Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:33])[NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([I:32])[CH:26]=4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=1)(C)(C)C.CO.CN(C=O)C>C(Cl)Cl>[I:32][C:27]1[CH:26]=[C:25]([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:34])=[O:3])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)=[N:18][CH:19]=2)=[O:33])[CH:30]=[CH:29][C:28]=1[CH3:31]
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)c1
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)cc1I

Procedure:
4-{4-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared by the hydrolysis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester with LiOH monohydrate in manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid, above. The product was isolated after a silica gel column chromatography with a 0-5% MeOH in CH2Cl2 to 0-100% DMF in CH2Cl2 gradient. HRMS m/z calcd for C24H23N4O3I [M+H]+: 543.0888. Found: 543.0886.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]([CH3:27])[C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].CCOC(C)=O.O.[CH2:37]1[CH2:41]OC[CH2:38]1>>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]([CH3:27])[C:10]=1[CH:11]([OH:12])[CH2:41][CH:37]=[CH2:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1c(C)c(OCc2ccccc2)c(C=O)c(C)c1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC(O)c1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2,5-Bis(benzyloxy)-3,4,6-trimethylbenzaldehyde (3.90 g, 12.16 mmol) was dissolved into 50 mL THF and cooled to 0° C. prior to the addition of 15 mL allyl Grignard (1.0 M in THF, 15 mmol). The pale yellow solution browned over the course of the addition. After 15 minutes at 0° C. the reaction was not complete by HPLC and an additional portion of allyl Grignard (3 mL, 1.0 M in THF, 3 mmol) was added and stirred for 0.6 h at which time the reaction was judged complete by HPLC. The reaction was treated carefully at 0° C. with 50 mL 10% aqueous NH4Cl stirred for five minutes post addition and 100 mL EtOAc added. The layers were stirred vigorously until they clarified, an additional 100 mL H2O and 100 ml EtOAc was added, the layers separated and the aqueous phase extracted 3×100 mL EtOAc. The combined organics were washed with 2×50 mL saturated aqueous NaCl and dried over Na2SO4 prior to concentration to a pale brown oil. Storage under vacuum gave a brown solid. Flash chromatography (gradient elution 0-20% EtOAc/heptane) yielded 3.91 g of 1-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)but-3-en-1-ol as a white, waxy solid. M++H—H2O=385 m/z; 1H NMR (400 MHz, CDCl3) δ=7.55 (d, 4H), 7.51-7.42 (m, 6H), 5.91 (m, 1H), 5.19-5.10 (m, 3H), 5.01 (d, 1H), 4.90 (d, 1H), 4.78 (s, 2H), 3.35 (d, 1H), 2.76 (m, 1H), 2.55 (m, 1H), 2.39 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([OH:13])([CH2:12][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CN2CCOCC2)CC1
Yield: 64.7 %

Procedure:
1-Oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (100 mg, 0.47 mmol) and morpholine (42 μL, 0.48 mmol, 1.03 eq) were stirred in EtOH at RT overnight. Solvent was removed in vacuo and the residue purified by flash chromatography (silica gel, 4% MeOH/DCM) to give 4-hydroxy-4-morpholin-4-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester as a white solid (91.4 mg, 67%).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][CH:9]=1)[CH2:5][CH:6]=[CH2:7].O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[CH3:19][S:16]([NH:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH:4]([CH2:5][CH:6]=[CH2:7])[C:3]([OH:20])=[O:2])=[CH:9][CH:10]=1)(=[O:18])=[O:17]
Reactant: C=CCC(C(=O)OC)c1ccc(CNS(C)(=O)=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCC(C(=O)O)c1ccc(CNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-[4-(methanesulfonylamino-methyl)-phenyl]-pent-4-enoic acid methyl ester (1.85 g, 6.55 mmol) in a 1:1 mixture of tetrahydrofuran (25 cm3) and methanol (25 cm3) at ambient temperature under an atmosphere of dry nitrogen was added lithium hydroxide hydrate (1.16 g, 26.2 mmol) dissolved in water (25 cm3). The mixture was stirred at ambient temperature for 16 hours and volatile fractions removed in vacuo to leave an aqueous mixture. The mixture was diluted with water (25 cm3) and acidified with 1 N hydrochloric acid to pH 1.0. The aqueous mixture was extracted with dichloromethane (3×30 cm3), The combined dichloromethane extracts washed with brine (1×30 cm3), dried over sodium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to a colorless oil (1.68 g, 90.7%) with a negative ion ESI (M−H)−282.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]2[C:14]([CH3:19])=[N:15][O:16][C:17]=2[CH3:18])=[CH:11][C:10]2[N:9]=[CH:8][C:7]3[N:20]=[C:21]([CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:22]([CH:23]([CH3:27])[CH2:24][O:25][CH3:26])[C:6]=3[C:5]=2[CH:4]=1>C(O)C>[CH3:1][O:2][C:3]1[C:12]([C:13]2[C:14]([CH3:19])=[N:15][O:16][C:17]=2[CH3:18])=[CH:11][C:10]2[N:9]=[CH:8][C:7]3[N:20]=[C:21]([CH:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[N:22]([C@@H:23]([CH3:27])[CH2:24][O:25][CH3:26])[C:6]=3[C:5]=2[CH:4]=1
Reactant: COCC(C)n1c(C2CCOCC2)nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c21
Solvent: CCO
Product: COC[C@H](C)n1c(C2CCOCC2)nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c21
Yield: 44.7 %

Procedure:
4-(8-methoxy-1-(1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole (85 mg) was dissolved in ethanol (ca. 4 ml) with heating and sonication. Injections (400 μl) were then made via plastic syringe. The fractions between 24 min and 26.5 min were collected and the combined fraction solutions were evaporated to dryness using a rotary evaporator (30° C. bath temp). The residue was transferred to a tared glass vial using ethanol (ca 12 ml). The solvent was then removed by evaporation under a stream of nitrogen gas (room temp) to give 4-(8-methoxy-1-((S)-1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole (38 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([NH:14][CH3:15])=[N:7][CH:6]=1)[CH3:2]>[Pd]>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:14][CH3:15])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(NC)c([N+](=O)[O-])c1
Agent: [Pd]
Product: CCOC(=O)c1cnc(NC)c(N)c1
Yield: 91.6 %

Procedure:
5-Amino-6-methylamino-nicotinic acid ethyl ester (723 mg) was prepared by following General Procedure B starting from 6-methylamino-5-nitro-nicotinic acid ethyl ester (911 mg) and Pd/C (10% by weight, 90 mg). The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:14]>>[CH2:13]([N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:14]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCCCCNCC
Product: CCCCCCC/C=C/C(=O)N(CC)CCCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N-ethyl-N-heptylamine as starting materials to give the aimed compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[N:17][C:18]([N+:21]([O-])=O)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)nc2)CC1
Yield: 97.5 %

Procedure:
Add palladium over carbon 10% (0.6 g) to a suspension of 4-(6-nitro-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (5.65 g) in a mixture tetrahydrofuran (THF)/methanol (30/30 mL/mL). Hydrogenate in a Parr apparatus at 2 atm overnight. Filter through a celite pad, wash with DCM and methanol. Purify by silica gel column chromatography eluting with DCM/methanol (10%)/ammonia (1%) to afford 5 g of the title compound. MS (ES+): m/z=294 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:54][O:55][C:56](=[O:63])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][NH2:62]>[Cl-].[Na+].O.CN(C=O)C>[CH3:54][O:55][C:56](=[O:63])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][NH:62][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([CH:14]=[N:13][N:12]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[CH:16][CH:17]=1
Reactant: COC(=O)CCCCCN
Reactant: O=C1Nc2ccc(F)cc2C1=NN=Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
4-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)benzoic acid (311 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 6-aminocaproic acid methyl ester hydrochloride (219 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (114 mg, 28% yield) as a brown solid. LC-MS (m/z) 439 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)(C)C.CCOC(C)=O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CN1CCNCC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1c(N2CCN(C)CC2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C

Procedure:
The 2,4-dichloro-5,7-difluoro-3-methylquinoline (300 mg, 1.20 mmol) and 1-methylpiperazine (140 μL, 1.20 mmol) were slurried in isopropanol (2.4 mL) and heated in a microwave reactor at 100° C. for 6 h. The reaction was cooled to rt and the resulting plug was slurried in EtOAc and filtered to give 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpiperazin-1-yl)quinoline. Mass Spectrum (ESI) m/e=312.1 (M+1).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([O:10][CH:11](OCC#C)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:8]#[CH:9].Cl>ClCCl.[Bi](Br)(Br)Br>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([O:10][CH2:7][C:8]#[CH:9])[C:5]#[N:6])=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)C#N
Reactant: C#CCOC(OCC#C)c1ccc(Cl)cc1
Agent: Br[Bi](Br)Br
Agent: Cl
Solvent: ClCCl
Product: C#CCOC(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
Under an atmosphere of nitrogen, trimethylsilyl cyanide (3.1 g) is added to bismuth (III)bromide (0.22 g) and 1-(bis-prop-2-ynyloxy-methyl)-4-chloro-benzene (6.7 g) in dichloromethane (50 ml) at room temperature. The reaction mixture is stirred for 48 hours at room temperature and then poured into 0.5 M hydrochloric acid (50 ml). The organic phase is separated, dried (magnesium sulfate) and evaporated. Crude (4-chloro-phenyl)-prop-2-ynyloxy-acetonitrile (3.7 g) is obtained as oil.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].OCC([C@H]([C@@H]([C@@H](CO)O)O)O)=O.OCC([C@H]([C@@H](CO)O)O)=O>>[O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
It was found that 21.9 mmol/l mannose, 74.4 mmol/l fructose, 70.4 mmol/l xylulose and 24.4 mmol/l lyxose were formed and accumulated in the respective reaction mixtures.
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][C:34]3([CH3:37])[CH2:36][CH2:35]3)[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19]CC)=O)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.NC1(C2NC(C3C=CC=C4C=3N=C(NC3(C)CC3)C(C)=N4)=CC=2C(O)=O)CC1.Cl.NC1(C2NC(C3C=CC=C4C=3N=C(NC(C)(C)C)C(C)=N4)=CC=2C(O)=O)CC1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:32][C:26]1[C:25]([NH:33][C:34]2([CH3:37])[CH2:35][CH2:36]2)=[N:24][C:23]2[C:28](=[CH:29][CH:30]=[CH:31][C:22]=2[C:14]2[NH:13][C:12]3[C:9]4([CH2:11][CH2:10]4)[NH:8][C:17](=[O:19])[C:16]=3[CH:15]=2)[N:27]=1
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC4(C)CC4)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1nc2cccc(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC(C)(C)C
Agent: Cc1nc2cccc(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC1(C)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)C3(CC3)NC4=O)c2nc1NC1(C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.2 %

Procedure:
Ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (329b) (925 mg, 1.829 mmol) was converted to 2-(1-aminocyclopropyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (329c: m/z (ESI, +ve) 378.1 (M+H)+) in a fashion similar to that described for Intermediate 324c. This material was used as crude. At RT, to a suspension of 2-(1-aminocyclopropyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)-quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (329c) in 10 mL of DMF and 10 mL of DCM was sequentially added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (619 mg, 3.23 mmol), 1-hydroxybenzotriazole (436 mg, 3.23 mmol) and DIEA (1.77 mL, 10.20 mmol). The homogeneous reaction mixture was stirred at RT for 18 h. It was diluted with 80 mL of DCM, washed sequentially with 5 mL of water, 5 mL of 1 N NaOH and 5 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (50-100% EtOAc in DCM followed by 1-5% MeOH in DCM) twice to give 2′-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (329) (192 mg, 30% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.28 (1H, br.), 8.00 (1H, d, J=7.4 Hz), 7.73 (1H, s), 7.54-7.68 (2H, m), 7.36 (1H, t, J=7.8 Hz), 7.22 (1H, s), 2.52 (3H, s), 1.50 (3H, s), 1.48 (2H, m), 1.31 (2H, m), 0.94 (2H, m), 0.74 (2H, m). m/z (ESI, +ve) 360.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1.[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.Cl>CCO>[ClH:1].[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][CH:14]=[C:4]3[N:3]=[C:2]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:7]=2)[CH2:11][CH2:10]1
Reactant: N#Cc1ccc(N)cc1
Reactant: Clc1cc(NC2CC2)n2nccc2n1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(Nc2cc(NC3CC3)n3nccc3n2)cc1
Temperature: 23 °C
Reaction time: 24 h
Yield: 62.7 %

Procedure:
5-chloro-N-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (208 mg, 1 mmol) was suspended in EtOH (1 mL). 4-aminobenzonitrile (236 mg, 2 mmol) and then conc. HCl (125 μL, 1.5 mmol) were added and the reaction was placed in a 95° C. oil bath. After 24 h, additional conc. HCl was added (62 μL). After an additional 24 h, the reaction was cooled to 23° C. and the filter cake was washed with EtOH (2 mL) to afford 4-(7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile hydrochloride (205 mg, 63%) as a light brown solid. LCMS (ES): >90% pure, m/z 291 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[CH2:28][CH2:27]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:29]([CH:26]2[CH2:28][CH2:27]2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1cccc(CNC2CC2)c1
Product: COc1cccc(CN(C(=O)CN(c2ccc(C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(3-methoxy-benzyl)-amine
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:4]2[O:3]1.I[CH2:33][CH2:34][OH:35].C([O-])([O-])=O.[Cs+].[Cs+].CN1C(=O)CCC1>CCOC(C)=O>[CH3:1][C:2]1([CH3:31])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([O:26][CH2:33][CH2:34][OH:35])=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:4]2[O:3]1
Reactant: OCCI
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(O)ccc43)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(OCCO)ccc43)cc2s1
Temperature: 100 °C
Yield: 38.8 %

Procedure:
A stirred mixture of 1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (60 mg, 0.14 mmol) from Step 1 of Example 171, 2-iodoethanol (60 mg, 0.35 mmol), Cs2CO3 (137 mg, 0.42 mmol), and NMP (2 mL) was heated at 100° C. for 24 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to afford 2-((1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)ethanol (26 mg, 39%) as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 7.32 (s, 1H), 7.16-7.19 (m, 2H), 6.91 (m, 1H), 5.36 (s, 2H), 4.13 (t, J=9.0 Hz, 2H), 3.98 (t, J=9.0 Hz, 2H), 3.65 (m, 1H), 3.08 (m, 1H), 2.80 (m, 1H), 2.14 (m, 1H), 1.84-1.92 (m, 2H), 1.78 (s, 3H), 1.63 (s, 3H), 1.28-1.40 (m, 4H); LCMS (ESI) m/z 479 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH2:1])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH2:10][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH3:13]
Reactant: c1ccncc1
Reactant: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN

Procedure:
A mixture of 43 parts by mass of the polymer (white solid) obtained through the production of an intermediate, 20 parts by mass of n-octadecylamine, 1 part by mass of pyridine, and 420 parts by mass of toluene is stirred at a temperature of 100° C. for 3 hours. After the mixture is cooled, the reaction solution is added to 8000 parts by mass of methanol in 15 minutes while stirring and is further stirred for 1 hour. The precipitated solid is filtered and is dried under depressurization, whereby 43 parts by mass of light yellowish white solid (specific copolymer) is obtained. The molecular weight measured through the use of a high-speed liquid chromatography method is 14,000. As the result of neutralization titration using a potassium hydroxide ethanol solution, the ratio of the semi-maleic acid amide component and the maleinimide component is 6:4.
Reaction SMILES: O=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][N:4]([CH2:5][CH2:6]2)[CH2:3]1>[OH-].[K+]>[N:4]12[CH2:10][CH2:9][CH2:8][N:7]([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: O=C1CN2CCCN1CC2
Agent: [K+]
Agent: [OH-]
Product: C1CN2CCN(C1)CC2
Reaction time: 0.33 h

Procedure:
The title compound of Example 2 (1.70 g, 12.1 mmol) was added portionwise at room temperature to a stirred solution of AIH3 (60 mL of a 1.0M solution, 60 mmol). The solution became warm. Stirring was continued for a further 20 minutes and the reaction mixture was poured into cold (5° C.) 30% aqueous KOH solution (100 mL) and the aqueous mixture was extracted with CHCl3 (200 mL). The organic extract was dried (Na2SO4) and evaporated to give the title compound in quantitative yield: mp 250° C. (dec) (EtOH); 1H-NMR (CDCl3) δ 3.02-3.25 (m, 1H), 2.66-3.02 (complex m, 3H), 2.59 (m, 1H), 2.43 (m, 1H), 2.25-2.40 (m, 1H), 1.87 (m, 1H), 1.04-1.77 (complex m, 6H); Anal (calcd for C17H16Cl2N2 ·0.33H2O): C 40.99, H 8.19, N 13.66. Found C 41.00, H 8.31, N 13.68.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33].O>O1CCCC1.C(OCC)(=O)C>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([N:9]1[C:8](=[O:13])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11][C:10]1=[O:12])(=[O:33])=[O:34]
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1S(=O)(=O)c1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
5,5-Diphenylimidazolidine-2,4-dione (0.5 g) was dissolved in tetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 2-naphthalenesulfonyl chloride (471 mg) was added at 0° C., and the mixture was stirred at room temperature overnight. After water was added carefully, ethyl acetate (100 mL) was added, and the layers were separated. The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=3:1 to 2:1) afforded 320 mg of white powder.