Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C@H:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:19](=[O:21])[CH3:20].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@@H:10]([N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:11][C@@H:2]1[CH3:1])(=[O:21])[CH3:20]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)N1c2ccccc2[C@@H](Nc2ccccc2)C[C@@H]1C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccccc2[C@@H](N(C(=O)c2ccco2)c2ccccc2)C[C@@H]1C
Temperature: 50 °C
Yield: 34 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with (±)-trans-1-(2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl)-ethanone (0.110 g, 0.39 mmol, 1.0 equiv) and 2-furoyl chloride (0.193 mL, 1.9 mmol, 5.0 equ), pyridine (1.0 equ.) and dry toluene (5 mL). The solution was heated to 50° C. for 5 h. The reaction mixture was evaporated in vacuo. The residue was purified by Biotage flash system (30% hexane/70% ethyl acetate to 50% hexane/50% ethyl acetate) to yield the trans isomer 34% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.O>CO>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Solvent: O
Solvent: CO
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 150 °C
Yield: 102.4 %

Procedure:
To 200.0 g of polyphosphoric acid (118%) were added 30.0 g (71.7 mmol) of 2,5-bis(p-chloroanilino)terephthalic acid and 0.6 g of phthalimidomethylquinacridone. The stirred mixture was irradiated in the microwave oven for 2.0 minutes. The reaction mixture was cooled to 150° C. and drowned in 400 g of methanol with vigorous stirring. The resultant methanol suspension was maintained at reflux for one hour, cooled to 60° C., added to 800 g of water, and heated at 60° C. for 30 minutes. The solid component was collected by filtration and washed with 8.0 liters of water. The presscake was dried overnight in an oven at 60° C. to give 28.0 g of 2,9-dichloroquinacridone (C. I. Pigment Red 202).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:17](=[O:21])[C:18]([OH:20])=O)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[N:33]1([CH2:39][CH2:40][O:41][C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]([NH2:52])=[CH:44][CH:43]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([C:17](=[O:21])[C:18]([NH:52][C:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:42]([O:41][CH2:40][CH2:39][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:43][CH:44]=2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2C(=O)C(=O)O)cc1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2C(=O)C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To the crude (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-oxo-acetic acid 34 (0.4 g, 1.4 mmol) in a 40 mL scintillation vial was added oxalyl Chloride (5 mL) and on drop of DMF. The suspension was stirred at rt for 1 h, and concentrated under vacuum. The resulting solid was dissolved in EtOAc (10 mL) and added to 4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1-ylamine (0.45 g, 1.2 mmol) dissolved in EtOAc (10 mL)/50% NaHCO3 (10 mL) and stirred overnight at rt. The mixture was diluted with EtOAc and extracted with NaHCO3. The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent removed affording a dark brown oil. The material was purified by column chromatography (50-100% EtOAc/Hexanes) providing 0.357 g (57%) of the desired compound as a yellow solid. Expected mass=540. Observed mass=541.
Reaction SMILES: C([O:9][CH2:10][CH:11]([CH3:20])[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)(=O)C1C=CC=CC=1.[OH-].[Na+].O>CO>[CH3:20][CH:11]([CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH2:10][OH:9]
Reactant: CC(COC(=O)c1ccccc1)COC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CO)COC1CCCCO1
Yield: 88.4 %

Procedure:
1-Benzoyloxy-2-methyl-3-tetrahydropyranyloxypropane (460 mg; 1.65 mmol) was dissolved in methanol (10 ml), and 1M sodium hydroxide solution (3 ml) and water (10 ml) were added thereto, and the resultant mixture was stirred at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate. The extracts were washed with water and dried over anhydrous magnesium sulfte. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography using a mixture of ethyl acetate and benzene (1:4) to give 2-methyl-3-tetrahydropyranyloxy-1-propanol (254 mg; yield, 88%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([NH2:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([NH:23][C:26](=[O:28])[CH3:27])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(N)CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC(C)CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1

Procedure:
A solution of 1-({trans-4-[6-(cyclopropylmethoxy)-1-benzofuran-2-yl]cyclohexyl}oxy)propan-2-amine (373 mg) and acetic anhydride (0.51 mL) in pyridine (4 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (NH, hexane/ethyl acetate). The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (265 mg) as white crystals.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2([C:19]([F:22])([F:21])[F:20])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:17])[C:14]=3[F:16])[NH:9][C:8](=O)[NH:7]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].NC(N)=[S:31]>P(Cl)(Cl)(Cl)=O>[CH:1]1([C:4]#[C:5][C:6]2([C:19]([F:22])([F:21])[F:20])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:17])[C:14]=3[F:16])[NH:9][C:8](=[S:31])[NH:7]2)[CH2:3][CH2:2]1
Reactant: O=C1Nc2ccc(F)c(F)c2C(C#CC2CC2)(C(F)(F)F)N1
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc2c(c1F)C(C#CC1CC1)(C(F)(F)F)NC(=S)N2
Temperature: 95 °C
Yield: 42.7 %

Procedure:
A solution of (+/-)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (0.32 g, 1.0 mmol) in phosphorous oxychloride (5 mL) containing Na2CO3 (160 mg, 1.5 mmol) was heated at 95° C. overnight. After cooling to room temperature, the phosphorus oxychloride was removed under reduced pressure. The residue was dissolved in ethanol (5 mL) and thiourea (0.44 g, 5.7 mmol) was added. The resulting mixture was heated at reflux for 24 hours, cooled to room temperature and concentrated. The material was dissolved in EtOAc (75 mL) and washed sequentially with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL). The organic extract was dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (38% EtOAc/hexanes) to afford the title compound as a white solid (142 mg, 43%): mp 241-243° C.; 1H NMR (300 MHz, acetone-d6) δ 7.52-7.43 (m, 1H), 7.06-7.03 (m, 1H), 1.43-1.40 (m, 1H), 0.89-0.86 (m, 2H), 0.79-0.74 (m, 2H); 19F NMR (282 MHz, acetone-d6) δ -83, -136, -145; Analysis calc'd for C14H9F5N2S: C, 50.60; H, 2.73; N, 8.43; found: C, 50.46; H, 2.78; N, 8.31.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:32])[CH:4]([C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=2)[N:12]=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: C=C(C)CC(C(=O)OC)c1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 99.8 %

Procedure:
A solution of 2-[2-(4-fluoro-phenyl)-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-4-methyl-pent-4-enoic acid methyl ester (80 mg, 0.18 mmol), Pd/C (10%, 10 mg) in methanol (10 mL) was hydrogenated for 4 h. The mixture was filtered through Celite, washed with methanol, and evaporated. The residue was dissolved in CH2Cl2, filtered and evaporated to give the product as a colorless oil (80 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=8.29 Hz, 2H), 8.08-8.18 (m, 2H), 7.75 (d, J=8.29 Hz, 2H), 7.66 (d, J=1.88 Hz, 2H), 7.13-7.24 (m, 2H), 3.80 (t, J=7.72 Hz, 1H), 3.72 (s, 3H), 2.09 (dt, J=7.72, 13.56 Hz, 1H), 1.75 (dt, J=7.06, 13.75 Hz, 1H), 1.54 (dt, J=6.73, 13.28 Hz, 1H), 1.46-1.48 (m, 0H), 0.96 (d, J=6.40 Hz, 6H). MS m/e 446.3 (M+H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([NH2:26])=[C:22]4[O:27][C:28](Cl)=[CH:29][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F:31][C:32]1[CH:33]=[C:34]([C:38]2[CH:46]=[CH:45][C:41]3[CH:42]=[N:43][S:44][C:40]=3[C:39]=2B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:36][CH:37]=1>>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:18]2[CH:17]=[N:16][N:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([OH:8])[CH2:10][CH2:11]3)[CH:19]=2)=[C:21]2[CH:29]=[C:28]([C:39]3[C:40]4[S:44][N:43]=[CH:42][C:41]=4[CH:45]=[CH:46][C:38]=3[C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([F:31])[CH:33]=3)[O:27][C:22]=12
Reactant: CC1(C)OB(c2c(-c3cccc(F)c3)ccc3cnsc23)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3c(-c4cccc(F)c4)ccc4cnsc34)oc12

Procedure:
The title compound was prepared from 4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]-2-chlorofuro[2,3-c]pyridin-7-amine and 6-(3-fluorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-benzothiazole by a procedure analogous to Example 229. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.55 (d, J=7.58 Hz, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.97 (s, 1H), 7.79 (d, J=7.83 Hz, 1H), 7.59-7.72 (m, 3H), 7.34-7.43 (m, 1H), 6.34 (br s, 2H), 4.70 (d, J=4.29 Hz, 1H), 4.21 (tt, J=3.98, 11.56 Hz, 1H), 3.49-3.60 (m, 1H), 2.09 (br d, J=12.40 Hz, 2H), 1.83-2.02 (m, 4H), 1.33-1.46 (m, 2H); MS (ESI): 526.08 [M+H]+; HPLC tR=2.37 min (ZQ3: nonpolar—4 min).
Reaction SMILES: [CH3:1][CH2:2][CH:3](O)[CH2:4][CH3:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[C:11]#[N:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[C:11]#[N:12]
Reactant: CCC(O)CC
Reactant: N#Cc1ccc(O)c(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)Oc1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a scintillation vial containing a solution of pentan-3-ol (22 mg, 0.25 mmol) dissolved in THF (2 mL) was added a solution of 3-chloro-4-hydroxy-benzonitrile (38 mg, 0.25 mmol) in THF (2 mL) followed by PS-PPh3 resin (357 mg, 0.5 mmol, loading 1.4 mmol/g) and a solution of DIAD (76 mg, 0.375 mmol) in THF (2 mL). The vial was capped and shaken at room temperature overnight. The reaction mixture was filtered and the resin was washed with THF (4 mL). The filtrate was concentrated to dryness to give 3-chloro-4-(1-ethyl-propoxy)-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:23]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]2[C:32]([O:34][C:35](=O)[C:25]=2[CH:24]=1)=[O:33]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:32](=[O:33])[C:26]5[C:25](=[CH:24][CH:23]=[C:28]([C:29]([OH:31])=[O:30])[CH:27]=5)[C:35]4=[O:34])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])=[N:16][C:15]=2[CH:17]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(OC)ccc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(OC)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-methoxybenzoxazole (74 mg, 0.25 mmol) and 1,2,4-benzenetricarboxylic anhydride (54 mg, 0.28 mmol) the title compound was obtained (68 mg, 58%). 1H NMR (DMSO) δ 8.46(t, 1H), 8.41(dd, 1H), 8.22(s, 1H), 8.07(m, 2H), 7.64(d, 1H), 7.45(dd, 1H), 7.37(d, 1H), 7.00(m, 2H), 3.84(s, 3H), 3.34(m, 2H), 1.75(m, 2H), 1.06(t, 3H). MS 470.1 m/z (M−H)−.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C@@H:3]1[NH:17][C:18]([C@@H:20]([O:22][C:23](=O)[O:24]C1C=CC([N+]([O-])=O)=CC=1)[CH3:21])=[O:19].[F:35][C:36]([F:43])([C:39]([F:42])([F:41])[F:40])[CH2:37][NH2:38]>ClCCl.C(OC(=O)C)C>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C@@H:3]1[NH:17][C:18]([C@@H:20]([O:22][C:23](=[O:24])[NH:38][CH2:37][C:36]([F:43])([F:35])[C:39]([F:42])([F:41])[F:40])[CH3:21])=[O:19]
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](OC(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Yield: 63 %

Procedure:
0.12 g (0.25 mmol) carbonic acid 4-nitro-phenyl ester (S)-1-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-ethyl ester and 543 μl 2,2,3,3,3. pentafluoropropylamine were stirred at room temperature over night. Chromatography on silicagel with dichloromethane/ethylacetate (100-0 to 75-25) yielded 0.075 g (63%) (2,2,3,3,3-pentafluoro-propyl)-carbamic acid (S)-1-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-ethyl ester as white solid. MS: m/e: 472.1 (M+H+), [α] 589=−76.4° (1% in MeOH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:18])[CH2:16]Br)=[CH:11][C:10]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O>[N:26]([CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=1)[OH:18])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)Nc1cc(C(O)CBr)ccc1OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN=[N+]=[N-])ccc1OCc1ccccc1
Reaction time: 120 h
Yield: 93.3 %

Procedure:
To a stirred solution of N-[2-benzyloxy-5-(2-bromo-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (Washburn, W. N., et al., EP 0 659 737) (15.05 g, 38 mmol) in dimethyl sulfoxide (150 ml) was added sodium iodide (3.76 g, 376 mmol) and sodium azide (9.48 g, 150 mmol). The mixture was stirred for 5 days under nitrogen atmosphere. The reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was triturated with water and hexanes to give the title compound as a yellow solid (12.85 g, 94%): 1H NMR (300 MHz, CDCl3) δ 2.93(s, 3 H), 3.47(d, J=5.4 Hz, 2 H), 4.84(t, J=5.4 Hz, 1 H), 5.11(s, 2 H), 6.80(s, 1 H), 6.99(d, J=8.4 Hz, 1 H), 7.15(dd, J=8.4 Hz, 2.1 Hz, 1H), 7.26(s, 1 H), 7.30-5.50(m, 5 H), 7.53(d, J=2.1 Hz, 1 H); MS (ES) m/z 361.4 ((M-H)-, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[O:11]1[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12]1.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][OH:11]
Reactant: COc1cccc(OC)c1
Reactant: CCCCC1CO1
Agent: Cl
Solvent: ClCCl
Product: CCCCC(CO)c1ccc(OC)cc1OC
Temperature: 3 °C
Reaction time: 0.5 h

Procedure:
To a stirred, 5° C. mixture of m-dimethoxybenzene 27.6g (0.20 mole), anhydrous stannic chloride 52.1g (0.20 mole) and 200 ml of methylene chloride which is constantly swept with nitrogen, is added dropwise, 1,2-epoxyhexane, 20.0g (0.20 mole) in 50 ml of methylene chloride. The exothermic reaction temperature is maintained at 3° C. by the rate of addition. After the addition is complete, the reaction is stirred at 5° C. for 30 minutes, at which time it is poured into iced concentrated hydrochloric acid. The layers are separated and the aqueous layer is extracted with methylene chloride. The combined organic layers are washed with water followed by 5% sodium bicarbonate solution and finally water. The last water wash is neutral to pH paper. The methylene chloride solvent is removed on a rotary evaporator at 40° C. bath temperature. This residue is then fractionally distilled in vacuo. The third fraction, 140°-142° C./0.2 mm, is shown by nmr and ir to be the desired product. The yield is 25.32g (55%, theory).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:3][C:4]1[N:5]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(C=O)cc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To a suspension of NaH (0.612 g, 15.3 mmol : 60% suspension of mineral oil) of in dry DMF (10 ml) cooled to 10° C. was added a DMF (8 ml) solution of 2-methylimidazole (1.23 g, 15 mmol) under a nitrogen atmosphere, and the mixture was stirred for 30 min at room temperature. 4-Fluorobenzaldehyde (1.90 g, 15.3 mmol) was added to the reaction mixture, and the resulting solution was stirred for 14 h. The reaction mixture was poured into an ice-cold saturated aqueous NH4Cl solution (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was washed with water (100 ml) and brine (80 ml), dried over MgSO4 and the solvent removed under reduced pressure. The resultant residue was purified by column chromatography (SiO2 ; hexane:ethyl acetate=1:1 then ethyl acetate) to give crude 4-(2-methylimidazol-1-yl)-benzaldehyde (1.0 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Clc1ccc2c(c1)NCC2
Yield: 117.7 %

Procedure:
Dissolve 6-chloro-1H-indole (2 g, 0.013 mol) in acetic acid (10 mL) under nitrogen. Add sodium cyanoborohydride (1.24 g, 1.5 eq) and stir 20 minutes at room temperature. Dilute with ethyl acetate and extract with sodium hydroxide (5 N aqueous). Dry over magnesium sulfate, filter and concentrate to give 2.35 g (116%) crude product. MS (ES, m/z): 154.0 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:17].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN(C)C(=O)C>[F:17][C:3]1[CH:4]=[C:5]([S:8]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1CNCCN1
Reactant: O=S(=O)(CCC(F)(F)F)c1ccc(F)c(F)c1
Solvent: CC(=O)N(C)C
Product: O=S(=O)(CCC(F)(F)F)c1ccc(N2CCNCC2)c(F)c1
Temperature: 80 °C

Procedure:
To 0.5 mmol 1,2-difluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-benzene in 5 ml N,N-dimethylacetamide was added 1.5 mmol piperazine, and the mixture was heated at 80° C. for 90 min. The mixture was then concentrated in vacuo, and the residue was chromatographed on silica gel (eluant: methanol/dichloromethane gradient) to afford the title compound. MS (m/e): 341.2 (M+H+, 100%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH3:10])[C:6]=2[C:11]=1[NH2:12].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[OH:17][C:16]1[C:15]([OH:19])=[N:12][C:11]2[C:2](=[CH:3][CH:4]=[C:5]3[N:9]=[N:8][N:7]([CH3:10])[C:6]3=2)[N:1]=1
Reactant: O=C(O)C(=O)O
Reactant: Cn1nnc2ccc(N)c(N)c21
Agent: Cl
Solvent: O
Product: Cn1nnc2ccc3nc(O)c(O)nc3c21

Procedure:
A solution of 6,7-diamino-1-methylbenzotriazole (1.63 g, 10 mmol) and oxalic acid dihydrate (2.0 g, 16 mmol) in 50 ml of 4M hydrochloric acid was refluxed on an oil bath for 2 h. The mixture was cooled on ice and the precipitate was collected by filtration, washed with water and ethanol affording 1.94 g (89%) of the title compound; m.p. >300° C.; IR (KBr): 3520-2400, 1700 cm-1 ; 1H-NMR (DMSO-d6): 4.63 (s, 3H, CH3), 6.70 (d, J=9 Hz, 1H; ArH), 7.60 (d, J=9 Hz, 1H, ArH), 11.3 (very broad s, 1H, OH), 12.1 (broad s, 1H, OH).
Reaction SMILES: [N:1]1([CH:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[Na]>>[N:1]1([CH:6]2[CH:15]3[CH:10]([CH2:11][CH2:12][CH2:13][NH:14]3)[CH2:9][CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cnc2c(c1)CCCC2N1CCCC1
Agent: [Na]
Solvent: CCO
Product: C1CNC2C(C1)CCCC2N1CCCC1

Procedure:
This product was obtained mixed with other diastereoisomers by reduction of the product obtained in Step B either by catalytic hydrogenation or by a sodium-ethanol mixture. The description of these two reductions is given at the end of Example 4.