Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:38][CH3:39])[C:5]([N:8]([C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C4CCCCO4)=[CH:20][CH:19]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:38][CH3:39])[C:5]([N:8]([C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[S:9]([C:12]2[C:13]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: COc1nc(Cl)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(O)cc1
Yield: 97.8 %

Procedure:
N-(5-Chloro-3-methoxypyrazin-2-yl)- N-(isobutoxycarbonyl)-4'-[2-(2 H)-tetrahydropyranyloxy]-2-biphenylsulphonamide (1.15 g) and pyridinium-p-toluenesulphonate (50 mg) in ethanol (50 ml) was heated at 60° C. for 3 hours. Volatile material was removed by evaporation and the residue was triturated with etherexane (1:1 v/v) to give N-(5-chloro-3-methoxypyrazin-2-yl)-4'-hydroxy- N-(isobutoxycarbonyl)-2-biphenylsulphonamide (0.96 g), m.p. 175°-177° C.; microanalysis found: C, 53.9; H, 4.8; N, 8.2%; C21H22C1N3O6 requires: C, 53.7; H, 4.5; N, 8.5%.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]2[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C>[N:14]1([CH2:17][C@@H:18]2[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CN2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](CN2CCNCC2)C1
Yield: 98.1 %

Procedure:
tert-Butyl (2S)-2-({4-[(benzyloxy)carbonyl]piperazin-1-yl}methyl)morpholine-4-carboxylate (11.16 g, 26.6 mmol) was hydrogenated over 10% palladium on carbon (500 mg) in ethanol (100 ml). The catalyst was then filtered off through a pad of celite and filtrate evaporated to dryness to give a dark yellow solid. This was then purified on Isco™ Companion (120 g column: 10% Methanolic ammonia/DCM) to give the product as a pale yellow solid (7.46 g, 26.1 mmol, 98%).
Reaction SMILES: [C:1]1(=[O:20])[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([N+:16]([O-])=O)[CH:15]=2)[C:10]([OH:12])=[O:11])[C:5](=[O:19])[CH2:4][CH2:3][CH2:2]1.[OH-:21].[Na+].Cl>[Pd]>[C:10]([C:9]1[CH:8]=[C:7]([CH:15]=[C:14]([NH2:16])[CH:13]=1)[NH:6][C:5](=[O:19])[CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:21])([OH:12])=[O:11]
Reactant: O=C(O)c1cc(N2C(=O)CCCC2=O)cc([N+](=O)[O-])c1
Reactant: [OH-]
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Product: Nc1cc(NC(=O)CCCC(=O)O)cc(C(=O)O)c1
Reaction time: 5 h

Procedure:
3-Glutarimido-5-nitrobenzoic acid (55.6 g.) was dissolved in 150 ml. of 10% aqueous sodium hydroxide, the pH adjusted to 8 with 3N hydrochloric acid, 1.0 g. of 10% palladium-on-carbon catalyst added, and the mixture hydrogenated in a Parr apparatus. Reduction was complete in 5 hours. The reaction mixture was filtered and the filtrate containing 3'-carboxy-5'-aminoglutaranilic acid iodinated as described below.
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][C@@H:2]1[CH2:15][NH:16][CH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[NH:22][CH:21]=1)[N:11]=[CH:10][CH:9]=[CH:8]3.C=O.[C:32]([BH3-])#N.[Na+].C(O)(=O)C>CO>[O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH:2]1[CH2:15][N:16]([CH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[NH:22][CH:21]=1)[CH3:32])[N:11]=[CH:10][CH:9]=[CH:8]3
Reactant: [BH3-]C#N
Reactant: Fc1ccc2[nH]cc(CCCNC[C@H]3COc4ccc5ncccc5c4O3)c2c1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCCc1c[nH]c2ccc(F)cc12)CC1COc2ccc3ncccc3c2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S)-(2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-[3-(5-fluoro-1H-indol-3-yl)-propyl]-amine (0.13 g, 0.33 mmol) and formaldehyde (37 wt. % in water, 0.26 g, 3.3 mmol) in methanol (20 mL) was added sodium cyanoborohydride (0.038 g, 0.59 mmol) and acetic acid (0.03 g, 0.5 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen overnight, then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (5% methanol-methylene chloride). The product-containing fractions were concentrated in vacuum to give 0.1 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as a yellow solid (decomposed at 78° C.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]12[CH2:19][CH:11]([CH2:12][CH:13]([C:15](OC)=[O:16])[CH2:14]1)[CH2:10][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8]2.O.[OH-].[Na+]>C1COCC1>[OH:16][CH2:15][CH:13]1[CH2:12][CH:11]2[CH2:19][CH:7]([CH2:8][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10]2)[CH2:14]1
Reactant: COC(=O)C1CC2CC(C1)CN(C(=O)OC(C)(C)C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CC(CO)CC(C2)C1
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Lithium aluminum hydride (2.54 g) was suspended in THF (140 mL), and a solution of 3-tert-butyl 7-methyl 3-azabicyclo[3.3.1]nonane-3,7-dicarboxylate (9.49 g) in THF (27 mL) was added dropwise under ice-cooling. The reaction mixture was stirred for 30 min under ice-cooling, and water (2.54 mL) was slowly added dropwise. To the reaction mixture was added dropwise 15% aqueous sodium hydroxide solution (2.54 mL), and then water (7.5 mL) was added, and the mixture was stirred at room temperature for 3 days. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.02 g).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH:13]1[CH2:20][CH2:19][CH:18]=[CH:17][CH2:16][CH2:15][CH:14]=1>>[CH:20]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: C1=CCCC=CCC1
Product: CC1(C)CC(O)CC(C)(C)N1OC1C=CCCC=CC1
Temperature: 100 °C
Yield: 17.1 %

Procedure:
A mixture of 29.4 g (0.17 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 148.0 g (1.37 mol) of 1,5-cyclooctadiene is heated under a nitrogen atmosphere at 100° C. for 24 hours. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate is diluted with heptane (250 mL). The organic phase is washed with 5% ascorbic acid (2×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous magnesium sulfate and the volatiles removed in vacuo. The residue is chromatographed to give 8.1 g (33% yield) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2].CCCCCC.[CH2:16]([O:28][CH2:29]Cl)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:31]([O-:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[K+]>CS(C)=O.C(Cl)(Cl)Cl>[C:31]([O-:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[C:1]([O:4][CH2:5][CH2:6][N+:7]([CH2:29][O:28][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH3:9])[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCN(C)C
Reactant: CCCCCCCCCCCCOCCl
Agent: O=C([O-])c1ccccc1
Agent: [K+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCOC[N+](C)(C)CCOC(C)=O
Temperature: 18 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
In a two-necked, round bottomed flask, equipped with a condenser and addition funnel, the 2-(dimethylamino)ethyl acetate (0.05 mol) was mixed with 30 mL of anhydrous hexane. Chloromethyl dodecyl ether (0.055 mol) was slowly added over 5 minutes. After 15 minutes, the reaction mixture was cooled to the temperature of minus 18° C. and the crude product was separated. The precipitate was washed with 30 mL of hexane and used in the next step without further purification. The crude (2-acetooxyethyl)-dodecyloxymethyldimethylammonium chloride was dissolved in 30 mL of water and aqueous solution of potassium benzoate (0.065 mol) was added. After 30 min, 30 mL of chloroform was added. The chloroform phase was separated and washed with distilled water until chloride ions were no longer detected using AgNO3. The obtained grease was dried under vacuum. The product was obtained as grease in 67% yield. Thermogravimetric analysis: Tonset=122° C. 1H and 13C NMR (DMSO) were obtained.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]=O>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc2ccccc2n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with commercially available quinoline-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 365.02 g/mol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Cl:19][C:20]1[N:24]=[CH:23][NH:22][N:21]=1>>[Cl:19][C:20]1[N:24]=[CH:23][N:22]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[N:21]=1
Reactant: Clc1nc[nH]n1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Cl)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.12) (0.4 g, 1.47 mmol) and commercially available 3-chloro-1H-[1,2,4]triazole (0.22 g, 2.17 mmol) according to the general procedure IVa. Obtained as a yellow solid (0.36 g, 72%). MS (ISP) 340.0 [(M+H)+]; mp 137.5° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>C(OCC)C>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:19]1([OH:22])[CH2:20][CH2:21][C:16]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:17][CH2:18]1
Reactant: Brc1nccs1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2nccs2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
To a −78° C. solution of n-butyl lithium (10.4 mL, 2.5M in hexane, 26 mmol) in diethyl ether (20 mL) was added 2-bromothiazole (3.28 g, 1.8 mL, 20 mmol) slowly via syringe. The reaction mixture was stirred for 15 minutes, followed by the slow addition of 1,4-dioxaspiro[4.5]decan-8-one (4.22 g, 27 mmol) in diethyl ether (55 mL). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with two portions of ethyl acetate. The combined organic layers were concentrated. The residue was chromatographed on silica gel eluting with 0%-40% ethyl acetate-hexane to obtain the title compound (4.53 g, 94%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.69 (d, 0.1=3.2, 1H), 7.55 (d, J=3.2, 1H), 3.88 (s, 4H), 2.11 (td, J=4.2, 12.8, 2H), 1.93-1.80 (m, 2H), 1.80-1.53 (m, 4H). MS (DCI) m/z 242 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2([CH:18]3[CH2:20][CH2:19]3)[C:9]3[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:8]=3[NH:7][C:6](=[O:17])[O:5]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24](Br)[CH:23]=1>>[Br:21][C:22]1[CH:23]=[C:24]([C:11]2[CH:12]=[CH:13][C:8]3[NH:7][C:6](=[O:17])[O:5][C:4]([CH:18]4[CH2:20][CH2:19]4)([CH:1]4[CH2:3][CH2:2]4)[C:9]=3[CH:10]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: O=C1Nc2ccc(B(O)O)cc2C(C2CC2)(C2CC2)O1
Product: O=C1Nc2ccc(-c3cc(F)cc(Br)c3)cc2C(C2CC2)(C2CC2)O1

Procedure:
Prepared according to Procedure B from (4,4-dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1,3-dibromo-5-fluorobenzene. A white solid: mp 228-229° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.76-7.72 (m, 2H), 7.65 (dd, 1H, J=8.32, 1.74 Hz), 7.60 (d, 1H, J=10.36 Hz), 7.51 (d, 1H, J=8.3 Hz), 6.93 (d, 1H, J=8.31 Hz), 1.63-1.54 (m, 2H), 0.58-0.41 (m, 6H), 0.30-0.28 (m, 2H); MS (APCI) m/z 402/404 ([M−H]−, 100%); Anal. Calc. For C20H17BrFNO2: C, 58.48; H, 4.17; N, 3.41. Found: C, 58.77; H, 4.23; N, 3.32.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[N:9]([CH2:13][CH2:14]Cl)[CH2:10][CH2:11]Cl)([CH3:6])([CH3:5])[CH3:4].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][C:23]#[N:24])=[CH:20][CH:19]=1>CN(C)C=O>[C:3]([O:7][C:8]([N:9]1[CH2:13][CH2:14][C:22]([C:21]2[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=2)([C:23]#[N:24])[CH2:11][CH2:10]1)=[O:16])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Temperature: 65 °C
Reaction time: 89 h
Yield: 70 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.9 g, 72.3 mmol) was added in small portions, over a period of 1 hour, to a solution of bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (6.74 g, 28 mmol) and 4-chlorobenzyl cyanide (3.8 g, 25 mmol) in anhydrous dimethylformamide (25 ml). The reaction mixture was heated at 65° C. for 1 hour and then stirred at room temperature for 89 hours. After this period, the reaction mixture was poured into ice/water (60 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with water and brine, dried, filtered and concentrated. Flash column chromatography on silica, eluting with hexane/dichloromethane/ethyl acetate (8:1:1), gave 4-(4-chlorophenyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (5.6 g, 17.5 mmol, 70%) as a white solid. LC-MS (LCT) m/z 320 [M+], Rt 7.71 min.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[C:25]([CH3:31])=[N:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC([Si](C)(C)[O:42][CH2:43][C@@H:44]1[CH2:53][N:52]2[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]2)[CH2:46][NH:45]1)(C)C.[Cl-].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[C@H:44]([CH2:43][OH:42])[CH2:53][N:52]4[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]4)[CH2:46]3)=[CH:22][C:23]=2[C:24]2[C:25]([CH3:31])=[N:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Reactant: Cc1nc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1nc(F)ccc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 16.4 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6′-chloro-6-fluoro-2-methyl-3,4′-bipyridin-3′-yl)-N,2-dimethylpropanamide (D54, 53.5 mg, 0.1 mmol), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 37 mg, 0.13 mmol) were dissolved in toluene (1.5 mL). Bis tritertbutylphosphine palladium (13 mg, 0.026 mmol), followed by hexadecyltrimethylammoium chloride (10 μL, 25% aq sol), and finally sodium hydroxide solution (0.13 mL, 50% aq sol). The mixture was degassed for 5 minutes before heating at 90° C. for 4.5 hours. Cooled to R.T., diluted with EtOAc, washed with sat. NaHCO3 solution, dried (MgSO4). Filtered. Solvent evaporated. Residue purified by SCX column, washing with MeOH before eluting with NH3 in MeOH. Solvent evaporated. Residue purified by column chromatography eluting with Pent to EtOAc to 10% MeOH/EtOAc. Solvent evaporated under reduced pressure to afford a colourless solid of the title compound (11 mg).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].[Br:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:30][C:31](=[O:42])[C:32]3[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=3)[C:27](O)=[O:28])=[CH:21][CH:20]=2)=[N:17][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[Br:12][C:13]1[CH:18]=[N:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:30][C:31](=[O:42])[C:32]3[CH:33]=[CH:34][C:35]([C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:36][CH:37]=3)[C:27]([NH:10][CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[O:28])=[CH:21][CH:20]=2)=[N:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCNC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
Prepared using General Procedure 7. A stirring solution of β-alanine tert-butyl ester hydrochloride (4.9 g, 27.4 mmol), (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoic acid (12.0 g, 24.9 mmol) and DIEA (11.1 mL, 62.0 mmol) in DMF (200 mL) was cooled to 0° C. A solution of HATU (9.9 g, 26.1 mmol) in DMF (75 mL) was added dropwise over 20 min. The reaction mixture was allowed to warm to room temperature over 2 h, then diluted with EA and washed with NaHCO3 (sat aq). The aqueous fraction was back-extracted with EA. The combined organic fractions were dried (Na2SO4) then concentrated onto celite and purified by column chromatography (EA/hexane) to provide 11 g (65%) of tert-butyl (S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanamido)propanoate INT-28. LCMS-ESI (m/z) calculated for C31H37BrN4O4; 609.6. found 610.2 [M+H]+, tR=3.99 min (Method 15), and 87.1% e.e. (Chiral Method, isocratic with 20% Solvent A, 80% Solvent B). 1H NMR (400 MHz, CDCl3) δ8.80 (s, 2H), 8.32 (t, J=6.5 Hz, 2H), 7.74-7.62 (m, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.35 (t, J=7.9 Hz, 2H), 6.91 (d, J=7.7 Hz, 1H), 6.53 (t, J=5.9 Hz, 1H), 4.93-4.81 (m, 1H), 3.52-3.34 (m, 2H), 3.34-3.14 (m, 2H), 2.46-2.24 (m, 2H), 1.34 (d, J=5.2 Hz, 9H), 1.31 (d, J=5.2 Hz, 9H).
Reaction SMILES: CCO[CH2:4][CH3:5].[C:6]1([CH:12]2[CH2:17][CH2:16]C(=O)[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[C:6]1([CH:12]2[CH2:17][CH2:16][C:4](=[CH2:5])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOCC
Reactant: O=C1CCC(c2ccccc2)CC1
Solvent: ClCCl
Product: C=C1CCC(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
BDAM (3.00 grams) was suspended in 30 milliliters of dry CH2Cl2. Two molar equivalents of ether were added dropwise to the chilled suspension. After about 10 minutes of stirring, a homogeneous solution was formed. At this point, 1 molar equivalent of TMAL (1.1 milliliter) was added. The reaction mixture was stirred at room temperature for 15 minutes and 2.00 grams of 4-phenylcyclohexanone were added. Vigorous reflux which quickly subsided was noticed. The reaction mixture was stirred at room temperature for 3 hours and hydrolyzed as described in Example 1. The aqueous layer was acidified to help separate the organic layer. After the usual work up and column separation, 1.75 grams of 4-phenyl-1-methylenecyclohexane were isolated (88% yield).
Reaction SMILES: [OH-].[Na+].N1CCC[C@H]1C(O)=O.[N-:11]=[N+:12]=[N-:13].[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[C:30](I)=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH:35]=[N:34][CH:33]=[CH:32]3)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CS(C)=O.[Cu]I.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[C:30]([N:11]=[N+:12]=[N-:13])=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH:35]=[N:34][CH:33]=[CH:32]3)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2I)CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2N=[N+]=[N-])CC1
Temperature: 60 °C
Yield: 100.2 %

Procedure:
Under argon atmosphere 40 μL (0.04 mmol) of 1N NaOH, 4.6 mg (0.04 mmol) of L-proline, 3.8 mg of (0.02 mmol) CuI and 15.6 mg (0.24 mmol) of NaN3 were added to a solution of 91 mg (0.2 mmol) of 4-(5-iodo-isoquinoline-6-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (12) in 2 mL of DMSO. The mixture was heated to 60° C. for 18 h. NaN3, NaOH and L-proline were added in the same amounts again and the reaction was heated to 60° C. for 5 h. After cooling to room temperature water was added. The precipitate was filtered, washed with water and dried in vacuo to give 74 mg of compound 17, which was used without any additional purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:9])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=1[F:19]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: COc1ccc(F)c(F)c1C(=O)c1ccc(Cl)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1ccc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 39) and 1-(4-amino-piperidin-1-yl)-ethanone (prepared as described in Manetti et al, Biorg. Med. Chem. Lett., 13 (2003), 2303-2306) using the procedure described in Step B. Example 6. HRMS, observed: 405.1734, Calcd for (M+H)+: 405.1733.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4]Br.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C=O.CCCCCC.C(OCC)C>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[CH3:8]
Reactant: COC(CBr)OC
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(COc1cc([N+](=O)[O-])ccc1C)OC
Temperature: 20 °C

Procedure:
Add bromoacetaldehyde dimethylacetal (30.3 g, 179 mmol) to 2-methyl-5-nitrophenol (25 g, 163 mmol) and potassium carbonate (50 g, 362 mmol) in dimethylformamide (200 mL). Stir and reflux under nitrogen for 2.5 hours. Cool to 20° C. temperature and add aqueous sodium hydroxide (200 mL, 1 M). Dilute the mixture with hexane, diethyl ether (1:1), wash with 0.2 M aqueous sodium hydroxide, aqueous saturated sodium chloride, dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Recrystallize the product from hexane to obtain the desired compound, as tan colored solid 30.6 gm (77%).