Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)[Cl:3].[CH3:6][C:7]1[CH2:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C([Li])CCC.[Cl-].[Li+]>CCCCCC.O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][Si:2]([Cl:3])([CH3:5])[CH:15]1[C:14]2[C:9](=[C:10]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:6]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2cccc(-c3cccc4ccccc34)c2C1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3cccc4ccccc34)cccc2C1[Si](C)(C)Cl
Reaction time: 3 h

Procedure:
23 g (180 mmol) of dimethyldichlorosilane was dissolved in 200 ml of dry n-hexane (dried over Na-K alloy), to which was added a solution of 2-methyl-7-(1-naphthyl)indenyllithium (i.e., a solution of 9.2 g (36 mmol) of 2-methyl-7-(1-naphthyl)indene in a mixed solvent of 75 ml of dry toluene and 5 ml of tetrahydrofuran to which was dripped down 22.5 ml of a 1.6 M hexane solution of n-butyllithium at -78° C., followed by stirring at room temperature for 3 hours and by addition of 50 ml of tetrahydrofuran) under ice cooling. The mixture was stirred as was at room temperature for 3 hours to deposit white salt of lithium chloride. After standing the mixture so that the white salt precipitated, the supernatant was extracted with a syringe and transferred into another flask and low boiling components (solvent and unreacted dimethyldichlorosilane) were distilled off under reduced pressure at 8 mmHg to obtain dimethyl(2-methyl-4-(1-naphthyl)indenyl)silyl chloride.
Reaction SMILES: Br[CH2:2][C@H:3]1[NH:8][CH2:7][C@H:6]([O:9][CH:10]([C:21]2[CH:22]=[CH:23][C:24]3[O:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:25]=3[CH:35]=2)S(C2C=CC(C)=CC=2)(=O)=O)[C@@H:5]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH2:4]1.[C:44]([O:49][CH3:50])(=[O:48])[CH2:45][CH2:46][CH3:47]>>[CH3:50][O:49][C:44](=[O:48])[CH:45]([CH2:2][C@@H:3]1[CH2:4][C@H:5]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C@@H:6]([O:9][CH2:10][C:21]2[CH:22]=[CH:23][C:24]3[O:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:25]=3[CH:35]=2)[CH2:7][NH:8]1)[CH2:46][CH3:47]
Reactant: COCCCN1CCOc2ccc(C(O[C@H]3CN[C@H](CBr)C[C@@H]3c3ccc(OC)cc3)S(=O)(=O)c3ccc(C)cc3)cc21
Reactant: CCCC(=O)OC
Product: CCC(C[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1)C(=O)OC

Procedure:
According to example 65c, 6-[(3R,4R,6S)-6-bromomethyl-4-(4-methoxy-phenyl)-1-(toluene-4-sulfonyl)-piperidin-3-yloxymethyl]-4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazine (from example 65d) and methyl butyrate are used to afford the title compound which is identified based on its Rf values.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]1[CH2:26][CH2:25][CH:24](O)[CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:24]2[CH2:25][CH2:26][N:22]([CH3:21])[CH2:23]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Product: CN1CCC(Oc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)C1

Procedure:
The title compound was prepared using Mitsunobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 1-Methyl-3-pyrrolidinol.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1)[CH2:2][CH3:3].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1.CC(C)([O-])C.[K+]>>[C:36]([O:35][C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:8]2[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=[C:4]2[CH2:1][CH2:2][CH3:3])=[CH:22][CH:23]=1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCCc1nc(C(=O)OCC)c(C(=O)OCC)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 89.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 9.0 g of diethyl 2-propylimidazole-4,5-dicarboxylate (prepared as described in Preparation 12), 12.3 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate and 4.1 g of potassium t-butoxide as a base. 16.47 g of the title compound were obtained as a viscous oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH:12](O)([CH3:14])[CH3:13]>>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH:12]([CH3:14])[CH3:13])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)O
Reactant: O=C(O)c1ccc(CCl)cc1
Product: CC(C)OC(=O)c1ccc(CCl)cc1

Procedure:
Isopropyl 4-(chloromethyl)benzoate 13d was prepared by reacting 4-(chloromethyl)benzoic acid 24 with isopropanol according to the procedure described for the compound 13a in Example 16 (scheme 7). The benzoate 13d was isolated as colorless oil in 89% yield (1.90 g). 1H NMR (400 MHz, CDCl3): δ 1.35 (6H, m); 4.59 (2H, s); 5.25 (2H, m); 7.42 (1H, m); 7.44 (1H, broad s); 8.00 (1H, broad s); 8.02 (1H, s).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:18]2[CH2:19][CH2:20][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:16][CH2:17]2)[CH2:4][CH2:3]1
Reactant: CC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1CCN(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
To a stirred solution, 1 h, at 0° C. of 4-methylpiperidine (15.0 g, 151 mmol), 1-boc-4-piperidone (30.1 g, 151 mmol) and HOAc (18.2 g, 303 mmol) in THF (100 mL) was added sodium triacetoxyborohydride (64.2 g, 303 mmol) in 3 portions. The mixture was stirred at rt for 18 h. The reaction was neutralized with saturated K2CO3 and the pH was adjusted to 8 with saturated Na2CO3. The mixture was diluted with DCM and separated. The organic layer was washed with H2O and concentrated to provide the title compound of step A (33.0 g, 117 mmol, 77%). 1H NMR (400 MHz, CDCl3) δ ppm 0.71-0.90 (m, 3H), 1.11-1.20 (m, 2H), 1.31-1.50 (m, 9H), 1.50-1.65 (m, 1H), 1.70-1.90 (m, 4H), 2.01-2.30 (m, 2H), 2.71-3.10 (m, 4H), 3.60-3.91 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][CH:11]=[CH:12]2)=[N:7]1)[CH3:2].C1C(=O)N([Cl:23])C(=O)C1>ClCCl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][N:6]1[C:14]([Cl:23])=[C:13]2[C:8]([N:9]=[CH:10][CH:11]=[CH:12]2)=[N:7]1)[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cn1cc2cccnc2n1
Solvent: ClCCl
Product: CCOC(=O)Cn1nc2ncccc2c1Cl
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a solution of pyrazolo[3,4-b]pyridin-2-yl-acetic acid ethyl ester 57 (40.2 mg, 0.2 mmol, 1 equiv) in 1 mL of dichloromethane was added NCS (32.7 mg, 1.2 mmol, 1.2 equiv). The resultant mixture was heated at 70° C. for 30 min., cooled to room temperature, and diluted with 100 mL of dichloromethane. The organic solution was washed with 50 mL of saturated sodium bicarbonate aqueous solution, and 50 mL of brine. The organic layer was separated and dried over sodium sulfate. Evaporation of solvent in vacuo gave 46.7 mg of (3-chloro-pyrazolo[3,4-b]pyridin-2-yl)-acetic acid ethyl ester as yellow solid.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:20]3[C:21]([Cl:37])=[CH:22][C:23]([F:36])=[C:24]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[CH:25]=3)[C:13](=[O:19])[N:14]2[CH2:17][CH3:18])=[CH:9][N:8]=1.[C:38]([CH2:40][C:41](OCC)=[O:42])#[N:39]>CN1C(=O)CCC1>[Cl:37][C:21]1[CH:22]=[C:23]([F:36])[C:24]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:28])=[CH:25][C:20]=1[C:12]1[C:13](=[O:19])[N:14]([CH2:17][CH3:18])[C:15]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([NH:6][C:41](=[O:42])[CH2:40][C:38]#[N:39])[CH:16]=2
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(N)cc21
Reactant: CCOC(=O)CC#N
Agent: CS(=O)(=O)O
Solvent: CN1CCCC1=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC(=O)CC#N)cc21
Temperature: 125 °C
Yield: 10.7 %

Procedure:
A suspension of Example 21 (0.180 g, 0.398 mmol) in ethyl cyanoacetate (3 ml, 28.1 mmol) was heated at 125° C. overnight. The mixture was treated with NMP (0.3 mL), heated at 125° C. for 24 h, then cooled to RT and purified via silica gel chromatography (EtOAc/Hex). The material was re-purified via silica gel chromatography (THF/Hex), dissolved in 4:1 MeCN/H2O, frozen and lyophilized, treated with MTBE and the resulting solid collected via filtration and dried to afford N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide (22 mg, 11% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.10 (s, 1H), 8.75 (s, 1H), 8.73 (s, 1H), 8.23 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.58 (d, J=11.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.0 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 4.05 (s, 2H), 1.26 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 519.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[CH:25][NH:24][N:23]=2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]([NH:21][C:22]3[CH:26]=[CH:25][NH:24][N:23]=3)[N:12]=2)=[CH:5][CH:4]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: COc1ccc(O)cc1
Product: COc1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methoxy-phenol and (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine to give [1-(4-methoxy-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 333(MH+).
Reaction SMILES: C1C2C(COC([C:18]3[C:31](OC)=[CH:30][C:21]([O:22][CH2:23][CH2:24][CH2:25]CC(O)=O)=[C:20](CN)[C:19]=3OC)=O)C3C(=CC=CC=3)C=2C=CC=1.[Cl:38][C:39]1[C:44]([Cl:45])=[CH:43][CH:42]=[C:41]([Cl:46])[C:40]=1O.C1OC2C(=C(O)C=CC=2)O1.CC(C)([O-])C.[K+].C(Br)C#C>CN(C=O)C>[Cl:45][C:44]1([C:19]2[CH:18]=[CH:31][CH:30]=[C:21]([O:22][CH2:23][C:24]#[CH:25])[CH:20]=2)[CH:43]=[CH:42][C:41]([Cl:46])=[CH:40][CH:39]1[Cl:38]
Reactant: COc1cc(OCCCCC(=O)O)c(CN)c(OC)c1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Oc1c(Cl)ccc(Cl)c1Cl
Agent: C#CCBr
Agent: CC(C)(C)[O-]
Agent: Oc1cccc2c1OCO2
Solvent: CN(C)C=O
Product: C#CCOc1cccc(C2(Cl)C=CC(Cl)=CC2Cl)c1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
1,2,4-trichlorophenyl-3-(2-propynyloxy) benzene (TCPB) and 1-(2-propynyloxy)methylenedioxyphenyl ether (MDPPE) were synthesized by the method of F. Albericio et al., "Preparation and Application of the 5-(4-(9-Fluorenylmethyloxy carbonyl)-Aminomethyl-3,5-Dimethoxyphenoxy)-Valeric Acid Handle for the Solid Phase Synthesis of C-Terminal Peptide Amides under Mild Conditions," J. Org. Chem. vol. 55, pp. 3730-3743 (1990) (FIG. 2). A mixture of 2,3,6-trichlorophenol or methylenedioxyphenol (0.05 mole), potassium tert-butoxide (6.16 g, 0.055 mole), propargyl bromide (6.6 g, 0.055 mole) in dry DMF (60 mL) was heated and stirred at 110° C. for 5 h, after which the solvent was removed under high vacuum. Ethyl acetate was added, the inorganic salts were removed by filtration, and the organic extract was washed sequentially with water, 2 M NaOH, and saturated aqueous NaCl. The organic phase was dried overnight (Na2SO4) to give a crude product. MDPPE, a liquid product, was purified by silica gel chromatography using hexane-ethyl acetate (7:3) as the eluting solvent. Yield: 6.5 g (74%). 1H NMR (CDCl3): d 2.54 (t, 1H, CH), 4.61 (d, 2H, --OCH2 --), 5.92 (s, 2H, --OCH2O--), 6.38-6.73 (m, 3H, aromatics). GC-MS (m/z): M+· =176.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>ClCCl.CN(C)C(N)CC>[C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)(=[O:25])[CH2:23][CH3:24]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: CCC(=O)Cl
Agent: CCC(N)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(NC(=O)CC)cc1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a mixture of ethyl 4-aminocinnamate (300 mg), triethylamine (167 mg) and dichloromethane (3 ml) was added a solution of propionyl chloride (182 mg) in dichloromethane (1 ml) in an ice-water bath, and the mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added 4 drops of N,N-dimethylpropanediamine, and the mixture was further stirred for 5 minutes. The reaction mixture was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give ethyl 4-propionamidocinnamate (341 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]#[C:15][Si](C)(C)C)[S:13][C:6]=12.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(O)=O>[C:14]([C:12]1[S:13][C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:2]=2[F:1])[CH:11]=1)#[CH:15]
Reactant: C[Si](C)(C)C#Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of the alkyne 409 (2.2 g, 5.69 mmol) in THF (30 ml) was added a solution of TBAF (8.53 mL, 1.5 eq, 1M soln in THF) in HOAc (30 ml), and the reaction mixture was stirred at RT overnight. It was then concentrated to dryness and partitioned between water and EtOAc. The organic phase was washed well with satd. NaHCO3 soln, collected, dried over anhydrous Na2SO4, filtered and concentrated. The crude mixture was adsorbed onto silica gel then purified by column chromatography (30% EtOAc in hexane) to afford 410 (1.4 g, 72% yield). LCMS: 415.2 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:25]([OH:27])=O)[CH2:9]2)=[O:7])[CH2:3]1.O[N:29]=[C:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>>[OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:25]3[O:27][N:34]=[C:30]([CH:31]([CH3:33])[CH3:32])[N:29]=3)[CH2:9]2)=[O:7])[CH2:3]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: CC(C)C(N)=NO
Product: CC(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1

Procedure:
185 mg (about 0.400 mmol) of the compound from Example 110A and 55 mg (0.600 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 28 mg (16% of theory)
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([NH2:28])[CH:24]=1.CC(C)([O-])C.[Na+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:28][C:25]2[CH:24]=[C:23]([CH3:22])[O:27][N:26]=2)[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: Cc1cc(N)no1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)no1
Temperature: 70 °C
Yield: 48.2 %

Procedure:
A mixture of 5A (40 mg, 0.123 mmol), 5-methylisoxazol-3-amine (30.1 mg, 0.307 mmol) and sodium t-butoxide (29.5 mg, 0.307 mmol) in THF (1.5 mL) was heated at 70° C. for 2 h, the cooled to room temperature. The solvent was removed and the residue was purified by ISCO column chromatography (4 g column, MeOH/DCM=0-10%) to give 51A (23 mg, 48%). HPLC Rt=3.043 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=388.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.CS(O[CH2:27][CH:28]1[CH2:32][O:31][C:30]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[Cl:46])([CH2:33][N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[O:29]1)(=O)=O.[OH-].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:46][C:40]1[CH:41]=[C:42]([Cl:45])[CH:43]=[CH:44][C:39]=1[C:30]1([CH2:33][N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[O:29][CH:28]([CH2:27][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][N:7]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:6][CH2:5]3)[CH2:32][O:31]1
Reactant: COc1ccc(CCN2CCc3cc(O)ccc3C2)cc1
Reactant: CS(=O)(=O)OCC1COC(Cn2ccnc2)(c2ccc(Cl)cc2Cl)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CCN2CCc3cc(OCC4COC(Cn5ccnc5)(c5ccc(Cl)cc5Cl)O4)ccc3C2)cc1

Procedure:
1.4 g of 6-hydroxy-2-[2-(4-methoxyphenyl)ethyl]-1,2,3,4-tetrahydroisoquinoline, 2.1 g of (2RS,4SR)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methanesulfonate and 0.3 g of tetrabutylammonium bromide are heated to reflux, with vigorous stirring, for 9 hours in a mixture of 40 ml of toluene and 10 ml of 50% strength sodium hydroxide solution. After cooling, 50 ml of water are added, and the organic phase is washed with water, dried over magnesium sulfate and evaporated in a rotary evaporator. The crude product is purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol 19:1. 2.2 g of a colorless oil (76% of theory) which crystallizes on trituration with diethyl ether are obtained. Melting point: 121°-122°.
Reaction SMILES: [Cl-].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:13][C:14]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:15]O.[OH-].[Na+]>O>[F:13][C:14]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:15][O:10][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:12])=[CH:7][CH:6]=1)(=[O:11])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: OCC(F)(F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Temperature: 50 °C
Yield: 82.3 %

Procedure:
To p-toluenesulfonate chloride (400.66 gm/2.10 mol) in water at 25° C. was added 2,2,3,3,3-pentafluoro-1-propanol (300.8 gm). The mixture was heated in a 5 liter, 3-neck separatory funnel type reaction flask, under mechanical stirring, to a temperature of 50° C. Sodium hydroxide (92.56 gm/2.31 mol) in 383 ml water(6M solution) was added dropwise to the reaction mixture via addition funnel over a period of 2.5 hours, keeping the temperature below 55° C. Upon completion of this addition, when the pH of the aqueous phase was approximately 6, the organic phase was drained from the flask while still warm, and allowed to cool to 25° C. The crude product was recrystallized from petroleum ether to afford white needles of 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate (500.7 gm/1.65 mol, 82.3%).
Reaction SMILES: [CH:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19](I)[CH3:20]>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:1]1([C:7]2[N:8]([CH2:19][CH3:20])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc2[nH]c(C3CCCCC3)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(C2CCCCC2)cc2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 2-cyclohexyl-5-nitro-1H-indole (5 g; 20.5 mmol) in DMF (100 ml) sodium hydride (50% suspension) (1 g, 20.5 mmol) was added; the mixture was left under stirring for 30 minutes, then ethyl iodide (2.5 ml; 30.8 mmol) in DMF (10 ml) was added dropwise and the resulting mixture was left under stirring at room temperature for 18 hours. The reaction mixture was poured in NaHCO3 (saturated solution, 100 ml) and stirred for 30 minutes. The solid was filtered under vacuum to give 2-cyclohexyl-1-ethyl-5-nitro-1H-indole (4.8 g) which was used without any further purification.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]=[O:16]>C(O)CCCCCCC>[C:1]1([C@@H:7]([N:9]([CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[CH2:15][O:16][CH2:8][CH2:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: C[C@H](NC[Si](C)(C)C)c1ccccc1
Solvent: CCCCCCCCO
Product: CCCCCCCCOCN(C[Si](C)(C)C)[C@@H](C)c1ccccc1

Procedure:
The title compound was prepared from (S)-(-)-N-1-phenylethyl-N-trimethylsilylmethylamine by reaction with n-octanol and aqueous formaldehyde following the procedure of Example 2 to give the crude acetal (90% pure) as a colourless oil (9.1 g, 91%)δC (CD2Cl2)--1.28 (SiMe3), 14.29, 23.08, 30.31, 29.74, 29.89, 26.82, 33.32, 63.13 (O Octyl), 19.37 (CMe), 40.11 (NCH2Si), 62.10 (CH), 84.69 (NCH2O), 126.82, 127.96, 128.31, 145.95 (Ph).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27]>>[OH:28][C:26]([CH3:29])([CH3:27])[CH2:25][NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: CC(C)(O)CN
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC(C)(C)O)cn1
Yield: 49 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 1-amino-2-methyl-propan-2-ol instead of 2-aminoethyl isopropylether, to the title compound (215 mg, 49%) which was obtained as a white solid. MS: m/e=380.0 [M−H]−.