Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:11]([Mg]Cl)([CH3:13])[CH3:12].[S:16]1[CH:20]=[CH:19][C:18]2=[CH:21][C:22]3[S:23][CH:24]=[CH:25][C:26]=3[CH:27]=[C:17]12.[Sn](Cl)Cl>O1CCCC1.Cl>[C:1]([C:21]1[C:22]2[S:23][CH:24]=[CH:25][C:26]=2[C:27]([C:12]#[C:11][CH2:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:17]2[S:16][CH:20]=[CH:19][C:18]=12)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: c1cc2cc3sccc3cc2s1
Reactant: C#CCCCCCCCC
Reactant: CC(C)[Mg]Cl
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: CCCCCCCCC#Cc1c2ccsc2c(C#CCCCCCCCC)c2ccsc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
More specifically, a process for the preparation of the polymers illustrated herein, and more specifically, for the preparation of poly[bis(ethynyl)heteroacene]s, poly(4,8-didecynylbenzo[1,2-b:4,5-b′]dithiophene-2,6-diyl) (1a) and poly(4,8-bis(4-pentylphenylethynyl)benzo[1,2-b:4,5-b′]dithiophene-2,6-diyl) (1b), is shown in Scheme 1. First, 1-decyne (available from Sigma-Aldrich) is reacted with about 1 molar equivalent of isopropylmagnesium chloride (available from Sigma-Aldrich) in tetrahydrofuran (THF) at elevated temperatures like 60° C. for a suitable period of time like 30 minutes. Then to the reaction mixture is added benzo[1,2-b:4,5-b′]dithiophene (this starting material is prepared according to Beimling, P., et al, Chem. Ber. 1986, 119, 3198) followed by stirring at elevated temperatures like 60° C. for a suitable period of time like 1 hour. Subsequently, a tin (II) chloride (SnCl2) solution in 10 percent HCl is added to the reaction mixture and stirred at elevated temperatures like 60° C. for a suitable period of time like 30 minutes to afford 4,8-didecynylbenzo[1,2-b:4,5-b′]dithiophene. Lithiation of 4,8-didecynylbenzo[1,2-b:4,5-b′]dithiophene using n-butyllithium (n-BuLi) in THF at a suitable temperature like −70° C., followed by the addition of carbon tetrabromide (CBr4) and reacting at a suitable temperature like −70° C. and then 0° C. results in 2,6-dibromo-4,8-didecynylbenzo[1,2-b:4,5-b′]dithiophene. 2,6-Dibromo-4,8-didecynylbenzo[1,2-b:4,5-b′]dithiophene is then polymerized using zinc in the presence of nickel (II) chloride (NiCl2), 2,2′-dipyridil, triphenylphosphine (PPh3) in N,N-dimethylacetamide (DMAc) at elevated temperatures like 80° C. for a suitable period of time like 48 hours. Poly(4,8-didecynylbenzo[1,2-b:4,5-b′]dithiophene-2,6-diyl) (1a) is thus obtained. Similarly, poly(4,8-bis(4-pentylphenylethynyl)benzo[1,2-b:4,5-b′]dithiophene-2,6-diyl) (1b) is prepared starting from 1-ethynyl-4-pentylbenzene instead of 1-decyne.
Reaction SMILES: O.[NH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]=[CH:8][CH2:9][NH2:10].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH4-].[Na+].C(O)(=O)C>CO.O>[CH2:25]([NH:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]=[CH:8][CH2:9][NH2:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCC=CCc1cc(N)c(Oc2ccccc2)c(S(N)(=O)=O)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: NCC=CCc1cc(NCc2ccccc2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
A solution of (3-amino-4-phenoxy-5-sulfamylbenzyl)allylamine hydrate (3.3 g; prepared as described in Example 111) and benzaldehyde (1.2 g) in methanol (35 ml) is refluxed for 16 hours. Sodium borohydride (1.0 g) is then during 30 minutes added in portions while stirring at 0°-5° C. After additional stirring for 2 hours, acetic acid (1.0 ml) followed by water (120 ml) is cautiously added to precipitate crude (3-benzylamino-4-phenoxy-5-sulfamylbenzyl)allylamine. After filtration and recrystallization twice from aqueous ethanol, it is obtained with a melting point of 139°-140° C. The material (IR, analysis) is identical with the material prepared as in Example 150.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:3]=1.[CH:18](=O)[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21]>CO.C(O)(=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][C:2]([N:1]=[CH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[OH:21])=[N:3]2)=[CH:8][C:9]=1[C:14]([F:17])([F:15])[F:16]
Reactant: O=Cc1ccccc1O
Reactant: NC1=NN(c2ccc(Br)c(C(F)(F)F)c2)CC1
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccccc1C=NC1=NN(c2ccc(Br)c(C(F)(F)F)c2)CC1
Reaction time: 3 h
Yield: 80.1 %

Procedure:
3-Amino-1-(4-bromo-3-trifluoromethylphenyl)-2-pyrazoline (prepared in Example 39 of our European patent specification No. 22-578) (140 mg) and salicylaldehyde (100 mg) were dissolved together in methanol (2 ml) and 1 drop of glacial acetic acid. The mixture was heated to reflux for 1 hour. During this time a deep orange-red colour developed and the mixture crystallised. It was kept at 0° for 3 hours, then the solid was collected, washed with methanol and dried in vacuo to yield 150 mg 1-(4-bromo-3-trifluoromethylphenyl)-3-(2-hydroxybenzylideneamino)-2-pyrazoline, m.p. 170° (decomp).
Reaction SMILES: [O:1]=[C:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[BH4-].[Na+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([OH:1])[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH3:7]
Reactant: CCOC(=O)C(=O)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(O)c1cccs1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of ethyl 2-oxo-2-(thiophen-2-yl)acetate (5.00 g, 27.1 mmol) in ethanol (50 mL) is cooled at 0° C. with an ice bath. NaBH4(0.31 g, 8.14 mmol) is added in four portions under stirring. The mixture is stirred at 0° C. for 10 minutes, then allowed to warm at RT and stirred for additional 30 minutes. Reaction is concentrated under vacuum and the residue is partitioned between Et2O and ice-cooled water. The organic layer is separated, washed with water and brine, dried over Na2SO4, filtered and evaporated to give a colorless liquid (5.05 g, 91% yield).
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]([CH:21]1[CH2:23][O:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C1C=C(C=N[C@H]2[C@H](N=CC3C([O-])=C(C(C)(C)C)C=C(C(C)(C)C)C=3)CCCC2)C([O-])=C(C(C)(C)C)C=1)(C)C.[Co+2].C(O)(=O)C.O>[CH:8]([C@@H:21]1[CH2:23][O:22]1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(C(c2ccccc2)C2CO2)cc1
Agent: [Co+2]
Agent: CC(C)(C)c1cc(C=N[C@@H]2CCCC[C@H]2N=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2[O-])c([O-])c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(C(c2ccccc2)[C@@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A mixture of (R,R)-(−)-N,N′-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane diaminocobalt (II) (0.22 g, 0.37 mmol, 0.8%), toluene (5 ml), and acetic acid (0.044 g, 0.74 mmol) was stirred for 1 h at room temperature. The solvent was removed in vacuo and the residue was dried. 2-Benzhydryl-oxirane (9.6 g, 45.7 mmol) was added in one portion and stirred, the mixture was then cooled by means of an ice-bath. H2O (0.58 g, 32 mmol) was slowly added over a 30-min period. After water addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 72 h. Compounds were separated via flash chromatography on silica gel column to give (2R)-2-benzhydryl-oxirane (23a) 4.5 g ([α]D=(+)9.58, c=1, MeOH) and (2S)-3,3-diphenyl-propane-1,2-diol 24.3.53 g ([α]D=(+)48, c=1, MeOH, ee=97%). The proton and carbon NMR data of (2R)-2-benzhydryl-oxirane was identical to the racemate 2-benzhydryl-oxirane.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11]1(C)C(S(O)(=O)=O)=CC=CC=1.[C:22]([O-:25])(O)=O.[Na+]>CO.C(OC)(OC)OC>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]([O:25][CH3:22])[O:6][CH3:11])[C:3]=1[CH3:10]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: O=C([O-])O
Reactant: Cc1c(Br)cccc1C=O
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: COC(OC)c1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The 3-bromo-2-methyl-benzaldehyde ((Example 6: step c) 813 mg, 4.08 mmol) was dissolved in dry MeOH (50 mL) and trimethyl orthoformate (8 mL). Toluenesulfonic acid (100 mg) was added and the solution was stirred for 6 h at rt. Solid NaHCO3 (200 mg) was added, the solution was stirred for 30 min, and the volatile components were removed in vacuo. The residue was dissolved in dry EtOAc (10 mL), the solution was filtered (45 micron filter), and the solvent was removed in vacuo. 1H NMR analysis of the crude material (918 mg, 92%) revealed approximately a 90% conversion of the starting material to the title compound, which was used without further purification. 1H-NMR (CDCl3): δ 7.47 (dd, 1H, J=1.2, 8.1 Hz), 7.44 (dd, 1H, J=0.9, 7.9 Hz), 6.99 (t, 1H, J=7.9 Hz), 5.37 (s, 1H), 3.25 (s, 6H), 2.37 (s, 3H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.N1CCCC1.[C:27]1([CH2:33][CH2:34][CH:35]=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[C:27]1([CH2:33][CH2:34][CH:35]=[C:18]2[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=CCCc1ccccc1
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1OC(=CCCc2ccccc2)C(=O)N1CCCCSc1cccc2nccn12
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
1.53 g (5 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 20 ml of ethanol were placed in a reaction flask, followed by stirring at 60° C. for 20 minutes, to dissolve the starting materials. After this mixture was kept standing to 50° C., an ethanol solution of 0.05 ml (0.5 mmol) of pyrrolidine was added. Next, an ethanol solution of 0.66 ml (5 mmol) of 3-phenylpropionaldehyde was added, followed by refluxing for 19 hours. Six hours later, 0.66 ml (5 mmol) of 3-phenylpropionaldehyde and 0.05 ml (0.5 mmol) of pyrrolidine were added. After the reaction mixture was cooled, the solvent was distilled off, followed by extraction with dichloromethane and water. After the organic layer was dried with sodium sulfate, the solvent was distilled off. The residue was eluted by column chromatography (eluent, hexane/ethyl acetate=1/1) to yield 26 mg (1.2%, yellow oily substance) of the desired product.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C@H:28]3[O:37][C@@H:31]4[O:32][C:33]([CH3:36])([CH3:35])[O:34][C@@H:30]4[C@@H:29]3[CH2:38][CH2:39][OH:40])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.O>ClCCl>[CH3:8][S:9]([O:40][CH2:39][CH2:38][C@H:29]1[C@@H:30]2[C@@H:31]([O:32][C:33]([CH3:36])([CH3:35])[O:34]2)[O:37][C@@H:28]1[CH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:25][CH:24]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)O[C@H]2O[C@H](CCc3ccc(-c4ccc(Cl)cc4)cc3)[C@@H](CCO)[C@H]2O1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)O[C@H]2O[C@H](CCc3ccc(-c4ccc(Cl)cc4)cc3)[C@@H](CCOS(C)(=O)=O)[C@H]2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.43 ml) and methanesulfonyl chloride (0.21 mL) were added to a solution of the compound obtained from step i above (0.6 g) in dichloromethane (15 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. Dichloromethane and water were added to reaction mixture. The organic layer was separated, washed with water, dried, and concentrated under reduced pressure to furnish the title compound (0.6 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[C:11]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:10]=1>>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[C:11]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:10]=[C:9]2[O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:15]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccccc3)c2c1

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (7-Methoxy-1-phenoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:57][NH:58][O:59][CH3:60]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([N:58]([O:59][CH3:60])[CH3:57])=[O:16])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: CNOC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To a cold (0° C.) solution of 1-(tert-butoxycarbonyl)-3-piperidine carboxylic acid (7.000 g, 30.531 mmol) in dichloromethane (200 mL) including triethylamine (4.681 mL, 33.584 mmol) were added benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (15.885 g, 30.531 mmol), N,O-dimethylhydroxyamine (3.276 g, 33.584 mmol) and triethylamine (4.255 mL, 30.531 mmol) successively. The mixture was allowed to warm to room temperature, and the stirring was continued for 12 hrs. The reaction mixture was diluted with dichloromethane and washed with an aqueous 1N HCl solution, saturated aqueous NaHCO3 solution, and brine, successively. The organic phase was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=10/1-9/1) to give 3-{[methoxy(methyl)amino]carbonyl}-1-piperidine-carboxylic acid tert-butyl ester as a white solid. (8.050 g, yield; 96%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:18])([CH3:17])[C@@H:12]2[C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23](O)[C:24]#[C:25][CH2:26][OH:27]>>[OH:27][CH2:26][C:25]#[C:24][CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:17])([CH3:18])[C@@H:12]2[C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: OCC#CCO
Product: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCO)cc2)CCSC1(C)C
Yield: 65.2 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 0.10 g (0.288 mmoL) of methyl (3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.031 g (0.363 mmol) of 2-butyne-1,4-diol gave 0.078 g of methyl (3S)-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxylate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([Cl:23])[CH:12]=3)[O:8][C:7](=[O:24])[C:6]=2[CH:25]=1.[CH3:27][NH2:28]>O1CCCC1>[Cl:23][C:13]1[CH:12]=[C:11]([C:9]([NH:10][C:5]2[C:6]([C:7]([NH:28][CH3:27])=[O:24])=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:26])=[O:8])[N:15]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:14]=1
Reactant: CN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Example 3, Step E) (6.32 g, 15.47 mmol) in tetrahydrofuran (50 mL) was added methylamine (2.0 M solution in THF, 38 mL, 77.38 mmol), and the reaction mixture was heated to 60° C., stirred for 1 hour and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (4.57 g) melting at 225-226° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]1=2.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30](O)[CH:29]=1>CO.C(Cl)Cl>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([O:1][CH:2]2[C:3]3[C:8](=[N:7][CH:6]=[C:5]([C:12]4[CH:13]=[CH:14][C:15]([C:18]([N:20]5[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]5)=[O:19])=[CH:16][CH:17]=4)[CH:4]=3)[NH:9][CH2:10][CH2:11]2)[CH:29]=1
Reactant: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Reactant: CC(=O)c1ccc(F)cc1O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc(F)cc1OC1CCNc2ncc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)cc21
Yield: 53 %

Procedure:
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone (30 mg) was reacted with 1-(4-fluoro-2-hydroxyphenyl)ethanone (39.4 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (53% yield). LCMS: m/z=489.14 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.11-2.25 (m, 2H), 2.32 (s, 3H), 2.32-2.58 (m, 4H), 2.45 (s, 3H), 3.40-3.68 (m, 4H), 3.70-3.90 (m, 2H), 5.31 (bs, 1H), 5.51 (t, J=3.3 Hz, 1H), 6.75-6.82 (m, 1H), 6.89 (dd, J=2.1 and 10.7 Hz, 1H), 7.41-7.51 (m, 4H), 7.57-7.61 (m, 1H), 7.80 (dd, J=7.1 and 8.6 Hz, 1H, 8.33 (bs, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:38]=[CH:37][C:12]([NH:13][C:14]2[CH:26]=[C:25]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[N:29][CH:28]=3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][CH:10]=1.O.[OH-].[Na+]>C(OCC)(=O)C>[F:8][C:9]1[CH:38]=[CH:37][C:12]([NH:13][C:14]2[CH:26]=[C:25]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[N:29][CH:28]=3)[CH:24]=[CH:23][C:15]=2[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cncc3ccccc23)cc1Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)c1ccc(-c2cncc3ccccc23)cc1Nc1ccc(F)cc1
Yield: 52.6 %

Procedure:
Trifluoroacetic acid 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-(isoquinolin-4-yl)benzoate 110 mg was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and it was adjusted to pH6.0 with 1.0 mol/L sodium hydroxide aqueous solution. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-(isoquinolin-4-yl)benzoic acid 50 mg of pale green solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:11](Cl)(=[O:13])=[O:12])[S:5][C:6]=1[CH2:7][CH2:8][O:9][CH3:10].[O:15]([C:17]#[N:18])[Na].N1C=CC=CC=1.[Br:25][C:26]1[CH:31]=[C:30]([NH2:32])[N:29]=[C:28]([NH2:33])[CH:27]=1>C(#N)C>[NH2:33][C:28]1[N:29]=[C:30]([NH:32][C:17]([NH:18][S:11]([C:4]2[S:5][C:6]([CH2:7][CH2:8][O:9][CH3:10])=[C:2]([Cl:1])[CH:3]=2)(=[O:13])=[O:12])=[O:15])[CH:31]=[C:26]([Br:25])[CH:27]=1
Reactant: N#CO[Na]
Reactant: Nc1cc(Br)cc(N)n1
Reactant: COCCc1sc(S(=O)(=O)Cl)cc1Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: COCCc1sc(S(=O)(=O)NC(=O)Nc2cc(Br)cc(N)n2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.9 %

Procedure:
4-Chloro-5-(2-methoxy-ethyl)-thiophene-2-sulfonyl chloride (73 mg) was dissolved in acetonitrile (1.5 mL), NaOCN (38 mg) and pyridine (130 mL) was added to the solution. The mixture was stirred for 4 h at 25° C. After that 4-bromo-pyridine-2,6-diamine (50 mg) was added to the mixture as solid. The resulting yellow suspension was stirred for 2 h at 25° C. The suspension was evaporated to dryness, dissolved in DMSO (1.5 mL) and purified with preparative HPLC. N-[(6-amino-4-bromopyridin-2-yl)carbamoyl]-4-chloro-5-(2-methoxyethyl)-thiophene-2-sulfonamide (21 mg, 16.8% yield) was obtained as amorphous white solid.
Reaction SMILES: C([N:4](CC)[CH:5]([CH3:7])[CH3:6])(C)C.OC(C(F)(F)F)=O.[N:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]3([C:30]4[N:34]5[CH:35]=[C:36]([C:39]6[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=6)[C:42]([OH:44])=O)[CH:37]=[N:38][C:33]5=[N:32][CH:31]=4)[CH2:29][CH2:28]3)=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C1(N)CC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CO>[CH:5]1([NH:4][C:42](=[O:44])[C:41]2[CH:45]=[CH:46][CH:47]=[C:39]([C:36]3[CH:37]=[N:38][C:33]4[N:34]([C:30]([C:27]5([C:23]6[CH:22]=[C:21]7[C:26](=[CH:25][CH:24]=6)[N:17]=[CH:18][CH:19]=[CH:20]7)[CH2:29][CH2:28]5)=[CH:31][N:32]=4)[CH:35]=3)[CH:40]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1cccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(NC1CC1)c1cccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N,N-Diisopropylethylamine (194 μL, 1.11 mmol) was added to a mixture of 3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid TFA salt (126.9 mg, 0.2 mmol), cyclopropylamine (17.1 mg, 0.3 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (97.3 mg, 0.22 mmol) in N,N-dimethylformamide (1.0 mL). The mixture was stirred at RT for 3 h, and was diluted with methanol (0.8 mL). The resulting solution was purified by RP-HPLC (pH=10) to give the desired product. LCMS: (M+H)=446.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]1([C:20](=O)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:29][C:30]([NH2:32])=[O:31].Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:32][C:30](=[O:31])[NH:29]2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2cc(F)c(O)c([N+](=O)[O-])c2)N1
Temperature: 86 °C
Yield: 41.4 %

Procedure:
A mixture of 3-fluoro-4-hydroxy-5-nitrobenzaldehyde (Intermediate 63) (150 mg, 0.81 mmol), 1,2-diphenylethanone (159 mg, 0.81 mmol), urea (145 mg, 2.43 mmol), concentrated hydrochloric acid (0.5 mL) in ethanol (2 mL) was refluxed at 86° C. for 46 hours. After cooling, the mixture was evaporated and the crude product was purified by preparative HPLC to give Compound 127 (136.1 mg, yield 41.4%). 1HNMR (DMSO-d6 400 MHz): δ 11.25 (s, 1H), 8.77 (s, 1H), 7.70 (s, 1H), 7.59 (s, 1H), 7.52-7.49 (m, 1H), 7.27-7.22 (m, 5H), 7.06-6.98 (m, 3H), 6.83 (d, J=6.4 Hz, 2H), 5.27 (d, J=2.4 Hz, 1H); MS (ESI): m/z 406.0 [M+H]+.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)=O>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)=[S:10]
Reactant: O=C(Nc1ccc(F)cc1F)c1ccccn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(NC(=S)c2ccccn2)c(F)c1
Yield: 94.7 %

Procedure:
Lawesson's reagent (29.8 g, 74 mmol) and N-(2,4-difluorophenyl)-2-pyridinecarboxamide (14.37 g, 61 mmol) were combined in toluene (185 mL) and refluxed for 3 hours. After evaporation of the solvent, the residue was dissolved in dichloromethane, preadsorbed on silica gel, and flash chromatographed (eluted with 2% acetate in petroleum ether) to provide N-(2,4-difluorophenyl)-2-pyridinecarbothioamide as a yellow solid (14.45 g, 94%) m.p. 124°-129° C.