Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:11]([N:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:21]=[CH:20]1)[CH2:12][CH2:13]OS(C)(=O)=O)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[SH:39].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Si:1]([O:8][C@H:9]([C@H:11]([N:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:21]=[CH:20]1)[CH2:12][CH2:13][S:39][C:30]1[CH:31]=[CH:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=1)[CH3:10])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn([C@H](CCOS(C)(=O)=O)[C@H](C)O[Si](C)(C)C(C)(C)C)cn1
Reactant: Sc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@H](CCSc2ccc3ccccc3c2)[C@H](C)O[Si](C)(C)C(C)(C)C)cn1
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a mixture of ethyl 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxylate (160 mg, 0.368 mmol) and 2-naphthalenethiol (118 mg, 0.736 mmol) in DMF (5 ml) was added potassium carbonate (102 mg, 0.736 mmol) at room temperature and the reaction mixture was stirred for 2 hours. The resulting reaction mixture was poured into water (25 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (10 g) chromatography eluting with chloroform/methanol (100:1 to 50:1) to give ethyl 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxylate (146 mg, 79.5%).
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCCCc1nc2ccccc2[nH]1
Product: CCCCc1nc2ccccc2n1Cc1ccc(C#N)cc1
Yield: 117 %

Procedure:
Using the procedure of Step B of Example 1, 3.5 g of 2-butyl-1H-benzimidazol [POOL et al., Am. Soc., Vol. 59, p. 178 (1937)] and 4.3 g of 4-bromomethyl benzonitrile were reacted to obtain 6.8 g of the desired product melting at 130° C. which was dissolved in methylene chloride, treated with activated charcoal, filtered and evaporated to dryness to obtain 6 g of product melting at 130° C. which was crystallized from isopropyl ether to obtain 4.7 g of the expected product melting at 148° C. The analytical sample was obtained by two successive crystallizations of 1.2 g of the product from isopropyl ether to obtain 700 mg of purified product melting at 150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 21.3 %

Procedure:
A mixture of 4-chloro-3-nitro-phenol (5.00 g, 28.81 mmol), phenylboronic acid (7.03 g, 57.62 mmol), copper(II) acetate (5.23 g, 28.81 mmol) and 4 Å molecular sieves (0.5 g) in dichloromethane (200 mL) and triethylamine (20.08 mL, 144.04 mmol) was placed in a round bottomed flask. The resulting suspension was stirred under a dry ambient atmosphere at room temperature for 4 days. The mixture was filtered through diatomaceous earth and the solvent was evaporated. The resulting residue was re-dissolved in EtOAc, adhered to silica gel and flash chromatographed (2% EtOAc/hexane) to give 1-chloro-2-nitro-4-phenoxy-benzene as a yellow oil (1.53 g, 22.0% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14]>>[OH:14][CH2:13][C:12]([NH:11][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:16])[CH3:15]
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1ccc(Cl)cn1

Procedure:
The title compound was prepared by the same method as that described in Example 26, using 5-chloro-2-pyridinecarboxylic acid obtained in Example 40-2) and 2-amino-2-methyl-1-propanol.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[CH:6]([NH2:15])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([C:31](O)=[O:32])=[CH:30][C:24]=3[N:23]=2)=[CH:18][CH:17]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(NC(C)C)(C)C>CN(C)C=O>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[CH:6]([NH:15][C:31]([C:29]1[CH:28]=[CH:27][C:25]2[NH:26][C:22]([C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)=[N:23][C:24]=2[CH:30]=1)=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc2[nH]c(-c3ccncc3)nc2c1
Reactant: NC(CCc1ccccc1)c1nnco1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=C(NC(CCc1ccccc1)c1nnco1)c1ccc2[nH]c(-c3ccncc3)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
220 mg of 1-[1,3,4]oxadiazole-2-yl-3-phenylpropylamine were dissolved in 10 ml of dry dimethylformamide at RT, treated with 260 mg of 2-pyridin-4-yl-1H-benzimidazol-5-carboxylic acid, 350 mg of TOTU, and 0.15 ml of diisopropylamine, and stirred at RT for 4 h. The reaction mixture was concentrated, the residue was taken up in ethyl acetate, and the mixture was washed successively with water, saturated sodium hydrogencarbonate solution, water, and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel using dichloromethane/methanol (8/1) and yielded 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid (1-[1,3,4]oxadiazol-2-yl-3-phenylpropyl)amide, which melts at 103° C. with decomposition.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[C:18]1([CH:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: c1ccc(C2CCCN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CCCC3c3ccccc3)cnc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 2-phenylpyrrolidine (21 mg, 0.14 mmol), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature and concentrated to dryness. LC/MS showed the presence of the target compound and no starting material after 24 h. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a pale yellow solid. This solid as triturated in acetone, filtered, washed with acetone and dried to give the title compound (7 mg, 17%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[OH2:32].[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O
Product: O=C(O)CCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 81.4 %

Procedure:
A mixture of ethyl 3,4,5-triphenyl-1H-pyrazol-1-octanoate (3 g, 6.4 mmol), 3N aqueous sodium hydroxide solution (6.4 mL, 19 mmol) and methanol (40 mL) was heated on a steam bath for 25 minutes before being cooled and concentrated in vacuo. The residue was diluted with water (25 mL) and 2N hydrochloric acid solution added until pH=1. The mixture was extracted with dichloromethane and the combined extracts washed with water and saturated NaCl solution before being dried over sodium sulfate. Removal of the solvent left an oil that slowly crystallized. Recrystallization from a mixture of hexane and dichloromethane (2:1) afforded 3,4,5-triphenyl-1H-pyrazol-1-octanoic acid hydrate (1.19 g, 42%); m.p.=97.5°-99.5° C. MS(CI): m/e=439 (MH+).
Reaction SMILES: C(OCC[CH:7]1[CH2:13][CH2:12][C:11]2[C:14]([O:24]C)=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[C:17]([O:18]C)[C:10]=2[CH2:9][CH2:8]1)(=O)C.N1C(C(O)=O)=CC=C[C:27]=1[C:35]([OH:37])=[O:36].[CH2:38]1COC[CH2:39]1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[CH3:21][O:20][C:16]1[C:17](=[O:18])[C:10]2[CH2:9][CH2:8][CH:7]([CH2:27][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:13][CH2:12][C:11]=2[C:14](=[O:24])[C:15]=1[O:22][CH3:23]
Reactant: C1CCOC1
Reactant: O=C(O)c1cccc(C(=O)O)n1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOC(C)=O)CC2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)CC1CCC2=C(CC1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h

Procedure:
To a mixture of 2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethyl acetate (800 mg), 2,6-pyridinedicarboxylic acid (1.14 g), THF (16 ml), and water (8 ml) was dropwise added a solution of CAN (4.98 g) in water (8 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=4:1) to yield the entitled compound (604 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:19][C:5]2=[N:6][CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=[C:4]2[CH:3]=1.I[C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])[N:27]=2)=[CH:24][N:23]([CH:37]([CH3:39])[CH3:38])[N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:37]([N:23]1[CH:24]=[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])[N:27]=2)[C:21]([C:8]2[CH:9]=[C:4]3[CH:3]=[C:2]([CH3:1])[NH:19][C:5]3=[N:6][CH:7]=2)=[N:22]1)([CH3:39])[CH3:38]
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)cnc2[nH]1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc2cc(-c3nn(C(C)C)cc3-c3ccnc(NC[C@H](C)O)n3)cnc2[nH]1
Temperature: 80 °C
Reaction time: 30 h
Yield: 18.6 %

Procedure:
To a suspension of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (B-7-7) (1.8 g, 2.3 mmol in the theory) and (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1-3) (0.45 g, 1.2 mmol) in toluene/EtOH (3:1, 50 mL) was added aq. Na2CO3 (1.7 mL, 2 M). The mixture was degassed under N2 for 2 minutes, Pd(PPh3)4 (0.05 g, 0.042 mmol) was added into the mixture and degassed again. The mixture was stirred at 80° C. for 30 hours. TLC (CH2Cl2: MeOH=20:1) showed that the reaction was complete. Water (50 mL) and EtOAc (50 mL×3) were added into the mixture. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give crude product which was purified via prep. HPLC to afford (2S)-1-(4-(1-isopropyl-3-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-7) (0.169 g, 18.6%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][C:3]=1[CH3:10].[CH:11]([Mg]Br)([CH3:13])[CH3:12].Cl.CC[O:19]CC>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:19])[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(C)[Mg]Br
Reactant: Cc1cc(C#N)ccc1Cl
Reactant: CCOCC
Agent: Cl
Solvent: c1ccccc1
Product: Cc1cc(C(=O)C(C)C)ccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 4-chloro-3-methyl-benzonitrile (5 g, 33 mmol) in benzene (100 mL) was slowly added isopropylmagnesium bromide (1 M in THF, 66 mL, 66 mmol) at room temperature. The solution was then heated to reflux for 3 hours. After cooling in an ice bath, the reaction mixture was carefully treated with 6 M HCl (52 mL). It was then heated to reflux for 2 hours with vigorous mechanical stirring. The mixture was allowed to cool to room temperature, diluted with Et2O (100 mL) and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude was purified by Kugelrohr distillation (110-130° C./0.1 Torr). Contaminated fractions were further purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[CH:31]=[CH:30][C:29]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35](O)=[O:36])=[CH:28][C:22]=3[C:23]=2[C:24](=[O:27])[NH:25][CH3:26])=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[CH:31]=[CH:30][C:29]([C:32]4[CH:40]=[CH:39][CH:38]=[C:34]([C:35]([N:8]5[CH2:9][CH2:10][CH2:11][CH:7]5[C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[O:36])[CH:33]=4)=[CH:28][C:22]=3[C:23]=2[C:24]([NH:25][CH3:26])=[O:27])=[CH:15][CH:14]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: c1ccc(C2CCCN2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)N4CCCC4c4ccccc4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
2-Phenylpyrrolidine (20 mg, 0.14 mmol) was added to a stirred suspension of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (20 mg, 0.051 mmol), HATU (25 mg, 0.066 mmol), and DIPEA (50 μL, 0.29 mmol) in DMF (0.5 mL). The reaction was stirred at r.t. overnight. The reaction was then diluted with MeOH, filtered, and purified by prep HPLC. Concentration afforded the title compound (21 mg, 78% yield) as a light pink solid. 1H NMR (˜3:2 ratio of amide rotamers, 500 MHz, DMSO-d6) δ ppm 8.44-8.56 (m, 1 H) 7.96-8.07 (m, 2 H) 7.74-7.89 (m, 3 H) 7.56-7.67 (m, 2 H) 7.30-7.45 (m, 5.4; H) 7.16-7.29 (m, 2.6; H) 7.09 (d, J=7.02 Hz, 1H) 5.19 (t, J=6.71 Hz, 0.6; H) 4.98 (d, J=6.41 Hz, 0.4; H) 3.75-3.92 (m, 1.4; H) 3.53-3.64 (m, 0.6; H) 2.87 (m, 3 H) 2.40 (dd, J=12.36, 6.56 Hz, 0.6; H) 2.30-2.38 (m, 0.4; H) 1.73-1.92 (m, 3 H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=3 min, stop time=4 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.86 min, (ES+) m/z (MH+)=519. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=14.38 min, purity=99%; column: Waters Xbridge Phenyl column 3.5 μm 4.6×150 mm, Rt=13.01 min, purity=99%.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[CH2:3]1.C(N(CC)CC)C.CC1(C)C2C(=CC=C([C:33]#[C:34][Si:35]([CH3:38])([CH3:37])[CH3:36])C=2)NC(=O)C1>[Cu]I.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>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([C:33]#[C:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2ccc(C#C[Si](C)(C)C)cc21
Reactant: CC1(C)CC(=O)Nc2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)Nc2cc(C#C[Si](C)(C)C)ccc21
Yield: 74 %

Procedure:
2.2398 g (8.8 mmol) of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-7-bromoquinoline (Compound 18), 371 mg (1.9 mmol) of CuI, 1.087 g (1.5 mmol) of Pd(PPh3)2Cl2, 35 ml (0.251 mol) of triethylamine and 4.0 ml (28.0 mmol) of trimethylacetylene were reacted substantially in accordance with the procedure used for the preparation of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-6-[(trimethylsilyl)ethynyl]quinoline (Compound 2) to give the title compound as pale orange solids (74%).
Reaction SMILES: [CH2:1]([N:7]1[C:20]2[CH:19]=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:23][CH3:24])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH:30](N1CCCCC1)=[O:31]>C(OCC)C.O1CCCC1>[CH2:1]([N:7]1[C:8]2[CH:9]=[CH:10][C:11]([O:23][CH3:24])=[C:12]([CH:30]=[O:31])[C:13]=2[S:14][C:15]2[C:20]1=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1c2ccc(OC)cc2Sc2cc(OC)ccc21
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCN1c2ccc(OC)cc2Sc2c1ccc(OC)c2C=O
Yield: 64.3 %

Procedure:
A solution of 3.42 g (10.0 mmol) of 10-hexyl-3,7-dimethoxy-phenothiazine in 50 ml of diethyl ether/tetrahydrofuran (4:1) was reacted with 8.12 ml of n-butyllithium solution (1.6M in hexane) and 3.35 g (29.6 mmol) of N-formylpiperidine analogously to that described in Example 4.1.1.c. The product was chromatographed on silica gel with ethyl acetate/hexane (1:4), whereupon 2.39 g (64.4%) of 10-hexyl-3,7-dimethoxy-phenothiazine-4-carbaldehyde were obtained as a red oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([NH:23][C:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)=[O:25])[CH:15]=[C:16]([Sn](C)(C)C)[CH:17]=3)[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:32]1[CH:37]=[CH:36][N:35]=[C:34]2[N:38]([S:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:39]=[CH:40][C:33]=12>CN(C=O)C>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([NH:23][C:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)=[O:25])[CH:15]=[C:16]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]5[N:38]([S:41]([C:44]6[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=6)(=[O:42])=[O:43])[CH:39]=[CH:40][C:33]=45)[CH:17]=3)[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Reactant: C[Sn](C)(C)c1cc(NC(=O)c2ccco2)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1ccco1

Procedure:
A stirred solution of N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-2-furancarboxamide (216 mg) and 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (182 mg) with Solvias catalyst (11 mg) in DMF (3 ml) was heated at 120° C. for 20 min in the microwave. The solvent was evaporated and the residue was purified on 20 g silica cartridge using ether and then 10% ethyl acetate:ether. The appropriate fractions were evaporated to dryness and triturated with ether to give the title compound, 90 mg as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:34]=1[CH2:35]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CN(C=O)C.C(OCC)C>[CH3:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:34]=1[CH2:35][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1cccc(C)c1CO
Reactant: CCOC(=O)c1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of Ethyl 3-hydroxybenzoate (12.21 g, 73.47 mmol) and triphenylphosphine (21.01 g, 80.13 mmol) in dry THF (100 ml) was added dropwise a solution of 2,6-Dimethylbenzyl alcohol (10 g, 73.5 mmol) and diisopropyl azodicarboxylate (16.19 g, 80.13 mmol) in dry THF (35 ml) and dry DMF (15 ml) at ambient temperature. After three hours of stirring at room temperature, the reaction mixture was diluted with diethyl ether and washed twice with water and brine. The combined organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography using ethyl acetate:hexane (1:3) as elutent.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:19][C:20](=O)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[C:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:19]=[C:20]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:11]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)Cc1cc(NC(N)=S)ncc1Br
Reactant: O=C(CBr)CCc1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Temperature: 70 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A flask was charged with ethyl 2-(5-bromo-2-thioureidopyridin-4-yl)acetate (2.200 g, 6.914 mmol), 1-bromo-4-phenylbutan-2-one (1.884 g, 8.297 mmol), DIEA (1.806 mL, 10.37 mmol) and ethanol (100 mL). The mixture was heated stirred at 70° C. for 2 hours, then cooled. The reaction was concentrated, and the residue was partitioned between chloroform and dilute sodium bicarbonate solution. The organic phase was washed with dilute sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The solid residue was recrystallized from hexane/ethyl acetate to give the desired product (1.815 g, 58.81% yield) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][C:7]=1[C:16]1[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:16]1[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1ccc(OCCN(C)C)c(-c2ccnn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Compound N-[4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (0.50 g, 1.7 mmol) was dissolved in ethanol (25 mL), sodium hydroxide (1.5 g, pallets) in 8 mL of water was added and reaction mixture stirred at 80° C. overnight then concentrated. Water and brine were added then extracted with EtOAc four times. Organic layers were combined, dried over anhydrous Na2SO4 then solvent removed under reduced pressure to afford 4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine as a light brown oil in 87.5% yield. LCMS m/z (%)=261 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.82 (s, 1H), 9.71 (bs, 1H), 7.48-7.45 (m, 3H), 6.93 (d, J=8.74 Hz, 1H), 6.23 (s, 1H), 3.7 (s, 3H), 2.0 (s, 3H).