Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.Cl.[NH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]([O:26]CC)=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:19]2[CH2:20][CH2:21][O:22][CH2:23][C:24]2=[O:26])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: CCOC(=O)COCCN
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(OC)c1nc2c(cc1CN1CCOCC1=O)CCCN2
Reaction time: 1 h

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 1.50 g, 5.40 mmol), ethyl 2-(2-aminoethoxyl)acetate hydrochloride (intermediate 105, 1.24 g, 6.75 mmol) and triethylamine (0.97 ml, 7.02 mmol) in 1,2-dichloroethane (25 ml) at room temperature was stirred for 1 h and then sodium triacetoxyborohydride (1.83 g, 8.63 mmol) was added. The reaction mixture was stirred for 18 h at room temperature and additional sodium triacetoxyborohydride (0.92 g, 4.32 mmol) was added. After a further 5 h stirring at room temperature the reaction mixture was partitioned between saturated aqueous NaHCO3 solution and DCM, the mixture extracted with DCM (3×), the combined organic layers dried over Na2SO4 and evaporated. The residue was applied to a 80 g RediSep® silica and purified by normal phase chromatography, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as an yellow solid. (UPLC-MS 6) tR 0.42; ESI-MS 322.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=1.CS(O[CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=2)[CH2:25][CH2:24]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[N:14][C:13]([O:16][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=3)[CH2:25][CH2:24]2)=[CH:12][N:11]=1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Reactant: CSc1ccc(-c2cnc(O)cn2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(-c2cnc(OCC3CCN(c4nc(C(C)C)no4)CC3)cn2)c(F)c1
Temperature: 25 °C
Yield: 44 %

Procedure:
A mixture of 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinol (and tautomers thereof) (0.35 g, 1.48 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Step 4, 0.61 g, 2.0 mmol) and K2CO3 (0.42 g, 2.96 mmol) in DMF (14 mL) was stirred at 100° C. in a preheated oil bath for 5 h. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (70 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a brown solid, which was purified by chromatography on a silica gel column eluted with 1:25 acetone/CH2Cl2 to give 2-[2-fluoro-4-(methylthio)phenyl]-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyrazine (0.3 g, 44% yield) as a light beige solid. 1H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 8.28 (d, 1H, J=1.3 Hz), 7.86 (t, 1H, J=8.3 Hz), 7.10 (dd, 1H, Ja=8.3 Hz, Jb=1.7 Hz), 7.00 (dd, 1H, Ja=12.1 Hz, Jb=1.9 Hz), 4.30-4.20 (m, 4H), 3.20-3.05 (m, 2H), 2.92 (septet, 1H, J=7.0 Hz), 2.50 (s, 3H), 2.20-2.05 (m, 1H), 2.00-1.90 (m, 2H), 1.55-1.40 (m, 2H), 1.29 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 444 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:16]=[C:15]([CH3:23])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.C1O[C@H]1CO>>[OH:12][CH2:11][C:10]([NH:9][CH2:8][C@@H:7]([OH:14])[CH2:6][O:5][C:4]1[C:3]([CH3:1])=[CH:18][C:17]([C:19](=[NH:22])[NH:20][OH:21])=[CH:16][C:15]=1[CH3:23])=[O:13]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: OC[C@H]1CO1
Product: Cc1cc(C(=N)NO)cc(C)c1OC[C@H](O)CNC(=O)CO

Procedure:
The title compound is obtained as a yellow oil (0.60 g) in analogy to N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide starting from 4-hydroxy-3,5-methyl-benzonitrile and (S)-glycidol; LC-MS: tR=0.47 min, [M+H]+=311.99.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:23][CH2:24]OS(C)(=O)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CN(C=O)C.CN1C(=O)CCC1.CC(O)C.CCCCC>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[C:16]1([CH:22]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:23][CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: c1ccc(C(CCOc2ccc(N3CCNCC3)cc2)c2ccccc2)cc1
Temperature: 60 °C

Procedure:
4-(4-Hydroxyphenyl)piperazine (0.356 g, 2 mmol) is added to a stirred a pentane washed suspension of 60% NaH (0.088 g, 2.2 mmol) in DMF (5 mL) under N2 and the reaction mixture was heated to 60° C. for approximately 10 min (until the effervescence ceased). To the clear dark solution 3, 3-diphenyl-1-methanesulfonyloxypropane in NMP (3 mL) is added at once and the reaction mixture is heated to 90° C. over the weekend. (~65 h) NMP is removed in vacuo at 100° C. and the residue is taken up in CH2Cl2. The solution is washed (H2 O), separated, dried (Na2SO4) and evaporated in vacuo. The residue is purified by chromatography on silica using increasing proportion of MeOH in CH2Cl2 containing 0.5% Et3N. Two major products are isolated. The less polar one eluted with 4% MeOH / CH2Cl2 (0.5% Et3N) as an oil (0.19 g) is characterized as the N, O-dialkylated product . MS 568 (MH+). The more polar product (desired), is eluted with 10% MeOH/CH2Cl2 and obtained as an oil, 0.52 g (70%), which crystallizes in to a waxy solid upon drying at 50° C. in vacuo : mp 114°-116° C. This compound is converted in to an oxalate salt by treatment with one equivalent of oxalic acid in i-PrOH and recrystallization from the same solvent: mp, decomposing above 170° C. 1NMR (CDCl3) d 7.60 (d, 2H), 7.40-7.24 (m, 8H), 7.19 (t, 2H), 7.06 (d, 2H), 5.71 (br s, H2O / H+) 4.22 (t, 2H), 4.90 (t, 2H) 3.82 (b s, 2H), 3.59 (b s, 2H) 2.5 (bs, 2H, superimposed over DMSO signal). IR 3440, 3080-2710, 2588, 1599, 1583, 1512,1237, 702 cm-1. MS 373 (MH+ free base). Anal. Calc'd. for C25H28N2O·C2H2O4 : C, 70.11, H, 6.54, N, 6.06. Found: C, 70.65, H, 6.57, N, 6.19.
Reaction SMILES: CC([O-])(C)C.[K+].[Br-].[C:8]([O:12][C:13](=[O:20])[CH2:14][S+]1CCCC1)([CH3:11])([CH3:10])[CH3:9].C(O)C(F)(F)F.[C:27]([O:31][C:32]([NH:34][C@:35]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:39]=[CH:38][C:37](=[O:40])[CH2:36]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(#N)C.O.CC(OC)(C)C>[C:44]([O:43][C:41]([C@:35]1([NH:34][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:36][C:37](=[O:40])[C@@H:38]2[C@H:39]1[C@H:14]2[C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:20])=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)C=CC(=O)C1
Reactant: CC(C)(C)OC(=O)C[S+]1CCCC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: OCC(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 4 °C
Reaction time: 1.5 h

Procedure:
Add KOtBu (42 mL, 42 mmol, 1 M solution in THF, 2.5 equiv) to a 0° C. solution of 1-(2-tert-butoxy-2-oxoethyl)tetrahydrothiophenium bromide (11.9 g, 42 mmol, 2.5 equiv., Preparation 48) in acetonitrile (30 mL) under N2 over 10 minutes keeping the temperature below 5° C. Stir the milky solution cold for 1.5 hours. Add trifluoroethanol (6.9 g, 69 mmol, 4.1 equiv) dropwise. Add a solution of (1S)-1-(tert-butoxycarbonylamino)-1-(tert-butoxycarbonyl)-cyclopent-4-en-3-one (5 g, 16.8 mmol, Preparation 47) and trifluoroethanol (13.3 g, 132 mmol, 7.9 equiv) in acetonitrile (20 mL), over 5 minutes, maintaining the temperature at 3-5° C. Stir the solution for 4.5 hours at 0-5° C. Add MTBE (155 mL) and H2O (80 mL) to the cold reaction mixture. Separate the layers and wash the organic layer with H2O (50 mL), then 20% brine (50 mL). Concentrate the organic layer via atmospheric pressure distillation to approximately 30 mL. Add heptane (100 mL) and concentrate the solution. Add additional heptane as needed until the vapor temperature of the distillate reaches 93° C. Add THF (65 mL) to yield a solution of the title compound.
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8].[Cl-].C[Al+]C.[H-].C([Al+]CC(C)C)C(C)C.[C-]#[C-].[Al+3].[C-]#[C-].[C-]#[C-].[Al+3].[CH:34]1([O:39][C:40]2[CH:41]=[C:42]([C:48]3[CH2:53][CH2:52][CH2:51][C:50](=[O:54])[CH:49]=3)[CH:43]=[CH:44][C:45]=2[O:46][CH3:47])[CH2:38][CH2:37][CH2:36][CH2:35]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>CCOCC.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[CH:34]1([O:39][C:40]2[CH:41]=[C:42]([C:48]3([C:11]#[C:10][Si:7]([CH3:9])([CH3:8])[CH3:6])[CH2:53][CH2:52][CH2:51][C:50](=[O:54])[CH2:49]3)[CH:43]=[CH:44][C:45]=2[O:46][CH3:47])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(C2=CC(=O)CCC2)cc1OC1CCCC1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)C[Al+]CC(C)C
Solvent: CCOCC
Product: COc1ccc(C2(C#C[Si](C)(C)C)CCCC(=O)C2)cc1OC1CCCC1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
n-Butyllithium (2.45M in hexanes, 5.7 mL, 13.96 mmol) was added dropwise over 5 min to a solution of trimethylsilylacetylene (1.97 mL, 13.96 mmol) dissolved in dry ether (30 mL) at -45° C. under an argon atmosphere. After 1.5 h, this solution was cannulated into a solution of dimethylaluminum chloride (1.0M in hexanes, 13.96 mL, 13.96 mmol). After 3.5 h at room temperature, the mixture was filtered through Celite® under an argon atmosphere. In a separate flask, diisobutylaluminum hydride (1.0M in toluene, 1.4 mL, 1.4 mmol) was added dropwise to a stirred mixture of nickel acetylacetonate (360 mg, 1.4 mmol) in dry ether (25 mL) at 0° C. under an argon atmosphere. After 10 min, the mixture was further cooled to -10° C. and the solution of aluminum acetylide was added via cannulation over 15 min. 3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-2-en-1-one (2.0 g, 6.98 mmol, prepared as described in U.S. Pat. No. 5,362,915) dissolved in dry ether (70 mL) was added dropwise over 20 min. After 18 h at room temperature, the mixture was poured into a 100 mL saturated aqueous solution of potassium phosphate (monobasic) at 0° C., 100 mL of aqueous 3N HCl solution was added and the aqueous layer was extracted twice with ether. The combined extract was washed with brine, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ether followed by trituration from ether/hexanes, then furthur purification of the mother liquor by flash chromatography, eluting with 4:1 hexanes/ethyl acetate followed by trituration from ether/hexanes, provided a white solid. mp 102°-103° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:9][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:12][C:13]=3[O:14][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([S:29]([O-:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.[Na+]>>[Cl:22][C:23]1[CH:24]=[C:25]([S:29]([C:2]2[CH:7]=[CH:6][C:5]3[C:8]4[CH2:9][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:12][C:13]=4[O:14][C:4]=3[CH:3]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: O=S([O-])c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3cc(Br)ccc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3cc(S(=O)(=O)c4cccc(Cl)c4)ccc3c2C1
Yield: 52 %

Procedure:
The product of step A was coupled with sodium 3-chlorobenzenesulfinate following the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 100:0 to 30:70 hexanes/ethyl acetate) provided tert-butyl 7-(3-chlorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (66 mg, 52%) as an oil: 1H NMR (CDCl3, 300 MHz) δ 8.06 (d, J=1.3 Hz, 1H), 7.92 (t, J=1.9 Hz, 1H), 7.83 (td, J=7.9, 1.4 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.50 (m, 1H), 7.42 (t, J=7.9 Hz, 1H), 4.55 (br s, 2H), 3.83 (br s, 2H), 2.89 (br s, 2H), 1.49 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:22]3[CH2:23][CH2:24][N:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)[CH2:20][CH2:21]3)[C:7]=2[CH:8]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: c1ccc(N2CCNCC2)nc1
Product: Clc1ccc2scc(CN3CCN(c4ccccn4)CC3)c2c1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene and 1-(2-pyridinyl)piperazine were processed as described in Example 2 to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 3.15 (m, 2H), 3.49 (m, 6H), 3.75 (s, 2H), 6.61 (dd, 1H, J=7.5, 4.5 Hz), 6.80 (d, 1H, J=8.7 Hz), 7.40 (dd, 1H, J=8.7, 1.5), 7.52 (m, 1H), 7.70 (s, 1H), 8.00 (d, 1H, J=8.7 Hz), 8.08 (m, 2H). MS (DCI/NH3) m/z 344.0 (M+H)+. Anal. Calcd for C18H18N3SCl: C, 62.87;H, 5.28; N, 12.22. Found: C, 62.71;H, 5.23; N, 12.26.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:29]=[C:28]([F:30])[C:26]([NH2:27])=[C:25]([F:31])[CH:24]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:27][C:26]3[C:28]([F:30])=[CH:29][C:23]([Cl:22])=[CH:24][C:25]=3[F:31])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1c(F)cc(Cl)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Yield: 81.2 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 9, 7-benzyloxy-4-chloro-6-methoxyquinazoline (184 mg, 0.61 mmol), (prepared, for example, as described in WO 97/22596, Example 1, but the free base was generated prior to use), was reacted with 4-chloro-2,6-difluoroaniline (200 mg, 1.22 mmol) in the presence of sodium hydride (60%, 87 mg, 1.4 mmol) in DMF (8 ml) to give 7-benzyloxy-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquinazoline (212 mg, 74%).
Reaction SMILES: O[C:2]1([CH3:13])[CH2:7][CH2:6][CH:5]([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.C(N(S(F)(F)[F:20])CC)C.CO.[BH4-].[Li+]>ClCCl.C(OCC)(=O)C.O1CCCC1>[F:20][C:2]1([CH3:13])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)C1CCC(C)(O)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(F)CCC(CO)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.6 %

Procedure:
A solution of ethyl 4-hydroxy-4-methylcyclohexanecarboxylate (2.50 g, 13.42 mmol) in dichloromethane (35 mL) at 0° C. was added with diethylaminosulfur trifluoride (14.2 mL, 107.40 mmol) slowly under nitrogen. The resulting mixture was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and poured into ice (200 g). The organic layer was washed with saturated sodium bicarbonate (3×100 mL) and brine (100 mL); dried with anhydrous sodium sulfate; filtered and concentrated in vacuo to provide the crude product as an oil; which was dissolved in anhydrous tetrahydrofuran (60 mL) and anhydrous methanol (1.10 mL, 26.8 mmol). To the mixture was added lithium borohydride (4 M solution in tetrahydrofuran, 6.70 mL, 26.8 mmol) dropwise and the resulting mixture was refluxed under nitrogen for 4 hours. The reaction mixture was cooled to ambient temperature and quenched with water and then 3 M aqueous hydrochloric acid solution. The mixture was diluted with ethyl acetate (150 mL) and the organic layer was washed with saturated sodium bicarbonate (2×100 mL) and brine (100 mL); dried with anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (2:1 hexanes:ethyl acetate) to provide the title compound as a colorless oil (0.66 g, 34%): 1H NMR (300 MHz, CDCl3) δ 3.50-3.43 (m, 2H), 1.97-1.86 (m, 1H), 1.85-1.71 (m, 2H), 1.69-1.52 (m, 4H), 1.49-1.24 (m, 5H), 1.20-1.03 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([CH2:14][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH:8]=[CH:9]2)=[C:16]([O:23][CH3:24])[CH:17]=1)#[N:20]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: COc1cc(C#N)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C#N)ccc1Cn1ccc2ccc([N+](=O)[O-])cc21
Yield: 78 %

Procedure:
6-Nitroindole was alkylated with 4-bromomethyl-3-methoxybenzonitrile in the presence of potassium carbonate using the general procedure described in Ex 1(a) to give 1-(4-cyano-2-methoxybenzyl)-6-nitroindole (W) in 78% yield as a solid, m.p. 190.5°-191° C. (b) The nitrile W was converted to the corresponding tetrazole, 1-(2-methoxy-4-[1-(H)-tetrazol-5-yl]benzyl)6-nitroindole (X), obtained in 86% yield as a yellow-green solid, m.p. 258°-260° C. (d) using the general procedure of Example 67.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([S:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:12]([Cl:21])=[CH:11][C:10]=1[Cl:22].[S-:23][C:24]#[N:25].[K+].CCCCCC.C(OCC)(=O)C>C(O)C>[S:23]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([S:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:12]([Cl:21])=[CH:11][C:10]=1[Cl:22])[C:24]#[N:25]
Reactant: N#C[S-]
Reactant: FC(F)(F)CSc1cc(OCCCCCCBr)c(Cl)cc1Cl
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CSCCCCCCOc1cc(SCC(F)(F)F)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 72.5 %

Procedure:
In 30 ml of ethanol were added 1.51 g (3.43 mmol) of 6-bromohexyl-[2,4-dichloro-5-(2,2,2-trifluoroethylthio)phenyl]ether and 1.67 g (17.2 mmol) of potassium thiocyanate. The mixture was refluxed for 3 hours under heating. The mixture was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. Then extraction was conducted by adding ethyl acetate and water. The organic phase obtained was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=10:1), to obtain 1.04 g (yield: 73%) of an intended product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH:24]([CH3:26])[CH3:25].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH2:23]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CI
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A mixture of 1-(4-nitrophenyl)piperazine (8 g, 38.6 mmol) (Acros Organics), powdered potassium carbonate (3.58 g, 25.98 mmol), 1-Iodo-2-methylpropane (4.66 ml, 40.5 mmol), and a catalytic amount of 18-crown-6 in acetonitrile (60 mL) was heated at reflux overnight. The mixture was filtered, and the filter cake was washed with acetonitrile. The solvent was evaporated from the combined filtrates and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, evaporated and dried under vacuum to give 1-(isobutyl)-4-(4-nitrophenyl)piperazine) (9.4 g, 92%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:20]=[O:21])C>O1CCCC1>[Br:1][C:2]1[C:3]([CH:20]=[O:21])=[C:4]([Cl:8])[N:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Clc1cc(Br)ccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Br)ccnc1Cl
Temperature: -70 °C
Yield: 30.2 %

Procedure:
To a solution of 4-bromo-2-chloropyridine (12.0 g, 60.0 mmol) in anhydrous tetrahydrofuran (300 mL) cooled at −70° C. was added the solution of lithium diisopropylamide (30.0 mL, 60.0 mmol, 2.0 M) over a period of 30 minutes and stirred for another at −70° C. 2 h. Anhydrous DMF (12.0 g) was introduced over a period of 10 minutes and stirred for another 30 minutes. It was then quenched with saturated NaHCO3 (200 mL), extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over anhydrous Mg2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (20:1) to afford 104a as a yellow solid (4.0 g, 29%). 1H NMR (500 MHz, DMSO) δ 10.23 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 7.94 (d, J=5.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-])=O)=[C:4]([F:13])[CH:3]=1.O.C(OCC)C>C(O)(=O)C.[Fe]>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH2:10])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1Br
Agent: [Fe]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc(N)c(F)cc1Br
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of 30.0 g (0.12 mole) of 4-bromo-2-fluoro-5-methoxynitrobenzene in 200 mL of acetic acid was added 40 mL of water, followed by the portionwise addition of 30.0 g (0.54 mole) of iron filings during a 2.5 hour period. Upon complete addition, the reaction mixture was stirred at 25°-35° C. for one hour. Diethyl ether, 200 mL, was added, and the reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was washed with 200 mL of water. The organic layer was separated and neutralized with solid sodium bicarbonate. The mixture was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residual solid. The solid was recrystallized from petroleum ether to give 23.5 g of 4-bromo-2-fluoro-5-methoxyaniline; m.p. 60°-62° C.
Reaction SMILES: C(O)(=O)C.[C:5]([C:7]1[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=1)#[CH:6].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1)#[CH:6]
Reactant: C#Cc1ccc(C=O)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C#Cc1ccc(N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Glacial acetic acid (0.2 mL) was added to a mixture of 4-ethynylbenzaldehyde (1 g, 7.5 mmol), pyrrolidine (1.2 mL, 15 mmol) and NaBH(OAc)3 (2.5 g, 11.5 mmol) in DCE (35 mL). The resulting mixture was stirred for 2 h at rt. The reaction was quenched with saturated aqueous NaHCO3 (50 mL). The product was extracted into CH2Cl2 (2×100 mL), and the combined organic layer was washed with brine (25 mL), dried (MgSO4) and evaporated in vacuo to give 1-(4-ethynylphenyl)pyrrolidine in quantitative yield. 1H NMR (CDCl3) δ: 7.45 (d, J=7.8 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 3.62 (s, 2H), 3.06 (s, 1H), 2.51 (bs, 4H), 1.80 (bs, 4H).