Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.I[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:14][Si:15]([C:18]#[C:19][C:9]1[S:10][CH:11]=[CH:12][N:13]=1)([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1nccs1
Temperature: 50 °C

Procedure:
Copper(I)iodide (38 mg, 0.20 mmol), dichlorobis(triphenylphosphine)palladium(II) (250 mg, 0.40 mmol) and N,N-diisopropylamine (1.40 g, 14 mmol) were added to a solution of 2-iodothiazole (1.50 g, 7.0 mmol; prepared as described in J. Org. Chem. 1988, 53, 2489) and dry tetrahydrofuran (50 mL). The reaction mixture was degassed and trimethylsilylacetylene (1.40 g, 14 mmol) was added in two portions under nitrogen atmosphere. The reaction was heated to 50° C. for 12 h. The formed precipitate and separated palladium were removed by filtration through a short path of silica gel. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel Fluka 60: hexane/ethyl acetate 98:2-90:10) yielding 2-(trimethylsilylethynyl)thiazole as yellow oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH:11]1([CH2:17]Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O>CO>[CH:11]1([CH2:17][O:10][C:9]2[C:4]([NH2:3])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrCC1CCCCC1
Reactant: Nc1ncccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ncccc1OCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At RT, 96 g of sodium hydroxide (45%; 1081 mmol, 1 equivalents) were initially charged in 1170 ml of methanol, 119 g of 2-amino-3-hydroxypyridine (1080 mmol, 1 equivalent) were added and the mixture was stirred at RT for 10 min. The reaction mixture was concentrated under reduced pressure, the residue was taken up in 2900 ml of DMSO and 101 g of cyclohexylmethyl bromide (1135 mmol, 1.05 equivalents) were added. After 16 h at RT, the reaction mixture was stirred into 6 l of water, and the aqueous solution was extracted twice, in each case with 2 l of ethyl acetate. The combined organic phases were washed with in each case 1 l of saturated aqueous sodium bicarbonate solution and water, dried, filtered and concentrated. The residue was stirred with 500 ml of pentane, filtered off and dried under reduced pressure. This gave 130 g (58.3% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]1([CH:30]([CH2:34][CH3:35])[C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:31](=[O:32])[CH:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:34][CH3:35])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CCC(C(=O)Cl)c1ccccc1
Product: CCC(C(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CC)c1ccccc1

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-butyramide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2-phenylbutyryl chloride (148 μl, 0.88 mmol). The title compound was obtained as yellow powder (69 mg, 19%).
Reaction SMILES: [CH2:1]([O:8][C:9](=O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:13]([Cl:15])=[O:14]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][CH2:9][C:13]([Cl:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of carbonic acid monobenzyl ester (3.50 g, 21.0 mmol) in the 50 ml of DCM and 0.50 ml of DMF was cooled to −78° C. followed by addition of oxalyl chloride (11.79 ml, 105 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. After the completion of the reaction mixture (TLC monitoring), concentrated it to give 2-benzyloxyacetyl chloride (3.0 g, 96%). To an ice cold solution of 3-amino-4-chloro-benzoic acid methyl ester in 10 ml of DCM was added triethylamine (2.47 ml, 17.78 mmol) followed by addition of 2-benzyloxyacetyl chloride (3.0 g, 17.78 mmol) in 10 ml of DCM. The reaction mixture was stirred at 25° C. for 12 hr. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (1.70 g, 31%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][S:15][CH2:16][CH2:17]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(N2CCSCC2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(N2CCSCC2)c2ccccc2c1=O

Procedure:
The product from Example 91B and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H), 8.30 (d, J=7.9 Hz, 1H), 7.84-8.02 (m, 3H), 7.05-7.19 (m, 3H), 3.73 (s, 2H), 2.83-2.87 (m, 4H); MS (APCI+) M/Z 417 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][N:9]=1.[CH2:19]([C:21]1[CH:22]=[C:23]([CH3:33])[C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:25][CH:26]=1)[CH3:20]>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[N:9]=[CH:10][C:11]([C:12]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[C:23]([CH3:33])=[CH:22][C:21]([CH2:19][CH3:20])=[CH:26][N:25]=3)[CH2:28][CH2:29]2)=[O:14])=[CH:16][CH:17]=1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)nc1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 46.3 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)nicotinate (107 mg) described in Preparation Example 45 and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (81 mg) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Example 109, [6-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)pyridin-3-yl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (81 mg) was obtained. The obtained [6-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)pyridin-3-yl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (81 mg) was dissolved in ethyl acetate/methanol, 2N hydrogen chloride/ethanol solution was added, and the solvent was evaporated under reduced pressure. The obtained residue was suspension washed with diisopropyl ether to give the title compound (83 mg).
Reaction SMILES: C([O:3][C:4]([CH:6]([CH3:18])[C:7]([N:9]1[CH2:17][C@H:15]([OH:16])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=[O:5])C>CO.[OH-].[Na+]>[C:4]([CH:6]([CH3:18])[C:7]([N:9]1[CH2:17][C@H:15]([OH:16])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)C(=O)N1C[C@H](O)C[C@H]1C(=O)O

Procedure:
1-(2-Ethoxycarbonylpropanoyl)-L-hydroxyproline is dissolved in a mixture of methanol (20 ml.) and N sodium hydroxide (20 ml.). After 6 hours the solvent is concentrated in vacuo to half volume and applied to a column of resin Dowex 50 (50 ml.) and eluted with water to obtain 1-(2-carboxypropanoyl)-L-hydroxyproline.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[F:70][C:71]([F:83])([F:82])[S:72]([C:75]1[CH:80]=[CH:79][C:78]([NH2:81])=[CH:77][CH:76]=1)(=[O:74])=[O:73]>O1CCOCC1.C(OCC)(=O)C>[F:19][C:18]([F:21])([F:20])[C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:81][C:78]4[CH:79]=[CH:80][C:75]([S:72]([C:71]([F:83])([F:70])[F:82])(=[O:74])=[O:73])=[CH:76][CH:77]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)C3)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
A mixture of 4-chloro-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.100 g, 0.000314 mol) tris(dibenzylideneacetone)dipalladium(0) (0.058 g, 0.000063 mol), Cesium Carbonate (0.311 g, 0.000944 mol) and Xantphos (0.018 g, 0.000031 mol) in 1,4-Dioxane (3 mL, 0.04 mol) was stirred at room temperature for 10 minutes in a 5 mL microwave vial. 4-(trifluoromethylsulfonyl)benzenamine (0.15 g, 0.00063 mol) was then added as a solution in dioxane (0.5 mL) and the mixture was stirred for an additional 5 minutes. The mixture was heated via microwave in a sealed tube at 140° C. for 30 minutes, allowed to cool, and reduced in vacuo. The resulting black solid was taken up in ethyl acetate (50 mL) and washed with brine and water (2×50 mL), dried over magnesium sulfate, and reduced in vacuo. The mixture was purified by flash chromatography using an ethyl acetate:hexanes (0-100%) gradient. The combined pure fractions were reduced in vacuo to yield the desired product as a tan solid (0.087 g).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[SH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH3:7]
Reactant: Oc1ccc(S)cc1
Reactant: CCOC(=O)C(Br)c1ccccc1OC
Product: CCOC(=O)C(Sc1ccc(O)cc1)c1ccccc1OC
Yield: 89 %

Procedure:
Ethyl(2-methoxyphenyl)[(4-hydroxyphenyl)sulfanyl]acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl bromo(2-methoxyphenyl)acetate (24 g, 87.5 mmol) and 4-mercaptophenol (11.0 g, 87.5 mmol); 24.9 g amber colored oil. Yield 89%; MS: 320 (M+H)+
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=1[C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[O:4].[I-].[Na+].[NH3:27]>O1CCCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[NH:5][C:3](=[O:4])[CH2:2][N:27]=1
Reactant: N
Reactant: CCOC(=O)c1cc(C(=O)c2ccccc2Cl)c(NC(=O)CCl)s1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(s1)NC(=O)CN=C2c1ccccc1Cl
Temperature: -65 °C

Procedure:
Ethyl 5-(2-chloroacetylamino)-4-(2-chlorobenzoyl)thiophene-2-carboxylate (325 g) and sodium iodide (151.3 g) were added to tetrahydrofuran (3500 ml), and the mixture was refluxed under heating for 1.5 hours. The mixture was cooled to -65° C., and ammonia (164 ml) was added. The reaction temperature was raised slowly to room temperature. The solvent was evaporated, and chloroform and water were added. The organic layer was taken out, washed with water and dried over sodium sulfate. The solvent was evaporated. Toluene (7 l) and silica gel (1365 g) were added thereto, and the mixture was refluxed under heating for 1.5 hours. The silica gel was collected by filtration, and a mixed solvent of chloroform-methanol (10:1) was added to elute the obtained product. The solvent was evaporated, and ethyl acetate was added. The resulting crystals were collected by filtration and washed with ethyl acetate to give 70.0 g of ethyl (5-(2-chlorophenyl)-1,2-dihydro-3H-thieno[2,3-e] [1,4]diazepin-2-on-7-yl)-carboxylate.
Reaction SMILES: CI.[C:3](=[O:6])([O-])[O-].[K+].[K+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1O>O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:6][CH3:3]
Reactant: Oc1c(F)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Methyl iodide (850 μl, 13.646 mmol) and potassium carbonate (943 mg, 6.824 mmol) were added to 2-chloro-6-fluorophenol (1.0 g, 6.824 mmol) in tetrahydrofuran (10 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between diethyl ether (50 ml) and water (50 ml). The organic phase was extracted and further washed with water (2×20 ml) then dried over sodium sulphate and concentrated in vacuo to afford the title compound as a colourless liquid in 94% yield, 1.03 g.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:25][CH2:24]1>>[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([C:18]([C:12]3[S:13][C:14]4[CH2:15][CH2:16][O:17][C:8]5[CH:7]=[C:6]([C:4]6[CH:5]=[N:1][NH:2][CH:3]=6)[CH:22]=[CH:21][C:9]=5[C:10]=4[N:11]=3)=[O:19])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1
Reactant: C1CN(CC2CC2)CCN1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(CC2CC2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(cyclopropylmethyl)piperazine (1.2 equiv) to give 195 (M+1 436.0)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:18][CH:17]=3)[CH:12]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[C].[Pd].ClCCl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[N:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])=[CH:20][CH:21]=3)[CH:12]=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=c1n(-c2ccc(OCC(F)(F)C(F)F)cc2)cnn1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(-n2ncn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Yield: 90.2 %

Procedure:
2-(4—Nitrophenyl)-4-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-3(2H,4H)-1,2,4-triazolone (5.5 g) and 10% palladium-carbon (50% wet, 0.5 g) were added to methanol (200 ml). The mixture was subjected to catalytic hydrogenation at ordinary temperature under ordinary pressure. When hydrogen absoption stopped, dichloromethane (200 ml) was added thereto and the catalyst was removed by filtration. The catalyst was washed with dichloroethane (50 ml). The washings and the filtrate were combined and distilled under reduced pressure to give 2-(4-aminophenyl)-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (4.6 g, 90%) as a white solid. This compound was used for next process without purification.
Reaction SMILES: CS(O[CH2:6][CH:7]1[S:11][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]([CH3:31])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)(=[O:24])=[O:23])=[N:9][CH2:8]1)(=O)=O.[NH:32]1[CH:36]=[CH:35][N:34]=[C:33]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][N:21]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)(=[O:24])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12]([C:10]1[S:11][CH:7]([CH2:6][N:32]3[CH:36]=[CH:35][N:34]=[C:33]3[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:8][N:9]=1)=[CH:20]2
Reactant: CN(c1cccc2cc(C3=NCC(COS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nccn1CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 83.2 %

Procedure:
A mixture of (2-{7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)methyl methanesulfonate (250 mg), ethyl 1H-imidazole-2-carboxylate (146 mg), potassium carbonate (144 mg) and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 4.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=15:85-100:0) to give the title compound (227 mg, yield 83%) as a orange oil.
Reaction SMILES: [CH:1]1([CH2:4]CN)C[CH2:2]1.C[CH:8]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])CC>>[CH:1]1([CH2:8][NH:11][CH2:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])[CH2:4][CH2:2]1
Reactant: NCCC1CC1
Reactant: CCC(C)NCCC(=O)NC
Product: CNC(=O)CCNCC1CC1

Procedure:
Using 2-Cyclopropylethanamine—Aldrich and analogous conditions to Intermediate 89 the title compound was obtained as a pale yellow oil (590 mg)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])=[CH:6][CH:5]=1)([O-])=O.[CH2:17]([OH:19])[CH3:18]>[Pd]>[F:15][C:11]([F:16])([O:10][C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:17](=[O:19])[CH3:18])=[CH:5][CH:6]=1)[CH:12]([F:14])[F:13]
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)cc1
Agent: [Pd]
Product: CC(=O)Nc1ccc(OC(F)(F)C(F)F)cc1
Yield: 97 %

Procedure:
55 g of 1-nitro-4-(1,1,2,2-tetrafluoroethoxy)-benzene are hydrogenated in 300 ml of ethanol over 0.5 g of 10% strength palladium-on-charcoal in a circulatory hydrogenation apparatus under atmospheric pressure at 20°-45° C. for 1 hour, the catalyst is filtered off and the solution is concentrated in vacuo at 40° C. The 4-(1,1,2,2-tetrafluoroethoxy)aniline is diluted with 100 ml of glacial acetic acid, 23 ml of acetic anhydride are added dropwise at room temperature, 2 ml of water are added after 30 minutes, the solution is concentrated at 50° C. in vacuo after a short time and 500 ml of icewater are added. 56 g (97% of theoretical) of N-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-acetamide of m.p. 121°-122° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].COCCOC>C(Cl)Cl>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1F
Temperature: 100 °C

Procedure:
A solution of methyl 2-bromo-4-nitrobenzoate (5.20 g), 2-fluorophenylboronic acid (3.92 g) and potassium carbonate (4.98 g) in a 10:1 mixture of DME:water (120 ml) was degassed by gently bubbling though nitrogen for 30 minutes. Tetrakis(triphenylphosphine) palladium(0) (2.32 g) was then added and the mixture was degassed for a further 10 minutes before being sealed under nitrogen. The reaction mixture was heated to 100° C. for 14 hours. The solvents were removed under vacuum. The residue obtained was redissolved in DCM and washed with water (2×). The organic phase was passed through a hydrophobic frit and then concentrated to dryness under vacuum. The crude residue was purified by chromatography on silica gel, eluting with petrol containing increasing amounts of ethyl acetate.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][CH2:26][CH:27]3[CH2:29][O:28]3)[CH:22]=[CH:21][C:19]=2[N:20]=1>C(O)C>[OH:28][C@H:27]([CH2:26][O:25][C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([CH3:15])[S:17][C:18]=2[CH:24]=1)[CH2:29][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@@H:2]1[CH3:1]
Reactant: Cc1nc2ccc(OCC3CO3)cc2s1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCO
Product: Cc1nc2ccc(OC[C@@H](O)CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)cc2s1

Procedure:
The compound of formula (B) was reacted with 2-methyl-6-(oxiran-2-ylmethoxy)benzothiazole (3 g, 7.3 mmol), a compound of formula (C), in ethanol. The reaction was refluxed for about 24 hours. When the reaction was substantially complete, the solvent was removed under reduced pressure, followed by preparative thin layer chromatography to render tert-butyl (3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-6-yloxy)propyl]-3-methylpiperazinecarboxylate, a compound of formula (D).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:15]=[C:14]([CH3:16])[C:11]([C:12]#[N:13])=[C:10]([CH3:17])[CH:9]=1.Br[CH2:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21]>CC(C)=O>[CH:22]1([C:20](=[O:21])[CH2:19][O:7][C:8]2[CH:9]=[C:10]([CH3:17])[C:11]([C:12]#[N:13])=[C:14]([CH3:16])[CH:15]=2)[CH2:24][CH2:23]1
Reactant: O=C(CBr)C1CC1
Reactant: Cc1cc(O)cc(C)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cc(OCC(=O)C2CC2)cc(C)c1C#N
Yield: 94.1 %

Procedure:
Cesium carbonate (30.7 g, 111.16 mmol) was added to a solution of 4-hydroxy-2,6-dimethylbenzonitrile (15.27 g, 101.89 mmol), in acetone (377 ml). Then 2-bromo-1-cyclopropylethanone (15.1 g, 62.6 mmol), in acetone (100 ml), was added dropwise, over 5 minutes, to the suspension and the reaction mixture was heated at reflux for 1.5 hours. The reaction mixture was then concentrated under reduced pressure and the residue was partitioned between a saturated aqueous solution of potassium carbonate (300 ml) and dichloromethane (300 ml). The organic layer was separated and washed with brine (250 ml), dried over magnesium sulphate, filtered and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:pentane (50:50 to 80:20, by volume) to provide the title compound (13.5 g, 64%) as a solid. 1H-NMR (400 MHz, CDCl3): δ=0.97-1.01 (m, 2H), 1.12-1.15 (m, 2H), 2.19 (m, 1H), 2.47 (s, 6H), 4.71 (s, 2H), 6.61 (s, 2H); LRMS: APCl+: 230 [MH+]
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][N:4]=1.[NH2-].[Na+].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:21])[C:18]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=2)[C:3]([N:2]([CH3:13])[CH3:1])=[N:4]1)=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)c1n[nH]c2cc(Cl)ccc12
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)n1nc(N(C)C)c2ccc(Cl)cc21

Procedure:
0.04 mol of 3-dimethylamino-6-chloroindazole and 0.04 mol of sodium amide in 50 ml of toluene are heated to the boil for 1 hour. 0.04 mol of dimethylcarbamic acid chloride is added dropwise at 60° C and this temperature is maintained for 7 hours, while stirring. After cooling, the solution is filtered and evaporated in vacuo. Distillation of the residue gives 3-dimethylamino-6-chloroindazole-1-carboxylic acid dimethylamide (boiling point0.35 170° C, melting point: 65°-66° C; 75% of theory).