Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([NH:23][C:24]([C:26]2([C:29](=[O:38])[NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:28][CH2:27]2)=[O:25])[C:20]([F:39])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11]C(=O)OC(C)(C)C)[CH:6]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:11][C:7]1[CH:6]=[C:5]([O:4][C:3]2[C:2]([F:1])=[CH:22][C:21]([NH:23][C:24]([C:26]3([C:29]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)=[O:38])[CH2:28][CH2:27]3)=[O:25])=[C:20]([F:39])[CH:19]=2)[CH:10]=[CH:9][N:8]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of tert-butyl 4-(2,5-difluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-ylcarbamate (1.8 g, 3.3 mmol) in CH2Cl2 (100 mL) was added TFA (5 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was adjusted to pH>7 with saturated NaHCO3 solution and the separated organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (1.2 g, yield 82% yield). 1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 9.76 (s, 1H), 8.04 (dd, J=12.4, 7.6 Hz, 1H), 7.79 (d, J=6.0 Hz, 1H), 7.58-7.55 (m, 2H), 7.47 (dd, J=10.8, 7.2 Hz, 1H), 7.16 (t, J=8.8 Hz, 2H), 6.16 (dd, J=6.0, 2.4 Hz, 1H), 6.00 (br s, 2H), 5.81 (d, J=2.0 Hz, 1H), 1.65-1.62 (m, 2H), 1.56-1.53 (m, 2H); MS (ESI): m/z 443.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].Br[CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[H-].[Na+]>>[CH2:1]([C:3]1[N:4]([CH2:12][CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C)cc(=O)[nH]1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: [H-]
Agent: [Na+]
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(C=O)cc1
Yield: 41.8 %

Procedure:
The title compound (1.7 g, 42%) was prepared from 2-ethyl-4-methyl-1,6-dihydro-6-pyrimidone (2.0 g, 14.49 mmol), 4-[2-bromoethoxy]benzaldehyde (332 g, 14.19 mmol). LIBr (2.9 g, 33.33 mmol) and NaH (0.45 g, 18.84 mmol) as base, by a similar procedure to that described in preparation 1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:24][CH:21]1[CH2:22][CH2:23][N:19]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:20]1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: OC1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC(O)C3)n2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (160 mg, 0.53 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 3-Pyrrolidinol (Fluka) (55.4 mg; 0.64 mmol; 1.20 eq.) and triethylamine (0.22 ml; 1.59 mmol; 3 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (43) as a white-off powder (40.1 mg; 21.5%). 1H NMR (DMSO-d6, 300 MHz) δ 1.75-2.12 (m, 3H), 2.12 (s, 3H), 2.48 (s, 3H), 3.45-3.70 (m, 2H), 3.90-4.25 (m, 2H), 4.31-4.40 (m, 1H), 7.97 (s, 1H), 12.13 (s, 1H). M− (ESI): 353.07; M+ (ESI): 351.09. HPLC(method A), Rt: 2.21 min (purity: 99.3%).
Reaction SMILES: Cl.O[CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].O.[NH2:15][NH2:16]>CO>[NH2:5][C@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[CH:3]=[N:15][NH2:16]
Reactant: NN
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: CO
Solvent: O
Product: NN=C[C@H](N)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 8 h

Procedure:
A mixture of 2.0 g of glucosamine hydrochloride, 5 ml of methanol and 5 ml of hydrazine hydrate was stirred overnight and then evaporated to dryness giving 2-amino-2-deoxy-D-glucose hydrazone.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].O.[C:12](=[S:15])([S-:14])[NH2:13].[NH4+]>C(O)C>[CH3:9][O:8][C:6]([CH2:5][CH2:4][C:3]1[N:13]=[C:12]([SH:15])[S:14][CH:2]=1)=[O:7]
Reactant: NC(=S)[S-]
Reactant: COC(=O)CCC(=O)CBr
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)CCc1csc(S)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a mixture of methyl 5-bromolevulinate (1.22 g), water (5.2 ml) and ethanol (2.6 ml) was added ammonium dithiocarbamate (642 mg) at room temperature. After stirring at room temperature for 2 hours, the resulting crystal was collected by filtration and washed with a cold mixture of water and ethanol at first and diisopropyl ether (×2) to give 4-(2-methoxycarbonylethyl)-2-mercaptothiazole (0.61 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:35]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCC[CH2:36]1.CC1(C)C(C)(C)OB(C=C)O1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[N:9]1([CH2:8][CH2:7][N:5]2[CH:6]=[C:2]([CH:35]=[CH2:36])[N:3]=[C:4]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCN2CCCC2)CC1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cn(CCN2CCCC2)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 426.3 %

Procedure:
Add tert-butyl 4-(4-bromo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (0.26 g, 0.60 mmol) in 1,4-dioxane (4 mL) and water (1 mL). Add potassium phosphate, tribasic, N-hydrate (0.26 g, 2.0 eq) and dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (0.036 g, 0.15 eq). Add 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.22 mL, 2.05 eq) and degas for 10 minutes. Add bis(dibenzylideneacetone)palladium(0) (0.03 g, 0.06 eq) and reflux at 150° C. for 1 hour. Filter through Celite®. Wash with dichloromethane. Concentrate the filtrate to dryness in vacuo. Purify by silica gel chromatography, eluting with 25% methanol/ethyl acetate, to give the title compound as a yellow foam (0.14 g, 38%). MS (ES) m/z=375 [M]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][CH2:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:21]([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:21][N:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:15][CH2:16]1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)Nc1cccc2c1NCCC2
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Product: CN1CCCc2cccc(NC(=O)OC(C)(C)C)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a stirred solution of 8-(N-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline (0.876 g, 3.52 mmol) in CH2Cl2 (35 mL), at room temperature was added excess methyl iodide (2 mL, 32.12 mmol). The mixture was stirred at room temperature for 48 hours. The mixture was poured into saturated aqueous NaHCO3 (25 mL) and diluted with CH2Cl2 (25 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by flash chromatography (36 g silica gel, 10:1 hexanes-ethyl acetate) provided 0.83 g (90%) of 1-methyl-8-(N-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline as a colorless oil. 1H NMR (CDCl3) δ 1.53 (s, 9H), 1.84–1.92 (m, 2H), 2.62 (s, 3H), 2.79 (t, 2H, J=6.6 Hz), 3.03–3.07 (m, 2H), 6.73 (d, 1H, J=7.8 Hz), 6.95 (dd, 1H, J=7.8, 7.8 Hz), 7.18 (br s, 1H, NH), 7.82 (br d, 1H, J=7.8 Hz).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:40])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)cc3)c(C)c2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)O)cc3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.068 mL, 0.068 mmol) was added to a solution of (4′-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 125-(5); 11.6 mg, 0.023 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (8.1 mg, 71%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:17]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=1.CO.Cl.O1CCOCC1>>[NH2:17][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][Si:13]([CH3:15])([CH3:14])[CH3:16])[CH:6]=1)[CH2:2][OH:1]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(C#C[Si](C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[Si](C)(C)C#Cc1cccc(C[C@H](N)CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
tert-Butyl ((1S)-2-hydroxy-1-{3-[(trimethylsilyl)ethynyl]benzyl}ethyl)carbamate (0.84 g, 2.4 mmol), methanol (2.0 mL, 49 mmol), and 4.0 M hydrogen chloride in dioxane (5.0 mL, 20 mmol) were mixed together and stirred at room temperature for 1 h. The solvent was removed under vacuum to give 0.61 g (98% yield) of the desired product. LC-MS found: 248.0 (m+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C[Al](C)C.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[C:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][O:26][C:27]=2[CH3:28])[CH:16]=1.S([O-])([O-])(=O)=O.[Mg+2]>O1CCOCC1.O>[CH3:28][C:27]1[O:26][N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]=1[C:22]#[C:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][N:18]=1)[C:14]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1)=[O:13]
Reactant: Cc1csc(N)n1
Reactant: COC(=O)c1ccnc(C#Cc2c(-c3ccccc3)noc2C)c1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: C1COCCO1
Product: Cc1csc(NC(=O)c2ccnc(C#Cc3c(-c4ccccc4)noc3C)c2)n1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
To a solution of 2-amino-4-methylthiazole (57 mg, 0.50 mmol) in dioxane (1.2 mL) was added trimethylaluminium (2 M in heptane, 251 μl, 0.50 mmol). The resulting red-brown solution was stirred for 1 h at ambient temperature before 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-isonicotinic acid methyl ester (40 mg, 0.13 mmol) was added. The reaction mixture was heated for 2.25 h at 110° C. before cooling to ambient temperature. Water (29 μL) was added and the mixture was stirred for 10 min at ambient temperature. Magnesium sulfate was added and the mixture was filtered over Hyflo®. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 0:100) was followed by separation between hydrochloric acid (1 M, 30 mL) and ethyl acetate (100 mL). The organic layers were washed with brine, dried over sodium sulfate and were concentrated affording the title compound (48 mg, 96%) as an off-white solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: BrC1SC(S(C)(=O)=O)=CC=1.[F-].[Cs+].C1(C=C(B2OC(C)(C)C(C)(C)O2)CO)CCCCC1.[CH:32]1(/[CH:38]=[C:39](\[C:42]2[S:43][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[CH:45][CH:46]=2)/[CH:40]=[O:41])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[BH4-].[Na+]>O1CCOCC1.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH:32]1(/[CH:38]=[C:39](\[C:42]2[S:43][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[CH:45][CH:46]=2)/[CH2:40][OH:41])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CS(=O)(=O)c1ccc(/C(C=O)=C\C2CCCCC2)s1
Agent: [Pd]
Agent: CC1(C)OB(C(=CC2CCCCC2)CO)OC1(C)C
Agent: CS(=O)(=O)c1ccc(Br)s1
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)CO)s1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Add 2-bromo-5-methanesulfonyl-thiophene (2.26 g, 9.39 mmol), caesium fluoride ( 2.85 g, 18.78 mmol) and tetrakis-(triphenylphosphin)-palladium(0) (543 mg, 0.47 mmol) to a solution of 3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (2.5 g, 9.39 mmol) in dioxane (50 mL). Stir at 80° C. for 24 h, monitor completion of the reaction by LCMS. Treat the reaction mixture with water and extract with dichloromethane. Dry organic layers over sodium sulfate and remove solvents under vacuum to obtain 4.85 g crude product. Purify by siliga gel chromatography, eluting with gradient from 10:0 to 7:3 hexane:ethyl acetate. 690 mg isolated product was (Z)-3-cyclohexyl-2-(5-methanesulfonyl-thiophen-2-yl)-propenal. MS (m/e): 299.0 (M+H). Add a solution of (Z)-3-cyclohexyl-2-(5-methanesulfonyl-thiophen-2-yl)-propenal (690 mg, 2.31 mmol) in methanol (2 mL) to a suspension of NaBH4 in methanol (3 mL) at 0° C. and stir for 1 h, monitor completion of the reaction by LCMS. Dilute reaction mixture with water, extract with ethyl acetate, wash combined organic layers with water and saturated sodium chloride, dry over sodium sulfate and remove solvent under vacuum to obtain 704 mg crude product. MS (m/e): 301.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH2:15]O)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:23])CC)C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH2:15][F:23])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1COCC(CO)(c2cccc(Br)n2)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(CF)(c2cccc(Br)n2)N1
Reaction time: 4 h

Procedure:
To a solution of 5-(6-bromo-pyridin-2-yl)-5-hydroxymethyl-morpholin-3-one (2.8 g, 9.756 mmol) in dry THF (30 ml), diethylamino sulfur trifluoride (4.72 g, 29.268 mmol) was added at rt and stirring continued for 4 h. Na2CO3 was then added to the resultant reaction mixture and stirred for further 30 min. The reaction mixture was concentrated under reduced pressure and the product was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhy. Na2SO4 and concentrated under reduced pressure to obtain crude compound as gummy residue. Purification of the crude product with 45% ethyl acetate in hexane solvent system furnished the title compound as off-white solid. Yield=1.15 g (40%). TLC (70% ethyl acetate in hexane) Rf=0.49; LCMS: RtH7=0.383, [M+1]+=289 and 289; HPLC RtH9=3.27 min (84%); 1H NMR (400 MHz, CDCl3): δ 7.62 (t, 1H), 7.49 (dd, 1H), 7.32 (d, 1H), 7.09 (br. s, 1H), 4.92 (dd, 1H), 4.52 (dd, 1H), 4.32-4.17 (m, 3H), 3.98-3.93 (dd, 1H); 19F NMR (376.2 MHz): 6-255.65 (t, 1F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I:15]Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CC(O)=O>[I:15][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: COc1ccc(NC(C)=O)cc1OC
Reactant: ClI
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(I)c(NC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of N-(3,4-dimethoxyphenyl)acetamide (6.3 g, 32.0 mmol) in DCM (100 mL) and AcOH (6.5 mL) was added a solution of iodine monochloride (6.3 g, 39 mmol) in DCM (50 mL) dropwise. The reaction mixture was stirred at r.t. for 16 h. Aqueous sat. Na2S2O3 (500 mL) was added. The organic fraction was separated, washed with water (2×250 mL), then brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 50% EtOAc/hexanes) gave the title compound (7.5 g, 72%) as a dark solid. LCMS (ES+) 321.8 (M+H)+, RT 2.67 minutes (Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([C:26]#[N:27])=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH:34]1([CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:41]5[CH2:42][CH2:43][N:38]([CH2:37][CH:34]6[CH2:36][CH2:35]6)[CH2:39][CH2:40]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([C:26]#[N:27])=[N:8]2)=[C:4]([C:30]([F:32])([F:31])[F:33])[CH:3]=1
Reactant: C1CN(CC2CC2)CCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C#N)nn3Cc2ccc(Cl)cc2C(F)(F)F)S1
Product: N#Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=C3SC(N4CCN(CC5CC5)CC4)=NC3=O)cc12

Procedure:
1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-({2-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxo-1,3-thiazol-5(4H)-ylidene}methyl)-1H-indazole-3-carbonitrile was prepared from 1-(4-Chloro-2-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrile and 1-Cyclopropylmethyl-piperazine following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([CH3:12])[CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[CH3:15][NH:16][C:17]([C:19]1[S:20][CH:21]=[C:22]([CH3:33])[C:23]=1[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27](Cl)[N:26]=1)=[O:18].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C>[CH3:15][NH:16][C:17]([C:19]1[S:20][CH:21]=[C:22]([CH3:33])[C:23]=1[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][N:10]([CH3:12])[CH2:9][C:8](=[O:13])[NH:7][C:6]=3[CH:14]=2)[N:26]=1)=[O:18]
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: CN1CC(=O)Nc2cc(N)ccc2C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1scc(C)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CN(C)C3)ncc1Cl
Yield: 3.4 %

Procedure:
A mixture of 8-amino-4-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (25 mg, 0.13 mmol), 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide (49.6 mg, 0.16 mmol), and camphorsulfonic acid (33 mg, 0.13 mmol) were heated in IPA (3 mL) at 120° C. for 16 hours. Concentration and chromatography on preparative TLC with methylene chloride and methanol (100:8) gave 2.1 mg of 3-[5-chloro-2-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide (3.4%): 1H NMR (300 MHz, CD3OD) δ 8.1 (d, 1H), 7.98 (s, 1H), 7.7 (m, 1H), 7.35 (m, 2H), 7.15 (s, 1H), 3.65 (s, 1H), 3.61 (s, 1H), 3.2 (s, 2H), 2.85 (s, 3H), 2.52 (s, 3H), 2.1 (s, 3H); MS (m/e): 472.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14](Br)=[CH:13][N:12]=2)[CH2:7]1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(N(CC)CC)C>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:13][N:12]=2)[CH2:7]1
Reactant: Clc1ccc(CN[C@H]2CCN(c3ncc(Br)cn3)C2)c(Cl)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
In a sealed vessel, heat a mixture of (S)-(2,4-dichlorobenzyl)-[1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-yl]-amine (404 mg, 1.01 mmol), (trimethylsilyl)acetylene (250 μL, 1.76 mmol), dichlorobis(triphenylphosphine)palladium (II) (71.4 mg, 0.10 mmol), copper(I) iodide (20.7 mg, 0.11 mmol) and triethylamine (3 mL) at 100° C. for 4 hours. Cool to room temperature and dilute with water (30 mL). Filter through a pad of Celite®, washing with ethyl acetate. Extract the aqueous with additional ethyl acetate (3×50 mL) and wash the combined organics with saturated aqueous sodium chloride (50 mL). Concentrate and dissolve the residue in dichloromethane, filter, and concentrate to give a residue. Chromatograph the residue on silica gel to give (S)-(2,4-dichlorobenzyl)-[1-(5-trimethylsilanylethynylpyrimidin-2-yl)-pyrrolidin-3-yl]-amine as a yellow oil (337 mg, 80%).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:13](OCC)=O)=[C:7]([CH3:12])[C:8]=1[CH2:9][CH2:10][CH3:11])[CH2:2][CH3:3].C=O>>[CH2:1]([C:4]1[NH:5][C:6]([CH3:13])=[C:7]([CH3:12])[C:8]=1[CH2:9][CH2:10][CH3:11])[CH2:2][CH3:3]
Reactant: CCCc1[nH]c(C(=O)OCC)c(C)c1CCC
Agent: C=O
Product: CCCc1[nH]c(C)c(C)c1CCC

Procedure:
2,3-di-(n-propyl)-4-methyl-5-carbethoxy-pyrrole was reductively alkylated with paraformaldehyde to yield 2,3-di-(n-propyl)-4,5-dimethyl-pyrrole. ##STR96##
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[F:23][CH2:24][CH:25]([O:28][CH2:29][C:30](Cl)=[O:31])[CH2:26][F:27].C(O)(=O)C>C1(C)C=CC=CC=1.O>[F:23][CH2:24][CH:25]([O:28][CH2:29][C:30]([CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]1)=[O:31])[CH2:26][F:27]
Reactant: O=C(Cl)COC(CF)CF
Reactant: O=C1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1CCOCC1C(=O)COC(CF)CF
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
At 0° C., the toluene (5 mL) solution of tetrahydro-4H-pyran-4-one (0.344 mL, 3.72 mmol) was treated with LiHMDS, 1M solution in THF (3.97 mL, 3.97 mmol) under N2 atmosphere. After 2 minutes 2-(1,3-difluoropropan-2-yloxy)acetyl chloride (428 mg, 2.48 mmol) in toluene (1 mL) was added. After 5 minutes, acetic acid (0.270 mL, 4.71 mmol) and 10 ml water were added. The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The solvent was removed in vacuo and the residual oil was purified by silica flash chromatography (EtOAc/Heptane gradient) to afford the title product (0.095 g, 16% yield).