Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:16][CH2:17][C:18]#[CH:19])[CH:6]=1)(=[O:3])[CH3:2].O(C1C=CC=CC=1)C1C=CC=CC=1>>[C:1]([NH:4][C:5]1[C:6]2[CH:19]=[CH:18][CH2:17][O:16][C:7]=2[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[Cl:15])(=[O:3])[CH3:2]
Reactant: C#CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCC=C2
Temperature: 230 °C
Reaction time: 0.75 h
Yield: 33.8 %

Procedure:
A mixture of 40 parts of methyl 4-(acetylamino)-5-chloro-2-(2-propynoxy)benzoate and 172 parts of phenoxybenzene was stirred for 45 min. at 230° C. After cooling, the reaction mixture was poured into petroleumether. The organic layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 97:3). The eluent of the desired fractions was evaporated and the residue was crystallized from acetonitrile, yielding 11.9 parts (33.8%) of methyl 5-(acetylamino)-6-chloro-2H-1-benzopyran-8-carboxylate (interm. 11).
Reaction SMILES: C([Li])CCC.C[Si]([O:10][CH2:11][C:12]#[CH:13])(C)C.[CH2:14]([N:21]1[C@@H:26]2[C@H:27]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH2:28][C@@:22]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:23](=[O:38])[CH2:24][CH2:25]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([N:21]1[C@@H:26]2[C@H:27]([S:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)(=[O:30])=[O:31])[CH2:28][C@@:22]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@:23]([C:13]#[C:12][CH2:11][OH:10])([OH:38])[CH2:24][CH2:25]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#CCO[Si](C)(C)C
Reactant: O=C1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]2(O)C#CCO
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A solution of n-butyl lithium in hexanes (1.6M, 20 ml, 32 mmol) was added to a stirred, −78° C. solution of O-trimethylsilylpropargyl alcohol (5 ml, 34.8 mmol) in tetrahydrofuran (50 ml). After 30 minutes a solution of (1R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-one (Description 7; 4.6 g, 10.7 mmol) in tetrahydrofuran (20 ml) was added. The mixture was stirred for 30 minutes then quenched by addition of saturated ammonium chloride. The mixture was diluted with ethyl acetate and washed (2×100 ml) with water. The organic layer was separated and treated with a solution of tetrabutylammonium fluoride (11.5 ml, 1.0M solution in tetrahydrofuran) for 20 minutes at room temperature. The solution was washed with water (2×100 ml) then dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1:1, 3:2 and 2:1 ethyl acetate/iso-hexanes to yield the title compound (4.12 g, 79%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[S:14])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccc(Br)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc(Br)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-bromophenyl)ethanol (Chen, L.; et al., US 20060004045) and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.58 g, 98%): 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.41-8.05 (m, 3H), 8.03-7.68 (m, 2H), 7.68-6.95 (m, 10H), 5.88-5.44 (m, 1H), 4.25-3.80 (m, 2H); ESIMS m/z 578 ([M+H]+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9]([O:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[C:15]([CH3:28])[CH:14]=1)([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>COCCOC.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]>[CH:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:3]([OH:8])=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:15]([CH3:28])[CH:14]=1)([CH3:10])[CH3:11]
Reactant: Cc1cc(OC(C)C)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Oc1ccccc1I
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1cc(OC(C)C)ccc1-c1ccccc1O
Temperature: 25 °C
Yield: 32 %

Procedure:
2-Iodophenol (1.54 g, 7.00 mmol) was combined with 2-(4-isopropoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Preparation 38, 2.00 g, 7.24 mmol), cesium carbonate (4.56 g, 13.99 mmol) and palladium tetrakis(triphenylphosphine) (0.24 g, 0.21 mmol) in 1,2-dimethoxyethane (40 mL). The reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and then acidified with a 1 N aqueous HCl solution. The organics were extracted 3 times with diethylether. The organic layers were combined, washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography using as eluant a mixture heptane/ethyl acetate to afford 543 mg (31% yield) of 4′-isopropoxy-2′-methylbiphenyl-2-ol as a pale yellow oil. MS m/z 243 [MH]+
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-])=O)=[C:8]([CH3:10])[CH:9]=1)[CH3:2].[OH2:14].NN>CCO.[Pd]>[NH2:11][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][C:8]=1[CH2:10][OH:14]
Reactant: O
Reactant: CCOc1ccc([N+](=O)[O-])c(C)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CCOc1ccc(N)c(CO)c1
Temperature: 90 °C

Procedure:
To a solution of (5-ethoxy-2-nitro-phenyl)-methane (592 mg, 3.0 mmol) in absolute EtOH (20 mL) at rt was added 150 mg of Pd/C (Aldrich, 10 wt. % on activated carbon), followed by slow addition of hydrazine hydrate (1.5 mL). The resulting reaction mixture was refluxed at 90° C. for 1h. It then cooled to rt, filtered through Celite, and then concentrated in vacuo to afford crude (2-amino-5-ethoxy-phenyl)-methanol as a pale yellow oil: MS (ESI) 168 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:27][CH:28]([CH3:33])[CH2:29]B(O)O.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:27][CH:28]([CH3:33])[CH3:29])[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1OCc1ccccc1
Reactant: CC(C)CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCOC(=O)c1nc(CC(C)C)c2ccccc2c1OCc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of 4-Benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester (207 mg, 0.5 mmol, see example D-86a), Pd(PPh3)4 (58 mg, 0.05 mmol), 2-methylpropylboronic acid (78 mg, 0.75 mmol), K2CO3 (207 mg, 1.5 mmol), and 1,4-dioxane (4 ml) was refluxed with stirring for 48 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (5 ml) and the mixture was extracted with EtOAc (2×20 ml). The organic phase was dried over MgsO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes EtOAc=88 12 as the eluent gave the title compound as a yellowish oil (136 mg); MS-(+)-ion M+1=392.3.
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1>>[CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([O:10][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2c(o1)CN(C)CC2O
Product: Cc1cc2c(o1)CN(C)CC2Oc1ccc(C(F)(F)F)cc1

Procedure:
The same method as in Example 1 was conducted using 2,6-dimethyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 2) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-fluorobenzotrifluoride instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:22]1([B-](F)(F)F)[CH2:24][CH2:23]1.[K+].C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.P.[OH-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:22]1([C:2]2[C:3]([O:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH2:24][CH2:23]1
Reactant: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1cnc(OCC2CC2)c(C2CC2)c1
Temperature: 120 °C

Procedure:
In a 50 mL two-necked flask, 5-bromo-6-(cyclopropylmethoxy)nicotinic acid (1 g, 3.68 mmol, Eq: 1.00, CAN 912454-38-7) and cesium carbonate (3.59 g, 11.0 mmol, Eq: 3) were combined with toluene (25 mL) and water (2.8 mL) to give a colorless solution. The reaction mixture was 3× degassed and purged with argon, then palladium(II) acetate (16.5 mg, 73.5 μmol, Eq: 0.02), potassium cyclopropyltrifluoroborate (598 mg, 4.04 mmol, Eq: 1.1) and butyldi-1-adamantylphosphine (79.1 mg, 221 μmol, Eq: 0.06) were successively added. The evacuating-purging cycle was repeated after each addition. The reaction mixture was then heated to 120° C. for 4 h when TLC indicated the presence of some remaining starting material. The same amount of palladium acetate and phosphine ligand was once more added, and the reaction allowed proceeding over night at 120° C. The mixture was cooled to rt, poured into 20 mL 1N NaOH and extracted with CH2Cl2 (2×20 mL). The aqueous layer was acidified with 30 mL 2N HCl and extracted with AcOEt (2×50 ml). The organic layers were washed with H2O/NaCl solution, combined, dried over Na2SO4 and concentrated in vacuo. Crystallization from AcOEt/heptane finally yielded 609 mg of the title compound as off-white solid; MS (EI) 232.6 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][CH3:16])[C:9]=1[O:10]COC)[CH:5]=[O:6].[C:17]([Cu])#[N:18].CCOC(C)=O>CN(C=O)C>[CH2:15]([O:14][C:8]1[C:9]([OH:10])=[C:2]([CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=1)[C:17]#[N:18])[CH3:16]
Reactant: CCOc1cc(C=O)cc(Br)c1OCOC
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(C=O)cc(C#N)c1O
Temperature: 180 °C
Yield: 49.8 %

Procedure:
A mixture of 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (600 mg, 2.1 mmol) and CuCN (280 mg, 3.1 mmol) in DMF (10 mL) was heated at 180° C. for 4 hours. TLC (PE:EtOAc=1:1) indicated that the most of the starting material was consumed. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the 3-ethoxy-5-formyl-2-hydroxybenzonitrile (200 mg, yield: 50.0%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([NH2:29])([CH3:28])[CH3:27].[F:30][CH:31]([F:63])[O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH3:42])[N:37]=[C:36]2[C:43]1[N:44]=[C:45]2[C:51]([C:52](O)=[O:53])=[CH:50][N:49]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[C:46]2=[N:47][CH:48]=1>CN(C=O)C>[C:26]([NH:29][C:52]([C:51]1[C:45]2[C:46](=[N:47][CH:48]=[C:43]([C:36]3[C:35]4[C:39](=[CH:40][CH:41]=[C:33]([O:32][CH:31]([F:30])[F:63])[CH:34]=4)[N:38]([CH3:42])[N:37]=3)[N:44]=2)[N:49]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:50]=1)=[O:53])([CH3:28])([CH3:27])[CH3:25]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (28.0 mg, 73.5 μmol.20) and 2-methylpropan-2-amine (17.9 mg, 245 μmol) then 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (30 mg, 61.3 μmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight. TLC and LCMS showed incomplete reaction, added 2-methylpropan-2-amine (17.9 mg, 245 μmol) and HATU (28.0 mg, 73.5 μmol.20) then the reaction continued at 25° C. for 3 h. Solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 50% EtOAc in hexanes over 30 min to yield N-tert-butyl-2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33.4 mg, 61.3 μmol, 100%) as an off-white solid. 1H NMR (CDCl3) δ: 9.21 (s, 1H), 8.35 (s, 1H), 8.29 (d, J=2.3 Hz, 1H), 8.04 (s, 1H), 7.44-7.53 (m, 1H), 7.30-7.38 (m, 1H), 7.27 (s, 2H), 6.39 (t, J=74.0 Hz, 1H), 5.72 (s, 2H), 4.21 (s, 3H), 3.50-3.65 (m, 2H), 1.61 (s, 9H), 0.86-1.07 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].CC[O-].[Na+].[CH2:10](Br)[CH:11]=[CH:12][CH3:13].[Br-].[Na+]>C(O)C>[CH2:10]([NH:5][C:3](=[O:4])[CH2:2][NH2:1])[CH:11]=[CH:12][CH3:13]
Reactant: CC=CCBr
Reactant: NCC(N)=O
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CC=CCNC(=O)CN
Temperature: 50 °C
Yield: 80.4 %

Procedure:
7.4 g of glycine amide and 6.8 g of sodium ethylate were charged into a 100 ml four-necked flask, and 30 ml of ethyl alcohol was added to the mixture. To the resulting solution was then added dropwise 13.5 g of crotyl bromide over a period of one hour at room temperature. After completion of the addition, the mixture was heated at a temperature of 50° C. for 2 hours. After completion of the reaction, sodium bromide which precipitated upon cooling the reaction mixture was removed by filtration and the solvent was removed by distillation under reduced pressure to obtain 10.3 g of the desired N-crotylglycine amide as a pale yellow oily substance having nD23.5 1.4991.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CCCCCC>[CH:8](=[C:1]1[C:2](=[O:3])[CH2:4][O:5][C:6]1=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1COC(=O)C1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCCCCC
Product: O=C1COC(=O)C1=Cc1ccccc1

Procedure:
Tetronic acid (300 mg, 3 mmol) was added to benzaldehyde (1.0 mL, 9 mmol), and the resulting solution was stirred. HCl (37.7%, 0.1 mL) was added drop wise. The reaction mixture was vigorously stirred until it solidified. The solid product was crushed, soaked in hexane and washed with hexane. The crude product was purified by recrystallization (ethyl acetate/hexanes=8/2) to give compound TC-I-49 (0.27 g, 48%) as a yellow solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17]C1C=NC(Br)=CN=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.C(OCC)(=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][NH2:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cnc(Br)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CN)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of 3-cyclopentyloxy-4-methoxy-benzaldehyde (417 mg, 1.895 mmol), 2-amino-5-bromopyrazine (300 mg, 1.724 mmol), sodium triacetoxyborohydride (1.5 eq) and glacial acetic acid (3 eq) in dichloromethane (10 ml) was stirred at room temperature overnight. Then the reaction mixture was diluted with ethyl acetate, and washed with water. The oraganic layer was dried over MgSO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by ISCO (SiO2 flash column chromatography) (Hexane/ethyl acetate=100/0 to 3/2) to give about 400 mg of 6-bromo-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine. Yield: 61%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.F[C:16]1C=CC=CN=1>>[CH3:16][C:4]1[CH:5]=[CH:6][N:1]=[C:2]([C:7]2([C:13]#[N:14])[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH:3]=1
Reactant: Fc1ccccn1
Reactant: N#CC1(c2ccccn2)CCNCC1
Product: Cc1ccnc(C2(C#N)CCNCC2)c1

Procedure:
4-(4-methylpyridin-2-yl)piperidine-4-carbonitrile was prepared by the procedure described for the synthesis of 4-pyridin-2-ylpiperidine-4-carbonitrile in Example 1, substituting 2-fluoro-4-methylpyridine for 2-fluoropyridine.
Reaction SMILES: CCCCCCCCCCC.[C:12]([CH2:14][CH2:15][NH:16][C:17](=[O:36])[C:18]#[C:19][C:20]([CH2:34][F:35])([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:21][F:22])#[N:13]>>[F:22][CH2:21][C:20]1([CH2:34][F:35])[CH:19]=[C:18]([C:17]([NH:16][CH2:15][CH2:14][C:12]#[N:13])=[O:36])[C:29]2[CH:28]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:24]=2[O:23]1
Reactant: N#CCCNC(=O)C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Solvent: CCCCCCCCCCC
Product: N#CCCNC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Yield: 90 %

Procedure:
To undecane (0.8 ml) being heated under reflux, N-(2-cyanoethyl)-5-fluoro-4-fluoromethyl-4-(4-trifluoromethylphenoxy)-2-pentynamide (60 mg) was added and the mixture was heated under reflux for 1 hour. After concentrating under reduced pressure, the resulting residue was subjected to silica gel column chromatography (eluent; dichloromethane/ethyl acetate=10/1) to give the titled compound (54 mg), which was identical to the authentic sample.
Reaction SMILES: [CH3:1][NH:2][C:3]1(NC)[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:11])=[O:10])=[C:5]([N+:23]([O-])=O)[CH2:4]1.Cl[Sn]Cl.Cl.[CH3:32]CO>>[NH2:23][C:5]1[CH:4]=[C:3]([N:2]([CH3:32])[CH3:1])[CH:8]=[CH:7][C:6]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:10])=[O:11]
Reactant: CNC1(NC)C=CC(S(=O)(=O)Nc2cccc3cccnc23)=C([N+](=O)[O-])C1
Reactant: CCO
Agent: Cl
Agent: Cl[Sn]Cl
Product: CN(C)c1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Yield: 74 %

Procedure:
In a similar fashion using route 2 general procedure 4,4-dimethylamino-2-nitro-N-quinolin-8-yl-benzenesulfonamide 500 (140 mg, 0.37 mmol), SnCl2 (210 mg, 1.12 mmol), 6N HCl (1 ml) and EtOH (5 ml) at 80° C. for 6 h gave the title compound (95 mg, 74%) which was used in the next step without further purification.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:45])(=[N:34]C(OCC3C=CC=CC=3)=O)=[O:33])=[CH:28][CH:27]=2)=[O:25])=[O:15])=[N:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:45])(=[NH:34])=[O:33])=[CH:28][CH:27]=2)=[O:25])=[O:15])=[N:11][CH:12]=1
Reactant: CS(=O)(=NC(=O)OCc1ccccc1)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CS(=N)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 0.29 h
Yield: 94.4 %

Procedure:
Sulfuric acid (50 mL) was cooled to 0-5° C. To this was added product of step 7 (10 g, 0.016 mol) and reaction mixture was stirred at same temperature for 15-20 min. Above reaction mixture was slowly poured in chilled water and basified using aqueous potassium carbonate solution. Precipitated product was filtered and washed with water. Drying afforded 7 g of titled compound in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[BH4-].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: OCc1ccc(Cl)nn1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
4.3 g (21.4 mmol) of 6-chloropyridazine-3-carboxylic acid are dissolved in 60 ml of dry toluene and heated to 60° C. At this temperature, 3.8 g (32.2 mmol) of thionyl chloride are added, and the mixture is stirred at this temperature for 3 h. The mixture is then heated at reflux for 4 h. After cooling to RT, the solvent is removed on a rotary evaporator. 20 ml of toluene are added, and the mixture is again evaporated to dryness. The residue is dissolved in 40 ml of methyl tert-butyl ether and cooled to 5° C. At this temperature, a solution of 1.7 g (47.2 mmol) of sodium borohydride in 37 ml of water is added dropwise. The mixture is stirred at RT for 20 h. 50 ml of ethyl acetate are then added, and the aqueous phase is extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases are washed in each case twice with in each case 10 ml of sat. sodium bicarbonate solution and water. The solvent is removed on a rotary evaporator and the residue is purified chromatographically on silica gel 60 (mobile phase: gradient dichloromethane/ethanol 100:1→20:1).
Reaction SMILES: C([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(C)(C)C>N1C=CC=CC=1>[C:8]([C:9]([C:8]1[CH:7]=[CH:6][CH:5]=[CH:13][CH:12]=1)=[O:10])([CH3:12])([CH3:9])[CH3:7]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
2′-Deoxy-2′-N-phthaloyl derivative (21a) (5.4 g, 8.45 mmol) was dissolved in anhydrous pyridine and 4-tert-butylbenzoyl chloride (1.2 eq) was added at 0° C. and the reaction mixture left overnight at room temperature. The reaction was subsequently quenched with methanol (10 mL), solvents removed in vacuo and the residue dissolved in toluene and evaporated to dryness. The resulting oil was dissolved in dichloromethane, washed with saturated aq. NaHCO3 and brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica, using EtOAc-Hexanes (1:2) mixture as an eluent to give 5.06 g (75%) of the fully protected synthon (22a, R=t-BuBz).
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:16][C:3]1=2.[C:29]([O:33]C)(=[O:32])[CH2:30]O>>[C:29]([CH2:30][O:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:16][C:3]1=2)([OH:33])=[O:32]
Reactant: COC(=O)CO
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Product: O=C(O)COC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21

Procedure:
11-Hydroxy-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and methyl glycolate were used and reacted in the same manner as in Example 26 to obtain the title compound.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:13])=O>>[CH:1]1([O:6][CH2:7][C:8]([Cl:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COC1CCCC1
Product: O=C(Cl)COC1CCCC1
Yield: 100 %

Procedure:
2-(Cyclopentyloxy)acetic acid (476mg, 3.3 mmol) was heated to reflux in thionyl chloride (0.365 ml, 5.00 mmol). After 30 min the excess of thionyl chloride was evaporated to afford (2-(cyclopentyloxy)acetyl chloride (3.3 mmol) that was used directly in the next step.