Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][NH:14]3)=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[N:3]=1.Br[CH2:25][CH2:26][O:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH2:25][CH2:26][O:27][CH3:28])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[N:3]=1
Reactant: Cc1cc(C)n(-c2nc(Nc3ccccc3)c3nc[nH]c3n2)n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCn1cnc2c(Nc3ccccc3)nc(-n3nc(C)cc3C)nc21
Temperature: 120 °C
Yield: 8.4 %

Procedure:
[2-(3,5-Dimethyl-pyrazol-1-yl)-9H-purin-6-yl]-phenyl-amine (300 mg, 0.88 mmol), 2-bromoethylmethylether (0.12 mL, 1.32 mmol), potassium carbonate (121 mg, 0.88 mmol) and acetonitrile were mixed and heated in a microwave oven at 120° C. for 40 min. Water was added resulting in a white precipitate. The crude product was purified by preparative LCMS to give [2-(3,5-dimethyl-pyrazol-1-yl)-9-(2-methoxy-ethyl)-9H-purin-6-yl]-phenyl-amine (27 mg, 9%) as a white crystalline compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:21]([O:20][CH:19]([O:23][CH2:24][CH3:25])[CH2:18][N:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:22]
Reactant: CCOC(=O)c1cc2c([nH]1)CCCC2
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1CC(OCC)OCC)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a suspension of NaH (1.44 g, 60.2 mmol) in N,N-dimethylformamide (DMF)(30 mL) was slowly added 121a (5.80 g, 30.1 mmol) at 0° C. The resulting mixture was stirred at room temperature for 0.5 h, followed by the addition of 2-bromo-1,1-diethoxyethane (11.9 g, 60.2 mmol). The reaction was heated at 70° C. for 30 h and quenched with water (100 mL). The mixture was then extracted with ethyl acetate (3×100 mL). The combined organic phase was concentrated under reduced pressure and the residue was purified with silica-gel column chromatography eluting with 40:1 petroleum ether/ethyl acetate to afford 121b (4.7 g, 51%). MS-ESI: [M-ethanol+H]+ 264. 1H NMR (500 MHz, DMSO-d6) δ 6.65 (s, 1H), 4.59 (t, J=5.0 Hz, 1H), 4.17-4.16 (m, 4H), 3.59-3.57 (m, 2H), 3.27-3.26 (m, 2H), 2.61 (t, J=6.0 Hz, 2H), 2.51 (t, J=6.0 Hz, 2H), 1.73-1.71 (m, 2H), 1.63-1.61 (m, 2H), 1.25 (t, J=7.0 Hz, 3H), 1.02 (t, J=7.0 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].O1CCCC1>C(=O)([O-])[O-].[K+].[K+].O.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>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: Brc1cccc2[nH]ccc12
Reactant: COc1ccc(B(O)O)cc1OC
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: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cccc3[nH]ccc23)cc1OC
Temperature: 100 °C

Procedure:
In a microwave safe tube, 4-Bromoindole (1.383 g, 0.007054 mol), 3,4-dimethoxyphenyl boronic acid (3.21 g, 0.0176 mol), and Tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.00035 mol) were mixed in 1.00 M of Potassium carbonate in Water (21 mL) and Tetrahydrofuran (34 mL, 0.42 mol). The resulting mixture was heated at 100° Celsius in the microwave for 10 minutes. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layers were combined, washed with brine and dried over sodium sulfate. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to the yield 1.02 g of the titled compound as a light green solid. MS(ESI) [M+H+]+=254.20.
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].[H-].[Na+].[Br:9][C:10]1[C:11](Cl)=[N:12][C:13]([Cl:16])=[N:14][CH:15]=1>C1COCC1>[Br:9][C:10]1[C:11]([O:5][C@H:3]([CH3:4])[C@H:2]([OH:6])[CH3:1])=[N:12][C:13]([Cl:16])=[N:14][CH:15]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: C[C@@H](O)[C@@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](C)Oc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.35 g (15.0 mmol) of (R,R)-(−)-2,3-butanediol in 50 ml of THF is mixed at 0° C. in portions with 480 mg (11.0 mmol) of sodium hydride (55% dispersion) and then stirred for 10 minutes at room temperature. The solution that is produced is added at 0° C. to 2.27 g (10.0 mmol) of 5-bromo-2,4-dichloropyrimidine in 25 ml of THF. The batch is slowly heated to room temperature and stirred for 12 hours. The solvent is drawn off, and the residue that is obtained is purified by chromatography (hexane/ethyl acetate 1:1). 2.29 g (8.1 mmol, corresponding to 81% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][N:6]=1.CC[N:13](CC)CC>>[Cl:1][C:2]1[S:3][C:4]([S:7]([NH2:13])(=[O:9])=[O:8])=[CH:5][N:6]=1
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1cnc(Cl)s1
Product: NS(=O)(=O)c1cnc(Cl)s1
Yield: 61 %

Procedure:
Prepared by general procedure III from 2-Chloro-thiazole-5-sulfonyl chloride (1.1 g, 5 mmol) and NH40H (0.42 mL, 6 mmol) with Et3N (0.77 mL, 6 mmol to give the title compound as a light-brown solid (610 mg, 61%). MS (ISN) 197[(M−H)−].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C([O-])(=O)C.[Na+].[Br:16]Br.O>C(Cl)(Cl)Cl.CCOC(C)=O>[Br:16][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: BrBr
Reactant: O=C1Cc2ccccc2N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1Cc2cc(Br)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of oxindole (2.0 g, 15.0 mmol) and sodium acetate (2.1 g, 25.5 mmol) in CHCl3 (20 cm3) was treated with bromine (2.4 g, 15.0 mmol) in CHCl3 (10 cm3). After 30 min. the mixture was allowed to warm to RT and stirred for 1 h. The reaction mixture was diluted with EtOAc (500 cm3) and poured into water. The aqueous layer was extracted with EtOAc (×2), the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, brine, dried (MgSO4), and evaporated to give the title compound (3.1 g, 14.6 mmol, 96%) as an off-white solid which was used without further purification: m.p. 221–223° C.; 1H NMR (DMSO-d6) δ 3.51 (s, 2H), 6.76 (d, 1H, J=8.1 Hz), 7.33(dd, 1H, J=8.1, 1.7 Hz), 7.37 (s, 1H), 10.49 (br s, 1H); 13C NMR (DMSO-d6) δ 36.10 (t), 111.21 (d), 113.16 (s), 127.54 (d), 128.3 (s), 130.40 (d), 143.34 (s), 176.24 (s); MS (EI) m/z 211, 213 (M)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][C@@:7]2([C:16]3[C:11](=[CH:12][C:13]([Cl:26])=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=4)[CH:15]=3)[CH2:10][O:9]2)[C@H:6]([OH:27])[C@@H:5]([OH:28])[C@@H:4]1[OH:29].N1C=CC=CC=1.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:26][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)[C@:7]1([C@H:6]([OH:27])[C@@H:5]([OH:28])[C@H:4]([OH:29])[C@@H:3]([CH2:2][NH:1][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[O:8]1)[O:9][CH2:10]2
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CNC(=O)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
To a stirred solution of (1S,3′R,4′S,5′S,6′R)-6′-(aminomethyl)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-3′,4′,5′-triol (20 mg, 0.047 mmol) and 0.04 mL of pyridine in 1 mL of dichloromethane was added of pivaloyl chloride (60 μL, 0.05 mmol) and 3 mg of 4-dimethylaminopyridine. After being stirred for 2 h at ambient temperature, the reaction mixture was diluted with 20 mL of dichloromethane, washed with 1 M hydrochloric acid and concentrated. The residue was dissolved in 1 mL of methanol and cooled in an ice bath. After addition of 0.3 mL of 4 M potassium hydroxide solution, the mixture was stirred for 2 h at ambient temperature. The reaction mixture was then neutralized with 1 M hydrochloric acid and concentrated. The residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was separated and dried over sodium sulfate. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 6.8 mg of title compound. 1H NMR (CD3OD, 300 MHz) δ 7.37 (s, 1H), 7.16 (s, 1H), 7.10 (s, 4H), 5.07 (s, 2H), 4.12 (d, J=15.8 Hz, 1H), 4.04 (d, J=15.8 Hz, 1H), 3.82-3.59 (m, 3H), 3.45-3.39 (m, 2H), 3.43 (dd, J=9.9, 8.4 Hz, 1H), 2.60 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H), 1.11 (s, 9H); MS ESI (m/z) 504 (M+1)+, calc. 503.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]NCCCCCCC)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38](S(C1C=CC(C)=CC=1)(=O)=O)[C:39]([NH2:41])=[O:40].C(O[CH2:56][CH3:57])(=O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH:19]([CH2:56][CH3:57])[CH2:20][CH2:21][CH2:22][CH2:23][NH:41][C:39]([NH:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)=[O:40])[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N(C(N)=O)c2ccccn2)cc1
Reactant: CCOC(C)=O
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCC(CCCCNC(=O)Nc1ccccn1)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (4.35 g; 0.01 mol) and pyridyltosylurea (3.2 g; 0.011 mol; Frigola Conatansa, Jordi; ES 534,782) in diphenyl ether (35 mLs) was stirred under nitrogen at 180° C. for 30 minutes. The cooled solution was chromatographed with 1:1 hexane:ethyl acetate to give the title compound (4.03 g; 0.0073 mol) as an orange oil. 1H NMR (CDCl3) δ 8.15-8.05(m, 1H), 7.9(d, 1H, J=8.4 Hz), 7.6-7.4(m, 5H), 7.3-7.1 (m, 8H), 6.9-6.8 (m, 1H), 3.32 (t, 2H, J=7.2 Hz), 3.25(t,2H, J=7.9 Hz), 3.05(t,2H, J=6.6 Hz), 1.8-1.45(m,8H), 1.4-1.2(m, 8H), 0.9(t,3H, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:17]([O-:20])([O-:19])=O.[K+].[K+].Br[CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C(#N)C>[C:4]([OH:27])(=[O:8])/[CH:5]=[CH:15]/[C:17]([OH:20])=[O:19].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(CO)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(CO)CN1CCC(c2noc3cc(F)ccc23)CC1
Product: O=C(O)/C=C/C(=O)O

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6 mmol), K2CO3 (12.5 g, 17.5 mmol), 3-bromo-2,2-dimethyl-1-propanol (3 g, 21 mmol, 1.5 eq.), tetra-butylammonium hydrogen sulfate (1 g, phase transfer catalyst) in water (5 ml) and acetonitrile (150 ml) was heated at reflux for 43 days. TLC showed a small spot for the expected product. The mixture was diluted with EtOAc (400 ml) and washed with brine. The organic solution was dried and concentrated to a dark brown mixture. The crude mixture was purified carefully by flash chromatography (SiO2, 95 g to afford the dried pure product; 260 mg, (6%) as an oil. This oil was converted to the fumarate salt by treatment with fumaric acid (98.5 mg, 1.0 eq.) in ethanol. Recrystallization from ethanol:ether yielded 210 mg of white crystals, m.p.=144°-145° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([O:24]CC)=O)[C:4]1=[O:27])[CH3:2].[NH2:28][CH2:29][CH2:30][N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:28][CH2:29][CH2:30][N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33])=[O:24])[C:4]1=[O:27])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Reactant: CN(CCN)S(C)(=O)=O
Product: CCn1c(=O)c(C(=O)NCCN(C)S(C)(=O)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 67.2 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (38 mg, 0.103 mmol), and N-(2-aminoethyl)-N-methylmethanesulfonamide (489 mg, 3.21 mmol), was prepared 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (33 mg, 67% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.42 (br s, 1 H), 8.55 (s, 1 H), 7.38 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 4.19 (m, 2 H), 4.14 (s, 2 H), 3.66 (m, 2 H), 3.41 (m, 2 H), 2.97 (s, 3 H), 2.84 (s, 3 H), 1.23 (m, 3 H); HRMS m/z calcd for C22H26FN4O5S: 477.1602. Found: 477.1610.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:9]([C:11](C#N)=[C:12]([C:15]#[N:16])[C:13]#[N:14])#[N:10]>O>[C:9]([C:11]1[C:12]([C:13]#[N:14])=[C:15]([NH2:16])[N:3]([C:4]([NH2:6])=[O:5])[N:2]=1)#[N:10]
Reactant: N#CC(C#N)=C(C#N)C#N
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1nn(C(N)=O)c(N)c1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
To a mixture of semicarbazide hydrochloride (11.2 g, 0.1 mol), water (200 ml) and sodium hydroxide (4.0 g, 0.1 mol) cooled in an ice-bath was added dropwise tetracyanoethylene (12.8 g, 0.1 mol). The reaction mixture was warmed to room temperature, stirred for 1.5 hours and then allowed to stand for 24 hours. The white precipitate which formed during the course of the reaction was collected by filtration and washed with water to afford 15.6 g (89%) of 3-cyano-4-cyano-5-amino-1H-pyrazole-1carboxamide as a white solid, m.p. 225° C. (dec.) when dried at 85° C. in high vacuum.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH3:32])=[C:9]([CH:30]=1)[C:10]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:11])#[N:4].CC(C)=O>C(O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH3:32])=[C:9]([CH:30]=1)[C:10]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][C:18](=[C:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[OH:29])[CH2:17][CH2:16]1)=[O:11])#[N:4]
Reactant: COc1ccc(C#N)cc1C(=O)NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1ccc(C#N)cc1C(=O)NCCN1CCC(=C(O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.38 g (0.01 mol) of sodium borohydride are added, while stirring, to a suspension of 4.1 g (0.01 mol) of 5-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]ethyl]-2-methoxybenzamide in 50 ml of ethanol and the whole is stirred for 1 hour at room temperature. There is added to the resulting clear solution 1 ml of acetone and the whole is then concentrated in a water-jet vacuum. The residue is taken up in methylene chloride and water, the layers are separated in a separating funnel and, after being dried over magnesium sulphate, the organic phase is concentrated by evaporation. 5-Cyano-N-[2-[4-[(4-fluorophenyl)hydroxymethylene]-piperidinyl]-ethyl]-2-methoxybenzamide of melting point 135°-137° is obtained as residue.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH2:7][C:6]1([CH2:10][C:11](Cl)=[O:12])[CH2:5][CH2:4][CH2:3]2.[CH3:14][C:15]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:67])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:66])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:65])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:64])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:63])[CH2:42][CH2:43][CH:44]=[C:45]([CH3:62])[CH2:46][CH2:47][CH:48]=[C:49]([CH3:61])[CH2:50][CH2:51][CH:52]=[C:53]([CH3:60])[CH2:54][CH2:55][CH:56]=[C:57]([CH3:59])[CH3:58])=[CH:16][CH2:17][S:18][CH2:19][CH2:20][NH2:21]>N1C=CC=CC=1>[CH3:14][C:15]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:67])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:66])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:65])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:64])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:63])[CH2:42][CH2:43][CH:44]=[C:45]([CH3:62])[CH2:46][CH2:47][CH:48]=[C:49]([CH3:61])[CH2:50][CH2:51][CH:52]=[C:53]([CH3:60])[CH2:54][CH2:55][CH:56]=[C:57]([CH3:59])[CH3:58])=[CH:16][CH2:17][S:18][CH2:19][CH2:20][NH:21][C:11](=[O:12])[CH2:10][C:6]12[CH2:7][CH2:8][CH2:9][N:2]1[CH2:3][CH2:4][CH2:5]2
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCSCCN
Reactant: O=C(Cl)CC12CCCN1CCC2
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCSCCNC(=O)CC12CCCN1CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
(1-Azabicyclo[3.3.0]octan-5-yl)acetyl chloride hydrochloride (2.00 g, 8.93 mmol) was added to a solution of 2-(3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaen-1-ylthio)ethylamine (5.00 g, 6.61 mmol, prepared as described in Example 4) in 75 ml of pyridine at the temperature below 20° C. and the solution was stirred at 25° C. for 3 hours. (1-Azabicyclo[3.3.0]octan-5-yl)acetyl chloride hydrochloride (0.9 g, 4.02 mmol) was further added to the reaction mixture at the temperature below 20° C. and the solution was stirred at 25° C. for an hour. The solvent in the reaction mixture was evaporated in vacuo to dryness and the remaining residue was partitioned between chloroform and 10% sodium hydroxide aqueous solution. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness to give a brown residue. The residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (10:0-10:1.5) to afford 5.2 g (86.7%) of the desired compound, as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:14][N:15]1[C:19](B(O)O)=[CH:18][C:17]([CH3:23])=[N:16]1.[NH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1>>[CH3:14][N:15]1[C:19]([C:5]2[CH:4]=[N:3][C:2]([NH:24][C:25]3[N:26]=[C:27]([CH3:30])[S:28][CH:29]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[CH:18][C:17]([CH3:23])=[N:16]1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Cc1nc(N)cs1
Reactant: Cc1cc(B(O)O)n(C)n1
Product: Cc1ccc2c(-c3cc(C)nn3C)cnc(Nc3csc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=351.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 1,3-dimethyl-1H-pyrazole-5-boronic acid (Example J) and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[CH:38][C:39]([F:43])=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[CH:38][C:39]([F:43])=[CH:40][CH:41]=2)[CH2:36][CH2:35]1)=[O:31]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: NC1CCc2cc(F)ccc21
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2CCc3cc(F)ccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-5-fluoro-indane
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[N+:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33].COCCOC>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:32]([O-:34])=[O:33])[CH:40]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 85 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (380 mg, 1 mmol) was mixed with K2CO3 (280 mg, 2 mmol), 3-nitro-phenylboronic acid (334 mg, 2 mmol), Pd(Ph3)4 (115 mg, 0.1 mmol), 4 mL of 1,2-dimethoxyethane and 5 drops of water. The mixture was heated and stirred in an 85° C. oil bath for 3 h. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removal of solvent gave the crude product, which was purified by column chromatography to give 310 mg (88% yield) of 3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: [CH3:1]C(OC(N(C)C)N(C)C)(C)C.[CH3:13][C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[C:16]([CH3:23])[C:15]=1[Br:24]>CN(C=O)C.[Zn]>[Br:24][C:15]1[C:16]([CH3:23])=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:1][NH:20]2
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1Br
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: [Zn]
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]ccc2c1Br
Temperature: 25 °C
Yield: 29 %

Procedure:
Bredereck's reagent (tert-butoxybis(dimethylamino)methane—16 g, 91 mmol) is added at room temperature to a solution of 2,6-dimethyl-3-nitrobromobenzene (20 g, 87 mmol) in anhydrous DMF (120 ml). The reaction mixture is heated at 120–125° C. under N2 for 5 hours or until starting material is mostly consumed according to TLC. The reaction mixture is allowed to cool to room temperature, poured into water (300 ml), and extracted with dichloromethane (100 ml×3). The combined extracts are dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of enamines as a dark brown oil. This material is carried on to the next step without purification. The crude mixture is dissolved in acetic acid/water (250 ml of 4:1), cooled to 0° C. and treated with zinc dust (57 g, 870 mmol) added slowly in portions. After complete addition, the reaction mixture is heated at 110° C. for 4 h. Zinc is removed by filtration through a celite pad and the filtrate is extracted with dichloromethane (100 ml×3). The combined extracts are dried over anhydrous sodium sulfate, concentrated and purified by flash chromatography on silica gel (EtOAc/Hexane 1:20) to obtain 4-bromo-5-methylindole (5.3 g) (21) as a light purple oil.