Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=5)=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:41]=[CH:42][CH:43]=[CH:44][C:4]=2[N:3]=1.[C:45](Br)(=[O:47])[CH3:46].C(N(CC)C(C)C)(C)C>ClCCl>[C:45]([NH:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]([N:20]2[CH2:21][CH2:22][C:17]([CH2:16][CH2:15][N:14]3[CH:12]4[CH2:11][CH2:10][CH:9]3[CH2:8][CH:7]([N:6]3[C:5]5[CH:41]=[CH:42][CH:43]=[CH:44][C:4]=5[N:3]=[C:2]3[CH3:1])[CH2:13]4)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:18][CH2:19]2)=[O:24])=[CH:30][CH:29]=1)(=[O:33])=[O:32])(=[O:47])[CH3:46]
Reactant: CC(=O)Br
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(S(N)(=O)=O)cc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NS(=O)(=O)c1ccc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a precooled (0° C.) solution of 4-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-benzene-sulfonamide (20 mg, 0.033 mmol) in dichloromethane (2 mL) was added acetyl bromide (4.2 mg, 0.034 mmol) and N,N-diisopropylethyl amine (12 μL, 0.66 mmol). The resulting mixture was stirred overnight at ambient temperature. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 15-30% methanol in ethyl acetate to afford N-acetyl-4-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene-sulfonamide as amorphous solid (14 mg, 66%). 1H NMR (300 MHz, DMSO-d6) δ 7.83 (d, J=8.1 Hz, 2H), 7.48-7.46 (m, 3H), 7.37-7.33 (m, 5H), 7.21 (br, 1H), 7.13-7.05 (m, 2H), 4.51 (t, J=8.1, 1H), 3.88 (br, 1H), 3.67-3.15 (m, 6H), 2.42 (s, 3H), 2.37-2.30 (m, 2H), 2.11-2.07 (br, 2H), 1.96-1.72 (m, 13H), 1.59 (d, J=7.4, 2H). HRMS m/z (M+H)+ calcd: 654.3114, obsd: 654.3095.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:8]=1[C:9]([OH:11])=[O:10]>>[Cl:6][C:7]1[C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][CH:13]=[C:12]([Cl:16])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: O=C(O)c1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Temperature: 150 °C
Yield: 85 %

Procedure:
Chlorosulfonic acid was slowly added to 2,6-dichlorobenzoic acid at RT under N2. The reaction was heated to 150° C. for 3 h, then slowly poured over ice and the product extracted into Et2O. The organic layer was dried over MgSO4, filtered and concentrated to give 2,6-dichloro-3-(chlorosulfonyl)benzoic acid 880-1a as a brown solid (12.9 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.[CH3:19][O:20][CH:21]([O:27]C)[CH2:22][C:23](OC)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[C:2](=[C:16]([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:1]=[CH:23][C:22]=1[C:21]([O:20][CH3:19])=[O:27]
Reactant: COC(=O)CC(OC)OC
Reactant: Cc1cc(C)c(N)c(C(=O)c2ccccc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1cnc2c(C)cc(C)cc2c1-c1ccccc1Cl
Yield: 58.5 %

Procedure:
A mixture of 2-amino-2'-chloro-3,5-dimethylbenzophenone (2.59 g), methyl 3,3-dimethoxypropionate (3.7 g), p-toluenesulfonic acid hydrate (0.19 g) and benzene (30 ml) was refluxed for 16 hrs., with removal of water by a Dien-Stark apparatus. The mixture was distilled to remove the solvent, and the residue was purified by a column chromatography on silica gel to give methyl 4-(2-chlorophenyl)-6,8-dimethyl-3-quinolinecarboxylate as crystals (1.90 g, 58.5%), which was recrystallized from isopropyl ether as colorless prisms. m.p. 117°-118° C.
Reaction SMILES: N[CH:2]([CH3:33])[C:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[F:27])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[NH:28][C:29](=[O:32])[CH:30]=[CH2:31])=[O:4].[CH2:34]=O.[C:36]([BH3-])#[N:37].[Na+]>C1COCC1.CO>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([N:37]([CH3:36])[CH3:34])[CH3:33])=[C:10]([NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:11]=3)[N:16]=[CH:15][N:14]=2)=[C:21]([F:27])[CH:22]=1
Reactant: C=O
Reactant: C=CC(=O)Nc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCNC(=O)C(C)N
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(=O)Nc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCNC(=O)C(C)N(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
N-[7-[2-(2-amino-propionylamino)-ethoxy]-4-(4-bromo-2-fluoro-phenylamino)-quinazolin-6-yl]-acrylamide (30 mg, 0.06 mmol) and 37 weight % of formaldehyde (9 μl, 0.12 mmol) were diluted with THF (1 ml) and methanol (1 ml), and stirred at room temperature for 10 min. Sodium cyanoborohydride (11 mg, 0.17 mmol) was added thereto, and the solution was stirred for 4 hours. The resulting solution was distilled under a reduced pressure to remove the solvent, saturated sodium bicarbonate aqueous solution (20 ml) was added thereto, and extracted with chloroform (20 ml) twice. The separated organic layer was dried over magnesium sulfate, filtered and distilled under a reduced pressure, and resulting impure residue was subjected to column chromatography to obtain the title compound 23 mg (yield: 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:24]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[C:5]([O:7][CH3:24])=[O:6]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1B1OC(C)(C)C(C)(C)O1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a suspension of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (Synthech BC3558-001, 800 mg; 3.05 mmol; 1 eq.) in MeOH (16 mL) was added dropwise thionyl chloride (0.89 mL; 12.2 mmol; 4 eq.) and the reaction mixture was stirred at room temperature for 4 hours. The solvent evaporated in vacuo and the crude residue was diluted with Ethyl acetate (20 mL). The organic layer was washed with a sat. aq. NaHCO3 (5 mL), water (5 mL) and brine (5 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound (751 mg, 89%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([F:35])[CH:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:31]2[CH:30]=[C:29]([F:28])[CH:34]=[C:33]([F:35])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(-c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VI as described above, the arylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3,5-difluorophenylboronic acid gave the title compound. ES-MS m/e (%): 493.1 (M+H+).
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:9][N:10]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:5][C:6]([NH:9][N:10]1[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=O
Reactant: NN1CC=CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)NN1CC=CCC1
Temperature: 5 °C
Yield: 25.4 %

Procedure:
To a solution of tert-butyl isocyanate (0.991 g) in methylene chloride (8 ml) was added dropwise to a mixture of N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylamine (1.012 g) in methylene chloride (40 ml) under ice bath cooling. The mixture was stirred for an hour at about 5° C. The reaction mixture was evaporated to dryness, and then the residue was dissolved in ethyl acetate (50 ml). The solution was washed with water (40 ml), dried over magnesium sulfate and evaporated to dryness. The crude residue was washed with ether and dried to give N-[(tert-butylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine (0.50 g).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>ClCCl>[C:27]([N:1]1[CH2:2][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:4]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
To a stirred solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (100 mg, 0.42 mmol) in dichloromethane (10 mL) cooled to 0° C. was added diisopropylethylamine (160 mg, 1.26 mmol) and acetic anhydride (45 mg, 0.51 mmol). The resulting mixture was stirred at RT for 3 h before it was quenched by addition of water (10 ml). The aqueous layer was extracted with dichloromethane (3×10 ml) and the combined organic layers were washed with saturated aqueous NaHCO3 (10 ml), dried (Na2SO4), filtered and concentrated. Purification by silica FCC (using a gradient of eluents; 100:0 to 99:1 DCM:2M NH3 in MeOH) followed by purification by preparative HPLC (Method 2) gave the title compound (35 mg, 30% yield) as colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.C(O)(=O)C.[OH:32][C:33]1([C:37]([O:39][CH3:40])=[O:38])[CH2:36][NH:35][CH2:34]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][N:35]2[CH2:36][C:33]([OH:32])([C:37]([O:39][CH3:40])=[O:38])[CH2:34]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: COC(=O)C1(O)CNC1
Solvent: CC(=O)O
Product: COC(=O)C1(O)CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (0.209 g, 0.56 mmol) and methyl 3-hydroxyazetidine-3-carboxylate acetate (0.14 g, 0.73 mmol) according to Reference R and general procedure for reductive amination afforded methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-methyl)-3-hydroxyazetidine-3-carboxylate. MS (ESI) m/z: Calculated: 489.2; Observed: 490.0 (M++1).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([OH:13])=O)[CH2:3]2.S(Cl)([Cl:16])=O.C(N(CC)CC)C.[N+:25]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[CH:36]=[C:35]([NH2:38])[CH:34]=[CH:33]2)([O-:27])=[O:26].Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[ClH:16].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[CH:4]([CH2:10][C:11]([NH:38][C:35]1[CH:34]=[CH:33][C:32]3[C:37](=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=[CH:30][CH:31]=3)[CH:36]=1)=[O:13])[CH2:3]2
Reactant: O=C(O)CC1CN2CCC1CC2
Reactant: Nc1ccc2cccc([N+](=O)[O-])c2c1
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CC1CN2CCC1CC2)Nc1ccc2cccc([N+](=O)[O-])c2c1

Procedure:
200 mg (0.97 mmol) of 1-azabicyclo[2.2.2]oct-3-ylacetic acid hydrochloride are heated under reflux in 2 ml (27.42 mol) of thionyl chloride for 2 h. The mixture is then freed of excess thionyl chloride in vacuo, and the residue is taken up in 4 ml of DMF. 0.54 ml (3.89 mmol) of triethylamine, 5.9.4 mg (0.4 mmol) of DMAP and 183.0 mg (0.97 mmol) of 8-nitro-2-naphthylamine are added to this solution. After reaction overnight and purification by preparative. HPLC, the resulting product fractions are mixed With 1 M hydrochloric acid and concentrated in vacuo. Recrystallization of the residue from isopropanol and drying under high vacuum result in 59 mg (15% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:5]2[O:6][CH:7]([CH2:9][NH2:10])[CH2:8][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].CC1C=CC(S(OC)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:5]2[O:6][CH:7]([CH2:9][NH:10][C:26](=[O:27])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cc(Cl)c3c(c2O1)CCC3
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cc(Cl)c3c(c2O1)CCC3)OCc1ccccc1
Yield: 82.7 %

Procedure:
Treatment of (±)-1-(5-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine (0.51 g, 1.96 mmol) with diisopropylethylamine (0.76 g, 5.88 mmol) followed by benzyl chloroformate (0.50 g, 2.94 mmol) generally according to the procedure described for Intermediate 7 provided 0.58 g (84%) of (±)-benzyl (5-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate as a white solid. mp 118-121° C.; Anal. calcd. for C20H20ClNO3: C, 67.13; H, 5.63; N, 3.91. Found: C, 66.95; H, 5.93; N, 3.82. Chiral HPLC separation of (±)-benzyl (5-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate (Chiralpak AD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rt=11.191 min, Chiralpak AD, hexane:isopropanol 9:1); Fraction 2 (Rt=12.735 min, Chiralpak AD, hexane:isopropanol 9:1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([O:19][CH3:20])[N:17]=[CH:18][C:11]=3[N:10]=[C:9]2[CH3:21])=[CH:4][CH:3]=1.Br.Br[CH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:11]2[N:10]=[C:9]([CH3:21])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:7][CH:6]=3)[C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: COc1cc2c(=O)n(-c3ccc(O)cc3)c(C)nc2cn1
Reactant: BrCCCN1CCCC1
Agent: Br
Product: COc1cc2c(=O)n(-c3ccc(OCCCN4CCCC4)cc3)c(C)nc2cn1

Procedure:
The title compound was synthesized as a white solid (m.p.: 123-126° C.) by the method according to Example 63, using 3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one synthesized in Example 197 and 1-(3-bromopropyl)pyrrolidine hydrobromide as starting materials, followed by recrystallization (ethyl acetate/diethyl ether).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:21]3[S:22][C:23]([CH2:25][CH3:26])=[CH:24][C:20]=3[C:19](=[O:27])[N:18]([CH:28]([CH3:33])[C:29](OC)=[O:30])[C:17]2=[O:34])=[CH:11][CH:10]=1)#[N:2].CN1CCOCC1.C(Cl)(=O)OCC.[BH4-].[Na+]>CO.O1CCCC1>[CH2:25]([C:23]1[S:22][C:21]2[N:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)[C:17](=[O:34])[N:18]([CH:28]([CH3:33])[CH2:29][OH:30])[C:19](=[O:27])[C:20]=2[CH:24]=1)[CH3:26]
Reactant: CCc1cc2c(=O)n(C(C)C(=O)OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN1CCOCC1
Product: CCc1cc2c(=O)n(C(C)CO)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: -15 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a mixture of methyl 2-[1-[(2′-cyanobiphenyl-4-yl)methyl]-6-ethyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]propanoate (3 g), N-methylmorpholine (0.86 mL) and tetrahydrofuran (50 mL) was added ethyl chlorocarbonate (0.75 mL) at 0° C., and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was cooled to −15° C., sodium borohydride (0.74 g) and methanol (12 mL) were added, and the mixture was allowed to gradually warm to room temperature. The reaction mixture was extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (2 g, 69%).
Reaction SMILES: [CH2:1]([CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19][C:4]1=2)[CH3:2].C([Sn](CCCC)(CCCC)[C:33]1[CH:34]=[N:35][NH:36][CH:37]=1)CCC.[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C.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]([CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[N:19][C:4]1=2)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn[nH]c1
Reactant: CCC1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1c2ncccc2C(=O)N(C)c2ccc(-c3cn[nH]c3)nc21
Temperature: 120 °C
Yield: 15 %

Procedure:
A mixture of 5,11-dihydro-11-ethyl-2-trifluoromethanesulfonyloxy-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.084 g), 4-tributylstannylpyrazole (0.096 g), lithium chloride (0.052 g) and Pd(Ph3P)2Cl2 (0.009 g) in dimethylformamide (1 mL) was heated at 120° C. in a sealed tube 16 hours. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave 5,11-dihydro-11-ethyl-2-(4-pyrazolyl)-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.010 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[N:6]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:7]=[CH:8][C:9]=1[C:10](O)=[O:11])[CH2:3][CH3:4].FC(F)(F)C(O)=O.N[C@@H](C1N(S(C2C=CC(C)=CC=2)(=O)=O)C=CC=1C(O)=O)CC.CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[CH2:3]([C@@H:2]1[C:5]2[N:6]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:7]=[CH:8][C:9]=2[C:10](=[O:11])[NH:1]1)[CH3:4]
Reactant: CC[C@@H](N)c1c(C(=O)O)ccn1S(=O)(=O)c1ccc(C)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1NC(=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c21
Reaction time: 0.33 h
Yield: 89 %

Procedure:
To a solution of (R)-2-(1-aminopropyl)-1-tosyl-1H-pyrrole-3-carboxylic acid compound with TFA (1:1) (505d, 5.64 g, 12.92 mmol) and DIEA (6.74 mL, 38.8 mmol) in EtOAc (50 mL) was added 1-propanephosphonic acid cyclic anhydride (50 wt. % in EtOAc, 7.69 mL, 12.92 mmol) dropwise via syringe. After 20 min, the reaction was judged complete by LCMS. The reaction was partitioned between sat'd NaHCO3 and EtOAc. The organic layer was washed with sat'd NaHCO3 once, sat'd NaCl once, and the organics were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give (R)-6-ethyl-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (505e, 3.49 g, 11.47 mmol, 89% yield) as an orange-brown foam. m/z (ESI, +ve) 305.1 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=4)=[O:22])=[CH:16][C:14]=3[CH:15]=2)=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.[CH3:31][S@:32]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])(=[NH:34])=[O:33].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:34]=[S:32]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])([CH3:31])=[O:33])=[O:7])=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)=[O:22])=[CH:16][C:14]=2[CH:15]=1
Reactant: COC(=O)CCCC[S@@](C)(=N)=O
Reactant: Cc1cccc(NC(=O)Nc2ccc3sc(-c4cc(C(=O)O)cnc4N)cc3c2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(-c2cc3cc(NC(=O)Nc4cccc(C)c4)ccc3s2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinic acid (418 mg, 1 mmol, 1 equiv.) and (S)-methyl 5-(S-methylsulfonimidoyl)pentanoate (232 mg, 1.2 equiv.) in anhydrous DMF (6 mL) under nitrogen atmosphere was added diisopropylethylamine (0.348 mL, 2.0 equiv.) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (486.5 mg, 1.1 equiv.). The reaction mixture was heated to 60° C. and stirred for 2 hours. After the reaction was cooled to room temperature, it was diluted with EtOAc and washed sequentially with saturated aqueous NaHCO3, brine, aqueous NH4Cl, and brine. After the organic layer was dried (anhydrous Na2SO4), it was decanted, concentrated, and the brown oily residue was subject to a column chromatography (EtOAc-Hex 1:4 to 6:1). methyl 5-[N-({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate was obtained as a yellow foam in amount of 394 mg (66%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[CH3:26][O:27][C:28]1[CH:35]=[C:34](OC)[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].C(N(CC)CC)C.C1C[O:48][CH2:47]C1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:31][CH2:30][C:29]4[CH:32]=[C:33]([O:48][CH3:47])[CH:34]=[CH:35][C:28]=4[O:27][CH3:26])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(Cl)n3)cc(C)c21
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(NCc4cc(OC)ccc4OC)n3)cc(C)c21
Temperature: 60 °C
Yield: 51 %

Procedure:
A solution of [6-(2-chloro-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.50 g, 1.38 mmol) in THF (10 mL) was treated with 2,4-dimethoxybenzylamine (0.41 mL, 2.73 mmol) followed by triethylamine (0.77 mL, 5.52 mmol). The mixture was heated at 60° C. in a sealed tube for 2 days. The solid was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (CH3CN/0.1% formic acid in water) to give {6-[2-(2,5-dimethoxy-benzylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester as a light yellow solid (0.35 g, 51%). 1H NMR (400 MHz, CD3OD) δ 8.04 (d, J=5.71 Hz, 1H), 7.17 (s, 1H), 7.04 (s, 1H), 6.60-6.22 (m, 3H), 6.14 (d, J=5.71 Hz, 1H), 5.69-5.64 (m, 1H), 4.10-4.00 (m, 4H), 3.78 (s, 3H), 3.75 (s, 3H), 3.16 (dd, J=14.91, 2.86 Hz, 1H), 2.43 (dd, J=14.91, 8.73 Hz, 1H), 2.36 (s, 3H), 1.20 (t, J=7.30 Hz, 3H).