Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:20]([O:28][C:29]1[CH:30]=[CH:31][C:32]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][C:44](=[O:51])[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[CH:39][CH:38]=3)[S:34][C:33]=2[CH:52]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:1].[C:20]([O:28][C:29]1[CH:30]=[CH:31][C:32]2[C:36]([C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)=[CH:19][CH:18]=3)=[C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][C:44](=[O:51])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[CH:39][CH:38]=3)[S:34][C:33]=2[CH:52]=1)(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Reactant: O=C(Oc1ccc(-c2cc3ccc(OC(=O)c4ccccc4)cc3s2)cc1)c1ccccc1
Agent: Cl
Product: O=C(Oc1ccc(-c2sc3cc(OC(=O)c4ccccc4)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
The process of this example was run as was the process of Example 9, starting with the acid chloride formed from 18.9 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, and 20 g. of 6-benzoyloxy-2-(4-benzoyloxyphenyl)benzo[b]thiophene. The reaction mixture was stirred for 1.5 hours, and was then worked up as described in Example 9 to obtain the desired product as an oil. A small portion of the crude product was crystallized from denatured ethanol to provide an analytical sample, m.p. 230°-233°, the identity of which was confirmed by nmr analysis. δ1.30-2.50 (6H, m, NH(CH2CH2)2CH2); 2.50-3.75 (6H, m, NH(CH2CH2)2CH2 and OCH2CH2N); 4.56 (2H, m, OCH2CH2N); 6.77 (2H, d, J=9 Hz, aromatic o to OCH2); 7.10 (2H, d, J=9 Hz, aromatic o to OCO); 7.10-7.90 (17H, m, aromatic); 8.00-8.27 (6H, m, aromatic o to CO); 12.30-12.80 (1H, broad s, NH).
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].O=[C:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[Si](OCC)(OCC)(OCC)OCC.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:3]2[NH:4][C:12]3[CH:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:15][C:16]=3[C:2]=2[CH:8]=1
Reactant: CCOC(=O)CC1CCCC1=O
Reactant: COc1ccc(N)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OC)cc21
Temperature: 135 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
2-Iodo-4-methoxyaniline (2.0 g, 8.03 mmol) and ethyl 2-(2-oxocyclopentyl)acetate (2.05 g, 12.1 mmol) were dissolved in DMF (30 mL) and tetraethyl orthosilicate (2.12 g, 10.4 mmol) and pyridium p-toluenesulfonate (PPTS) (0.081 g, 0.321 mmol) were added. The reaction mixture was heated and stirred at 135° C. for 4 h. After cooling to 120° C., DIEA (3.11 g, 24.09 mmol) and palladium (II) acetate (0.054 g, 0.241 mmol) were added. The reaction mixture was stirred for 3 h and then partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant solution was diluted with 50% ethyl acetate in hexanes and filtered through a pad of silica gel. The filtrate was concentrated and purified by silica gel column chromatography to give 1.9 g of ethyl 2-(7-methoxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate containing residual ethyl 2-(2-oxocyclopentyl)acetate. The mixture was dissolved in DCM (80 mL) and cooled to 0° C. Boron tribromide (21.0 mL, 21.0 mmol, 1.0 M in DCM) was added and the reaction was stirred for 1.5 h. Ice water was added and the reaction mixture was allowed to reach room temperature. The aqueous mixture was extracted three times with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (650 mg). LCMS m/z=260.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J=7.2 Hz, 3H), 2.05-2.14 (m, 1H), 2.50 (dd, J=16.8, 11.2 Hz, 1H), 2.68-2.86 (m, 4H), 3.48-3.58 (m, 1H), 4.16-4.24 (m, 2H), 6.66 (dd, J=8.6, 2.4 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 8.4 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:36])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[O:35][CH:34]=[N:33][CH:32]=4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH:37]([N:40]=[C:41]=[O:42])([CH3:39])[CH3:38]>C(Cl)(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:36])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[O:35][CH:34]=[N:33][CH:32]=4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][N:14]([C:41](=[O:42])[NH:40][CH:37]([CH3:39])[CH3:38])[CH2:13][CH2:12]1
Reactant: CC(C)N=C=O
Reactant: O=C(CC1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCNCCS1(=O)=O)NOC1CCCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=O)N1CCC(CC(=O)NOC2CCCCO2)(c2ccc(-c3ccc(-c4cnco4)cc3)s2)S(=O)(=O)CC1
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a mixture of N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (100 mg) in chloroform (1 ml) was added a solution of isopropyl isocyanate (18 mg) in chloroform (1 ml) at 0° C. under nitrogen atmosphere. After being stirred for 1 hour, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with water, a saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10-1, v/v) to give N-(2-tetrahydropyranyloxy)-2-[4-isopropylcarbamoyl-7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (92 mg) as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2>[Pd]>[CH:7]1[C:8]2[C:3](=[CH:2][CH:11]=[CH:10][C:9]=2[NH2:12])[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Agent: [Pd]
Product: Nc1cccc2ccncc12

Procedure:
The product from Example 57B was treated with Pd/C under a hydrogen atmosphere to provide the title compound.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][O:5]C[CH2:3]1.[C:8]([O:12][C:13]([NH:15][C@@H:16]([C@@H:20]([CH3:23])[CH2:21][CH3:22])[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.N1CC(O)C1>CN(C=O)C.C(Cl)Cl>[OH:5][CH:6]1[CH2:7][N:2]([C:17](=[O:19])[C@@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:9])([CH3:10])[CH3:11])[C@@H:20]([CH3:23])[CH2:21][CH3:22])[CH2:3]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(O)C1
Reaction time: 20 h
Yield: 97.5 %

Procedure:
NMM (6.12 mL, 55.6 mmol) in DMF (5 mL) was added to (2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanoic acid (4.15 g, 17.9 mmol), which is commercially available, in DCM (45 mL) under a nitrogen atmosphere. TBTU was added portionwise and the resultant mixture was stirred at rt for 15 min. Azetidin-3-ol hydrochloride (2.359 g, 21.53 mmol) was added and the stirring continued for 20 h. The mixture was diluted with DCM, washed with NaHCO3 and brine, filtered through a phase separator and concentrated under reduced pressure. The residue was dissolved in Et2O, washed with water, filtered through a phase separator and concentrated under reduced pressure to give the title compound (5 g, 97%). The obtained crude product was used without further purification. 1H NMR (600 MHz, CDCl3) δ 0.81-0.95, 1.04-1.16, 1.35-1.48, 1.48-1.70, 3.79-4.09, 4.14-4.24, 4.25-4.42, 4.52-4.74, 5.05-5.16.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][CH2:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH2:5][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)CC(C)=O
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CCC(=O)CC(=O)CCc2ccc(OC)cc2)cc1

Procedure:
Using 2,4-pentanedione (37.3 g, 0.37 mol) and 4-methoxybenzyl chloride (133 g), the reaction was carried out in the same manner as described in Example 17, (1), and the solid residue was purified by recrystalization from ethanol to give the title compound as pale yellow microneedles which were not shown any methylene singlet at δ3.0-4.0 ppm in the 1HNMR spectrum; yield: 95.1 g; mp 73.5°-76.2° C.
Reaction SMILES: [CH2:1]([O:17][C:18]([O:20][CH2:21][C:22](=[CH2:51])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([O:17][C:18]([O:20][CH2:21][C:22](=[CH2:51])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(COCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)COC(=O)OCCCCCCCCCCCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=C(COCCCCCCO)COC(=O)OCCCCCCCCCCCCCCCC

Procedure:
3-Hexadecyloxycarbonyloxy-1-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropane (from Preparation 50) (1.95 g), 4-toluenesulfonic acid monohydrate (60 mg) and water (0.15 ml) were stirred in methylene chloride (30 ml) for 24 hours at 22° C. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate, dried over magnesium sulfate, filtered and evaporated in vacuo to dryness. Purification was achieved by chromatography on Waters PrepLC®/System 500A using a prepPAK®-500 cartridge with ether/chloroform/pentane 1:1:10 followed by ether/chloroform 1:1 as eluents.
Reaction SMILES: COC(=O)NC(C([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:20][C:19]2[CH2:21][O:22][C:23]3[CH:24]=[C:25]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([C:39]6[NH:40][C:41]([CH:44]7[CH2:48][CH2:47][CH2:46][N:45]7[C:49](=[O:62])[CH:50]([NH:57][C:58]([O:60][CH3:61])=[O:59])[C:51]7[CH:56]=CC=C[CH:52]=7)=[N:42][CH:43]=6)[CH:35]=5)[CH:30]=4)[CH:26]=[CH:27][C:28]=3[C:18]=2[N:17]=1)=O)C(C)C.[CH3:64][O:65][C:66]([NH:68][CH:69]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:70]([OH:72])=O)=[O:67]>>[CH3:61][O:60][C:58](=[O:59])[NH:57][CH:50]([C:49]([N:45]1[CH2:46][CH2:47][CH2:48][CH:44]1[C:41]1[NH:40][C:39]([C:34]2[CH:33]=[CH:32][C:31]3[C:36](=[CH:37][CH:38]=[C:29]([C:25]4[CH:26]=[CH:27][C:28]5[C:18]6[NH:17][C:16]([CH:12]7[CH2:13][CH2:14][CH2:15][N:11]7[C:70](=[O:72])[CH:69]([NH:68][C:66]([O:65][CH3:64])=[O:67])[C:73]7[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=7)=[N:20][C:19]=6[CH2:21][O:22][C:23]=5[CH:24]=4)[CH:30]=3)[CH:35]=2)=[CH:43][N:42]=1)=[O:62])[CH:51]([CH3:56])[CH3:52]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc5c(c4)OCc4[nH]c(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)nc4-5)ccc3c2)[nH]1)c1ccccc1
Reactant: COC(=O)NC(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc1OC2)c1ccccc1

Procedure:
Synthesized similar to (1-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-3,4-dihydro-chromeno[3,4-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester with the corresponding methoxycarbonylamino-phenyl-acetic acid replacement.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:41]([O:45][C:46](=[O:49])[CH2:47]Br)([CH3:44])([CH3:43])[CH3:42]>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:15]([CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[CH2:47][C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:49])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCCC1CCCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(CCCC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -30 °C
Reaction time: 0.75 h

Procedure:
A solution of (4S)-4-benzyl-3-(5-cyclohexylpentanoyl)-1,3-oxazolidin-2-one (70.0 g, 204 mmol anhydrous tetrahydrofuran (650 ml) was cooled to −70° C. and treated dropwise with sodium hexamethyldisilazide (1M in tetrahydrofuran, 224 ml, 224 mmol) over 45 minutes. The mixture was stirred for a further 45 minutes before being treated with t-butylbromoacetate (31.6 ml, 214 mmol). This mixture was stirred at −70° C. for 30 minutes then warmed to −30° C. and quenched with an aqueous solution of ammonium chloride (20% w/v, 400 ml) and warmed to room temperature. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The solid was recrystallised from hexane to afford the title compound as a white solid (71.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[O:16])=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)CC1

Procedure:
4-(Tert-butoxycarbonylamino-methyl)-benzoic acid was reacted with WSCI, HOBt, triethylamine and N-methylpiperazine in dichloromethane, to obtain a crude product of [4-(4-methyl-piperazine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester, and then treated with TFA, to obtain (4-aminomethyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-aminomethyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone (159 mg) instead of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine used in Step D in Example 1-D-18, in the same manner as Step D in Example 1-D-18, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid 4-(4-methyl-piperazine-1-carbonyl)-benzylamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-293) as a colorless powder (64 mg, 62%).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][C@@H:18]([N:20]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH:33]=[CH2:34])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][CH3:22])[CH3:19])=[CH:16][C:11]=2[CH2:10][CH2:9]1>CN(C)C=O>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][C@@H:18]([N:20]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH2:34][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:31])=[O:32])[CH2:26][CH2:25]3)[CH2:21][CH3:22])[CH3:19])=[CH:16][C:11]=2[CH2:10][CH2:9]1
Reactant: CS(N)(=O)=O
Reactant: C=CS(=O)(=O)N1CCC(CN(CC)[C@@H](C)Cc2ccc3c(c2)CCO3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC1CCN(S(=O)(=O)CCNS(C)(=O)=O)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 120 °C
Yield: 71.3 %

Procedure:
To a solution of methane sulfonamide (0.18 grams, 1.84 mmole) in dimethylformamide (2 ml) was added 60% sodium hydride (0.048 grams, 1.2 mmole) in mineral oil. The reaction mixture was heated at 120° C. for 30 minutes, and cooled to 100° C. A solution of (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-ethenesulfonylpiperidin-4-ylmethyl)amine (0.36 grams, 0.92 mmol) in dimethylformamide was added all at once. The reaction mixture was heated at 100° C. for 40 minutes. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was dried over potassium carbonate and evaporated to leave a residue, which was purified by flash chromatography using ethyl acetate. Appropriate fractions were combined and evaporated to give (S)-N-{2-[4-({[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamino}methyl)piperidine-1-sulfonyl]ethyl}-methanesulfonamide as an oil (0.32 grams, 71%). M+H 488. Analysis % of the hydrochloride salt: Found: C, 48.26; H, 7.09; N, 8.10. Requires: C, 48.59; H, 7.42; N, 7.73.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[N+](C1C=C2NN=CC2=NC=1)([O-])=O.O1C=CCCC1.CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([NH2:1])[CH:5]=2)[CH:10]=[N:11]1
Reactant: O=[N+]([O-])c1cnc2cnn(C3CCCCO3)c2c1
Agent: C1=COCCC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Nc1cnc2cnn(C3CCCCO3)c2c1

Procedure:
6-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine. A solution of 6-nitro-1H-pyrazolo[4,3-b]pyridine (2 g, 12.19 mmol), 3,4-dihydro-2H-pyran (1.538 g, 18.28 mmol) and methanesulfonic acid (0.119 mL, 1.828 mmol) in tetrahydrofuran (100 mL) was heated to 70° C. overnight. The reaction was cooled and neutralized with aqueous sodium bicarbonate to pH 7, and then extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, concentrated on a rotary evaporator. Flash chromatography (eluting with 0-50% ethyl acetate in hexane) gave the desired product as an off white solid (1.3 g, 5.24 mmol, 43.0% yield). (ESI) m/z 249.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:31]([F:34])([F:33])[F:32])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCCCCCC.C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:31]([F:32])([F:34])[F:33])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][CH:29]=[O:30])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C(NCCO)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-hydroxyethyl)-1-naphthamide (Preparation 8, 730 mg, 1.4 mmol) in EtOAc (100 mL) was added Dess-Martin reagent (725 mg, 1.7 mmol). The reaction was stirred at room temperature for 2 hours. TLC 65:35 EtOAc:heptane shows complete conversion to less polar spot. 50 mL NaHCO3 was added to reaction mixture and stirred for 15 minutes. Contents were diluted with water, extracted with EtOAc (2×75 mL), dried (Na2SO4), and concentrated under vacuum to afford the intermediate (713 mg, 98%) as a solid. m/z (Cl) 513 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].Cl.[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:32](Cl)=O.C(N(CC)CC)C>C(#N)C>[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:32]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cnccc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cnccc2Cl)n1
Temperature: 150 °C
Yield: 10.9 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 4-chloro-3-pyridinecarbonyl chloride hydrochloride (0.223 g, 1.10 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.015 g (11% yield) of pure product: MS (ES) m/z 445 (M+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:18](=[O:20])[CH3:19])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>[Zn]>[OH:20][C:18]([CH3:19])([CH:17]=[CH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CC(=O)C=CCCc1ccc(OCc2ccc(F)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C=CCCc1ccc(OCc2ccc(F)cc2)cc1
Yield: 94.4 %

Procedure:
Using 900 mg of 6-[p-(p-fluorobenzyloxy)phenyl]-3-hexen-2-one, 660 mg of ethyl bromoacetate and 260 mg of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 1.10 g of ethyl 3-hydroxy-3-methyl-7-[p-(p-fluorobenzyloxy)phenyl]-4-heptenoate.
Reaction SMILES: C1(C(Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Br:28])C1C=CC=CC=1.BrN1C(=O)CCC1=O.[CH3:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH:48]=[CH:47][CH:46]=[C:45]2[C:49]#[N:50])=[CH:40][CH:39]=1>>[CH3:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH:48]=[C:47]([Br:28])[CH:46]=[C:45]2[C:49]#[N:50])=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Product: Cc1ccc(-n2cc(Br)cc2C#N)cc1

Procedure:
4-(2-(2H-2-trityltetrazol-5-yl)-1-pyrrolyl)-benzyl bromide is prepared as described in EP 0 480 204 A1 preparation 1 and 8, and as described in EXAMPLE 10. To this end 1-(4-methylphenyl)-2-cyanopyrrole is reacted with tributyltin azide to give 4-(2-(1H-tetrazol-5-yl)-1-pyrrolyl)-methylbenzene, which is protected by reaction with triphenylmethyl chloride. The benzylic methyl group of (2-(2H-2-trityltetrazol-5-yl)-1-pyrrolyl)-methylbenzene is then converted to the benzyl bromide with N-bromosuccinimide. An analog with a bromo substituent in the pyrrole ring is prepared from the same starting material 1-(4-methylphenyl)-2-cyanopyrrole by reaction with N-bromosuccinimide at room temperature to give 1-(4-methylphenyl)-4-bromo-2-cyanopyrrole. This is further reacted by analogy to the unsubstituted compound.