Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][C:3]1[N:10]2[C:6](=[N+:7]([CH3:19])[C:8]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=32)[S:5][CH:4]=1.[CH3:20][O-:21].[Na+]>CO>[CH3:19][N:7]1[C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][C:9]=2[N:10](/[C:3](/[CH3:2])=[CH:4]\[S:5][CH3:6])[C:20]1=[O:21]
Reactant: Cc1csc2n1c1cc(C(F)(F)F)ccc1[n+]2C
Reactant: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CS/C=C(/C)n1c(=O)n(C)c2ccc(C(F)(F)F)cc21
Yield: 85 %

Procedure:
90 mg (0.23 mmol) of 3,9-dimethyl-6-(trifluoromethyl)[1,3]thiazolo[3,2-a][3,1]benzimidazol-9-ium iodide 6a were solubilised in MeOH (20 mL). NaOMe was added (8 eq, 100 mg) and the solution stirred under reflux for 2 h. The solvent was then evaporated and water was added (15 mL). The resulting mixture was extracted 3×15 mL of CH2Cl2, the organic layer dried with MgSO4 and evaporated under reduced pressure to yield 1-methyl-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one 7a (58 mg, orange oil, 85%). 1H NMR (300 MHz, CDCl3) δ=2.14 (3H, d, J=1.2, CH3), 2.27 (3H, s, SCH3), 3.47 (3H, s, NCH3), 6.29 (1H, q, J=1.2, H5), 7.03-7.10 (2H, m, Ar), 7.38-7.42 (1H, m, Ar); 13C NMR (75 MHz, CDCl3) δ=16.90, 20.33, 27.36, 106.06 (q, J=4), 107.28, 119.02 (q, J=4), 123.69 (q, J=33), 124.55 (q, J=271), 125.83, 127.36, 128.53, 132.82, 152.50; HRMS m/z C13H14F3N2OS [M+H]+ calcd: 303.0773, found: 303.0775.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[F:19])[N:11]([CH2:20][CH2:21][OH:22])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)C(C1C2C3C(=CC(F)=CC=3)N(CCO)C=2CCC1)=O)C.N1C=CC=CC=1.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>ClCCl>[CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([CH:6]1[C:18]2[C:13]3[C:12](=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]([CH2:20][CH2:21][O:22][S:56]([CH3:55])(=[O:58])=[O:57])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)C(=O)C1CCCc2c1c1c(F)cccc1n2CCO
Agent: CCN(CC)C(=O)C1CCCc2c1c1ccc(F)cc1n2CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CCCc2c1c1ccc(F)cc1n2CCOS(C)(=O)=O
Temperature: 0 °C
Yield: 1 %

Procedure:
To a solution of a mixture of 5-fluoro-9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (42) and 7-fluoro-9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (743 mg, 2.2 mmol) in dichloromethane (30 mL) was added pyridine (1.74 g, 22.0 mmol, 1.8 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (1.01 g, 8.8 mmol, 0.7 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×50 mL) and water (2×50 mL), dried and concentrated in vacuo. The crude material was purified by semi preparative HPLC eluting with water (A) and methanol (B) (Gemini 5u, C18, 110A, 150×21 mm, 50-95% B over 20 min, 21 mL/min) to afford 10 mg (1%) of methanesulfonic acid 2-(4-diethylcarbamoyl-7-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester as a white solid and 30 mg (9%) of a mixture of methanesulfonic acid 2-(4-diethylcarbamoyl-7-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester and methanesulfonic acid 2-(4-diethylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester (precursor compound 10) as a white solid. Using these purification conditions, methanesulfonic acid 2-(4-diethylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester (precursor compound 10) could not be isolated as a single component. The structure of methanesulfonic acid 2-(4-diethylcarbamoyl-7-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.18 (3H, t, J=7 Hz, N(CH2CH3)2), 1.39 (3H, t, J=7 Hz, N(CH2CH3)2) 1.70-2.30 (4H, m, 2- and 3-CH2), 2.58 (3H, s, OSO2CH3), 2.60-2.80 (2H, m, 1-CH2), 3.40-3.65 (4H, m, N(CH2CH3)2), 4.02 (1H, t, J=6 Hz, 4-CH), 4.20 (2H, t, J=7 Hz, NCH2CH2O Ms), 4.35 (2H, t, J=7 Hz, NCH2CH2O Ms), 6.70-6.85 (1H, m, NCCHCFCHCH), 6.90-7.00 (1H, m, NCCHCFCHCH), and 7.05-7.15 (2H, m, NCCHCFCHCH).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6](CC1C=CC(OC)=CC=1OC)[C:7]1[N:12]=[C:11]([S:13][CH2:14][CH3:15])[N:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:9](=[O:28])[CH:8]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[NH2:6][C:7]1[N:12]=[C:11]([S:13][CH2:14][CH3:15])[N:10]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[CH:20][CH:21]=2)[C:9](=[O:28])[CH:8]=1
Reactant: CCSc1nc(N(Cc2ccc(OC)cc2OC)Cc2ccc(OC)cc2OC)cc(=O)n1-c1ccc(OCC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCSc1nc(N)cc(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
A mixture of 6-[bis(2,4-dimethoxybenzyl)amino]-2-(ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)-one (0.68 g), anisole (0.459 mL) and trifluoroacetic acid (7 mL) was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.[C:38](OC(=O)CN)([CH3:41])([CH3:40])[CH3:39].C(OC(=O)[C@H](CC(C)C)N)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C@@H:23]([CH2:39][CH:38]([CH3:41])[CH3:40])[C:24]([OH:26])=[O:25])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)N[C@@H](CC(C)C)C(=O)O

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, L-leucine tert-butyl ester was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>CN(C)C=O>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC(F)(F)F)N1CCC(N2CCCC2)CC1
Yield: 46 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide to give the desired product as a yellow solid (46%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C
Reactant: c1nc[nH]n1
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17](O)=[O:18])=[C:12]3[N:11]=[CH:10][C:9]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[O:21])=[CH:5][CH:4]=[N:3]1.[CH2:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH3:35]>>[CH3:1][N:2]1[C:6]([NH:7][C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH:39][S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])=[O:18])=[C:12]3[N:11]=[CH:10][C:9]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[O:21])=[CH:5][CH:4]=[N:3]1
Reactant: CCS(N)(=O)=O
Reactant: Cn1nccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccnn3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 30.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(1-methylpyrazol-5-yl)amino-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.074 g, 0.167 mmol) obtained in step 2 and ethanesulfonamide (0.091 g, 0.833 mmol), the title compound (0.027 g, 30%) was obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)(=[S:3])[NH2:2].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])=O.C(N(C(C)C)CC)(C)C.C1COCC1>O>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[N:2]=[C:1]([N:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:8][CH2:9]2)[S:3][CH:21]=1
Reactant: NC(=S)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(CBr)c1ccccc1F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 120 °C
Yield: 27.2 %

Procedure:
A solution of benzyl 4-thiocarbamoylpiperazine-1-carboxylate (2.7 g, 9.7 mmol), 2-bromo-1-(2-fluorophenyl)ethanone (2.1 g, 9.7 mmol), diisopropyl ethylamine (1.9 mL, 11 mmol), and THF (32 mL) was sealed in a microwave vessel and heated by microwave irradiation at 120° C. for 20 seconds. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0%-30% EtOAc/hexanes) to give benzyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate (1.05 g, 27% yield). LC/MS: m/z 398.3 (M+H)+ at 3.84 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]=[CH:22]3)[C:11](=[O:26])[C@:10]([CH2:28][CH:29]3[CH2:33][O:32]C(C)(C)[O:30]3)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]=[CH:22]3)[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:30])[CH2:33][OH:32])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N(C3C=CCC3)C2=O)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@]1(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C2C=CCC2)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one (Example 28, Step C) (310 mg, 0.603 mmol) in THF (3 mL) at room temperature was added aq. HCl (1 M) (3013 μL, 3.01 mmol). The reaction mixture was stirred at room temperature for 19 h. The reaction mixture was diluted with EtOAc and the layers were separated. The organic layer was washed with sat. NaHCO3, sat. aq. NaCl solution and dried over Na2SO4 and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[F:21][C:22]([F:35])([F:34])[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1)=[O:24]>>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][C:31]([CH:28]3[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C:22]([F:35])([F:21])[F:34])[CH2:30][CH2:29]3)=[O:32])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: O=C(Cl)C1CCN(C(=O)C(F)(F)F)CC1
Product: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)C1CCN(C(=O)C(F)(F)F)CC1

Procedure:
This compound was prepared according to the procedure of Example 35 using 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 1-(trifluoroacetyl)piperidine-4-carbonyl chloride as the starting materials. LCMS for C19H14BrF4N6O5 (M+H)+: m/z=549.0, 550.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15]([NH:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([C:29](O)=[O:30])[CH2:24]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:29]([C@@H:25]3[CH2:26][CH2:27][CH2:28][C@H:23]([NH:22][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:24]3)=[O:30])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](C(=O)O)C1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a mixture of 4-(3,4-dichlorophenyl)piperazine (350 mg, 1.51 mmol), cis-3-(N-Boc-amino)cyclohexane carboxylic acid (368 mg, 1.51 mmol), HOBt (209 mg, 1.51 mmol) and EDC (291 mg, 1.51 mmol) was added dichloromethane followed by TEA (153 mg, 1.51 mmoL). Upon completion of addition, the resulting solution was allowed to stir overnight. At the conclusion of this period, the reaction mixture was concentrated and then purified via silica gel chromatography (20% to 50% EtOAc/hexanes) to provide the title compound (640 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23].[C:26](O)(=O)C>C1(C)C=CC=CC=1>[C:8]1([C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:26])=[O:23])[NH:14][C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(-c2ccccc2)cc1NC(=O)CCCCCCC(=O)[O-]
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCc1nc2ccc(-c3ccccc3)cc2[nH]1
Temperature: 110 °C

Procedure:
To a solution of 8-(4-aminobiphenyl-3-ylamino)-8-oxooctanoate (120 mg, 0.34 mmol) in toluene was added a drop of acetic acid. The reaction was heated to 110° C. overnight and concentrated. The residue was purified by biotage column chromatography to give methyl 7-(6-phenyl-1H-benzo[d]imidazol-2-yl)heptanoate (99 mg)
Reaction SMILES: C(OC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[CH2:27]([S:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([N+:47]([O-])=O)[C:40]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]([OH:37])=[O:36])[CH:28]=[CH:29][CH3:30]>>[NH2:47][C:39]1[C:40]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[C:32]([S:31][CH2:27][CH:28]=[CH:29][CH3:30])[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[O:36]
Reactant: CC=CCSc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Agent: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Product: CC=CCSc1cc(C(=O)O)cc(N)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 3-crotylthio-5-nitro-4-phenylbenzoic acid, and following the procedure described, 5-amino-3-crotylthio-4-phenylbenzoic acid is obtained with a melting point of 102°-104° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][C@H:30]([O:32][Si](C(C)(C)C)(C)C)[CH2:29][C:28]4=[O:40])[CH2:23][CH2:22]3)=[CH:16][NH:17]2)=[CH:13][CH:12]=1.Cl>CO.C(Cl)Cl.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][C@H:30]([OH:32])[CH2:29][C:28]4=[O:40])[CH2:23][CH2:22]3)=[CH:16][NH:17]2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)N(C2CCN(Cc3c[nH]c4cc(Oc5nc6ccccc6s5)ccc34)CC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1C[C@@H](O)CN1C1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
To a solution of (R)-1-{1-[6-(benzothiazol-2-yloxy)-1H-indol-3-ylmethyl]-piperidin-4-yl}-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-2-one (200 mg, 0.35 mmol) in MeOH:DCM (1:1, 15 mL) was added 4 M HCl in dioxane (5 mL) and the resulting reaction mixture was stirred (rt, 3 h). The reaction mixture was concentrated in vacuo to provide the title compound as a tan solid (112 mg, 70%). MS (ESI): mass calcd. for C25H26N4O3S, 462.5; m/z found, 463.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.00 (br s, 1H), 7.73-7.71 (m, 2H), 7.62 (d, J=7.9, 1H), 7.39-7.33 (m, 2H), 7.28-7.23 (m, 1H), 7.12-7.07 (m, 2H), 4.35 (t, J=8.4, 1H), 3.95-3.90 (m, 1H), 3.69 (s, 2H), 3.37-3.33 (m, 1H), 3.21-3.15 (m, 1H), 3.04-3.02 (m, 2H), 3.41-3.38 (m, 1H), 2.10-2.04 (m, 2H), 1.94-1.89 (m, 1H), 1.77-1.73 (m, 2H), 1.64-1.60 (m, 2H)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:11][CH:10]=3.[F:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:28][C:23]1[C:22]([C:12]2[CH:13]=[C:14]3[C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[CH:32][N:31]=[C:30]([F:29])[CH:35]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(-c3ccnc(F)c3)cc12
Temperature: 110 °C
Yield: 74.5 %

Procedure:
A vial was charged with (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (546.36 mg, 1.435 mmol), 2-fluoropyridin-3-ylboronic acid (303 mg, 2.153 mmol), potassium phosphate (914 mg, 4.31 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (50.8 mg, 0.072 mmol). The vial was flushed with Argon, and then dioxane (5383 μL) and water (1794 μL) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 20 min at 90° C. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by chromatography (0-100% EtOAc/Hexane) to give (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (510.4 mg, 95% purity) as an off-white solid. Step 2: A vial was charged with (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (104.72 mg, 0.264 mmol), 2-fluoropyridin-4-ylboronic acid (74.4 mg, 0.528 mmol), potassium phosphate (168 mg, 0.792 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (9.34 mg, 0.013 mmol). The vial was flushed with Argon, then dioxane (990 μL) and water (330 μL) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 110° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (30-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (S)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (90 mg) as a light-yellow solid. MS m/z=458.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Br:20])[CH:14]=1>COCCOCCOC>[F:19][C:17]1[CH:16]=[C:15]([Br:20])[CH:14]=[C:13]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: Oc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: Fc1ccc(Oc2cc(F)cc(Br)c2)cc1
Temperature: 165 °C
Reaction time: 21 h

Procedure:
Under a nitrogen atmosphere, a solution of 11.9 grams (0.106 mole) of 4-fluorophenol in 50 mL of diglyme is stirred, and 24.1 mL (0.106 mole) of methanolic 25% sodium methoxide is added dropwise. Upon completion of addition, the reaction mixture is heated to about 165° C. to remove methanol. After the methanol is removed, the heating is ceased, and 26.9 grams (0.106 mole) of 1,3-dibromo-5-fluorobenzene (commercially available) and 1.3 grams of cuprous bromide are added. Upon completion of the additions, the reaction mixture is heated to reflux where it is stirred for about 21 hours. The reaction mixture is then cooled and filtered. The filter cake is washed with diethyl ether, and the wash is combined with the filtrate. The combination is washed with two 20 mL portions of aqueous 20% sodium hydroxide, and then with two 75 mL portions of an aqueous solution saturated with sodium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 3-fluoro-5-(4-fluorophenoxy)phenyl bromide.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]1([C:22]2[O:23][C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH2:21][CH2:20]1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]4[CH2:20][CH2:21]4)[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)c1nc(C2CC2)oc1-c1ccccc1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C4CC4)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-cyclopropyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][NH:12][C:13](=O)[CH3:14]>>[CH3:11][N:12]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:13]1[CH3:14]
Reactant: CNC(C)=O
Reactant: O=[N+]([O-])c1ccccc1I
Product: Cc1nc2ccccc2n1C
Yield: 84.8 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and N-methylacetamide (44 mg, 0.6 mmol) yielded the title compound as pale yellow solid (62 mg, 85%). mp 101° C. to 103° C. 1H NMR (DMSO) δ 2.79 (s, 3H), 3.92 (s, 3H), 7.46-7.55 (m, 2H), 7.78 (d, J=7.4Hz, 1H), 7.89 (d, J=7.1Hz, 1H); 13C NMR δ 11.6, 30.8, 112.3, 114.1, 124.9, 125.3, 132.6, 151.9, 158.3. HRMS (FAB): cal. for C9H11N2 [M+H+]: 147.0922; found: 147.0917. Method C afforded 38 mg of the title compound (52% yield).