Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:11]1[CH:12]=[C:13]([CH:25]=[O:26])[N:14]2[C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:17]=3[S:16][C:15]=12>C1COCC1>[C:5]1([CH2:4][CH2:3][CH:25]([C:13]2[N:14]3[C:15]([S:16][C:17]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]=43)=[N:11][CH:12]=2)[OH:26])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCc1ccccc1
Reactant: O=Cc1cnc2sc3c(n12)CCCCCC3
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(CCc1ccccc1)c1cnc2sc3c(n12)CCCCCC3
Yield: 77.7 %

Procedure:
Magnesium (0.29 g) in THF (70 mL) was treated with (2-bromoethyl) benzene (2.22 g) and the Grignard reagent was generated during 24 hours. Solid 5,6,7,8,9,10-Hexahydro-cyclooct[d]imidazo[2,1-b]thiazole-3-carboxaldehyde (Formula H-6) (0.70 g) was added, reacted for 2.5 hours and the supernate was decanted into 5% ammonium chloride solution. The precipitated 5,6,7,8,9,10-Hexahydro-α-(2-phenylethyl)cyclooct[d]imidazo-[2,1-b]-thiazole-3-methanol (Formula H-7) was extracted into ethyl acetate, the extracts were washed, dried, and evaporated to a viscous residue (1.51 g). Crystallization of the residue from acetonitrile solution provided pure 5,6,7,8,9,10-Hexahydro-α-(2-phenylethyl)cyclooct[d]imidazo-[2,1-b]thiazole-3-methanol (Formula H-7) (0.79 g), m.p. 123-124°.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C@H:16]([OH:17])[C@H:15]([Cl:18])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH2:4]1>CO.[Pd]>[ClH:18].[NH2:2][C@H:3]1[C@H:16]([OH:17])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH2:4]1
Reactant: N[C@@H]1Cc2ccc3ccccc3c2[C@@H](Cl)[C@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N[C@@H]1Cc2ccc3ccccc3c2C[C@H]1O
Yield: 90.5 %

Procedure:
A solution of (±)-(2R,3S,4R)-2-amino-4-chloro-1,2,3,4-tetrahydro-3-phenanthrenol hydrochloride (396 mg) in methanol (50 ml) was hydrogenated over 10% palladium on charcoal (109 mg) under atmospheric pressure at room temperature. When the theoretical amount of hydrogen was absorbed, the catalyst was filtered and the solvent evaporated under vacuum to give the title compound as a solid (315 mg).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][O:8][CH:7]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6]1)=[O:4].C1COCC1.[OH-].[Li+]>O>[C:12]([O:11][CH2:10][C@@H:7]1[O:6][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:9][O:8]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H]1COC(COC(=O)c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OC[C@H]1OC[C@H](C(=O)O)O1)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of methyl-2-(R, S)-benzoyloxymethyl-1,3-dioxolane-4-(R)-carboxylate, (411 g, 1.54 mmol, 1 eq., 2:1 mixture of cis and trans isomers) in a 1:1 mixture of THF and water, lithium hydroxide (64.8 g, 1.54 moles, 1 eq) was added portionwise over a period of 30 min., keeping the reaction flask temperature below 30° C. After 90 min., THF was removed by vacuum and the aqueous solution was acidified to pH 2.5-3.2, by dropwise addition of 30% (w/w) sulphuric acid. The resulting solution was extracted with dichloromethane (4×400 mL). The combined organic phase was washed with brine, dried over sodium sulphate and concentrated to produce 380 g of a dark oil. The isomers were separated by column chromatography on silica gel, using 2% acetic acid in dichloromethane to produce 220 g of the cis isomer (56.5%) and 116 g of the trans isomer (30%). Each of isomers was independently used for next step.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[CH:5]([OH:10])[C:6]([F:9])([F:8])[F:7].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>C1COCC1>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:10][CH:5]([C:6]([F:9])([F:8])[F:7])[C:4]([F:12])([F:11])[F:3])=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OC(C(F)(F)F)C(F)(F)F)nc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
2.45 g (61.2 mmol) of sodium hydride was introduced to 15 ml of THF and cooled to 5° C., and then 10.6 g of 1,1,1,3,3,3-hexafluoro-2-propanol was added dropwise thereto. The resulting solution was stirred at 5° C. for 30 minutes, and then 5.0 g of 2-chloro-5-nitropyridine dissolved in 10 ml of THF was added dropwise thereto and stirred at room temperature for 3 hours. The reaction solution was allowed to stand at room temperature for 3 days, the water was added thereto, and the mixture was extracted with ethyl acetate and then washed with saturated salt water. The resultant was dried over anhydrous magnesium sulfate, and then the solvent was removed under a reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography (n-hexane AcOEt=10:1) to obtain 8.4 g of the desired product (Yield: 92%) as yellow oil.
Reaction SMILES: C([NH:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][C:17]([C:19]([O:21]C)=[O:20])=[CH:18][C:5]1=2)=O.O1CCOCC1.[ClH:29]>O>[ClH:29].[NH2:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:5]1=2
Reactant: COC(=O)c1ccc2c(c1)C(NC=O)c1ccccc1CO2
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC1c2ccccc2COc2ccc(C(=O)O)cc21

Procedure:
Heat together 340 mg. of methyl 6,11-dihydro-11-formamidodibenz[b,e]oxepin-2-carboxylate, 10 ml. of dioxane and 10 ml. of concentrated hydrochloric acid at 100° C. for 5 hours. Strip to dryness and dissolve the residue in water and pass through a Bio-Red AG-50W-X8 resin (sulfonic acid type). Collect the acid by elution with 10% ammonium hydroxide solution. Evaporate to dryness, dissolve the residue in tetrahydrofuran and acidify with aqueous hydrochloric acid. Strip to dryness and recrystallize from methanol/ether to obtain the title product (m.p. 245° dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.Cl.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:28]1([C:18]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:26]3[CH:22]([CH2:23][N:24]([C:8](=[O:10])[CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccnc3)CC12
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
N,N'-Carbonyldiimidazole (0.81 g) is added to a solution of 2-(3-pyridyl)acetic acid (0.685 g) in dry dichloromethane (15 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.6 g) and triethylamine (0.7 cc) in dichloromethane (10 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in a mixture of ethyl acetate (100 cc) and water (75 cc). The organic phase is washed with saturated sodium chloride solution (50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a basic alumina column (diameter 2 cm, height 15 cm), eluting with ethyl acetate and collecting 50 cc fractions. Fractions 4 to 24 are concentrated to dryness under reduced pressure (2.7 kPa). The crystals obtained are recrystallized from acetonitrile (cc) to give (3aRS,7aRS)-7,7-diphenyl-2-[2-(3-pyridyl)acetyl]-4-perhydroisoindolone (0.9 g) in the form of white crystals melting at 208° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([CH:10]([NH:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:41])OC4C=CC=CC=4)[CH:27]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)=[O:15])[CH2:11][CH3:12])[CH3:9].C(C(NC(N1C2C(=CC(OC3C=CN=C(NC(N4CCC(N5CCCC5)CC4)=O)C=3)=CC=2)C=C1)=O)CC)C>CN(C)C=O>[CH2:11]([CH:10]([NH:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:41])[CH:27]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)=[O:15])[CH2:8][CH3:9])[CH3:12]
Reactant: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Reactant: OC1CCNCC1
Agent: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(O)CC4)c3)ccc21
Reaction time: 2 h
Yield: 29.6 %

Procedure:
N,N-Dimethylformamide (4 ml) and 4-hydroxypiperidine (360 mg, 3.56 mmol) were added to a mixture (456 mg) of phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-carbamate and phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate synthesized in Example 96; and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=10:1) to yield the title compound as white crystals (1.37 mg, 0.294 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:18](Cl)([CH3:21])([CH3:20])[CH3:19].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:18]([C:10]1[CH:9]=[C:8]2[C:17]3=[C:16]4[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[C:15]4=[CH:14][CH:13]=[C:12]3[CH:11]=1)[CH:6]=[CH:7]2)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc2ccc3cccc4ccc1c2c34
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2ccc3cc(C(C)(C)C)cc4ccc1c2c34
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
Next, a mixed solution of 4.4 g of 1-methylpyrene, 2 g of t-butylchloride and 33 ml of dichloromethane was cooled to 0° C. under a nitrogen gas stream and then 2.7 g of aluminum chloride was added. This mixed solution was stirred at room temperature for 3 hours and 30 ml of water was poured into the solution, followed by extraction with 30 ml of dichloromethane. The organic layer was washed twice with 20 ml of water, dried over magnesium sulfate and then evaporated. The concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 3 g of 7-t-butyl-1-methylpyrene.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][O:14][CH2:15]Cl)=[CH:11][CH:10]=1.[Cl:19][C:20]1[CH:21]=[N:22][C:23](=[O:26])[NH:24][CH:25]=1.C(N(CC)CC)C>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][O:14][CH2:15][N:24]2[CH:25]=[C:20]([Cl:19])[CH:21]=[N:22][C:23]2=[O:26])=[CH:11][CH:10]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCOCc1ccc(COC2CCCCO2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(Cl)cn1COCc1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Chloromethyl 4-(tetrahydropyran-2-yloxymethyl)benzyl ether (see Preparation 12) (4.7 mmol) in dichloromethane (40 ml) was added dropwise with stirring to a solution of 5-chloropyrimidin-2-one (4.7 mmol) and triethylamine (4.7 mmol) in dichloromethane (10 ml). The mixture was stirred at room temperature for 2 hours and was then washed with water, the organic solution dried (MgSO4) and the solvent distilled off to yield a crude product in 89% yield (1.53 g), which was extracted with ether and the residual material purified on neutral alumina eluting with dichloromethane and subsequently with 10% MeOH in dichloromethane; yield 0.42 g (26%) of the non-crystalline title compound. 1H NMR (CDCl3): δ1.4-2.0 (6H, m, THP), 3.3-4.3 (2H, m), 4.5-4.9 (2CH2, CH), 5.37 (NCH2), 7.38 (Ph), 7.88 and 8.53 (H-4, H-6, J 4 Hz).
Reaction SMILES: CS(O)(=O)=O.[O:6]=[C:7]1[N:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:19][C:11]2[C:12]3[CH:13]=[N:14][NH:15][C:16]=3[CH:17]=[CH:18][C:10]=2[CH2:9][C@H:8]1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.[C:45](OC(=O)C)(=[O:47])[CH3:46].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:45]([N:24]1[CH2:25][CH2:26][CH:21]([N:20]2[C:7](=[O:6])[C@H:8]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:9][C:10]3[CH:18]=[CH:17][C:16]4[NH:15][N:14]=[CH:13][C:12]=4[C:11]=3[CH2:19]2)[CH2:22][CH2:23]1)(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(C2CCNCC2)C1=O)OCc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)OCc3ccccc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
(R)-benzyl 8-oxo-9-(piperidin-4-yl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate methanesulfonate (100 mg, 0.19 mmol) was dissolved in a mixture of dichloromethane (4 mL) and triethylamine (500 μL, 3.6 mmol). Acetic anhydride (500 μL, 5.3 mmol) was added to the mixture. Reaction stirred at room temperature overnight. Reaction mixture was washed successively 1× water, 2×1N hydrochloric acid, 2×1N sodium hydroxide, and 1× brine. Organic was dried (magnesium sulfate), and filtered. Filtrate was concentrated in vacuo. Residue was treated with methanol (3 mL). Potassium carbonate (40 mg, 0.29 mmol) was added to the mixture. Reaction stirred at room temperature for 2 hours. Reaction was quenched with 1N hydrochloric acid (6 mL). Methanol was removed from the mixture in vacuo. Remaining aqueous mixture was made basic with sodium bicarbonate. Mixture was extracted with ethyl acetate. Organic layer was dried (magnesium sulfate), filtered and concentrated. Title compound was obtained as yellow solid in 43% yield. MS m/e (M+H)+=476.
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@H:35]([CH3:39])[CH2:36][NH:37][CH3:38])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@H:35]([CH3:39])[CH2:36][N:37]([CH3:38])[C:5]([C:2]3([OH:1])[CH2:4][CH2:3]3)=[O:7])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C(O)C1(O)CC1
Product: C[C@H](CN(C)C(=O)C1(O)CC1)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 19 %

Procedure:
The procedure described in Example 1 was repeated using hydroxy-1-cyclopropane carboxylic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 2.3, preparation of starting materials) to give the title compound as a foam in 19% yield; NMR spectrum (DMSO-d6) 0.70 (s, 4H), 1.40 (d, 3H), 3.23 (s, 3H), 3.36 (m, 1H), 4.19 (m, 1H), 5.15 (m, 1H), 5.29 (s, 2H), 6.20 (s, 1H), 7.24 (m, 2H), 7.35 (m, 2H), 7.58 (m, 2H), 7.71 (t, 1H), 7.87 (dt, 1H), 8.09 (d, 1H), 8.44 (s, 1H), 8.58 (d, 1H), 9.86 (s, 1H); Mass spectrum MH+ 534.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH2:14])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:26]1[N:27]=[N:28][C:29]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:30]([NH:32][C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[CH:36][N:37]3[CH3:42])[N:31]=1>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][C:26]1[N:27]=[N:28][C:29]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:30]([NH:32][C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[CH:36][N:37]3[CH3:42])[N:31]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1nnc(Cl)nc1Nc1cccc2c1ccn2C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc2c1ccn2C

Procedure:
Tert-butyl((1S,2R)-2-aminocyclohexyl)carbamate (302 mg) and diisopropylethylamine (0.40 ml) were added successively to a solution of ethyl 3-chloro-5-(1-methyl-1H-indol-4-ylamino)-1,2,4-triazine-6-carboxylate (390 mg) obtained in the above-described Step 1 in THF (10 ml), and the reaction solution was allowed to react at 70° C. for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with an aqueous sodium bicarbonate solution and a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum, and the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain ethyl 3-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-(1-methyl-1H-indol-4-ylamino)-1,2,4-triazine-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][CH:5]([CH3:9])[NH:4][C:3]1=[N:10]C(=O)[O-].[C:14](O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:9]([CH:5]1[NH:4][C:3](=[NH:10])[N:2]([CH3:1])[C:7](=[O:8])[CH2:6]1)[CH3:14]
Reactant: O=C(O)C(F)(F)F
Reactant: CC1CC(=O)N(C)C(=NC(=O)[O-])N1
Solvent: ClCCl
Product: CCC1CC(=O)N(C)C(=N)N1

Procedure:
(S)-tert-butyl 4-(3-3-chloro-6-hydroxyphenyl)phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF3; R1═R6=Me, R21=3-chloro-6-hydroxyphenyl) (23 mg, 0.05 mmol) was treated with 1 mL of 30% TFA/CH2Cl2 at RT for 30 min. The volatiles were removed in vacuo. The residue was redissolved in acetonitrile (5 mL) and evaporated again to afford 17 mg of the crude product as a yellow solid. The crude product was purified via reverse phase HPLC to provide 10 mg (60%) of (S)-6-(3-3-chloro-6-hydroxy-phenyl)phenyl)-6-ethyl-2-imino-3-methyl-tetrahydropyrimidin-4 (1H)-one (CF4; R1═R6=Me, R21=3-chloro-6-hydroxyphenyl) as a white solid. 1HNMR (CDCl3, 300 MHz): 11.4 (br s, 1H), 7.6-4.25 (m, 3H), 7.24-6.84 (m, 3H), 3.68 (br s, 1H), 5.18 (br s, 1H), 3.39 (d, J=16.1 Hz, 1H), 3.20 (s, 3H), 2.95 (d, J=15.8 Hz, 1H), 1.74 (s, 3H). MS (ESI): MH+=344.1. HPLC (A) Rt=5.07 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11](=[O:37])([S:13][CH2:14][CH2:15][C@H:16]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:18])[CH3:12]>C(Cl)Cl>[C:11](=[O:37])([S:13][CH2:14][CH2:15][C@H:16]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:17](=[O:18])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[O:25])[CH3:12]
Reactant: CC(=O)SCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)SCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCCC=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
To a solution of oxalyl chloride (2 M solution in DCM, 0.093 mL, 1.1 mmol) in DCM (1.5 mL) cooled to −78° C. was added DMSO (0.150 mL, 2.12 mmol) dropwise followed by a solution of (S)—S-3-(benzyloxycarbonylamino)-4-(5-hydroxypentylamino)-4-oxobutyl ethanethioate (300 mg, 0.757 mmol) in DCM (3 mL). After the addition, the resulting solution was stirred at −78° C. for 45 min. Then, TEA (0.464 mL, 3.33 mmol) was added. The mixture was stirred at −30° C. to −35° C. for 1 hr. The reaction was quenched with addition of EtOAc and 5% of aqueous KHSO4. The separated organic layer was washed with 5% aqueous KHSO4, water, saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (S)—S-3-(benzyloxycarbonylamino)-4-oxo-4-(5-oxopentylamino)butyl ethanethioate (200 mg, 0.507 mmol, 67.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.76 (s, 1H), 7.45-7.28 (m, 5H), 6.42 (s, 1H), 5.53 (d, J=6.6 Hz, 1H), 5.12 (s, 2H), 4.13 (d, J=6.7 Hz, 1H), 3.28 (dd, J=12.9, 6.4 Hz, 2H), 2.97 (dd, J=14.2, 7.1 Hz, 1H), 2.91-2.76 (m, 1H), 2.48 (dd, J=10.0, 3.8 Hz, 2H), 2.34 (s, 3H), 2.12 (td, J=14.0, 6.3 Hz, 1H), 1.91 (dt, J=14.3, 7.3 Hz, 1H), 1.74-1.47 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:20])=[CH:5][C:6]([CH2:12][CH:13]([C:17](=O)[CH3:18])[C:14](=O)[CH3:15])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2.[NH:21]([CH2:23][CH2:24][OH:25])[NH2:22].C(O)(=O)C>C(O)C.C(OCC)C>[CH3:1][O:2][C:3]1[C:4]([CH3:20])=[CH:5][C:6]([CH2:12][C:13]2[C:17]([CH3:18])=[N:22][N:21]([CH2:23][CH2:24][OH:25])[C:14]=2[CH3:15])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2
Reactant: COc1c(C)cc(CC(C(C)=O)C(C)=O)c2c1CCC2
Reactant: NNCCO
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: COc1c(C)cc(Cc2c(C)nn(CCO)c2C)c2c1CCC2
Temperature: 70 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
To a stirred solution of 3-(7-Methoxy-6-methyl-indan-4-ylmethyl)-pentane-2,4-dione (1.0 gm 0.0036 mole) in Ethanol (15 ml), a solution of 2-Hydrazino-ethanol (0.33 gm, 0.0043 mole) in Ethanol (5 ml) was added at 25-30° C. and reaction mixture was heated to 70° C. for an hour. The Acetic acid (2 ml) was added. Further the reaction mixture was stirred at 70° C. for 3 hours. Ethanol was distilled under vacuum to give a residue which was partitioned between Ethyl acetate (50 ml) and water (25 ml). Ethyl acetate was distilled under vacuum to give a crude product The crude product was solidified after stirring in Diethyl ether (10 ml). The solid was filtered under vacuum and dried to give a 700 mg of desired compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:26]=[C:21]([O:20][CH3:19])[CH:22]=[CH:23][C:24]=3[O:27][CH3:28])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: COc1ccc(OC)c(B(O)O)c1
Product: COc1ccc(OC)c(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)c1
Yield: 84 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2,5-dimethoxyphenylboronic acid (118 mg, 0.65 mmol) were reacted. After purification the title compound (101 mg, 85% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (bm, 1H), 7.85 (a dd, J=2.2, 7.6 Hz, 1H), 7.73 (m, 2H), 6.95 (m, 2H), 6.91 (m, 1H), 3.77 (s, 3H), 3.63 (s, 3H), 2.96 (m, 1H), 0.88 (m, 2H), 0.65 (m, 2H). MS APCI, m/z=365, HPLC 2.42 min.
Reaction SMILES: CS(O)(=O)=O.OO.[Cl:8][C:9]1[CH:44]=[CH:43][CH:42]=[CH:41][C:10]=1[CH2:11][N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]([CH3:24])[C:15]=2[C:14](C=O)=[C:13]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28]1.S([O-])([O-])=[O:46].[Na+].[Na+]>CO>[Cl:8][C:9]1[CH:44]=[CH:43][CH:42]=[CH:41][C:10]=1[CH2:11][N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]([CH3:24])[C:15]=2[C:14]([OH:46])=[C:13]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])[CH2:28]1
Reactant: Cn1c(=O)c2c(c(C=O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reactant: O=S([O-])[O-]
Agent: CS(=O)(=O)O
Agent: OO
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)c2c(c(O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonic acid (21 μl) and a 30% aqueous hydrogen peroxide solution (54 μl) were added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-formyl-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (132 mg) in methanol (4 ml), and the resulting mixture was stirred at room temperature for 2 hours. A 10% aqueous sodium sulfite solution was added to the reaction solution, followed by extraction with ethyl acetate (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain the title compound (54 mg).