Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2OCCO3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid (351 mg, 1.95 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (400 mg, 1.95 mmol), HATU (1.11 g, 2.93 mmol) in anhydrous DMF (8 mL) is added DIPEA (484 μL, 2.93 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (59) as white solid (650 mg, 91%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22].Cl>CO>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:22][NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: NNc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=NNc2ccccn2)CC1
Yield: 61.4 %

Procedure:
The following are charged to a round-bottomed flask with a magnetic stirrer: 5 g of N-Boc-piperidone, 2.45 g of pyridin-2-ylhydrazine, 100 ml of methanol and 95 ml of a solution of methanol saturated with HCl. The mixture is left to react under a nitrogen stream for 2 h at reflux temperature. The solvent is evaporated off under vacuum, the resulting product is dissolved with dichloromethane and washing is carried out with a saturated aqueous solution of NaHCO3. The organic phase is dried over Na2SO4 and the solvent is evaporated off, and 4.0 g of the title product are isolated in the form of a red oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:25]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: NCC1CCNC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(N2CCC(CN)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 35.4 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-aminomethylpyrrolidine (80 mg), DBU (110 mg) and anhydorous acetonitrile (3 ml) was refluxed for 2.5 hours. After cooling, the resulting precipitate was collected by filtration and recrystallized from a solution of dichloromethane-methanol (1:1) to give the title compound (90 mg) as white powdery crystals, mp 198°-200° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CC2CCCN2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC2Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 2-benzylpyrrolidine (9.7 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (6.8 mg). Calcd for C22H22N2O2: 346.1681, found 346.1694.
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[B:4]([OH:7])([OH:6])[OH:5].C1(C)C(C)=CC=CC=1>O>[B:4]([O-:7])([O-:6])[O-:5].[Ca+2:2].[B:4]([O-:7])([O-:6])[O-:5].[Ca+2:2].[Ca+2:2]
Reactant: OB(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: [O-]B([O-])[O-]
Temperature: 60 °C

Procedure:
200 g of the same neutral calcium alkylsalicylate (A) as used in Example 1, 26 g of calcium hydroxide (B), 43.4 g (2.0 moles per mole of the calcium hydroxide) of orthoboric acid (C) and 400 g of xylene (F) were put in a 1000-ml four-necked flask fitted with a condenser and heated to 60° C. while agitating. To this mixture was added 20 g of water, and the resulting mixture was heated up to a refluxing temperature (66° C.) under agitation and reacted for 4 hours to obtain a reaction product. The reaction product was further heated to 140° C. for 1.5 hours to distill out the water and xylene. Finally the reaction product was diluted twofold with hexane and filtered to remove any residual solids present, and the hexane was distilled out to obtain a calcium borate overbased alkylsalicylate.
Reaction SMILES: [C:1]([C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9](Cl)=[CH:10][CH:11]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:15]>CO>[C:1]([C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9]([NH2:15])=[CH:10][CH:11]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)c1cc2nc(Cl)ccc2[nH]1
Solvent: CO
Product: CC(C)(C)c1cc2nc(N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 10 h
Yield: 26 %

Procedure:
In a 500 mL autoclave, a solution of 2-tert-butyl-5-chloro-1H-pyrrolo[3,2-b]pyridine (5.0 g, 24 mmol) and CuSO4′5H2O (0.5 g, 2.0 mmol) in aqueous ammonia (200 mL) and CH3OH (100 mL) was heated at 180° C. (at this temperature, the pressure in the autoclave was about 2 MPa) and stirred for 10 hours. The mixture was allowed to cool down to room temperature. The solvent was removed by evaporation under vacuum. The resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by the preparative HPLC to give 2-tert-butyl-1H-pyrrolo[3,2-b]pyridin-5-amine (1.15 g, 26%). 1H NMR (CDCl3, 300 MHz) δ 10.63 (brs, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.23 (d, J=8.7 Hz, 1H), 5.86 (d, J=1.5 Hz, 1H), 5.40 (brs, 2H), 1.29 (s, 9H); MS (ESI); m/e (M+H+): 190.2.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[NH:4].[CH2:12](OC(OCC)OCC)C>O>[O:1]1[CH:12]=[N:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)=[N:2]1
Reactant: CCOC(OCC)OCC
Reactant: N=C(NO)c1ccc(O)cc1
Solvent: O
Product: Oc1ccc(-c2ncon2)cc1
Reaction time: 8 h
Yield: 23.1 %

Procedure:
A mixture of 6.2 parts of N,4-dihydroxybenzenecarboximidamide and 44.6 parts of triethoxymethane was stirred overnight at reflux temperature. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH 99:1). The eluent of the desired fraction was evaporated, yielding 1.5 parts (23.1%) of 4-(1,2,4-oxadiazol-3-yl)phenol (interm. 10).
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[C:13](B(O)O)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH3:18])[CH:10]=2)[N:5]=1.[NH4+].[Cl-]>CCOCC.O>[Br:3][C:4]1[C:13]([OH:1])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH3:18])[CH:10]=2)[N:5]=1
Reactant: COc1ccc2nc(Br)c(B(O)O)cc2c1
Reactant: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2nc(Br)c(O)cc2c1
Reaction time: 13 h
Yield: 100 %

Procedure:
Aqueous H2O2 (30%, 32.8 mL, 321 mmol) was added dropwise to a stirred solution of (2-bromo-6-methoxyquinolin-3-yl)boronic acid (4.64 g, 16.45 mmol) and NH4Cl (3.29 g, 61.5 mmol) in Et2O (82 mL) and water (82 mL). After 13 h, NH4Cl (3.29 g, 61.5 mmol) and aqueous H2O2 (30%, 32.8 mL, 321 mmol) were added, and the mixture was stirred for 48 h. The precipitate was collected and washed with water, then dried at 50° C. to afford the title compound (4.18 g, 100%) as a solid that was used directly in the subsequent step. LCMS (ES+) m/z 254, 256 (M+H)+,
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26]Br)[CH:22]=[N:23][C:24]=1[Cl:25]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH:22]=[N:23][C:24]=1[Cl:25]
Reactant: Clc1cc(CBr)cnc1Cl
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cnc(Cl)c(Cl)c1
Yield: 73.2 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (480 mg), N,N-dimethylformamide (6 ml), potassium carbonate (420 mg) and 5,6-dichloro-3-(bromomethyl)pyridine (720 mg) according to the similar method described in Production Example 4 was obtained 698 mg of 2-((5,6-dichloro-3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (15)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[C:4]([N+:21]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C1COCC1.O.[Zn]>[NH2:21][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Br)cc2[N+](=O)[O-])CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(Br)cc2N)CC1
Yield: 72.6 %

Procedure:
Using similar reaction conditions as described in step ii of Intermediate-27, tert-butyl 4-(4-bromo-2-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (450 mg, 1.17 mmol) was reduced using zinc dust (610 mg, 9.39 mmol) and ammonium chloride (1.0 g, 18.72 mmol) in THF/water 10/5 ml to afford 300 mg (72.4% yield) of the titled product after purification with (60/120 silica gel) column chromatography using 30% ethyl acetate in hexane as eluent. MS: m/z=295.1 (M-Boc+1).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1([C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([N:19]([CH2:28][C@H:29]([O:37][Si](C(C)(C)C)(C)C)[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:6])[CH:2]=[CH2:3].F.N1C=CC=CC=1>C1COCC1>[CH2:48]([O:47][C:45]([C:7]1([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([N:19]([CH2:28][C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:37])[C:20]([O:22][CH2:23][C:24]([Cl:25])([Cl:27])[Cl:26])=[O:21])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:46])[CH:49]=[CH2:50]
Reactant: C=CCOC(=O)C1(C(=O)OCC=C)Oc2ccc(C[C@@H](C)N(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CCOC(=O)C1(C(=O)OCC=C)Oc2ccc(C[C@@H](C)N(C[C@H](O)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Temperature: 25 °C
Reaction time: 22 h
Yield: 83 %

Procedure:
To a 0° C. solution of 650 mg (0.82 mmol) 5-{(2R)-2-[[(2R)-2-(tert-butyl-dimethyl-siloxy)-2-(3-chloro-phenyl)-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diallyl ester and 20 mL THF was added 1.0 mL of HF·pyridine, and the reaction mixture was warmed to room temperature. After 22 h, TLC indicated that some starting material remained (Rf =0.62 (2/1 hexanes/EtOAc), and an additional 1.0 mL of HF·pyridine was added. After a total of 26 h, TLC indicated the disappearance of starting material and the formation of the title compound (Rf =0.28 (2/1 hexanes/EtOAc). The reaction mixture was slowly quenched with 30 mL of sat. aq. NaHCO3, extracted with 2×75 mL Et2O and then with 1×75 mL EtOAc. The combined organics were washed with 1×100 mL brine, dried over MgSO4, filtered and evaporated to a colorless oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (2/1), gave 460 mg (0.68 mmol, an 83% yield) of the title compound (Rf =0.28; 2/1 hexanes/EtOAc) as a colorless oil; 1H NMR (300 MHz, CDCl3): δ 1.20-1.37 (m, 3H), 2.60-2.78 (m, 2H), 2.80-2.91 (m, 1H), 2.98-3.18 (m, 1H), 3.23-3.40 (m, 1H), 3.41-3.54 (m, 2H), 4.10-4.26 (br m, 1H), 4.73-4.92 (5H), 5.22-5.40 (complex m, 4H), 5.81-5.98 (complex m, 2H), 6.62-6.87 (m, 4H), 7.17-7.41 (m, 3H); MS (ES) m/z (relative intensity): 700 (M+ +Na, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22](O)=[O:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:22]([C:19]2([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[CH2:21][CH2:20]2)=[O:23])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCOC(=O)C1CCCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Yield: 167.5 %

Procedure:
A solution of piperidine-3-carboxylic acid ethyl ester (10.0 g, 0.032 mol), 1-(4chloro-phenyl)-cyclopropylcarboxylic acid (9.57 g, 0.049 mol), diisopropylethyl amine (21.0 g, 0.16 mol) in dichloromethane (160 mL) was stirred at room temperature. PyBroP (22.6 g, 0.49 mol) was added and the reaction mixture continued stirring at room temperature. After 12 h the reaction mixture was quenched with 10% KOH. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to yield a crude oil. The crude material was purified using silica gel chromatography (80:20 hexane:ethyl acetate) to yield the amide (18.0 g).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)(=O)/C=C/C(O)=O>C(OCC)(=O)C.C(O)C>[O:9]([CH2:8][CH2:7][N:6]1[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=[C:2]1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCNCC1
Reactant: Clc1nc2ccccc2n1CCOc1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCN(c2nc3ccccc3n2CCOc2ccccc2)CC1

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(phenoxy)ethyl]benzimidazole (3.00 g), N-methylpiperazine (3.00 g) and fumaric acid (2.14 g), there are obtained crude crystals, which are recrylstallized from ethyl acetate-ethanol to give 1-[2-(phenoxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole.3/2 fumarate (2.99 g) as pale yellow plates, m.p. 152°-153.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: NCc1ccccn1
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCc3ccccn3)nc21
Temperature: 130 °C
Reaction time: 0.03 h
Yield: 38.7 %

Procedure:
A mixture of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37, 1.08 g (10.0 mmol) of 2-(aminomethyl)pyridine and 0.5 mL of dimethylformamide was heated with stirring in a 130° C. oil bath. After 2 minutes, solution was complete. After 2 hours, the excess amine and dimethylformamide were evaporated at reduced pressure. Ether (5 mL) was added to the residue. Crystals immediately developed. Water (5 mL) was added, and the entire mixture was filtered. The cake was washed 5 mL of ether, 5 mL of water, and then dried; wt 0.164 g. Recrystallization from ethyl acetate gave 0.075 g of pure product; mp 198°-201° C.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:21][CH:22]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Nc1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Yield: 53.3 %

Procedure:
A mixture of N-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-methanesulfonamide (83 mg, 0.22 mmol) and 10% palladium on activated carbon (30 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. The mixture was cooled to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-phenyl}-methanesulfonamide (45 mg, 54%): LC/MS m/e calcd for C21H25N3O2S [M+H]+ 384.52, observed 384.0; 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J=4.0 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.25-7.31 (m, J=8.3 Hz, 2H), 7.14-7.21 (m, J=8.3 Hz, 2H), 7.00 (dd, J=7.7, 4.9 Hz, 1H), 6.30 (s, 1H), 4.60 (br. s., 1H), 4.13 (t, J=7.8 Hz, 1H), 2.89 (s, 3H), 2.19 (dt, J=13.7, 7.2 Hz, 1H), 2.00-2.08 (m, 1H), 1.57-1.84 (m, 5H), 1.42-1.53 (m, 2H), 1.12-1.26 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][OH:16])[CH2:12][CH2:13][C:7]=2[C:6]([O:17][CH3:18])=[C:5]([O:19][CH3:20])[C:4]=1[O:21][CH3:22].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:30][S:31]([O:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][C:7]2[C:6]([O:17][CH3:18])=[C:5]([O:19][CH3:20])[C:4]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[C:8]=2[CH2:9][CH2:10]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCO)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOS(C)(=O)=O)CC2
Reaction time: 0.25 h

Procedure:
To a solution of 2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethanol (2.50 g) and triethylamine (1.68 ml) in acetonitrile (50 ml) was dropwise added methanesufonyl chloride (0.750 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, saturated aqueous sodium bicarbonate was added to the solution with cooling with ice, which was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (3.12 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1.C[S-:23].[Na+].O>CC(N(C)C)=O>[CH:16]1([O:15][CH2:14][C:8]2[N:5]3[CH:6]=[CH:7][C:2]([SH:23])=[CH:3][C:4]3=[N:10][C:9]=2[CH:11]([CH3:13])[CH3:12])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)c1nc2cc(Br)ccn2c1COC1CCCCC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)c1nc2cc(S)ccn2c1COC1CCCCC1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
7-Bromo-3-cyclohexyloxymethyl-2-isopropylimidazo[1,2-a]pyridine (50.0 mg, 0.142 mmol) obtained in step 3 of Example 28 was dissolved in DMA (1.0 mL), and the solution was stirred at 160° C. for 30 minutes after adding sodium thiomethoxide (80.0 mg, 1.14 mmol). After adding water to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform/methanol=95/5) to give 3-cyclohexyloxymethyl-2-isopropylimidazo[1,2-a]pyridine-7-thiol (35.3 mg, yield 82%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][N:14]([CH3:20])[C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(Cl)Cl>[CH3:13][N:14]([CH3:20])[C@@H:15]1[CH2:19][CH2:18][N:17]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH2:16]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CC[C@@H](N(C)C)C2)cc1
Yield: 98.8 %

Procedure:
Methyl 4-(bromomethyl)benzoate 5 (0.5 g, 2.2 mmol), (R)—N,N-dimethylpyrrolidin-3-amine (0.523 g, 4.6 mmol) and potassium carbonate (0.392 g, 2.8 mmol) were stirred at room temperature for 18 h in ethyleneglycol dimethylether (3 mL) then diluted with DCM (20 mL), washed with brine, dried over MgSO4 and concentrated to give title compound 6 (0.57 g, 96% yield).
Reaction SMILES: [C:1]([N:5]1[C:19]2[C:20]3[C:7]([CH2:8][C@@H:9]4[C@@:14]([O:21][CH3:22])([C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:13][C@@H:12]([CH2:23][OH:24])[CH2:11][N:10]4[CH3:25])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].O>N1C=CC=CC=1>[C:1]([N:5]1[C:19]2[C:20]3[C:7]([CH2:8][C@@H:9]4[C@@:14]([O:21][CH3:22])([C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:13][C@@H:12]([CH2:23][O:24][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:11][N:10]4[CH3:25])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@]12C[C@@H](CO)CN(C)[C@@H]1Cc1cn(C(C)(C)C)c3cccc2c13
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CO[C@]12C[C@@H](COS(=O)(=O)c3ccc(C)cc3)CN(C)[C@@H]1Cc1cn(C(C)(C)C)c3cccc2c13
Reaction time: 6 h
Yield: 76.6 %

Procedure:
To a solution of 1.8 g of 1-(t-butyl)-10-methoxy-6-methyl-8β-hydroxymethyl-ergoline, prepared as described in Example 2, in 20 ml of pyridine, 2.8 g of tosyl chloride in 15 ml of pyridine were slowly added. After the addition had been completed, the mixture was stirred for about six hours and was then poured into cold water and extracted with dichloromethane. The organic layer was evaporated off and the residue was chromatographed over 18 g of silica gel using dichloromethane with increasing amounts of methanol (from 0 to 4 percent) as the eluant. 2 g of 1-(t-butyl)-10-methoxy-6-methyl-8β-tosyloxymethyl-ergoline were obtained, melting at about 150° to 152° C.
Reaction SMILES: O=S(Cl)[Cl:3].[Br:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][N:9]1[C:13]([CH2:14][CH2:15][CH2:16]O)=[CH:12][N:11]=[CH:10]1>C(Cl)Cl>[Br:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][N:9]1[C:13]([CH2:14][CH2:15][CH2:16][Cl:3])=[CH:12][N:11]=[CH:10]1
Reactant: O=S(Cl)Cl
Reactant: OCCCc1cncn1Cc1ccccc1Br
Solvent: ClCCl
Product: ClCCCc1cncn1Cc1ccccc1Br

Procedure:
To a solution of SOCl2 (0.55 mL, 7.54 mmol) in CH2Cl2 (15 mL) at 0° C. is added 3-[3-(2-bromobenzyl)-3H-imidazol-4-yl]propan-1-ol in portion and the resulting white suspension is refluxed for 1.5 h. The mixture is cooled with ice and collected to give a buff-colored solid, which is partitioned between CH2Cl2 and saturated aqueous NaHCO3. The organic layer is washed with brine, dried over anhydrous Na2SO4, and concentrated to give an oil. MS (ESI) m/z 313 (M+H).