Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:15]2[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)[C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:29]=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>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:26]2[CH:27]=[C:28]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])[CH:29]=[C:24]([Cl:23])[CH:25]=2)=[CH:9][C:10]=1[C:15]1[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1
Reactant: O=C(c1cc(Cl)cc(B(O)O)c1)N1CCOCC1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
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: C1COCCO1
Solvent: O
Product: CC(C)n1cc(-c2cc(-c3cc(Cl)cc(C(=O)N4CCOCC4)c3)cnc2N)nn1
Temperature: 120 °C
Yield: 15.4 %

Procedure:
Cs2CO3 (682 mg, 2.10 mmol) was added to a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and (3-chloro-5-(morpholine-4-carbonyl)phenyl)boronic acid (210 mg, 0.78 mmol) in dioxane: water (8 mL: 4 mL) degassed the reaction mixture for 10 min with nitrogen. Then added Pd(PPh3)4 (40 mg, 0.035 mmol), degassed the reaction mixture for additional 10 min with nitrogen, the reaction mixture was heated to 120° C. in microwave for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 80-90% ethyl acetate in pet-ether to afford 46 mg (Yield: 47.0%) of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1.[C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH3:16].[Li]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([C:1](=[O:13])[CH2:16][C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: COC(=O)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
Dimethyl isophthalate (67.9 g) was treated with lithium tert.-butyl acetate according to general procedure K (method b) to give crude 3-tert-butoxycarbonylacetyl-benzoic acid methyl ester (74.5 g) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].O>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:14][CH2:11][C:12]#[CH:13])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: C#CCN
Solvent: O
Solvent: CC#N
Product: C#CCNc1cc(Cl)nc(SC)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 99.4 %

Procedure:
A mixture of 1.00 g (5.13 mmol) of 4,6-dichloro-2-(methylthio)pyrimidine and 0.7 ml (10.3 mmol) of propargylamine in 10 ml of acetonitrile was stirred for 12 hours at 60° C. The reaction solution was poured onto cold water. Then, the formed precipitate was filtered, washed several times with cold water and dried. 1.09 g of a light yellow solid were obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[CH2:24]([O:12][C:11](=[O:13])[C:10](=[O:14])[CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:17][CH3:18])([CH3:16])[CH3:15])[CH3:25]
Reactant: COc1c(F)cccc1C(C)(C)CC(=O)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC(C)(C)c1cccc(F)c1OC
Yield: 90.6 %

Procedure:
4.14 g (16.28 mmol) of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 97 ml of ethanol, mixed with 1.79 ml of sulfuric acid and refluxed for four hours. The ethanol is drawn off in a rotary evaporator, and the residue is carefully mixed with saturated sodium bicarbonate solution until a pH of 9 is reached. It is extracted twice with 100 ml each of ethyl acetate, and the combined organic extracts are washed with water and then with brine. After the desiccant is dried and filtered off, and after the solvent is spun in, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 4.16 g (90.6%) of the desired compound is isolated.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][C:16]([C:19]3[C:27]4[C:22](=[C:23]([F:28])[CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)=[CH:15][CH2:14]2)[C:3]1=[O:29].C(O)(=O)C.[H][H].[ClH:37]>C(O)C.[Pt]=O.C>[ClH:37].[CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([F:28])[CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:17][CH2:18]2)[C:3]1=[O:29]
Reactant: [H][H]
Reactant: CC1(C)C(=O)N(CCN2CC=C(c3c[nH]c4c(F)cccc34)CC2)c2ccccc21
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)C(=O)N(CCN2CCC(c3c[nH]c4c(F)cccc34)CC2)c2ccccc21

Procedure:
3,3-Dimethyl-1-{2-[4-(7-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-1,3-dihydro-2H-indol-2-one (0.6 g, 1.36 mmol) dissolved in ethanol (40 mls) and acetic acid (4 mls) was added to 10% platinum oxide/charcoal. Hydrogen was admitted for 12 h at 60 psi the catalyst was then removed by filtration, the catalyst washed with ethanol (3×75 mls), concentrated in vacuo and the resulting oil purified by column chromatography on silica with ethyl acetate/Hexane. The fractions containing product were collected and the solvent evaporated in vacuo to give a solid which was converted to the hydrochloride, which was subsequently dried in vacuo to give a solid, mp 172-174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][C:3]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:2]([F:1])[CH:7]=2)=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1F)OCc1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)c(F)c2)cn1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
To a solution of benzyl {2-fluoro-4-[(6-nitropyridin-3-yl)oxy]phenyl}carbamate (40 g, 104.3 mmol) in ethanol (1020 mL)/water (180 mL) were added reduced iron (29.1 g, 521.7 mmol) and calcium chloride (5.8 g, 52.2 mmol), and the mixture was heated under reflux for 8 hr. The reaction mixture was cooled to room temperature, filtered through celite, and washed with ethanol. The solvent was evaporated under reduced pressure, water (200 mL) was added to the residue, and the mixture was extracted with ethyl acetate (800 mL). The organic layer was washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, hexane/ethyl acetate (=3/1) was added, and the precipitate was collected by filtration to give the title compound (28.2 g, 76%).
Reaction SMILES: CO.[NH:3](C(OCC1C=CC=CC=1)=O)[C@H:4]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[H][H]>[Pd].C(O)(=O)C>[NH2:3][C@H:4]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
300 ml of absolute methanol, 2 ml of acetic acid, and palladium black were added to 9.68 g (20.26 mmol) of Z-Lys(Boc)-Pro-OH, and hydrogenation was performed in the stream of dry hydrogen at room temperature under 1 atm for 8 hours. Then, the catalyst was filtered off and washed on the filter with methanol. Pooled filtrate was evaporated to dryness. The residue was precipitated with ether from the absolute methanol. Then, it was dried under vacuum, while desiccant was changed several times.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:18].S(=O)(=O)(O)O.[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)[CH3:25]>CN(C)C=O>[CH3:25][C:24]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:1][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8]([C:7](=[O:17])[C:6]=3[CH:5]=[CH:4][C:3]=2[NH:18]1)=[CH:9][CH:10]=[CH:11][CH:12]=4
Reactant: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Reactant: CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)Nc2ccc3c(c2N1)C(=O)c1ccccc1C3=O
Reaction time: 72 h

Procedure:
1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto after acetophenone (0.5 ml, 6 mmol) is added thereinto. After mixing and reacting in room temperature for 72 hours, the reacted mixture is transferred into icy water (200 mL) for precipitation. The precipitate is collected and recrystallized by hot alcohol, so as to obtain the black compound 21, and the production rate is 28%.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])O[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[O:17]=[S:18]1(=[O:34])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:20]([CH2:28]C(OCC)=O)=[N:19]1.[H-].[Na+].C(O)(=O)C>C1COCC1.Cl>[CH2:1]([N:5]1[C:10]2[C:9](=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]([OH:15])=[C:28]([C:20]2[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:18](=[O:34])(=[O:17])[N:19]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2ccccc2N1
Reactant: CCCCn1c(=O)oc(=O)c2cccnc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc21
Temperature: 0 °C
Yield: 32.6 %

Procedure:
To a solution of the product of Example 1B (0.220 g, 1.0 mmol) and the product of EXAMPLE 1C (0.268 g, 1.0 mmol) in anhydrous THF (10 mL) under nitrogen at 0° C. was added sodium hydride (95%, 0.10 g, 4.0 mmol). The reaction was heated to reflux for 3 hours, cooled to 0° C., and to it was added dropwise glacial acetic acid (2 mL). The resulting mixture was heated to reflux for 2 hours, cooled to ambient temperature, and diluted with aqueous hydrochloric acid (0.1 M, 10 mL). The resulting precipitate was collected by filtration, washed with water and diethyl ether and dried to give the title compound (0.130 g, 33%). MS (ESI−) m/z 397 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12.[H-].[Na+].[CH3:19]I>CN(C)C=O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH3:19])[C:5](=[O:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture of 2.8 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 620 mg. of 50% sodium hydride in mineral oil in 30 ml. of dry dimethylformamide is stirred for 11/4 hours. A 2.1 g. portion of methyl iodide is added and the mixture is stirred overnight. The mixture is poured onto ice water and the solid is collected and dried. The solid changes to a glass which is dissolved in methylene chloride, washed with water, filtered and concentrated to dryness. The crude oily solid is triturated in hexane and ether. The ether hexane mixture is concentrated to a yellow gum, dissolved in 15 ml. of 30% methylene chloride in hexane and chromatographed on an alumina column, eluting with the same solvent. Four 200 ml. fractions are collected. The solvent is changed to methylene chloride:hexane (50:50) for fractions 5-8 (200 ml.). The solvent is changed to 100% methylene chloride for fractions 8-11 (200 ml.). The solvent is changed to 20% ethyl acetate in benzene for fractions 12-19 (200 ml.). Fractions 11-19 are combined and concentrated to a yellow oil which crystallizes with trituration in hexane, giving the desired product, mp. 101°-102° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([N:14]([CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:25][CH:24]=2)=[CH:29][CH:30]=1
Reactant: CC(C)CCN(c1ccc(OCc2ccc(F)cc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCN(c1ccc(OCc2ccc(F)cc2)cc1)C1CCNCC1
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
4-{[4-(4-fluorobenzyloxy)-phenyl]-(3-methyl-butyl)-amino}-piperidine-1-carboxylic acid tert-butyl ester (If, 1.80 g, 3.82 mmol) was dissolved in CH2Cl2 (12 mL), treated with TFA (12 mL), and stirred for 20 minutes. The reaction was concentrated and placed under vacuum for 20 minutes, then diluted with EtOAc (200 mL), washed twice with saturated sodium bicarbonate solution and once with brine, dried over Na2SO4, and concentrated to give 0.89 g (74%) of the desired product.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[C:8]([NH:33][C@@H:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:35][OH:36])=[CH:9][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([F:22])[CH:20]=3)[N:15]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:14]=2)=[N:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:36][CH2:35][C@@H:34]([NH:33][C:8]1[C:7]([F:6])=[CH:12][N:11]=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([F:22])[CH:20]=3)[N:15]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:24])=[O:25])[CH:14]=2)[CH:9]=1)[C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:4])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CO)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](COS(C)(=O)=O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (1.83 mL, 23.67 mmol) was added to a cold (0° C.) solution of (S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutan-1-ol, 54a, (9.50 g, 18.94 mmol) and triethylamine (3.30 mL, 23.67 mmol) in dichloromethane (118 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water (100 mL) and EtOAc (200 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure to afford 10.5 g of the desired product as a pale yellow foam: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 580.41 (M+H) RT=2.00 minutes.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:6]=[CH:5][N:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]([CH2:32][C@H:33]([OH:38])[C:34]([F:37])([F:36])[F:35])[C:28](=[O:31])[NH:29][N:30]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]([CH2:32][C@H:33]([OH:38])[C:34]([F:36])([F:37])[F:35])[C:28](=[O:31])[N:29]([CH2:2][C:3]3[CH:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]([F:18])([F:17])[F:16])[N:6]=[CH:5][N:4]=3)[N:30]=2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccccc1-c1cc(CBr)ncn1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2cc(-c3ccccc3C(F)(F)F)ncn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
37 mg (0.12 mmol) of the compound from Example 82A were dissolved in 2 ml of acetonitrile, and 39 mg (0.13 mmol) of the compound from Example 5A and 57 mg (0.18 mmol) of cesium carbonate were added. The mixture was stirred at 60° C. for 2.5 h. After cooling to RT, the solid was filtered off and rinsed with a little acetonitrile. The filtrate was concentrated under reduced pressure and directly purified chromatographically [Method 19]. The product obtained was subjected to a further chromatographic purification on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1, then 3:2). This gave 28 mg (41% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[OH:23])=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:24])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](I)[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[O:23][CH2:31][CH3:32])=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:24])=[CH:4][N:3]=1
Reactant: CCI
Reactant: Oc1cnccc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cnccc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.4 %

Procedure:
Treat a solution of 4-[2-(2-chloro-5-fluoro-pyrimidin-4-yl)-benzo[b]thiophen-7-yl]-pyridin-3-ol (100 mg, 0.28 mmol) and cesium carbonate (100 mg, 0.28 mmol) in dimethylformamide (1 mL) with ethyl iodide (44 mg, 0.28 mmol). Stir the mixture at room temperature for 12 hours. Dilute the mixture with ethyl acetate and wash the solution with three portions of water, one portion of saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate in vacuo. Purify the crude product by column chromatography on 12 g silica gel eluting with a gradient of dichloromethane to ethyl acetate to give the title compound (48 mg, 45%) as a brown solid. MS (ES) m/z 386 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([F:9])=[CH:7][C:6](Br)=[CH:5][C:4]=1[F:11].[C:12]([Cu])#[N:13]>CN(C=O)C.O>[F:11][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([F:9])[C:3]=1[O:2][CH3:1])[C:12]#[N:13]
Reactant: N#C[Cu]
Reactant: COc1c(F)cc(Br)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(F)cc(C#N)cc1F
Temperature: 120 °C
Reaction time: 48 h
Yield: 30.9 %

Procedure:
A mixture of 4-bromo-2,6-difluorophenyl methyl ether (11.5 g, 0.0516 mol; see step (ii) above) and CuCN (6.92 g, 0.0774 mol) in dry DMF (15 mL) was stirred at 120° C. for two days under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by column chromatography over silica gel, using 2% ethyl acetate in petroleum ether as eluent, yielded 2.7 g of the sub-title compound as a pale yellow solid.
Reaction SMILES: [SH:1][CH2:2][C:3]([NH2:5])=[O:4].O1CCOCC1.[Cl:12][C:13](=[CH2:18])[C:14]([O:16][CH3:17])=[O:15]>N1C=CC=CC=1>[Cl:12][CH:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:18][S:1][CH2:2][C:3]([NH2:5])=[O:4]
Reactant: C=C(Cl)C(=O)OC
Reactant: NC(=O)CS
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)C(Cl)CSCC(N)=O
Reaction time: 1 h

Procedure:
2-Mercaptoacetamide (18.79 g) was stirred in a mixture of dry 1,4-dioxan (200 ml) and dry pyridine (33.5 ml)) whilst methyl 2-chloroacrylate (24.88 g) was added dropwise over 15 minutes. The mixture was stirred for 1 hour then stood overnight. The resultant mixture contained the title compound.
Reaction SMILES: Cl.[NH2:2]O.C([O-])=O.[Na+].[CH2:8]([O:10][C:11]([C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]=O)[CH:19]=2)=[N:15][C:14]=1[CH3:27])=[O:12])[CH3:9].O>C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]#[N:2])[CH:19]=2)=[N:15][C:14]=1[CH3:27])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1sc(-c2ccc(O)c(C=O)c2)nc1C
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CCOC(=O)c1sc(-c2ccc(O)c(C#N)c2)nc1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (35.82 g, 0.515 mol) and sodium formate (46.73 g, 0.687 mol) were added to a solution of ethyl-2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazole carboxylate (100 g, 0.343 mol) in formic acid (anhydrous, 300 mL) and the reaction mixture was heated to a temperature of about 100° C. for about 8 hours. After completion of reaction, the reaction mixture was cooled to about 40° C. and water was added to it. The reaction mixture was cooled to about 25° C. and stirred for about 1 hour. The solid obtained was filtered, washed with water and dried. The solid was then dissolved in acetone at about 50° C. and water was added slowly over a period of about 30 minutes. The mixture was cooled to about 25° C. and again stirred for about 1 hour. The solid thus obtained was filtered, washed with acetone:water (1:1) mixture and dried to obtain the title product. (Yield: 85 g, 85.9%)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[N:30]1(C2C=CC(N)=CC=2)[CH:34]=[CH:33][CH:32]=[CH:31]1>>[N:30]1([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]3[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH2:1])[N:14]=3)=[CH:21][CH:20]=2)[CH:34]=[CH:33][CH:32]=[CH:31]1
Reactant: Nc1ccc(-n2cccc2)cc1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-n2cccc2)cc1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(1H-pyrrol-1-yl)aniline in step 1. MS: 392.4 (M+H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10](=[NH:22])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]=2[O:2]1.C(=O)(O)[O-].[Na+].Br[CH2:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32]>C(O)(C)C>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([N:11]2[CH2:29][C:30]([OH:35])([C:31]([F:34])([F:33])[F:32])[N:22]=[C:10]2[C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc3c(c2)OCO3)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc3c(c2)OCO3)cc1
Yield: 46.7 %

Procedure:
To a mixture of 3,4-methylenedioxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide from Step 1 (2.32 g, 7.3 mmol) and sodium bicarbonate (1.23 g, 14.6 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (5.4 mL, 52 mmol) was added. After heating the reaction mixture to reflux for 24 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture (7.1 g) was purified by chromatography (silica gel, toluene/ethyl acetate, 1/1) to give 5-[1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl)-1,3-benzodioxole (1.46 g, 47%) as a white solid: mp 200–202° C. Anal. Calc'd. for C18H15N2SO5F3.0.25 PhCH3: C, 52.55; H, 3.80; N, 6.21. Found: C, 52.73; H, 3.78; N, 6.01.