Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][OH:18])[C:11]=2[CH3:19])[CH2:4][O:3]1.[OH-].[Na+].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:18][CH2:17][C:12]2[C:11]([CH3:19])=[C:10]([O:9][CH2:8][CH:5]3[CH2:6][O:7][C:2]([CH3:20])([CH3:1])[O:3][CH2:4]3)[C:15]([CH3:16])=[CH:14][N:13]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cnc(CO)c(C)c1OCC1COC(C)(C)OC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2ncc(C)c(OCC3COC(C)(C)OC3)c2C)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 88 %

Procedure:
To a tetrahydrofuran (30 ml) solution of (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methanol (738 mg, 2.61 mmol), powdered sodium hydroxide (313 mg, 7.84 mmol) was added and the mixture was stirred at room temperature for 35 minutes. The mixture was further stirred for 10 minutes under ice-cool and p-toluenesulfonyl chloride (1.09 g, 5.74 mmol) was added little by little for one minute. The reaction mixture was stirred at room temperature for 17 hours and 40 minutes and diluted with tetrahydrofuran, and then insoluble substance was removed by filtration. To the filtrate, silica gel was added, and the mixture was concentrated, and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1) to obtain the title compound (1.00 g, 88%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[N:13]=[N:12][S:11][C:8]2=[N:9][CH:10]=1)=[O:4].[OH-].[Na+]>O1CCCC1>[N:13]1[C:7]2[C:8](=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[S:11][N:12]=1
Reactant: COC(=O)c1cnc2snnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnc2snnc2c1
Yield: 96.3 %

Procedure:
The ester (ii) (0.94 g) was hydrolysed with aqueous sodium hydroxide in tetrahydrofuran to afford a solid (0.84 g).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C:14]2[NH:15][C:16]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[N:20]=[C:21]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:22]([CH3:28])=[N:23]4)=[CH:17][C:13]=2[C:12](=[O:34])[NH:11]1)C1C=CC=CC=1.C(OC[C@@H]1C2NC(C3C=CC=C4C=3N=C(NC(C)(C)C)C(C)=N4)=CC=2C(=O)N1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[C:30]([NH:29][C:21]1[C:22]([CH3:28])=[N:23][C:24]2[C:19]([N:20]=1)=[C:18]([C:16]1[NH:15][C:14]3[CH:10]([CH2:9][OH:8])[NH:11][C:12](=[O:34])[C:13]=3[CH:17]=1)[CH:27]=[CH:26][CH:25]=2)([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@H](COCc3ccccc3)NC4=O)c2nc1NC(C)(C)C
Agent: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](COCc3ccccc3)NC4=O)c2nc1NC(C)(C)C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(CO)NC4=O)c2nc1NC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a 100-mL round-bottomed flask was added (6R)-6-((benzyloxy)methyl)-2-(3-(tert-butylamino)-2-methyl-5-quinoxalinyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one and (6S)-6-((benzyloxy)methyl)-2-(3-(tert-butylamino)-2-methyl-5-quinoxalinyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (468) (0.55 g, 1.20 mmol) and DCM (15 mL). The reaction mixture was cooled to 0° C. and under a nitrogen atmosphere boron trichloride (2.40 mL, 2.40 mmol, 1 M in DCM) (Sigma-Aldrich) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and at RT for 1 h. The reaction was quenched by the addition of NaHCO3 (200 mg in MeOH, 5 mL) and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 4% 2M NH3/MeOH in DCM to provide 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-(hydroxymethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (469) (0.25 g, 57% yield, 50% ee) as a yellow solid and as a mixture of enantiomers. 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.86 (dd, J=1.37, 7.63 Hz, 1H), 7.63 (dd, J=1.37, 8.02 Hz, 1H), 7.58 (s, 1H), 7.36 (t, J=7.73 Hz, 1H), 6.88 (d, J=1.57 Hz, 1H), 6.02 (s, 1H), 5.09 (t, J=5.58 Hz, 1H), 4.48 (t, J=6.06 Hz, 1H), 3.66 (td, J=5.53, 10.86 Hz, 1H), 3.54 (td, J=6.16, 10.76 Hz, 1H), 2.56 (br. s., 3H), 1.56 (s, 9H). m/z (ESI, +ve) 366.0 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:7]=1[CH3:15])(=[O:3])[CH3:2]>CO.[Pd]=O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:7]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cccc([N+](=O)[O-])c1C
Agent: O=[Pd]
Solvent: CO
Product: CC(=O)OCc1cccc(N)c1C
Yield: 97.6 %

Procedure:
Using a Parr hydrogenator, 30.0 g (0.143 mol) of 2-methyl-3-nitrophenylmethyl acetate in 250 mL of methanol was hydrogenated in the presence of 0.5 g of palladium oxide on charcoal to give 25.0 g of 3-amino-2-methylphenylmethyl acetate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:10]([CH3:25])([CH3:24])[CH2:9]1)=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:25])[CH3:24])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 23.0 g (66.1 mmol) 2,2-dimethyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester in 200 mL DCM was treated with 34.5 mL (448 mmol) TFA. The reaction mixture was stirred at RT over night and concentrated in vacuo. The residue was triturated with diethyl ether. The solid was filtered, washed with diethyl ether and dried.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[C:8]([C:10]1[CH:14]=[N:13][N:12]([CH3:15])[C:11]=1[NH:16][C:17]([C:19]1[C:27]2[S:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:24][C:23]=2[C:22]([O:34][CH3:35])=[CH:21][CH:20]=1)=[O:18])#[N:9].C=O.C([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[C:8]([C:10]1[CH:14]=[N:13][N:12]([CH3:15])[C:11]=1[NH:16][C:17]([C:19]1[C:27]2[S:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH3:2])[CH2:30][CH2:29]3)=[N:24][C:23]=2[C:22]([O:34][CH3:35])=[CH:21][CH:20]=1)=[O:18])#[N:9]
Reactant: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(N3CCNCC3)nc12
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(N3CCN(C)CC3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.1 %

Procedure:
A suspension of 4-methoxy-2-(piperazin-1-yl)benzothiazole-7-carboxylic acid (4-cyano-2-methyl-2H-pyrazol-3-yl)amide trifluoroacetic acid salt (275 mg) in acetonitrile (20 ml) was treated with formaldehyde (0.44 ml, 37% aqueous solution), sodium cyanoborohydride (102 mg), and acetic acid (0.3 ml) and the mixture stirred at room temperature of 12 hours. The solvent was evaporated in vacuao and the residue partitioned between aqueous sodium hydroxide (10 ml, 1M) and dichloromethane (100 ml). The aqueous layer was separated, was neutralised with acetic acid, and extracted with 2% methanol in dichloromethane (2×75 ml). The extracts were combined, dried over magnesium sulphate (5 g), filtered, and the filtrate evaporated in vacuo. Purification by column chromatography (eluent 5% methanol in dichloromethane) followed by trituration with diethyl ether yielded the title compound as a pale yellow solid (40 mg). TLC Rf 0.14 (10% methanol in dichloromethane); Mpt 249-251° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.O[CH2:9][C:10]#[N:11]>O>[NH2:11][CH2:10][CH2:9][NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCO
Reactant: Nc1cccnc1
Solvent: O
Product: NCCNc1cccnc1
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
3-aminopyridine(1.88 g) and hydroxyacetonitrile(2.49 g) were refluxed in water(20 ml) with stirring for 1.5 hours and then the reaction mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. The solution of the residue in tetrahydrofuran(30 ml) was dropped into the suspension of lithium aluminium hydride(1.13 g) in tetrahydrofuran (40 ml) while being cooled with ice and the mixture was stirred at room temperature for 30 minutes. A small amount of water was added to the reaction mixture and then the resulting deposit was filtrated out. The filtrate was concentrated under a vacuum, thereby yielding 2.24 g of the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=[O:24])=[C:4]([S:25][CH3:26])[N:3]=1.[BH4-].[Na+]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[O:11])[C:5]([CH2:23][OH:24])=[C:4]([S:25][CH3:26])[N:3]=1
Reactant: CSc1nc(N)nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CSc1nc(N)nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a 25 mL round bottom flask is added 2-(2-amino-5-formyl-6-methylsulfanyl-pyrmidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide (40.0 mg, 0.10 mmol, 1.0 eq.), EtOH (2.0 mL), and sodium borohydride (5.0 mg, 0.13 mmol, 1.3 eq.). The reaction was stirred at RT for 1 hr, concentrated to remove EtOH, and partitioned between H2O and EtOAc. The aqueous layer was extracted once more with EtOAc. The combined EtOAc layers were then washed with brine, dried with Na2SO4, and concentrated to give pure 2-(2-amino-5-hydroxymethyl-6-methylsulfanyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as a white solid (37.0 mg, 95%). LC/MSD (BP Series 1100 MSD): Expected MW: 387, Observed M+H, 388.1, Retention time: 1.35 min. ANALYTICAL HPLC: >94%, Retention time: 2.82 min (8 minute run). 1H-NMR (d-MeOH): 8.00 (s, 1H), 7.78 (d, 1H), 7.50 (t, 1H), 7.39 (d, 1H), 4.62 (s, 2H), 4.38 (s, 2H), 2.42 (s, 3H) ppm.
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O>>[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccco1
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(I)ccc21
Product: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(-c3ccco3)ccc21
Yield: 8 %

Procedure:
Prepared from 3-(7-iodo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 11 using the same conditions used to prepare Example 1 but using 2-furanboronic acid instead of benzene boronic acid. The title compound (10 mg) was obtained as a brown solid, (yield=8%).
Reaction SMILES: C([N:4]1[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([NH:16][C:17](=[O:35])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][C:19]=3[NH:24][CH2:25][C:26]3[N:31]=[C:30]4[NH:32][CH:33]=[CH:34][C:29]4=[CH:28][CH:27]=3)=[CH:9][CH:10]=2)[CH2:5]1)(=O)C.Cl.C([O-])(O)=O.[Na+]>CCO>[CH3:14][C:12]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([NH:16][C:17](=[O:35])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][C:19]=3[NH:24][CH2:25][C:26]3[N:31]=[C:30]4[NH:32][CH:33]=[CH:34][C:29]4=[CH:28][CH:27]=3)=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:13]1
Reactant: CC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccc4cc[nH]c4n3)ccc2C(C)(C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CNCc2cc(NC(=O)c3cccnc3NCc3ccc4cc[nH]c4n3)ccc21
Temperature: 75 °C

Procedure:
N-(2-Acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-6-ylmethyl)amino]nicotinamide (0.180 g, 0.384 mmol, Example 2) was dissolved into 10 mL of EtOH and 5 mL of concentrated HCl was added. The mixture was heated to 75° C. for 4 days. The volume was reduced to ⅓. Sat'd. NaHCO3 was added until the solution became cloudy. The aqueous phase was extracted with CH2Cl2 and the combined organic phases were dried over Na2SO4, filtered and concentrated to give a brown residue. The residue was purified by HPLC (Beckman) to afford the title compound. MS (ES+): 427 (M+H). Calc'd. for C25H26N6O—426.52.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][C@@H:23]1OS(=O)(=O)[N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]1>CN(C=O)C>[C:33]([O:32][C:30]([NH:25][CH2:24][C@H:23]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:22])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@H](C)CNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
A stirred suspension of 60% NaH (371 mg, 9.3 mmol) in DMF (10 mL) is cooled in an ice bath, and a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 2.6 g, 10.1 mmol) in DMF (10 mL) is added. The mixture is stirred for 20 min, then a solution of tert-butyl (5S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (2.0 g, 8.4 mmol) in DMF (10 mL) is added. The reaction mixture is stirred for 30 min at 0° C. and then warmed to room temperature and stirred for 48 h. The reaction is poured into ice water and the resultant solid is removed by filtration. The filtrate is acidified to pH 3 with 1N aqueous HCl and extracted with EtOAc. The combined extracts are washed with water, brine, dried (Na2SO4) and concentrated to afford the title compound (2.7 g, crude) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([S:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH:25]=1>>[CH3:37][N:35]([CH3:36])[CH2:34][CH2:33][S:32][C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])[CH:29]=[CH:28][C:27]=1[O:30][CH3:31]
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: COc1ccc(N)cc1SCCN(C)C
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1SCCN(C)C

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 4-amino-2-(2-dimethylaminoethylthio)anisole (D48) using a similar procedure to Example 1 (50%) mp 138°-9° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccncc1
Temperature: 100 °C
Yield: 13.9 %

Procedure:
A mixture of 1-(6-fluoro-1-pyridin-4-yl-1H-benzoimidazol-2-yl)ethylamine (60 mg, 0.23 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (59 mg, 0.25 mmol) and DIPEA (125 μL, 0.70 mmol) in n-butanol (0.5 mL) was heated at 100° C. in a sealed vial for 23 h. After cooling to RT, the resulting mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-60%, 0.1% NH4OH in acetonitrile/water) to afford 303 as a pale orange solid (12 mg, 14%). LCMS (Method K): RT 2.70 min [M+H]+ 375.05. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, s), 8.72-8.66 (2H, m), 8.09-8.01 (2H, m), 7.73-7.67 (3H, m), 7.19-7.01 (2H, m), 5.68-5.11 (1H, m), 1.62 (3H, d, J=7.26 Hz)
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([C:5]1[O:6][CH:7]=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][N:2]([CH3:13])[CH2:3][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)c1ccoc1C(=O)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccoc1CN(C)C
Yield: 63.2 %

Procedure:
A solution of N,N-dimethyl-3-(1-methylethyl)-2-furanecarboxamide (12 g) in dry tetrahydrofuran (250 ml) was treated with lithium aluminium hydride (4.2 g). After 1 hour water (6 ml) was added and the filtered solution evaporated in vacuo. The residue was dissolved in 1 M hydrochloric acid (100 ml) and the solution was washed with diethyl ether (100 ml). The aqueous phase was basified and extracted with diethyl ether (2×150 ml), which was dried over anhydrous sodium sulphate. The solvent was removed in vacuo to yield the title compound (7 g) as an oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[C:10]2[CH:11]=[C:12]([O:29][CH:30]([CH3:32])[CH3:31])[C:13]([N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:9]=2[O:8][C:7]=1[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[F:39][C:36]1[CH:35]=[CH:34][C:33]([C:7]2[O:8][C:9]3[CH:14]=[C:13]([N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[S:16]([CH3:19])(=[O:18])=[O:17])[C:12]([O:29][CH:30]([CH3:32])[CH3:31])=[CH:11][C:10]=3[C:6]=2[C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C4=NCCN4)c3cc2OC(C)C)S(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(-c4ncc[nH]4)c3cc2OC(C)C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-(4,5-dihydro-1H-imidazol-2-yl)-2-(4-fluorophenyl)-5-isopropoxybenzofuran-6-yl)-N-(4-methoxybenzyl)methanesulfonamide (0.54 g, 0.98 mmol) was dissolved in dimethylsulfoxide (5 mL) and was treated with potassium carbonate (0.15 g, 1.08 mmol) and iodobenzene diacetate (0.35 g, 1.08 mmol). The initially yellow solution changed to a reddish-brown solution within 15 minutes of iodobenzene diacetate addition. The reaction mixture was stirred for one hour at room temperature. The reaction mixture was stirred with 50 mL ethyl acetate and 50 mL 10% aqueous sodium bicarbonate for 20 minutes, the layers were separated and the aqueous layer was extracted with 50 mL additional ethyl acetate. The combined organic extracts were washed with 10% aqueous sodium chloride, dried over anhydrous sodium sulfate(s), and filtered. The solvent was removed in vacuo leaving an orange oily residue, which was purified by reverse phase HPLC yielding an off-white solid. 40 mg, 7.4%. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (d, 6H) 3.13 (s, 3H) 3.67 (s, 3H) 4.37-5.02 (m, 3H) 6.73-6.92 (m, 2H) 7.06-7.22 (m, 4H) 7.22-7.41 (m, 4H) 7.79-7.98 (m, 2H) 12.37 (s, 1H); MS (ESI+) m/z 550.2 (M+H)+, MS (ESI−) m/z 548.1.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[C:4]=1[O:13][CH3:14])#[N:2].[OH-:15].[Na+].OO>CS(C)=O.C(O)C>[NH2:2][C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[C:4]=1[O:13][CH3:14])=[O:15]
Reactant: [OH-]
Reactant: COc1c(C#N)ccc(C(=O)O)c1C
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: COc1c(C(N)=O)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 63 %

Procedure:
To a solution of 4-cyano-2-methyl-3-(methyloxy)benzoic acid (80 mg, 0.42 mmol) in DMSO:ethanol (1:4, 1 mL) was added 1N aqueous sodium hydroxide (1 mL), and hydrogen peroxide (30% wt. in water, 1 mL). The mixture was stirred at room temperature for 72 hours, then partitioned between 1N aqueous sodium hydroxide and ethyl acetate and the organic layer discarded. The pH of the aqueous portion was adjusted to 7 using 1N aqueous hydrochloric acid. The aqueous portion was extracted several times using ethyl acetate, and the combined organic portion was washed with brine then dried over anhydrous sodium sulfate. Filtration and concentration afforded 55 mg, 0.26 mmol (63%) of 4-(aminocarbonyl)-2-methyl-3-(methyloxy)benzoic acid. 1H NMR (400 MHz, d6-DMSO): 7.77 (br s, 1H), 7.60 (br s, 1H), 7.54 (d, 1H), 7.41 (d, 1H), 3.72 (s, 3H), 2.41 (s, 3H). MS (EI) for C10H9NO3: 190 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[C:6]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: O=C1CCc2c(Cl)cccc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2c(Cl)cccc2C1=O
Yield: 81 %

Procedure:
A solution of 14.0 g of 4-chloro-1-indanone, 17.3 ml of 3-buten-2-ol and 140 mg of p-toluenesulfonic acid in 140 ml of 2,2-dimethoxy-propane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 6:1). 15.2 g (81%) of (RS)-2-(2-buten-1-yl)-4-chloro-1-indanone were obtained as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[N:18]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[C:17]3[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:26]=[CH:27][C:16]=3[N:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][O:22][CH2:21][CH2:20][CH2:19][N:18]1[C:17]2[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:26]=[CH:27][C:16]=2[N:15]=[C:14]1[CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COCCCn1c(C2CCCN(C(=O)OC(C)(C)C)C2)nc2cccc(C(=O)OC)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCn1c(C2CCCNC2)nc2cccc(C(=O)OC)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
Methyl 2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-7-carboxylate (44B) (1.91 mmol, 400 mg) in DCM (10 mL) was added TFA (2 mL). The reaction solution was stirred at rt for 1 hr and then concentrated in vacuo. The residue was purified by preparative LC/MS (15-40% CH3CN in H2O) to afford methyl 1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole-7-carboxylate (44C) (0.36 mmol, 120 mg, yield: 18.8%). EST-MS: m/z 332.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Na+].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[F:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:15][CH:14]=[CH:19]2
Reactant: Nc1ccc(F)cc1Br
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: OCC(O)CO
Product: Fc1cc(Br)c2ncccc2c1
Temperature: 150 °C

Procedure:
To a mixture of 2-bromo-4-fluoroaniline (commercially available, 7.0 g), glycerol (7.0 g) and m-nitrobenzene sulfonic acid sodium salt (13.0 g) was added 20 ml of 70% sulfuric acid dropwise. The reaction temperature was raised to 150° C. for 4 hr. The mixture then was cooled to room temperature, poured on ice water and filtered through celite. The filtrate was neutralized with NaOH and the resulting precipitate was collected by vacuum filtration to yield 3.47 g of the title compound as a light yellow solid; MP=75-78° C.; MS (ES) m/z (relative intensity): 227 (M+H)+ (100).