Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[C:10]([O:15]C)[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3]1.B(Br)(Br)Br.O.O.NN>C(Cl)Cl>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([OH:15])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccc(Cl)cc2)c2cc(SC)c(OC)cc2S(=O)(=O)C1
Agent: BrB(Br)Br
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CCCCC1(CCCC)CN(c2ccc(Cl)cc2)c2cc(SC)c(O)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.8 %

Procedure:
To a solution of 1,1-dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 98; 0.26 g 0.52 mmol) in anhydrous DCM (10 ml) was added boron tribromide (2.63 g, 10.48 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 2.5 h. The reaction flask was cooled to 0° C., water (20 ml) and hydrazine monohydrate (0.5 ml) was added. The organic layer was separated, dried and evaporated under reduced pressure. The crude product was purified by column chromatography using DCM/EtOAc (100:5 and 100:10) as eluent to give the title compound 0.20 g (80%). NMR (500 MHz) 0.85 (t, 6H), 1.03–1.28 (m, 8H), 1.35–1.46 (m, 4H), 2.39 (s, 3H), 3.21 (s, 2H), 3.73 (s, 2H), 7.04 (d, 2H), 7.29–7.34 (m, 3H), 7.44 (s, 1H); m/z 482.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:10][C:11]=3[C:12]2([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.[CH:32]([C:34]1[S:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33]>>[CH2:19]([C:12]1([CH2:15][CH2:16][CH2:17][CH3:18])[C:13]2[CH:14]=[C:2]([C:37]3[S:38][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=3)[CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][C:9]([N:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:8][CH:7]=2)[CH2:20][CH2:21][CH3:22]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCCCN(CCCC)c1ccc2c(c1)C(CCCC)(CCCC)c1cc(Br)ccc1-2
Product: CCCCN(CCCC)c1ccc2c(c1)C(CCCC)(CCCC)c1cc(-c3ccc(C=O)s3)ccc1-2

Procedure:
As shown in Scheme 2, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-dibutylamine (21). Then, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-dibutylamine (21) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-(9,9-Dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (22a). Finally, in acetonitrile, 5-(9,9-Dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (22a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 2-Cyano-3-[5-(9,9-dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophen-2-yl]-acrylic acid (23a).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=2)[C:43]([CH3:54])=[CH:42][C:41]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:63]([O:70][C:71](=[O:89])[NH:72]/[C:73](/[NH:85][CH2:86][CH:87]=[CH2:88])=[N:74]\[C:75](=[O:84])[O:76][CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:77]([O:76][C:75]([NH:74][C:73]([NH:85][CH2:86]/[CH:87]=[CH:88]/[C:50]1[CH:51]=[CH:52][C:47]([CH2:46][C:44]2[C:43]([CH3:54])=[CH:42][C:41]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:40]([C@@H:10]3[O:11][C@H:12]([CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C@@H:13]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C@H:9]3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:45]=2)=[CH:48][CH:49]=1)=[N:72][C:71]([O:70][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:89])=[O:84])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)cc1
Reactant: C=CCN/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)cc1
Yield: 45.4 %

Procedure:
To an acetonitrile solution (3 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-methylphenyl]-D-glucitol (271 mg, 0.305 mmol) were added dibenzyl[(Z)-(allylamino)methylylidene]biscarbamate (335 mg, 0.914 mmol), palladium(II) acetate (18 mg, 0.0791 mmol), tri-O-tolylphosphine (61 mg, 0.201 mmol) and triethylamine (154 mg, 1.52 mmol), and reacted at 120° C. for 20 minutes with microwave manufactured by Biotage. The reaction solution was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (163 mg, 46%) as a pale yellow amorphous compound.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(-c2ccccn2)c2ccccc12
Product: O=Cc1c(N2CCNCC2)n(-c2ccccn2)c2ccccc12
Yield: 72 %

Procedure:
2-Chloro-1-(pyridin-2-yl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 2-(piperazin-1-yl)-1-(pyridin-2-yl)-1H-indole-3-carboxaldehyde (72% yield) as an orange solid. ESI/MS 307 (M+H); RT=2.23 min; NMR 10.30 (1H, s); 8.75 (1H, m); 8.26 (1H, d, J=9 Hz); 7.98 (1H, m); 7.46 (5H, m); 3.30 (4H, m); 2.81 (4H, m).
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]1=[O:21].Cl[C:23]1[C:28]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)=[CH:27][N:26]=[C:25]([S:34]([CH3:37])(=[O:36])=[O:35])[N:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(=O)OCC>[CH:31]1([CH2:30][O:29][C:28]2[C:27]([C:10]3[C:9]4[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=4[C:3](=[O:21])[N:2]([CH3:1])[CH:11]=3)=[N:26][C:25]([S:34]([CH3:37])(=[O:35])=[O:36])=[N:24][CH:23]=2)[CH2:32][CH2:33]1
Reactant: CS(=O)(=O)c1ncc(OCC2CC2)c(Cl)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1=O)CCCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2c(c1=O)CCCC2
Temperature: 70 °C
Yield: 67 %

Procedure:
The title compound of step 3 (200 mg, 0.69 mmol), the title compound of Example 152, step 4 (218 mg, 0.83 mmol), K3PO4 (440 mg, 2.07 mmol) and Pd(dppf)Cl2 (51 mg, 0.7 mmol) in 6:1 dioxane/water (7 mL) were purged with nitrogen and heated at 70° C. for 8 h. After silica gel chromatography (PE: EA=1:1), the title compound (180 mg, yield: 67%) was obtained as a light yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.42 (s, 1H), 7.48 (s, 1H), 4.04 (d, J=7.2 Hz, 2H), 3.60 (s, 3H), 3.35 (s, 3H), 2.65-2.62 (m, 2H), 2.54-2.50 (m, 2H), 1.80-1.78 (m, 2H), 1.77-1.67 (m, 2H), 1.28-1.25 (m, 1H), 0.73-0.71 (m, 2H), 0.41-0.38 (m, 2H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=2)[CH2:7]1.C1(OC)C=CC=CC=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[N+:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][NH:6][CH2:14]2)([O-:17])=[O:16]
Reactant: COc1ccc(CN2Cc3ccc([N+](=O)[O-])cc3C2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)CNC2
Temperature: 120 °C

Procedure:
2-(2,4-dimethoxy-benzyl)-5-nitro-2,3-dihydro-1H-isoindole (13 g) in TFA (18 ml) was treated with anisole (6 ml) then heated in a CEM microwave synthesiser at 120° C. (30 Watts) for 20 minutes (carried out batch wise, 6 times). The reaction mixture was evaporated in vacuo and the residue partitioned between DCM and water. The water layer was separated, washed with DCM (×3) then evaporated and re-evaporated with toluene/MeOH (×3) to give 9.8 g of 5-nitro-2,3-dihydro-1H-isoindole trifluoroacetic acid salt as a beige solid. 1H NMR (DMSO-d6) 9.85 (2H, br s), 8.32 (1H, d), 8.25 (1H, dd), 7.70 (1H, d), 4.68 (2H, s), 4.65 (2H, s).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7](=[C:17]([F:19])[F:18])[CH2:8][CH2:9][S:10][CH:11]1[NH:15][C:14](=O)[CH2:13][O:12]1.N1C=CC=CC=1>ClCCl>[Cl:3][C:14]1[N:15]=[C:11]([S:10][CH2:9][CH2:8][C:7]([F:6])=[C:17]([F:19])[F:18])[O:12][CH:13]=1
Reactant: O=C1COC(SCCC(F)=C(F)F)N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: FC(F)=C(F)CCSc1nc(Cl)co1
Temperature: 75 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
2 g of phosphorus oxychloride were added dropwise to a mixture of 1 g of 2-(3,4,4-trifluoro-3-butenylthio)oxazolidin-4-one and 0.35 g of pyridine under ice cooling and stirred at 70-80° C. for 3 hours. After addition of ice water to the reaction mixture and stirring for 30 minutes, the mixture was extractred with dichloromethane. The extracted layer was washed with water, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane) to obtain 0.7 g of 4-chloro-2-(3,4,4-trifluoro-3-butenylthio)oxazole (yield 65%). n20D=1.4813.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:11]1[CH:12]=[C:13]([NH:23][C:24](=[O:46])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[C:35]([CH2:39][N:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[CH:34]=3)[CH:26]=2)[C:14]([O:21][CH3:22])=[C:15]([CH:20]=1)[C:16](OC)=[O:17])([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:7]([C:11]1[CH:20]=[C:15]([CH2:16][OH:17])[C:14]([O:21][CH3:22])=[C:13]([NH:23][C:24](=[O:46])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[C:35]([CH2:39][N:40]4[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]4)[CH:34]=3)[CH:26]=2)[CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)c1cc(C(C)(C)C)cc(NC(=O)c2ccc(C)c(Oc3ccnc(CN4CCNCC4)c3)c2)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)c1ccc(C)c(Oc2ccnc(CN3CCNCC3)c2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.78 ml of a 1 M solution of LiAlH4 in tetrahydrofuran are added to a solution of 210 mg methyl 5-tert-butyl-2-methoxy-3-[4-methyl-3-(2-piperazin-1-ylmethyl-pyridin-4-yloxy)-benzoylamino]-benzoate in 4 ml tetrahydro-furan which has been cooled to 0° C. The solution is stirred for 2 h at 0° C. and then combined with 0.80 ml of an aqueous 2 N NaOH solution. The mixture is diluted with ethyl acetate and filtered through Celite. The filtrate is dried on MgSO4 and evaporated to dryness.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.CO.[Li+].[OH-]>C1COCC1>[C:16]([C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1)#[N:17]
Reactant: CCOC(=O)c1oc2cccc(C#N)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)oc2cccc(C#N)c12
Reaction time: 2 h

Procedure:
To 550 mg of 4-cyano-3-methyl-benzofuran-2-carboxylic acid ethyl ester (2.4 mmol) in 15 mL of THF was added 5 mL of MeOH and 5 mL of 1N LiOH. The reaction was complete in 2 h. After quenching with 5 mL of 1 N HCl and work up, 4-cyano-3-methyl-benzofuran-2-carboxylic acid was obtained in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.7 (s, 3 H) 7.7 (m, 1 H) 7.9 (d, J=7.3 Hz, 1 H) 8.1 (m, 1 H).
Reaction SMILES: [O-]CC.[Na+].[Na].[CH:6]1([C:9](=[NH:11])[NH2:10])[CH2:8][CH2:7]1.C([O:14][C:15]([C:17]1[N:18]=[CH:19][C:20]2[NH:21][C:22]3[C:27]([C:28]=2[CH:29]=1)=[CH:26][CH:25]=[CH:24][CH:23]=3)=O)C>O.C(O)C.C1(C)C=CC=CC=1>[CH:6]1([C:9]2[N:10]=[C:15]([C:17]3[N:18]=[CH:19][C:20]4[NH:21][C:22]5[C:27]([C:28]=4[CH:29]=3)=[CH:26][CH:25]=[CH:24][CH:23]=5)[O:14][N:11]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: N=C(N)C1CC1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)[nH]c1cnc(-c3nc(C4CC4)no3)cc12
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of sodium ethoxide, prepared from sodium metal (0.6 g, 26 mmol) and anhydrous ethanol (50 mL), cyclopropylmethanimidamide (1.67 g, 16 mmol) and 9H-β-carboline-3-carboxylic acid ethyl ester (2.0 g, 8.0 mmol) were added. Toluene (50 mL) was added and the resulting mixture was heated to 120°-130° C. The ethanol and water formed during the reaction were removed by azeotropic distillation. The reaction was complete after 30 min. The solid was filtered from the reaction mixture, washed with water and dried. This afforded the title compound (1.15 g, 52%) as an yellow solid. M.p. 256°-257° C.
Reaction SMILES: [C:1]1(=[O:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.[BH4-].[Na+].O>CO>[CH:1]1([OH:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: O=C1CC2CCCc3cccc1c32
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1CC2CCCc3cccc1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2a,3,4,5-Tetrahydro-2H-acenaphthylen-1-one (4.85 g) was dissolved in methanol (70 ml). Sodium borohydride (1.07 g) was added to the solution under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated to give 2a,3,4,5-tetrahydro-2H-acenaphthylen-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.[N:38]1([C:45](=O)[CH2:46]Cl)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:45][CH2:46][O:37][C:36]2[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:3][C:2]=2[F:1])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: O=C(CCl)N1CCCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCCCC3)c(F)c2)c1
Yield: 35.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azepan-1-yl-2-chloroethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.5 mg) was obtained.
Reaction SMILES: BrBr.[OH-:3].[Na+].[Br:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14](=[O:16])C>OS([O-])=O.[Na+]>[Br:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]([OH:16])=[O:3]
Reactant: [OH-]
Reactant: COc1ccc(C(C)=O)c(Br)c1
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Product: COc1ccc(C(=O)O)c(Br)c1
Temperature: 36 °C
Reaction time: 17 h
Yield: 68 %

Procedure:
Br2 (8.5 mL, 165.89 mmol) is added dropwise to 20% NaOH (97 mL) at 0-10° C. in a 15-min period. The resulting solution is warmed to room temperature before 1-(2-bromo-4-methoxyphenyl)ethanone (2) (9.50 g, 41.47 mmol) is added. The mixture is stirred at 36° C. for 29 h and at room temperature for 17 h, diluted with 0.5 M NaHSO3 (25 mL), and extracted with ether (100 mL and 70 mL). The aqueous layer is acidified with conc. HCl (30 mL) to give 6.56 g (68%) of 3 as a white solid, mp 195-197° C. IR 2997, 1686, 1596, 1290 cm−1; 1H NMR (CDCl3) δ 3.80 (s, 3H, CH3O), 6.83 (dd, J=7.2, 2.0 Hz, 1H, 5-PhH), 7.15 (d, J=2.0 Hz, 1H, 3PhrH), 7.90 ppm (d, J=7.2 Hz, 1H, 6-PhH).
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[N:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccccc1C=NNC(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CNNC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
1.8 mL (11.4 mmol) triethylsilane was added to a solution of 1.45 g (5.7 mmol, crude product from 5.1) benzoic acid [1-(2-methoxyphenyl)methylidene]hydrazide in 10 mL trifluoroacetic acid at 0° C., then the mixture was stirred, first for 2 hr at 0° C. and then for 4 hr at room temperature. The yellow reaction solution was then combined with 120 mL 2 N HCl and extracted with methylene chloride, and the organic phase was then shaken with 1 N NaOH, dried with Na2SO4, and concentrated on a rotary evaporator. Stirring in diisopropyl ether and subsequent drying resulted in approximately 1.1 g product in the form of a white solid.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([O:15]CC)=[O:14])=[CH:4]2.[OH-].[Na+].Cl>CO>[N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=[O:14])=[CH:4]2
Reactant: CCOC(=O)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1=Cc2cnc3cccc(n23)S1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 74.5 %

Procedure:
To a solution of 3.00 g (12.18 mM) of ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate in methanol (9 ml) was added 18 ml (18 mM) of 1N-aqueous solution of sodium hydroxide at room temperature and the mixture was stirred for 2.5 hours. This reaction mixture was cooled to 0° C. and 1N-hydrochloric acid was added until the pH had been brought to 5. The resulting crystals were harvested by filtration. This crystal crop was rinsed with water, ethanol and diethyl ether to provide the title compound as orange-colored solid (yield 1.98 g, 69%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:21]([N:28]1[CH2:32][C:31]([CH2:33][CH2:34]OS(C)(=O)=O)=[CH:30][NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC1(C)CCCC(C)(C)N1>CC#N>[CH2:21]([N:28]1[CH2:32][C:31]([CH2:33][CH2:34][N:9]2[C@H:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:30][NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Reactant: CS(=O)(=O)OCCC1=CNN(Cc2ccccc2)C1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CC#N
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCC1=CNN(Cc2ccccc2)C1
Yield: 77.2 %

Procedure:
A mixture of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′2″]terpyridine (0.320 g, 1.20 mmol), methanesulfonic acid 2-(2-benzyl-1 H-pyrazol-4-yl)-ethyl ester (0.540 g, 1.60 mmol) and 2,2,6,6-tetramethylpiperidine (0.255 g, 1.80 mmol) in CH3CN (5 mL) was stirred and heated at reflux overnight. The solvent was then removed, water (20 mL) was added, and the mixture was extracted with CH2Cl2 (3×20 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (500:15:1 CH2Cl2/CH3OH/NH4OH), affording (2′R,6′S)-1′-[2-(2-benzyl-1H-pyrazol-4-yl)-ethyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine as a pale yellow oil (0.420 g, 93%).
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1C=CC=CC=1>[C:16]([N:5]1[C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[NH:8][C:9](=[O:11])[C:10]2=[CH:1][S:2][CH:3]=[C:4]12)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)Cl
Reactant: O=C1Nc2ccccc2Nc2cscc21
Solvent: c1ccccc1
Product: CCCCCC(=O)N1c2ccccc2NC(=O)c2cscc21

Procedure:
A 9 g. portion of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 6.3 g. (6.6 ml.) of hexanoyl chloride in 100 ml. of benzene is refluxed for 3 hours. The benzene is distilled off. The residue is triturated in ether, washed with ether and dried. This solid is heated to boiling in 250 ml. of benzene, filtered and the filtrate is diluted with 250 ml. of hexane. This mixture is filtered and then cooled. The solid is collected, washed with hexane and dried giving the desired product, mp. 127°-129° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4].CO.[Na].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28]>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:28][CH2:27][N:29]([CH2:33][CH3:34])[CH2:30][CH3:31])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)CCCl
Reactant: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(O)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(OCCN(CC)CC)cc1

Procedure:
To a solution of 1.4 g. (0.0042 mol.) of 2-n-butyl-3-(4-hydroxyphenylsulfonyl)benzofuran in 20 ml. of methanol was added 25 ml. of methanol containing 110 mg. (0.0048 g.-atom) of sodium. The reaction mixture was heated on a steam bath for 30 minutes then evaporated to dryness. The residue was dissolved in 25 ml. of toluene and ca. 1 ml. of methanol, a suspension of 0.615 g. (0.0048 mol.) of distilled 2-diethylaminoethyl chloride in 15 ml. of toluene was added and the resulting mixture was heated on a steam bath for 3 hours. The solution was filtered through MgSO4 and chromatographed on silica gel with 50:50 ether-acetone to give the title compound.
Reaction SMILES: CO.C[O-].[Na+].[N+](C(C)C)([O-])=[O:7].Br[CH2:13][C:14]1[C:15]([CH3:28])=[C:16]([CH:21]=[CH:22][C:23]=1[S:24]([CH3:27])(=[O:26])=[O:25])[C:17]([O:19][CH3:20])=[O:18]>Cl>[CH:13]([C:14]1[C:15]([CH3:28])=[C:16]([CH:21]=[CH:22][C:23]=1[S:24]([CH3:27])(=[O:26])=[O:25])[C:17]([O:19][CH3:20])=[O:18])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1C
Reactant: CC(C)[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1C
Yield: 88.3 %

Procedure:
Into 20 ml of methanol was added 2.60 g of a methanol solution of 28% sodium methylate, and 1.30 g of 2-nitropropane was added dropwise at room temperature, followed by adding 4.40 g of methyl 3-bromomethyl-4-methylsulfonyl-2-methylbenzoate. The resulting solution was heated at reflux for an hour. After the reaction solution was cooled down, 50 ml of IN hydrochloric acid was added to the solution to extract with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure to give 3.10 g of the title compound as crystals. m.p. 108~110° C.