Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].Cl.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:21]
Reactant: CCOC(=O)C1=C(O)c2cc(OC)ccc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C21CCOCC1
Temperature: 95 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of ethyl 4-hydroxy-6-methoxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.6 g, 2 mmol), tert-butyl 2-aminoacetate hydrochloride (0.5 g, 3 mmol) in 5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.7 g, 5 mmol). The mixture was warmed to 95° C. and stirred for 4 hours, M+1=418. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.74 g of the title compound as a white yellow solid. MS (m/z)=418 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]([NH:30][C:31](OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][C:12]=1C1OCCO1)=O)(C)(C)C.[ClH:38]>C(O)C>[ClH:38].[ClH:38].[NH2:8][C:9]1[N:30]=[CH:31][C:12]2[C:11](=[CH:16][C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[N:10]=1
Reactant: COc1ccnc(-c2ccc(C3OCCO3)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: CCO
Product: COc1ccnc(-c2ccc3cnc(N)nc3c2)c1
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(2-(1,3-dioxolan-2-yl)-5-(4-methoxylpyridin-2-yl)phenyl)guanidine (200 mg) in ethanol (2 ml) was added hydrochloric acid (36%, 1 ml), and the mixture was stirred for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (50 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 2-amino-7-(4-methoxypyridin-2-yl)quinazoline dihydrochloride (89 mg).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:4].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.[H-].[Na+].Cl>O1CCCC1>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=2)=[CH:6][C:5]=1[C:3](=[N:2][O:1][CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=1)[CH3:4]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COc1ccc(-c2cccc(CC(=O)O)c2)cc1C(C)=NO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc(CC(=O)O)c2)cc1C(C)=NOCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.9 %

Procedure:
9 mg of [3′-(1-Hydroxyiminoethyl)-4′-methoxybiphenyl-3-yl]acetic acid was dissolved in 0.2 mg of tetrahydrofuran, then 25 mg of 4-trifluoromethylbenzyl bromide and 10 mg of sodium hydride were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was neutralized with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography to give 5.21 mg of the title compound.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[C:10]([NH2:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[CH:7][C:6]=1[O:14][CH2:15][CH:16]([OH:32])[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19]1.[C:33](Cl)([Cl:35])=[O:34]>>[ClH:35].[OH:32][CH:16]([CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:20][CH2:19]1)[CH2:15][O:14][C:6]1[C:5]2[NH:4][C:33](=[O:34])[NH:11][C:10]=2[C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=1
Reactant: Cc1cc(OCC(O)CN2CCC(COc3ccccc3)CC2)c(N)c(N)c1C
Reactant: O=C(Cl)Cl
Agent: Cl
Product: Cc1cc(OCC(O)CN2CCC(COc3ccccc3)CC2)c2[nH]c(=O)[nH]c2c1C
Yield: 24 %

Procedure:
2,3-Diamino-4,5-dimethyl-1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-benzene trihydrochloride is reacted with phosgene analogously to Example 1 to give 4-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-6,7-dimethyl-2-benzimidazolinone hydrochloride in a yield of 24% of theory; m.p. 273°-275° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[NH:19][C:20]1[NH:21][CH2:22][CH2:23][N:24]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:23][CH2:22][N:21]=[C:20]2[NH:19][C:13]2[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[O:8])=[CH:4][N:3]=1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(O)nc1)N1CCN=C1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3.25 g (22.9 millimoles) of 6-hydroxy-nicotinic acid are dissolved in 600 ml of absolute tetrahydrofuran and 60 ml of absolute hexamethylphosphorotriamide, 3.8 g (22.9 millimoles) of N,N'-carbonyl-diimidazole are added and the mixture is stirred for 45 minutes at room temperature. A solution of 5.3 g (11.0 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 100 ml of absolute tetrahydrofuran is then added dropwise and the mixture is left to stand overnight. The solvents are then stirred off under reduced pressure on a rotary evaporator, the residue is treated with 50 ml of 0.5% strength sodium bicarbonate solution and the mixture is decanted. 3.2 g of semi-crystalline, crude (6-hydroxynicotinoyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline are obtained, which on recrystallization from isopropanol give a pure product of melting point 256°-258° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17][CH2:16]2.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].CO>C(OCC)(=O)C>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][CH:16]3[CH2:17][CH2:18][CH:19]4[CH2:22][CH2:23][N:15]3[CH2:21][CH2:20]4)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: C1CC2CCN(C1)CC2
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CC1CCC2CCN1CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-azabicyclo[3.2.2]nonane. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 85% overall yield. FDMS m/e=314 (M+ of free base). α[D]589=−20.39 (c=0.48, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C)P(N(C)C)(N(C)C)=O>[CH2:26]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C#N)cc1
Temperature: 120 °C

Procedure:
p-Aminobenzonitrile (11.8 g., 0.1 mole) and 1-bromohexadecane (15.25 g., 0.05 mole) are dissolved in hexamethylphosphoramide (200 ml.) and heated under nitrogen in an oil bath maintained at 120° C. for 22 hours. The reaction mixture is cooled to room-temperature, and water (50 ml.) is added gradually. The mixtue is then chilled in an ice-bath. The precipitate separated is filtered, washed thoroughly with water and dried. It is then washed repeatedly with hexane and dried, providing 14.2 g. of a pale brownish yellow granular solid as a homogeneous product. Recrystallization from ether-hexane affords p-hexadecylaminobenzonitrile as pale yellow prisms, m.p. 63°-64° C.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH:16]([C:18]2[C:19]([CH:34]3[CH2:36][CH2:35]3)=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:22][CH:23]=2)[CH3:17])=[CH:11][C:10]=1[CH3:37])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:34]1([C:19]2[C:18]([CH:16]([S:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:38])=[O:5])=[C:10]([CH3:37])[CH:11]=3)[CH3:17])=[CH:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=3)[N:20]=2)[CH2:35][CH2:36]1
Reactant: Cc1cc(SC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)ccc1OCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(SC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)ccc1OCC(=O)O
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of 146 mg (0.268 mmol) [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid tert-butyl ester in 2 ml dichloromethane was added 0.5 ml trifluoroacetic acid. The reaction mixture was stirred for 4 h and then the trifluoroacetic acid was removed under reduced pressure. The crude product was suspended in AcOEt/heptane 1:19. The resulting crystalline product was filtered off to give 118 mg of pure [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:31]([OH:48])[CH2:32][C@H:33]([C:37](=[O:47])[NH:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[CH:34]([CH3:36])[CH3:35])[CH2:10][C@@H:11]([CH:28]([CH3:30])[CH3:29])[CH2:12][NH:13][C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])=O)(C)(C)C.[ClH:49]>O1CCOCC1>[ClH:49].[ClH:49].[NH2:8][C@H:9]([C@@H:31]([OH:48])[CH2:32][C@H:33]([C:37](=[O:47])[NH:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[CH:34]([CH3:36])[CH3:35])[CH2:10][C@@H:11]([CH:28]([CH3:29])[CH3:30])[CH2:12][NH:13][C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26]
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCCN1CCOCC1)C(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)NCCN1CCOCC1)C(C)C)C(C)C

Procedure:
(2S,4S,5S,7S)-N-[4-(tert-Butoxycarbonyl)amino-5-hydroxy-2-isopropyl-8-methyl-7-(2-morpholin-4-ylethylcarbamoyl)-nonyl]-2-(3-methoxypropoxy)-benzamide (64 mg) is stirred in 2 ml of a 4N hydrochloric acid solution in dioxane at 0° C. for one hour, in a manner analogous to that described in Example 21). Removal of the solvent and drying under a high vacuum yield (2S,4S,5S,7S)-N-[4-amino-5-hydroxy-2-isopropyl-8-methyl-7-(2-morpholin-4-ylethylcarbamoyl)-nonyl]-2-(3-methoxypropoxy)-benzamide dihydrochloride: Rf (W)=0.13. HPLC Rt =9.59 min. MS(FAB) m/e 579 (M+ +1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClCCl>[Br:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Temperature: 25 °C

Procedure:
A solution of methyl-o-toluate (0.93 mL, 6.6 mmol), N-bromosuccinimide (1.25 g, 7.0 mmol) and azaisobutryonitrile (11 mg, 0.07 mmol) in chloroform (10 mL) was heated at 65° for 16 h. After cooling to rt, the mixture was diluted with dichloromethane and washed with H2O and then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give methyl 2-(bromomethyl)benzoate.
Reaction SMILES: [CH:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:5]=1[O:6][C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])=[O:8])([CH3:3])[CH3:2].Cl.C([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])(C)(C)C.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:6][C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:34][CH2:33][CH2:32][C:31]([OH:35])=[O:30])=[O:12])=[O:8])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(C)c1cccc(C(C)C)c1OC(=O)c1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1OC(=O)c1ccccc1C(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 38 %

Procedure:
To a solution containing (102) (2.1 g, 6.4 mmol) and beta-alanine tert-butyl ester hydrochloride (1.16 g, 6.4 mmol) in DMF (20 mL) was added diisopropylethylamine (2.4 mL, 13.7 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.5 g, 6.5 mmol). The resulting reaction mixture was stirred at room temperature for 14 h, diluted with ethyl acetate (100 mL), washed with 10% aqueous citric acid solution (5mL), followed by saturated aqueous NaHCO3 solution (50 mL) and brine (2×50 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The crude residue was dissolved in anhydrous dichloromethane (30 mL) and cooled to 0° C. before a solution of hydrochloric acid (10 mL, 4 N in dioxane) was added. The reaction was stirred for 1 h at 0° C. and 1 h at room temperature. The solvent was removed in vacuo and the crude residue was purified by preparative LC/MS to afford 0.85 g (38% yield over three steps) of the title compound (101). 1H NMR (400 MHz, CD3OD): δ 8.20 (dd, J=7.6, 0.8 Hz, 1H), 7.70-7.68 (m, 1H), 7.63-7.59 (m, 1H), 7.49 (dd, J=7.6, 0.8 Hz, 1H), 7.22-7.17 (m, 3H), 3.54 (t, J=7.2 Hz, 2H), 3.06-3.00 (m, 2H), 2.57 (t, J=6.8 Hz, 2H), 1.19 (d, J=6.8 Hz, 12H). MS (ESI) m/z 398.3 (M+H+).
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=CC=1.[OH2:11]>>[CH2:4]([O:11][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc2ncccc2c1
Reactant: O
Product: c1ccc(COCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of 57.8 g (0.095 mol) α-pivalyl-α-[4-(p-benzyloxyphenylsulfonyl)-phenoxy]-2-chloro-5-amino acetanilide and 13 g quinoline, cooled to 0° C., was added in one portion 45 g (0.095 mol) of the acid chloride B1Cl prepared in Example 4. After stirring 1 h the reaction mixture was poured into 3 L cold water to produce 98 g (after oven drying) crude product. Recrystallization from toluene yielded 84.5 g (0.018 mol) white crystalline dibenzyl ether of the desired coupler. A suspension of 10.4 g (0.01 mol) of this product in 200 mL ethanol and 200 mL tetrahydrofuran was shaken 3 h under 35 psi hydrogen with palladium on charcoal catalyst. Removal of catalyst by filtration, concentration of the filtrate and trituration in hot cyclohexane gave a good yield of coupler Y-2 with the correct elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CO.CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
(4-Bromo-phenyl)-acetic acid (2.84 g, 13.2 mmol, 1.1 equiv.) was dissolved in DCM (60 mL) and DMF (15 mL) to form a suspension and was cooled to an ice-water bath. To this was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.4 g, 12 mmol, 1.0 equiv.), followed by N-methylmorpholine (4 mL, 3.68 g, 3 equiv.), 1-Hydroxylbenzotriazole (HOBT) (22.12 g, 15.7 mmol, 1.3 equiv.), sequentially. It was still a suspension. More DMF (10 mL) was added but did not dissolve. EDC.HCl (3.13 g, 16.3 mmol, 1.3 equiv.) was added at 0° C. The suspension slowly (15 min.) turned into a light yellow clear solution. The resultant clear light yellow solution was stirred at r.t. for 1 h, it turned into cloudy again. The mixture was stirred overnight. TLC (5 % MeOH in DCM) and LC/MS detected the product peak at retention time of 3.608 min with MS 334/336. The reaction was quenched with saturated sodium bicarbonate aqueous solution (100 mL) and 10 mL of DCM. The suspension was stirred for 1 h at rt and then filtered, rinsed with plenty of water. The white powder was air-dried under suction overnight to get 4.62 g (96.9% yield) of the title compound as a very white crystalline material.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[O:13])[NH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.ClCCl>[CH3:18][N:9]1[C:8](=[O:13])[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:10]1
Reactant: O=c1[nH][nH]c2cc([N+](=O)[O-])ccc12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1[nH]c2cc([N+](=O)[O-])ccc2c1=O
Temperature: 60 °C

Procedure:
1.66 g (9.27 mmol) of 6-nitro-1,2-dihydro-3H-indazol-3-one were initially charged in 20 ml of DMF, and 1.75 ml (18.5 mmol, 2.0 eq.) of dimethyl sulphate were added. The reaction mixture was heated at 60° C. for 8 h and then diluted with dichloromethane and shaken with saturated aqueous sodium carbonate solution. The aqueous phase was washed three times each with dichloromethane and with ethyl acetate and the organic fractions were discarded. Using 4N aqueous hydrochloric acid, the aqueous phase was then carefully adjusted to pH 4.5 and extracted three times with ethyl acetate. These combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 50, mobile phase: gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate/methanol 15:1), giving the title compound. Yield: 770 mg (43% of theory)
Reaction SMILES: [NH2:1][CH:2]([CH3:12])[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1.CS([C:16]1[N:21]=[C:20]([NH:22][C:23]2[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=[C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:24]=2)[CH:19]=[CH:18][N:17]=1)=O.CCOC(C)=O>CN1C(=O)CCC1>[OH:11][CH2:10][C:6]1[CH:5]=[C:4]([CH2:3][CH:2]([NH:1][C:16]2[N:21]=[C:20]([NH:22][C:23]3[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=[C:25]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:24]=3)[CH:19]=[CH:18][N:17]=2)[CH3:12])[CH:9]=[CH:8][CH:7]=1
Reactant: Cn1c(Nc2ccnc(S(C)=O)n2)nc(-c2ccccc2)cc1=O
Reactant: CC(N)Cc1cccc(CO)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(Cc1cccc(CO)c1)Nc1nccc(Nc2nc(-c3ccccc3)cc(=O)n2C)n1
Temperature: 100 °C

Procedure:
A mixture of [3-(2-amino-propyl) -phenyl]-methanol (300 mg, 1.8 mmol) and 2-(2-methanesulfinyl-pyrimidin-4-ylamino) -3-methyl-6-phenyl-3H-pyrimidin-4-one (300 mg, 0.9 mmol) in NMP (8 mL) was heated to 100° C. for 16 h. The reaction was cooled to room temperature and EtOAc was added. The mixture was then washed with H2O three times, brine once, dried (MgSO4), filtered, concentrated under vacuum, and purified by preparative-scale TLC to give the product. M+1: 443.
Reaction SMILES: [NH3:1].[C:2]12([C:12]3[CH:13]=[C:14]([C:25]#[C:26][C:27]4[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.O>C1COCC1>[C:2]12([C:12]3[CH:13]=[C:14]([C:25]#[C:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([NH2:1])=[O:32])=[CH:29][CH:28]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: COCCOCOc1ccc(C#Cc2ccc(C(=O)Cl)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1ccc(C#Cc2ccc(C(N)=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 3 h

Procedure:
500 μl (9.1 mmol) of an aqueous ammonia solution (32%) and 20 ml of THF were introduced into a round-bottomed flask. A solution of 1.1 g (2.3 mmol) of 4-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl]benzoyl chloride dissolved in 30 ml of THF was added dropwise and stirring was carried out at room temperature for three hours. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[C:9]1([CH:19]=[O:20])[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][N:10]=1>O1CCCC1>[OH:20][CH:19]([C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][N:10]=1)[CH3:4]
Reactant: CCOCC
Reactant: O=Cc1nccc2c1CCCC2
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1nccc2c1CCCC2
Temperature: 25 °C
Yield: 87.4 %

Procedure:
Methylmagnesium bromide in diethyl ether (9.3 ml, 28 mmole) is dissolved in 10 ml tetrahydrofuran at 0° C. in an oven dried 100 ml two neck round bottom flask under nitrogen. The solution is treated with 5,6,7,8,-Tetrahydroisoquinoline-1-carbaldehyde (3.61 g, 22.4 mmole) followed by 10 ml diethyl ether. The reaction mixture is warmed to room temperature and then to reflux for 1 h. The mixture is cooled, is quenched with 20 ml 10% hydrochloric acid, and the pH is adjusted to 9 with 2N sodium hydroxide. The layers are separated, the aqueous layer is washed with 4×50 ml dichloromethane, and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to give 3.47 g (87%) of 1-(1-hydroxyethyl)-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.CC1C=CC=C2C=1C=CC(=O)N2.[OH-].[Na+].O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc2ccc(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cc1cccc2[nH]c(=O)ccc12
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2ccc(Cl)nc2c1
Temperature: 25 °C

Procedure:
A mixture of 18a and 18b (2.53 g, 15.9 mmol) was diluted in POCl3 (˜35 mL), and the mixture was heated at reflux for 70 min, before the clear orange solution was cooled to room temperature and poured into ice-H2O (300 mL) in a large beaker. The beaker was immersed in ice and cooled to 0° C. with stirring, and solid NaOH was added until the pH of the mixture was approximately 7. The resultant cloudy suspension was extracted with EtOAc (300 mL) and the organic layers were washed with H2O (100 mL) and sat. aq. NaCl (100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by flash column chromatography (SiO2), eluting with a gradient of hexanes to 12% ethyl acetate in hexanes to afford orange crystals. Fractional crystallization from hot isopropanol yielded pure 19a (0.850 g, 30%) as light orange iridescent crystals; the analytical data for this compound is identical to prior literature reports. H-NMR (500 MHz; CDCl3): δ 8.05 (d, J=8.5 Hz, 1 H), 8.00 (m, 1 H), 7.71 (d, J=8.3 Hz, 1 H), 7.39 (dd, J=8.3, 1.5 Hz, 1 H), 7.32 (d, J=8.5 Hz, 1 H), 2.56 (s, 3 H).