Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2=[N:6][C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16]([C:17]([O:19]C)=[O:18])=[C:4]2[CH:3]=[CH:2]1)=[CH:13][CH:12]=[CH:11][CH:10]=4.Cl>>[CH2:15]([N:8]1[C:7]2[N:6]=[C:5]3[S:1][CH:2]=[CH:3][C:4]3=[C:16]([C:17]([OH:19])=[O:18])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1c2ccsc2nc2[nH]c3ccccc3c12
Agent: Cl
Product: O=C(O)c1c2ccsc2nc2c1c1ccccc1n2Cc1ccccc1
Yield: 74 %

Procedure:
A solution of 9H-1-thia-9,10-diaza-cyclopenta[b]fluorene-4-carboxylic acid, methyl ester, (0.025 g, 0.089 mM) in 3 mL DMF was added to a 60% NaH mineral oil dispersion (0.007 g, 0.178 mM) at room temperature. Following cessation of gas evolution, benzyl bromide (0.012 mL, 0.017 g, 0.098 mM) was added and the mixture stirred at room temperature for 3.5 h. The mixture was diluted with ethyl acetate and H2O, the solvent layers separated, and the aqueous layer extracted with ethyl acetate (4×25 mL). The combined ethyl acetate extracts were washed with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 0.013 g of an oily solid that was identified as unreacted 9H-1-thia-9,10-diaza-cyclopenta[b]fluorene-4-carboxylic acid, methyl ester. Adjusted the above aqueous layer from the initial reaction workup to pH 1 with 1N HCl, and extracted with ethyl acetate (4×25 mL). The combined ethyl acetate extracts were washed with H2O, 1N HCl, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 0.023 g (74%) of the title compound 9-benzyl-9H-1-thia-9,10-diaza-cyclopenta[b]fluorene-4-carboxylic acid as a yellow solid (MW 358.42, C21H14N2O2S).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:26].CSC.C(Cl)(=O)C>>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:26]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CCC(N)=O)OC3=O)cc2)CC1F
Solvent: CC(=O)Cl
Solvent: CSC
Product: NC(=O)CC[C@H]1CN(c2ccc(N3CCC(=O)C(F)C3)cc2)C(=O)O1
Temperature: 40 °C
Reaction time: 96 h
Yield: 61 %

Procedure:
The mixture of (S)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), freshly fused zinc chloride (3.1 mmol), dimethyl sulphide (5.1 mmol), acetyl chloride (3.1 mmol) in tetrahydrofuaran (50 ml) was stirred at 40° C. for 4 days. The reaction mixture was extracted with ethyl acetate water mixture and the organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel to give title compound in 61% yield.
Reaction SMILES: [OH-].[Ba+2].[OH-].[OH-].[Na+].C([NH:14][C:15]1[NH:16][N:17]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][C:27]=2[Cl:34])[C:18](=[O:25])[C:19]=1[N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1)(=O)C1C=CC=CC=1>CO>[NH2:14][C:15]1[NH:16][N:17]([C:26]2[C:27]([Cl:34])=[CH:28][C:29]([Cl:33])=[CH:30][C:31]=2[Cl:32])[C:18](=[O:25])[C:19]=1[N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: O=C(Nc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c(=O)c1-n1cccn1)c1ccccc1
Agent: [Ba+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c(=O)c1-n1cccn1
Temperature: 70 °C

Procedure:
As specific representative example of the producing method of the invention, barium hydroxide and a 25% (W/V) aqueous solution of sodium hydroxide are added to a methanol suspension of 3-benzoylamino-4-(1-pyrazolyl)-1-(2,4,6-trichlorophenyl)-5-pyrazolone, and the reaction mixture is agitated at about 70° C. After the raw material is consumed, an excessive amount of concentrated hydrochloric acid is added to the reaction system, and the resulting barium chloride precipitate is eliminated by filtration, and the filtrate is extracted twice with toluene, and the aqueous phase is neutralized with a 25% (W/V) aqueous solution of sodium hydroxide to adjust the pH value of the system to 3.5. Resulting crystals are separated by filtration, washed and dried. Thus, a desired 3-amino-4-(1-pyrazolyl)-1-(2,4,6-trichlorophenyl)-5-pyrazolone is isolated.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].[S:23]1C2C(=CC=CC=2)C(NC2C(CC)=NC=C(CC)N=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:23][CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCSc3ccccc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCSc3ccccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,4-dihydro-2H-thiochromen-4-yl)-3,6-diethylpyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.28, 7.19, 7.04, 5.38, 4.50, 3.53, 2.99, 2.84, 2.64, 2.55, 2.13, 1.31, 1.24; 13C NMR (100 MHz, CDCl3) δ 152.50, 149.99, 141.71, 134.14, 134.03, 131.10, 128.59, 127.30, 125.65, 124.88, 48.74, 29.40, 27.58, 25.83, 23.05, 12.52, 11.26; HRMS (EI) calcd for C17H20BrN3S 377.0562, found 377.0565.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH:7]1[CH2:8][CH2:9][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC(OS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (2.4 mL, 31 mmol) was slowly added to a dichloromethane solution (75 mL) of ethyl 4-hydroxycyclohexanecarboxylate (4.63 mL, 28.7 mmol) and triethylamine (8.2 mL, 59 mmol) at 0° C. The reaction mixture was stirred for 30 minutes, concentrated in vacuo and diluted in diethyl ether (100 mL). The solution was washed with 10% hydrochloric acid (25 mL), water (25 mL), and saturated sodium bicarbonate (15 mL). The organics were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 1.23 (t, J=7.1 Hz, 3H), 1.54-1.82 (m, 4H), 1.87-1.97 (m, 2H), 2.00-2.08 (m, 2H), 2.34-2.41 (m, 1H), 3.00 (s, 3H), 4.13 (q, J=7.1 Hz, 2H), 4.88-4.92 (m, 1H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([O:29]CC)=O)[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:29])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1ccc(F)cc1Cl
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3ccc(F)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 61.4 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chloro-4-fluorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (4.98 g, 10.60 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (1.43 g, 7.97 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (2.95 g, 93%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:23]=[C:24](I)[C:25]2[N:26]([CH:28]=[CH:29][N:30]=2)[CH:27]=1.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.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:24]3[C:25]4[N:26]([CH:28]=[CH:29][N:30]=4)[CH:27]=[C:22]([Br:21])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1cc(I)c2nccn2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3cc(Br)cn4ccnc34)nc2)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
A mixture of 6-amino-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (971 mg, 3.0063 mmol), 6-bromo-8-iodo-imidazo[1,2-a]pyridine (1 g, 3.6075 mmol), Pd2(dba)3 (138 mg, 0.1503 mmol), XantPhos (174 mg, 0.3006 mmol), and Cs2CO3 (2 g, 6.0126 mmol) were combined in dioxane (20 mL) and the solution was stirred at 90° C. under N2 atmosphere for 5 h at which point the TLC showed little starting material remained. The solution was poured onto water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel (DCM: MeOH, 60:1 eluent) afforded the desired product as yellow solid (1.15 g, 81%). 1H NMR (300 MHz, CDCl3): δ 8.44 (d, J=1.5 Hz, 1H), 8.20 (d, J=2.1 Hz, 1H), 7.92 (s, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.49 (s, 2H), 7.42 (dd, J=8.4, 2.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.27-4.23 (m, 2H), 2.85-2.77 (m, 2H), 2.68-2.58 (m, 1H), 1.84-1.79 (m, 2H), 1.67-1.57 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7](S(C)(=O)=O)[S:8][C:4]=2[CH:3]=1.[NH:15]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[I:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([N:15]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16]3)[S:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nc2ccc(I)cc2s1
Reactant: O[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H]1CCN(c2nc3ccc(I)cc3s2)C1
Temperature: 150 °C

Procedure:
A stirred mixture of 6-iodo-2-(methylsulfonyl)benzo[d]thiazole (Reference Example 6c, 1.50 g, 4.42 mmol), (S)-pyrrolidin-3-ol (0.500 g, 5.74 mmol), and potassium carbonate (1.222 g, 8.84 mmol) in N,N-dimethylformamide (21.5 mL) was heated to 150° C. under microwave irradiation for 10 minutes. The reaction mixture was cooled to room temperature, then poured into water (350 mL) to give a precipitate. The precipitate was collected by filtration, rinsed with water, and then dissolved in ethyl acetate. The ethyl acetate solution was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a crude solid that was purified by silica gel chromatography (100% CHCl3 to 97:3 CHCl3/methanol). Fractions containing product were combined an concentrated under reduced pressure to provide (S)-1-(6-iodobenzo[d]thiazol-2-yl)pyrrolidin-3-ol. 1H NMR (300 MHz, CD3OD) δ ppm 2.03-2.14 (m, 1H), 2.15-2.29 (m, 1H), 3.47-3.55 (m, 1H), 3.58-3.75 (m, 3H), 4.53-4.59 (m, 1H), 7.23 (d, J=8 Hz, 1H), 7.53-7.59 (m, 1H), 7.95-7.98 (m, 1H); MS (DCI/NH3) m/z 347 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:18][C@@H:17]3O[C@@:16]3([CH2:20]O)[C@@H:7]2[C@H:8]([O:11][C:12](=[O:15])[NH:13][CH3:14])[O:9][CH:10]=1)=[O:4].C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:18][CH:17]=[C:16]([CH2:20][Cl:33])[C@@H:7]2[C@H:8]([O:11][C:12](=[O:15])[NH:13][CH3:14])[O:9][CH:10]=1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@@]3(CO)[C@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CCl)[C@H]12
Yield: 24 %

Procedure:
2.0 g of (1S,4aS,6S,7R,7aR)-6,7-epoxy-7 -(hydroxymethyl)-1-(methylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydrocyclopenta [c] pyrane-4-carboxylic acid methylester described in Example 19 were dissolved in dichloromethane followed by addition of 2.5 ml of triethylamine and 1.4 ml of methanesulfonylchloride while stirring and cooling with ice. After stirring for 12 hours at the same temperature, the reaction mixture was extracted with ethyl-acetate. After washing the organic phase with saturated aqueous sodium bicarbonate and brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a pale yellow oil from the hexane-ether eluate in the form of (1S,4aS,7aR)-7-(chloromethyl)-1-(methylcarbamoyloxy )-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (770 mg, yield: 24%). The physicochemical properties of this compound are described below.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)=[CH:23][CH:22]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[C:24]1[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: Fc1ccc([C@@H]2CCCN2)cc1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCC[C@H]1c1ccc(F)cc1

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (2S)-2-(4-fluorophenyl)-pyrrolidine (0.10 g, 0.60 mmol) gives the title compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (96.5 g, 0.216 mol), N-methyl-4-aminopiperidine (29.3 g, 0.259 mol), HOBt (35 g, 0.259 mol), diisopropylethylamine (45 mL, 0.259 mol) in anhydrous DMF (2.6 L) was cooled in ice bath under nitrogen. EDCI (49.8 g, 0.259 mol) was added and the resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into ice water (8 L) and ethyl acetate (3 L) and separated. The aqueous phase was extracted with ethyl acetate (4 L×2) and all organic extracts were combined, washed with water, brine, dried over MgSO4 and concentrated. The resulting solid was triturated with diethyl ether to give 47 g of the title compound. DSC peak at 241.42° C.
Reaction SMILES: C(OC([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][C@H:9]1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=O)(C)(C)C.Cl>C(O)C>[CH:18]1([C@H:9]2[NH:8][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH2:10]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2OC[C@H]1C1CCCCC1
Agent: Cl
Solvent: CCO
Product: c1ccc2c(c1)N[C@H](C1CCCCC1)CO2
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 100 %

Procedure:
A mixture of (R)-4-tert-butoxycarbonyl-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (3.98 g, 12.5 mmol), 5 N hydrochloric acid (10 ml) and ethanol (10 ml) was stirred at 70° C. for 50 min. Ethanol was removed in vacuo and the residue was partitioned between dichloromethane and 2 N sodium hydroxide solution. The aqueous layer was extracted with dichloromethane and combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford (R)-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (2.72 g, 12.5 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][C:17](=O)[CH2:18][CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:17]([C:18]1([CH3:19])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH3:16]
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 2-butanone (1.0 mL), p-toluenesulfonic acid monohydrate (0.0096 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 1 h at 70° C. The reaction mixture was poured into aqueous sodium hydrogen carbonate (200 mL). Extraction with ethyl acetate (200 mL, 100 mL), washing with aqueous sodium hydrogen carbonate, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a residue, which was triturated with dichloromethane/ethyl acetate (1:1, 6 mL), and the precipitate was collected by filtration to afford the title compound (0.095 g, 69%) as a yellow solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6](I)=[CH:5][CH:4]=1.C[Sn](C)(C)[C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1>>[NH2:30][C:26]1[CH:25]=[C:24]([C:6]2[C:7]3[S:11][C:10]([NH:12][C:13]([C:15]4[S:16][C:17]([CH3:20])=[CH:18][CH:19]=4)=[O:14])=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(I)c2sc(NC(=O)c3ccc(C)s3)nc12
Reactant: C[Sn](C)(C)c1cccc(N)c1
Product: COc1ccc(-c2cccc(N)c2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 56 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid [7-(3-amino-phenyl)-4-methoxy-benzothiazol-2-yl]-amide is synthesized from 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-iodo-benzothiazol-2-yl)-amide (300 mg, 0.70 mmol) and 3-trimethylstannanyl-phenylamine (291 mg, 1.14 mmol) using the general procedure B as a light brown solid in 56% yield. MS: m/e=396 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[C:10]1[CH:11]=[CH:12][C:13](S(O)(=O)=O)=[CH:14][CH:15]=1>C(CC(=O)C)C(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:14]([CH3:13])=[CH:15][CH:10]=[C:11]2[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)CCC(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1-c1cccc(Br)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 3-bromoaniline (2.50 mL, 23.0 mmol) in acetonylacetone (3.00 mL, 25.6, mmol) containing a small amount of p-TSA was heated at reflux in a round bottom flask fitted with a Dean Stark trap and a reflux condenser for 5 h. The reaction mixture was allowed to cool to rt and diluted with EtOAc. The solution was washed with 1N HCl and sat. NaHCO3 solution. The organic solutions were dried over Na2SO4, filtered, and concentrated to give the desired product as a light brown solid (5.5 g, 96%) which was used without further purification.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].C([O-])([O-])=O.[K+].[K+].[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>C(Cl)Cl>[CH2:1]([N:5]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[C:20](=[O:23])[CH:21]=[CH2:22])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCNc1ccc(OC)cc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCCN(C(=O)C=C)c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
To a solution of N-but-3-en-1-yl-4-methoxyaniline (340 mg, 1.92 mmol) in methylene chloride (5 mL) was added K2CO3 (530 mg, 3.80 mmol) and acryloyl chloride (234 μL, 2.88 mmol) at 0° C. After 15 min., the reaction was quenched with NaHCO3 (2 mL, sat. aq.) and the organic layer was isolated, concentrated and subjected to flash chromatography (Hexanes:EtOAc 4:1) to yield N-but-3-en-1-yl-N-(4-methoxyphenyl)acrylamide (395 mg, 89%).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([CH3:17])([S:7]([CH2:10][CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])(=[O:9])=[O:8])[CH3:6])C.C[Si](C)(C)[O-].[K+].Cl>C1COCC1>[CH3:17][C:5]([S:7]([CH2:10][CH2:11][CH2:12][C:13]([F:15])([F:16])[F:14])(=[O:9])=[O:8])([CH3:6])[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)CCCC(F)(F)F
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)S(=O)(=O)CCCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
To a solution of 170 g (585.6 mmol) of 2-methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionic acid ethyl ester in THF (3.4 L) are added 225.4 g (1756.8 mmol) of potassium trimethylsilanolate in portions over 0.5 h. The reaction is stirred at room temperature for 18 h. The reaction mixture is acidified with 2M aqueous HCl solution (2 L) to pH 2 and extracted with DCM (2×2 L). The combined organic extracts are dried (Na2SO4) and filtered. The filtrate is concentrated under reduced pressure to afford 143 g of 2-methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionic acid as yellow solids. Yield: 93%; ES-MS: m/z 261 [M−H]. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.71 (6 H, s), 2.18-2.28 (2 H, m), 2.30-2.42 (2 H, m), 3.38 (2 H, t, J=7.48 Hz), 6.96 (1 H, br. s.).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]=[O:3].[N+:11](=[C:13]1[N:17]=[CH:16][N:15]=[C:14]1[C:18]([NH2:20])=[O:19])=[N-:12]>CS(C)=O>[C:18]([C:14]1[N:15]=[CH:16][N:17]2[C:2](=[O:3])[N:1]([CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:12]=[N:11][C:13]=12)(=[O:19])[NH2:20]
Reactant: CCOC(=O)CCN=C=O
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: CCOC(=O)CCn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 3-isocyanatopropionate (Alfa Lancaster) (0.504 mL, 3.83 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.450 g, 3.65 mmol) in dry dimethylsulfoxide (4.5 mL) at room temperature under nitrogen. The reaction was stirred in the dark at room temperature. After 16 hours, the reaction mixture was poured onto ice (approximately 25 mL) and the resulting precipitate was washed with ethyl acetate (10 mL) and ether (10 mL) to afford the title compound as a pale brown solid. Yield: 770 mg, 2.75 mmol, 75%. LCMS (ES+), m/z 281 (M+H)+ at 1.60 minutes. 1H NMR (400 MHz, d6-DMSO) δ: 8.86 (1H, s), 7.75 (1H, br s), 7.62 (1H, br s), 4.51 (2H, t), 4.07 (2H, q), 2.89 (2H, t), 1.17 (3H, t).