Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH2:24]([O:26][C:27]([CH:29]1[C:33](=[O:34])[CH2:32][N:31]([C:35](=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:30]1)=[O:28])[CH3:25]>O>[CH2:24]([O:26][C:27]([CH:29]1[CH:33]([OH:34])[CH2:32][N:31]([C:35](=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[CH2:30]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1CN(C(=O)CCCCCNC(=O)OCc2ccccc2)CC1=O
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: CCOC(=O)C1CN(C(=O)CCCCCNC(=O)OCc2ccccc2)CC1O
Temperature: 32 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
To a solution of sucrose (3 g) in distilled water (40 mL) was added Baker's yeast (2 g). The suspension was heated at 32° C. for 1 h. The content of the flask was then poured into a flask containing ketoester 60 (4 g, 9.88 mmol, dissolved in 4 mL of methanol). Stirring was continued at 32° C. for 24 h after which additional sucrose (3 g) in warm (40° C.) distilled water was added. After 48 h, the suspension was filtered through a pad of Celite. The pad was washed with water and the aqueous layer was extracted with ethyl acetate (3×250 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography (30% EtOAc/Hexane) to afford alcohol 62 (1.7 g, 42%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[CH:16][C:15]([NH2:28])=[N:14]2)=[CH:9][CH:8]=1.N1C=CC=CC=1>C(#N)C.O1CCCC1.C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[CH:16][C:15]([NH:28][C:2](=[O:3])[O:4][CH3:5])=[N:14]2)=[CH:11][CH:12]=1
Reactant: COC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(N)nn2-c2ccc(F)cc2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)Nc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Methyl chloroformate (0.163 ml) in acetonitrile (0.7 ml) was added dropwise to a stirred solution of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-amine (0.7 g) and pyridine (0.171 ml) in acetonitrile (6 ml) and tetrahydrofuran (7 ml) at -20° C. The mixture was stirred at 5° C. for 1 hour, diluted with ethyl acetate, washed with water, dried, and concentrated. The residue (0.9 g) was recrystallized from a mixture of chloroform and ethanol to give pale brown crystals of methyl N-{1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-pyrazolyl}carbamate (0.51 g).
Reaction SMILES: O[CH:2]([CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10].CCN(S(F)(F)[F:25])CC.CO>O1CCOCC1>[F:25][CH:2]([CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1nccn1CC(O)CN1CCCCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: O=[N+]([O-])c1nccn1CC(F)CN1CCCCC1

Procedure:
To a solution of 2.2 g (8.65 mmol) of 1-(2'-hydroxy-3'-piperidylpropyl)-2-nitroimidazole in 20 ml of dry dioxane, 2.5 g (15.5 mmol) of DAST was dropwise added with cooling by ice and reacted for 5 hours at room temperature. After reaction, to the solution, 10 ml of methanol was added to decompose excess DAST. Then, the solution was concentrated and partitioned between chloroform and water. The pH of the aqueous phase was adjusted to 12 by the addition of an aqueous solution of sodium hydroxide and the liquid was again partitioned between chloroform and water. The chloroform phase was dried on magnesium sulfate and filtered. The filtrate was concentrated and subjected to isolation and purification by silica gel chromatography to give 1-(2'-fluoro-3'-piperidylpropyl)-2-nitroimidazole, which was treated with hydrochloric acid to form a hydrochloride and crystallized from ethanol to give 560 mg of crystalline hydrochloride of 1-(2'-fluoro-3'-piperidylpropyl)-2-nitroimidazole.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12]C(C)C)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:3]=1.B(Cl)(Cl)Cl>>[Cl:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:3]=1
Reactant: CC(C)Oc1c(Cl)cc(-c2cccnc2)c2cccnc12
Agent: ClB(Cl)Cl
Product: Oc1c(Cl)cc(-c2cccnc2)c2cccnc12
Yield: 94.6 %

Procedure:
Cleavage of the isopropyl ether 22 (20 mg, 0.07 mmol) with boron trichloride following the method outlined in Example 8, gave 7-chloro-5-(pyridin-3-yl)-quinolin-8-ol (PBT 1057) as a pale straw-coloured solid (17 mg, 94%). 1H NMR (CD3OD, 400 MHz): δ 9.16 (m, 2H), 9.04 (d, J=5.8, 1H), 8.93 (dd, J=1.2 and 8.6, 1 H), 8.84 (m, 1H), 8.30 (dd, J=5.8 and 8.1, 1H), 8.09 (s, 1H), 8.08 (dd, J=5.1 and 8.6, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:28]([O-])=O)[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([C:26]#[N:27])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:28][C:17]1[C:18]([NH:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([C:26]#[N:27])[CH2:24][CH2:25]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: N#C[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#C[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1

Procedure:
A suspension of trans 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanecarbonitrile (5.00 g, 11.8 mmol), iron powder (−325 mesh, 2.59 g, 47.0 mmol) and ammonium chloride (3.74 g, 70.5 mmol) in a mixture of ethanol and water (3:1, 400 mL) was mechanically stirred at reflux for 4 hours. The cooled mixture was filtered through Celite®. The filtrate was concentrated under vacuum to low volume and the residue extracted into DCM (3×). The combined extracts were washed with water and brine, dried over sodium sulphate and concentrated under vacuum. Purification by diethyl ether trituration afforded 4.51 g (97%) of trans 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanecarbonitrile as a light grey solid. LCMS (Method Q, ESI): RT=2.69 min, m+H=396.1; 1H NMR (400 MHz, DMSO) δ: 8.02 (dd, 2H), 7.65 (m, 1H), 7.57 (m, 3H), 7.47 (d, 1H), 6.76 (d, 1H), 5.09 (d, 2H), 4.36 (s, 2H), 3.76 (m, 2H), 2.70 (m, 1H), 2.04 (dd, 2H), 1.94 (m, 2H), 1.72 (m, 2H), 1.29 (m, 2H).
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[CH2:11][CH2:12][C:13]([Cl:21])=[C:14]2[C:18]([OH:20])=[O:19].C(=O)(O)[O-].[Na+].[C:27]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CC(C)=O.O>[C:27]1([CH2:33][C:34]([NH:8][C@H:9]2[C:16](=[O:17])[N:15]3[C@@H:10]2[CH2:11][CH2:12][C:13]([Cl:21])=[C:14]3[C:18]([OH:20])=[O:19])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N[C@H]1C(=O)N2C(C(=O)O)=C(Cl)CC[C@H]12
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: O
Product: O=C(Cc1ccccc1)N[C@H]1C(=O)N2C(C(=O)O)=C(Cl)CC[C@H]12
Reaction time: 3 h
Yield: 55 %

Procedure:
In this example, 150 mg (0.45 mmole) of trifluoroacetate of (±)-cis-7-amino-3-chloro-1-azabicyclo[4,2,0]oct-2-en-8-on-2-carboxylic acid is suspended in a mixed solvent of 2 ml of water and 2 ml of acetone, 134 mg (1.5 mmole) of sodium bicarbonate is added thereto to make a homogeneous solution. To the solution is added dropwise a solution of 84.2 mg (0.54 mmole) of phenylacetyl chloride in 0.5 ml of acetone under ice cooling in one hour. The mixture is stirred for 3 hours, adjusted to pH 2 with 1 N hydrochloric acid and extracted 5 times with each 2 ml of ethyl acetate. The extract is concentrated under reduced pressure and the residue is dried to obtain 80 mg (55.0%) of the desired compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:26]2
Reactant: Brc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(Br)c4C3)c(F)cc2c1=O
Yield: 18.6 %

Procedure:
142 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 149 mg of 4-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 43 mg of the target compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])S[CH2:4][CH2:3]1.OO.[S:20]([O-:23])(O)=[O:21].[Na+]>C(O)(=O)C>[CH3:17][C:2]1([CH3:1])[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])[S:20](=[O:23])(=[O:21])[CH2:4][CH2:3]1
Reactant: O=S([O-])O
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCCC2(C)C
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2(C)C
Temperature: 80 °C
Yield: 90 %

Procedure:
4 ml of acetic acid was added to 5 g (0.02 mol) of 4,4,5,8-tetramethylthiochroman-6-carboxylic acid, further, 6.9 g (0.06 mol) of a 30% hydrogen peroxide aqueous solution was added, and the mixture was heated at 80° C. for 2 hours. 50 ml of a 2% sodium hydrogensulfite aqueous solution was added to the reaction mixture, and a precipitated solid was recovered by filtration to give 5.1 g (yield 90%) of 4,4,5,8-tetramethylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.C(O[C:15]([C:17]1[NH:18][CH:19]=[C:20]([Br:27])[C:21]=1[NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:16])C>C(Cl)Cl>[Br:27][C:20]1[C:21]2[N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:10](=[S:11])[NH:9][C:15](=[O:16])[C:17]=2[NH:18][CH:19]=1
Reactant: CCOC(=O)c1[nH]cc(Br)c1NCC(C)C
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CC(C)Cn1c(=S)[nH]c(=O)c2[nH]cc(Br)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzoyl isothiocyanate (0.034 g, 0.2 mmol) was added to a solution of 4-bromo-3-(isobutylamino)-1H-pyrrole-2-carboxylic acid ethyl ester (0.050 g, 0.17 mmol) in CH2Cl2 and the resulting mixture was stirred at r.t. for 1 h before it was concentrated in vacuo. The residue was dissolved in ammonia (7M in methanol, 1.5 mL) and stirred at 70° C. for 4 h. Additional ammonia (7M in methanol, 1 mL) was added and the mixture was stirred at 80° C. for 5 h. The mixture was cooled to r.t. and the precipitated product was filtered and washed with diethyl ether. After recrystallization with methanol the title compound (0.028 g, 55%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]([OH:23])=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[NH2:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:36][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH3:35])[NH:26][C:21](=[O:23])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:25])([F:1])[F:24])[CH:4]=3)=[CH:13][CH:12]=2)[CH2:15][CH2:16]1
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 28 (30 mg, 0.085 mmol), tert-butyl 2-amino-2-methylpropanoate (15.0 mg, 0.088 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.01-1.16 (m, 2 H), 1.26-1.31 (m, 6 H), 1.35 (s, 9 H), 1.40-1.53 (m, 2 H), 1.68-1.77 (m, 1 H), 1.77-1.90 (m, 4 H), 1.93-2.02 (m, 2 H), 8.01 (s, 1 H), 13.98 (s, 1 H); MS (ESI) m/z 494 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[CH2:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:21][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(OCCCCl)cc1
Reactant: CC(C)(C)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CNS(=O)(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3.5 g (13 mmol) of 4-(3-chloropropoxy)-benzenesulfonyl chloride in 100 ml of CH2Cl2, a solution of 1.62 g (18.56 mmol) of neopentyl amine in 15 ml of CH2Cl2 and 2.59 ml (18.56 mmol) of triethyl amine are added dropwise at 0-5° C. After stirring for 2.5 h at r.t., the reaction mixture is neutralized with 1N aqueous HCl and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 4-(3-chloropropoxy)-N-(2,2-dimethyl-propyl)benzenesulfonamide; NMR (CDCl3): 0.879 (s, 9H), 2.20-2.35 (m, 2H), 2.66 (d, 2H, J=6.88 Hz), 3.76 (t, 2H, J=6.28 Hz), 4.20 (t, 2H, J=5.84 Hz), 4.35-4.465 (m, 1H), 6.98 (d, 2H, J=8.88 Hz), 7.77 (d, 2H, J=8.88 Hz).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9](B1OC(C)(C)C(C)(C)O1)([CH3:11])=[CH2:10].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]([CH3:11])=[CH2:10])=[N:3][CH:4]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(I)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
5-Bromo-2-isopropenyl-pyridine was prepared according to the scheme shown in FIG. 9. In the sealed round bottom flask, 2-Iodo-5-bromopyridine (4.34 g, 15.3 mmol), isopropenylboronic acid pinacol ester (2.57 g, 15.3 mmol), PdCl2(dppf) (1.87 g, 2.3 mmol) and potassium phosphate (8.2 g, 38 mmol) were dissolved in 25 mL DME and 8 mL water. The resulting solution was stirred at 80° C. for 3 hours and was then cooled down to room temperature. After separation, the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After removing the solvent, fairly pure product (about 3.0 g) was obtained as yellow solid, which was directly used for next step without further purification. ESI MS m/z 198, 200 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[I:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=O)=[CH:19][CH:20]=2)[N:15]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:14]=1>N1CCCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:22]/[C:18]1[CH:17]=[C:16]2[C:21]([C:13]([I:12])=[N:14][N:15]2[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][CH:19]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Solvent: CO
Solvent: C1CCNCC1
Product: C[Si](C)(C)CCOCn1nc(I)c2ccc(/C=C3/C(=O)Nc4ccc(F)cc43)cc21
Temperature: 55 °C
Yield: 77.1 %

Procedure:
A round bottom flask was charged with 5-fluoroindolin-2-one (100 mg, 0.661 mmol), 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (266.18 mg, 0.661 mmol), piperidine (13 uL, 0.013 mmol) and methanol (7.5 mL). The reaction was then heated to 55° C. for 4 h prior to cooling the reaction mass to room temperature. Filtration and washing with methanol (0.50 mL×2) gave the title compound as a yellow solid (273 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 8.00 (s, 1H), 7.85 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.0, 2.4 Hz, 1H), 6.97 (td, J=6.4, 2.4 Hz, 1H), 6.85 (dd, J=8.4, 4.4 Hz, 1H), 5.80 (s, 2H), 3.58 (t, J=8.4 Hz, 2H), 0.92 (t, J=8.4 Hz, 2H), 0.03 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14][C:15]1[S:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:18]2[S:19][C:15]([CH3:14])=[CH:16][CH:17]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: Cc1ccc(B(O)O)s1
Reactant: COc1cc(OC)c(C=O)cc1Br
Product: COc1cc(OC)c(-c2ccc(C)s2)cc1C=O
Yield: 100 %

Procedure:
Ex-40A: 2,4-Dimethoxy-5-(5-methyl-thiophen-2-yl)-benzaldehyde was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and 5-methyl-thiophene-2-boronic acid in a similar manner as described in Ex-3A, 100% yield. 1H-NMR (CDCl3) δ 10.33 (s, 1H), 8.05 (s, 1H), 7.22 (d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H), 6.49 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 2.50 (s, 3H). HMRS (EI) calcd. for C14H14O3S: 262.0664; found: 262.0665.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][C:8]=2[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6][CH2:5]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(c2ccc(C#C[Si](C)(C)C)cc2C(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OCC)CC2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-trimethylsilane (Intermediate 111, 215.0 mg, 0.69 mmol) in methanol (10 mL) was treated with potassium carbonate (80.0 mg, 0.58 mmol) and stirred overnight at ambient temperature. The crude alkyne, 169 mg, was used directly in the next reaction.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[O:8][CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].[C-:21]#[N:22].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][O:8][C:7]1[CH:18]=[C:3]([CH2:2][C:21]#[N:22])[CH:4]=[CH:5][C:6]=1[O:19][CH3:20]
Reactant: COc1ccc(CBr)cc1OCc1c(C)cccc1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC#N)cc1OCc1c(C)cccc1C

Procedure:
The solution of 2-((5-(bromomethyl)-2-methoxyphenoxy)methyl)-1,3-dimethylbenzene (Step D, 3.28 g, 9.7 mmol) and NaCN (0.624 g, 12.7 mmol) in dry DMF (20 ml) was heated at 120° C. for 2.5 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: C1[C:10]2[C:5](=CC(C3SC(N)=NC=3)=CC=2)[CH:4]=CN=1.[Br:17][C:18]1[S:22][C:21]([N:23]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:24][C@@H:25]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:26][C:27]2[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=2)=[N:20][CH:19]=1.B(O)O>>[Br:17][C:18]1[S:22][C:21]([NH:23][C:45](=[O:46])[O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[N:20][C:19]=1[CH:10]1[CH2:5][CH2:4]1.[Br:17][C:18]1[S:22][C:21]([N:23]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:24][C@@H:25]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])[CH2:26][C:27]2[CH:28]=[N:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=2)=[N:20][CH:19]=1
Reactant: Nc1ncc(-c2ccc3cnccc3c2)s1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)nc1)CN(C(=O)OC(C)(C)C)c1ncc(Br)s1
Agent: OBO
Product: CC(C)(C)OC(=O)Nc1nc(C2CC2)c(Br)s1

Procedure:
Example 170, N—((S)-2-amino-3-(6-trifluoromethyl)pyridine-3-yl)propyl)-5-(isoquinolin-6-yl)thiazol-2-amine: The title compound was synthesized in a manner similar to that described for Example 81 using (S)-tert-butyl 1-(5-bromothiazol-2-yl-(Boc)-amino)-3-(6-(trifluoromethyl)pyridin-3-yl)propan-2-ylcarbamate to couple with the boronic acid. (S)-tert-butyl 1-(5-bromothiazol-2-yl-(Boc)-amino)-3-(6-(trifluoromethyl)pyridin-3-yl)propan-2-ylcarbamate was synthesized as shown in Scheme 39. Theoretical (M+H) 430.4 found 430.4.
Reaction SMILES: NC1C=C(Cl)C=C[C:3]=1[CH2:4][N:5]1[CH:9]=C[CH:7]=[C:6]1C#N.[NH2:17][C:18]1[CH:31]=[C:30]([Br:32])[C:29]([Br:33])=[CH:28][C:19]=1[CH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]#[N:27]>>[Br:33][C:29]1[C:30]([Br:32])=[CH:31][C:18]2[N:17]=[C:26]([N:27]3[CH2:7][CH2:6][N:5]([CH3:9])[CH2:4][CH2:3]3)[C:22]3=[CH:23][CH:24]=[CH:25][N:21]3[CH2:20][C:19]=2[CH:28]=1
Reactant: N#Cc1cccn1Cc1cc(Br)c(Br)cc1N
Reactant: N#Cc1cccn1Cc1ccc(Cl)cc1N
Product: CN1CCN(C2=Nc3cc(Br)c(Br)cc3Cn3cccc32)CC1

Procedure:
The general procedure of Example 7 is repeated but replacing the 1-(2-amino-4-chlorobenzyl)-2-pyrrolecarbonitrile employed in that example with an equivalent amount of 1-(2-amino-4,5-dibromobenzyl)-2-pyrrolecarbonitrile whereby there is obtained the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-])=O)=[CH:4][N:3]=1>CC(O)=O.O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:15])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CN1CCN(c2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(c2cc(Cl)ncc2N)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
1-(2-chloro-5-nitro-4-pyridyl)-4-methyl-piperazine (580 mg, 2.260 mmol) was dissolved in AcOH (20 mL)/Water (2 mL) and Fe (2.524 g, 45.20 mmol) was added. The resulting mixture was stirred at 50° C. for 30 minutes. The reaction was cooled to ambient temperature then loaded onto 50 g SCX-2 cartridge (pre-washed with MeOH). The cartridge was washed with DCM/MeOH mixtures, before the product was eluted with 2M NH3 in MeOH/DCM mixtures. The solvent was removed in vacuo to give 6-chloro-4-(4-methylpiperazin-1-yl)pyridin-3-amine as a purple solid (510 mg, 99% Yield). MS (ES+) 227.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([S:13]([CH:16]2[CH2:18][CH2:17]2)(=[O:15])=[O:14])[N:10]=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:73]([NH2:77])([CH2:75][CH3:76])C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([S:13]([CH:16]2[CH2:18][CH2:17]2)(=[O:15])=[O:14])[N:10]=[C:9]([NH:77][CH:73]2[CH2:76][CH2:75]2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(S(=O)(=O)C2CC2)c1
Reactant: CC[C@H](C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(NC2CC2)nc(S(=O)(=O)C2CC2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 58.4 %

Procedure:
Add 2-chloro-6-cyclopropanesulfonyl-isonicotinic acid tert-butyl ester (0.190 g, 0.607 mmol), palladium acetate (0.020 g, 0.091 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.057 g, 0.091 mmol), cesium carbonate (0.297 g, 0.911 mmol), and (S)-sec-butylamine (0.063 mL, 0.911 mmol) in toluene (5 mL) to a sealed tube flushed with nitrogen. Heat and stir the reaction mixture at 90° C. for 18 h. Cool and filter the mixture through a pad of filtering agent, concentrate and purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes) to give the title compound (0.120 g, 59%).