Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([C:38](=O)[CH3:39])[CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:42][OH:43].C(O)(=O)C>CO.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34](/[C:38](=[N:42]/[OH:43])/[CH3:39])[CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: C/C(=N\O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 50 °C
Yield: 67.5 %

Procedure:
To a mixture of 1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone (0.10 g, 0.168 mmol) and hydroxylamine hydrochloride (0.0125 g, 0.188 mmoL) in methanol (2.0 mL) was added 0.2 mL of acetic acid. The mixture was heated at 50° C. for 3 hours. After cooled to room temperature, the mixture was diluted with dichloromethane (10 mL), washed with saturated aqueous sodium bicarbonate (5 mL×3), water (5 mL), dried over sodium sulfate and concentrated. Product was purified by flash chromatography on silica gel (methanol:dichloromethane:ethylacetate=0.5:7:2) to afford 0.069 g (67%) of the title compound as an off-white solid. M.p.=156-158° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 11.08 (s, 1H), 8.70 (br. s, 1H), 8.11 (d, J=4.8 Hz, 1H), 7.87 (s, 1H), 7.77-7.74 (m, 2H), 7.71-7.59 (m, 3H), 7.59-7.56 (m, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 6.40 (d, J=5.2 Hz, 1H), 3.93 (br. s, 1H), 3.74-3.71 (m, 1H), 3.48-3.45 (m, 1H), 2.48-2.45 (m, 1H), 2.33 (t, J=7.6 Hz, 1H), 2.15 (s, 3H), 1.89-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.39-1.34 (m, 1H); LCMS: 608 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[N+:31]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O1CCCC1.O>C(O)C.[Fe]>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH2:31])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2[N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2N)c1
Yield: 90.9 %

Procedure:
A solution of the product of Example 95B (2.87 g, 5.28 mmol), iron powder (1.5 g, 26.4 mmol) and ammonium chloride (0.43 g, 8.0 mmol) in an ethanol (75 mL), tetrahydrofuran (75 mL), and water (25 mL) solution was heated to reflux for 6 hours. The resultant mixture was diluted with ethanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound as a yellow powder (2.47 g, 91%).
Reaction SMILES: [O:1]([CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][C:10]([CH:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:9])=[N:11][CH:12]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)nc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To a solution of 6-(1-phenoxyethyl)nicotinic acid (100 mg, 0.41 mmol) in dichloromethane (20 mL) were added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol), N-hydroxybenzotriazole (81 mg, 0.60 mmol) and triethylamine (122 mg, 1.20 mmol). The resultant reaction mixture was stirred for 30 minutes at room temperature. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.50 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified through pre-HPLC and the obtained solution was freeze-dried to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1-phenoxyethyl)nicotinamide (50 mg, 32.2%) as a white solid. LRMS (M+H+) m/z: calcd 378.17. found 378. 1H NMR (300 MHz, DMSO) δ 8.91 (d, J=2.1 Hz, 1H), 8.14 (dd, J1=8.1 Hz, J2=2.1 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.17 (m, 2H), 6.85 (m, 3H), 6.10 (s, 1H), 5.45 (m, 1H), 4.48 (s, 2H), 2.35 (s, 3H), 2.24 (s, 3H), 1.64 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:13])[CH2:3][CH2:2]1.Cl.[C:31](=[NH:36])([O:33]CC)[CH3:32].CC[OH:39]>>[C:32]1(=[O:39])[N:36]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[NH:11][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:13])[CH2:3][CH2:2]2)[C:31]1=[O:33]
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NCC1CCNCC1)c1ccccc1F
Reactant: CCOC(C)=N
Reactant: CCO
Agent: Cl
Product: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NCC1CCN(n2c(=O)c2=O)CC1)c1ccccc1F

Procedure:
A solution of N-(piperidin-4-ylmethyl)-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide (from EXAMPLE 53, 70 mg, 0.17 mmol), ethyl acetimidate hydrochloride (40 mg, 0.32 mmol) and TEA (0.070 mL, 0.50 mmol) in EtOH (3 mL) was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (37 mg). MS 460.1 and 462.1 (M+H, Cl pattern).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[C:18]([C:21](=[O:35])[CH2:22][N:23](CC2C=CC=CC=2)[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:17]=[CH:16][C:15]=3[O:36]CC2C=CC=CC=2)=[O:11])[CH2:3][CH2:2]1>CO.C(OCC)C>[C:10]([OH:11])(=[O:9])[CH3:12].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[C:18]([CH:21]([OH:35])[CH2:22][NH:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:17]=[CH:16][C:15]=3[OH:36])=[O:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)N(CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(C(=O)OCCN3CCOCC3)cc12)Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: CC(=O)O
Product: CC(C)(C)NCC(O)c1ccc(O)c2[nH]c(C(=O)OCCN3CCOCC3)cc12
Yield: 153.7 %

Procedure:
408 mg of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)indole-2-carboxylic acid 2-(morpholino)ethyl ester is hydrogenated under the conditions of Example 14(E) and worked up, thus obtaining 250 mg of 7-hydroxy-4-(1-hydroxy-2-tert-butylaminoethyl)indole-2-carboxylic acid 2-(morpholino)ethyl ester monoacetate, decomposition point 177°-177.5° C. (from methanol/diethyl ether).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=5)[N:23]([CH2:31][CH2:32][N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[N:22]=4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH3:8])[CH:2]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=5)[N:23]([CH2:31][CH2:32][N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[N:22]=4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH3:8])[CH:2]=1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN4CCOCC4)c4cc(Cl)ccc34)nc12)c1cccnc1
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(CCN4CCOCC4)c4cc(Cl)ccc34)nc12)c1cccnc1
Reaction time: 2 h
Yield: 71.9 %

Procedure:
2-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide (50 mg, 0.076 mmol) was combined with dichloromethane (1 mL) and trifluoroacetic acid (0.17 ml, 2.27 mmol) was added. After stirring for 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL) and ethylenediamine (0.15 ml, 2.27 mmol) was added. The reaction mixture was stirred for 20 min then concentrated in vacuo and the residue was triturated with water (2 mL). The precipitate was filtered, washed with water and dried to afford 29 mg (68%) of 2-[6-chloro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide as a yellow solid. MS: (M+H)+=531; 1H NMR (DMSO-d6) δ: 9.11 (s, 1H), 8.71 (br. s., 1H), 8.43-8.58 (m, 3H), 8.29-8.38 (m, 1H), 8.05 (s, 1H), 7.86 (d, J=7.3 Hz, 1H), 7.36 (br. s., 1H), 7.15 (d, J=8.3 Hz, 1H), 5.35 (t, J=6.9 Hz, 1H), 4.65 (br. s., 2H), 3.50 (br. s., 4H), 3.33 (br. s., 4H), 2.84 (br. s., 2H), 1.68 (d, J=6.3 Hz, 3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([OH:38])=O.CCN(C(C)C)C(C)C.[C:48]1([CH2:54][CH:55]([C:57]2[N:61]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:60]=[N:59][CH:58]=2)[NH2:56])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([NH:56][CH:55]([C:57]1[N:61]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[N:60]=[N:59][CH:58]=1)[CH2:54][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:38]
Reactant: NC(Cc1ccccc1)c1cnnn1-c1ccccc1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1c[nH]c2ccc(O)cc12)NC(Cc1ccccc1)c1cnnn1-c1ccccc1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 9D (26.5 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, CD3OD) δ 7.76 (s, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.39 (t, J=7.6 Hz, 2H), 7.21-7.01 (m, 6H), 6.96 (s, 1H), 6.84 (d, J=1.9 Hz, 1H), 6.78 (d, J=6.8 Hz, 2H), 6.68 (dd, J=8.6, 2.3 Hz, 1H), 5.46 (s, 2H), 5.21 (t, J=7.6 Hz, 1H), 2.96 (ddd, J=21.5, 13.3, 7.6 Hz, 2H); MS (m/z) 438 [M+H]+.
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:4]=1.[CH3:32][N:33]([CH3:50])[C@@H:34]([CH3:49])[C:35]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([O:47][CH3:48])=[C:43]([NH2:46])[CH:44]=2)[CH2:39][CH2:38]1)=[O:36].[CH3:51][NH2:52].[OH-].[K+]>C1COCC1.C(OCC)(=O)C>[CH3:32][N:33]([CH3:50])[C@H:34]([C:35]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([O:47][CH3:48])=[C:43]([NH:46][C:3]3[NH:4][C:5]4=[N:21][CH:20]=[CH:19][C:6]4=[C:7]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=4[C:15]([NH:52][CH3:51])=[O:17])[N:16]=3)[CH:44]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:49]
Reactant: CN
Reactant: COc1cc2c(cc1N)N(C(=O)[C@H](C)N(C)C)CC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)[C@H](C)N(C)C)[nH]c2nccc1-2
Temperature: 65 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (500 mg, 1.043 mmol) and 1-[(2S)-2-(dimethylamino)propanoyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (302 mg, 1.147 mmol) in THF (50 ml) was heated at 65° C. for 4 hrs. The reaction was diluted with ethyl acetate (200 ml) and washed with saturated NaHCO3 (300 ml). Organic layer was removed, concentrated by rotary evaporation, solids triturated from ethyl acetate/hexanes, and dried under house vacuum prior to next step. ESIMS (M+H)+=670. The solids were then added to THF (50 ml)mmol) followed by methylamine 2.0M/THF (16.80 ml, 33.6 mmol) and the resulting mixture was stirred at rt overnight. Next, the crude reaction was adsorbed onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM over 30 min). ESIMS (M+H)+=701. The isolated pure amide was redissolved in 1,4-dioxane (10 ml), potassium hydroxide (2.497 ml, 12.49 mmol) added and the reaction was heated in the microwave at 120° C. for 20 min. The resulting solution was adsorbed onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM) to afford the title compound (0.2 g, 35% over three steps). ESIMS (M+H)+=547. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (d, J=6.42 Hz, 3 H) 2.20 (s, 6 H) 2.80 (d, J=4.41 Hz, 3 H) 3.06-3.18 (m, 2 H) 3.55-3.66 (m, 1 H) 3.77 (s, 3 H) 4.11-4.21 (m, 1 H) 4.38-4.48 (m, 1 H) 6.25-6.31 (m, 1 H) 6.83-6.94 (m, 1 H) 6.94-7.02 (m, 2 H) 7.26-7.37 (m, 1 H) 7.57 (s, 1 H) 8.36 (d, J=8.43 Hz, 1 H) 8.54 (s, 1 H) 8.62 (s, 1 H) 10.16 (s, 1 H) 11.26 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C@H:4]([CH2:12][O:13][CH3:14])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:16])=[O:15])[CH2:12][O:13][CH3:14])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:24][CH2:23]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: COC[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: COC[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of N,N,O-trimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-serinamide (434 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (780 mg) in 2-propanol (10 mL) was added piperidinium acetate (334 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (409 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]3[C:17](=[O:18])[N:16](C(OC(C)(C)C)=O)[S:15][C:8]=3[N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:27].[C:28]([O:32][C:33](=[O:54])[NH:34][CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:41]=2)[CH2:36]1)([CH3:31])([CH3:30])[CH3:29].CN(C)C=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.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.CO>[C:28]([O:32][C:33](=[O:54])[NH:34][CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:2]3[CH:11]=[C:10]4[C:5]([C:6](=[O:26])[C:7]5[C:17](=[O:18])[NH:16][S:15][C:8]=5[N:9]4[CH:12]4[CH2:14][CH2:13]4)=[CH:4][C:3]=3[F:27])[CH:41]=2)[CH2:36]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)n1sc2c(c(=O)c3cc(F)c(Br)cc3n2C2CC2)c1=O
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1
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: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCc2cc(-c3cc4c(cc3F)c(=O)c3c(=O)[nH]sc3n4C3CC3)ccc2C1

Procedure:
A mixture containing 7-bromo-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione (8) (31.8 mg, 0.090 mmol), 30 (68.0 mg, 0.182 mmol), tetrakis(triphenylphosphine)palladium(0) (7.2 mg, 0.006 mmol), dimethylformamide (1.5 mL), and a 1 M aqueous solution of sodium bicarbonate (360 μL, 0.360 mmol) is sparged with argon gas and irradiated with microwaves (5-min irradiation at 120° C.). The resulting green, gelatinous mixture was filtered and evaporated to dryness under reduced pressure (˜6 mm Hg, 40° C.). The recovered residue (orange oil) is washed with diethyl ether (10 mL) to give a yellow solid. This material is dissolved in a mixture containing 25% methanol in chloroform (2.0 mL), precipitated via addition of diethyl ether (10 mL), and collected by filtration; this process is repeated once. The product is washed further with water (2×10 mL) and dried in vacuo to give (rac)-tert-Butyl[6-(9-cyclopropyl-6-fluoro-3,4-dioxo-2,3,4,9-tetrahydro-isothiazolo[5,4-b]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate as a yellow solid (93% purity by HPLC; the remaining material is 9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione). 1HNMR (CDCl3/CD3OD (12:1 v/v), 50° C.): δ 1.10 (m, 2H, c-Pr CH2), 1.21 (m, 2H, c-Pr CH2), 1.48 (s, 9H, C(CH3)3), 1.76 (m, 1H, H-3), 2.10 (m, 1H, H-3), 2.68 (m, 1H, H-1), 2.86 (m, 2H, H-4), 3.08 (m, 1H, c-Pr CH), 3.12 (m, 1H, H-1), 3.94 (m, 1H, H-2), 7.11 (m, 1H, aromatic), 7.20 (m, 2H, aromatic), 7.71 (m, 1H, aromatic), 7.92 (m, 1H, aromatic). 19F{1H} NMR (CDCl3/CD3OD (12:1 v/v), 50° C.): δ −123.8 (s). NMR spectra collected at room temperature contained broad, unresolved signals. LCMS m/z calcd for C28H28FN3O4S ([M]+) 521. Found 522 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:23])=[CH:13]/[C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:40][C:41]1[NH:45][N:44]=[N:43][N:42]=1>C(Cl)(Cl)Cl.CN(C)C=O.CN(C)C=O.C(Cl)(Cl)Cl>[NH:42]1[C:41]([NH:40][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14](/[CH:13]=[C:12](/[C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[O:5][CH2:4][CH2:3][C:2]4([CH3:1])[CH3:24])\[CH3:23])=[CH:22][CH:21]=2)=[N:45][N:44]=[N:43]1
Reactant: Nc1nnn[nH]1
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCO2
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C/C(=C\c1ccc(C(=O)Nc2nnn[nH]2)cc1)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 0.5 g (1.55 mmole) of 4-[(E)-2-(4,4-dimethyl-6-chromanyl)-2-methylvinyl]benzoic acid in 20 ml of chloroform-N,N-dimethylformamide (1:1) at -25° C., under nitrogen, was added 0.17 g of triethylamine followed by 0.23 g (1.7 mmole) of isobutyl chloroformate. Stirring was continued for 15 minutes at -25° C. and then a solution of 0.177 g (1.7 mmole) of 5-aminotetrazole in 4 ml of N,N-dimethylformamide was added dropwise during 2 minutes. Stirring was continued for 1 hour as the reaction mixture was allowed to warm to 25° C. The reaction mixture was then diluted with 50 ml of chloroform and washed with 50 ml of 1N hydrochloric acid. The insoluble material was recovered by filtration to give a first crop of the title compound. The layers were then separated and the chloroform layer was washed with 1N hydrochloric acid followed by saturated sodium chloride, dried (MgSO4) and concentrated in vacuo. The residue was triturated under hot chloroform and the insoluble material was collected by filtration to give a second crop of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.Cl.[CH2:31]([NH2:33])[CH3:32].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:33][CH2:31][CH3:32])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 168 h
Yield: 90 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (126 mg, 0.30 mmol) obtained in Example 12 in methylene chloride (3 ml), ethylamine hydrochloride (27 mg, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), 4-methylmorpholine (0.073 ml, 0.66 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (63 mg, 0.33 mmol) were added at room temperature. After stirring for 7 days at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=7:3 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and hexane, and was collected by filtration, to obtain the title compound (120 mg, 0.27 mmol, 89%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1C=O)([O-:15])=[O:14].[CH:24]1C=CC=CC=1>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[CH:24]([C:21]1[CH:20]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:23][CH:22]=1)[O:12][CH2:11][CH2:10]2
Reactant: c1ccccc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(CCO)cc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Cl)CCOC2c1ccc([N+](=O)[O-])cc1
Yield: 45 %

Procedure:
Hydrogen chloride gas that is dried for 7 hours is introduced into a suspension of 15.70 g (72.0 mmol) of 2-(3-chloro-4-methoxyphenyl)-ethanol (L. S. Fosdick i.a., J. Am. Chem. Soc. 68 (1946), 840-843), 10.23 g (72.0 mmol) of nitrobenzaldehyde and 9.18 g (72 mmol) of freshly melted zinc chloride in anhydrous benzene (200 ml). Then, the reaction mixture is diluted with ethyl acetate and washed neutral with water, dried and concentrated by evaporation. The residue is recrystallized from ethyl acetate (60 ml). 10.4 g (45%) of 6-chloro-7-methoxy-1-(4-nitrophenyl)-isochroman, melting point 150-153° C., is obtained.