Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:34])[C:29]([O:31]CC)=[O:30])=[CH:24][CH:23]=1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Cl.[OH-].[Na+]>C1COCC1.CCCCCC.C(O)C>[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39][C:28]([C:25]1[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=1)([CH3:34])[C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)C(C)c1ccc(Cl)cc1
Reactant: ClCc1cccc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(Cc1cccc(Cl)c1)(C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of LDA in THF (1 liter), which had been prepared from diisopropylamine (35 g) and a 1.6M solution of n-butyl lithium in hexane (216 ml), was added dropwise a solution of ethyl 2-(4-chlorophenyl)propionate (70 g) in THF (100 ml) which had been obtained in paragraph 1), at a temperature of -45° to -40° C. under an atmosphere of nitrogen gas. At the same temperature, the reaction mixture was stirred for 0.5 hours, and m-chlorobenzyl chloride (55.7 g) was added dropwise thereto. The mixture was subjected to the same post-treatment as described in paragraph 1), and the residue was dissolved in ethanol (700 ml). To this solution was added dropwise 40% aqueous sodium hydroxide (40 ml), followed by heating under reflux for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was added dropwise to 10% aqueous hydrochloric acid under ice-cooling, and extracted several times with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crystalline residue was washed with hexane to give 2 -(3-chlorobenzyl)-2-(4-chlorophenyl)propionic acid (yield, 93 g) as white crystals, m.p., 154.8° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:33])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O: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][CH3:32])=[CH:14][CH:13]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>C(Cl)Cl>[C:34]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9](=[O:33])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O: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][CH3:32])=[CH:16][CH:17]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCOc1ccc(COC(=O)NCc2ccccn2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(COC(=O)N(Cc2ccccn2)C(C)=O)cc1
Temperature: 100 °C
Yield: 43.3 %

Procedure:
A mixture of 3.0 g of product from Example 95, 13.5 g of acetic anhydride, 0.081 g of 4-N,N-dimethylaminopyridine, 3.34 g of triethylamine and 25 ml of methylene chloride is heated, in a sealed tube, at 100° C. for 54 hours. The reaction is concentrated in vacuo, dissolved in methylene chloride, washed with saturated sodium bicarbonate, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 20% ethyl acetate/hexane) to give 1.42 g of the desired product as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH2:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[CH2:39][CH2:38][N:37]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:6]=[C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)[CH:8]=2)[CH2:36][CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 97.7 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one and 1-benzylpiperazine were reacted to yield the title compound as a yellow oil (yield: 97.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:17][CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10]([CH3:15])=[CH:11][CH:12]=[C:13]2[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:17][CH3:18]
Reactant: CCBr
Reactant: Cc1ccc(C)n1-c1ccc(O)c(Cl)c1
Product: CCOc1ccc(-n2c(C)ccc2C)cc1Cl

Procedure:
Using the general procedure outlined in EXAMPLE 1, 1-(3-chloro-4-hydroxyphenyl)-2,5-dimethylpyrrole (1.11 g, 5 mmol) and an excess of bromoethane (1.0 mL) reacted to give 1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 7.27 (d, 1H), 7.08 (dd, 1H), 6.99 (dd, 1H), 5.89 (s, 2H), 4.18 (q, 2H), 2.04 (s, 6H), 1.53 (t, 3H); MS (ESI) 250 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](O)=[C:7]([NH:12][C:13](=[O:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]2[O:24][C:13]([C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])=[N:12][C:7]=2[CH:6]=1
Reactant: COC(=O)Cc1ccc(O)c(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A mixture of methyl(3-heptafluorobutyramido-4-hydroxyphenyl)acetate (20.0 g, 0.053 mol) and para-toluenesulfonic acid (1.71 g) in toluene (150 ml) was heated at reflux (a Dean & Stark™ assembly was fitted to remove water) for 24 hours. The mixture was cooled to room temperature and the mixture was diluted with ethyl acetate (150 ml). The mixture was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane to give methyl(2-heptafluoropropylbenzoxazol-5-yl)acetate (12.9 g) as an off-white solid.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>>[Cl:8][C:7]1[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[N:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:6]=1
Reactant: Clc1ccc(-c2cnc(Br)c(Cl)c2)cc1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ncc(-c2ccc(Cl)cc2)cc1Cl

Procedure:
The product was obtained analogously to Example 7.1b starting from 2-bromo-3-chloro-5-(4-chlorophenyl)pyridine and trimethylsilylacetylene. Yield: 0.57 g (quant. yield); C16H15Cl2NSi (M=320.288); calc.: molpeak (M+H)+: 320/322/324 (2Cl); found: molpeak (M+H)+: 320/322/324 (2Cl); HPLC-MS: 8.02 minutes (method B).
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]1([NH:19][C:20](=S)[S:21]C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(O)C>[CH2:3]([CH:2]1[NH:1][C:20](=[S:21])[N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]1=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CSC(=S)Nc1ccccc1
Reactant: NC(Cc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1C(Cc2ccccc2)NC(=S)N1c1ccccc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of DL-phenylalanine (1.65 g, 10 mmol), methyl N-phenyldithiocarbamate (1.85 g, 10 mmol), and triethylamine (1.4 mL, 10 mmol) in ethanol (30 mL) was heated at reflux for 5 h, the mixture was cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in ethyl acetate, washed with 1N aqueous HCl and water. The organic layer was concentrated and the residue recrystallized form ethanol to provide 2.48 g (88%) of the titled product:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([C:33]([OH:35])=O)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:32])[CH3:31].[F:36][C:37]1[CH:38]=[C:39]2[C:43](=[C:44](/[C:46](/[NH:49]O)=[N:47]/[H])[CH:45]=1)[NH:42][CH:41]=[C:40]2[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:33]2[O:35][N:47]=[C:46]([C:44]3[CH:45]=[C:37]([F:36])[CH:38]=[C:39]4[C:43]=3[NH:42][CH:41]=[C:40]4[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:49]=2)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:31])[CH3:32]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: [H]/N=C(\NO)c1cc(F)cc2c(CCC(=O)OCC)c[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cc(F)cc12
Reaction time: 1 h
Yield: 105.1 %

Procedure:
HOBT (211 mg) and EDCI (260 mg) were added to a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (148 mg) in THF (4 mL). The resulting solution was stirred for 1 hour. Ethyl 3-{5-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D136) (302 mg) in THF (4 mL) was added, and the reaction mixture was stirred at RT for 1.5 hours. TBAF (780 mg) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 1.5 hours. After cooling, the reaction was quenched with water, and extracted with EA for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D139) (341 mg) as a pale yellow solid. δH (CDCl3, 400 MHz): 1.26 (3H, t), 1.47 (6H, d), 2.73 (2H, t), 3.12 (2H, t), 4.15 (2H, q), 5.52 (1H, m), 7.24 (1H, d), 7.47 (1H, dd), 7.86 (1H, dd), 8.43 (1H, d), 8.93 (1H, d), 9.54 (1H, br s). MS (ES): C23H22ClFN4O4 requires 472; found 473.2 (M+H+).
Reaction SMILES: [OH-].[K+].Cl[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][CH:5]=1.[F:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:20]=1[OH:27]>>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:16][CH3:17])[N:7]=[CH:6][CH:5]=[C:4]2[O:27][C:20]1[CH:21]=[C:22]([OH:26])[C:23]([CH3:25])=[CH:24][C:19]=1[F:18]
Reactant: Cc1cc(F)c(O)cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2nccc(Oc3cc(O)c(C)cc3F)c2cc1OC
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 22.2 %

Procedure:
Powdered potassium hydroxide (55 mg, 0.98 mmol) followed by 4-chloro-6,7-dimethoxyquinoline (200 mg, 0.89 mmol), (prepared as described for the starting material in Example 2), was added to 2-fluoro-5-hydroxy-4-methylphenol (600 mg, 4.2 mmol) heated at 130° C. and the mixture then stirred for 1.5 hours at 145° C. The mixture was allowed to cool then partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7 with 5M hydrochloric acid. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by preparative reverse-phase HPLC eluting with water/methanol (90/10 to 30/o) to give 6,7-dimethoxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)quinoline (65 mg, 22%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[C:32]([C:35]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]1)(=[O:34])[NH2:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:38]3[CH2:37][CH2:36][C:35]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:32]([NH2:33])=[O:34])[CH2:40][CH2:39]3)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: NC(=O)C1(c2ccccc2)CC[NH2+]CC1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C(=O)N2CCC(C(N)=O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Yield: 52.3 %

Procedure:
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq, 130 mg, 0.306 mmol), 4-carbamoyl-4-phenylpiperidin-1-ium trifluoroacetate (1.1 eq, 69 mg, 0.337 mmol), benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1.1 eq., 149 mg, 0.337 mmol), and triethylamine (3 eq, 0.13 mL, 0.92 mmol) was stirred in tetrahydrofuran (5 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 1-{[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide (98 mg, 52%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.10 (dd, J=9.75, 3.63 Hz, 1H) 2.18 (s, 3H) 2.20-2.28 (m, 1H) 2.46 (d, J=14.03 Hz, 2H) 3.65 (t, J=10.31 Hz, 1H) 3.75-3.88 (m, 1H) 3.95-4.07 (m, 1H) 4.15-4.28 (m, 1H) 5.17-5.50 (m, 2H) 7.00 (d, J=8.38 Hz, 2H) 7.12-7.50 (m, 10H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>ClCCl>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH:15][C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27]
Reactant: O=C(Cl)C1CC1
Reactant: NCCCc1c(F)ccc2c1CCO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCc1c(F)ccc2c1CCO2)C1CC1
Reaction time: 16 h

Procedure:
3-(2,3-Dihydro-5-fluorobenzofuran-4-yl)propylamine hydrochloride (0.27 g) in dichloromethane (5 ml) containing triethylamine (0.5 ml) was cooled in ice. Cyclopropanecarbonyl chloride (0.12 ml) was added and stirring continued at 5° for 2 h and at room temperature for 16 h. The mixture was washed with water and passed through a solid phase extraction cartridge using ethyl acetate/hexane (1:1) to give the title compound as a white solid (0.21 g).
Reaction SMILES: [Mg].BrCCBr.Cl[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15].[CH2:16]([N:23]1[CH2:28][CH2:27][O:26][CH:25]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([N:23]1[CH2:28][CH2:27][O:26][CH:25]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([OH:30])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccccc1CCl
Reactant: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Mg]
Solvent: CCOCC
Solvent: BrCCBr
Product: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 122 %

Procedure:
Solid magnesium turnings (9.5 g, 28 equiv.) under nitrogen atmosphere at room temperature were stirred vigorously with a magnetic stirring bar overnight. The magnesium was then covered with dry diethyl ether and to the suspension was added 1,2-dibromoethane (50 μL). A cold bath was then applied followed by dropwise addition of 1-chloromethyl-2-methoxy-benzene (18.18 g, 5 equiv. available from Aldrich Chemical Company) in diethyl ether (71 mL) which maintained the temperature at up to 15° C. The resulting black suspension was stirred at room temperature for 30 minutes and cooled down at −20° C. A solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (4 g, 1 equiv.) in diethyl ether (50 mL) was then added dropwise via canula. The reaction mixture was left to warm to room temperature over two hours and then quenched by addition of aqueous saturated solution of NaHCO3 (50 mL). The aqueous solution was extracted with diethyl ether, the organic phase dried with MgSO4, evaporated in vacuo to give 7 g of a yellow amorphous solid. The compound was taken without further purification in the next step. FIA [M+H]+=404.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Br:15][C:16]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:17]=1[CH:18]=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Br:15][C:16]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:41][C:38]1[CH:37]=[CH:36][C:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)=[CH:40][CH:39]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: FC(F)(F)c1ccc(CNc2ccc(-c3ccc(Cl)cc3)cc2)c(Br)c1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (1.4 g, 6.8 mmol) was added to a DCE solution (10 mL) of 2-bromo-4-(trifluoromethyl)benzaldehyde (860 mg, 3.4 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (761 mg, 3.7 mmol), and AcOH (0.78 mL, 13.6 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: C(OC([N:11]1[CH2:16][C@@H:15]([CH2:17][OH:18])[CH2:14][C@H:13]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:22]=2[O:32][CH3:33])[C@@H:12]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O)C1C=CC=CC=1.[OH-].[Na+]>CO.[OH-].[OH-].[Pd+2]>[OH:18][CH2:17][C@@H:15]1[CH2:16][NH:11][C@@H:12]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:13]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][C:28]([F:29])([F:30])[F:31])[CH:24]=[CH:23][C:22]=2[O:32][CH3:33])[CH2:14]1
Reactant: COc1ccc(OC(F)(F)F)cc1CN[C@H]1C[C@H](CO)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(OC(F)(F)F)cc1CN[C@H]1C[C@H](CO)CN[C@H]1c1ccccc1
Yield: 102.1 %

Procedure:
To a solution of (2S*,3S*,5S*)-1-benzyloxycarbonyl-5-hydroxymethyl-3-[-N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-2-phenylpiperidine (0.545 g, 1.00 mmol) and HCO2NH4 (0.252 g, 4.00 mmol) in MeOH (15.0 ml) was added 20% Pd(OH)2 /C (0.159 g) in one portion. The mixture was stirred and heated at reflux for 30 minutes. The catalyst was filtered off by the aid of Celite, and washed with MeOH. The combined filtrate and washings were concentrated in vacuo to give a yellow syrupy residue, which was basified with IM NaOH aq. solution. The mixture was extracted CH2Cl2, and the combined CH2Cl2 extracts were dried (Na2SO4), and concentrated in vacuo to give a pale yellow oil (0.419 g). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 4.0 g). Elution with CH2Cl2 --MeOH (30:1/20:1) gave title compound (0.380 g, 92.7%) as a yellow oil. IRmax (film): 3320(br., s), 1608(m), 1498(s), 1487(s), 1230(br., s), 1160(br., s), 1030(s), 810(m), 740(m), 700(s) cm-1 ; 1H-NMR δ: 7.40-7.20(m, 5H), 6.99(dd, J=8.8, 2.9 Hz, 1H), 6.85(d, J=2.9 Hz, 1H), 6.63(d, J=8.8 Hz, 1H), 3.86(d, J=2.2 Hz, 1H), 3.64(d, J=14.5 Hz, 1H), 3.60-3.47(m, 2H), 3.50(s, 3H), 3.46-3.36(m, 1H), 3.38(d, J=14.5 Hz, 1H), 2.92-2.84(m, 1H), 2.54(dd, J=1.5, 11.5 Hz, 1H), 2.28-2.10(m, 1H), 2.12(dm, J=12.9 Hz, 1H), 1.69(br.s, 3H; NH×2+OH), 1.35(ddd, J=12.9, 12.9, 2.8 Hz, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].C1COCC1.C(O)C.[BH4-].[Na+]>O>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:8][CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1cccnc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a mixture of methyl 2-chloronicotinate (5 g), dehydrated THF (30 ml) and ethanol (30 mL) was added sodium borohydride (4.41 g) at 0° C. The reaction mixture was stirred at room temperature overnight, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.22 g) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH2:20]([SH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: SCc1ccccc1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSCc3ccccc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and benzylmercaptan.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:12]([N:19]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N(C)C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:12]([N:19]1[CH:23]=[C:22]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Reactant: Nc1nc2cccc(Br)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc2cccc(-c3cnn(Cc4ccccc4)c3)n2n1
Temperature: 150 °C

Procedure:
A vial was charged with 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2.00 g, 9.39 mmol), 1-benzylpyrazole-4-boronic acid, pinacol ester (3.20 g, 11.3 mmol), potassium phosphate (4.00 g, 18.8 mmol) and tetrakis(triphenylphosphine)palladium (1.10 g, 0.94 mmol). Dimethylacetamide (24 ml) and water (8 ml) were added and the reaction mixture was heated under microwave irradiation to 150° C. for 10 min. The mixture was partitioned between ethyl acetate and water, and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed several times with water, once with brine, dried over magnesium sulfate and concentrated in vacuo. Trituration in the minimum amount of dichloromethane and diethyl ether afforded an orange solid which required no further purification. Yield: 1.82 g, 67%; LCMS method: 2, RT: 2.37 min, MI: 291 [M+1].
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:10][CH2:11][N:12]=[C:13]=[S:14].C(N(CC)CC)C.[CH3:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH2:28][S:29][CH2:30][CH2:31][SH:32]>>[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:13](=[S:14])[S:32][CH2:31][CH2:30][S:29][CH2:28][C:24]1[N:25]=[CH:26][NH:27][C:23]=1[CH3:22]
Reactant: Cc1[nH]cnc1CSCCN=C=S
Reactant: Cc1[nH]cnc1CSCCS
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1[nH]cnc1CSCCNC(=S)SCCSCc1nc[nH]c1C

Procedure:
5-Methyl-4-(2-isothiocyanatoethylthiomethyl)imidazole hydrochloride may be treated with one equivalent of triethylamine and 2-(5-methyl-4-imidazolylmethylthio)ethanethiol according to the general procedure of Example 1(b) to give the title product.