Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Al](C)C.[C:5]([C:8]1[N:9]=[C:10]([Cl:17])[S:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:7])[CH3:6]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:17][C:10]1[S:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:5]([OH:7])([CH3:1])[CH3:6])[N:9]=1
Reactant: COC(=O)c1sc(Cl)nc1C(C)=O
Reactant: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(Cl)nc1C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
A solution of 5.6 ml (11.2 mmol) 2N AlMe3 in toluene was added to a dry ice-acetone bath of 1.14 g (5.2 mol) of methyl 4-acetyl-2-chloro-1,3-thiazole-5-carboxylate (Intermediate 212) in 20 ml dry CH2Cl2. The mixture was allowed to warm to room temperature slowly before being quenched with MeOH. After stirring at room temperature overnight, the mixture was diluted with 1N HCl and stirred 15 min before being diluted with water and extracted twice with EtOAc. The EtOAc was washed with brine, dried (MgSO4) and concentrated to give an oil that was purified by chromatography (50% hexanes in CH2Cl2 with gradient elution to 100% CH2Cl2) affording 720 mg of product as an oil. NMR (CDCl3): 1.5 (s, 6H), 3.8 (s, 3H), 5.7 (s, broad, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7].OC1C=C(C=CC=1)C(C1C2C=CC=CC=2OC=1C1C=CC=CC=1)=O.[CH2:50]([N:52]([CH2:57][CH3:58])[CH2:53][CH2:54]CCl)[CH3:51]>>[CH2:50]([N:52]([CH2:57][CH3:58])[CH2:53][CH2:54][CH2:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])[CH3:51]
Reactant: CCN(CC)CCCCl
Reactant: COc1cccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)c1
Agent: O=C(c1cccc(O)c1)c1c(-c2ccccc2)oc2ccccc12
Product: CCN(CC)CCCOc1cccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)c1

Procedure:
Demethylation of 3-(3-methoxybenzoyl)-2-phenylbenzofuran followed by reaction of 3-(3-hydroxybenzoyl)-2-phenylbenzofuran with 3-diethylaminopropyl chloride as described in Example 1 gives the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:45])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:36][C:37]([C:39]1[N:40]=[CH:41][N:42]([CH3:44])[CH:43]=1)=[O:38])=[O:4].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:45][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:36][C:37]([C:39]1[N:40]=[CH:41][N:42]([CH3:44])[CH:43]=1)=[O:38])=[O:4]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Temperature: 0 °C
Yield: 25 %

Procedure:
1-methyl-1H-imidazole-4-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-amide (0.289 mmol) was dissolved in tetrahydrofuran (2.0 mL), cooled to 0° C. and treated with 5% perchloric acid in acetic acid (8 mL) for 3 h. The material was carefully poured into saturated sodium bicarbonate and extracted into ethyl acetate. The organic layer was washed with saturated sodium bicarbonate (3×), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 1-methyl-1H-imidazole-4-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-amide (35.8 mg, 27.9%). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 3.0 (s, 3H), 3.06 (s, 3H), 3.73 (s, 3H), 3.83 (s, 3H), 7.05 (dt, J=7.0 Hz, J=1.0 Hz, 1H), 7.13 (bd, J=7.5 Hz, 1H), 7.30 (dd, J=1.5, J=7.0 Hz 1H), 7.61 (dd, J=1.5 Hz, J=7.5 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.73 (8.33 (d, J=7.5 Hz, 1H), 7.77 (br s, 1H), 7.81 (dd, J=2.0, J=8.5 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 8.19 (s, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.57 (d, J=2.0 Hz, 1H), 10.07 (s, 1H), 11.83 (s, 1H). MS: m/z 496 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C@H:6]([OH:8])[C@@H:5]([NH:9][C@@H](C2C=CC=CC=2)C)[CH2:4][O:3]1.[H][H]>[Pd].CO>[NH2:9][C@H:5]1[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[CH2:7][C@@H:6]1[OH:8]
Reactant: [H][H]
Reactant: C[C@@H](N[C@H]1COC(C)(C)C[C@@H]1O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1(C)C[C@H](O)[C@@H](N)CO1
Yield: 189.4 %

Procedure:
A suspension mixture of (4S,5S)-2,2-dimethyl-5-((R)-1-phenylethylamino)-tetrahydro-2H-pyran-4-ol (1.0 g, 4.0 mmol) and 10% palladium on carbon (200 mg) in methanol (20 mL) was stirred at room temperature under 1 atm hydrogen atmosphere (hydrogen balloon) overnight. After that, the mixture was filtered through a pad of celite, and the filtrate was concentrated to get the title compound (1.1 g, crude) as a yellow oil, which was used directly for the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[OH:13])([O-:3])=[O:2].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[NH:47]1[CH2:51][CH2:50][C@@H:49]([OH:52])[CH2:48]1>ClCCl>[OH:13][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:47]1[CH2:51][CH2:50][C@@H:49]([OH:52])[CH2:48]1)=[O:9]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: O[C@@H]1CCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc([N+](=O)[O-])c1O)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 757.2 %

Procedure:
A mixture of 4.86 g (26 mmol, 1 eq) of 3-nitrosalicylic acid and 12.16 g (26 mmol, 1 eq) of bromotripyrrolidinophosphonium hexafluorophosphate in 65 ml of dichloromethane and in the presence of 13.7 ml (78 mmol, 3 eq) of N,N-diisopropylethylamine was stirred at ambient temperature for 30 minutes. 4.52 g (4.10 mmol, 2 eq) of (R)-(+)-3-pyrrolidinol in solution in 10 ml of dichloromethane were added dropwise and the reaction medium was stirred at ambient temperature overnight. The reaction medium was extracted with a 1 N sodium hydroxide solution and separated by settling out. The aqueous phase was acidified with a 1N hydrochloric acid solution and extracted with ethyl acetate (5×150 ml). The organic phases were combined, dried over magnesium sulfate, filtered and evaporated. 7.83 g of (2-hydroxy-3-nitrophenyl)-((R)-3-hydroxypyrrolidin-1-yl)methanone were obtained in the form of a golden yellow amorphous solid. Crude yield>100%. HPLC: 93% [252].
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].O[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[CH3:1][CH2:2][CH:3]([O:6][C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:20][CH:21]=2)=[CH:12][CH:13]=1)[CH2:4][CH3:5]
Reactant: CCC(O)CC
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(O)cc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)Oc1ccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)cc1
Reaction time: 72 h

Procedure:
14.7 μl (0.14 mmol) 3-pentanol, 40 mg (0.14 mmol) N-(1-(4-((4-hydroxyphenyl)-ethynyl)phenyl)propan-2-yl)acetamide (I74.1) and 69.8 mg (0.21 mmol) polymer bound triphenylphosphine (˜3 mmol/g) are added to 1 mL THF followed by 31.4 mg (0.14 mmol) DBAD. After stirring the mixture for 2 h at r.t. further 7.5 μl (0.07 mmol) 3-pentanol and 16 mg (0.07 mmol) DBAD are added and stirring is continued for 72 h. The reaction mixture is filtered and the filtrate is purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]>O1CCCC1>[CH3:1][N:2]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8](=[O:17])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]1=[O:16]
Reactant: CNCCCCN1C(=O)c2ccccc2C1=O
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCCCN1C(=O)c2ccccc2C1=O)CCCCN1C(=O)c2ccccc2C1=O
Temperature: 165 °C

Procedure:
209 mg (0.9 mmol) of 2-[4-(methylamino)butyl]-1H-isoindole-1.3(2H)-dione is solubilized in 5 ml of tetrahydrofuran, then 385 μl (2.7 mmol; 3 equivalents) of triethylamine and 254 mg (0.9 mmol; 1 equivalent) of 2-(4-bromobutyl)-1H-isoindole-1.3(2H)-dione are added to the reaction mixture which is maintained for 25 minutes under microwaves at 165° C. The precipitate obtained is filtered and the filtrate concentrated under reduced pressure. The expected product is purified by chromatography on a silica column (eluent: dichloromethane/methanol: 95/5).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH2:19]([O:26][CH2:27][C:28](Cl)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:28](=[O:29])[CH2:27][O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ccc(NC(=O)COCc3ccccc3)c(O)c21
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (251 mg, 0.928 mmol) was dissolved in pyridine (10 mL), (benzyloxy)acetyl chloride (160 μL, 1.01 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (285 mg, yield 80%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH:5]([O:14][CH3:15])[O:4]1.C[O:17][CH:18]1[C:22](C2C=CC(CCC)=CC=2)=[CH:21]C(OC)O1.COC1C(C2C=CC(CCC)=CC=2)CC(OC)O1>>[CH3:1][O:2][CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:18](=[O:17])[CH2:22][CH3:21])=[CH:10][CH:9]=2)[CH2:6][CH:5]([O:14][CH3:15])[O:4]1
Reactant: CCCc1ccc(C2=CC(OC)OC2OC)cc1
Reactant: COC1CC(c2ccccc2)C(OC)O1
Agent: CCCc1ccc(C2CC(OC)OC2OC)cc1
Product: CCC(=O)c1ccc(C2CC(OC)OC2OC)cc1
Yield: 100 %

Procedure:
As described in Example 1(b) for the preparation of 2,5-dimethoxy-3-phenyltetrahydrofuran, 2,5-dihydro-2,5-dimethoxy-3-(4-propylphenyl)-furan (320 mg, 1.29 mmol) was hydrogenated to give 322 mg (100%) of a diastereomeric mixture of 2,5-dimethoxy-3-(4-propylphenyl)-tetrahydrofuran as a viscous colorless oil that was unstable and used immediately without further purification. 1H NMR (CDCl3): δ 7.24 (d, 2H, J=8.1 Hz), 7.12 (d, 2H, J=8.1 Hz), 5.24 (t, 1H, J=5.9 Hz), 3.60-3.30 (m, 6H), 2.59 (d, 1H, J=7.5 Hz), 2.52 (d, 1H, J=8.1 Hz), 2.32 (bs, 3H), 1.62 (q, 2H, J=7.5 Hz), 0.92 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:9]([CH3:27])[C:8](=[O:28])[CH2:7][CH2:6]2.I.CSC1NCCN=1.[CH2:37](O)[CH2:38][CH3:39]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:37][CH2:38][CH3:39])[C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:9]([CH3:27])[C:8](=[O:28])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N(C)C(=O)CC2
Reactant: CCCO
Agent: CSC1=NCCN1
Agent: I
Solvent: CCOC(C)=O
Product: CCCN1CCC[C@H](NCc2cc3c(cc2OC)CCC(=O)N3C)[C@@H]1c1ccccc1
Yield: 21 %

Procedure:
2-Imidazolidinethione (10 g, 97.89 mmol) and methyl iodide (6.70 mL, 107.67 mmol) were stirred in 20 mL of absolute ethanol at reflux for 2 hours. The reaction was cooled and an equal volume of diethyl ether was added. The suspension was filtered to give 22.9 g (96%) of 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydrogen iodide as an off-white solid that was used in the next reaction. 6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one (500 mg, 1.32 mmol) and 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydrogen iodide (402 mg, 1.65 mmol) were stirred in 5 mL of n-propanol at reflux for 2 days. The reaction was diluted with ethyl acetate, washed 1× with satd. K2CO3, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (95:5 ethyl acetate/methanol) gave 123 mg (21%) of the title compound, a pale yellow oil. Rf=0.12 (9:1 ethyl acetate/methanol). 1H NMR (400 MHz, CDCl3): δ 0.67–0.70 (t, J=7.4 Hz, 3H), 1.36–1.49 (m, 4H), 1.72–1.79 (m, 1H), 1.92–2.04 (m, 3H), 2.39–2.43 (m, 1H), 2.51–2.55 (t, J=7.3 Hz, 2H), 2.63 (s, 1H), 2.73–2.78 (t, J=7.3 Hz, 2H), 3.12 (s, 3H), 3.16–3.19 (m, 1H), 3.30 (s, 1H), 3.34–3.38 (d, J=14.4 Hz, 1H), 3.49 (s, 3H), 3.60–3.64 (d, J=14.4 Hz, 1H), 6.46 (s, 1H), 6.60 (s, 1H), 7.15–7.32 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 11.8, 19.3, 20.3, 25.4, 27.5, 29.5, 31.7, 45.1, 53.4, 55.4, 56.2, 57.9, 72.1, 109.7, 115.9, 124.8, 126.5, 127.7, 128.7, 133.3, 141.7, 152.8, 169.9. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)[N:6]=1)=[NH:4].[C:22](OCC)(=O)C.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Cl-]>C1COCC1.C(OCC)(OCC)OCC>[O:1]1[CH:22]=[N:4][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[CH:12]=[N:13][N:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[N:6]=2)=[N:2]1
Reactant: CCOC(C)=O
Reactant: N=C(NO)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(OCC)OCC
Product: c1cncc(-n2cc(-c3cccc(-c4ncon4)n3)cn2)c1
Reaction time: 2 h

Procedure:
0.24 g of N-hydroxy-6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carboxamidine (crude product from the previous step) was dissolved in THF/triethyl orthoformate, and 0.2 g of BF3-ET2O was added. After 2 h, ethyl acetate, aq. citrate buffer pH=6 and aq. NaCl were added and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were dried with MgSO4 and concentrated by evaporation, and the residue was purified by chromatography on silica gel (petroleum ether/acetone).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[F:16][CH:17]([F:29])[O:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1F>CS(C)=O.ClCCl>[F:16][CH:17]([F:29])[O:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9]
Reactant: COc1ccc[nH]c1=O
Reactant: O=[N+]([O-])c1ccc(F)c(OC(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cccn(-c2ccc([N+](=O)[O-])cc2OC(F)F)c1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
302 mg (2.41 mmol) of 3-methoxypyridone are dissolved in 8.2 ml of anhydrous dimethyl sulfoxide and admixed with 325 mg (2.89 mmol) of potassium tert-butoxide. After 30 min, 500 mg (2.41 mmol) of 2-(difluoromethoxy)-1-fluoro-4-nitrobenzene are added and the mixture is heated to 80° C. for 20 h. The reaction solution is diluted with dichloromethane and washed with water and 1N hydrochloric acid. After the organic phase has been dried over sodium sulfate, it is filtered and concentrated to dryness under reduced pressure. The residue is dissolved in dimethyl sulfoxide and purified by preparative HPLC with a water/acetonitrile gradient. The product fractions are combined and concentrated to dryness under reduced pressure. This affords 207 mg (28% of theory) of the desired product.
Reaction SMILES: N#N.[Mg].Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[C:14]([CH:21]=[O:22])[CH:13]=1.Cl>O1CCCC1.O>[Br:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:19][CH:20]=1)[C:16](=[O:18])[O:22][CH:21]2[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Brc1ccccc1
Reactant: O=Cc1cc(Br)ccc1C(=O)O
Agent: Cl
Agent: N#N
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: O=C1OC(c2ccccc2)c2cc(Br)ccc21
Temperature: 30 °C
Reaction time: 0.75 h
Yield: 93.8 %

Procedure:
A tricol of 1 L with a condenser and an addition funnel is purged with N2 and magnesium turnings (5 g, 206 mmol) in tetrahydrofuran (80 mL) are added. Bromobenzene (32 g, 206 mmol) in tetrahydrofuran (80 mL) is added dropwise over 1¼ hour by maintaining the mixture temperature at 30° C. The resulting mixture is stirred for 45 min. at 30° C. 4-Bromo-2-formyl-benzoic acid (C3) (18.9 g, 83 mmol) in anhydrous tetrahydrofuran (200 mL) is added dropwise over 45 min. The mixture is stirred for 2 h at 30° C. The mixture is cooled in an ice-water bath and water (120 mL) and 5N HCl solution (80 mL) are added. The mixture is stirred overnight. THF is removed in vacuo and extracted with DCM (3×100 mL). The combined organics are washed with water (2×100 mL), dried over Na2SO4, filtered and the solvent is removed in vacuo to yield 5-bromo-3-phenyl-3H-isobenzofuran-1-one (22.5 g, 94%). Recrystallization: 5-bromo-3-phenyl-3H-isobenzofuran-1-one is dissolved in hot acetone (250 mL) and the mixture cooled in an ice-water bath over night. The resultant solid is filtered, rinsed with cold ACN (2×15 mL), and then vacuum dried over KOH to yield 5-bromo-3-phenyl-3H-isobenzofuran-1-one (D3) (14.4 g, 61%, mp: 189° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](I)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:16]2[N:15]([CH3:13])[C:18]3[C:19]([CH:17]=2)=[CH:4][CH:3]=[CH:2][CH:10]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: CCN(CC)CC
Reactant: O=C1NCc2c(Cl)ccc(I)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: Cn1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2ccccc21
Yield: 164.2 %

Procedure:
In a similar manner to Step 2 of Example 1, 4-chloro-7-iodoisoindolinone (84.0 mg, 0.286 mmol) was dissolved in acetonitrile (3 mL), and the solution was treated with Compound BK (100 mg, 0.571 mmol), palladium acetate (5.2 mg, 0.023 mmol) and triethylamine (0.400 mL, 2.87 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=7/3, 3/2, 1/1) to obtain Compound 156 (69.7 mg, yield 82%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]#[CH:10])SC)#[N:2].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>>[C:1]([NH:3][C:4]([NH:7][CH2:8][C:9]#[CH:10])=[N:21][CH2:20][CH2:19][S:18][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)#[N:2]
Reactant: NCCSCc1ccccn1
Reactant: C#CCN=C(NC#N)SC
Product: C#CCNC(=NCCSCc1ccccn1)NC#N

Procedure:
The product of Step A is reacted with about an equimolar amount of 2-[(2-pyridyl)methylthio]ethylamine in a nonreactive solvent to give after workup, the title product.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([C:14]3[C:15](=[O:30])[NH:16][CH:17]=[CH:18][C:19]=3[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].C1COCC1.O[C@@H](C1C=CC=CC=1)CNC1C=CNC(=O)C=1C1NC2C(C(O)=O)=CC=CC=2N=1>O>[Cl:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][NH:20][C:19]2[CH:18]=[CH:17][NH:16][C:15](=[O:30])[C:14]=2[C:11]2[NH:12][C:13]3[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=3[N:10]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12
Agent: O=C(O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12

Procedure:
2-{4-[2-(3-Chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid was synthesized from 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid methyl ester, LiOH, THF, and water using a similar procedure as 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid yielding 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2(N(Cc3ccccc3)Cc3ccccc3)CC2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C2(N(Cc3ccccc3)Cc3ccccc3)CC2)cc1
Temperature: 70 °C
Yield: 88.8 %

Procedure:
Using General Procedure D; dibenzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 125, 45.0 mg, 0.11 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.35 g, 3.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (35.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5 d. The title compound 40 mg (88%) was isolated by chromatography (hexanes).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][CH:23]1[CH2:27][N:26]([CH3:28])[C:25](=[O:29])[CH2:24]1>>[CH3:28][N:26]1[C:25](=[O:29])[CH2:24][CH:23]([NH:22][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:27]1
Reactant: CN1CC(N)CC1=O
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: CN1CC(NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)CC1=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 4-amino-1-methylpyrrolidin-2-one hydrochloride (CAN 1228838-07-0) as starting materials. MS (EI): m/e=381.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[SH:11][CH2:12][CH2:13][CH2:14][OH:15]>>[Cl:1][C:2]1[CH:9]=[C:8]([S:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OCCCS
Reactant: N#Cc1ccc(F)cc1Cl
Product: N#Cc1ccc(SCCCO)cc1Cl

Procedure:
4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with 3-mercapto-1-propanol to afford 2-chloro-4-(3-hydroxypropylthio)benzonitrile. 1 g of 2-chloro-4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(3-hydroxypropylthio)benzoic acid. 1.2 g of 2-chloro-4-(3-hydroxypropylthio)benzoic acid was reacted via Procedure R to yield 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.0 (M)+.