Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:18][C:5]2=[N:6][C:7]([CH3:17])=[CH:8][C:9]([NH:10][S:11]([CH:14]3[CH2:16][CH2:15]3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1.C([O-])([O-])=O.[K+].[K+].[NH:33]1[CH:37]=[C:36](B(O)O)[CH:35]=[N:34]1>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>[CH3:17][C:7]1[N:6]=[C:5]2[S:18][C:2]([C:36]3[CH:37]=[N:33][NH:34][CH:35]=3)=[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:4]2=[C:9]([NH:10][S:11]([CH:14]2[CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH:8]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)C4CC4)c23)c1
Reactant: OB(O)c1cn[nH]c1
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: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(-c3cn[nH]c3)sc3nc(C)cc(NS(=O)(=O)C4CC4)c23)c1
Temperature: 130 °C

Procedure:
To a suspension of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}cyclopropanesulfonamide (Example 95) (58 mg, 0.128 mmol), K2CO3 (57 mg, 0.412 mmol) and 1H-pyrazol-4-ylboronic acid (30 mg, 0.268 mmol) in 1,4-dioxane (1 mL) and water (0.4 mL), was added tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol). The reaction mixture was heated at 130° C. in a microwave reactor for 1 h and was then directly loaded onto a silica column, eluting with a gradient of 0-75% of ethyl acetate in cyclohexane and further purified by MDAP (acidic then basic conditions) to give the desired product and a white solid thought to be a salt of the desired product. The solid material was subsequently dissolved in DCM (1 mL) and treated with acetic acid (ca. 0.5 mL). The solvent was then removed to give a residue which was combined with the initially obtained product and the mixture further purified on silica, eluting with a gradient of 0-75% ethyl acetate in cyclohexane, to give the title compound (18 mg). LCMS (A) m/z: 441 [M+1]+, Rt 1.08 min (acidic).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:5])[CH3:2].C(O)(=O)C.[ClH:21].OO>O>[Cl:21][C:13]1[CH:14]=[C:15]([CH3:16])[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: Cl
Reactant: CCOC(=O)Nc1c(C)cccc1C(=O)O
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1c(C)cc(Cl)cc1C(=O)O
Temperature: 37.5 °C
Reaction time: 1 h

Procedure:
A 2-L reactor equipped with overhead stirrer and thermocouple was charged with 150 g (0.672 mol) of 2-[(ethoxycarbonyl)amino]-3-methylbenzoic acid (ca. 98% purity) and acetic acid (500 g). The resulting slurry was heated to 35-40° C. to give a solution, which was cooled to 30° C., and then hydrochloric acid (37%, 150 g, 1.5 mol, 2.2 eq) was added. The mixture was maintained at 30° C. while aqueous hydrogen peroxide (30%, 96 g, 0.85 mol, 1.25 eq) was added over about 1 h. The mixture was then warmed to 35° C. and held at that temperature for about 1 h. About 600 mL of water was metered in over about 30 minutes, while maintaining the temperature at 30-35° C. The mixture was cooled to 10° C., and the product was collected by filtration, and the wet cake was washed with water (3×100 mL); the third wash tested negative with KI-starch paper. The wet cake was dried to constant weight in a vacuum oven at 50° C. The crude yield was about 150 g (about 84% based on an estimated purity of 2-[(ethoxycarbonyl)amino]-3-methylbenzoic acid of 98% and estimated product purity of 95%). A portion of the crude product was first recrystallized from toluene and then recrystallized from aqueous methanol to give an analytical sample melting at 124-126° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH:25][CH2:26][C:27]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39](Br)[CH:40]=1)(=[O:34])=[O:33])([CH2:29][OH:30])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39]([C:14]#[C:13][C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][C:6]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)=[N:7][C:8]=23)[CH:40]=1)(=[O:34])=[O:33])([CH2:29][OH:30])[CH3:28]
Reactant: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (81 mg, 0.25 mmol) (Example B.4) according to general procedure II. Obtained as a yellow solid (81 mg, 57%). MS (ISP) 572.3 [(M+H)+]; mp 190-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18](Cl)=[O:19])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[C:17](/[C:18](/[O:19][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH2:13][CH:10]4[CH2:12][CH2:11]4)[CH:16]=3)=[CH:8]/[C:7]3[C:6]([Cl:9])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:12][CH2:11]1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OCC1CC1
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OCC3CC3)c2)cc1OCC1CC1

Procedure:
The compound was obtained starting from 3,5-dichloro-4-methyl-pyridine and 3-(cyclopropylmethoxy)-4-methoxy-benzoyl chloride, following the procedure of Example 31.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.[C:6]1([S:12]([OH:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[C:6]1([S:12]([CH:5]2[CH2:4][CH2:3][CH2:2][O:1]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(O)c1ccccc1
Reactant: C1=COCC1
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2,3-dihydrofuran (1.40 g, 19.97 mmol) and benzene sulfinic acid (3.12 g, 21.97 mmol) in methylene chloride (80 mL) was stirred at 25° C. for 2 h. The reaction was then transferred to a separatory funnel and washed with a saturated aqueous sodium carbonate solution (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was then recrystallized using diethyl ether/petroleum ether to afford 2-benzenesulfonyl-tetrahydro-furan as a white solid: mp 55.9–56.8° C.
Reaction SMILES: [Cl-].[Li+].O.[CH2:4]([C:11]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])(C(OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]>CS(C)=O>[F:37][C:26]([F:38])([C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])[CH2:25][CH2:24][CH2:23][CH2:22][CH:11]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C=CCCCCCC(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCC(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reaction time: 12 h
Yield: 49.5 %

Procedure:
Lithium chloride (0.75 g, 17.72 mmol) and water (0.16 ml, 8.86 mmol) were added to a solution of diethyl 2-(6-heptenyl)-2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)malonate (4.7 g, 8.86 mmol) in dimethyl sulfoxide (100 ml) followed by stirring for 12 hours at a temperature of 170° C. to 180° C. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with ethyl acetate (100 ml). The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/50) to give ethyl 2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)-8-nonenoate (2.01 g, Yield 49.5%).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:33][C:32]4[CH:34]=[CH:35][C:29]([N:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)=[CH:30][CH:31]=4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: CN1CCN(c2ccc(NC(=O)COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)cc2)CC1
Yield: 94.6 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and 4-(4-methylpiperazin-1-yl)aniline (0.133 g, 0.69 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)acetamide as a white solid (0.30 g, 93.4% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH3:9])[CH:5]=[C:4]([OH:15])[CH:3]=1.O[C:17]([C:20]1[CH2:25][CH:24]=[C:23]([O:26][CH3:27])[CH2:22][CH:21]=1)([CH3:19])[CH3:18].B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:27][O:26][C:23]12[CH2:22][CH:21]([C:20](=[C:17]([CH3:18])[CH3:19])[CH2:25][CH2:24]1)[C:3]1=[C:4]([OH:15])[CH:5]=[C:6]([CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH3:9])[CH:7]=[C:2]1[O:1]2
Reactant: COC1=CCC(C(C)(C)O)=CC1
Reactant: COCCCC(C)c1cc(O)cc(O)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: COCCCC(C)c1cc(O)c2c(c1)OC1(OC)CCC(=C(C)C)C2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.05 g. of 1,3-dihydroxy-5-(5-methoxy-2-pentyl)- benzene and 1.06 g. (6 mmoles) of 1-(2-hydroxy-2-propyl)- 4methoxy-1,4-cyclohexadiene [R.A. Archer et. al. J. Org. Chem., 42, 2277 (1977)]are dissolved in 25 ml. of abs. benzene. 0.5 ml. (3.4 mmoles) of borontrifluoride etherate are added and the mixture is stirred at room temperature for 5 hours. Further 0.40 g. (2.4 mmoles) diene are added and the mixture is stirred overnight. The solution is poured off from the precipitated gum and extracted with 3 ×10 ml. of 1 N sodium hydroxide. The benzene solution is dried, evaporated and the residue is chromatographed on a column with a 8.1 mixture of benzene: ethyl acetate. The product is a colorless resin.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)[NH2:31]>>[N:35]1[CH:36]=[CH:37][C:32]([C:30]2[N:31]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:26][N:29]=2)=[CH:33][CH:34]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ccncc1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccncc3)no2)C1

Procedure:
250 mg (about 0.65 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid and 97 mg (0.71 mmol) of N′-hydroxypyridine-4-carboximidamide were reacted according to the General Method 1. Yield: 45 mg (14% of theory)
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[N:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[C:26](=[O:33])N(CCO)N=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:1]([C:3]3[CH:4]=[N:5][C:6]4[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=4[N:8]=3)[N:2]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: NNc1cnc2ccccc2n1
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3cnc4ccccc4n3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 2-hydrazino-1,4-benzodiazine as described for compound 35. Purified by chromatography and crystallized from diethyl ether. M.p. 154°-156° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].[I-:17].[Na+]>CC(C)=O>[I:17][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC=C(C(=O)OC)c1ccccc1CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC=C(C(=O)OC)c1ccccc1CI

Procedure:
A solution of methyl 2-[2-(chloromethyl)phenyl]-3-methoxypropenoate (1.0 equiv) and sodium iodide (1.5 equiv) in acetone was stirred at room temperature and monitored to completion by GC. The resulting mixture was filtered, concentrated under vacuum, then diluted with chloroform and filtered again to remove the remaining sodium salts. The filtrate was concentrated and purified by chromatography over silica gel eluted with ethyl acetate hexane mixtures to afford methyl 2-[2-(iodomethyl)phenyl]-3-methoxypropenoate as a yellow solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH3:11][C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[N:16][C:17]=1[CH3:18]>>[CH3:11][C:12]1[C:13]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[N:14][C:15]([Cl:19])=[N:16][C:17]=1[CH3:18]
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1nc(Cl)nc(Cl)c1C
Product: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Yield: 68.7 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 1,2,3,4-tetrahydroisoquinoline(2.9 g, 23 mmol) and 5,6-dimethyl-2,4-dichloropyrimidine(3.8 g, 21 mmol) and 1,2,3,4-tetrahydroisoquinoline(2.9 g, 23 mmol) prepared in Step 1 of Example 12 were used as starting materials, 3.95 g of the titled compound was prepared.
Reaction SMILES: [Na].Cl[C:3]1[C:8]([O:9][CH:10]([F:12])[F:11])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:13][OH:14]>>[F:11][CH:10]([F:12])[O:9][C:8]1[C:3]([O:14][CH3:13])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: FC(F)Oc1cccnc1Cl
Agent: [Na]
Product: COc1ncccc1OC(F)F
Temperature: 100 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
As shown in step 3-ii of Scheme 3, an excess of sodium metal was dissolved into 20 mL anhydrous methanol and 2-chloro-3-(difluoromethoxy)pyridine (2.0 g, 11.1 mmol) in anhydrous methanol was added. The reaction mixture was stirred in a sealed vessel at 100° C. for 6 hours. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and brine. The brine was extracted with EtOAc and the combined organics were dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography (DCM) to yield 3-(difluoromethoxy)-2-methoxypyridine as a colorless oil (Compound 1007, 1.1 g, 56% yield: ESMS (M+H) 176.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>C(O)CCC>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:19][NH2:20])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccccn2)CC1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2ccccn2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (1.33 g, 5.66 mmol) and hydrazine hydrate (0.55 ml, 11 mmol) in n-butanol (1 ml) was heated at 120° C. for 68 h. After cooling to room temperature the reaction mixture was evaporated and dried in high vacuo (ca. 1-2 mbar) at 100° C. for 2 h to give the crude title compound (1.28 g, 96%) as white solid, which was used in the next step without further purification. MS m/e: 236 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[C:11]=3[CH:22]=2)=[N:4][N:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:23][S:24]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[C:11]3[CH:22]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[N:3][N:4]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)=[CH:20][CH:19]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(O)cc4)c3c2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc3occ(-c4ccc(OS(C)(=O)=O)cc4)c3c2)o1
Temperature: 60 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
A suspension of 4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenol (351 mg, 1.20 mmol), methanesulfonyl chloride (0.111 mL, 1.44 mmol) and potassium carbonate (332 mg, 2.40 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 hr and at 60° C. overnight. The reaction mixture was diluted with ethyl acetate. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) and recrystallized from hexane/ethyl acetate to give the title compound (107 mg, yield 24%) as colorless crystals.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]([CH3:28])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1>CS(C)=O>[CH3:28][C:10]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:2][O:9]1
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(CN2CCN(C(=O)OCc3ccccc3)CC2)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
Trimethylsulfoxonium iodide (1.96 g, 8.91 mmol) was added to a suspension of sodium hydride (0.37 g, 9.32 mmol) in DMSO (20 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 30 minutes. To the mixture a solution of benzyl 4-(2-oxopropyl)piperazine-1-carboxylate (2.24 g, 8.10 mmol) in DMSO (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to afford benzyl 4-(2-methyl-2-oxiranylmethyl)piperazine-1-carboxylate (1.51 g, yield 64%) as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:19][C:18](=[O:20])[C:17]3[N:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:23][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:21]1[C:17]2[C:18](=[O:20])[NH:19][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15][C:16]=2[N:23]=[CH:22]1)[CH3:29]
Reactant: CCOC(=O)Cn1cnc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c(=O)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1cnc2cc(N3CCNCC3)[nH]c(=O)c21
Reaction time: 1.5 h

Procedure:
4-(3-ethoxycarbonylmethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester, 4 was dissolved in dry methylene chloride at room temperature under N2. CF3COOH (5 equiv.) was added, and the reaction mixture was stirred for 1.5 h. Then methylene chloride was removed in vacuo and the residue was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=[O:14])[NH:13][C:4]=2[CH:3]=1.[C:18]1(C)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12]([O:14][CH3:18])=[N:13][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)c2sccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1nc2cc(Cl)ccc2c(=O)c2sccc12
Temperature: 108 °C
Reaction time: 5 h

Procedure:
A 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, addition funnel and a condenser with nitrogen inlet-outlet is charged with 7-Chloro-9H-3-thia-9-aza-benzo[f]azulene-4,10-dione (559.6 g), toluene (6.8 kg) and dimethylformamide (100.73 g). To the stirred suspension phosphorus oxychloride (357.2 g) is added over 5 min at 20-25° C. The pipes are flushed with toluene (774 g), then the temperature is raised to 108° C. over 1 hour and stirring continued for about 5 hours. Then the mixture is cooled to −5° C. and a 30% solution of sodium methylate (1.43 kg) is added over 30 min at −5° C. After addition the mixture is warmed to 40° C. over an hour and the solvent is distilled at 20-45° C. under reduced pressure. To the residue deionized water (6.7 kg) is added and the mixture is concentrated under reduced pressure to 7 L. Then heptane (3.06 kg) is added and the temperature is raised to 70° C. over 1 hour, followed by additional stirring of 10 min. The suspension is then cooled to 0° C. and the solid is collected by filtration, washed with heptane (2×383 g) and deionized water (2×1.1 kg) and dried under vacuum at 65° C. to yield the title compound with a melting point of >195-197° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>C(O)CCC>[Cl:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([NH:15][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=2[O:11][CH3:10])[CH:28]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2cc(Cl)ncn2)c(OC)c1
Temperature: 100 °C
Yield: 85.2 %

Procedure:
N,N-Diisopropylethylamine (8.10 mL, 46.50 mmol) and 2,4-dimethoxybenzylamine (2.52 mL, 16.78 mmol) were added to a solution of 4,6-dichloropyrimidine (2.50 g, 16.78 mmol) in butanol (80 mL) and reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and washed with water (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic layers were dried over anhydrous MgSO4, filtered and evaporated. The residue was triturated in heptane to give the title compound (4.00 g, 85%) as a solid.