Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=1.BrC1NC2C=CC=CC=2N=1.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Agent: Brc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c([N+](=O)[O-])cc(Br)cc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of 6-bromo-2-methyl-4-nitro-1H-benzo[d]imidazole, prepared as described in Example 1 (22 g), (bromomethyl)benzene (15 g) and K2CO3 (35 g) in DMF (250 mL) was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was then poured into water. It was then filtered to afford a solid and the solid was washed with water and then dried in-vacuo to afford the desired product (28 g, 93%). 1H NMR (300 MHz, DMSO-d6): δ ppm 2.60 (s, 3H), 5.62 (s, 2H), 7.12-7.15 (m, 2H), 7.29-7.39 (m, 3H), 8.12 (d, 1H, J=1.8 Hz), 8.32 (d, 1H, J=1.8 Hz); LC-MS: m/e=346 [M+1]+.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19]([OH:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH3:24]>CN(C=O)C>[CH2:19]([O:25][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:7][CH2:6][CH:5]=[CH:4][CH:3]=[CH:2][CH3:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[CH:20]=[CH:21][CH:22]=[CH:23][CH3:24]
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC=CC=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CC=CCOc1ccc(C(=O)c2ccc(OCC=CC=CC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
4,4'-Difluorobenzophenone (34) (4.8 grams, 22 mmol) was dissolved in anhydrous DMF (1 liter). NaH (95%; 5.6 grams, 220 mmol) was added and the solution was cooled to 0° C. 2,4-Hexadienol (5.8 mL, 51 mmol) was slowly added to the solution and the reaction mixture was allowed to warm to room temperature with stirring under argon overnight. The reaction mixture was concentrated in vacuo, dissolved in dichloromethane, and washed with water. The organic phase was dried (MgSO4) and concentrated and purified by column chromatography (silica gel; hexane/CH2Cl2, 1/3) to afford 2.07 grams (25%) of compound 35 as a white solid. 1H H NMR (300 MHz, DMSO-d6) δ1.73 (d, J=6.6 Hz, 6H), 4.68 (d, J=6.0 Hz, 4H), 5.69-5.84 (m, 4H), 6.05-6.19 (m, 2H), 6.31-6.45 (m, 2H), 7.08 (d, J=9.0 Hz, 4H), 7.68 (d, J=10.2 Hz, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH3:2].Br[C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][CH:19]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]=[C:6]([C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][CH:19]=1)[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH3:2]
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CCOC(=O)C=Cc1c[nH]c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Product: CCOC(=O)C=C(c1ccc2cc[nH]c2c1)c1c[nH]c2ccccc12
Temperature: 114 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A sealed tube flushed with N2 was charged with 3-(1H-indol-3-yl)-acrylic acid ethyl ester (323 mg, 1.5 mmol), 6-bromoindole (196 mg, 1 mmol), tetra-butylammonium bromide (64.4 mg, 0.2 mmol), TEA (209 μl, 1.5 mmol) and palladium-dichloro-[bis(tri-ortho-tolyl)phosphine] (39.3 mg, 0.05 mmol). The mixture was stirred at 114° C. for 1 hour, cooled to room temperature, dissolved in DCM, and purified via flash chromatography (hexane/EtOAc) to afford 3-(1H-indol-6-yl)-3-(1H-indol-3-yl)-acrylic acid ethyl ester XXVI (250 mg, yellow oil) as a mixture of geometric isomers.
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]([CH3:16])[C:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH2:9][CH3:10])[CH2:7][OH:8].[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22](OC)=[O:23])=[C:20]([O:28][CH3:29])[C:19]=1[Cl:30]>C1(C)C=CC=CC=1>[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:8][CH2:7][C:6]([N:5]([CH3:4])[CH3:16])([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:9][CH3:10])=[O:23])=[C:20]([O:28][CH3:29])[C:19]=1[Cl:30]
Reactant: CCC(CO)(c1cccs1)N(C)C
Reactant: COC(=O)c1ccc(N)c(Cl)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(COC(=O)c1ccc(N)c(Cl)c1OC)(c1cccs1)N(C)C
Temperature: 110 °C
Reaction time: 96 h
Yield: 25 %

Procedure:
Sodium methoxide (0.4 g) is added to a solution of 2-dimethylamino-2-(2-thienyl)-1-butanol (7.5 g) and methyl 4-amino-3-chloro-2-methoxybenzoate (16.2 g) in toluene (150 ml) and the mixture is stirred at 110° C. for 96 hours while removing methanol which is produced during the reaction. After cooling, the mixture is washed with water, dried and concentrated to remove solvent. The residue is purified by silica gel column chromatography (solvent, chloroform:ethanol=50:1), whereby 2-dimethylamino-2-(2-thienyl)butyl 4-amino-3-chloro-2-methoxybenzoate (3.6 g) is obtained as colorless crystals.
Reaction SMILES: [O-]CC.[Na+].[Na].C(O)C.C([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][N:15]=1)(=O)C>C(Cl)(Cl)Cl.O.C(O)(=O)C>[C:23]([O:22][C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][OH:12])=[N:15][CH:16]=1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(=O)OCc1ccc(C(=O)OC(C)(C)C)cn1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium ethoxide, prepared from 0.5 g of sodium and 12.5 ml of dry ethanol, is added to a solution of the crude 5-t-butoxycarbonyl-2-pyridylmethanol acetate in 26 ml of chloroform, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is neutralized by adding a solution of 3.3 ml of acetic acid in 65 ml of water and extracted with three 70-ml portions of chloroform. The combined extracts are dried over magnesium sulfate and concentrated to give 4.1 g of 5-t-butoxycarbonyl-2-pyridylmethanol.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=4)=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 4-fluoro-benzoic acid, the title compound was prepared as white powder. MS: m/e=403(M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[NH:10][C:9](=[O:12])[C:8](=[O:13])[NH:7][C:6]=2[S:5][CH:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:19]Br.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:19][C:4]1[S:5][C:6]2[NH:7][C:8](=[O:13])[C:9](=[O:12])[NH:10][C:11]=2[C:3]=1[CH2:1][CH3:2]
Reactant: BrBr
Reactant: CCc1csc2[nH]c(=O)c(=O)[nH]c12
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1c(Br)sc2[nH]c(=O)c(=O)[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
A suspension of 7-ethylthieno[2,3-b]pyrazine-2,3(1H,4H)-dione (1.0 g, 5.1 mmol) and sodium acetate (0.84 g, 10.2 mmol) in 225 ml of acetic acid was stirred at 10°-15° C. under a dry nitrogen atmosphere. A solution of bromine (0.26 ml, 5.1 mmol) in 2 ml of acetic acid was added during 0.5 h. Stirring was continued for further 0.5 h at room temperature and the reaction mixture was poured into ice water. The reddish mixture was decolourized by the addition of a small amount of aqueous sodium dithionite. The precipitate was filtered off, washed with water, resuspended in alcohol, filtered and washed with ether. Drying at 60° C. in vacuo afforded 720 mg (51%) of the title compound. M.p. 295°-297° C. 1H-NMR (DMSO-D6, δ): 1.04 (t, 3H), 2.62 (q, 2H), 12.01 (s, 1H), 12.19 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][CH2:11][C@H:10]([OH:12])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Product: O[C@@H](CNCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Benzyl-(S)-(+)-glycidyl ether (3.28 g) was dissolved in benzylamine (15 ml) and the mixture was stirred at room temperature for 4 days. Excess benzylamine was removed by evaporation in vacuo and the resulted residue was purified with a silica gel column chromatography (eluting solvent: chloroform to chloroform/methanol=9/1) to give (2S)-1-(benzylamino)-3-(benzyloxy)propane-2-ol (4.50 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]([CH2:14][C:15]2[CH:34]=[CH:33][C:18](/[CH:19]=[CH:20]/[C@@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:37]([O:41][C:42]([N:44]1[CH2:48][CH2:47][CH2:46][C@H:45]1[C:49](O)=[O:50])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1/[CH:20]=[CH:19]/[C:18]1[CH:33]=[CH:34][C:15]([CH2:14][N:7]([CH2:6][C:5]2[CH:35]=[CH:36][C:2]([NH:1][C:49]([C@@H:45]3[CH2:46][CH2:47][CH2:48][N:44]3[C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])=[O:50])=[CH:3][CH:4]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:16][CH:17]=1)=[O:27])([CH3:31])([CH3:32])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CN(Cc2ccc(N)cc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)OC(C)(C)C)cc2)c2ccccc2)cc1
Yield: 24.3 %

Procedure:
The product from Example 149F (700 mg, 1.45 mmol) and (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (374 mg, 1.74 mmol) were processed using the method described in Example 43 to afford 240 mg (23%) of the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.92 (s, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.18 (m, 4H), 7.07 (m, 2H), 6.64 (d, J=8.1 Hz, 2H), 6.55 (t, J=7.7 Hz, 1H), 6.31 (d, J=15.6 Hz, 1H), 6.14 (dd, J=15.5, 6.5 Hz, 1H), 4.63 (s, 2H), 4.60 (s, 2H), 4.22 (m, 1H), 4.17 (m, 1H), 3.38 (m, 2H), 3.28 (m, 2H), 1.85 (m, 8H), 1.38 (s, 9H), 1.30 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@H:18]([CH2:22][CH2:23][CH2:24][N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.ClC1(S(N[C@H](CCCN2C(=O)C3C(=CC=CC=3)C2=O)C(O)=O)(=O)=[O:50])C=CC(C2C=CC=CC=2)=CC1.[OH-].[Li+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]([C:19]([OH:21])=[O:20])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]([OH:50])=[O:34])(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)C1(Cl)C=CC(c2ccccc2)=CC1
Reactant: O=C(O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)NCCC[C@@H](NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of the title compound of Example 1, (2R)-(4-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid (20.0 mg, 0.039 mmol), in 2 mL of tetrahydrofuran is treated with 1M aqueous lithium hydroxide. After 2 h, the solution is acidified with 0.2 mL of 1N aqueous HCl, and the mixture is concentrated to an oil. Chomatography on LiChoprep DIOL (eluant; ethyl acetate) affords 12.8 mg (62%) of (4R)-N-[4-(4′-chlorobiphenyl-4-sulfonylamino)-4-carboxybutyl]phthalamic acid as a white solid: m.p. 119-121° C. (dec); IR 1737, 1701, 1649, 1344, 1168; ESI-MS 529 (M−−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[N:16]=[N:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:6]=2[CH:18]=1.[C:19]([O:23][C:24](=[O:30])[NH:25][C:26](=O)[CH2:27]Cl)([CH3:22])([CH3:21])[CH3:20]>CC(N(C)C)=O>[C:19]([O:23][C:24](=[O:30])[NH:25][C:26]1[N:17]=[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][N:7]3[C:6]4[CH:18]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=4[N:9]=[N:8]3)=[N:16][N:15]2[CH:27]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Nc1ccc(Cn2nnc3ccc(Br)cc32)nn1
Reactant: CC(C)(C)OC(=O)NC(=O)CCl
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1
Temperature: 135 °C
Reaction time: 4 h
Yield: 30.9 %

Procedure:
A mixture of compound 10G (1.0 g, 3.28 mmol), (2-chloro-acetyl)-carbamic acid tert-butyl ester (1.0 g, 5.0 mmol) and Na2HPO4 (1.4 g, 10 mmol) in DMA (50 mL) was stirred at 135° C. for four hours. Solvent was removed under reduced pressure. The residue was sonicated in ethyl acetate/water, and the precipitate was filtered off. Ethyl acetate solution was separated and concentrated and loaded on silica gel. The silica column was eluted with hexane/ethyl acetate (1/2) to give 0.45 g of desired product (10H). ESI-MS:m/z 444.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([OH:13])([C:9]([F:12])([F:11])[F:10])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([I+:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.[C:44](Cl)(=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:46][C:45]([CH3:48])([CH3:47])[C:44]([O:13][C:3]([C:2]([F:1])([F:14])[F:15])([C:9]([F:12])([F:10])[F:11])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6])=[O:49].[C:33]([C:30]1[CH:31]=[CH:32][C:27]([I+:26][C:23]2[CH:22]=[CH:21][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:25][CH:24]=2)=[CH:28][CH:29]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: O=S(=O)([O-])CC(O)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)c1ccc([I+]c2ccc(C(C)(C)C)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC(CS(=O)(=O)[O-])(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
Into a mixture solution of 6.5 g (0.010 mole) of bis(4-tert-butylphenyl)iodonium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate prepared in Synthesis Example 1-13, 2.2 g (0.022 mole) of triethylamine, 0.2 g (0.002 mole) of 4-dimethylaminopyridine, and 25 g of methylene chloride was added 2.4 g (0.020 mole) of pivaloyl chloride, and they were stirred at room temperature for 8 hours. Thereafter, the reaction was terminated by adding 22 g of 5% hydrochloric acid, and then the organic layer was separated, washed by water, and concentrated under reduced pressure. Into the concentrated solution was added methyl isobutyl ketone, and the resulted mixture was concentrated again under reduced pressure to distil the remaining water out. The obtained residue was recrystallized by adding diisopropyl ether, and then the crystals were recovered and dried to obtain the intended bis(4-tert-butylphenyl)iodonium 2-(2,2-Dimethylpropionyloxy)-3,3,3-trifluoro-2-trifluoromethylpropane-1-sulfonate (1.8 g of white crystals (yield 23%)). The structure of the intended product is shown below.
Reaction SMILES: [CH2:1]([C@H:8]1[NH:23][C:22](=[O:24])[C@@H:21]([CH3:25])[NH:20][C:19](=[O:26])[CH2:18][C@@H:17](/[CH:27]=[CH:28]/[CH2:29][CH2:30][S:31]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:16][C:15](=[O:51])[CH2:14][NH:13][C:12](=[O:52])[C@@H:11]([CH:53]([CH3:55])[CH3:54])[NH:10][C:9]1=[O:56])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C@H:8]1[NH:23][C:22](=[O:24])[C@@H:21]([CH3:25])[NH:20][C:19](=[O:26])[CH2:18][C@@H:17](/[CH:27]=[CH:28]/[CH2:29][CH2:30][SH:31])[O:16][C:15](=[O:51])[CH2:14][NH:13][C:12](=[O:52])[C@@H:11]([CH:53]([CH3:55])[CH3:54])[NH:10][C:9]1=[O:56])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](C)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC1=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](C)NC(=O)C[C@@H](/C=C/CCS)OC(=O)CNC1=O
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
To a stirred solution of 15 (9 mg, 0.012 mmol) in CH2Cl2 (500 □L) Et3SiH (3.83 μL, 0.024 mmol) and TFA (60 μL) were added. After 15 minutes stirring the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (2-7% MeOH/CH2Cl2) to give thiol 16 (2.3 mg, 0.0043 mmol, 36%) as a white solid: Rf 0.58 MeOH/CH2Cl2 (1:9); LRMS (ES+) m/z 555.4 (100%, [M+Na]+).
Reaction SMILES: ON1C(=O)CCC1=O.C(N(CC)CC)C.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.[CH2:28]([C:32]1[NH:33][C:34]2[CH2:39][CH:38]([C:40]([O:42][CH3:43])=[O:41])[NH:37][CH2:36][C:35]=2[N:44]=1)[CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH2:28]([C:32]1[NH:33][C:34]2[CH2:39][CH:38]([C:40]([O:42][CH3:43])=[O:41])[N:37]([C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:36][C:35]=2[N:44]=1)[CH2:29][CH2:30][CH3:31]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCc1nc2c([nH]1)CC(C(=O)OC)NC2
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc2c([nH]1)CC(C(=O)OC)N(C(=O)OCc1ccccc1)C2
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
N-Hydroxysuccinimide (0.69 g) and triethylamine (0.6 g) are dissolved in dry dimethylformamide (5 ml), and thereto is added dropwise benzyloxycarbonyl chloride (1.02 g) under ice-cooling. The mixture is stirred for 10 minutes, and thereto is added triethylamine (2.0 g). To the mixture is further added a solution of methyl 2-n-butyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylate hydrochloride (1.55 g) in dimethylformamide (5 ml), and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure, and thereto are added water and chloroform. The aqueous layer is extracted with chloroform, and the extract is combined with the chloroform layer, dried, and evaporated under reduced pressure to remove the solvent. The resulting oily residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give methyl 2-n-butyl-5-benzyloxycarbonyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylate (1.21 g) as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].I[CH:30]([CH3:32])[CH3:31]>O>[NH2:1][C:2]1[N:3]([CH:30]([CH3:32])[CH3:31])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)[nH]c(=O)c23)c(C)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C(C)C)c(=O)c23)c(C)c1
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a solution of 2-amino-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (156 mg, 0.55 mmol) and N,N-dimethylformamide (5 ml) was added sodium hydride (60% in oil, 24 mg, 0.60 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of 2-iodopropane (102 mg, 0.60 mmol) and N,N-dimethylformamide (2 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 3 hours, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) to give 88 mg (49%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[C:12]([O:16][C:17](=[O:20])[C:18]#[CH:19])([CH3:15])([CH3:14])[CH3:13].CN1CCOCC1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]/[CH:19]=[CH:18]\[C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:20])=[CH:7][CH:6]=1
Reactant: COCCc1ccc(O)cc1
Reactant: C#CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COCCc1ccc(O/C=C\C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
a mixture of 4-(2-methoxy ethyl)phenol (1.547 g, 10.3 mmol), propiolic acid tert-butyl ester (1.367 g, 10.8 mmol) and N-methyl morpholine (1.18 mL, 10.8 mmol) in CH2Cl2 (15 mL) was stirred at room temperature for 24 hours. The mixture was absorbed on SiO2 (20 g) and purified by column chromatography using a mixture of methylene chloride/hexane. The product was obtained as a two to one mixture of (E)/(Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate isomers (2.0 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[C:5]([Cl:8])=[CH:6][CH:7]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:13])[C:3]=1[F:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Cl)ccc(Br)c1F
Agent: [K+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: COc1c(Cl)ccc(Br)c1F
Yield: 96.9 %

Procedure:
A heterogeneous mixture of 3-bromo-6-chloro-2-fluorophenol (14.4 g, 0.064 mol), methyl iodide (13.5 g, 0.096 mol) and potassium carbonate (8.8 g, 0.064 mol) in acetonitrile (100 mL) was heated under reflux for two hours. The mixture was cooled, diluted with water (100 mL) and extracted with diethyl ether (2×150 mL). The combined extracts were dried and concentrated. The dark oil was purified by chromatography (5% ethyl acetate in hexanes) to give 1-bromo-4-chloro-2-fluoro-3-methoxybenzene (14.8 g, 0.062 mol) 1H NMR (CDCl3): δ 7.20 (m, 1H), 7.10 (dd, 1H), 4.0 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[C:32]([C:37]([NH:39][CH3:40])=[O:38])=[N:33][CH:34]=[CH:35][CH:36]=1.C(O)(C(F)(F)F)=O>O>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[C:32]([C:37](=[O:38])[NH:39][CH3:40])=[N:33][CH:34]=[CH:35][CH:36]=3)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CNC(=O)c1ncccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccnc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (30.0 mg, 0.0661 mmol) and 3-amino-N-methylpyridine-2-carboxamide (Compound 231C, 15.0 mg, 0.0992 mmol) were taken up in TFE (2.7 mL, 37 mmol) and treated with TFA (15.3 uL, 0.198 mmol). This mixture was irradiated on the CEM for 120 min at 100° C. R×n mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified on an ISCO CombiFlash system (eluting with 0-4% MeOH/DCM) to isolate, after concentrating the relevant fractions and drying in vacuo, the desired product as 20.8 mg of a white solid. 1H NMR (400 MHz, DMSO-d6) δ1.19 (t, J=7.07 Hz, 6H), 2.81 (d, J=4.80 Hz, 3H), 3.28 (d, J=20.50 Hz, 2H), 3.74 (s, 3H), 3.94-4.04 (m, 4H), 6.90 (dt, J=8.15, 1.99 Hz, 1H), 7.05 (s, 1H), 7.33-7.51 (m, 2H), 8.21 (d, J=3.54 Hz, 1H), 8.41 (s, 1H), 9.08 (br. s., 1H), 9.11 (q, J=4.21 Hz, 1H), 12.45 (s, 1H). MS (ES+): m/z=569.10 (100) [M+1]. HPLC: tR=1.52 min (UPLC TOF, polar—3 min).