Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@H:5]([CH:13]([CH3:15])[CH3:14])[C@:4]([CH2:17][C:18](O)=[O:19])([OH:16])[CH2:3]1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31][CH2:32][CH2:33][NH:34][CH3:35].N1C2C=CC=CC=2N=C1CCCN(C)C(=O)C[C@@]1(O)C([2H])([2H])C([2H])([2H])C2C(=CC=C(F)C=2)[C@@H]1C(C)C>>[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31][CH2:32][CH2:33][N:34]([CH3:35])[C:18](=[O:19])[CH2:17][C@@:4]1([OH:16])[CH2:3][C:2]([F:1])([F:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@@H:5]1[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@]1(O)CC(=O)O
Reactant: CNCCCc1nc2ccccc2[nH]1
Agent: [2H]C1([2H])c2cc(F)ccc2[C@H](C(C)C)[C@@](O)(CC(=O)N(C)CCCc2nc3ccccc3[nH]2)C1([2H])[2H]
Product: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@]1(O)CC(=O)N(C)CCCc1nc2ccccc2[nH]1

Procedure:
Intermediate 17d is prepared from 15c and 16e in a manner analogous to that of Example 2, step 1 for 17b.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].O.[C:15]1(C)[CH:20]=CC=[CH:17][CH:16]=1>>[CH2:20]1[C:2]2([CH2:3][CH2:4][CH2:5][CH2:6][C:1]2=[O:7])[CH2:17][CH2:16][CH2:15]1
Reactant: Cc1ccccc1
Reactant: O=C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCCCC12CCCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cyclohexanone (3.0 mL) was dissolved in toluene (60 mL), and cooled to 0° C. in nitrogen atmosphere. Potassium tert-butoxide (6.86 g) was added to the reaction mixture at 0° C. and stirred for 30 minutes. To the resulting suspension, 1,4-dibromomethane (3.65 mL) was added, and then the reaction mixture was stirred at 150° C. for 6 hours. Cooling the reaction mixture to room temperature, water was added thereto, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation, and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=50/1) to provide 690.0 mg of the title compound as a colorless, oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1ccc(F)cc1F
Agent: N
Product: Fc1ccc(-c2cc(-c3cncc(Cl)c3)no2)c(F)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-ethynyl-2,4-difluorobenzene (Aldrich, 41 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.30-7.43 (m, 1H), 7.61 (ddd, J=11.4, 9.2, 2.8 Hz, 1H), 7.68 (d, J=3.2 Hz, 1H), 8.07 (td, J=8.5, 6.3 Hz, 1H), 8.54 (t, J=2.0 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 9.15 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 293 (M+H)+, 295 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH3:20])=[CH:15][CH:14]=1)([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[NH2:23][OH:24].C(O)C>N1C=CC=CC=1>[F:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:23][OH:24])[CH3:20])=[CH:15][CH:14]=1)([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NO
Reactant: CC(=O)c1ccc(C(F)(F)C(F)(F)c2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccc(C(F)(F)C(F)(F)c2ccccc2)cc1

Procedure:
A solution of 1.1 g. (0.00372 mole) of 4'-(α,α,β,β-tetrafluorophenethyl)-acetophenone, 0.7 g. (0.0071 mole) of hydroxylamine hydrochloride, 8.5 ml. of absolute ethanol, and 1.5 ml. of dry pyridine is heated to refluxing for 6 hours. Solvents are evaporated under reduced pressure and the residual solid is triturated with water. The crystalline product, m.p. 137°-139°C., is collected and recrystallized from hexane to obtain white needles, m.p. 139°-141°C. Recrystallization from hexane affords the analytical sample, m.p. 140°-141°C.
Reaction SMILES: [OH-].[Na+].S([O-])(O)=O.[Na+].[CH3:8][C:9]1[C:10](=[O:20])[C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2>>[CH3:10][C:9]1[CH:18]=[CH:8][C:9]2[C:10](=[O:20])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17](=[O:19])[C:18]=2[CH:8]=1
Reactant: CC1=CC(=O)c2ccccc2C1=O
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Reaction time: 0.5 h

Procedure:
A 0.5N aqueous sodium hydroxide solution was added to the oil phase obtained in Example 14, and, after 30 minutes stirring, air was blown thereinto at 70° C. for 2 hours. Then, the oil phase and the aqueous phase containing the precipitate were separated, and the aqueous phase was dried under reduced pressure to obtain 5.5 kg of 2-methylanthraquinone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:25](OC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:14]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CNc2ccccc2)COC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CN(Cc2ccccc2)c2ccccc2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-phenylaminomethyl-oxazolidine-3-carboxylic acid tert-butyl ester (495 mg; example 2.a) at r.t. in 1,2-dichloroethane (10 ml) under an argon atmosphere were added benzaldehyde dimethyl acetal (0.37 ml), trifluoroacetic acid (0.13 ml) and sodium triacetoxyborohydride (571 mg). The mixture was stirred at room temperature overnight. The mixture was directly adsorbed on silica gel and purified by chromatography (SiO2; gradient:heptane->heptane/EtOAc 7:3) to give (S)-4-[(benzyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (492 mg, 77%) as a colourless viscous oil. MS (ISP): 397.4 ([M+H]+)
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N.Br[C:32]1[CH:33]=[CH:34][N:35]=[C:36]2[C:41]=1[N:40]=[C:39]([O:42][CH3:43])[CH:38]=[CH:37]2>[Cu]I.O1CCOCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:42][CH3:43])[N:40]=3)[N:35]=[CH:34][CH:33]=2)[C:10](=[O:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc2nccc(N3CCN(C(=O)OC(C)(C)C)CC3=O)c2n1
Temperature: 110 °C
Yield: 11.6 %

Procedure:
A glass vial was charged with 1-Boc-3-oxo-piperazine (commercial; 503 mg, 2.5 mmol), CuI (40 mg, 0.21 mmol) and K3PO4 (888 mg, 4.2 mmol), evacuated and backfilled with argon. Trans-1,2-diaminocyclohexane (24 mg, 0.21 mmol), 8-bromo-2-methoxy-[1,5]naphthyridine (500 mg, 2.1 mmol) and dioxane (2 mL) were added under a flow of argon. The tube was sealed and the mixture was heated at 110° C. for 18 h. The resulting suspension was filtered through a pad of SiO2 (EA). The filtrate was concentrated under reduced pressure and the residue was chromatographed over SiO2 (DCM-MeOH—NH4OH 1000-50-4) to afford the title intermediate as a pale yellow oil (87 mg, 12%).
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[CH3:13].[O:14]1CCCC1>>[OH:14][CH2:13][C:7]1[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][N:6]=1
Reactant: Cc1ccnc(C)c1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: Cc1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
n-Butyllithium (24 ml of a 1.6 N solution in hexanes, 38.4 mmol) was added to a stirred solution of 2,4-lutidine (4.28 g, 40 mmol) in tetrahydrofuran (70 ml) at −70° C. under an inert atmosphere. After 1 hour, air was bubbled through (for 1 hour), methanol (50 ml) was added and the reaction allowed to warm to ambient temperature. The reaction mixture was filtered and then evaporated in vacuo. Purification of the crude product by flash chromatography on silica gel, eluting with ethyl acetate, yielded 2-(hydroxymethyl)-4-picoline (700 mg, 14% yield) as a white solid. b) Sodium hydride (150 mg of an 80% dispersion in mineral oil, 5.00 mmol) was added to a stirred solution of 2-(hydroxymethyl)-4-picoline (590 mg, 5.00 mmol) in N-methylpyrrolidine (20 ml) at ambient temperature. 2-Fluoro-5-nitrotoluene (775 mg, 5.00 mmol) was added, the reaction was stirred for 18 hours at ambient temperature and the reaction was poured into water (60 ml). Collection of the yellow solid which precipitated, followed by drying in vacuo, yielded 2-((4-methyl-2-pyridyl)methoxy)-5-nitrotoluene (900 mg, 70% yield) as a yellow solid. c) 5% Platinum on carbon (50 mg) was added to a solution of 2-((4-methyl-2-pyridyl)methoxy)-5-nitrotoluene (750 mg, 2.91 mmol) in ethanol (150 ml) and the solution was stirred for 2 hours at ambient temperature under an atmosphere of hydrogen. Filtration of the reaction mixture, followed by solvent evaporation in vacuo, yielded 3-methyl-4-((4-methyl-2-pyridyl)methoxy)aniline (420 mg, 63% yield) as a yellow gum.
Reaction SMILES: BrC1C=C2C(C([C:13]3[C:14](F)=[C:15](NS(CCC)(=O)=O)[CH:16]=[CH:17][C:18]=3F)=O)=CNC2=NC=1.N1C=C([C:33]([OH:35])=[O:34])C=N1.[F:36][C:37]1[C:42]([C:43]([C:45]2[C:53]3[C:48](=[N:49][CH:50]=[C:51]([C:54]4[CH:55]=[N:56][NH:57][CH:58]=4)[CH:52]=3)[NH:47][CH:46]=2)=[O:44])=[C:41]([F:59])[CH:40]=[CH:39][C:38]=1[NH:60][S:61]([CH2:64][CH2:65][CH3:66])(=[O:63])=[O:62]>>[F:36][C:37]1[C:42]([C:43]([C:45]2[C:53]3[C:48](=[N:49][CH:50]=[C:51]([C:54]4[CH:55]=[N:56][NH:57][CH:58]=4)[CH:52]=3)[NH:47][CH:46]=2)=[O:44])=[C:41]([F:59])[CH:40]=[CH:39][C:38]=1[NH:60][S:61]([CH2:64][CH2:65][CH3:66])(=[O:62])=[O:63].[C:18]1([O:35][C:33]([N:56]2[CH:55]=[C:54]([C:51]3[CH:52]=[C:53]4[C:45]([C:43](=[O:44])[C:42]5[C:41]([F:59])=[CH:40][CH:39]=[C:38]([NH:60][S:61]([CH2:64][CH2:65][CH3:66])(=[O:62])=[O:63])[C:37]=5[F:36])=[CH:46][NH:47][C:48]4=[N:49][CH:50]=3)[CH:58]=[N:57]2)=[O:34])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: O=C(O)c1cn[nH]c1
Agent: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cn[nH]c4)cc23)c1F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnn(C(=O)Oc5ccccc5)c4)cc23)c1F

Procedure:
Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide 23 is prepared according to Scheme 1a, replacing N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fluoro-benzenesulfonamide 21 with propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide and replacing 2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine 22 with 1H-pyrazole-4-carboxylic acid. Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide 23 is further reacted according to Scheme 1b to provide 4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyrazole-1-carboxylic acid phenyl ester P-1016.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[C:31]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:13]1)(=[O:33])[CH3:32]
Reactant: NCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
680 mg of triethylamine was added to a solution of 1.0 g of 1-(3-aminopropyl)-4-(diphenylmethylene)-piperidine (prepared as described in Preparation 15') in 10 ml of methylene chloride at room temperature; a solution of 680 mg of acetyl chloride in 2 ml of methylene chloride was then added dropwise to it at -10° C., after which the mixture was stirred at the same temperature for 5 minutes. Methylene chloride was then added to the mixturem, which was then washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 1.14 g (a quantitative yield) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)=O>C(O)(C)C>[Br:36][C:33]1[CH:34]=[CH:35][C:30]([C:28]2[N:20]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=2)=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccc(Br)cc3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 82.5 °C
Yield: 63.6 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216 mg, 2.59 mmol) in isopropanol (30 mL), 2,4′-dibromoacetophenone (720 mg, 2.58 mmol) was added. After heating the reaction mixture at 80-85° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (810 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 4-(4-bromophenyl)-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (400 mg, 64%) as a pale yellow solid: mp 145-48° C. Anal. Calc'd. for C22H16N2SO2BrCl: C, 54.17, H, 3.31, N, 5.74, S, 6.57. Found: C, 54.41, H, 3.33, N, 5.50, S, 6.52.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([CH3:13])[CH:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>>[CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[C:6]([CH3:13])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C2CC2)ccc1C(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1cc(C2CC2)ccc1C(=O)Cl
Yield: 95.8 %

Procedure:
4-Cyclopropyl-2-methylbenzoic acid (25.01 g, 142 mmol) and phosphorus pentachloride (32.84 g, 158 mmol) were charged into a 100 mL round bottom flask fitted with a stir bar, reflux condenser, and calcium chloride drying tube exhausted through a dilute aqueous solution of NaOH as a gas trap. Refluxed the mixture at a bath temperature of 120° for 2 hr. Removed the POCl3 byproduct by distillation at atmospheric pressure. Vacuum distilled the residue. Collected the fraction distilling at 116-118°/3 torr to obtain 4-cyclopropyl-2-methylbenzoyl chloride as a clear colorless liquid (26.39 g, 136 mmol). 1H NMR (300 MHz, chloroform-d) ppm 0.77-0.86 (m, 2H) 1.06-1.16 (m, 2H) 1.87-1.99 (m, 1H) 2.54 (s, 3H) 6.93-7.03 (m, 2H) 8.14 (d, J=8.29 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:41]=[CH:42][CH:43]=4)[C:35](N(OC)C)=[O:36])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:41]=[CH:42][CH:43]=4)[CH:35]=[O:36])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of 3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin-4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide (0.05 g, 0.078 mmol) in anhydrous tetrahydrofuran (THF) (3.0 mL) at 0° C. was added a solution of lithium aluminum hydride (LAH) (2.0 M in THF) (0.078 mL, 0.15 mmol). The mixture was stirred at 0° C. for 30 minutes, then quenched with methanol (0.5 mL), diluted with dichloromethane (5 mL), washed with a solution of 10% aqueous potassium sodium tartrate (5 mL), water (5 mL), dried over sodium sulfate and concentrated. Product was purified by flash chromatography on silica gel (methanol:dichloromethane:ethylacetate=0.5:7:2) to afford 0.033 g (73%) of the title compound as a pale yellow solid. M.p.=124-126° C.; 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 10.06 (s, 1H), 8.70 (br. s, 1H), 8.14-8.12 (m, 2H), 7.96-7.91 (m, 2H), 7.77-7.74 (m, 2H), 7.70-7.64 (m, 3H), 7.43 (d, J=4.4 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.39 (d, J=5.2 Hz, 1H), 3.93 (bs, 1H), 3.74-3.71 (m, 1H), 3.48-3.45 (m, 1H), 2.49-2.4 (m, 1H), 2.35 (t, J=10.8 Hz, 1H), 1.89-1.82 (m, 2H), 1.60-1.56 (m, 1H), 1.39-1.32 (m, 1H). LCMS: 580 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][CH2:18][C:19]2([C:22]([F:25])([F:24])[F:23])[CH2:21][O:20]2)[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]=2[CH:10]=1.[CH2:26]([NH2:28])[CH3:27]>O1CCCC1>[CH2:26]([NH:28][CH2:21][C:19]([CH2:18][NH:17][C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:20])[C:22]([F:24])([F:23])[F:25])[CH3:27]
Reactant: CCN
Reactant: Cc1cc(NCC2(C(F)(F)F)CO2)c2cnn(-c3ccccc3)c2c1
Solvent: C1CCOC1
Product: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.9 %

Procedure:
To a solution of 6-methyl-1-phenyl-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine (1.1 g, 3.17 mmol) in anhydrous tetrahydrofuran (5 ml) was added ethylamine (2M in tetrahydrofuran) (10 ml, 20 mmol). The reaction was stirred at room temperature for 6 hours and then evaporated in vacuo to give the title compound (1.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:21]=[C:20]([C:22]#[C:23][CH2:24][OH:25])[S:19][C:13]=3[N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][OH:25])[S:19][C:13]=3[N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)=[O:9])=[CH:27][CH:28]=1
Reactant: CC(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCO)sc21
Yield: 45.8 %

Procedure:
A solution of N-(4-chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-isopropyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 27) (0.225 g) in ethanol (50 mL) is hydrogenated over 10% Pd/C (68 mg) at 35 psi for 2 h. The reaction mixture is filtered through a Celite pad, and the filtrate is concentrated in vacuo. The resulting pale yellow solid is recrystallized from ethyl acetate/heptane to yield 0.104 g (46%) of the desired product as an off-white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[N:19]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1.Br[CH2:38][CH2:39][CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl>O.O1CCCC1>[CH2:42]([O:41][CH2:40][CH2:39][CH2:38][C:22]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20][N:19]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:24][CH2:23]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: BrCCCOCc1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)C1(CCCOCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 20 mL of a tetrahydrofuran solution containing 1.2 mL of diisopropylamine, 5.8 mL of 1.6 mol/L butyllithium/hexane was added dropwise at −78° C., and the mixture was stirred at the same temperature for 1 hour. Thereto was added dropwise 2 mL of a tetrahydrofuran solution containing 2.0 g of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate, and the mixture was stirred for 1 hour. Thereto was added 1.7 mL of benzyl 3-bromopropyl ether, and the temperature of the reaction mixture was increased to room temperature, and the reaction mixture was stirred for 10 hours. Water was added thereto, and the reaction mixture was adjusted to pH 2.0 with 6 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1 ] to obtain 2.0 g of a colorless oily substance, 1-tert-butyl 4-ethyl 4-(3-(benzyloxy)propyl)piperidine-1,4-dicarboxylate.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:21])[NH:11][C:12]1([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13]1)[CH3:9])(C)(C)C.Cl>C(Cl)Cl>[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][C:12]1([C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)[CH2:14][CH2:13]1)=[O:21]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ncccn2)CC1
Agent: Cl
Solvent: ClCCl
Product: C[C@H](N)C(=O)NC1(c2ncccn2)CC1
Reaction time: 1.5 h

Procedure:
[(S)-1-(1-Pyrimidin-2-yl-cyclopropylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (54 mg, 0.18 mmol) was dissolved in CH2Cl2 (1 mL). HCl solution (4M in 1,4-dioxane, 1.5 mL, 6.0 mmol) was added via in one portion via syringe and the reaction was allowed to stir for 1.5 h. Solvents were removed in vacuo yielding (S)-2-Amino-N-(1-pyrimidin-2-yl-cyclopropyl)-propionamide as a white powder, m/z 207.41 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:16]([OH:18])=O)[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2].[OH-].[NH4+].CC[N:31]=C=NCCCN(C)C>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:16]([NH2:31])=[O:18])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2]
Reactant: N#Cc1c(N2CCOC(CF)C2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1c(N2CCOC(CF)C2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 55.9 %

Procedure:
A mixture of 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxylic acid (68.0 mg, 0.000164 mol), 33% ammonium hydroxide (33:67, ammonia:water, 0.1416 mL), EDCI (94.2 mg, 0.000491 mol) and 1-HOBT (66.4 mg, 0.000491 mol) in DCM (7 mL, 0.1 mol) was stirred at it overnight. The reaction mixture was diluted with DCM and washed with water, the organic layer was dried and purified by column chloromatography to afford 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxamide (38 mg, 56%). LCMS: (FA) ES+ 414, ES− 412; 1H NMR (400 MHz, d1-chloroform) δ: 7.59 (d, 1H), 7.42 (dd, 1H), 7.31 (d, 1H), 6.00 (s, 1H), 4.50 (dd, 2H), 4.12-4.08 (m, 2H), 4.00-3.78 (m, 4H), 3.36-3.25 (m, 1H), 3.22-3.15 (m, 1H)