Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](B2OC(C)(C)C(C)(C)O2)=[N:22]1>>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][CH2:13][CH2:14][C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[N:3]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: Cn1ncc2c(NCCc3cccnc3)nc(Cl)nc21
Product: Cn1ncc2c(NCCc3cccnc3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-pyridin-3-yl-ethyl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification by preparative HPLC yielded 144. NMR (CDCl3) 3.08 (t, H, CH2, J=7.06 Hz), 4.01 (m, 2H, CH2), 4.09 (s, 3H, CH3), 5.4 (sbr, H, NH), 7.20 (m, H, ArH), 7.46 (m, H, ArH), 7.55 (m, 2H, 2×ArH), 7.84 (s, H, ArH), 8.35 (d, H, ArH, J=7.21 Hz), 8.45 (m, H, ArH), 8.50 (s, H, ArH), 10.13 (sbr, H, NH). MS: (ESI+) MH+=371.15
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.C(N(C(C)C)C=O)(C)C.[CH2:16]([C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[C:24](=O)[NH:25][CH:26]=[N:27][CH:28]=2)=[CH:20][CH:19]=1)[CH3:17].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:4][C:24]1[C:23]([O:22][C:21]2[CH:30]=[CH:31][C:18]([CH2:16][CH3:17])=[CH:19][CH:20]=2)=[CH:28][N:27]=[CH:26][N:25]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1ccc(Oc2cnc[nH]c2=O)cc1
Agent: CC(C)N(C=O)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc(Oc2cncnc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (Aldrich) (1.97 g, 15.2 mmoles) in dichloromethane (6 mL) was added in several portions to a stirred, ice-bath cooled solution of diisopropylformamide (Aldrich) (2.00 g, 15.17 mmoles) in dichloromethane (25 mL). The ice-bath was removed, and the solution was stirred at ambient temperature for 10 minutes. Solid 5-(4-ethylphenoxy)pyrimidin-4(3H)-one (1.00 g, 4.62 mmoles) was added, and the mixture was refluxed with stirring for 45 minutes. The solution was cooled and poured into a cold solution of vigorously stirred, saturated aqueous sodium bicarbonate (80 mL). The organic layer was washed with cold saturated aqueous sodium bicarbonate (80 mL), with cold water (80 mL) and then dried over sodium sulfate. The dry solution was spin evaporated in vacuo to give the intermediate 4-chloro-5-(4-ethylphenoxy)pyrimidine as an orange liquid. The liquid was dissolved in ethanol (50 mL) and trans-4-hydroxycyclohexylamine hydrochloride (Aldrich) (1.79 g, 11.45 mmoles) was added. A solution of sodium ethoxide, which had been prepared from sodium hydride (60% in mineral oil) (Aldrich ) (0.41 g, 10.25 mmoles) and ethanol (15 mL) was added. The flask was rinsed with ethanol (10 mL), and the reaction was refluxed with stirring for 65 hours. The volatiles were removed by spin evaporate in vacuo to a small volume, and the residue was triturated with water (100 mL). The gummy residue was extracted with dichloromethane (150 mL). The solution was washed with water (80 mL), dried over sodium sulfate and spin evaporated in vacuo. This material was dissolved in ethyl acetate-hexanes and chromatographed on Silica Gel 60 (E.M.
Reaction SMILES: [OH-].[K+].O.O.NN.[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16](=O)[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[CH:26]=1>C(O)COCCO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[CH:13][C:12]=2[CH:26]=1
Reactant: COc1ccc(C(=O)c2cc3cc(Br)ccc3o2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc(Cc2cc3cc(Br)ccc3o2)cc1
Yield: 82.5 %

Procedure:
5.07 g of potassium hydroxide was added to 30 ml of diethylene glycol, and the mixture was stirred at room temperature during which 5.5 g of 80% hydrazine dihydrate.2H2O and 5.0 g of 5-bromo-2-(4-methoxybenzoyl)-benzofuran were further added. The thus prepared mixture was refluxed under heating. After cooling, the resulting reaction solution was adjusted to pH 4-5, extracted with benzene, and then dried. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a n-hexane/isopropanol mixture as an elution solvent, thereby obtaining 3.95 g of 5-bromo-2-(4-methoxybenzyl)benzofuran as a brown oily material.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[CH:10]=[C:11]([C:13]([O-:15])=O)[S:12][C:5]=12.[Li+]>>[CH3:1][NH:2][C:13]([C:11]1[S:12][C:5]2[C:6](=[N:7][CH:8]=[CH:9][C:4]=2[Cl:3])[CH:10]=1)=[O:15]
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CN
Agent: [Li+]
Product: CNC(=O)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from methylamine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: n.d.; HPLC Rf: 3.70 min.; HPLC purity: 89%.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:33]=[C:32]([CH3:34])[C:20]([O:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[C:19]([CH2:35][CH3:36])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:37][CH3:38])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C1COCC1.[Li+].[OH-]>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:33]=[C:32]([CH3:34])[C:20]([O:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:19]([CH2:35][CH3:36])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:37][CH3:38])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNCCOc1c(C)cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCNCCC(=O)O
Yield: 75.8 %

Procedure:
A solution of ethyl 3-((2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methyl-phenoxy)ethyl)amino)propanoate (88 mg, 0.168 mmol) in MeOH (0.5 mL), THF (0.5 mL) and 2 N aq. LiOH (0.2 mL) is stirred at rt for 2 h. The mixture is concentrated, diluted with 2 N aq. HCl (10 mL) and extracted four times with DCM (4×20 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (63 mg) as an off-white solid; LC-MS: tR=0.93 min, [M+H]+=495.12; 1H NMR (CDCl3): δ 8.37 (s br, 2H), 7.78 (s, 1H), 7.72 (s, 1 H), 7.43 (s, 1H), 7.20 (s, 1H), 4.07-4.18 (m, 2H), 3.99 (s, 3H), 3.34-3.42 (m, 2H), 3.16-3.34 (m, 3H), 2.62-2.76 (m, 4H), 2.33 (s, 3H), 2.09 (m, 2H), 1.81-1.94 (m, 4H), 1.68-1.79 (m, 2H), 1.27 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:14]=[CH:13][C:12]=1[S:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1)(=[O:23])=[O:22]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Product: O=S(=O)(Nc1ccc(O)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(3-chloro-4-hydroxy-phenyl)-4-trifluoromethylbenzenesulfonamide was synthesized (92%) from 4-amino-2-chlorophenol (Aldrich) and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride in a similar manner as described in Example 421. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.17 (s, 1H), 8.14 (d, J=1.0 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.88 (dd, J=8.5, 1.4 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 6.88 (dd, J=8.7, 2.5 Hz, 1H), 6.82 (d, J=8.7 Hz, 1H). MS (EI): m/z 384 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1)=[O:17]
Reactant: CSc1cc(CC#N)ncn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cc(CC#N)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.8 %

Procedure:
To a suspension of [6-(methylthio)-4-pyrimidinyl]acetonitrile (Intermediate 15, 292 mg, 1.767 mmol) in DCM (15 mL) was added 3-chloroperoxybenzoic acid (457 mg, 2.65 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and kept stirring for 3 hours. The reaction mixture was quenched with saturated sodium thiosulfate solution (10 mL) and vigorously stirred for 30 minutes, then treated with DCM (75 mL). The reaction mixture was partitioned between DCM and water. The organic layer was washed with saturated ammonium carbonate solution, water and brine sequentially, then dried over sodium sulfate, concentrated under pressure to give the title compound as a brown solid (150 mg);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.C(Cl)Cl.[N:14]([S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])=[C:15]=[O:16]>C(Cl)CCC>[CH3:10][C:4]1[C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:15]([NH:14][S:17]([C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])=[O:16])[N:3]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1nc(N)nc(C)c1C
Solvent: ClCCl
Solvent: CCCCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c(C)c(C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 1.0 gram (0.0073 mole) of 2-amino-4,5,6-trimethylpyrimidine and 5.0 ml of dried methylene chloride stirring magnetically in a 50 ml RB single neck flask, 2.1 grams of methyl 2-(isocyanatosulfonyl)benzoate was added at room temperature and the mixture stirred at room temperature for 24 hours. Butyl chloride (4 ml) was added with constant stirring and the insoluble product filtered, washed immediately with butyl chloride and dried. (Yield 1.3 grams, m.p. 152°-161°). IR (Nujol): 5.60, 5.75 (C=O), 11.25 11.90 microns; NMR (TFA-d): δ 2.30 (s, 3H, CH3), 2.65 (s, 6H, 2CH3), 4.00 (s, 3H, CO2CH3), 7.60-8.60 (m, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(Cl)=[O:13]>O1CCOCC1>[Cl:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:12](=[O:13])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
In a 250 mL round-bottom flask under N2 was dissolved 2-amino-6-chlorobenzoic acid (11.69 g, 68 mmol) in 100 mL of 1,4-dioxane. The solution was cooled to 0° C. and to this solution was added phosgene (36 ml, 68 mmol) via a dropping funnel The reaction mixture was stirred for 24 hours allowing to warm to 23° C. (rt). The resulting white solid was filtered off and washed with 1,4-dioxane and Et2O. Yield=12.5 g, 93%
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[CH:14]=[C:13]([CH2:16][NH:17][C@@:18]([CH3:24])([C@@H:21]([OH:23])C)[CH2:19][OH:20])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1C2C=C(C=O)C3C(=CC=CC=3)C=2C=CC=1.NC(C)(COC)CO>>[ClH:1].[CH3:25][O:20][CH2:19][C:18]([CH3:24])([NH:17][CH2:16][C:13]1[C:12]2[C:7]([C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:15]=3[CH:14]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:21][OH:23]
Reactant: O=Cc1cc2ccccc2c2ccccc12
Reactant: C[C@H](O)[C@@](C)(CO)NCc1cc2ccccc2c2ccccc12
Agent: COCC(C)(N)CO
Agent: Cl
Product: COCC(C)(CO)NCc1cc2ccccc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined in 7G, phenanthrene-9-carbaldehyde (Aldrich) and 2-amino-3-methoxy-2-methyl-1-propanol (9C) gave 3-methoxy-2-methyl-2-((9-phenanthrenylmethyl)amino)-1-propanol hydrochloride mp 211°-213° (dec), (EtOH/Et2O), (C,H,Cl,N).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:8]=[CH:7][C:4]=1[CH:5]=O.Cl.[NH2:75][OH:76].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:8]=[CH:7][C:4]=1[CH:5]=[N:75][OH:76]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(C=O)c(OC)c1
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(C=NO)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
2-Methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzaldehyde (50 mg, 0.049 mmol) was dissolved in dichloromethane (1 ml), hydroxylamine hydrochloride (18 mg, 0.26 mmol) and triethylamine (51 μl, 0.37 mmol) were added, and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated, and the residue was precipitated with acetonitrile to give 2-methoxy-4-[2,2,2-tris(octadecyloxymethyl)ethoxy]benzaldoxime (43 mg, 0.041 mmol, 85%).
Reaction SMILES: ClC1C=CC(C([C:8]2[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[N:11]([CH3:13])[CH:12]=2)=O)=CC=1.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1.CN1C=CC=C1CC#N>>[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C:25]([C:12]2[N:11]([CH3:13])[C:10]([CH2:14][C:15]#[N:16])=[CH:9][CH:8]=2)=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cn1cc(C(=O)c2ccc(Cl)cc2)cc1CC#N
Agent: Cn1cccc1CC#N
Product: Cc1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Yield: 25 %

Procedure:
The uncatalyzed aroylation process of this invention surprisingly affords better yields of the product, 4-R1 -1-loweralkyl-5-aroylpyrrole-2-acetic acid ester or nitrile. Moreover, when R1 is hydrogen, the usual alpha to beta ratio of product in acylation reactions, that is, the distribution of α-aroylated and β-aroylated isomers, is very greatly shifted in favor of the α-substituted product. For example, in the AlCl3 catalyzed Friedel Crafts reaction of p-chlorobenzoyl chloride with 1-methylpyrrole-2-acetonitrile, a 21% yield of the α-product, 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, is obtained and the ratio of this α-isomer to the corresponding β-isomer, 4-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, is about 2.5:1; and in the similarly catalyzed reaction of p-toluoyl chloride with 1-methylpyrrole-2-acetonitrile, a 25% yield of the α-product, 5-(p-toluoyl)-1-methylpyrrole-2-acetonitrile, is obtained with an alpha to beta isomer ratio of 3.7:1 [see Carson et al., J. Med. Chem., 14, 646 (1971)]. In contrast, the uncatalyzed reaction of p-chlorobenzoyl chloride with 1-methylpyrrole-2-acetonitrile in refluxing xylene for about 24 hours affords 46% of the corresponding α-product with an α/β ratio of about 440:1; and the uncatalyzed reaction of p-toluoyl chloride with 1-methylpyrrole-2-acetonitrile in refluxing o-dichlorobenzene for about 4 hours affords 55% of the corresponding α-product with an α/β ratio of about 180:1.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH2:7]1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>O.CC(C)=O>[Cl:19][CH2:20][C:21]([N:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH2:7]1)=[O:22]
Reactant: C1CNCC2(C1)CC1CCC2CC1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCl)N1CCCC2(CC3CCC2CC3)C1

Procedure:
An amount of 20 g (0.244 mole) of sodium acetate and 18 g (0.100 mole) of spiro[bicyclo[2.2.2]octane2,3'-piperidine] is dissolved in 100 ml of water and 300 ml of acetone. A two-phase system is formed, to which is added dropwise at 0° to 5° an amount of 10.2 ml (14.4 g, 0.13 mole) of chloroacetyl chloride. An addition is then made to the mixture, at 0° to 5°, of 700 ml of water, whereupon the reaction product precipitates in flake form. Stirring is maintained for a further hour and the reaction product subsequently filtered off. After washing and then drying of the product over phosphorus pentoxide in a desiccator, there is obtained 1'-chloroacetyl-spiro [bicyclo[2.2.2]octane-2,3'-piperidine], M.P. 63° (with decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:38])[CH:34]=[C:35]([OH:37])[CH:36]=1.[H-].[Li+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:37][C:35]2[CH:34]=[C:33]([OH:38])[CH:32]=[C:31]([Br:30])[CH:36]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: Oc1cc(O)cc(Br)c1
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(O)cc(Br)c2)c1CCC(=O)OCC
Reaction time: 48 h
Yield: 49.7 %

Procedure:
To a solution of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (4.48 g, 9.5 mmol) and 5-bromo-benzene-1,3-diol (1.79 g, 9.47 mmol) in dimethylsulfoxide (30 mL) was added lithium hydride (160 mg, 20 mmol) at room temperature. The resulting suspension was stirred for 48 h and then the reaction mixture was diluted with water (100 mL). The organic compound was extracted into ethyl acetate (3×50 mL) and the combined organic extracts were washed with water (100 mL) and brine solution (100 mL). The organic layers were dried over anhydrous magnesium sulfate and filtration of the drying agent and concentration of the solvent under vacuum gave the crude product which was purified by using an ISCO 120 g column, eluting with 0-30% ethyl acetate in hexanes to afford 4-[3-[6-(3-bromo-5-hydroxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.73 g, 74%) as a white solid: ES(+)-HRMS m/e calcd for C29H39BrO7 (M+Na)+ 601.1771, found 601.1773.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.[CH:17]1([C:20]2[C:21]([N:29]3[CH2:34][CH2:33][N:32]([C:35]([C:37]4[CH:42]=[CH:41][C:40](I)=[CH:39][C:38]=4[F:44])=[O:36])[CH2:31][CH2:30]3)=[N:22][CH:23]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[C:21]([N:29]3[CH2:30][CH2:31][N:32]([C:35]([C:37]4[CH:42]=[CH:41][C:40]([N:11]5[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]5(=[O:15])=[O:16])=[CH:39][C:38]=4[F:44])=[O:36])[CH2:33][CH2:34]3)=[N:22][CH:23]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=2)[CH2:18][CH2:19]1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: O=C(c1ccc(I)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: O=C(c1ccc(N2[C@H](CO)CCS2(=O)=O)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 43.6 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (393 mg) described in Preparation Example 1 and [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (800 mg) described in Preparation Example 164 and by the reaction and treatment in the same manner as in Example 32, the title compound (365 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:34](=[O:35])[C:33]4[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=4)[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1
Reactant: NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCN1CCN(c2csc3cc(F)ccc23)CC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1.17 h
Yield: 64.8 %

Procedure:
To a 0° C. solution of 4-(6-fluorobenzo[b]thien-3-yl)-1-piperazine-butanamine (2.45 g, 7.97 mmol), triethylamine (1.23 g, 12.2 mmol), and dichloromethane (30 mL) under a nitrogen atmosphere was added 4-fluorobenzoyl chloride (1.61 g, 10.2 mmol) in one portion. The reaction was stirred at 0° C. for 70 minutes and then at room temperature for 3 hours. The reaction was diluted with dichloromethane (50 mL) and the mixture was washed successively with 5% aqueous NaOH (50 mL) and water (50 mL), dried (Na2SO4), and concentrated in vacuo to a tan solid. The crude product was chromatographed on silica gel with 10% ethanol/dichloromethane as eluent to afford an 2.22 g of an off-white solid. Recrystallization from ethyl acetate/heptane gave 1.60 g (46%) of the title compound as beige needles, m.p. 161°-163° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[S:21](=[O:35])(=[O:34])[NH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH3:33])[CH:28]=[CH:27]2)[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[C:3]([N:22]([CH2:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH3:33])[CH:28]=[CH:27]3)[S:21]([C:20]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[CH3:10])(=[O:34])=[O:35])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Fc1ncc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)c(C)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C)c2)c2ncc(Cl)cc2Cl)c(C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 3-methyl-4-(N-((1-methyl-1H-indol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 11).
Reaction SMILES: [CH3:1][Li].[Si:3]([O:10][CH:11]1[CH2:15][CH:14]=[C:13](OS(C(F)(F)F)(=O)=O)[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>[Cu]I.C(OCC)C>[Si:3]([O:10][CH:11]1[CH2:15][CH:14]=[C:13]([CH3:1])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: [Li]C
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(OS(=O)(=O)C(F)(F)F)C1
Agent: [Cu]I
Solvent: CCOCC
Product: CC1=CCC(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h
Yield: 41 %

Procedure:
To an ether solution of dimethylcopper-lithium obtained by using 8.41 ml of 1.4 M diethyl ether solution of methyllithium, 1.16 g of copper (I) iodide and 15 ml of diethyl ether was added at -30° C. under nitrogen stream 700 mg of 3-trifluoromethanesulfonyloxy-3-cyclopenten-1-yl (t-butyldimethylsilyl) ether and the resulting mixture was stirred for 1 hour. The reaction liquid obtained was after-treated and purified in the same manner as in (1) of the intermediate preparation example 1 to obtain 176 mg of 3-methyl-3-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 41%
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=2[Cl:13])[CH2:3][CH2:2]1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C(N(CC)CC)C.BrC1C=CC(C2C3C(=C(Cl)C=C(Cl)C=3)CN(C)C2)=CC=1>O1CCOCC1>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=2[Cl:13])[CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:2][CH2:3]1
Reactant: O=C(CBr)c1ccccc1
Reactant: Clc1ccc(CNC2CC2)c(Cl)c1
Agent: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(Br)cc2)C1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(CN(Cc1ccc(Cl)cc1Cl)C1CC1)c1ccccc1

Procedure:
Intermediate 1 was reacted with alpha-bromoacetophenone in the presence of triethylamine in dioxane by the method described in example 1, intermediate 3. For workup, the solvent was distilled off, and the residue was taken up in ethyl acetate. It was washed twice with H2O and twice with 2 N HCl, dried with MgSO4 and concentrated. The crude product obtained in this way was reacted further without further purification.