Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH2:16]O)[C@@H:14]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:13]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:12]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:60]I.[O-]S([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH2:16][I:60])[C@@H:14]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:13]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:12]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1[C@H](COCc2ccccc2)[C@@H](CO)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1[C@H](COCc2ccccc2)[C@@H](CI)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Yield: 211.4 %

Procedure:
To a stirred mixture of (2S*,3S*,4S*,5S*)-1-benzyloxycarbonyl-4-benzyloxymethyl-3-[N-(t-butoxycarbonyl)amino]-5-hydroxymethyl-2-phenylpyrrolidine (9.00 g, 16.5 mmol), Ph3P (10.8 g, 41.3 mmol) and Im (2.81 g, 41.3 mmol) in dry PhMe (240 ml) was added I2 (8.38 g, 33.0 mmol) in one portion at room temperature. After stirring and heating at a gentle reflux for an hour, the dark brown mixture was allowed to cool to room temperature, and then sat. Na2SO3 aq. solution (70 ml) was added until the dark color due to the excess I2 was discharged. The layers were separated, and the organic layer was washed with sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give a deep red oil (22.9 g). This was chromatographed over SiO2 (Merck Kieselgel 60, 230 g). Elution with n-hexane-AcOEt (30:1→10:1→6:1) gave the title compound (9.95 g, 92%) as a white solid. A portion of it (105 mg) was recrystallized from isopropyl ether (IPE) to afford an analytical sample of the title compound as white powders (mp 107.5-108.5 C.); IRmax (nujol): 3440(s), 1705(vs), 1500(s), 1165(s), 780(m), 770(m), 755(m), 740(m), 707(s), 695(s) cm-1 ; 1H-NMR δ: 7.60-7.15(m, 14H), 7.09(br.s, 2H), 5.19(d, J=8.8 Hz, 1H), 5.03(br.s, 2H), 2H), 4.44(ddd, J=9.0, 9.0, 9.0 Hz, 1H), 4.15-3.97(m, 1H), 3.97-3.75(m, 2H), 3.71(dd, J=9.7, 5.3 Hz, 1H), 3.64(dd, J=9.7, 5.3 Hz, 1H), 2.34-2.18(m, 1H), 1.36(br.s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16].Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:21][CH2:20]1)=[O:16]
Reactant: Brc1ccccc1
Reactant: COc1ccc(C(=O)NCC2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NCC2CCN(c3ccccc3)CC2)cc1OCCc1ccc(Cl)cc1Cl

Procedure:
A mixture of 100 mg (0.2 mmol) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide, 50 mg (0.32 mmol) Bromobenzene, 70 mg sodium-t-butoxide in 5 ml dioxane were purged with argon for 10 min. Then 37 mg of 2-(Dicyclohexylphosphino)biphenyl and 20 mg Pd2(dba)3 were added under argon and the mixture refluxed overnight. The residue was taken up in 3 ml saturated NaHCO3 solution and filtered through a chem elut® cartridge by elution with ethyl acetate. Subsequent removal of the solvent under reduced pressure and purification by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.5% TFA) the fractions containing the product were evaporated and lyophilised.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=1.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=3)[N:11]=2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(C(F)(F)F)cc3)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(4-trifluoromethyl-phenyl)-1H-imidazole (9.6 g, 25 mmol) was treated as described in general procedure B using 1-fluoro-4-nitrobenzene to give 2-(4-bromo-benzyl)-1-(4-Nitro-phenyl)-4-(4-trifluoromethyl-phenyl)-1H-imidazole.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:3]=1.[CH3:16][NH:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:21]1)=[O:19].CCN(C(C)C)C(C)C>C(O)CCC>[C:14]([C:11]1[S:10][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([CH:22]4[CH2:23][CH2:24][N:20]([C:18]([NH:17][CH3:16])=[O:19])[CH2:21]4)[CH2:26][CH2:27]3)[CH:3]=2)=[N:13][CH:12]=1)#[N:15]
Reactant: CNC(=O)N1CCC(N2CCNCC2)C1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N1CCC(N2CCN(c3cc(Nc4ncc(C#N)s4)ncn3)CC2)C1

Procedure:
35-1 (0.106 g, 0.45 mmol), 45-5 (0.095 g, 0.45 mmol) and DIEA (0.18 g, 1.79 mmol) were heated at 150° C. for 3 hours in n-butanol. Upon cooling the precipitate was filtered off, washed with n-butanol and ethyl ether and then dried to afford 45-6. Hi-Res MS: calc: 414.1819 found: 414.1827. 1H-NMR (DMSO-d6): 12.08(s, 1H); 8.42(s, 1H); 8.26(s, 1H); 6.22(s, 1H); 6.02(d, 1H); 3.55(m, 4H); 3.38 (m, 1H); 3.13(m, 1H); 2.97(m, 1H); 2.78(m, 1H); 2.50(complex, 6H); 2.45(m, 2H); 2.06(m, 1H); 1.69(m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[C:14]1([CH2:20][N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:3][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:26][CH2:25]2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 15.0 g ( 0.8054 mol) of 1-(1,1-dimethylethoxycarbonyl)piperazine and 14.26 ml (0.08053 mol) of 1-(phenylmethyl)-4-piperidinone in 250 ml of methanol was adjusted to a pH of between 5 and 6 by dropwise addition of acetic acid and mixed in batches with a total of 4.13 g ( 0.0624 mol) of 95% sodium cyanoborohydride, whilst taking care to maintain a pH of 5 to 6 by further dropwise addition of acetic acid. After stirring for 18 hours at room temperature the mixture was evaporated down in vacuo, the residue was made alkaline with soda and divided between water and ethyl acetate. After working up the ethyl acetate phase in the usual way 21.76 g (75.2% of theory) of a highly viscous colourless oil were obtained, Rf 0.66 (FM1).
Reaction SMILES: [NH:1]1[N:9]2[CH:4]([O:5][CH2:6][CH:7]=[CH:8]2)[CH2:3][CH:2]1[CH2:10][OH:11]>CCl.O=[Mn]=O>[N:1]1[N:9]2[C:4]([O:5][CH2:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[CH:10]=[O:11]
Reactant: OCC1CC2OCC=CN2N1
Agent: O=[Mn]=O
Agent: CCl
Product: O=Cc1cc2n(n1)CCCO2
Yield: 104.7 %

Procedure:
To the stirred solution of 2,3-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl-methanol (2.08 g, 13.5 mmol) in 60 ml of CH3Cl was added 9.38 g of MnO2. Th suspension was refluxed for 2 hour under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to give yellow oil. The product was purified by chromatography. 2.15 g of the product was obtained (78%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=CC=C[CH:17]=1.B(O)O>C1(C)C=CC=CC=1.O.CCO.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:21])=[CH2:17]
Reactant: COC(=O)c1ccc(Br)c(S(C)(=O)=O)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C=C(C)c1ccc(C(=O)OC)cc1S(C)(=O)=O
Yield: 189.8 %

Procedure:
23 mmol of methyl 4-bromo-3-methylsulfonylbenzoate, 54 mmol of Na2 CO3, 2.9 mmol of triphenylphosphine and 1.5 mmol of Pd(OAc)2 are stirred intensively at RT for 5 min in 200 ml of toluene and 15 ml of H2O. A solution of 23 mmol of boronic acid according to Preliminary Stage 1 is then added in 50 ml of EtOH and the mixture is boiled under reflux for 1.5 h. After phase separation, the organic phase is washed twice with 50 ml of NaCl solution and the aqueous phase is extracted twice with 100 ml of EA. The combined organic phases are dried over Na2 SO4, the solvents are removed in vacuo and the residue is chromatographed on silica gel using DIP. 1.4 g of a colorless oil are obtained.
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([C:18]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCC1
Reactant: C1CNCCN1
Solvent: CCO
Solvent: O
Product: O=C(C1CCCC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Piperazine hexahydrate (8.55 g, 44.0 mmol) was dissolved in absolute ethanol (50 ml) and then refluxed for 10 min. Cyclopentanecarbonyl chloride (5.83 g, 44 mmol) was added dropwise at 65° C. and the reaction mixture was refluxed for 30 min and then stirred at room temperature for 18 h. The reaction mixture was cooled, filtered and the filtrate was concentrated in vacuo to give ˜20 ml of solution. The concentrate was cooled and then filtered again. Ethanolic hydrogen chloride was added to the mother liquor, and the reaction mixture was concentrated to give a white solid, which was dissolved in water (15 ml). The solution was basified to pH 14 and the product was extracted with dichloromethane (7×50 ml). The extracts were dried, (Na2SO4) and concentrated to give the title compound as a yellowish residue, which was distilled to give the product (1.28 g, 7.0 mmol, 16%)
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=[CH:8][C:7]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[O:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:7]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:6]([CH:11]=1)[C:5]([OH:40])=[O:4])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1cc(OCCCCCCCCCCCCOc2ccccc2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(OCCCCCCCCCCCCOc2ccccc2)ccc1OCc1ccccc1
Yield: 94 %

Procedure:
Sodium hydroxide hydrolysis of 5-[(12-phenoxydodecyl)oxy]-2-(phenylmethoxy)benzoic acid methyl ester using conditions described in Example 60 gave 5-[(12-phenoxydodecyl)oxy]-2-(phenylmethoxy)benzoic acid (94% yield, mp 85°-87° ).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:28])[C:11]([O:26][CH3:27])=[C:12]([CH:25]=2)[C:13]([NH:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[CH3:24])=O)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:28])[C:11]([O:26][CH3:27])=[C:12]([CH2:13][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=3[CH3:22])[CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)Nc1c(C)ccc(O)c1C
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(C)ccc(O)c1C
Temperature: 60 °C
Yield: 44.3 %

Procedure:
To a solution of 5-(3-fluorophenyl)-N-(3-hydroxy-2,6-dimethyl-phenyl)-2-methoxy-3-methyl-benzamide (270 mg, 0.71 mmol, 1.0 eq) in THF (5 mL) at 0° C. under N2 was added a solution of BH3 (1M in THF, 1.07 mL, 1.07 mmol, 1.5 eq) dropwise. The reaction mixture was heated at 60° C. for 4 h, then cooled and quenched with water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc 30:1 to 20:1) to give the title compound as a yellow oil (115 mg, 44%)
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].[Na]>CO.O1CCCC1.C(O)(=O)C>[CH2:17]([N:24]1[C@@H:6]2[C@@H:5]([CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:7]2)[CH2:4][C:3]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CC1Cc2ccccc2CC1=O
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: O=C1C[C@@H]2Cc3ccccc3C[C@@H]2N1Cc1ccccc1
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
Acetic acid (12.5 ml) was added to a stirred mixture of 2-oxo-1,2,3,4-tetrahydronaphthalene-3-acetic acid methyl ester (3.62 g, 17 mmol), and benzylamine (7.2 ml, 66 mmol) in a 1:1 mixture of tetrahydrofuran and methanol (120 ml) at 0° C. under argon. After 0.5 h, sodium cyanoborohydride (2.09 g, 33 mmol) was added and the resultant mixture stirred at room temperature. After 16 h, aqueous 10% sodium hdyroxide was added and the solvent evaporated in vacuo. The residue was partitioned between water (100 ml) and dichloromethane (2×200 ml). The combined extracts were washed with water (100 ml), brine (100 ml), then dried (Na2SO4) and evaporated in vacuo to give a brown solid (4.38 g). Chromatography on silica using 0-5% methanol-ethyl acetate gradient elution afforded the title compound as a yellow solid (1.75 g, 38%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH:22]1([NH2:25])[CH2:24][CH2:23]1>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]([S:12]([NH:25][CH:22]2[CH2:24][CH2:23]2)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1Cl
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COC(=O)c1cccc(S(=O)(=O)NC2CC2)c1Cl
Yield: 54.2 %

Procedure:
To a solution of methyl 2-chloro-3-(chlorosulfonyl)benzoate (608 mg, 2.26 mmol) and K2CO3 (770 mg, 5.6 mmol) in 10 mL benzene was added cyclopropylamine (0.78 mL, 11.2 mmol). Purification of the product provided methyl 2-chloro-3-[(cyclopropylamino)sulfonyl]benzoate (355 mg, 54%) as a solid. 1H NMR (400 MHz, CDCl3), δ 8.28 (dd, 1H, J=7.9, 1.7 Hz), 7.90 (dd, 1H, J=7.8, 1.7 Hz), 7.48 (t, 1H, J=7.8 Hz), 5.63 (s, 1H), 3.93 (s, 3H), 2.17 (m, 1H), 0.65-0.58 (m, 2H), 0.57-0.50 (m, 2H); ESI-MS 290 (M+H), 312 (M+Na). Methyl 2-chloro-3-[(cyclopropylamino)sulfonyl]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(cyclopropylamino)sulfonyl]benzoic acid as a solid, which was used without further purification. ESI-MS 276 (M+H), 298 (M+Na).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.C([O-])(O)=O.[Na+].[OH-].[K+].[OH-].[Na+].C(N(C(C)C)CC)(C)C.CN(C)C>O1CCCC1.O1CCOCC1.CN(C)C=O.C(#N)C.C(N(CC)CC)C.N1C=CC=CC=1>[Cl:12][C:13]1[N:18]=[C:17]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([CH3:11])=[CH:5]3)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: Clc1ccnc(Cl)n1
Agent: CN(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1cc2cc(Oc3ccnc(Cl)n3)ccc2[nH]1

Procedure:
The title compound 3 can prepared by the reaction of 5-hydroxyl-2-methyl-indole (compound 1) with 2,4-dichloropyrimidine (compound 2) in the presence of a base, such as but not limited to NaHCO3, KOH, NaOH, K2CO2, KHCO3, diisopropylethylamine (DIPEA), pyridine, triethylamine (TEA) or trimethylamine; in a solvent, such as but not limited to acetonitrile, N,N-dimethylforamide (DMF), dioxane, tetrahydrofuran (THF). The reaction may be carried out at a suitable temperature, such as a temperature ranging from 0 to 60° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccc(Cl)nc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CNC
Product: CN(C)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cn1
Temperature: 130 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
To a seal tube was added 1′-((6-chloropyridin-3-yl)methyl)-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indolin]-2′-one (0.10 g, 0.25 mmol) and dimethylamine (2.00 mL of 2 M THF solution, 4.00 mmol). The mixture was stirred at 130° C. overnight. After cooling down to ambient temperature, the mixture was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/2) to give 1′-{[6-(dimethylamino)pyridin-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one as a white solid (50 mg, 48%), which was treated with 2.0 M HCl in diethyl ether to give the title compound: mp 146-150° C.; 1H NMR (300 MHz, CD3OD) δ 8.03 (d, 1H), 7.95 (dd, 1H), 7.36 (td, 1H), 7.25-7.12 (m, 4H), 6.57 (s, 1H), 6.09 (s, 1H), 5.90 (s, 2H), 5.07-4.87 (m, 3H), 4.72 (d, 1H), 3.27 (s, 6H); 13C NMR (75 MHz, CD3OD) δ 179.9, 157.6, 154.6, 150.5, 143.8, 143.4, 142.9, 137.7, 133.5, 130.2, 125.1, 121.8, 120.6, 113.2, 110.4, 103.7, 103.0, 94.3, 81.4, 59.7, 41.1, 39.5; MS (ES+) m/z 416.5 (M+1).
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[OH:1][N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[C:29](=[O:30])[NH:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=P(O)(O)CCCNO
Reactant: O=C=Nc1ccccc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N(O)CCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
A mixture of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g), dichloromethane (30 ml) and bis(trimethylsilyl)acetamide (10 g) was stirred at ambient temperature for 3 hours. The mixture was cooled to 0-5° C. and phenyl isocyanate (1.80 g) was added thereto. The reaction mixture was stirred at the same temperature for an hour and at ambient temperature for 3 hours and then allowed to stand overnight. The resultant mixture was concentrated under reduced pressure. To the residue was added water (60 ml), and then the mixture was stirred at ambient temperature for 3 hours. Insoluble materials were removed by filtration and the filtrate was washed twice with ethyl acetate (50 ml). To the aqueous layer was added an additional 90 ml of water, whereafter the aqueous solution was subjected to a column chromatography using activated charcoal. The object compound was eluted with 70% aqueous acetone. The eluate was evaporated to dryness under reduced pressure, whereafter the resulting crystals were washed with acetone and dried to give crystalline 3-(N-hydroxy-N-phenylcarbamoylamino)propylphosphonic acid (1.13 g). Mp 126-130° C. (dec.)
Reaction SMILES: [CH:1]([NH:4][C:5]([CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18][CH2:17]2)[CH:13]=[CH:12][C:11]=1[N+:24]([O-])=O)=[O:6])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:24][C:11]1[CH:12]=[CH:13][C:14]([N:16]2[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18][CH2:17]2)=[CH:15][C:10]=1[C:9]([NH:8][CH2:7][C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])=[O:27]
Reactant: CC(C)NC(=O)CNC(=O)c1cc(N2CCCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)NC(=O)CNC(=O)c1cc(N2CCCN(C)CC2)ccc1N
Reaction time: 5 h
Yield: 100 %

Procedure:
A mixture of N-(isopropylcarbamoylmethyl)-5-(4-methylperhydro-1,4-diazepin-1-yl)-2-nitrobenzamide (510 mg, 1.4 mmol) and 10% Pd/C (60 mg) in MeOH (30 mL) was shaken under 50 psi H2 (g) in a Parr shaker for 5 h. The mixture was filtered through a pad of celite and the solvent removed in vacuo to afford 2-amino-N-(isopropylcarbamoylmethyl)-5-(4-methylperhydro-1,4-diazepin-1-yl)benzamide (INTERMEDIATE V.1) (470 mg, 1.4 mmol, 100%) as a brownish-green glass.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])(=[O:13])=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[N:25]([CH2:28][CH2:29][CH3:30])=[C:26]=[O:27]>ClCCl.CN(C1C=CN=CC=1)C>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C:26]([NH:25][CH2:28][CH2:29][CH3:30])=[O:27])[S:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])(=[O:12])=[O:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCCN=C=O
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCNC(=O)N(C1CCN(C(C)C)CC1)S(=O)(=O)CCNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 200 mg (0.50 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide in 3 ml dichloromethane were added 0.1 ml (2 equiv.) 1-isocyanato-propane and 6 mg DMAP. The reaction mixture was stirred overnight at room temperature. The next day further 0.1 ml (2 equiv.) 1-isocyanato-propane and 6 mg DMAP were added. After stirring for 48 h at room temperature, the reaction mixture was washed with 3 ml water and concentrated under reduced pressure. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-propylaminocarbonyl-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].[H-].[Na+].[Br:8][C:9]1[N:10]=[C:11](Br)[N:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[C:13]=12>CN(C=O)C>[Br:8][C:9]1[N:10]=[C:11]([S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[N:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[C:13]=12
Reactant: Nc1nccn2c(Br)nc(Br)c12
Reactant: CC(C)(C)S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1nc(Br)c2c(N)nccn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A bohdan block vessel was charged with 2-methyl-2-propanethiol (20 uL, 0.0002 mol) in DMF (2 mL) and the reaction mixture was degassed 3×. Sodium hydride (0.01 g, 0.0004 mol) was then added and the reaction mixture was stirred at rt for 10 min. 1,3-Dibromo-imidazo[1,5-a]pyrazin-8-ylamine (30 mg, 0.0001 mol) was added to the reaction mixture and the reaction mixture was heated at 70° C. overnight. The reaction mixture turned red in color as the reaction progressed. The reaction mixture was concentrated and purified by prep TLC using a mixture of 7 N5% NH3 in MeOH/DCM to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD-d4): δ=1.37 (s, 9H), 7.13 (d, J=5.05 Hz, 1H), 7.84 (d, J=5.05 Hz, 1H). MS(ES+): m/z 303.02 (100)[MH+]. HPLC: tR=2.30 min (Open Lynx polar—5 min).