Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14](=[O:27])[C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][C:18]([CH3:26])([CH3:25])[C:17]=3[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1COCC1.[BH4-].[Na+].Cl>CO>[OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][CH:14]([OH:27])[C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][C:18]([CH3:25])([CH3:26])[C:17]=3[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C(C)(C)CCC3)cc1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.95 g (22 mol) of methyl 2-hydroxy-4-[3-oxo-3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoate, 150 ml of THF and 20 ml of methanol are introduced into a round-bottomed flask. 660 mg (17.4 mmol) of sodium borohydride are added portionwise and the mixture is stirred at room temperature for two hours. The reaction medium is poured into ice-water, neutralized with hydrochloric acid and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (80/20). After evaporation of the solvents, 3.8 g (47.5%) of the expected product are collected in the form of an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21](=[O:23])[C:20]3([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:19]=2)=[CH:14][CH:13]=1>CN1CCOCC1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([NH:19][C:20]2([C:21]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:23])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22])=[CH:16][CH:17]=1
Reactant: CSCC[C@H](N)C(=O)O
Reactant: COc1ccc(C2=NC3(CCCCC3)C(=O)O2)cc1
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)NC2(C(=O)N[C@@H](CCSC)C(=O)O)CCCCC2)cc1
Yield: 12.7 %

Procedure:
10 ml of N-methylmorpholine was added to 298 mg (2 mmol) of L-methionine and 259 mg (1 mmol) of 2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium hydrogensulfate and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 52 mg (13%) of the title compound.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1)=O)(C)(C)C.Cl.CO>O1CCOCC1>[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1
Reactant: COC(=O)C1CCCC(NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C1CCCC(N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flask, methyl 3-(tert-butoxycarbonylamino)cyclohexanecarboxylate (5.13 g, 19.94 nmol) in 1,4-dioxane (15 ml) was reacted with hydrochloric acid in dioxane (4M) (15 mL). Methanol (2 mL) was added to aid in solubility. The reaction was stirred at room temperature for 1 hour. Upon completion the reaction was concentrated, and the crude (3.86 g) was progressed to the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[C:6]([NH2:8])[CH:7]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[C:18]([CH3:34])=[CH:17][N:16]=1.CS(O)(=O)=O>CC(O)C>[Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([O:9][CH:10]([CH3:11])[CH3:12])=[C:6]([NH:8][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH:31]([CH3:32])[CH3:33])(=[O:30])=[O:29])[C:18]([CH3:34])=[CH:17][N:16]=2)[CH:7]=1
Reactant: Cc1cnc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Reactant: Cc1cc(OC(C)C)c(N)cc1Br
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Product: Cc1cc(OC(C)C)c(Nc2ncc(C)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)cc1Br

Procedure:
5-Bromo-2-isopropoxy-4-methyl-phenylamine from the previous step (537 mg, 2.20 mmol) and 2-chloro-N-(2-(iso-propylsulfonyl)phenyl)-5-methylpyrimidin-4-amine (Intermediate 1, 652 mg, 2.00 mmol) in the presence of methanesulfonic acid (0.143 mL) in 4 mL 2-propanol are condensed at 140° C. for 30 min in a sealed tube under microwave irradiation. Following workup, N2-(5-Bromo-2-isopropoxy-4-methyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine is obtained. MS (ES+): 535.1 (MH+).
Reaction SMILES: Cl[C:2]([O:4][C:5]([CH3:11])([CH3:10])[C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[CH2:12]([O:14][C:15]([C:17]1[C@@H:18]2[N:44](C)[C@H:22]([CH2:23][C:24]=1[C:25]1[CH:26]=[N:27][C:28]([O:31][CH2:32][CH2:33][O:34][C:35]3[C:40]([Cl:41])=[CH:39][C:38]([CH3:42])=[CH:37][C:36]=3[Cl:43])=[CH:29][CH:30]=1)[CH2:21][N:20]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:19]2)=[O:16])[CH3:13]>>[Cl:7][C:6]([Cl:9])([Cl:8])[C:5]([O:4][C:2]([N:44]1[C@H:18]2[C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[C:24]([C:25]3[CH:26]=[N:27][C:28]([O:31][CH2:32][CH2:33][O:34][C:35]4[C:40]([Cl:41])=[CH:39][C:38]([CH3:42])=[CH:37][C:36]=4[Cl:43])=[CH:29][CH:30]=3)[CH2:23][C@@H:22]1[CH2:21][N:20]([C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])[CH2:19]2)=[O:3])([CH3:11])[CH3:10]
Reactant: CC(C)(OC(=O)Cl)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Product: CCOC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 44.3 %

Procedure:
2,2,2-Trichloro-1,1-dimethylethyl chloroformate (2.77 g, 11.6 mmol) was added to a sol. of compound C4 (1.40 g, 2.31 mmol) in CH2ClCH2Cl (30 mL), and the mixture was heated to reflux for 2 h. 2,2,2-Trichloro-1,1-dimethylethyl chloroformate (1.40 g, 5.5 mmol) was added again, and the mixture was heated to reflux for 2 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was diluted with EtOAc, and washed with aq. 1M NaOH (2×). The combined aq. layers were extracted back with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4) yielded the title compound (815 mg, 44%). LC-MS: tR=1.25 min; ES+: 796.32.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][N:11]([CH2:14][C:15](=O)[CH3:16])[CH2:10][C:9]=3[C:18](=[O:20])[O:19][C:4]=2[CH:3]=1.[CH3:21][NH:22][CH3:23]>>[CH3:21][N:22]([CH3:23])[CH:15]([CH3:16])[CH2:14][N:11]1[CH2:12][CH2:13][C:8]2[C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[O:19][C:18](=[O:20])[C:9]=2[CH2:10]1
Reactant: CNC
Reactant: CC(=O)CN1CCc2c(c(=O)oc3cc(C)ccc23)C1
Product: Cc1ccc2c3c(c(=O)oc2c1)CN(CC(C)N(C)C)CC3
Yield: 57.1 %

Procedure:
Prepared by the method described for Example 38 from 1,2,3,4-tetrahydro-8-methyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.0 g, 0.007 moles) and dimethylamine (5 g, 0.111 moles). Recrystallization from ethanol gave the product (1.2 g) as the dihydrochloride 10:7 hydrate, mp 224° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH:8]([OH:11])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1.[C:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[C:17]([Cl:22])[CH:16]=1)(=[O:14])[NH2:13]>>[C:12]([C:15]1[CH:20]=[CH:19][C:18]([O:11][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[C:2]([CH3:1])[S:10][C:9]2=3)=[C:17]([Cl:22])[CH:16]=1)(=[O:14])[NH2:13]
Reactant: Cc1cc2c(s1)C(O)CNC2
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Product: Cc1cc2c(s1)C(Oc1ccc(C(N)=O)cc1Cl)CNC2

Procedure:
The same method as in Example 1 was conducted using 2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 30) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>O1CCCC1>[Cl:19][CH2:20][CH2:21][CH2:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)=[O:24]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1cccc2cccnc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCCl)Nc1cccc2cccnc12
Yield: 53 %

Procedure:
A solution of 8-aminoquinoline (10 L g, 0.069 mole) and triethylamine (10 ml, 0.072 mole) in dry tetrahydrofuran (40 ml) was treated dropwise at room temperature with 4-chlorobutyryl chloride (about 0.07 mole) until the green reaction mixture turned yellow in colour. The reaction was filtered and the solids (triethylamine hydrochloride) were washed with tetrahydrofuran. The combined filtrates were concentrated by vacuum distillation, (≃15 mm Hg), filtered over alumina in methylene chloride, concentrated and recyrstallized from ether/petroleum ether affording 4-chloro-N-(8-quinolyl)butyramide. An analytical sample was prepared by recrystallization (m.p. 62°-63°), yield 53%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[N:5]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15]([NH2:23])[C:14]=1[N+:24]([O-])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[N:5]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15]([NH2:23])[C:14]=1[NH2:24])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(N)c1N
Yield: 59.8 %

Procedure:
Crude ethyl-[2-Amino-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylcarbamate (65 gm, 170 mmol) was dissolved in ethanol (1000 mL) and 10% Pd—C (6 gm) was added. Hydrogenation at 40° C. and 40 psi for 1 hour gave complete reduction of the nitro group. The catalyst was removed by filtration and the filtrate evaporated to dryness under reduced pressure to give a light brown semi-solid. Trituration with t-butyl methyl ether (150 mL) followed by filtration and washing with the same solvent (30 mL) gave the title compound (36 gm, 60% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[CH2:8]([C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29](=O)[CH3:30])=[CH:25][C:24]=3[F:32])=[CH:20][C:19]=2[CH:33]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:8]([C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([N:1]4[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]4)[CH3:30])=[CH:25][C:24]=3[F:32])=[CH:20][C:19]=2[CH:33]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C1CNC1
Reactant: CC(=O)c1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(c1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(F)c1)N1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of azetidine-3-carboxylic acid (0.015 g, 0.15 mmol), 1-(4-(5-benzylbenzofuran-2-yl)-3-fluorophenyl)ethanone (0.050 g, 0.15 mmol), acetic acid (0.013 mL, 0.22 mmol) in methanol (3.0 mL) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (0.037 g, 0.17 mmol) was added and the mixture was stirred for 1 h at room temperature. Evaporation and purification by flash chromatography (5% AcOH in CHCl3 and MeOH). The resulting solid was suspended in in an aqueous buffered solution (pH 6, phosphate buffer) and sonicated. The solids were collected by filtration, washed with water and Et2O to give title compound [hS1P1 EC50=313 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (t, J=7.9 Hz, 1H), 7.51-7.59 (m, 2H), 7.14-7.34 (m, 9H), 4.04 (s, 2H), 2.92-3.50 (m, 6H partially overlapping with HDO signal), 1.11 (d, J=6.3 Hz, 3H). MS (ESI) m/z: Calculated; 429.2 Observed: 430.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[Br:13]Br>CO>[Br:13][CH2:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: BrBr
Reactant: CC(=O)CCc1ccc(Br)cc1
Solvent: CO
Product: O=C(CBr)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
To a solution of 4-(4-bromophenyl)-2-butanone (1 mmol) in methanol (8 mL) stirred at room temperature, a solution of bromine (160 mg, 51.6 μL, 1 mmol) in methanol (1 mL) was added in one portion. The orange reaction mixture was then stirred at room temperature for 2 h, and, after the starting material had been consumed (TLC monitoring, hexanes-ethyl acetate 4:1 v/v), the reaction was quenched by adding a 0.3 M sodium thiosulfate solution (618 μL), and diluted with ethyl acetate (15 mL). The resulting mixture was washed with water (15 mL), the organic layer was separated, and the aqueous layer was extracted further with ethyl acetate (3×15 mL). The combined organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue that was chromatographed on a silica gel column using hexanes-ethyl acetate (15:1 v/v) as mobile phase to give 1-bromo-4-(4-bromophenyl)-2-butanone as a white solid (193 mg, 63%): mp 63-64° C., Rf=0.42 (hexanes-ethyl acetate 4:1 v/v); 1H NMR (400 MHz, CDCl3): δ 2.89 (t, J=6.8 Hz, 2H). 2.96 (t, J=6.8 Hz, 2H), 3.84 (s, 2H), 7.07 (d, J=8 Hz, 2H), 7.41 (d, J=8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 29.3, 34.3, 41.2, 120.2, 130.2, 131.7, 139.4, 201.0; HRMS (EI) Calcd. for C10H10Br2O: 303.9098 (M+). Found: 303.9090.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([CH2:31][CH2:32][O:33]C(=O)C)[C:9]1[C:10]([I:30])=[C:11]([C:17]([I:29])=[C:18]([NH:21][C:22](=[O:28])[CH2:23][O:24]C(=O)C)[C:19]=1[I:20])[CH2:12]CC([O-])=O)=[O:7])(=O)C.Cl.C[OH:39]>O.[OH-].[Na+]>[OH:4][CH2:5][C:6]([N:8]([CH2:31][CH2:32][OH:33])[C:9]1[C:10]([I:30])=[C:11]([C:17]([I:29])=[C:18]([NH:21][C:22](=[O:28])[CH2:23][OH:24])[C:19]=1[I:20])[CH2:12][OH:39])=[O:7]
Reactant: CO
Reactant: CC(=O)OCCN(C(=O)COC(C)=O)c1c(I)c(CCC(=O)[O-])c(I)c(NC(=O)COC(C)=O)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CO)Nc1c(I)c(CO)c(I)c(N(CCO)C(=O)CO)c1I
Reaction time: 2 h

Procedure:
N,N'-Bis(acetoxyacetyl)-N-(2-acetoxyethyl)-3,5-diamino-2,4,6-triiodobenzylacetate (0.50 g, 0.59 mmol) was dissolved in a mixture of methanol (5 ml), water (5 ml) and aqueous 1M NaOH (1 ml). The solution was stirred for 2 h, pH was adjusted to 2 using aqueous HCl and the product was purified by preparative HPLC. Yield: 240 mg (67%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[C:4]([F:11])[CH:5]=1)#[N:8]
Reactant: CCOP(OCC)OCC
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: CCOP(=O)(Cc1ccc(C#N)cc1F)OCC
Temperature: 150 °C
Yield: 103.8 %

Procedure:
A mixture of 1.5 g (7.0 mmol) of 4-(bromomethyl)-3-fluorobenzonitrile [ref. J.Med.Chem., 40, 2064 (1997)] and 1.4 g (8.4 mmol) of triethyl phosphite was heated at 150° C. for 2 hours. At the end of this time, the reaction mixture was concentrated under reduced pressure. Volatile materials in the residue thus obtained were removed by heating said residue at 100° C. in vacuo for 1 hour to afford 1.97 g (quantitative yield) of the title compound as an oil which solidified in the freezer. This oily product was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH3:17].Cl>CN(C=O)C>[CH2:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:16][CH3:17]
Reactant: CCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)C(=O)OCC
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 107.3 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 12.6 g, 315 mmol, 1.05 equiv) in DMF (300 mL) at 23° C. was added a solution of diethyl malonate (45.5 mL, 300 mmol, 1 equiv) in DMF (100 mL) via cannula over the course of 10 min. The addition caused a mild exotherm and H2 gas evolution was observed, cooling was not necessary. Following the addition, the reaction was stirred for 45 min at 23° C. then treated with 1-bromopropane (27.3 mL, 300 mmol, 1 equiv). The reaction was stirred at 23° C. for 25 min, then heated to 65° C. for 3 h, then stirred at 23° C. overnight. The reaction mixture was added to 1.0 N HCl (1 L) then extracted with diethyl ether (700 mL). The ether extracts were washed with H2O (400 mL), brine (200 mL), dried (MgSO4), filtered and concentrated to give 65.1 g of product as a clear oil. 13C NMR revealed approximately 4:1 mono to bis-alkylated product ratio. The product diethyl n-propylmalonate was used without further purification: 1H NMR (300 MHz, CDCl3) 4.18 (q, J=6.9 Hz, 4H), 3.32 (t, J=7.8 Hz, 1H), 1.91-1.79 (m, 2H), 1.41-1.25 (m, 2H), 1.25 (t, J=6.9 Hz, 6H), 0.92 (t, J=7.5 Hz, 3H); 13C NMR (300 MHz, CDCl3) (*denotes signal due to minor product of bis-alkylation) 169.6, 61.2, 60.9*, 51.8, 34.4*, 30.7, 20.5, 17.3*, 14.4*, 14.0, 13.7.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12](I)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:18])(=[O:4])=[O:3].[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1B(O)O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:27]2[N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[C:34]3[C:29]([CH:28]=2)=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:18])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: COc1cc(I)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(-c2cc3ccccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 92.6 %

Procedure:
In a similar manner to Step 2 of Example 1, 4-methanesulfonyloxy-5-methoxy-7-iodoisoindolinone (50.0 mg, 0.130 mmol) was dissolved in acetonitrile (3 mL), and the solution was treated with 1-(tert-butoxycarbonyl)indole-2-boronic acid (68.1 mg, 0.261 mmol), palladium acetate (2.3 mg, 0.010 mmol), tri(o-tolyl)phosphine (6.3 mg, 0.021 mmol) and triethylamine (0.181 mL, 1.30 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=7/3 to 1/1 to 3/7) to obtain 4-methanesulfonyloxy-5-methoxy-7-(1-(tert-butoxycarbonyl)indol-2-yl)isoindolinone (56.9 mg, yield 93%).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH:17]3[CH2:32][CH2:33][N:34]=[N+]=[N-])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[NH2:34][CH2:33][CH2:32][CH:17]1[CH:16]([NH:15][C:10]2[N:9]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[C:12]([Cl:14])[N:11]=2)[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: [N-]=[N+]=NCCC1C(Nc2nc(Cl)cc(N3CCCCCC3)n2)CCCN1C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCC1C(Nc2nc(Cl)cc(N3CCCCCC3)n2)CCCN1C(=O)OCc1ccccc1
Yield: 77.4 %

Procedure:
The compound 17 (75.5 mg), tetrahydrofuran (2 mL) and triphenylphosphine (46.3 mg) were stirred at room temperature for 1 day and then added water (0.01 mL). The reaction solution was heated at reflux for 1 day and then concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol:triethylamine=90:10:1) to obtain the title compound (55.5 mg) having the following physical properties.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:23][NH2:24])([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=1[C:29](OC)=[O:30].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:23][N:24]2[CH2:26][C:27]3[C:28](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:29]2=[O:30])([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1
Reactant: COC(=O)c1ccccc1CBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CN1CC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of (1-benzyl-4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methanamine (see above: synthesis of amine AM12) (1.22 mmol, 1.0 equiv.) and methyl 2-(bromomethyl)benzoate (1.22 mmol, 1.0 equiv.) in benzene (3 ml/mmol) was added triethylamine (2.44 mmol, 2.0 equiv.) and the resulting reaction mixture was refluxed for 25 h. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was successively washed with water and brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product which was purified by silica gel column chromatography. Yield: 51%.
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)(=[O:3])[NH2:2].Cl.C(=O)(O)[O-].[Na+].CCN(C(C)C)C(C)C.Br[CH2:48][CH2:49][O:50][CH3:51]>C(Cl)Cl>[CH3:51][O:50][CH2:49][CH2:48][NH:24][CH:21]1[CH2:22][CH2:23][CH:18]([O:17][C:8]2[N:9]=[CH:10][N:11]=[C:12]3[C:7]=2[C:6]2[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=2[S:13]3)[CH2:19][CH2:20]1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (200 mg, 0.45 mmol, 1.00 equiv) in DCM (10 mL) was added hydrogen chloride (conc., 0.5 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature. The pH value of the solution was adjusted to 10 with saturated aqueous sodium bicarbonate, extracted with DCM (40 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in DMF (5 mL) and DIEA (333 mg, 2.58 mmol, 6.00 equiv) and 1-bromo-2-methoxyethane (598 mg, 4.30 mmol, 10.00 equiv) were added. Stirring was continued for 2 h at 65° C. The mixture was diluted with DCM (50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (Waters): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with NH4HCO3 and CH3CN (5.0% CH3CN up to 43.0% in 10 min, up to 95.0% in 2 min, down to 5.0% in 2 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated under reduced pressure to give the desired 2-[(3R)-12-([4-[(2-methoxyethyl)amino]cyclohexyl]oxy)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide (50 mg) as a white solid. MS: m/z 405 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.52 (s, 1H), 5.32-5.23 (m, 2H), 3.91-3.83 (m, 1H), 3.52 (t, 2H, J=5.1 Hz), 3.38 (s, 3H), 3.19-2.98 (m, 3H), 2.91-2.71 (m, 3H), 2.69-2.55 (m, 1H), 2.39-2.21 (m, 4H), 2.11-2.01 (m, 2H), 1.72-1.23 (m, 4H).