Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:17]([CH3:42])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH2:40][CH3:41])[N:19]=3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:40]([C:32]1[N:31]([C:20]2[N:19]=[C:18]3[C:23]([N:24]=[C:16]([C:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[O:15])[N:17]3[CH3:42])=[C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:21]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1)[CH3:41]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCNCC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (58 mg, 0.10 mmol) in DCM (1 mL) was added TFA (1 mL) and the resulting mixture stirred at r.t. for 1 h. The reaction mixture was concentrated in vacuo and azeotroped with DCM affording [2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ylmethanone. LCMS (method A): RT 2.03 min, [M+H]+ 475.3
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@H:13]1[C@@H:16]([CH2:17][CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:15]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14]1=[O:32].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:12][C@H:13]1[C@@H:16]([CH2:17][CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:15]([CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C:14]1=[O:32])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)[C@H]1CCc1ccco1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@H]1CCc1ccco1
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
A solution of benzyl chloroformate (485 μL, 3.4 mmols) in methylene chloride (2.5 mL) was added dropwise to a stirred, cooled (ice/H2O bath) solution of (±)-t-butyl 2-[cis-3-amino-4-(2-(2-furyl)ethyl)-2-oxoazetidin-1-yl]acetate (1.0 g, 3.4 mmols) and diisopropylethylamine (592 μL, 3.4 mmols) in methylene chloride (10 mL). Stirring was continued with cooling for 0.5 hr and then for 0.33 hr at ambient temperatures. The solution was sequentially washed with 0.05M (pH 4) ammonium phosphate, H2O, dilute aqueous NaHCO3, and saturated NaCl. The solution was dried (Na2SO4) and concentrated, and the residue was chromatographed on SiO2 (50 g) with hexane-ethyl acetate (2:1). The appropriate fractions were combined and concentrated to leave a viscous oil which was crystallized from diethyl ether-hexane to afford the title compound (1.05 g, 72% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[NH2:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:18]2[N:19]=[CH:20][C:15]([NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([C:35]5[CH:40]=[C:39]([F:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=5)[N:11]=4)[N:6]=[CH:5][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](N)C2)nc1
Yield: 69 %

Procedure:
Following general procedure IV-2, (R)-tert-butyl 1-(5-(3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.16 mmol) was reacted with TFA (2.0 mL) to afford the desired product (56 mg, 67%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.27 (s, 1H), 8.40 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.16 (d, J=2.7 Hz, 1H), 7.59 (dd, J=9.1, 2.8 Hz, 1H), 7.44 (s, 1H), 7.20 (d, J=11.7 Hz, 1H), 6.97 (d, J=9.1 Hz, 1H), 4.39 (dd, J=12.6, 3.4 Hz, 1H), 3.38-3.94 (m, 2H), 3.43-3.21 (m, 5H), 2.79 (s, 3H), 2.17 (m, 2H), 1.93 (m, 1H), 1.80-1.66 (m, 2H).; ESI MS m/z 507 [M+H]+; HPLC 98.8% (AUC), tR=9.34 min.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:14])=[C:8]([CH2:12][CH3:13])[C:9]=2[CH3:11])[S:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].[C:19]([Cu])#[N:20]>CN1C(=O)CCC1>[C:19]([C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:14])=[C:8]([CH2:12][CH3:13])[C:9]=2[CH3:11])[S:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16])#[N:20]
Reactant: N#C[Cu]
Reactant: CCc1c(C)nc2sc(C(=O)OC)c(I)c2c1C
Solvent: CN1CCCC1=O
Product: CCc1c(C)nc2sc(C(=O)OC)c(C#N)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To the solution of methyl 3-iodo-5-ethyl-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate prepared above (5.18 g, 13.8 mmol) in NMP (100 mL), was added CuCN (2.47 g, 27.6 mmol). The mixture was stirred at room temperature overnight. Work-up was conducted as above and the crude product was chromatographed (EtOAc/CH2Cl2, 2.5/97.5) to give pure methyl 3-cyano-5-ethyl-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate (2.70 g, 71%). MS (ES+) m/z: 275.
Reaction SMILES: Cl.[CH2:2]([C:5]1([C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH:3]=[CH2:4].[CH3:21]O>>[CH2:2]([C:5]1([C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[CH:3]=[CH2:4]
Reactant: CO
Reactant: C=CCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: C=CCC1(C(=O)OC)CCNCC1

Procedure:
HCl (g) was bubbled through a solution of 4-allyl-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid [Jiang et al. (2004) Bioorg. Med. Chem. Lett. 14, 3675-3678] (6.50 g, 24.1 mmol,) in MeOH (200 mL). The solution was heated at reflux for 16 h and then concentrated in vacuo to give the title compound as the hydrochloride salt. MS: m/z=184(M+1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][O:16][CH3:17])[C:10]=2[O:18][CH3:19])[CH2:4][CH2:3]1.[CH2:20]([O:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][N:28]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][O:16][CH3:17])[C:10]=2[O:18][CH3:19])[CH2:4][CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCc1nccc(NC2CCC(=O)CC2)c1OC
Reactant: NOCc1ccccc1
Product: COCc1nccc(NC2CCC(=NOCc3ccccc3)CC2)c1OC

Procedure:
The synthesis was carried out analogously to Example 57 using 4-(4-oxocyclohexylamino)-3-methoxy-2-methoxymethylpyridine (Example 56) and O-benzylhydroxylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[NH:37]1[CH:41]=[N:40][C:39]([NH2:42])=[N:38]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:42][C:39]3[N:40]=[CH:41][NH:37][N:38]=3)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: Nc1nc[nH]n1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)Nc4nc[nH]n4)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and 1H-1,2,4-triazol-3-amine using diethyl cyanophosphonate as a coupling reagent. Mass: 575.13 (M+H).
Reaction SMILES: C[O:2][NH:3][CH2:4][C:5]([NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:6].CO.[OH-].[Na+]>O>[OH:2][NH:3][CH2:4][C:5]([NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:6]
Reactant: CONCC(=O)N[C@@H](CCCCN)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NCCCC[C@H](NC(=O)CNO)C(=O)O

Procedure:
To a magnetically stirred solution of MeO-GlyLys [ε-CBz] [α-Lys] [Boc]2 (1.0 g, 1.47 mmol), methanol (32 ml) and water (16 ml) was added 1M aq. NaOH solution (3 ml) at Rt. The reaction and product isolation were carried out according to the method described in Example 13.vi to afford HO-GlyLys [ε-CBz] [α-Lys] [Boc]2 (942 mg, 96%) as a colourless foam.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CC=CC=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: CC(C)CCCC(C)CCCC(C)CCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCC(C)CCCC(C)CCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 27 g (0.11 mol) of 5,9,13-trimethyl-1-tetradecanol and 10 g (0.13 mol) of pyridine in 200 ml of dry methylene chloride was added dropwise to a solution of 22.1 g (0.12 mol) of p-toluenesulfonyl chloride in 100 ml of dry methylene chloride under ice cooling. After the dropwise addition, the mixture was agitated at room temperature overnight, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated under reduced pressure to obtain 34.4 g of (5,9,13-trimethyltetradecyl)tosylate. Under a nitrogen gas stream, 25.8 g (0.21 mol) of erythritol was dissolved in 200 ml of dry DMF, and 4.2 g (0.11 mol) of 60% NaH was added in several batches under ice cooling. After the addition, the resultant was agitated at room temperature for 1 hour, and then was heated to 50° C. A half amount of (5,9,13-trimethyltetradecyl)tosylate obtained above (17.2 g) was added dropwise thereto, and was washed with 55 ml of DMF. The resultant was heated to 80° C. and then agitated for 4 hours, the resulting reaction solution was concentrated under reduced pressure, 500 ml of ether was added to the residual solution to perform extractive dissolution twice, the product was washed twice with saturated saline, and then it was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated, and purified by silica gel column chromatography to obtain 2.3 g of 1-O-(5,9,13-trimethyltetradecyl)erythritol having the following properties. As a result of HPLC analysis of the obtained product, the purity of 1-O-(5,9,13-trimethyltetradecyl)erythritol was 76.9% and that of 2-O-(5,9,13-trimethyltetradecyl)erythritol was 23.1%. The results of NMR analysis are as shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:47][CH2:48][OH:49]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:33][CH2:34][N:35]([CH2:47][CH2:48][OH:49])[CH2:36][CH2:37]3)[C:5]2=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OC2CCNCC2)N1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OC2CCN(CCO)CC2)N1
Temperature: 80 °C
Yield: 34 %

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(4-piperidinyloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.15 mmol) prepared in example 5a in ethanol (2 mL) was added triethylamine (45.7 mg, 0.46 mmol) and 2-bromoethanol (42.4 mg, 0.345 mmol) (Aldrich). The reaction mixture was heated at 80° C. for 18 h, then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH:EtOAc:NEt3=12:88:5) to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-{2-[1-(2-hydroxy-ethyl)-4-piperidinyloxy]-5-iodo-phenyl}spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 36 mg, 34%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:11]([OH:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:9]#[N:10])=[CH:4][CH:3]=1.ClC(Cl)C.[CH2:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:28][CH3:29]>C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:11]([O:22][S:30]([CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:20])([F:21])[F:19])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: N#CC(=C(O)c1ccccc1C(F)(F)F)c1ccc(Br)cc1
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCCS(=O)(=O)OC(=C(C#N)c1ccc(Br)cc1)c1ccccc1C(F)(F)F

Procedure:
60 mg of triethylamine was added to a mixture comprising 0.20 g of α-(4-bromophenyl)-β-hydroxy-β-(2-trifluoromethylphenyl)acrylonitrile and 6 ml of dichloroethane. Then, a mixture comprising 77 mg of n-propanesulfonyl chloride and 2 ml of dichloroethane, was dropwise added thereto. After completion of the dropwise addition, the mixture was reacted for 15 hours at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14](F)[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH:20]1[CH2:25]CCC[CH2:21]1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14]([N:20]([CH3:25])[CH3:21])[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: C1CCNCC1
Reactant: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Solvent: CCO
Product: CN(C)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1

Procedure:
Treatment of 4-(3-bromoanilino)-6-fluoropyrido[3,4-d]pyrimidine (see a previous experimental) at 100° C. in a pressure vessel with piperidine in ethanol gives 4-(3-bromoanilino)-6-dimethylaminopyrido[3,4-d]pyrimidine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:17][CH2:16][CH2:15][CH2:14][CH:13]([NH:18][C:19]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:25])[C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NC(CCCO)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCCOS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Methanesulfonyl chloride (0.511 mL, 6.60 mmol) was added dropwise to tert-butyl 1-(4-chlorophenyl)-4-hydroxybutylcarbamate (Intermediate 55) (1.80 g, 6.00 mmol) and triethylamine (1.004 mL, 7.20 mmol) in DCM (30.0 mL) at 25° C. over a period of 15 minutes under nitrogen. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was evaporated to dryness and the residue was suspended in DCM, filtered and the filtrate purified by flash silica chromatography, elution gradient 20 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-(tert-butoxycarbonylamino)-4-(4-chlorophenyl)butyl methanesulfonate (2.270 g, 100%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]1[CH2:16][C@@H:15]1[CH2:17]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:17][C@H:15]2[CH2:16][O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Product: CC(C)(C)OC(=O)N1CCN(C[C@H]2CO2)CC1
Yield: 70 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from piperazine-1-carboxylic acid tert-butyl ester and (R)-(−)-3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after flash chromatography the title compound as a yellow oil in a 70% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10]OS(C)(=O)=O.[C-:16]#[N:17].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:16]#[N:17]
Reactant: CS(=O)(=O)OCCCc1ccccc1Br
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCc1ccccc1Br
Temperature: 60 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
Methanesulfonyl chloride (7.7 mL, 97 mmol) in 100 mL dry THF is added to a solution of 3-(2-bromo-phenyl)-propan-1-ol (17.4 g, 80.9 mmol) and triethyl amine (14.7 g, 146 mmol) in 200 mL dry THF at 0° C. under an argon atmosphere. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give 23 g (97%) methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester as an oil. Methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester (23 g, 78 mmol) in 300 mL dry DMF is added to a suspension of potassium cyanide (15.3 g, 235 mmol) in dry DMF. The reaction mixture is stirred at 60° C. for 16 hours. Water is added and the mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo. The residue is placed on a plug of silica gel and eluted with ethyl acetate/heptane (1:4) and concentrated in vacuo to give 16.0 g 4-(2-bromo-phenyl)-butyronitrile (91%) as an oil. 300 mL concentrated HCl is added to 4-(2-bromo-phenyl)-butyronitrile (16.0 g, 71 mmol) in 150 mL acetic acid. The reaction mixture is stirred at 60° C. for 16 hours. The reaction mixture concentrated in vacuo partly and is poured into water. The mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo to give the title compound as a crystalline material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([C:18]([F:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[I:28])=[O:6].[Cl:32][C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>>[Cl:32][C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([NH:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:4]([C:5](=[O:6])[NH:7][C:8]2[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][C:11]([C:18]([F:27])([C:19]([F:20])([F:21])[F:22])[C:23]([F:24])([F:25])[F:26])=[CH:10][C:9]=2[I:28])[CH:3]=1)=[O:36]
Reactant: Nc1cccc(C(=O)Nc2c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c1
Reactant: O=C(Cl)c1cccnc1Cl
Product: O=C(Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc(NC(=O)c2cccnc2Cl)c1

Procedure:
According to the method of 1-7 of Example 1, a target compound was prepared from 3-amino-N-(2-iodo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)benzamide and 2-chloronicotinoylchloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][OH:15]>C(OCC)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:14]=[O:15])=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)cn1
Reactant: CO
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccc(Cl)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
In a dry 50 ml flask 2.47 g (10.3 mmole) 2-chloro-5-iodo-pyridine was dissolved in 20 ml of dry diethyl ether. The flask was placed under N2-atmosphere, cooled to −78° C. and 5.1 ml of a 2M solution (10.3 mmole) butyl lithium (BuLi) was added. The reaction mixture was stirred for one hour at −78° C. before adding 1 g (4.1 mmole) of the nitrile compound of example 7. Stirring was continued for 30 minutes at −78° C. and the reaction mixture was then allowed to slowly warm up to room temperature. After 16 hours at room temperature methanol was added in order to neutralise the excess BuLi, and the volatile components were evaporated. The reaction mixture was redissolved in 25 ml of a 1:1 mixture of methanol and 0.5M HCl. 0.5 g of silica gel was added and the mixture was stirred for 15 hours at room temperature. The pH was adjusted to approximately 8 by adding a concentrated NaHCO3 solution. The resulting reaction product was extracted three times by means of dichloromethane and the combined organic phases were dried over MgSO4. After filtration of the solids and evaporation of the volatile components, purification was performed by means of column chromatography, and any remaining 2-chloropyridine was removed by sublimation under high vacuum conditions. 7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]hept-1-yl)-(6-chloro-pyridin-3-yl)-methanone was obtained in a 62% yield and characterised by proton (1H-NMR) and carbon (13C-NMR) nuclear magnetic resonance, infrared (IR) spectrophotometry and mass spectrum (MSES) as follows:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:18][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: Oc1cc2onc(-c3ccccc3F)c2cc1Cl
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2onc(-c3ccccc3F)c2cc1Cl
Temperature: 25 °C

Procedure:
A solution of 5-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (14.8 g) in DMF (40 ml) is added dropwise to room temperature to a suspension of sodium hydride (3.0 g) in DMF (40 ml) and the mixture is stirred at room temperature for one half hour. A solution of ethyl bromoacetate (10.31 g) in DMF (40 ml) is then added dropwise and the mixture stirred 18 hours at room temperature. An additional 0.3 g of NaH suspended in DMF is added, followed by 1 g of ethyl bromoacetate. The mixture is warmed to 50° C. for 1 and one half hours, cooled and poured over ice/water and extracted with ether. The ether extracts are washed with water, saturated sodium chloride, dried over sodium sulfate and the solvent is removed to give a solid. Trituration with ether-petroleum ether (1:1) gives ethyl {[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 114°-115° C.
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:14][C@H:13]2[C:15]3[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4]1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[CH2:4]1[C:5]2=[C:15]3[C:9](=[CH:8][CH:7]=[CH:6]2)[CH2:10][CH2:11][CH2:12][C@H:13]3[CH2:14][C@@H:3]1[CH2:2][C:16]#[N:17]
Reactant: BrC[C@@H]1Cc2cccc3c2[C@@H](CCC3)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC[C@@H]1Cc2cccc3c2[C@@H](CCC3)C1

Procedure:
A solution of 1.6 g cis-2-bromomethyl-2,3,3a,4,5,6-hexahydro-1H-phenalene 13 and 330 mg NaCN in 7 ml DMSO (dimethylsulphoxide) was heated at 80°-85° C. for 4 hours. The reaction mixture was then poured into 50 ml water and the product extracted with ether. The organic layer was washed with water, dried and evaporated. This yielded 1.2 g of the nitrile 14.