Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:5]([C:23]([O:25]C)=[O:24])=[N:6][C:7]([N:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[S:15]2(=[O:22])=[O:21])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2.Cl>O1CCOCC1.O>[OH:3][C:4]1[C:5]([C:23]([OH:25])=[O:24])=[N:6][C:7]([N:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[S:15]2(=[O:22])=[O:21])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: COC(=O)c1nc(N2CCCN(C)S2(=O)=O)c2cccnc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCCN(c2nc(C(=O)O)c(O)c3ncccc23)S1(=O)=O
Temperature: 55 °C

Procedure:
Sodium hydroxide (3.85 mL, 3.85 mmol, 1N solution) was added to a suspension of methyl 8-hydroxy-5-(6-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)-1,6-naphthyridine-7-carboxylate (452 mg, 1.28 mmol) in a 2:1 solution of dioxane/water (10 mL) and the resulting mixture was heated overnight at 55° C. overnight. The opaque solution was acidified to a pH=7 using 1N HCl solution. The reaction was cooled and the solids that had precipitated out of solution were collected by vacuum filtration to give the desired product as an off-white solid.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:12][C:13]([CH2:15][N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19][CH:18]([NH2:27])[C:17]1=[O:28])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:29]([CH2:36][C:37](=O)[C:38]([OH:40])=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>CO>[CH2:5]([O:12][C:13]([CH2:15][N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19][CH:18]([NH:27][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:17]1=[O:28])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium cyanoborohydride (0.152 g, 0.0014 mol) was added to a solution of 1-benzyloxycarbonylmethyl-3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (0.45 g, 0.0014 mol) and benzylpyruvic acid (0.48 g, 0.0028 mol) in methanol (35 ml). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. Additional benzylpyruvic acid (0.48 g, 0.0028 mol) was added, and the reaction mixture stirred for an additional 18 hours. Concentrated hydrochloric acid (0.5 ml) was added and the resulting solution stirred for 1 hour. The solvents were removed under reduced pressure and the residue treated with dichloromethane (100 ml) to precipitate sodium chloride. After filtration, the solvent was removed under reduced pressure and the residue chromatographed on silica gel (30 g). Elution with ethyl acetate/methanol/acetic acid (90:10:0.2) gave 1-benzyloxycarbonylmethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as an oil; NMR(CDCl3) 7.35 (m, 14H), 5.10 (s, 2H), 4.60(m, 2H), 3.00(m, 12H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)C(C(O)=O)=[CH:20][CH:19]=[CH:18]3)[CH:9]=1.CN(C=O)C>C(Cl)Cl>[Cl:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:20][CH:19]=[CH:18]3)[CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 571 μl (6.66 mMol) oxalyl chloride in 15 ml CH2Cl2 is added to an ice-cooled solution of 1 g (3.33 mMol) 6-(6-chloro-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (preparation see WO 2006/59234; Step 25.1) and 10 μl DMF in 30 ml CH2Cl2. The reaction mixture is stirred at room temperature for 1 h. The solvent is then evaporated off under reduced pressure to afford the title compound as a brown solid, which is used directly without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:10]=1[CH3:11])=O)C.C1COCC1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>>[Cl:19][C:14]1[CH:13]=[C:12]([N:9]2[C:10]([CH3:11])=[C:6]([CH2:4][OH:3])[N:7]=[CH:8]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CCOC(=O)c1ncn(-c2ccc(Cl)c(Cl)c2)c1C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(CO)ncn1-c1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
To a solution of 1-(3,4-dichloro-phenyl)-5-methyl-1H-imidazole-4-carboxylic acid ethyl ester (0.82 g, 2.7 mmol) in THF (27 ml) lithium aluminum hydride (0.21 g, 5.4 mmol) was added portionwise keeping T<10° C. The mixture was stirred in an ice-bath for 2 h, then 1 ml saturated aqueous Seignette salt solution was slowly added. After dilution with AcOEt (100 ml) the mixture was filtered, concentrated and chromatographed [silica, elution with gradient CH2Cl2 to 80% (CH2Cl2/MeOH=9:1)]. The title compound was obtained as a white crystalline solid (0.46 g, 66%). Mp. 174-175° C. (CH2Cl2/iPr2O), MS: m/e=256 (M+)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][C:12]#[N:13])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[C:12]([CH2:11][C:10]1[CH:14]=[CH:15][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=1)#[N:13]
Reactant: N#CCc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(CC#N)cc1
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (3.22 ml, 41.6 mmol) was added dropwise to a solution of 4-aminobenzylcyanide (5.00 g, 37.8 mmol) and triethylamine (5.79 ml, 41.6 mmol) in dichloromethane (30 ml). The reaction mixture was stirred for 1 hour and then poured onto water, the organic layer was separated, dried (MgSO4), filtered and the solvent removed under reduced pressure to afford the title compound as a pale orange solid, 6.50 g.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=2[F:13])[C:7]([NH2:9])=O)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([CH2:7][NH2:9])[CH:10]=[CH:11][C:12]=2[F:13])[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(F)c(C2CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(F)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution of 3-cyclopropyl-4-fluoro-benzamide (Preparation 57, 66 g, 0.37 mol, 1.0 eq) in THF (500 mL) was added portionwise lithium aluminium hydride (42 g, 1.1 mol, 3.0 eq) at 10° C. Then the mixture was stirred at room temperature overnight. Water (100 mL) was added dropwise to the reaction mixture at 10° C. and the mixture was filtrated. The solid was washed with THF (3×700 mL), and filtrate was dried over sodium sulfate and concentrated in vacuum to give crude. The crude product was purified by column chromatography (MeOH/DCM 1:100→1:40) to give title compound as a yellow liquid (42.27 g, 0.257 mol, 69.5%).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8](=O)[NH:7][C:6]([NH2:12])=[N:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>C(N(CC)C1C=CC=CC=1)C>[NH2:12][C:6]1[N:5]=[C:4]2[C:9]([NH:10][C:2]([CH3:1])=[N:3]2)=[C:8]([Cl:15])[N:7]=1
Reactant: Cc1nc2nc(N)[nH]c(=O)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1nc2nc(N)nc(Cl)c2[nH]1

Procedure:
A suspension of 8-methylguanine (Daves et al., J. Am. Chem. Soc., 82, 2633-2640 (1960)) (1.0 g, 6.1 mmol) in phosphorous oxychloride (30 mL) and N,N-diethylaniline (1 mL) was refluxed for 3 h. The excess phosphorous oxychloride was evaporated under reduced pressure. The resulting brown oil was dissolved in ice-water and was neutralized with a concentrated aqueous NaOH solution. After evaporation of the solvent, the solid residue was suspended in 70 mL of H2O. Undissolved solid was filtered off, and the filtrate was loaded on a 3×80 cm Sephadex LH-20 column eluted with methanol/water (1:1) at 1 mL/min. Column eluent was continuously monitored at 280 nm and fractions (10 mL) were collected. Evaporation of pooled fractions 50-60 produced 2-amino-6-chloro-8-methylpurine as a crude solid. Crystallization from ethanol/water with charcoal treatment afforded 2-amino-6-chloro-8-methylpurine as a white solid: yield, 0.57 g (51%); mp>265° C. dec.; 1H NMR d 2.39 (s, 3 H, CH3), 6.62 (s, 2 H, NH2, exchange with D2O), 12.56 (s, 1 H, NH, exchanges with D2O); MS (EI) calcd. m/z for C6H6N535Cl 183.0312, found 183.0309; calcd. m/z for C6H6N537Cl 185.0283, found 185.0286.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH:40]1[CH2:42][CH2:41]1)(=O)=O.[CH3:45][O:46][C:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1B(O)O)=[O:48].COC(C1C=CC(B(O)O)=CC=1)=O>>[CH:40]1([N:11]2[C:12]3[C:8](=[C:7]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=4[C:47]([O:46][CH3:45])=[O:48])[CH:15]=[C:14]([C:16]([N:18]4[CH2:19][CH2:20][C:21]5([CH2:32][C:31](=[O:33])[C:30]6[C:25](=[CH:26][CH:27]=[C:28]([C:34]7[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=7)[CH:29]=6)[O:24]5)[CH2:22][CH2:23]4)=[O:17])[CH:13]=3)[CH:9]=[CH:10]2)[CH2:41][CH2:42]1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OS(=O)(=O)C(F)(F)F)c5ccn(C6CC6)c5c4)CC2)O3)cn1
Reactant: COC(=O)c1ccccc1B(O)O
Agent: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccccc1-c1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cnn(C)c4)ccc2O3)cc2c1ccn2C1CC1

Procedure:
The intended compound was produced according to the procedure described in Example 28-1 but using 1-cyclopropyl-6-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}-1H-indol-4-yl trifluoromethanesulfonate and [2-(methoxycarbonyl)phenyl]boronic acid in place of 8-cyclopropyl-2-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}quinolin-4-yl trifluoromethanesulfonate and [4-(methoxycarbonyl)phenyl]boronic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:22]N1C(=O)CCC1=O.O>C(O)(C)C>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)=[C:12]([Cl:22])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(c2ccc(NC(=O)OC(C)(C)C)cc2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(c2ccc(NC(=O)OC(C)(C)C)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
583 mg (2 mmol) of (4-(4-methyl-piperazin-1-yl)-phenyl]-carbamic acid tert-butyl ester (Example 65c) are dissolved in 10 ml of isopropanol and 286 mg (2.1 mmol) of N-chlorosuccinimide are added. The solution is stirred for 1 h at r.t. and 100 ml of water are added. The suspension is extracted with EtOAc and the organic phase is washed with water, dried over MgSO4 and evaporated to dryness. The residue is purified by MPLC to provide the title compound. Title compound: ES-MS: 326.3 (M+H)*; analytical HPLC: tret=4.43 minutes (Grad 2).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=2)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.O>C(Cl)Cl>[C:1]1([CH:7]=[CH:8][C:9]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc([C@H](C)NC(=O)C=Cc2ccccc2)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=O)C=Cc1ccccc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-3-phenyl-N-[1-(3-methoxyphenyl)ethyl]acrylamide (100 mg) in CH2Cl2 (0.5 mL) at −78° C. was added boron tribromide (1.0 M solution in CH2Cl2, 2.14 mL). The resulting solution was warmed to room temperature and stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with CH2Cl2 (three times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: CCOC(=O)/C=C/C1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)CCC1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C

Procedure:
A degassed solution of (E)-ethyl 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)-piperidin-2-yl)acrylate (4.19 mmol) in MeOH was hydrogenolysed with Pd(OH)2 (0.4 g) as the catalyst. The resulting crude product was employed in the following stage without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[NH:21]1[C:25]([CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)=[N:24][N:23]=[N:22]1.C([O-])([O-])=O.[K+].[K+].Cl>CN1CCCC1=O.O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[CH:3]=[C:2]([N:28]2[CH2:29][CH2:30][CH2:31][CH:26]([C:25]3[N:21]=[N:22][NH:23][N:24]=3)[CH2:27]2)[N:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: C1CNCC(c2nnn[nH]2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(N2CCCC(c3nn[nH]n3)C2)n1
Temperature: 140 °C
Yield: 74.9 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine [300 mg, 0.9 mmol], 3-(1H-tetrazol-5-yl)-piperidine [383 mg, 2.25 mmol] and K2CO3 (373 mg, 2.7 mmol) in N-methylpyrollidinone (5 mL) is heated at 140° C. for 16 hours. The mixture is diluted with water (50 mL), acidified to pH 3 with 10% HCl and extracted three times with EtOAc (40 mL). The organic extracts from the acidic layer are combined and dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 15% ethyl methanol:DCM to afford an oil which is diluted with water (20 mL). A solid is formed and collected by filtration to afford [2-(2,4-dichloro-phenyl)-ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine [303 mg, 75%, Example 96] as a solid. LCMS: RT=1.95 minutes, MS: 449 (M+H). IC50=5 nM
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].BrCC1OC(C(F)(F)F)=CC=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2([CH2:39][O:38][C:37]3[CH:40]=[C:41]4[C:45](=[CH:46][C:36]2=3)[CH2:44][CH2:43][O:42]4)[C:28]1=[O:47].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[O:47]=[C:28]1[C:29]2([CH2:39][O:38][C:37]3[CH:40]=[C:41]4[C:45](=[CH:46][C:36]2=3)[CH2:44][CH2:43][O:42]4)[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]1[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using N-(3-bromopropyl)phthalimide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 2-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione was obtained (39%) as a pale yellow solid: mp 214-217° C.; 1H NMR (300 MHz, CDCl3) δ 7.84 (dd, J=5.6, 3.0 Hz, 2H), 7.72 (dd, J=5.5, 3.0 Hz, 2H), 7.31-7.28 (m, 1H), 7.18 (dd, J=7.4, 0.8 Hz, 1H), 7.04 (ddd, J=8.4, 7.5, 0.8 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.58 (s, 1H), 6.40 (s, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.6 Hz, 2H), 3.98-3.89 (m, 1H), 3.85-3.75 (m, 3H), 3.01 (ddd, J=10.6, 8.4, 1.7 Hz, 2H), 2.20-2.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.7, 168.1, 161.7, 161.2, 141.9, 134.0, 133.0, 131.9, 128.7, 124.0, 123.3, 123.2, 120.2, 119.9, 118.9, 108.2, 93.1, 80.4, 72.4, 57.6, 38.0, 35.7, 29.0, 26.8; MS (ES+) m/z 466.9 (M+1).
Reaction SMILES: C(C1(C)N=[C:7]([CH2:9][CH3:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)C.N1C=CCNC1.C(=O)([O-])[O-:22].[Na+].[Na+]>Cl>[NH2:4][C:5]([CH3:11])([CH2:12][CH3:13])[CH2:6][C:7](=[O:22])[CH2:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CCC1=NC(C)(CC)NC(C)(CC)C1
Agent: C1=CNCNC1
Agent: Cl
Agent: [Na+]
Product: CCC(=O)CC(C)(N)CC

Procedure:
196.3 g of 2,4,6-triethyl-2,6-dimethyl-1,2,5,6-tetrahydropyrimidine were added dropwise to 300 ml of concentrated hydrochloric acid at 30°-40° C., with stirring. When all of the tetrahydropyrimidine had been added, the entire mixture was stirred for 4-5 hours and then neutralized with sodium carbonate and extracted with benzene. The resulting benzene solution was washed, in turn, with a 5% aqueous solution of sodium carbonate and with water, and was then dried over potassium carbonate. After removing the benzene, the residue was distilled under reduced pressure, giving 72.4 g of 5-amino-5-methyl-3-heptanone (bp 46°-48° C./2.5 mmHg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].S(Cl)([Cl:13])(=O)=O>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Cl:13][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1ccc(O)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCc1ccc(O)c(Cl)c1
Temperature: 70 °C
Yield: 76.3 %

Procedure:
A solution of 4-ethylphenol (25.4 g, 0.21 mol) and sulfuryl chloride (18.5 ml, 0.23 mol) in carbon tetrachloride (40 ml) was stirred under heating at 70° C. for 3 hr. The reaction mixture was diluted with chloroform and washed with water. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2-chloro-4-ethylphenol (25.1 g, 77%).
Reaction SMILES: [C:1]([CH2:5][C:6]1[CH:31]=[CH:30][C:9]([O:10][C:11]2[CH:12]=[C:13]([N:17]([CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)([O:3]C)=[O:2].[OH-].[Na+]>C1COCC1>[C:1]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[C:13]([N:17]([CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=[CH:30][CH:31]=1)([OH:3])=[O:2]
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(Oc2ccc(CC(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(Oc2ccc(CC(=O)O)cc2)c1
Reaction time: 8 h

Procedure:
N-(3-(4-Carbomethoxymethylphenoxy)phenyl)-N-(ethanesulfonyl)pyrid-3-ylmethylamine (1.0 equiv.) was dissolved in THF (3.3 M) and treated with 1N NaOH (3 equiv.). The reaction was stirred overnight then concentrated in vacuo to remove THF. The pH was adjusted to 4 with HCl, which caused the title compound to precipitate. The solid was collected via filtration washing with pH=4 water to give the title compound. Anal Calcd for C22H22N2O5S.0.2H2O: C, 61.44; H, 5.25; N, 6.51. Found: C, 61.39; H, 5.12; N, 6.59. MS found 427.0 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[Br:14][C:15]1[C:25]([Br:26])=[C:24]([Br:27])[C:23]([Br:28])=[C:17]2[C:18]([O:20][C:21](=O)[C:16]=12)=[O:19]>ClC1C(Cl)=C(Cl)C=CC=1>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([N:1]2[C:21](=[O:20])[C:16]3=[C:15]([Br:14])[C:25]([Br:26])=[C:24]([Br:27])[C:23]([Br:28])=[C:17]3[C:18]2=[O:19])=[C:3]2[C:8]=1[N:7]=[C:6]([CH3:13])[CH:5]=[CH:4]2
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: Cc1ccc2c(N)ccc(C)c2n1
Agent: Clc1cccc(Cl)c1Cl
Product: Cc1ccc2c(N3C(=O)c4c(Br)c(Br)c(Br)c(Br)c4C3=O)ccc(C)c2n1
Yield: 86 %

Procedure:
172 g (1.0 mole) of 5-amino-8-methylquinaldine and 464 g (1.0 mole) of 3,4,5,6-tetrabromophthalic anhydride were reacted in 2,000 g of trichlorobenzene for 2 hours under reflux to afford 532 g (0.86 mole) of 8-methyl-5-(3,4,5,6-tetrabromophthalimido)-quinaldine. 369 g (1.29 moles) of tetrachlorophthalic anhydride and 2,000 g of α-chloronaphthalene were added, and the mixture was reacted for 2 hours under reflux. The product was collected by hot filtration at 120° C., and dispersed in 1,000 g of α-chloronaphthalene, and the mixture was heated with stirring to wash the product. After hot filtration, the product was washed with ethanol and dried to afford 671 g (0.75 mole) of a yellow compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH3:11])=[N:8][C:7]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:6]=2[C:5]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH3:24][C:25]([CH3:32])([C:29](O)=[O:30])[C:26]([OH:28])=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:15]([N:12]1[C:7]2=[N:8][C:9]([CH2:10][CH3:11])=[C:4]([CH2:3][NH:2][C:29](=[O:30])[C:25]([CH3:32])([CH3:24])[C:26]([OH:28])=[O:27])[C:5]([NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:6]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CC(C)(C(=O)O)C(=O)O
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (400 mg, 1.18 mmol), dimethylpropanedioic acid (156 mg, 1.18 mmol), HBTU (535 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (8 mL) was stirred at room temperature overnight. It was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layers were dried over sodium sulfate, filtered, concentrated and purified with CombiFlash eluting with 10% methanol in DCM. The product fractions were combined and concentrated to give 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-2,2-dimethyl-3-oxopropanoic acid as a solid (165 mg, 34%). LC-MS m/z 418 (M+H)+.