Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH:19]1([N:22]2[CH2:26][CH2:25][CH:24]([CH2:27][NH2:28])[CH2:23]2)[CH2:21][CH2:20]1>C(#N)C>[CH:19]1([NH:22][CH2:23][CH:24]2[CH2:25][CH2:26][N:28]([C:2]3[N:11]=[C:10]4[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]4[CH2:12][CH3:13])=[CH:4][C:3]=3[F:18])[CH2:27]2)[CH2:20][CH2:21]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: NCC1CCN(C2CC2)C1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNC4CC4)C3)nc21
Yield: 53.4 %

Procedure:
A near solution of 0.82 g (3.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and 1.4 g (10 mmole) of cyclopropyl-3-pyrrolidinemethanamine in 50 mL of acetonitrile was heated at reflux for two hours. The solvent was removed in vacuo, the residue dissolved in water, filtered through a fiber glass pad to clarify and the filtrate adjusted to pH 2.0 with 6M hydrochloric acid. The resulting clear solution was lyophilized and the residue recrystallized from ethanol to give 600 mg of 7-[3-[(cyclopropylamino)methyl]-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid, mp 271°-274° C. as the hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>CN(C=O)C>[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of 5-bromo2-nitropyridine (2.03 g, 10.0 mmol) in DMF (30 mL) was added Cs2CO3 (4.9 g, 15.0 mmol) followed by 4-acetylaminophenol (1.66 g, 11.0 mmol) in DMF (30 mL) at 0° C. then stirred at room temperature overnight. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over. Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography and recrystalization from ethyl acetate gave 5-(4-acetamidophenoxy)-2-nitropyridine (1.62 g, 59%). Hydrogenation of 5-(4-acetamidophenoxy)-2-nitropyridine (879.0 mg, 3.22 mmol) with 5% Pd—C in MeOH (80 mL) gave the title compound (575.7 mg, 74%): MS m/e 244 (M+1).
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30])=O)C1C=CC=CC=1.[N:33]1[C:42]2[C:37](=[N:38][C:39]([CH:43]=O)=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.N1CCCCC1>CC(O)C>[F:32][C:29]([F:30])([F:31])[C:20]1[CH:21]=[C:22]([C:25]([F:26])([F:28])[F:27])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:12]1[NH:11][C:15](=[CH:43][C:39]2[CH:40]=[CH:41][C:42]3[C:37](=[CH:36][CH:35]=[CH:34][N:33]=3)[N:38]=2)[C:14](=[O:16])[N:13]=1
Reactant: O=Cc1ccc2ncccc2n1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(C(F)(F)F)cc2C(F)(F)F)=N1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: O=C1N=C(NCc2ccc(C(F)(F)F)cc2C(F)(F)F)NC1=Cc1ccc2ncccc2n1
Temperature: 25 °C
Yield: 23.2 %

Procedure:
To a mixture of 2-(2,4-bis-trifluoromethyl-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (94.5 mg, 0.20 mmol), 1,5-naphthyridine-6-carboxaldehyde (31.7 mg, 0.20 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4.5 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, ether and dried in vacuum at 100° C. for 3 h to give 2-(2,4-bis-trifluoromethyl-benzylamino)-5-[1,5]naphthyridin-2-ylmethylene-1,5-dihydro-imidazol-4-one as a light yellow solid (21.6 mg, 23.2%). HR-ES (+) m/e calcd. for C21H13F6N5O: (M+H)+ 466.1097. Found: 466.1098.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[C:45]3[O:44][C:43]([NH2:46])=[N:42][C:41]=3[C:40]([O:47][CH3:48])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[C:45]3[O:44][C:43]([NH:46][C:1](=[O:5])[CH2:2][CH3:3])=[N:42][C:41]=3[C:40]([O:47][CH3:48])=[CH:39][CH:38]=2)=[CH:35][CH:36]=1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Reactant: CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCC(=O)Nc1nc2c(OC)ccc(-c3ccc(F)cc3)c2o1

Procedure:
From propionic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-ylamine in dioxane and DMF. ES-MS m/e (%): 315 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2([CH3:17])[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[C:6]1=[O:18].CCN(CC)CC.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32]>C(Cl)Cl>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([O:16][CH:13]2[CH2:14][CH2:15][C:10]([N:7]3[CH2:8][CH2:9][CH:5]([CH2:4][C:3]4[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=4[Cl:1])[C:6]3=[O:18])([CH3:17])[CH2:11][CH2:12]2)=[O:39])=[CH:41][CH:42]=1)([O-:33])=[O:32]
Reactant: CC1(N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CCC(O)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CCC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 147.4 %

Procedure:
Dissolve 3-(2,4-dichlorobenzyl)-1-(4-hydroxy-1-methylcyclohexyl)pyrrolidin-2-one (0.50 g, 0.51 mmol) in DCM (100 mL) and cool the solution to 0° C. under N2. Add Et3N (0.71 g, 7.06 mmol) and 4-nitrobenzoyl chloride (0.52 g, 2.82 mmol) and stir the reaction overnight at room temperature. Add water (100 mL) and extract the aqueous with EtOAc (3×100 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 20-60% of EtOAc/Hexane) to give 0.38 g (54%) of the title compound as a white solid. 1H NMR (CDCl3) δ 8.25 (m, 2H), 8.16 (m, 2H), 7.38 (d, 1H), 7.20 (d, 1H), 7.16 (dd, 1H), 5.18 (m, 1H), 3.25 (m, 3H), 2.65 (m, 2H), 2.42 (m, 1H), 2.19 (m, 1H), 1.95 (m, 1H), 1.80 (m, 6H), 1.62 (m, 1H), 1.28 (s, 3H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[F:31][C:32]([F:44])([F:43])[CH:33]([CH3:42])[O:34][C:35]1[N:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1>>[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:41]([C:38]3[CH:39]=[N:40][C:35]([O:34][CH:33]([CH3:42])[C:32]([F:44])([F:31])[F:43])=[CH:36][CH:37]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:27])=[O:26]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(Oc1ccc(N)cn1)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Product: CC(Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cn1)C(F)(F)F

Procedure:
Light brown solid. MS (ESI): 568.13 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-ylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N1CCC[C@H:11]1C(O)=O.[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1.C=O>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:11][C@@H:23]3[CH2:22][CH2:21][C@H:20]2[CH2:19][C:18]3=[O:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1C=CCCC1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(N2C[C@@H]3CC[C@H]2CC3=O)cc1
Temperature: 50 °C

Procedure:
A solution of p-anisidine (E-2, 8.13 g, 66.0 mmol, 1.1 equiv), L-proline (2.07 g, 18.0 mmol, 0.3 equiv), 2-cyclohexen-1-one (E-1, 11.54 g, 120.0 mmol, 2.0 equiv), and 37% aqueous formaldehyde (4.47 mL, 60.0 mmol, 1.0 equiv) was made in DMSO (100 mL) and the reaction was heated to 50° C. for 24 h. The reaction was cooled and diluted with ethyl acetate (500 mL) and washed with water (5×100 mL). The organic phase was dried over MgSO4 and concentrated to an oil. The crude residue was purified by chromatography on silica gel (0 to 80% ethyl acetate in hexanes) to afford the E-3 as a beige solid. 1HNMR (500 MHz, CDCl3) δ 6.86 (d, J=9.0 Hz, 2H), 6.64 (d, J=9.0 Hz, 2H), 4.24-4.19 (m, 1H), 3.76 (s, 3H), 3.68-3.63 (m, 1H), 3.48 (d, J=9.5 Hz, 1H), 2.70-2.60 (m, 2H), 2.42 (d, J=18.5 Hz, 1H), 2.22-2.12 (m, 1H), 2.06-1.93 (m, 2H), 1.86-1.78 (m, 1H) ppm; ESI MS [M+H] for C14H17NO2=232.0.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+]([O-])=O)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21]>CN(C=O)C>[CH3:24][O:23][C:19]([C:20]1[S:21][C:4]2[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=2[CH:6]=1)=[O:22]
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(Cl)cc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 600 mg (3.23 mmol) of 4-chloro-2-nitro-benzaldehyde in DMF (7 ml) were added 559 mg (4.04 mmol) of potassium carbonate and 294 μl (3.23 mmol) of methyl thioglycolate at 0° C. The reaction mixture was stirred for 30 min at 0° C. and then for 24 h at RT. Then the mixture was poured into ice-water and the precipitate was collected by filtration and dissolved in ethyl acetate. The solution was dried (MgSO4) and concentrated to yield 630 mg (86%) of 6-chloro-benzo[b]thiophene-2-carboxylic acid methyl ester as a white solid. 1HNMR (CDCl3, 300 MHz): δ 3.95 (s, 3H), 7.88 (dd, J=8.6 and 1.9 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 8.02 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:13][CH3:14])[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[F:15][CH:16]([F:43])[C:17]([N:19]1[C@H:23]([CH2:24][F:25])[C@@H:22]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[O:21][C:20]1([CH3:42])[CH3:41])=[O:18].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:43][CH:16]([F:15])[C:17]([N:19]1[C@H:23]([CH2:24][F:25])[C@@H:22]([C:26]2[CH:31]=[CH:30][C:29]([C:2]3[CH:7]=[N:6][C:5]([CH:8]([NH:13][CH3:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)[O:21][C:20]1([CH3:41])[CH3:42])=[O:18]
Reactant: CNC(c1ccc(Br)cn1)C(F)(F)F
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1)C(F)(F)F
Temperature: 80 °C
Yield: 90.5 %

Procedure:
To a stirred solution of [1-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl]-methyl-amine (0.075 g, 0.279 mmol) and 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (0.115 g, 0.279 mmol) in toluene:ethanol:water (3:3:3 mL) is added Na2CO3 (0.073 g, 0.697 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 30 minutes followed by addition of Pd(PPh3)4 (0.032 g, 0.028 mmol) and heated to 80° C. for 3 h. The reaction mixture is concentrated in vacuo then is diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate and evaporated in vacuum. The crude material is purified by Combi-flash eluting in 20% ethyl acetate in hexane afford the title compound (0.120 g). 1H-NMR (400 MHz, DMSO) δ: 1.52 (s, 3H), 1.60 (s, 3H), 2.25 (d, J=5.76 Hz, 3H), 3.01-3.05 (m, 1H), 4.44-4.48 (m, 1H), 4.56-4.58 (m, 0.5H), 4.67-4.72 (m, 1H), 4.81-4.88 (m, 0.5H), 4.90-5.00 (m, 1H), 5.27 (d, J=3.68 Hz, 1H), 6.65 (t, J=52.36 Hz, 1H), 7.60 (d, J=8.24 Hz, 2H), 7.98-8.00 (dd, J1=2.04 Hz, J2=8.2 Hz, 1H), 8.06 (d, J=8.24 Hz, 1H), 8.15 (d, J=8.32, 2H), 8.73 (d, J=1.8 Hz, 1H). LC-MS (m/z): [M−H]=476.0.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[C:12](Cl)=[O:13])=[CH:3]1.Cl.C([O:20][C:21](=[NH:34])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[N:25]([CH3:33])[CH:24]=1)(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:33][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[C:23]([C:22]2[C:21](=[O:34])[NH:20][C:12](=[O:13])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:24]1
Reactant: Cc1ccc2c(CC(=N)OC(C)C)cn(C)c2c1
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)cn(C)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of the known (1-methyl-1H-indol-3-yl)-oxo-acetyl chloride (183 mg, 0.83 mm) and 2-(1,6-dimethyl-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride (233 mg, 0.83 mm) in CH2Cl2 (6 mL) which had been cooled to 0° C., was added Et3N (0.46 mL, 3.3 mm). The reaction was allowed to warm to room temperature overnight, then diluted with CH2Cl2 (20 mL), and extracted with H2O(15 mL) and 0.5N HCl(15 mL). The organic fraction was dried over MgSO4, filtered and evaporated, and the residue combined with toluene (3 mL). After cooling to 0° C., para-toluene sulfonic acid (pTsOH) (174 mg, 0.91 mm) was added, and the mixture was stirred at room temperature for 3 hours. The red solids which precipitated were collected and partitioned between CH2Cl2 (50 mL) and H2O(25 mL). The organic fraction was washed with saturated NaHCO3 (25 mL) solution, then dried over MgSO4, filtered and evaporated. The residue was washed with cold CH2Cl2 to yield 3-(1,6-dimethyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3yl)-pyrrole-2,5-dione; mp=264°-266° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.C([O-])([O-])=O.[Na+].[Na+]>CC(O)(C)C.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClCCOCCCl
Reactant: Nc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: c1cc2cc(N3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A heterogeneous, tan solution of 1H-indol-5-amine (4.5547 g, 34.5 mmol), 1-chloro-2-(2-chloroethoxy)ethane (6.06 mL, 51.7 mmol) and Na2CO3 (14.61 g, 138 mmol) in t-BuOH (90 mL) in a sealed pressure tube was heated to 100° C. for 2 days. The reaction was cooled to room temperature, diluted with EtOAc and filtered through a pad of CELITE®, and the filtrate was concentrated in vacuo. Water (50 mL) was added to the residue and basified to pH ˜11 with saturated aqueous NaHCO3; this was extracted with CH2Cl2 (4×75 mL). The organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give crude product. This was triturated with Et2O to give the first crop of desired product (3.7495 g) as a tan solid. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography using an ISCO 120 g column eluting with 20-50% EtOAc/hexanes to give the second crop of the desired product (1.9458 g).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>C1C=CC=CC=1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([O:4][CH2:3][CH:2]3[CH2:5][CH2:6][CH2:7][NH:1]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: OC[C@@H]1CCCN1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OCC3CCCN3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of prolinol (0.0243 g, 2.27 mmol) and sodium hydroxide (95 mg, 2.27 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.3 g, 0.78 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1-2% MeOH—CHCl3) to afford the title compound E22 as an off-white solid (0.35 g, quantitative). mp 84-86° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 24.67 min, 99.59% purity; MS (CI): m/z 447 (M+H, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:14])=O)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH:56]1[C:64]2[C:59](=[C:60]([CH2:65][NH2:66])[CH:61]=[CH:62][CH:63]=2)[CH:58]=[N:57]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:14])[NH:66][CH2:65][C:60]2[CH:61]=[CH:62][CH:63]=[C:64]3[C:59]=2[CH:58]=[N:57][NH:56]3)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: NCc1cccc2[nH]ncc12
Reactant: CCc1cc(C(=O)O)sc1C(=O)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.4 %

Procedure:
To a solution of 3-Ethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (130 mg, 0.61 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.26 mL, 1.83 mmol), HBTU (0.35 g, 0.92 mmol), HOBT (0.099 g, 0.73 mmol), and C-(1H-Indazol-4-yl)-methylamine (100 mg, 0.67 mmol). The mixture was stirred at room temperature 2 d, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-80% EtOAc in hexane to afford the desired product (0.095 g, 46% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:32])[C:15](=[O:31])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18](SCCOC)[CH:17]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.O[O:36][S:37]([O-:39])=O.[K+].[NH4+].[Cl-].[CH3:43][CH2:44][O:45][C:46](C)=O>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:32])[C:15](=[O:31])[C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([S:37]([CH2:43][CH2:44][O:45][CH3:46])(=[O:39])=[O:36])[CH:17]=2)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: O=S([O-])OO
Reactant: COCCSc1cc(C(=O)N(C)c2cnccc2-c2ccc(F)cc2OC)cc(C(F)(F)F)c1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COCCS(=O)(=O)c1cc(C(=O)N(C)c2cnccc2-c2ccc(F)cc2OC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To an ice-cold solution of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-(2-methoxyethylthio)-N-methyl-5-(trifluoromethyl)benzamide (0.032 g, 64.7 μmol) in MeOH (4 mL) and water (0.5 mL) was added Oxone® (99.5 mg, 162 μmol) and the reaction mixture was stirred at room temperature for 4.5 hours. The white suspension was poured on saturated aqueous NH4Cl solution and EtOAc. The two layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with aqueous sodium thiosulfate 10% solution and once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 5 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (0.027 g; 79%). MS (ESI): m/z=527.13 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17]CC2C=CC=CC=2)[C:10]=1[CH:11]=[O:12])C1C=CC=CC=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:10]=1[CH:11]=[O:12]
Reactant: O=Cc1c(OCc2ccccc2)cccc1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=Cc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,6-bis-benzyloxybenzaldehyde (1.9 g, 6 mmol) in methylene chloride (15 mL) is added BBr3 (18 mL, 18 mmol, 1M in methylene chloride) and the mixture is stirred at RT for 18 h. Water is added to the mixture and the methylene chloride is removed under reduced pressure. The aqueous is extracted with EtOAc and the organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (5:1) as eluent to give the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:11]([O:15][C:16](=[O:27])[C:17]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:19]([C:20](O)=[O:21])[CH:18]=1)([CH3:14])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[C:11]([O:15][C:16](=[O:27])[C:17]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:19]([C:20]([NH:10][C:8]2[CH:9]=[C:4]3[CH:3]=[CH:2][NH:1][C:5]3=[N:6][CH:7]=2)=[O:21])[CH:18]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)Nc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridin-5-ylamine (example c), 0.5 mmol) and 4-methyl-isophthalic acid 1-tert-butyl ester from example 1-1 (0.5 mmol) in THF (5 ml) were added TBTU (0.5 mmol), HOBT (0.5 mmol) and Hunig's base (0.6 mmol) and stirred at RT for overnight. Solvent was concentrated, residue was diluted with EtOAc ( ), washed with 1(N) NaOH. Organics was concentrated to get 2.8 g of the crude title product. LC-MS: (m/z 352)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(O[O:14][C:15]([CH3:18])(C)C)(C)(C)C.[C]=O.[CH2:21]([OH:23])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:21]([O:14][CH2:15][CH3:18])=[O:23])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1ccc(F)cc1
Reactant: CCO
Agent: [C]=O
Product: CCOC(=O)Cc1ccc(F)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
p-Fluorotoluene (1.65 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 76 mg ethyl p-fluorophenylacetate was obtained by column chromatography, in a yield of 84%. 1HNMR (400 MHz, CDCl3) δ 1.23 (t, J=7.2 Hz, 3H), 3.58 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 6.98-7.03 (m, 2H), 7.23-7.26 (m, 2H); 13CNMR (100 MHz, CDCl3) δ 14.2, 40.5, 60.9, 115.3, 115.5, 129.8, 129.9, 130.8, 130.9, 160.8, 163.2, 171.5; HRMS (ESI) calcd. for C10H11FNaO2 [M+Na]: 205.0635. found: 205.0634. The ethyl p-fluorophenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 59 mg product p-fluorophenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 91%.