Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1)[CH3:5])C.[NH:19]([C:21]1[N:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[NH2:20].O>ClCCl.CO>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([C:7]2[N:19]([C:21]3[N:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:20]=[C:4]([CH3:5])[N:6]=2)[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Reactant: CCOC(C)=NC(=O)c1cc(OC)cc(OC)c1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)cc(-c2nc(C)nn2-c2ccc(S(N)(=O)=O)cn2)c1
Reaction time: 8 h
Yield: 63.2 %

Procedure:
N-(1-ethoxy-ethylidene)-3,5-dimethoxy-benzamide 536 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(3,5-dimethoxy-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (496 mg, yield: 62%) was obtained as a solid phase.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH2:28]=O>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:16]3[CH2:21][N:20]([CH3:28])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Reactant: C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C)C3)cc1

Procedure:
Method as described for example 26 using 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 14) and formaldehyde as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Br[CH2:11][Cl:12].C(N(CC)CC)C>>[Cl:12][CH2:11][S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(S)cc1
Reactant: ClCBr
Solvent: CCN(CC)CC
Product: COc1ccc(SCCl)cc1

Procedure:
4-Methoxythiophenol (40 mmol) was dissolved in bromochloromethane (0.8 mol) and triethylamine (40 mmol) added dropwise with stirring and external cooling to keep the reaction below room temperature. Once the addition was completed the reaction mixture was stirred at room temperature for 1 h. The mixture was then washed with water, the organic solution dried (MgSO4), the solvent evaporated off and the residue distilled; yield: 3.90 g (52%), b.p. 70° C./0.01 mmHg. The physical data for the title compound are detailed in J. Hayami, N. Tanaka, S. Kurabayashi, Y. Kotani and A. Kaji; Bull. Chem. Soc. (Japan) 44, 3091 (1971).
Reaction SMILES: C1C2C(OC(=O)[N:16](C)[CH2:17][C:18](=[O:45])[NH:19][C:20]3[C:29]([NH2:30])=[C:28]4[C:23]([C@@H:24]([C:34]5[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([Br:44])[CH:35]=5)[C:25]([C:32]#[N:33])=[C:26]([NH2:31])[O:27]4)=[CH:22][CH:21]=3)C3C(=CC=CC=3)C=2C=CC=1.C(Cl)Cl.[OH-].[Na+]>CO>[NH2:16][CH2:17][C:18]([NH:19][C:20]1[C:29]([NH2:30])=[C:28]2[C:23]([C@@H:24]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([Br:44])[CH:35]=3)[C:25]([C:32]#[N:33])=[C:26]([NH2:31])[O:27]2)=[CH:22][CH:21]=1)=[O:45]
Reactant: COc1cc([C@H]2C(C#N)=C(N)Oc3c2ccc(NC(=O)CN(C)C(=O)OC2c4ccccc4-c4ccccc42)c3N)cc(Br)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc([C@H]2C(C#N)=C(N)Oc3c2ccc(NC(=O)CN)c3N)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To an oven-dried one-neck round bottom reaction flask charged with a magnetic stir bar at rt under argon was added (9H-fluoren-9-yl)methyl((R)-2,8-diamino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-4H-chromen-7-ylcarbamoyl)methylcarbamate (0.050 g, 0.072 mmol), CH2Cl2:MeOH, 1:1 (2.40 mL) and 2N NaOH (0.072 mL, 0.14 mmol). The orange suspension was stirred at rt overnight. The suspension was concentrated leaving a brown residue. The residue was extracted with CHCl3 (3×40 mL), dried over MgSO4, filtered and concentrated to give the crude product. Purification by flash column chromatography (silica gel 4 g pre-packed column, gradient elution with CH2Cl2:MeOH, 96:4 to 90:10 with trace Et3N) gave 0.012 g (35%) of the title compound as a yellow solid: 1H-NMR (CDCl3): 9.34 (br s, 1H), 6.90 (d, J=1.9 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.71 (d, J=1.9 Hz, 1H), 6.37 (d, J=8.2 Hz, 1H), 4.72 (br s, 2H), 4.64 (s, 1H), 4.29 (br s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.54 (br s, 2H).
Reaction SMILES: [CH:1]([C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:12]=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.[H-].[Na+].[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[N:29]1([CH2:28][CH2:27][CH2:26][O:20][C:17]2[CH:18]=[CH:19][C:14]([N:13]3[C:9]([CH:1]=[CH:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:10][C:11]([C:21]([F:24])([F:23])[F:22])=[N:12]3)=[CH:15][CH:16]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: ClCCCN1CCCC1
Reactant: Oc1ccc(-n2nc(C(F)(F)F)cc2C=Cc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(C=Cc2ccccc2)n(-c2ccc(OCCCN3CCCC3)cc2)n1
Temperature: 70 °C
Yield: 23.6 %

Procedure:
4-(5-Styryl-3-trifluoromethylpyrazol-1-yl)phenol (0.2 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 1-(3-chloropropyl)pyrrolidine (32 mg, 0.22 mmol), sodium hydride (9 mg, 60% dispersion in mineral oil, 0.22 mmol) and sodium iodide (33 mg, 0.22 mmol) were added. The reaction was heated at 70° C. overnight, then cooled to room temperature. Saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extracts were dried over MgSO4 and concentrated. Semi-prep LC-MS purification gave 20.8 mg of the desired product. LC-MS (C25H26F3N3O calculated 441) m/z 442 (M+H); 1H NMR (300 MHz, CDCl3) 7.42-7.30 (m, 7H), 7.12 (d, J=16.2 Hz, 1H), 7.00 (d, J=8.7 Hz, 2H), 6.88 (s, 1H), 6.77 (d, J=16.5 Hz, 1H), 4.10 (t, J=6 Hz, 2H), 2.93-2.86 (m, 6H), 2.21-2.12 (m, 2H), 1.94-1.90 (m, 4H).
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]3[NH:19][CH:18]=[N:17][N:16]=3)=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH3:20])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CO.O.[OH-].[Li+].OP(O)(O)=O>O>[CH:1]1([C:5]2[C:14]([C:15]3[NH:19][CH:18]=[N:17][N:16]=3)=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:20])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc(-c2nnc[nH]2)c(C2CCC2)cc1C
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C2CCC2)c(-c2nnc[nH]2)cc1C(=O)O
Temperature: 40 °C
Reaction time: 42 h
Yield: 98.8 %

Procedure:
To crude methyl 4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoate (compound 202.2, 0.24 mmol, 1.0 equiv) from the previous step in a 4-mL vial was added methanol (1.5 mL) and water (0.5 mL) and lithium hydroxide monohydrate (20 mg, 0.48 mmol, 2.0 equiv), The resulting mixture was stirred at 40° C. for 42 hours. The reaction mixture was diluted into water (5 mL), acidified to pH 3 with 1M H3PO4 and extracted with DCM (3×5 mL). The organics were dried (Na2SO4), filtered and concentrated in vacuo to obtain the title compound as a white solid (61 mg, 98% over 2 steps). m/z (ES+) 258 (M+H)+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[C:7]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH3:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[F:3][C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[C:7]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[CH2:25][CH2:26]3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: COCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3ccc(F)c4occc34)CC2)CC1
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3ccc(F)c4occc34)CC2)CC1

Procedure:
The title compound, white solid (60 mg, 56%), MS (ISP) m/z=431.5 [(M+H)+], mp 177° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(7-fluoro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate C) (104 mg, 0.25 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH2:1][C:2]1[CH:7]([O:8][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6](=[CH2:9])[CH:5]=[CH:4][N:3]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccnc(N)c1O
Product: C=C1C=CN=C(N)C1OCc1ccccc1

Procedure:
2-amino-3-phenylmethoxy-4-methlylpyridine was prepared as an oil by reacting 2-amino-3-hydroxy-4-methylpyridine with benzyl chloride followingthe procedures of Example 1, Step A herein.
Reaction SMILES: [CH:1]([O:10][CH:11]([CH3:13])[CH3:12])(OC(C)C)OC(C)C.[C:14]1(=O)[CH2:19][CH2:18]C[CH2:16][CH2:15]1.C(O)(C)C>[Fe](Cl)(Cl)Cl>[CH:11]([O:10][C:1]1[CH2:18][CH2:19][CH2:14][CH2:15][CH:16]=1)([CH3:12])[CH3:13]
Reactant: O=C1CCCCC1
Reactant: CC(C)OC(OC(C)C)OC(C)C
Agent: Cl[Fe](Cl)Cl
Solvent: CC(C)O
Product: CC(C)OC1=CCCCC1
Temperature: 5 °C
Yield: 92 %

Procedure:
A mixture of 190.3 g (1 mol) triisopropyl orthoformate, 98.15 g (1 mol) of cyclohexanone and 6.00 g (0.10 mol) of isopropanol was placed in a three-neck round bottom flask and cooled to about 5° C. in an ice bath. The mixture was stirred and 0.4 g (2 mmol) of reagent grade iron (III) chloride was added. Upon addition of the FeCl3 catalyst, the temperature of the mixture rose to about 15-20° C., indicating that the reaction was proceeding. The mixture was stirred at 20° C. until gas-chromatographic (“GC”) analysis indicated completion of the reaction. The by-products isopropyl formate and isopropanol were removed by distillation under reduced pressure. The remaining residue was subsequently distilled to provide 1-isopropoxy-1-cyclohexene (bp 34° C. @3 mm Hg) as a colorless liquid; the yield was 92% with a purity exceeding 99%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1.[C:20]([O:24][CH:25]([C:31]1[C:35](B2OC(C)(C)C(C)(C)O2)=[C:34]([CH3:45])[S:33][C:32]=1[CH3:46])[C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:20]([O:24][CH:25]([C:31]1[C:35]([C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=2)=[C:34]([CH3:45])[S:33][C:32]=1[CH3:46])[C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C1COc2ccc(Br)cc2N1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1-c1ccc2c(c1)NC(=O)CO2
Temperature: 100 °C
Yield: 30 %

Procedure:
Under argon atmosphere, sodium carbonate (11.2 mg, 0.11 mmol), water (0.7 mL), and 6-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-one (24.2 mg, 0.11 mmol) were added to a solution of ethyl 2-(tert-butoxy)-2-[2,5-dimethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl]acetate (28f) (48 mg, 0.10 mmol) in N,N-dimethylformamide (2.1 mL). The solution was degassed under argon and palladium tetrakis(triphenylphosphine) (23.4 mg, 0.02 mmol) was added. The mixture was heated at 100° C. for 15 hours. The mixture was then cooled at room temperature, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 70/30) to afford the desired product (35a) (14 mg, 0.03 mmol, 33%).
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][NH2:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:23]([CH2:25][CH2:26][C:27](OCCCC)=O)=[O:24]>>[CH2:1]([N:19]1[C:23](=[O:24])[CH2:25][CH2:26][CH:27]=[N:22][CH2:21][CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCOC(=O)CCC=O
Reactant: CCCCCCCCC=CCCCCCCCCNCCN
Product: CCCCCCCCC=CCCCCCCCCN1CCN=CCCC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 310.1 g (1 mole) of N-(9-octadecenyl)ethylenediamine and 158.2 g (1 mole) of butyl 3-formylpropionate. At 150° C. and under a reduced pressure of 50 mmHg, 18 g of water and 74 g of butanol were distilled off to obtain 4-(9-octadecenyl)-2,3,6,7-tetrahydro-1,4-diazocin-5-one.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[OH:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:35]([NH:36][C:37](=[O:44])[CH2:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:34](=[O:45])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CC(C)=O>[S:40]1[CH:41]=[CH:42][CH:43]=[C:39]1[CH2:38][C:37]([NH:36][C@@H:35]1[C:34](=[O:45])[N:16]2[C:17]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[C:12]([CH2:11][O:10][C:6](=[O:7])[NH:5][C:3](=[O:4])[C:2]([Cl:9])([Cl:8])[Cl:1])[CH2:13][S:14][C@H:15]12)=[O:44]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)NC(=O)C(Cl)(Cl)Cl)CS[C@H]12
Reaction time: 1 h
Yield: 93.4 %

Procedure:
Trichloroacetyl isocyanate (13.2 g, 70 mmole) was added to a stirred suspension of diphenylmethyl (6R,7R)-3-hydroxymethyl-7-(thien-2-ylacetamido)ceph-3-em-4 carboxylate (26.0 g, 50 mmole) in anhydrous acetone (600 ml) at 20°. The solid soon dissolved and after the mixture had been stirred at 20° for 1 hour it was chilled for 1 hour and the resulting solid was filtered off and washed with ether to give the title compound (33.1 g, 93%), m.p. 183° to 184°; [α]D21 + 24° (c 0.95 in DMSO); λinf.EtOH 235 nm (ε 14,500) and λinf.EtOH 256 nm (ε 8,820).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[CH3:25][O:26][C:27]([C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C(N(CC)CC)C>CO.COCCOC>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:32]3[CH:31]=[CH:30][C:29]([C:27]([O:26][CH3:25])=[O:28])=[N:34][CH:33]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Solvent: COCCOC
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 120 °C
Yield: 79 %

Procedure:
6-(((2S,4R)-1-Acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 2)(3.25 g, 8.44 mmol), {6-[(methyloxy)carbonyl]-3-pyridinyl}boronic acid (1.832 g, 10.12 mmol), {6-[(methyloxy)carbonyl]-3-pyridinyl}boronic acid (1.832 g, 10.12 mmol) and triethylamine (2.352 ml, 16.87 mmol) were combined in MeOH (30 ml) and DME (5 ml). The reaction mixture was divided between 2 vials and each heated at 120° C. for 45 min. The crude reaction mixtures were combined and concentrated in vacuo to give 4.4 g of crude brown solid. This was purified by chromatography on silica (100 g), eluting with over 1500 ml of EtOAc (compound leached off slowly) to give methyl 5-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinate (2.94 g, 6.66 mmol, 79% yield) as a brown foamy solid. LCMS (Formate, 2 min), Rt=0.81 min, MH+=442.
Reaction SMILES: O[CH2:2][CH:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH2:5][CH2:6]2.C=C1C(C)C2CC1CC2>>[CH3:2][C:3]1[CH:4]2[CH2:10][CH:7]([C:8]=1[CH3:9])[CH2:6][CH2:5]2
Reactant: CC1C2CCC(C2)C1CO
Agent: C=C1C2CCC(C2)C1C
Product: CC1=C(C)C2CCC1C2

Procedure:
In accordance with the same procedures as those conducted in Example 26, 2,200 g of a dehydration product of 2-hydroxymethyl-3-methylbicyclo[2.2.1]heptane containing 2-methylene-3-methylbicyclo-[2.2.1]heptane and 2,3-dimethylbicyclo[2.2.1]hept-2-ene was obtained. The obtained product was placed into a 5 liter four-necked flask in combination with 45 g of boron trifluoride diethyl etherate. The dimerization was conducted for 5 hours under stirring at 10° C. After the reaction mixture was washed with a dilute aqueous solution of NaOH and a saturated aqueous solution of sodium chloride, the unreacted olefin was removed by distillation, and a reaction mixture of the dimerization of the raw material was obtained. The dimer of the olefin in an amount of 1,500 g was placed into a 2 liter autoclave and heated at 300° C. for 7 hours under stirring. After the reaction mixture was cooled, 30 g of a nickel/diatomaceous earth catalyst for hydrogenation (manufactured by NIKKI CHEMICAL Co., Ltd.; “N-113”) was added, and the hydrogenation was conducted (the hydrogen pressure: 30 kg/cm2; the reaction temperature: 250° C.; the reaction time: 5 hours). After the reaction was completed, the catalyst was removed by filtration. The filtrate was rectified under a reduced pressure, and 155 g of methylcyclopentylmethyl-dimethylbicyclo[2.2.1]heptane was obtained as a fraction having a boiling point in the range of 127 to 130° C./68 mmHg. The results of the measurements of the properties and the traction coefficient of the fluid are shown in Table 9.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C([N:14]1[C:18]2[N:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([O:35][CH3:36])=[O:34])[CH:27]=3)[CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:17]=2[C:16]([I:37])=[N:15]1)C1C=CC=CC=1.OS([O-])(=O)=O.[K+].C(N(CC)CC)C>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:20]2[CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:17]3[C:16]([I:37])=[N:15][N:14]([CH:6]4[CH2:5][CH2:4][CH2:3][CH2:2][O:1]4)[C:18]=3[N:19]=2)=[CH:27][C:28]=1[C:33]([O:35][CH3:36])=[O:34]
Reactant: C1=COCCC1
Reactant: COC(=O)c1cc(-c2cc(C(=O)O)c3c(I)nn(Cc4ccccc4)c3n2)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(-c2cc(C(=O)O)c3c(I)nn(C4CCCCO4)c3n2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.9 %

Procedure:
para-Toluenesulphonic acid (38 mg/0.20 mmol) and 3,4-dihydro-2H-pyran (2.75 mL/30.1 mmol) are added successively to a solution of 1-benzyl-6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-iodo-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4.43 g/10.0 mmol) in 50 mL of DCM. The solution is stirred at ambient temperature for 12 hours. The reaction medium is run into a solution of KHSO4 (1 M) and extracted with EtOAc. The organic phase is washed with water and with a saturated aqueous solution of NaCl, dried over sodium sulphate, filtered and concentrated to dryness. The brown gum obtained is dissolved in 75 mL of DCM and added to the TEA scavenger resin (FL-TEA, Polymerlab, Variant, 3.53 mmol/g) (3.3 g/11 mmol). After stirring at ambient temperature for 2 h, the resin is filtered and washed with DCM. After drying under vacuum, the resin is then stirred for 20 minutes in a solution of triethylamine (2.6 mL/18 mmol) in 90 mL of DCM and then filtered and rinsed with DCM. The filtrate is acidified with a solution of KHSO4 (1 M). After extraction with EtOAc, the organic phase is washed with water and with a saturated aqueous solution of NaCl, dried over sodium sulphate, filtered and concentrated to dryness to give 4.3 g of an orange powder (yield: 82%).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][C:8]=2[C:9]=1[C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]#[N:21])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]>CO.[Ni]>[CH2:1]([C:5]1[O:6][C:7]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:23][C:8]=2[C:9]=1[C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCC#N)cc1
Agent: [Ni]
Solvent: CO
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.0 g of N-[2-butyl-3-{4-[2-cyanoethoxy]benzoyl}-1-benzofuran-5-yl]methanesulfonamide (IV) is dissolved in 300 ml of methanol and 5 g of Raney-Ni catalyst is added. The mixture is stirred at 25° C. at 10 bar H2 pressure for 24 hours. The catalyst is filtered, and the solvent is evaporated.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.Br[C:16]1[S:20][C:19]([C:21]#[N:22])=[CH:18][C:17]=1[CH3:23]>>[CH3:23][C:17]1[CH:18]=[C:19]([C:21]#[N:22])[S:20][C:16]=1[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Reactant: Cc1cc(C#N)sc1Br
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(C)N2

Procedure:
Prepared according to the procedure for Example 13 from 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine and 5-bromo-4-methyl-2-thiophenecarbonitrile. A yellowish solid: mp 145-146° C.; 1H-NMR (DMSO-d6) δ 7.79 (s, 1H), 7.18 (d, 1H, J=2.0 Hz), 7.13 (dd, 1H, J=8.4, 2.0 Hz), 6.68 (s, 1H), 6.54 (d, 1H, J=8.3 Hz), 4.83 (m, 1H), 2.26 (s, 3H), 1.49 (s, 3H), 1.46 (s, 3H), 1.28 (d, 3H, J=5.5 Hz); MS (ESI) m/z 299 [M+H]+.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:21])[C:7]([N:9]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:20]=1)[C:16]([O:18]C)=[O:17])[CH3:10])=[O:8])(=O)C.C(SCC(C)C(NC1N=CC=CC=1C(OC)=O)=O)(=O)C>>[SH:4][CH2:5][CH:6]([CH3:21])[C:7]([N:9]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:20]=1)[C:16]([OH:18])=[O:17])[CH3:10])=[O:8]
Reactant: COC(=O)c1cncc(N(C)C(=O)C(C)CSC(C)=O)c1
Agent: COC(=O)c1cccnc1NC(=O)C(C)CSC(C)=O
Product: CC(CS)C(=O)N(C)c1cncc(C(=O)O)c1

Procedure:
Following the procedure of Example 3, but substituting an equivalent amount of methyl 5-(2-acetylthiomethyl-N-methyl-propionamido)-nicotinate, obtained as disclosed in Example 16, for methyl 2-(2-acetylthiomethyl-propionamido)-nicotinate, 5-(2-mercaptomethyl-N-methyl-propionamido)-nicotinic acid is obtained; m.p. 190°-192° C., from methanol.