3:26])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])([OH:27])[CH3:26])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: CC(=O)c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(C)(O)c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Reaction time: 3 h

Procedure:
A solution of 36 (0.8 g, 2.23 mmol) in anhydrous tetrahydrofuran (8 mL) was stirred under nitrogen at room temperature and 1M ortho-methoxyphenyl magnesium bromide in tetrahydrofuran (3 mL, 1.35 equiv.) was slowly added. Stirring was continued at room temperature for 30 min and at 60° C. for 3 hr. After cooling, the reaction mixture was poured on saturated ammonium chloride (120 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×50 mL), dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator and the crude 37 thus obtained was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1
Reactant: CC1CCCCN1CCCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCCCN1CCCOc1ccc(N2CCNCC2)cc1
Yield: 74.5 %

Procedure:
1,1-Dimethylethyl 4-(4-{[3-(2-methyl-1-piperidinyl) propyl]oxy}phenyl)-1-piperazinecarboxylate (E76a) (1.66 g) was dissolved in dry dichloromethane (25 ml) and stirred under nitrogen. 50% Trifluoroacetic acid in dichloromethane (5 ml) was added, and the mixture was stirred at room temperature for 4 h. Saturated sodium bicarbonate solution was then added and the mixture was extracted with dichloromethane. The organic phase was separated using a hydrophobic frit, and evaporated in vacuo, however, most of the product was in the aqueous phase. The product was removed from the aqueous phase using an OASIS cartridge, washing with water and eluting with methanol, and further purified using an aminopropyl bond elut cartridge, eluting with dichloromethane and then SCX cartridge, eluting with 50% [0.880 ammonia-methanol (1:9)]-dichloromethane to give the title compound (0.94 g). LCMS RT=1.01 min, ES+ve m/z=318 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C[O-].[Na+].CO.C(O)(=[S:18])C>CO>[SH:18][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(O)=S
Reactant: Clc1ccc2nccn2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Sc1ccc2nccn2n1
Temperature: 150 °C

Procedure:
6-Chloroimidazo[1,2-b]pyridazine (13.5 g), 28 W/W% sodium methoxide-methanol solution (17.5 g) and thioacetic acid (7.0 g) were dissolved in 70 ml of methanol and this solution was heated at 150° C. in a sealed tube for 6 hours. The reaction mixture was cooled to room temperature and distilled to remove the organic solvent. The residue was washed three times with chloroform (50 ml), and the insoluble material was extracted six times with 50 ml of chloroform-methanol (1:1) solution. The combined extracts were distilled to remove the organic solvent. The precipitated crystals were collected by filtration, thereby obtaining 6-mercaptoimidazo[1,2-b]pyridazine (3.7 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([I:11])[C:5]2=[CH:4][CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CS(O)(=O)=O>C(Cl)Cl.O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:9]=[C:10]([I:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(I)n[nH]c2n1
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1ccc2c(I)nn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (0.70 g, 2.5 mmol), dihydropyran (690 μL, 7.5 mmol) and methanesulfonic acid (33 μL, 0.50 mmol) in methylene chloride (30 mL) and tetrahydrofuran (10 mL) in reaction flask was stirred at r.t. overnight. It was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.80 g). LCMS (M-84+H)+=279.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[Ca+2].[Cl-]>C(O)C.[Fe]>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:11]#[N:12])=[N:4][CH:5]=1
Reactant: N#Cc1ncc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: N#Cc1ncc(N)cc1Cl
Yield: 48 %

Procedure:
3-Chloro-2-cyano-5-nitropyridine (0.35 g, 1.9 mmol), iron powder (0.56 g, 10 mmol, 325 Mesh) and calcium chloride (0.06 g, 0.55 mmol) were combined in 10 mL of 90% ethanol and as described in example 772B. Purification of the crude product via silica gel chromatography using 10% ether/CH2Cl2 as the eluent gives compound 775D (0.14 g, 43%) as a light brown solid. HPLC: 95.5% at 1.69 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 154.03 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]([CH3:21])[CH3:20].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:18]([O:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:2][CH:3]([CH3:7])[CH3:4])=[CH:7][C:3]=1[C:4]([O:6][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:5])[CH:19]([CH3:21])[CH3:20]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: CC(C)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COC(=O)c1cc(OCC(C)C)ccc1OCC(C)C
Temperature: 110 °C
Reaction time: 6 h

Procedure:
In 200 ml of N,N-dimethylformamide are suspended 10 g of 2,5-dihydroxybenzoic acid, 148 g of potassium carbonate and 106 ml of isobutyl bromide. The mixture is stirred at 110° C. for 6 hours. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to obtain 18 g of isobutyl 2,5-diisobutoxybenzoate as a light yellow oily product.
Reaction SMILES: Cl.[C:2]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:26]=[N:27][C:28](Cl)=[N:29][CH:30]=1.CCCCCC>CCO>[Br:24][C:25]1[CH:26]=[N:27][C:28]([N:7]2[CH2:8][CH2:9][C:4]([C:2]#[N:3])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:6]2)=[N:29][CH:30]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)C1(C#N)CCNCC1
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C#N)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
To a solution of ethyl 4-cyanopiperidine-4-carboxylate hydrochloride (0.56 g, 2.6 mmol) in EtOH (10 mL) was added DIPEA (0.8 mL, 4.29 mmol) at rt and stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.33 g, 1.73 mmol). The reaction mixture was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 10% EtOAc:hexane to obtain the product as a yellow solid (0.4 g, 68% yield). 1H NMR (DMSO-d6): δ 1.20 (t, J=7.20 Hz, 3H), 2.04 (m, 2H), 2.22 (m, 2H), 3.22 (m, 2H), 4.15 (q, J=7.20 Hz, 2H), 4.32 (m, 2H) and 8.50 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[CH:27][N:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21][C:27]4[CH:28]=[CH:29][N:30]=[C:25]([Cl:24])[N:26]=4)=[CH:20][C:15]=3[O:14][N:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1noc2cc(O)ccc12
Reactant: Clc1ccnc(Cl)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1noc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 294 mg (0.91 mMol) 6-hydroxy-benzo[d]isoxazole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide (Step 1.3), 149 mg (1.00 mMol) 2,4-dichlorpyrimidine and 426 mg (2.0 mMol) K3PO4 in 5 ml NMP is stirred for 20 h at rt. The reaction mixture is diluted with CH2Cl2 and 5% citric acid in water, the aq. phase separated off and extracted with CH2Cl2. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2→CH2Cl2/EtOAc 99:1) gives the title compound: MS: [M+1]+=435; TLC(CH2Cl2/EtOAc 49:1): Rf=0.66.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[CH2:8]([NH:10][C:11](=[O:29])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)[CH3:13])[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:8]([NH:10][C:11](=[O:29])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:23]=[CH:24][C:25]([O:7][CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)[CH3:13])[CH3:9]
Reactant: CCNC(=O)C(C)c1ccc(C#Cc2ccc(O)cc2)cc1
Reactant: OCc1ccco1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCNC(=O)C(C)c1ccc(C#Cc2ccc(OCc3ccco3)cc2)cc1
Temperature: 0 °C

Procedure:
To 0.015 g (0.15 mmol) furan-2-ylmethanol in 0.75 mL THF are added 0.03 g (0.10 mmol) N-Ethyl-2-[4-(4-hydroxy-phenylethynyl)-phenyl]-propionamide (XVIII.2) and 40 mg polymer-bound triphenylphosphine (3 mmol/g resin). The mixture is cooled to 0° C. and 0.03 g (0.15 mmol) di-tert-butyl azodicarboxylate dissolved in 0.5 mL THF are added. The mixture is stirred over night at rt. After that time additional 0.03 g (0.15 mmol) di-tert-butyl azodicarboxylate dissolved in 0.5 mL THF are added and stirring is continued over night. Subsequently the mixture is filtered (Alox), washed (DMF/MeOH 9:1) and concentrated. The residue is dissolved in DMF and the desired product was purified using RP-HPLC (narrow gradient, water/MeOH+0.1% TFA).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CCN=C=NCCCN(C)C.[C:17]([C:19]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][C:20]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][CH:36]=[CH:37][C:38]=2[NH:39][S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])=[CH:30][CH:29]=1)#[N:18].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]([C:19]1[CH:24]=[C:23]([C:25]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:26])[CH:22]=[CH:21][C:20]=1[C:28]1[CH:29]=[CH:30][C:31]([C:34]2[S:35][CH:36]=[CH:37][C:38]=2[NH:39][S:40]([CH:43]([CH3:45])[CH3:44])(=[O:41])=[O:42])=[CH:32][CH:33]=1)#[N:18]
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C(=O)O)cc2C#N)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C(=O)NS(C)(=O)=O)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add methanesulfonamide (0.28 mmol), EDCI (0.28 mmol) and DMAP (0.28 mmol) to a solution of 2-Cyano-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid (0.235 mmol) in DCM. Stir 8 h at RT. Add 1N HCl and extract with DCM. Concentrate all organic layers to dryness. Purify by HPLC to provide the title compound. MS (ES−): 502 (M−1)
Reaction SMILES: C(OC([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27]CC=C)=[O:26])[CH2:9][C@H:8]1[CH2:31][O:32][CH2:33][CH2:34][Cl:35])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1.C(O)C>CC(C)CC(=O)C.[Pd].O>[Cl:35][CH2:34][CH2:33][O:32][CH2:31][C@@H:8]1[CH2:9][C@H:10]([S:12][C:13]2[C@@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([OH:27])=[O:26])[CH2:11][NH:7]1
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCCl)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd]
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)CC(C)C
Product: C[C@@H]1C(S[C@@H]2CN[C@H](COCCCl)C2)=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Reaction time: 5 h
Yield: 25.7 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-chloroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.28 g), triphenylphosphine (0.015 g) and dimedone (0.16 g) in a mixture of 4-methyl-2-pentanone (3.36 ml), ethanol (1.68 ml) and water (0.14 ml) was added triphenylphosphine)palladium(0) (30 mg) at ambient temperature in a stream of nitrogen. The mixture was stirred at the same condition for 5 hours to give a solid. The solid was collected by filtration to give (4S,5S,6S)-3-[(2S,4S)-2-(2-chloroethyloxymethyl)pyrrolidine-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.055 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[N:8]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]2=[O:12])=[CH:4][CH:3]=1.[C:32]([C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1)(=[O:34])[CH3:33].C(N(CC)CC)C>C1C=CC=CC=1>[C:32]([C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH:7]([C:24]4[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=4)[N:8]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]3=[O:12])=[CH:4][CH:3]=2)=[O:43])=[CH:37][CH:36]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)c2cc(N)ccc2CC1c1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)c1ccc(NC(=O)Nc2ccc3c(c2)C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2ccc(C#N)cc2)C3)cc1
Temperature: 100 °C

Procedure:
To a solution of Intermediate 13 (100 mg, 0.24 mmol) and 10 mL of anhydrous benzene under argon at 25° C. was added 4-acetylphenyl isocyanate (43 mg, 0.26 mmol) and triethylamine (50 mg, 0.48 mmol). The resulting mixture was heated to 100° C. for 12 hours and the reaction was quenched with water. The product was extracted with EtOAc, the layers were separated, and the organic layer was washed with brine, and dried over Na2SO4, and filtered, and concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography on silica gel using ethyl acetate:hexane (85:15) to yield Intermediate 23 as a light yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]2)[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(N)cccc1F
Reactant: OCC1CCCCN1
Product: N#Cc1c(N)cccc1OCC1CCCCN1

Procedure:
Prepared as in Example 24d from 2-piperidinemethanol and 2-amino-6-fluoro-benzonitrile as a light yellow solid (64%). MS 232 (MH+).
Reaction SMILES: [C:1]([C:3]1([NH:12]C(=O)C(O)CC(C)C)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:4]1)#[N:2].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.CN1CCOCC1.C(N)C1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:12][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:4]1
Reactant: CCCN1CCC(C#N)(NC(=O)C(O)CC(C)C)CC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: NCc1ccccc1
Solvent: ClCCl
Product: CCCN1CCC(N)(C#N)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 108.7 %

Procedure:
To a solution of 2-hydroxy-4-methyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide (0.316 g, 1.1 mmol) in CH2Cl2 (30 mL) was added DMAP (0.192 g, 1.6 mmol), p-nitrophenyl chloroformate (0.249 g, 1.2 mmol), and N-methylmorpholine (0.136 mL, 1.2 mmol). The resulting mixture was allowed to stir overnight (20 h) under argon at room temperature, then treated with benzylamine (1.68 g, 16 mmol) and allowed to stir overnight (20 h). When the reaction was complete the mixture was diluted with CH2Cl2 (50 mL), then washed with saturated aq. NaHCO3 (50 mL), water and brine, dried over Na2SO4, filtered and evaporated in vacuo to give 0.200 g (50% yield) of the desired product after purification by prep-HPLC;
Reaction SMILES: N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.[F:24][C:25]([F:42])([F:41])[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=2)[CH2:29]1)=[O:27]>C(Cl)(Cl)Cl>[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][S:37]([C:33]2[CH:34]=[C:35]3[C:30](=[CH:31][CH:32]=2)[CH2:29][N:28]([C:26](=[O:27])[C:25]([F:42])([F:24])[F:41])[CH2:36]3)(=[O:38])=[O:39])=[CH:19][CH:18]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(N1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(N1Cc2ccc(S(=O)(=O)Nc3ccc(F)cc3)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.7 %

Procedure:
Pyridine (2.57 mL, 31.9 mmol) and dimethylaminopyridine (195 mg, 1.59 mmol) were added to a solution of 4-fluoroaniline (1.86 g, 16.7 mmol) in chloroform (46 mL) at room temperature and the mixture was cooled in ice. 2-(Trifluoroacetyl)-2,3-dihydro-1 H-isoindole-5-sulfonyl chloride (5.00 g, 15.9 mmol) was added thereto and the mixture was warmed to room temperature and stirred for 15 hr. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate. The mixture was washed with 1 mol/L hydrochloric acid and brine, the organic layer was dried over anhydrous magnesium sulfate, and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was powdered with diethyl ether and collected by filtration to afford the title compound as a pale pink powder (5.85 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@@:26]4(OC)[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]4)[CH:22]=[CH:23][C:24]=3[Cl:25])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.C([SiH](CC)CC)C>C(#N)C.ClCCl>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:26]4[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]4)[CH:22]=[CH:23][C:24]=3[Cl:25])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)N(Cc3ccccc3)CCO4)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)N(Cc3ccccc3)CCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 74 %

Procedure:
To a stirred solution of (2S,3R,4S,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (5.0 g, 9.24 mmol) in acetonitrile-dichloromethane mixture (1:1 mixture, 40 mL) was added boron trifluoride diethyletharate complex (2.34 mL, 18.48 mmol), and triethylsilane (5.95 mL, 36.9 mmol) at −10° C. After stirring for 4 h at the same temperature, the reaction was quenched with aq. saturated sodium bicarbonate solution (15 mL). The volatiles were evaporated under reduced pressure; the resulting mixture was extracted with dichloromethane (2×30 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, concentrated and purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (3.5 g).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Br:30])=[C:13](/[CH:15]=[CH:16]/[C:17](OCC)=[O:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Na+].C(O)(=O)C>CCCCCCC>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Br:30])[C:17](=[O:18])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1ccc(Cl)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CO
Solvent: CC(=O)O
Product: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1ccc(Cl)cc1Br
Temperature: 80 °C
Yield: 61.6 %

Procedure:
A 250-mL RBF was charged with (E)-ethyl 3-(5-(benzylthio)-2-((2-bromo-4-chlorophenyl)amino)phenyl)acrylate (10.4 g, 20.68 mmol) and MeOH (103 ml) to give a thick, yellow suspension. Sodium methoxide (25 wt % in MeOH) (0.894 ml, 4.14 mmol) was added. A reflux condenser was attached, and the flask was heated to 80° C. overnight. The mixture was cooled to room temperature. Acetic acid (1.776 ml, 31.0 mmol) was added, and the mixture was concentrated. The residue was taken up in 2-PrOH and heated to boiling to give a brown solution. The mixture was cooled to room temperature with stirring then was concentrated. The residue was taken up in DCM and loaded onto a 25-g silica gel loading column. The column was eluted directly onto a pre-equilibrated 120-g Redi-Sep silica gel column with 0-50% EtOAc/Heptane to give a solid. The solid was taken up in heptane and filtered. The filtered solid was washed with heptane and dried under a stream of N2 (g) to give 6-(benzylthio)-1-(2-bromo-4-chlorophenyl)quinolin-2(1 H)-one (5.816 g, 12.73 mmol, 61.6% yield) as a tan solid. 1 H NMR (400 MHz, DMSO-d6)□=8.09 (d, J=2.3 Hz, 1 H), 8.01 (d, J=9.5 Hz, 1 H), 7.83 (d, J=2.2 Hz, 1 H), 7.72 (dd, J=2.3, 8.4 Hz, 1 H), 7.56 (d, J=8.4 Hz, 1 H), 7.41 (dd, J=2.2, 8.8 Hz, 1 H), 7.37-7.17 (m, 5 H), 6.71 (d, J=9.6 Hz, 1 H), 6.41 (d, J=8.8 Hz, 1 H), 4.25 (s, 2 H), 3.32 (s, 3 H). m/z (ESI) 456.0 (M+H)+.
Reaction SMILES: C(C1[S:5]C=CC=1)(=O)C.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([CH2:16][C:17]#[N:18])=[O:15].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[S:32][CH2:31][C:30](=O)[CH2:29][S:28]2)=[CH:23][CH:22]=1.N1CCOCC1.[S]>>[NH2:18][C:17]1[S:5][C:29]2[S:28][CH:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[S:32][CH2:31][C:30]=2[C:16]=1[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)=[O:15]
Reactant: N#CCC(=O)c1cccs1
Reactant: CC(=O)c1cccs1
Reactant: COc1ccc(C2SCC(=O)CS2)cc1
Agent: [S]
Solvent: C1COCCN1
Product: COc1ccc(C2SCc3c(sc(N)c3C(=O)c3cccs3)S2)cc1
Yield: 75 %

Procedure:
The procedure of Example 1 was followed except that 2-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophene-2-carbonyl)acetonitrile (Steps A and B). 2-(4-Methoxyphenyl)-1,3-dithian-5-one (Luettringhaus, Mohr, and Englehard, J. Liebig's Ann. Chem. (1963) 661: 84–94), 2-(thiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 75%; IR (KBr) cm−1: 3429, 3324, 1608, 1566, 1509, 1436, 1254, 1174, 1029, 838, 716; 1H NMR (CDCl3):δ 3.69 (d, 2H, J=6.8 Hz), 3.81 (s, 3H), 3.83 (s, 1H), 6.14 (bs, 2H), 6.87 (t, 2H, J=8.8 Hz), 7.11 (m, 1H), 7.38 (d, 2H, J=8.8 Hz), 7.56 (d, 1H, J=3.2 Hz), 7.62 (d, 1H, J=5 Hz); orange solid, mp: 138–140° C. (petroleum ether).