Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])(C(C)(C)C)(C)C.[C:20]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:25]=[CH:24][C:23]([CH:26]2[C:31]([CH3:33])([CH3:32])[O:30][C:29](OCC)=[N:28][S:27]2(=[O:38])=[O:37])=[CH:22][CH:21]=1>ClCCl>[C:20]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:25]=[CH:24][C:23]([CH:26]2[C:31]([CH3:32])([CH3:33])[O:30][C:29]([NH:19][C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[CH2:10][CH2:9][OH:8])=[N:28][S:27]2(=[O:37])=[O:38])=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1F
Reactant: CCOC1=NS(=O)(=O)C(c2ccc(-c3ccccc3)cc2)C(C)(C)O1
Solvent: ClCCl
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2F)=NS(=O)(=O)C1c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
In a round-bottom flask, 346 mg of 5-biphenyl-4-yl-2-ethoxy-6,6-dimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide were dissolved under inert gas in 2 ml of dichloromethane and admixed with 328 mg of (S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamine. After concentration by rotary evaporation, the residue was suspended in 0.5 ml of dichloromethane and stirred at room temperature for 18 hours. The conversion was checked by LCMS. Since reactant was still present, the reaction mixture, after the addition of 1 ml of toluene, was stirred at 50° C. for 1 hour. Even after stirring at 75° C. for a further 4 hours, the conversion remained incomplete. The solvent was removed under reduced pressure. To detach the protecting group, the residue was taken up in 1 ml of methanol and, after addition of 0.05 ml of concentrated hydrochloric acid, stirred at room temperature for 1 hour. After concentration by rotary evaporation, the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and freed of the solvent under reduced pressure. The aqueous residue was extracted with ethyl acetate, and the combined organic phases were dried using a diatomaceous earth cartridge (Varian Chem Elut®) and concentrated by rotary evaporation. The residue was dissolved in a mixture of acetonitrile and water and lyophilized. This gave the product (221 mg) with a molecular weight of 482.6 g/mol (C26H27FN2O4S); MS (ESI): m/e=483 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>CN(C=O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([Cl:16])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,4-difluorophenylacetic acid (206 mg), DMF (1 drop) and tetrahydrofuran (4 ml) was added oxalyl chloride (0.13 ml) dropwise. The resulting mixture was stirred at room temperature for 1 hour and the solvent was then distilled off to give 2,4-difluorophenylacetyl chloride. This chloride was dissolved in dichloromethane (5 ml) followed by addition of 3-amino-4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinoline (294 mg) and N,N-dimethylaniline (0.13 ml). The mixture was further stirred at room temperature for 3 hours, after which it was washed with water, saturated aqueous solution of NaHCO3 and water in the order mentioned and dried (over MgSO4). The solvent was then distilled off to give 4-(2-chlorophenyl)-3-(2,4-difluorophenylacetylamino)-7,8-dihydro-6H-cyclopenta(g)quinoline as oil. This oil was crystallized from isopropyl ether (yield 342 mg, 76.3%). Recrystallization from ethanol gave colorless prisms, mp. 179°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5].B.[H][H].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH3:12])[C:3]=1[CH2:4][NH2:5]
Reactant: [H][H]
Reactant: CCOc1cccc(Cl)c1C#N
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cccc(Cl)c1CN
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 2-chloro-6-ethoxybenzonitrile, 135, (93.2 g, 0.513 mol) in THF (350 mL) at room temperature under a dry nitrogen atmosphere was added borane in THF (1.0 M, 620 mL, 0.62 mol). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. Water (250 mL) was added very slowly to the solution allowing for the evolution of hydrogen. Concentrated HCl (50 mL) was then added over several minutes and the solution was heated to 50° C. for 2 hours. The mixture was cooled and partitioned between chloroform and water. The aqueous layer was washed 6 times with chloroform. The combined organic fractions were washed with HCl (1 M) and this organic layer was discarded. Chloroform was added to the combined aqueous layers and solid KOH was added until the aqueous phase was basic (pH>9). The aqueous layer washed with chloroform an additional five times. The organic fractions were combined and washed with water, brine, and dried over MgSO4 and silica gel (2 g). This mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-chloro-6-ethoxybenzylamine, 136, (60.1 g, 64% yield) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:35][C:12]2=[C:13]3[C:18](=[C:19]4[CH:24]=[C:23](B5OC(C)(C)C(C)(C)O5)[CH:22]=[CH:21][C:20]4=[C:11]2[N:10]=1)[C:17](=[O:34])[NH:16][CH:15]=[CH:14]3.Br[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([C:23]2[CH:22]=[CH:21][C:20]3=[C:11]4[N:10]=[C:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[NH:35][C:12]4=[C:13]4[C:18]([C:17](=[O:34])[NH:16][CH:15]=[CH:14]4)=[C:19]3[CH:24]=2)=[N:38][CH:39]=1
Reactant: CC1(C)OB(c2ccc3c(c2)c2c(=O)[nH]ccc2c2[nH]c(-c4c(F)cccc4F)nc32)OC1(C)C
Reactant: Clc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4F)nc3c3ccc(-c4ccc(Cl)cn4)cc3c12
Temperature: 90 °C

Procedure:
To a pressure flask with stir bar, the intermediate from Example 10 Step A (75mg, 0.16 mmol), 2-bromo-5-chloropyridine (33.5 mg, 0.17 mmol), and (Ph3P)2PdCl2 (11.1 mg, 0.02 mmol) were added. The flask was purged of air and back-filled with argon (3×). Toluene (0.79 ml) and ethanol (0.79 ml) were bubbled with argon for at least 10 min before addition to the flask. Na2CO3 (0.24 ml, 0.48 mmol) was bubbled with argon, and then added to the flask. The mixture was heated at 90° C. in an oil bath overnight. Water was added to quench the reaction. The water layer was extracted with ethyl acetate 3×. The combined organics were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude compound was purified by reverse phase HPLC (10-100% acetonitrile in H2O+0.05% TFA) to afford a light yellow solid. 1H NMR (600 MHz, CD3OD) δ 14.00 (m, 1H), 11.40 (m, 1H), 10.97 (s, 1H), 8.73 (s, 1H); 8.53 (d, 1H); 8.29 (s, 1H); 8.05 (s, 2H); 7.56 (m, 3H); 7.25 (d, 2H): [M+H]+ 459.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][C@@H:32]([F:33])[C@@H:28]([CH2:27][NH:26][CH:23]3[CH2:24][CH2:25]3)[CH2:29]2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:17][CH2:18]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N2C[C@H](CNC3CC3)[C@H](F)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 100 °C
Reaction time: 9 h
Yield: 68.6 %

Procedure:
5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (250 mg), (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), triethylamine (0.17 mL) and dimethylsulfoxide (4 mL) were mixed together. The mixture was stirred at 100° C. for 9 hours and was subsequently concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: methanol=40:1). The eluted yellow solid was recrystallized from ethanol to give 5-amino-1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid as yellow crystals (248 mg).
Reaction SMILES: [N+]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)([O-])=O.[Br:20]Br.[N+](C1C=CC=CC=1)([O-])=O>CO>[Br:20][C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1
Reactant: BrBr
Reactant: O=C1c2ccccc2C(=O)c2cc([N+](=O)[O-])ccc21
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CO
Product: O=C1c2ccccc2C(=O)c2cc(Br)ccc21
Temperature: 50 °C
Yield: 97 %

Procedure:
1265 parts by weight of 2-nitroanthraquinone are reacted at 270° C. with elemental bromine in the presence of 60 parts by weight of nitrobenzene in a laboratory apparatus as described in Example 1. When the reaction is complete, the melt is discharged into 2,000 parts by weight of vigorously stirred methanol at 200° C. The suspension so obtained is refluxed for 1 hour, cooled to 50° C., filtered and dried, affording 1390 g of 2-bromoanthraquinone (97% yield) in 98% purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[S:23])[CH2:6][CH2:5]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCc2cc(Br)c(Cl)cc2N1
Solvent: Cc1ccccc1
Product: S=C1CCc2cc(Br)c(Cl)cc2N1
Temperature: 100 °C

Procedure:
To a stirred solution of 6-bromo-7-chloro-3,4-dihydroquinolin-2(1H)-one (110-2; 2.95 g, 0.0113 mol) in toluene (50 mL) was added Lawesson's reagent (2.2 g, 0.00566 mol). Reaction mass was refluxed at 100° C. for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel (60-120 mesh) column chromatography using 7% ethyl acetate in hexane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 7.64 (s, 1H), 7.24 (s, 1H), 2.93-2.89 (t, J=6.8 Hz, 2H), 2.80-2.76 (t, J=8.0 Hz, 2H); MS (M+1): 275.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=O>C(O)C.N1CCCCC1>[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:13][C:12]1=[O:18]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.7 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (60 mg, 69%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:49]=[CH:48][C:28]([CH2:29][O:30][C:31]([NH:33][C:34]2[NH:35][C:36](=[O:47])[C:37]3[N:38]=[CH:39][N:40]([CH2:43][C:44](O)=[O:45])[C:41]=3[N:42]=2)=[O:32])=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:44](=[O:45])[CH2:43][N:40]1[CH:39]=[N:38][C:37]2[C:36](=[O:47])[NH:35][C:34]([NH:33][C:31]([O:30][CH2:29][C:28]3[CH:48]=[CH:49][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[O:32])=[N:42][C:41]1=2)[CH3:2]
Reactant: COc1ccc(COC(=O)Nc2nc3c(ncn3CC(=O)O)c(=O)[nH]2)cc1
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccc(OC)cc3)nc21
Yield: 77.9 %

Procedure:
The title compound (2.72 g, 78%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [2-N-(4-methoxybenzyloxycarbonyl)-guanin-9-yl]-acetic acid (1.89 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 8.26 (dd, 1H), 8.15 (dd, 1H), 7.80 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (m, 2H), 7.36 (d, 2H), 6.94 (d, 2H), 5.16 (s, 2H), 5.09 (s, 1.2H), 4.90 (s, 0.8H), 4.42 (s, 0.8H), 4.16 (q, 0.8H), 4.06 (s, 1.2H), 4.03 (q, 1.2H), 3.75 (s, 3H), 3.63(t, 1.2H), 3.43 (t, 1.2H), 3.39 (t, 0.8H), 3.20 (t, 0.8H), 1.21 (t, 1.2H), 1.12 (t, 1.8H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=O)[CH:8]([CH3:13])[CH2:7]1)=[O:5])[CH3:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]([CH3:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(=O)C(C)C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C1CCC(NCc2ccccc2)C(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture comprising 3-methyl-4-oxo-cyclohexanecarboxylic acid ethyl ester (1.00 g, 5.43 mmol) and benzylamine (0.58 g, 5.43 mmol) in DCE (50 mL) is treated with sodium triacetoxyborohydride (2.30 g, 10.9 mmol) and stirred at RT for 2 hours. The mixture is partitioned between DCM and water and the organic portion is separated, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with iso-hexane:EtOAc (4:1 increasing to 1:1) affords the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.32 (4H, m), 7.20 (1H, m) 4.04 (2H, q), 3.72 (2H, m), 2.50-1.30 (9H, m), 1.19 (4H, m), 0.89 (3H, d).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[OH:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[NH2:6])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Cl)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
174.5 g (1.52 mol) of methanesulfonyl chloride were added dropwise at 10°-15° C. to a solution of 218.7 g (1.52 mol) of 2-amino-4-chlorophenol and 153.8 g (1.52 mol) of triethylamine in 400 ml of methylene chloride. The mixture was stirred for 18 hours at 25° C. and was introduced into ice water, and the organic phase was separated off, washed twice with water and dried over Na2SO4. After the solvent had been distilled off, a gradually crystallizing residue of the product remained, which was sufficiently pure for further reaction (329.5 g, 98% of theory). The product could be recrystallized from methanol/water (mp. 70°-71° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=4)[CH:20]=3)[CH2:14][CH2:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:49]2[CH:56]=[CH:55][C:52]([CH2:53][Cl:54])=[CH:51][CH:50]=2)[CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:69].Cl>>[ClH:54].[ClH:69].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=4)[CH:20]=3)[CH2:16][CH2:17]2)[CH2:53][C:52]2[CH:55]=[CH:56][C:49]([C:41]3[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:39]([O:38][CH3:37])[CH:40]=3)=[CH:50][CH:51]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(-c2ccc(CCl)cc2)cc(OC)c1OC
Reactant: COc1cc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc(OC)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(OC)cc(N(Cc2ccc(-c3cc(OC)c(OC)c(OC)c3)cc2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)c1

Procedure:
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave yellow powder of the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=2)[N:4]([CH3:12])[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[C:24]([NH2:27])=[N:25][CH:26]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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>[NH2:27][C:24]1[N:25]=[CH:26][C:21]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=3)[N:4]([CH3:12])[N:3]=2)=[CH:22][C:23]=1[C:28]([F:31])([F:29])[F:30]
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: Cn1nc(Br)c2cnc(N)nc21
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc(N)c(C(F)(F)F)c2)c2cnc(N)nc21
Temperature: 25 °C

Procedure:
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) (0.1 g, 0.438 mmol), tetrakis(triphenylphosphine)palladium (0.031 g, 0.027 mmol), 5-(4,4,5,5-tetra methyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (Intermediate 10) (0.135 g, 0.669 mmol), cesium carbonate (0.290 g, 0.892 mmol) and water (1 ml) are suspended in 1,4-dioxane (4 ml) and heated using microwave radiation at 150° C. for 45 minutes. The reaction mixture is cooled to room temperature, filtered through Celite® (filter agent) and washed with EtOAc. The solvents are removed in vacuo and purification of the crude residue by flash chromatography on silica eluting with iso-hexanes:EtOAc (2:1) results in an off white solid. The solid is further purified by recrystallisation from 1:1 MeOH/EtOAc resulting in a white solid which is collected by filtration and dried under vacuum to afford the title compound.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=4)[N:23](C(OC(C)(C)C)=O)[CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=4)[NH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)c1ccc2c(c1)c(-c1cncc(N3CCC(NC(=O)OC(C)(C)C)CC3)n1)cn2C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2[nH]cc(-c3cncc(N4CCC(N)CC4)n3)c2c1
Temperature: 50 °C
Yield: 48.3 %

Procedure:
To a mixture of 1-tert-butyl 5-methyl 3-(6-(4-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-1H-indole-1,5-dicarboxylate (300 mg, 0.53 mmol) in chloroform (3.0 mL) was added TFA (3.0 mL) at 0° C. The reaction mixture was heated at 50° C. for 12 h. After removal of TFA the crude product was purified by preparative HPLC to obtain title compound (90 mg, 47%) as a brown solid. MS (ESI, pos. ion) m/z: 352.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[F:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[C:13]2[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: Fc1ccc2nccc(Cl)c2c1
Reactant: Cc1ccc2[nH]c(C)cc2c1
Product: Cc1ccc2[nH]c(C)c(-c3ccnc4ccc(F)cc34)c2c1

Procedure:
The sub-title compound was prepared by the method of Example 10 part a, using 2,5-dimethyl indole and 4-chloro-6-fluoroquinoline.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:25][CH3:24])=[C:31]([CH3:32])[CH:30]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C
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: COCCOC
Solvent: CCOC(C)=O
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)ccc2C)cc1C
Temperature: 80 °C
Yield: 80.2 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (0.1 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (98 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol) and the reaction mixture was heated to 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The aqueous layer was back extracted with ethyl acetate (5 mL). The organics were dried over sodium sulfate and evaporated. The resulting crude material was purified by silica gel chromatography (eluting with 0-30% ethyl acetate in hexanes) to yield the product (0.1 g, 84%). ESI-MS m/z calc. 415.48. found 416.1 (M+1)+. Retention time 2.03 minutes.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:12][S:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c(S)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1c[nH]c(SC)n1
Reaction time: 18 h

Procedure:
To a mixture of ethyl 2-mercapto-4-imidazole carboxylate (II) (49.82 g, 289 mmol) and K2CO3 (79.92 g, 579 mmol) in DMF (1500 mL) was added MeI (18.55 mL, 298 mmol) at room temperature, with stirring. After 18 hrs, it was filtered. The filtrate was concentrated under high vacuum to remove DMF. The residue was then filtered through a silica gel pad with EtOAc, and concentrated. PhMe (200 mL) was then added, followed by addition of Hexanes (1000 mL), precipitating III (50.5 g, 94%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): 7.69 (s, 1H), 4.35 (q, J=7.1 Hz, 2H), 2.67 (s, 3H), 1.35 (t, J=7.1 Hz, 3H).