Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[O:36]1[C:38]2([CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:37][C:38]5([OH:36])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[CH:31][CH:30]=4)[C:21]([C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: C1CC2(CCO1)CO2
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c2ccc(C(F)(F)F)c3-c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c2ccc(C(F)(F)F)c3-c2ccc(OCC3(O)CCOCC3)cc2)cc1
Temperature: 100 °C

Procedure:
((1S,2S)-2-{4-[(R)-4-(4-Hydroxy-phenyl)-5-trifluoromethyl-indan-1-yloxy]-phenyl}-cyclopro-panecarboxylic acid ethyl ester (crude from step 2), 1,6-dioxa-spiro[2.5]octane (US2012/46304, 44 mg) and cesium carbonate (198 mg) are suspended in dry N,N-dimethylformamide and heated at 100° C. for 3 hours. The mixture is diluted with water, acidified with 0.2 M HCl solution and extracted with ethyl acetate. The combined organic extracts are concentrated under vacuum and the residue purified by flash chromatography (0-30% EtOAc in cyclohexane) ti give the title compound (yield 50 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1.O>[CH2:11]([N:8]1[CH2:7][CH2:6][C:5]([NH:4][CH2:1][CH3:2])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)NC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCNC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Yield: 100.6 %

Procedure:
A solution of 5 g of 4-acetamido-1-benzyl-4-phenylpiperidine in 50 ml of THF is added to a suspension of 1.5 g of lithium aluminum hydride in 20 ml of THF and the mixture is refluxed for 3 hours. After cooling, a solution of 1 ml of concentrated NaOH in 8 ml of water is added, the inorganic salts are filtered and the filtrate is evaporated under vacuum. The oil obtained is dissolved in 50 ml of THF, this solution is added to a suspension of 1.5 ml of lithium aluminum hydride in 20 ml of THF and the mixture is refluxed for 1 hour. The reaction mixture is hydrolyzed by addition of a solution of 0.5 ml of concentrated NaOH in 6 ml of water, the inorganic salts filtered and the filtrate evaporated under vacuum. 4.8 g of the expected product are obtained, which product is used as it is in the next stage.
Reaction SMILES: [C:1]([N:4]1[CH2:9][C@H:8]2[CH2:10][C@@H:5]1[C:6](=[O:11])[O:7]2)(=[O:3])[CH3:2].[NH:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)(CC)(C)C>[N:12]1([C:6]([C@H:5]2[CH2:10][C@@H:8]([OH:7])[CH2:9][N:4]2[C:1](=[O:3])[CH3:2])=[O:11])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(=O)N1C[C@H]2C[C@@H]1C(=O)O2
Reactant: C1CNCCNC1
Solvent: CCC(C)(C)O
Product: CC(=O)N1C[C@H](O)C[C@@H]1C(=O)N1CCCNCC1
Reaction time: 17 h
Yield: 71.9 %

Procedure:
A mixture of (1R,4R)-5-acetyl-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-one (310.3 g, 2.0 mol) and [1,4]diazepane (500.85 g, 5 mol) in t-amyl alcohol (3.0 L) was held at 90° C. for 17 h. The mixture was then concentrated to remove t-amyl alcohol (2.4 L). The resulting slurry was filtered and washed with EtOAc (1 L) to provide the title compound as a solid (367 g, 72%). MS (ESI): mass calcd. for C12H21N3O3, 255.2; m/z found, 256.2 [M+H]+. 1H NMR (CDCl3): 5.95 (br s, 1H), 4.93-4.68 (m, 1H), 4.48-4.32 (m, 1H), 3.90-3.65 (m, 5H), 3.54-3.41 (m, 1H), 3.12-2.74 (m, 4H), 2.32-2.22 (m, 1H), 2.16-1.68 (m, 6H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:41]([CH3:43])[CH3:42])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][C@H:13]1[C:28]([NH:30][C@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1)=[O:29])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH:41]([CH3:43])[CH3:42])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][C@H:13]1[C:28]([NH:30][C@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1)=[O:29])=[O:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21

Procedure:
Compound 4 (15.50 g, 26.2 mmol) is BOC-deprotected using TFA (97 mL, 1.31 mol) in CH2Cl2 (500 mL) under the same conditions as for step 2. After workup, the desired free amine 5 is obtained as an off-white foam (12.57 g, 97% yield): 1H NMR δ (CDCl3) 7.28-7.42 (m, 5H), 7.03-7.19 (m, 4H), 6.07-6.35 (br m, 1H), 5.09-5.27 (br m, 3 H), 3.68-4.81 (br m, 3H), 2.66-3.53 (br m, 6H), 1.45-2.04 (br m, 8H), 0.74-1.00 (br m, 1H); LCMS (APCl+) 493.7 (MH+, 100%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1.B(Br)(Br)Br.N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>ClCCl.CN(C)C=O>[CH3:39][C:38]([Si:35]([CH3:37])([CH3:36])[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc2c(c1)C=Cc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Agent: BrB(Br)Br
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2c(o1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of the product from step (vii) (1.5 g) in dichloromethane (20 ml) was added a solution of boron tribromide (1M in dichloromethane) (6 ml). The mixture was stirred at room temperature for 2 hours. A further 10 ml of boron tribromide solution was added and the mixture was stirred for 2 hours before quenching with water. The pH was adjusted to 7 with sodium bicarbonate solution and the aqueous solution extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give a brown solid. The solid was dissolved in N,N-dimethylformamide (20 ml) and treated with imidazole (0.68 g) followed by tert-butyldimethylsilyl chloride (0.68 g). The mixture was stirred overnight then partitioned between water and ethyl acetate. The organic phase was dried (MgSO4) and evaporated under reduced pressure. Purification was by precipitation with methanol/dichloromethane/isohexane.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>ClCCl>[Br:1][CH2:2][C:3]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: Nc1ccccc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)Nc1ccccc1

Procedure:
To a solution of bromoacetyl bromide (9.6 mL) and potassium carbonate (11.4 g) in dichloromethane (100 mL) was added aniline (5 mL) dropwise over 15-20 mins causing the reaction mixture to get warm and a white precipitate to form. After 4.5 h the reaction mixture was poured into water, shaken for several minutes and then the phases were separated. The organic layer was washed with water and concentrated to a smaller volume resulting in precipitation of a solid that was filtered off to give the sub-titled compound (970 mg) as a white solid.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:11]([O:13][CH3:14])=[O:12])=[N:5][C:6]([CH3:10])=[C:7]([CH3:9])[N:8]=1.[CH3:15][OH:16]>>[CH3:15][O:16][C:3]1[C:4]([C:11]([O:13][CH3:14])=[O:12])=[N:5][C:6]([CH3:10])=[C:7]([CH3:9])[N:8]=1
Reactant: CO
Reactant: COC(=O)c1nc(C)c(C)nc1Cl
Agent: [Na]
Product: COC(=O)c1nc(C)c(C)nc1OC

Procedure:
To 20 ml. of a solution of 0.1 g. metallic sodium in methanol was added 0.3 g. of methyl 3-chloro-5,6-dimethylpyrazine-2-carboxylate and the mixture was refluxed for one hour. The methanol was distilled off from the reaction mixture and the residue obtained was added to 20 ml. of water and the mixture was extracted three times each time with 20 ml. of dichloromethane. The extracts were combined, dried over anhydrous magnesium sulfate, and then the dichloromethane was distilled off to provide 0.2 g of methyl 3-methoxy-5,6-dimethylpyrazine-2-carboxylate. The yellow prism crystals obtained by recrystallizing from n-hexane melted at 80°-81° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[CH:22]=[CH:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(-n3ccn4c5c(cc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A flask was charged with 4-chloro-2-(1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 103b (88 mg, 0.27 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (125 mg, 0.27 mmol), PdCl2(dppf) (18 mg, 0.02 mmol), K3PO4 (30 mg), in THF (5 mL) and H2O (1 mL). The system was evacuated and refilled with N2. The reaction mixture was refluxed for 4 h, and then cooled to room temperature. It was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography eluting with 10:1 of DCM/MeOH to afford 121a (90 mg, 56%) as a yellow solid. MS: [M+H]+ 633.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:13][CH3:14])[C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:10](=[O:12])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:15])=[CH:8][CH:7]=2)[O:13][CH3:14])=[CH:20][CH:19]=1)#[N:16]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccc(N(C)C)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(N(C)C)cc1

Procedure:
(RS)-(4-Dimethylamino-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(4-dimethylamino-phenyl)-2-methoxy-acetamide. Off-white solid. MS 324.2 ([M+H]+)
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].CC1C=C([N+]([O-])=O)C=C(C)C=1N.C[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([CH3:31])[C:23]=1[N:32]=[C:33]=[S:34]>>[CH3:31][C:24]1[CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=[CH:22][C:23]=1[N:32]=[C:33]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:34]1
Reactant: CC(C)C[C@H](N)CO
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1N=C=S
Agent: Cc1cc([N+](=O)[O-])cc(C)c1N
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2,6-Dimethyl-4-nitroaniline was converted into 2,6-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. 2,6-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(2,6-dimethyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[NH:20][CH2:19][CH2:18]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([Cl:14])=[CH:23][C:22]=3[Cl:24])[CH2:18][CH2:19]2)[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CSCCn1cc(Cl)nc(Cl)c1=O
Product: CSCCn1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 127–128° C.; 1H NMR (300 MHz, CDCl3): 7.19 (d, J=1.8 Hz, 1 H), 7.12 (d, J=2.2 Hz, 1 H), 6.93 (s, 1 H), 4.36 (t, J=8.1 Hz, 2 H), 4.06 (t, J=7.0 Hz, 2 H), 3.13 (t, J=7.9 Hz, 2 H), 2.89 (t, J=7.0 Hz, 2 H), 2.16 (s, 3 H); HRMS (CI) calcd for C15H14N3OSCl3 (M+): 388.9923; found m/z 388.9920.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]I.[Na+].[Cl-]>CN(C=O)C.O>[O:2]1[C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:16][CH2:15][CH2:14][Cl:13])=[CH:6][C:4]=2[O:5][CH2:1]1
Reactant: ClCCCI
Reactant: Oc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a solution of sesamol (2.00 g, 14.48 mmol) in DMF (15 mL) was slowly added over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.65 g of an 80% dispersion in mineral oil, 21.67 mmol) in DMF (10 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (3.55 g, 1 7.37 mmol), and the resulting brown mixture was stirred at ambient temperature for 4 h. Cold water (25 mL) was carefully added, followed by saturated NaCl solution (25 mL). The resulting mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered, concentrated by rotary evaporation to a residue that was dried briefly under high vacuum producing a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10]O)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C.O>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[N:7]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cc1cccc(Cl)n1)c1ccncc1
Agent: Cl[Fe]Cl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: Clc1cccc2cc(-c3ccncc3)nn12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.8 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-pyridinyl)ethanone oxime (6.0 g, 24 mmol) in 1,2-dimethoxyethane (40 mL) at 0° C. was added trifluoroacetic anhydride (3.4 mL, 24 mmol), keeping the temperature below 10° C. during the addition. After the addition was complete, the reaction was warmed to room temperature. The solution was then cooled to 4° C. and a solution of triethylamine (6.7 mL, 48 mmol) in 1,2-dimethoxyethane (15 mL) was added over a period of 0.5 hours. The mixture was allowed to warm to room temperature and was stirred for 1.5 hours. To this mixture was added iron(II) chloride (50 mg) and the reaction was heated at 75° C. for 15 hours. The reaction mixture was poured into water (300 mL). The resulting suspension was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid residue. This residue was purified by silica gel chromatography (1:1 ethyl acetate-hexane) to give 7-chloro-2-(4-pyridinyl)pyrazolo[1,5-a]pyridine (2.8 g, 500%) as a tan solid. 1H NMR (d6-DMSO): δ 8.62 (m, 2H), 7.93 (m, 2H), 7.76 (dd, 1H), 7.42 (m, 2H), 7.24 (m, 1H); MS m/z 230 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][CH2:9][CH2:8][CH:4]([C:5](O)=[O:6])[CH2:3]1.C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C=O)C>[CH3:1][N:2]1[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([Cl:14])=[O:6])[CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1CCCC(C(=O)O)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCCC(C(=O)Cl)C1

Procedure:
The hydrochloride salt of (±)-N-methylnipecotic acid (1.0 g) was suspended in dichloromethane (25 ml) and stirred at room temperature for 2 h with oxalyl chloride (0.58 ml) and DMF (1 drop). The solvent was then evaporated to yield the hydrochloride salt of N-methylnipecotyl chloride as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCc1ccccc1
Temperature: 0 °C

Procedure:
To an ice cooled solution of 4-phenyl-1-butanol (20 g) and triethyl amine (15 g) in 200 ml of dichloromethane, a solution of methanesulfonyl chloride (12 ml) in 50 ml of dichloromethane was added dropwise. After stirring for 1h at 10 ° C. the reaction mixture was washed with water. Extraction of the water phase with dichloromethane, drying of the combined organic phases over MgSO 4 followed by removal of the volatile components in vacuo, gave 29 g of a slightly yellow oil, 4-phenyl-1-butyl methanesulfonate, which was sufficiently pure for use in the next step. A mixture of spiro[isobenzofuran-1(3H),4'-piperidine] (2 g), 4-phenyl-1-butyl methanesulfonate (6 g) and potassium carbonate (14 g) in 75 ml of 4-methyl-2-pentanone was refluxed for 20 h. After cooling the reaction mixture was filtered and concentrated in vacuo. The remaining viscous oil was applied to a silica gel column (eluent: ether/methanol/triethyl amine=93:5:2) giving a colorless oil which crystallized as the fumarate salt, 2a, from acetone by addition of fumaric acid. Yield: 0.7 g, mp: 197°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:28]([O:17][CH2:16][C:13]1[N:14]([CH3:15])[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:18]([CH3:20])[CH3:19])[N:12]=1)(=[O:30])[CH3:29]
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
In dry methylene chloride (10 ml) was dissolved 220 mg (0.700 mmol) of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (Compound I-8), followed by addition of 201 mg (2.00 mmol) of triethylamine. Then, 78.0 mg (1.00 mmol) of acetyl chloride was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added for neutralization, and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:1) to give 170 mg of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methyl acetate (Compound I-40) (yield 69%). mp 92-93° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3CCCCC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and piperidine. Yellow solid. MS (m/e): 339.1 ({37Cl}M+H+, 29%), 337.1 ({35Cl}M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[C:13]([CH:17]=[O:18])[C:6]2[CH2:7][CH2:8][N:9]([CH3:12])[CH2:10][CH2:11][C:5]=2[C:4]=1[S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[C:13]([CH2:17][OH:18])[C:6]2[CH2:7][CH2:8][N:9]([CH3:12])[CH2:10][CH2:11][C:5]=2[C:4]=1[S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1c(C=O)c2c(c(Sc3ccccc3)c1OC)CCN(C)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(CO)c2c(c(Sc3ccccc3)c1OC)CCN(C)CC2
Reaction time: 1 h

Procedure:
The aldehyde (10.72 g., 0.03 mole) is dissolved in 50 ml. of methanol and 3.42 g. (0.09 mole) of sodium borohydride is added slowly. The mixture is stirred for 1 hour, quenched with acetic acid, evaporated, made basic and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to leave 7,8-dimethoxy-9-hydroxymethyl-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][SH:10].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].O>O1CCCC1.C(OCC)(=O)C>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][S:10][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COCCOCCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCCSc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
In a 100 mL round-bottomed flask was added sodium hydride (0.6 g) in tetrahydrofuran (10 ml) to give a suspension. 2-(2-Methoxyethoxy)ethanethiol (1 g) was added slowly. After the mixture stirred for 30 minutes, 4-fluoro-3-nitrobenzenesulfonamide (1.616 g) in 10 ml tetrahydrofuran was added slowly. After the mixture stirred overnight, water was added slowly, and ethyl acetate (20 ml×3) was used to extract the product. The combined organic layers were dried over Na2SO4. After the mixture was filtered and concentrated, the crude product was added to a silica gel column and purified eluting with 0-10% methanol in dichloromethane.