Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:14]2[CH:23]=[CH:22][C:17]([O:18][CH2:19][C:20]#[N:21])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].CCN(S(F)(F)[F:30])CC>>[F:30][C:2]1([C:14]2[CH:23]=[CH:22][C:17]([O:18][CH2:19][C:20]#[N:21])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCC#N)cc1
Product: CC(C)S(=O)(=O)NC1CCCC1(F)c1ccc(OCC#N)cc1

Procedure:
The title compound was prepared in a manner analogous to the procedure set forth in example 54 from 2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethanenitrile (90 mg, 0.27 mmol) and DAST (0.01 mL) to yield the title compound (95 mg) as an oil. This material was purified by silica gel chromatography employing the Chromatotron® and using a 1000 micron rotor while eluting with a solvent methylene chloride/ethyl acetate 19:1 to yield the title compound (80 mg, 87%) as an oil. Ion Spray M.S. 339.1 (M*−1) Calculated for C16H21N2O3SF: Theory: C, 56.45; H, 6.22; N, 8.23. Found: C, 56.18; H, 6.06; N, 8.13.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:26]3[CH:25]=[C:24]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:22][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: CC(=O)c1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)c1c[nH]c2c(-c3cc(C(C)=O)ccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 1-[4-cyclopropylmethoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethanone (example A46) the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:27]=2[O:28][CH2:29][C:30]#[N:31])[C:22]([Cl:37])=[CH:21][N:20]=1>>[C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:27]=4[O:28][CH2:29][C:30]#[N:31])[C:22]([Cl:37])=[CH:21][N:20]=3)[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2]
Reactant: Cc1cccc(OCC#N)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Product: CC(=O)N1CCC(=O)NCc2cc(Nc3ncc(Cl)c(Nc4c(C)cccc4OCC#N)n3)ccc21

Procedure:
Title compound was prepared from 1-Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one and [2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-methyl-phenoxy]-acetonitrile in an analogous manner to Example 1221d. Product was isolated as a white solid (104 mg, 76%). MP: 210-214, LCMS 506.15 (M+H), HPLC purity 97%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.65-9.63 (m, 1H), 8.83-8.85 (m, 1H), 8.15 (s, 1H), 7.6307.61 (m, 1H), 7.36-7.32 (m, 3H), 7.14 (d, J=8.5 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 5.11 (s, 2H), 2.58-2.54 (m, 2H), 4.15-4.11 (m, 1H), 3.60-3.52 (m, 1H), 2.85-2.81 (m, 1H), 2.28-2.24 (m, 1H), 2.16 (s, 3H), 1.60 (s, 3H).
Reaction SMILES: [CH2:1]1[C@H:6]2[C:7]3[N:8]([CH:16]=[CH:17][CH:18]=3)[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>>[C:23]1(=[O:32])[N:22]([CH2:21][CH2:20][N:2]2[CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][N:8]4[CH:16]=[CH:17][CH:18]=[C:7]4[C@@H:6]3[CH2:1]2)[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc2c(c1)Cn1cccc1[C@@H]1CNCCN21
Product: O=C1c2ccccc2C(=O)N1CCN1CCN2c3ccccc3Cn3cccc3[C@@H]2C1

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bS)-1,2,3,4,10,14b-hexahydropyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine and N-(2-bromoethyl)phthalimide, the title compound was obtained in a quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[N:25])[CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:15]3[CH2:16][CH2:17][C:18]4[C:23](=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=4)[CH2:14]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: N#Cc1ccc2c(c1)CNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: N#Cc1ccc2c(c1)CN(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,2,3,4-Tetrahydro-isoquinoline-7-carbonitrile to provide the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[CH:20][N:21]=4)[CH:18]=3)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.C([O-])([O-])=O.[K+].[K+].COCCOC>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.C(Cl)Cl>[N:21]1[CH:20]=[CH:19][N:17]2[CH:18]=[C:13]([CH:11]([C:8]3[N:6]4[N:7]=[C:2]([C:26]5[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[OH:12])[CH:14]=[CH:15][C:16]=12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OC(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: Cn1cc(-c2ccc3ncc(C(O)c4ccc5nccn5c4)n3n2)cn1
Temperature: 80 °C

Procedure:
A microwave tube was charged under argon atm. with (rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-imidazo[1,2-a]pyridin-6-yl-methanol (Stage 9.1, 89.9 mg, 0.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (62.4 mg, 0.3 mmol), Pd(PPh3)2Cl2 (6.3 mg) and 2 M K2CO3 (0.405 mL) and DME (1 mL). The mixture was heated at 80° C. for 3 h. The RM was taken up with DCM and washed with NaCl solution. After filtration of both layers, the solid part was dissolved in MeOH and evaporated to dryness. The residue was stirred in EtOAc and filtered to give the pure title compound. The organic layer of the first filtrate was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/MeOH=95:5—>80:20) to afford a second batch of the title compound (tR 2.57 min (conditions 3), MH+=346.2)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][OH:11])[NH2:9])[CH:5]=[CH:6][CH:7]=1.[Cl:12][CH:13]([CH3:17])[C:14](Cl)=O>C(Cl)Cl>[Cl:12][CH:13]([C:17]1[O:11][N:10]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)[CH3:14]
Reactant: CC(Cl)C(=O)Cl
Reactant: NC(=NO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(Cl)c1nc(-c2cccc(Cl)c2)no1
Temperature: 120 °C
Yield: 67 %

Procedure:
1.80 g 3-chloro-N′-hydroxybenzenecarboximidamide and 3.7 mL DEA were dissolved under Ar in DCM (100 mL) and cooled on an ice/water bath, followed by addition of 2-chloropropanoyl chloride. After 1 h at r.t. the mixture was concentrated and the crude taken up in DMF (120 mL), followed by heating for at 120° C. for 2 h. The mixture was concentrated onto celite and purified via column chromatography (hep 100% to hep/EA=7/3) yielding the title compound (1.72 g, 67%). 1H NMR: 8.09 (t, 1 H), 7.93-8.02 (m, 1 H), 7.38-7.54 (m, 2 H), 5.22 (q, 1 H), 2.02 (d, 3 H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.Cl.[NH:18]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[N:24][CH:25]=1)[NH2:19]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:18]([C:20]3[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[N:24][CH:25]=3)[N:19]=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: NNc1ccc(S(N)(=O)=O)nc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cn1
Yield: 87 %

Procedure:
A mixture of 1-(4-bromophenyl)-4,4,4-trifluoro-1,3-butanedione (prepared according to the method of J. Med. Chem., 1997, 40, 1347. 1.09 g, 3.71 mmol) and 5-hydrazino-2-pyridinesulfonamide hydrochloride (1.00 g, 4.45 mmol) in ethanol (50 ml) was refluxed for 18 hr. After evaporation, the obtained residue was chromatographed on a column of silica gel (200 g) eluting with ethyl acetate/hexane (1:2) to afford 1.44 g (87%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([NH2:16])[CH2:14][CH3:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(OCC)C.C(O)C>[ClH:1].[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([CH3:12])=[N:11][C:2]=1[NH:16][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1ccc(C)nc1Cl
Reactant: CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCCNc1nc(C)ccc1C(=O)OC

Procedure:
A stirred mixture of 37.1 g. (0.2 mole) of methyl 2-chloro-6-methyl-nicotinate, 11.8 g. (0.02 mole) of propylamine and 21.2 g. (0.02 mole) of sodium carbonate in 200 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with 200 ml. of water and was extracted with 100 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated to give 31 g. of an oil. A small amount of this oil was dissolved in diethyl ether and was acidified with an etheral hydrochloric acid solution. On cooling, the oil which separated crystallized to yield 6-methyl-2-propylaminonicotinic acid methyl ester, hydrochloride. The solid was collected and was recrystallized from ethyl acetate to give the analytical sample, m.p. 113°-15° C.
Reaction SMILES: [CH2:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH2:6]3)[CH2:4]1)[CH2:10]2)[CH3:2].[OH2:19]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([C:3]12[CH2:4][C:5]3([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:11][CH:9]([CH2:8][C:7]([OH:19])([CH2:6]3)[CH2:12]1)[CH2:10]2)[CH3:2]
Reactant: O
Reactant: CCC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCC12CC3CC(O)(C1)CC(c1ccccc1)(C3)C2
Temperature: 4 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
To a solution of 0.03 mol of chromiumtrioxide, in 20 ml glacial acetic acid and 20 ml acetic anhydride, add 0.0095 mol of 1-ethyl-3-phenyl adamantane (II) at 0° C. and stir for 24 hours at 4° C. Pour the reaction mixture into water and extract with three portions of pentane. Wash the organic phase with saturated sodium chloride solution, dry over magnesium sulfate, filter and evaporate to dryness under vacuum. Hydrolize the residue with 20 ml of 2N NaOH and 50 ml of methanol. Remove the methanol under vacuum and dilute the residue with water. Then extract with three portions of ether. Dry the organic phase, filter and evaporate to dryness under vacuum. Recrystallize the residue from cyclohexane. (Yield: 50%).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.Cl>O1CCCC1.O>[CH:14]1([CH2:13][C@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][N:6]=2)=[O:27])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Temperature: 60 °C
Yield: 4.4 %

Procedure:
A solution of 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared in Example 45, 188 mg, 0.45 mmol) in tetrahydrofuran (3 mL) was treated with a 3N aqueous hydrochloric acid solution (3 mL). The resulting reaction mixture was heated under reflux at 60° C. for 4 h. After such time, the reaction was cooled to 25° C, diluted with water (5 mL), and then extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate with 1% acetic acid) afforded 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid (8 mg, 4%) as a white solid: [α]23589=−41.4° (c=0.099, chloroform); FAB-HRMS m/e calcd for C20H20Cl2N2O3 (M+H)+407.0930, found 407.0928.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:35])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].I[CH3:39]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([O:35][CH3:39])[C:19]2[S:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(OC(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC(CCc1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl)c1ccc(-c2ccc(OC(F)(F)F)cc2)s1

Procedure:
2-(2,3-Dichloro-4-(3-methoxy-3-(5-(4-(trifluoromethoxy)phenyl)thien-2-yl)-propyl)phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethoxy)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 2.1 equivalents of sodium hydride and 2.1 equivalents of iodomethane according to general procedure H.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:17]=2[CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1ccncc1B(O)O
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccncc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 4-methylpyridine-3-boronic acid (0.28 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 45 h to give 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-3-yl)quinoline as a brown solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[C:18]1([O:23][CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:12][C:11]=1[C:18]1([O:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2(OC)CCCC2)c1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(COS(C)(=O)=O)cc2C2(OC)CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20.6 (30 mg, 91 mmol) in 1 mL of DCM at 0° C., was added TEA (11 mg, 109 μmol) followed by methanesulfonyl chloride (12 mg, 109 mmol). The mixture was stirred at room temperature for 30 minutes. The reaction was then quenched with water and extracted with EtOAc. The organic layers were combined, washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to give the product as a residue which was used without further purification. MS ESI m/e: 409.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18](=[S:27])[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[OH:26])=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41]O)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][O:26][C:20]2[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=2[C:18]([NH:17][C:16]2[C:11]([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[S:27])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 18 h
Yield: 88.5 %

Procedure:
To a 0° C. mixture of N-(5-chloropyridin-2-yl)-3-[2-hydroxy-4-methylthiobenzoylamino]pyridine-2-carboxamide (750 mg, 1.8 mmol), 1-t-butoxycarbonyl-4-hydroxymethylpiperidine (387 mg, 1.8 mmol), triphenylphosphine (568 mg, 2.26 mmol) and DMF (9 mL) was added DEAD (0.36 mL, 2.26 mmol), and the mixture was stirred for 18 h. The reaction mixture was concentrated and chromatographed (CH2Cl2; 10% EtOAc/CH2Cl2) to give the desired product as a white solid (950 mg, 86%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2([NH:14][C:15]([C:17]3[C:18]4[CH:19]=[N:20][N:21]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:22]=4[CH:23]=[C:24](Br)[CH:25]=3)=[O:16])[CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].[CH3:34][S:35](C1C=C(C2(NC(C3C4C=NN(C5C=CC(F)=CC=5)C=4C=C(I)C=3)=O)CC2)C=CN=1)(=[O:37])=[O:36]>>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2([NH:14][C:15]([C:17]3[C:18]4[CH:19]=[N:20][N:21]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:22]=4[CH:23]=[C:24]([S:35]([CH3:34])(=[O:37])=[O:36])[CH:25]=3)=[O:16])[CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(C2(NC(=O)c3cc(Br)cc4c3cnn4-c3ccc(F)cc3)CC2)ccn1
Reactant: CS(=O)(=O)c1cc(C2(NC(=O)c3cc(I)cc4c3cnn4-c3ccc(F)cc3)CC2)ccn1
Product: CS(=O)(=O)c1cc(C(=O)NC2(c3ccnc(S(C)(=O)=O)c3)CC2)c2cnn(-c3ccc(F)cc3)c2c1

Procedure:
The title compound is synthesized according to the coupling procedure described in Example 18 from a mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid [1-(2-methanesulfonyl-pyridin-4-yl)-cyclopropyl]-amide, and 1-(4-fluoro-phenyl)-6-iodo-1H-indazole-4-carboxylic acid [1-(2-methanesulfonyl-pyridin-4-yl)-cyclopropyl]-amide (100 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=2)[N:4]([CH3:13])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)O1>O1CCOCC1.O.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>[CH3:13][N:4]1[C:5]2=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=[C:10]2[C:2]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)=[N:3]1
Reactant: CSc1ncc2c(Br)nn(C)c2n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ncc2c(-c3ccc(N)cc3)nn(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a solution of 3-bromo-1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (2.6 g, 10 mmol) in dioxane (40 mL) and H2O (20 mL) was added anhydrous potassium carbonate (4.14 g, 30 mmol, 3 eq), followed by 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.28 g, 15 mmol, 1.5 eq). The reaction mixture was degassed and tetrakis(triphenylphosphine)palladium (58 mg, 0.5 mmol, 0.05 eq) was added. The system was then heated under reflux for 24 hours and cooled to room temperature. The mixture was treated with water (150 mL) and cooled to 0° C. and allowed to sit for three hours. The resulting mixture was then filtered. The filtrate was dried in a vacuum oven overnight to afford 1.66 g (61% yield) of 4-(1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenylamine; 1H-NMR (CDCl3): • 2.69 (s, 3H), 3.90 (br s, 2H), 4.08 (s, 3H), 6.82 (d, 2H), 7.77 (d, 2H), 9.11 (s, 1H); LC/MS (m/e)=272.4 (MH+). Rt=1.57 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16](Br)=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16]([C:35]3[CH:36]=[CH:37][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2c1c(Br)nn2C1CCN(Cc2ccccc2)CC1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(Cc2ccccc2)CC1
Yield: 50.1 %

Procedure:
1-(1-benzyl-4-piperidinyl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate D) (4.3 g, 11.10 mmol), 4-phenoxyphenylboronic acid (Intermediate V) (2.61 g, 12.21 mmol), palladium tetrakistriphenyphosphine(0.77 g, 0.67 mmol) and sodium carbonate(2.82 g, 26.65 mmol) were mixed with ethylene glycol dimethyl ether(100 ml) and water(50 ml). The reaction mixture was heated to reflux overnight. Organic solvent was removed and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed, dried and evaporated. The residue was purified via flash column chromatography using ethyl acetate/methanol (98/2) as mobile phase to give 2.65 g of 1-(1-benzyl-4-piperidinyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (CDCl3) 1.99 (d, J=1.02 Hz, 2H), 2.25(m, 2H), 2.47 (m, 2H), 3.07 (d, J=1.12 Hz), 3.59 (s, 2H), 4.80 (m, 1H), 5.52 (s, 2H), 7.07 (d, J=0.67, 1H), 7.15 (m, 3H), 7.37 (m, 6H), 7.66 (d, J=8.51, 2H), 8.37 (s,1H); LC/MS (MH+=477).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)CCl>[CH3:1][O:2][CH2:3][CH2:4][CH:5]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)[Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCCc1ccc(Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: COCCC(Br)c1ccc(Cl)cc1
Yield: 108.5 %

Procedure:
A mixture of 3-(4-chlorophenyl)propyl methyl ether (8.6 g, 46.5 mmol), N-bromosuccinimide (NBS; 9.43 g, 52.9 mmol), and a catalyst amount of 2,2′-azobisisobutyronitrile in ethylene dichloride (236 ml) was heated at 65° to 70° C. for three hours. The cooled reaction mixture was washed successively with water, saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford crude title compound (13.3 g) which was used without further purification.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:22]([C:11]([OH:13])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=[N:21]2)=[CH:23][CH:24]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1O

Procedure:
Using the procedure of Example 2, ethyl ethoxymethylene malonate and 3-methoxy-aniline were reacted and treated with phenyl oxide to obtain ethyl 7-methoxy-4-hydroxy-3-quinoline-carboxylate melting at >260° C.