Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2=[O:15])#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:14][C:8]1([CH3:13])[CH2:7][C:6](=[O:15])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:4]=2)[S:9]1
Reactant: C#Cc1ccc2c(c1)C(=O)CC(C)(C)S2
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CC(C)(C)S3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A solution of 6-ethynyl-2,2-dimethylthiochroman-4-one (82.0 mg, 0.38 mmol) and ethyl 4-iodobenzoate (104.9 mg, 0.38 mmol) in 5.0 mL Et3N was purged with argon for 10 minutes. To this solution were added bis(triphenylphosphine)-palladium (II) chloride (88.0 mg, 0.12 mmol) and copper (I) iodide (22.9 mg, 0.12 mmol). After purging for an additional 5 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was filtered through a pad of Celite using an Et2O wash. Concentration of the filtrate under reduced pressure, followed by column chromatography of the residual solid, afforded 100 mg (72%) of ethyl 4-[(2,2-dimethyl-4-oxo-thiochroman-6-yl)ethynyl]-benzoate as a yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.25 (1H, d, J=1.8 Hz), 8.00 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.53 (1H, dd, J=1.8, 8.2 Hz), 7.21 (1H, d, J=8.2 Hz), 4.37 (2H, q, J=7.1 Hz), 2.88 (2H, s), 1.47 (6H, s), 1.39 (3H, t, J=7.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O.C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([Cl:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1Cl
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Clc1cc(Br)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
4-Bromo-2-chlorobenzaldehyde (1 g, 4.56 mmol), morpholine (0.457 mL, 5.24 mmol), acetic acid (0.300 mL, 5.24 mmol) and sodium triacetoxyborohydride (1.45 g, 6.84 mmol) were mixed with THF (4 mL) in a sealed microwave vial. The mixture was stirred at r.t. for 2 hrs. The mixture was diluted with EtOAc, washed with H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude was purified on BIOTAGE® with 0-20% of EtOAc in hexane. The fractions containing the desired product was collected and concentrated to give 1.01 g titled product. MS (ESI) m/z 289.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1.O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cn2cncc2s1
Temperature: 105 °C
Reaction time: 24 h
Yield: 90.8 %

Procedure:
2-Bromoimidazo[5,1-b]thiazole-7-carboxylic acid (34.8 g, 141 mmol) was suspended in a mixed solvent composed of water (320 ml) and acetic acid (480 ml). Concentrated sulfuric acid (29.5 g, 301 mmol) was added to the suspension at room temperature, and the mixture was stirred at 105° C. for about 24 hr. After the completion of the reaction, sodium carbonate (35.1 g, 331 mmol) was added to the reaction solution, and the mixture was concentrated by removal of the solvent by distillation under the reduced pressure. Water (320 ml) was added to the concentrate, and the solvent was removed by distillation under the reduced pressure. Thereafter, water (200 ml) and ethyl acetate (400 ml) were again added to the residue, and the mixture was adjusted to pH 7 by the addition of a 25 wt % aqueous solution of sodium hydroxide with stirring. The insolubles were removed by filtration, followed by separation. The aqueous layer was extracted with ethyl acetate twice (200 ml, 100 ml). The organic layers were combined and were washed with 15 wt % brine (100 ml). After washing, while concentrating the washed organic layers, the solvent was replaced with hexane to crystallize 2-bromoimidazo[5,1-b]thiazole. The crystallizing liquid was cooled to 5° C. or below and was stirred overnight, and the crystals were collected by filtration. The crystals were washed with hexane (80 ml) and were dried under the reduced pressure to give 2-bromoimidazo[5,1-b]thiazole (26.0 g, yield 90.8%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][NH:23][CH3:24]>O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([N:23]([CH3:24])[CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: CNCCN(C)C
Solvent: C1COCCO1
Product: CN(C)CCN(C)c1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
0.118 g (0.0003 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 5 ml of dioxane and treated with 0.39 ml of N,N,N'-trimethylethylenediamine. The mixture was stirred at room temperature for 20 hrs., the solvent was removed and the residue was chromatographed on silica gel with 5% methanol in dichloromethane. There was obtained 0.123 g (99%) of N-[4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-yl]-N,N',N'-trimethylethane-1,2-diamine as a light yellow, amorphous solid. MS (ISP): me/e=415, 413 (C16H21BrN4O2S+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:4]=1.[CH3:19][O:20][C:21](=[O:28])[C@H:22]([CH2:24][CH2:25][S:26][CH3:27])[NH2:23].Cl.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:19][O:20][C:21](=[O:28])[C@H:22]([CH2:24][CH2:25][S:26][CH3:27])[NH:23][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][OH:1])=[CH:4][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: Cc1ccccc1-c1cc(CO)ccc1C(=O)O
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxymethyl-2-(2-methylphenyl)benzoic acid (69 g, 285 mmol), prepared as in example 1075E, L-methionine methyl ester.HCl (68.3 g, 342 mmol), 1-hydroxybenzotriazole (46.2 g, 342 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (65.6 g, 342 mmol) were dissolved at ambient temperature in DMF (700 mL). To this solution was added triethylamine (47.7 mL, 342 mmol) and the resulting thick slurry was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (700 mL) and washed with water (2×1L), saturated NaHCO3 (2×500 mL), 1N H3PO4 (2×500 mL), and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo to produce a pale yellow solid (110 g, 100% crude yield). 1H(300 MHz, CDCl3) δ 7.93 (1H, m), 7.44 (1H, dd, J=8, 2 Hz), 7.40-7.20 (4H, m), 7.19 (1H, bs), 5.92 (1H, m), 4.78 (2H, s), 4.63 (1H, m), 3.66 (3H, s), 2.20-2.00 (8H, m), 1.87 (1H, m), 1.75 (1H, m), 1.60 (1H, m). m/e (ESI) 386 (MH−).
Reaction SMILES: [Cl:1][C:2](Cl)([C:11]#[N:12])[CH2:3][S:4][C:5]([Cl:10])=[C:6]([Cl:9])[C:7]#[N:8].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]([C:11]#[N:12])=[CH:3][S:4][C:5]([Cl:10])=[C:6]([Cl:9])[C:7]#[N:8]
Reactant: N#CC(Cl)=C(Cl)SCC(Cl)(Cl)C#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC(Cl)=CSC(Cl)=C(Cl)C#N
Yield: 57.4 %

Procedure:
133 g of 1,2-dichloro-2-cyano-vinyl 2,2-dichloro-2-cyano-ethyl sulphide were dissolved in 350 ml of tetrahydrofuran, and 53.6 g of triethylamine were added dropwise at 5° to 10° C. The triethylamine hydrochloride which had precipitated out was filtered off with suction, the filtrate was concentrated and the residue was distilled (boiling point 120° to 145° C./2.5 mbar). 66.3 g of 1,2-dichloro-2-cyano-vinyl 2-chloro-2-cyano-vinyl sulphide were obtained as an oil, 1H-NMR: δ=7.1-7.4. A pure stereoisomer of melting point 58° to 60° C. crystallized out, 1H-NMR: δ=7.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21].[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:12][C:7]1[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:5](=[O:21])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=c1c2cc(Br)ccc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2ccc(Br)cc2c(=O)n1-c1ccccc1Cl
Yield: 41.4 %

Procedure:
Prepared according to Procedure C using Intermediate 2b (100 mg, 0.260 mmol), adenine (39 mg, 0.286 mmol), K2CO3 (40 mg, 0.286 mmol), and DMF (2 mL). The crude product was recrystallized from EtOH to provide 52 mg of an off-white solid (41%), mp 284.2-284.7° C. (decomposes). 1H NMR (DMSO-d6) δ: 8.24 (d, J=2.0 Hz, 1H); 8.05 (s, 1H); 8.03 (s, 1H); 7.98 (dd, J=1.9, 8.6 Hz, 1H); 7.74-7.83 (m, 2H); 7.59-7.68 (m, 2H); 7.46 (d, J=8.7 Hz, 1H); 7.22 (s, 2H); 5.12 (d, J=17 Hz, 1H); 4.94 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 159.5, 156.2, 152.9, 152.0, 150.1, 145.8, 141.8, 138.4, 133.1, 132.2, 131.9, 131.1, 130.9, 130.1, 129.4, 128.9, 122.4, 120.4, 118.4, 45.0. MS (ES): m/z 482.0 (M+). Anal. calcd. for C20H13ClBrN7O.0.1KCl: C, 49.01; H, 2.67; Cl, 7.96; N, 20.00. Found: C, 48.82; H, 2.82; Cl, 8.00; N, 19.79.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7]C(=O)[C:5]2=[O:15].[OH:16]O.Cl>[OH-].[Na+]>[NH2:7][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[C:5]([OH:15])=[O:16]
Reactant: OO
Reactant: O=C1Nc2c(cc(Cl)cc2[N+](=O)[O-])C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.17 %

Procedure:
To a slurry of 5-chloro-7-nitro-1H-indole-2,3-dione (3.2 g, 14.15 mmol) in aqueous 5N NaOH solution (30 mL) added an aq. solution of 33% hydrogen peroxide solution (3 mL) slowly at 0° C. After the addition, the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was acidified with an aq. solution of 2N HCl and the resulting precipitated was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (2 g, 70.17%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:8][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)Oc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 21 h
Yield: 97 %

Procedure:
A dry 5 1, 3-neck flask with mechanical stirrer, connected to a mineral oil bubbler, was charged with m-bromophenol (A) (150 g, 870 mmol), dry tetrahydrofuran (THF, 2 l) and triethylamine (132.1 g, 1.3 mol). The contents of the flask were cooled to 0° C., and chlorotrimethylsilane was added dropwise. A voluminous white precipitate was formed. The reaction was allowed to equilibrate to room temperature over a period of 21 h. The mixture was then filtered to remove triethylamine hydrochloride. Removal of solvents precipitated some remaining hydrochloride salt. The mixture was further purified by repeatedly adding hexane followed by filtration to yield 3-bromo-O-trimethylsilylphenol (B) (207 g, 97% yield).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[C:50]([Cl:52])[C:49]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])=[CH:55][CH:54]=3)=[C:48]([NH:76][C:77](=O)[C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[C:47]=2[Cl:85])=[CH:42][CH:41]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>ClC1C=CC=CC=1>[CH2:23]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[C:50]([Cl:52])[C:49]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])=[CH:55][CH:54]=3)=[C:48]([NH:76][C:77](=[S:10])[C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[C:47]=2[Cl:85])=[CH:42][CH:41]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCCCCCCCCCCCCOc1ccc(-c2cc(Cl)c(-c3ccc(OCCCCCCCCCCCCCCCC)cc3)c(NC(=O)c3ccccc3)c2Cl)cc1
Solvent: Clc1ccccc1
Product: CCCCCCCCCCCCCCCCOc1ccc(-c2cc(Cl)c(-c3ccc(OCCCCCCCCCCCCCCCC)cc3)c(NC(=S)c3ccccc3)c2Cl)cc1

Procedure:
Next, a Lawesson's reagent (2.2 g, 5.5 mmol) and chlorobenzene (20 ml) were added to 1,4-bis(4-hexadecyloxyphenyl)benzoylamino-2,5-dichloro-benzene 3 (4.0 g, 4.6 mmol) prepared above, and the mixture was heated under reflux for about 4 hr. After the completion of the reaction, the precipitated yellow powder was collected by filtration, was washed with ethanol, and was dried. Thereafter, the yellow powder thus obtained was recrystallized from DMF to give 1,4-bis(4-hexadecyloxyphenyl)thiobenzoylamino-2,5-dichloro-benzene 4 as the target compound (yield 90.2%).
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)[CH3:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.P.[F-].[K+]>C1COCC1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:22][C:21]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH2:6][O:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)[CH3:10])[CH:19]=[CH:20][C:2]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(=NOCc1ccc(Cl)c(C(F)(F)F)c1)c1ccc(CO)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=NOCc1ccc(-c2ccccc2)c(C(F)(F)F)c1)c1ccc(CO)cc1
Temperature: 100 °C

Procedure:
A mixture of 1-(4-hydroxymethyl-phenyl)-ethanone O-(4-chloro-3-trifluoromethyl-benzyl)-oxime (1 eq), phenyl boronic acid (1.5 eq), Pd(OAc)2 (0.03 eq), phosphine ligand (0.06 eq) and KF (3 eq) in dry THF is heated at 100° C. in microwave for 30 minutes. The resulting mixture is diluted with EtOAc and washed with brine. The organic layer is dried over Na2SO4. After concentration, the residue is purified by column chromatography (30% EtOAc in hexane) to give 1-(4-hydroxymethyl-phenyl)-ethanone O-(2-trifluoromethyl-biphenyl-4-ylmethyl)-oxime as a white solid [MS: (ES+) 400.1 (M+1)+].
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Br[C:25]1[C:30]([F:31])=[CH:29][C:28]([Cl:32])=[CH:27][N:26]=1>>[Cl:32][C:28]1[CH:29]=[C:30]([F:31])[C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])=[N:26][CH:27]=1
Reactant: Fc1cc(Cl)cnc1Br
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cc2F)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-bromo-3-fluoro-5-chloropyridine. ESI-MS (m/z): 444 [M+1]+.
Reaction SMILES: [ClH:1].[C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([N:12]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:15][CH:14]([NH:28]C(=O)OC(C)(C)C)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)#[N:3]>O1CCOCC1>[ClH:1].[NH2:28][CH:14]1[CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=2)[CH2:17][N:12]([C:10]([N:7]2[CH2:6][CH2:5][CH:4]([C:2]#[N:3])[CH2:9][CH2:8]2)=[O:11])[CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(C#N)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1CCN(C(=O)N2CC(N)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
78 ml of a 4N solution of hydrochloric acid in dioxane were added to 8.30 g (15.7 mmol) of the carbamate from Example 68A having a purity of 91%, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure and the residue was taken up in 1 N hydrochloric acid. After washing with diethyl ether, the organic phase was concentrated under reduced pressure and the residue was taken up in dichloromethane and extracted repeatedly with 1N hydrochloric acid. The combined aqueous phases were concentrated under reduced pressure, and the residue was dried under high vacuum. Yield: 4.93 g (71% of theory)
Reaction SMILES: COC1C2N=C(N)SC=2C(C2CCOCC2)=CC=1.O1CCC[C@@H]1C(O)=O.[CH3:27][O:28][C:29]1[C:34]2[N:35]=[C:36]([NH:38][C:39](=[O:47])[CH2:40][CH:41]3[CH2:46][CH2:45][O:44]CC3)[S:37][C:33]=2[C:32]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:31][CH:30]=1>>[CH3:27][O:28][C:29]1[C:34]2[N:35]=[C:36]([NH:38][C:39]([C@H:40]3[CH2:41][CH2:46][CH2:45][O:44]3)=[O:47])[S:37][C:33]=2[C:32]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)CC3CCOCC3)nc12
Agent: COc1ccc(C2CCOCC2)c2sc(N)nc12
Agent: O=C(O)[C@H]1CCCO1
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)[C@H]3CCCO3)nc12

Procedure:
Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine and (R)-tetrahydro-furan-2-carboxylic acid, the title compound was prepared in the same manner as described for N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-(tetrahydro-pyran-4-yl)-acetamide and obtained as off-white solid (62% yield). Mp 158-161° C., MS: m/e=363(M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([F:20])[CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>CCO.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.CN(C=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([CH3:11])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: Cc1cc(Br)cc(C(=O)O)c1C
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)O)c1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a solution of 5-bromo-2,3-dimethylbenzoic acid (500 mg, 2.18 mmol, 1.0 eq), (3,5-difluorophenyl)boronic acid (414 mg, 2.62 mmol, 1.2 eq) and Na2CO3 (925 mg, 8.73 mmol, 4.0 eq) in a mixture of EtOH (5 mL), DMF (20 mL) and water (5 mL) was added Pd(PPh3)4 (252 mg, 0.22 mmol, 0.1 eq) under nitrogen. The mixture was stirred at 100° C. overnight. Water was added and the mixture acidified to pH 3 by addition of 3M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (CH2Cl2:MeOH, 300:1 to 200:1) to give the title compound as a white solid (184 mg, 32%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[C:25]([CH3:26])=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)C(=O)OC(C)(C)C>O1CCOCC1>[ClH:1].[CH3:2][NH:3][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[C:25]([CH3:26])=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N(C)C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: C1COCCO1
Product: CNC1CCN(c2ncnc3[nH]cc(C)c23)CC1
Reaction time: 2 h

Procedure:
4M HCl in 1,4-Dioxane (6 mL) was added to 1,1-dimethylethyl methyl[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]carbamate D22 (0.793 g) and the mixture stirred for 2 hours. The mixture was filtered under vacuum. The solid was washed with dioxane and Et2O. The white powder was dried under vacuum all the night to give the desired product D23 in 0.6479 g. LCMS [M+H]+246.16@1.58 min (5 min run)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:16])[C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([O:20]CC)=[O:19])=[CH:4]1)[CH3:2].Cl>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:16])[C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(F)c(F)c21
Yield: 93.3 %

Procedure:
Employing ethyl 1-ethyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-caboxylate (6.51 g) and conc. hydrochloric acid : 90% acetic acid (1:4) (100 ml), the procedure of Reference Example 23 is repeated to give 1-ethyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4 -oxoquinoline-3-carboxylic acid (5.53 g), as colorless needles (recrystallized from dichloromethane--n-hexane), m.p. 203°-204° C.
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.[CH3:10][O:11][CH:12]([O:20][CH3:21])[CH2:13][NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18].Cl[CH2:23][C:24]([CH2:26][F:27])=[CH2:25]>O>[F:27][CH2:26][C:24](=[CH2:23])[CH2:25][N:14]([CH2:13][CH:12]([O:11][CH3:10])[O:20][CH3:21])[C:15](=[O:19])[O:16][CH2:17][CH3:18]
Reactant: C=C(CF)CCl
Reactant: CCOC(=O)NCC(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(CF)CN(CC(OC)OC)C(=O)OCC
Temperature: 90 °C
Reaction time: 1 h

Procedure:
8 g (0.26 mol) of sodium hydride (80% pure) are initially introduced into 200 ml of toluene and 35.8 g (0.2 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate are added dropwise at 90° C. The mixture is then stirred for one hour at 90° C. and 32.6 g (0.3 mol) of 1-chloro-2-fluoromethylprop-2-ene are then added dropwise. The mixture is stirred overnight at 90° C., salts are dissolved in water, and the aqueous phase is separated off and extracted with toluene. The organic phases are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:17]CN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([O:13][CH3:17])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a cooled (0° C.) solution of 3-(tert-butoxycarbonyl(methyl)amino)propanoic acid (1.095 g, max. 5.29 mmol) in extra dry MeOH (0.24 mL, 5.93 mmol) and DCM (5 mL) was added DMAP (0.066 g, 0.539 mmol). EDCI (1.239 g, 6.47 mmol) was added and the reaction mixture allowed to warm up to room temperature. The reaction mixture was washed with aqueous 0.5 N HCl (3×10 mL), and brine (25 mL). The organic phase was dried over Na2SO4, filtered, and evaporated in vacuo to afford the desired product (1.129 g, 98% over two steps) as a colourless oil.