Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13]([N:17]=[C:18]=[O:19])[CH:14]=[CH:15][CH:16]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:9])([F:20])[F:21])[CH:12]=2)=[O:19])=[N:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 5-bromopyridin-2-yl amine (1.190 g, 6.88 mmol, 1.0 eq.) in THF (20 mL), add 3-trifluoromethylphenyl isocyanate (0.96 mL, 6.88 mmol, 1.0 eq.) in a drop-wise manner at room temperature. Stir the reaction mixture at room temperature for 30 minutes. Filter the solid and wash with MeOH (2×10 mL). Dry the solid to afford 1.81 g (5.0 mmol, 73%) of the title compound. MS (ES), m/z 360, 362 (M+1).
Reaction SMILES: C([Li])CCC.[C:6]([Si:10]([CH3:20])([CH3:19])[O:11][CH2:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:9])([CH3:8])[CH3:7].CN([CH:24]=[O:25])C>O1CCCC1>[Si:10]([O:11][CH2:12][CH2:13][C:14]1[S:15][C:16]([CH:24]=[O:25])=[CH:17][CH:18]=1)([C:6]([CH3:7])([CH3:9])[CH3:8])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccs1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5M in hexanes, 30 mL) was added dropwise to a solution of tert-butyldimethyl(2-(thiophen-2-yl)ethoxy)silane (example 4, step a) (16 g) in tetrahydrofuran (250 mL) at −78° C. The reaction mixture was allowed to warm to 0° C. and stirred for 1 h. The reaction was then cooled to −78° C. and DMF (34 mL) was added over 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with water, dried over sodium sulphate, filtered and the solvent evaporated in vacuo. Purification was by silica gel chromatography, eluting with 93:7 isohexane:ethyl acetate to give the subtitled compound as a colourless oil. Yield 15.4 g.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:13][CH2:14][CH2:15][CH3:16])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH2:18].[BH4-].[Na+].O>CO>[C:1]([C:5]1[C:6]([O:13][CH2:14][CH2:15][CH3:16])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH:18][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CCCOc1c(C=O)cccc1C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCOc1c(CNC)cccc1C(C)(C)C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
3-tert-Butyl-2-propoxy-benzaldehyde (1.15 g, 5.21 mmol) was dissolved in anhydrous methanol (25 ml). Methylamine (2.00 ml of 33% solution in ethanol, 16.1 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (25 ml). Sodium borohydride (198 mg, 5.23 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (30 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×50 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (3-tert-butyl-2-propoxy-benzyl)-methyl-amine (1.18 g, 96%) as a clear oil: 1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.97 (y J=8.0, y1H), 3.79 (t, J=4.0 Hz, 2H), 3.61 (s, 2H), 2.28 (s, 3H), 1.80-1.75 (m, 2H), 1.33 (s, 9H), 1.03 (t, J=8.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12]>C(Cl)(Cl)Cl>[CH3:8][C:9]([CH3:14])=[CH:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)=CC(=O)Nc1ccccc1
Yield: 91 %

Procedure:
To a stirred solution of 4.1 g (0.44 mol) of aniline in 200 ml of chloroform, at 25° C., was added slowly a solution of 25 g (0.21 mol) of 3-methylcrotonoyl chloride in 100 ml of chloroform. The reaction mixture was refluxed for 1.5 hours, and then the precipitate was removed by filtration. The chloroform solution was washed successively with 1N hydrochloric acid and saturated sodium bicarbonate solution, and then it was dried (MgSO4) and evaporated in vacuo. This gave 33.5 g (91% yield) of the title compound as a solid, mp 122°-125° C.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[CH2:20]([O:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])[CH3:21].CCN(C(C)C)C(C)C>>[CH2:20]([O:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH3:21]
Reactant: CCOc1ccccc1N
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1NC1=NC(=O)/C(=C/c2ccc3ncncc3c2)S1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, 2-ethoxyaniline and DIEA to give 2-(2-ethoxy-phenylamino)-5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 377 (MH+).
Reaction SMILES: Br.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH:21][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[S:19][CH:20]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccc(OCc3ccccc3)cc2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(OCc4ccccc4)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of 0.5 g of 4-(4-benzyloxy-phenyl)-thiazol-2-ylamine hydrobromide with 0.29 g of p-toluenesulfonyl chloride was stirred for 4 houtd with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted with methylene chloride. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.7 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid the mixture was concentrated and the residue was chromatographed on 100 g of Kieselgel 60 with diethyl ether as the eluent. The product-containing fractions were concentrated and, after recrystallization from ethyl acetate, yielded 0.22 g of N-[4-(4-benzyloxy-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:35][N:36]([CH:45]=[O:46])[O:37]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:35][N:36]([CH:45]=[O:46])[OH:37])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(NC(=O)[C@@H]2CCN(C(=O)OCc3ccccc3)N2C(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(NC(=O)[C@@H]2CCNN2C(=O)[C@H](CC2CCCC2)CN(O)C=O)nc1
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a solution of phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-{[(5-methyl-2-pyridinyl)amino]carbonyl}-1-pyrazolidinecarboxylate (combined from Part A, Batches 1 and 2, 142 mg, 0.226 mmol) in methanol (6 ml) was added 20% palladium hydroxide on carbon (70 mg, 0.226 mmol). The mixture was hydrogenated under balloon pressure for 1 h 30 min. and then filtered. The mixture was purified by reverse-phase HPLC to yield (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-(5-methyl-2-pyridinyl)-3-pyrazolidine carboxamide (68 mg, 0.170 mmol, 75% yield). LC/MS: (M+H)+: 404.0. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.06-1.26 (m, 2H) 1.35-1.48 (m, 1H) 1.48-1.69 (m, 4H) 1.69-1.99 (m, 4H) 2.17-2.31 (m, 3H) 2.45-2.64 (m, 1H) 2.80-3.01 (m, 1H) 3.16-3.31 (m, 1H) 3.51 (dd, J=14.02, 4.42 Hz, 1H) 3.66-3.84 (m, 2H) 3.95 (dt, J=9.35, 4.67 Hz, 1H) 4.70 (td, J=7.96, 4.04 Hz, 1H) 7.61 (dd, J=8.08, 2.02 Hz, 1H) 7.88 (s, 1H) 7.98 (d, J=8.34 Hz, 1H) 8.13 (d, J=2.27 Hz, 1H).
Reaction SMILES: [C:1]1([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:13]1[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][N:16]([CH2:25][CH2:26][CH2:27][NH:28][C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[CH:15]3[CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:10].[CH2:13]1[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][N:16]([CH2:25][CH2:26][CH2:27][N:28]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:15]3[CH2:14]1
Reactant: Cc1cccc(NCCCN2CCc3cccc4c3C2CC4)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N(CCCN2CCc3cccc4c3C2CC4)S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
Benzenesulfonyl chloride (48.6 mg, 0.28 mmol) was added to a solution of [3-(2,2a,4,5-Tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propyl]-m-tolyl-amine dihydro-chloride (43.0 mg, 0.11 mmol) and N,N′-diisopropylethylamine (2 ml) in CH2Cl2 (2 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 ml), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (20.0 mg, 36% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-])=O.[H][H]>C(O)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cccc(CCC(=O)O)c1

Procedure:
A suspension of 100 g (0.52 moles) of 3-nitrocinnamic acid in 800 ml glacial acetic acid and 100 ml of methanol was hydrogenated at 50 pounds per square inch over 2.5 g 10% palladium on carbon until four equivalents of hydrogen were absorbed. The catalyst was filtered off, the filtrates combined and the solvent was concentrated in vacuo leaving a brown glass of 3-aminobenzenepropanoic acid. To this was added 1 liter of ethanolic hydrochloric acid which was brought to reflux for five hours. The solvent was evaporated off in vacuo leaving a purple solid. Recrystallization from ethyl acetate yielded 88.0 g of ethyl 3-aminobenzenepropanoate hydrochloride, mp 132°-135° C., (74% yield).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)=[CH:22][CH:21]=1
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1
Yield: 21.1 %

Procedure:
The 4-[(phenylmethyl)oxy]-1H-indazole (D1) (543 mg, 1.65 mmol), the [4-(methyloxy)phenyl]boronic acid (500 mg, 3.29 mmol), copper (II) acetate (448 mg, 2.47 mmol), powdered molecular sieves (400 mg) and pyridine (0.27 mL, 3.29 mmol) in DCM (75 mL) were stirred at room temperature in the presence of air. After 4 hours the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM and the combined organics were washed with brine and dried over MgSO4. The crude (880 mg) was purified by flash chromatography (Biotage SP4) with a gradient of Et2O (0 to 30%) in hexane to afford 115 mg of title compound (D32).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:17])[S:13][C:14]=2[CH2:15][OH:16])[CH:5]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:17])[S:13][C:14]=2[CH2:15][O:16][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[CH:5]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1cccc(-c2nc(C)sc2CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nc(C)sc2COC2CCCCO2)c1

Procedure:
3-(5-Hydroxymethyl-2-methyl-thiazol-4-yl)-benzoic acid methyl ester (0.38 g), dihydropyrane (2.01 mL) and p-toluenesulfonic acid hydrate (0.21 g) in AcOEt (25 mL) was stirred at 20° C. for 1 h. The solution was diluted AcOEt, washed with 5% NaHCO3 solution and with brine, dried and evaporated. The residual oil was purified by chromatography on silica gel using AcOEt/hexane (1:3) as eluent to give 3-[2-methyl-5-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-benzoic acid methyl ester (3.8 g) as a pale-yellow oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[CH:18][C:19]=3[O:20][C:21](=[O:22])[C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH3:24][O:23][C:17]1[CH:16]=[CH:15][C:14]2[C:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=3[C:21](=[O:22])[O:20][C:19]=2[CH:18]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccccc1)CC3
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Yield: 48.2 %

Procedure:
A solution of 3-benzyl-8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one (8.2 g, 26 mmol) in 150 mL of methanol and 100 mL of tetrahydrofuran is hydrogenated at room temperature over a palladium on carbon catalyst (0.85 g) for 18 hours. The catalyst is filtered and the filtrate evaporated. Recrystallization of the residue from acetonitrile with a small amount of added water gives 2.9 g (49%) of product; mp 179°-181° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:6]1[C:2]([CH3:21])([CH3:1])[C:3](=[O:20])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:5]1=[O:7]
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 3-chlorobenzyl bromide (26 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 14 mg of white crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([CH2:16][OH:17])[N:13]=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2=[N:29][N:30]=[C:31]([C:32]3[CH:36]=[C:35]([CH3:37])[O:34][N:33]=3)[N:21]2[N:20]=1>>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([CH2:16][O:17][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3=[N:29][N:30]=[C:31]([C:32]4[CH:36]=[C:35]([CH3:37])[O:34][N:33]=4)[N:21]3[N:20]=2)[N:13]=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(CO)nn1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cn(CCO[Si](C)(C)C(C)(C)C)nn4)nn23)no1
Yield: 85.8 %

Procedure:
The reaction was carried out according to Example 1 step 4 using {1-[2-(tert-butyldimethylsilanyloxy)ethyl]-1H-[1,2,3]triazol-4-yl}methanol (1.67 g, 6.49 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (1.85 g, 6.49 mmol). The crude residue was purified by column chromatography on silica using 2-3% MeOH/CH2Cl2 containing 1% NH3 to yield the desired phthalazine (2.82 g, 86%). 1H NMR (400 MHz, CDCl3) δ 8.75-8.70 (2H, m), 8.23 (1H, d, J=8.5 Hz), 7.94 (1H, t, J=8.5 Hz), 7.80 (1H, t, J=8.5 Hz), 6.91 (1H, s), 5.79 (2H, s), 4.46 (2H, t, J=5.7 Hz), 3.99 (2H, t, J=5.2 Hz), 2.60 (3H, s), 0.67 (9H, s), −0.16 (6H, s). m/z (ES+) 507 (M+H+).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([C@@H:35]([CH3:38])[CH2:36][CH3:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([C@@H:35]([CH3:38])[CH2:36][CH3:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21)C(=O)N(C)C

Procedure:
With 3.98 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 63-2 (15.5 mmol, crude form) as starting materials, respectively 1.28 g (Isomer A, colorless powder) and 2.60 g (Isomer B, colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@@H:9]([NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][O:25]3)=[CH:18][CH:17]=1)[CH2:8][CH2:7]2)[CH:2]=C.CC([OH:33])C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[O:33]=[CH:2][CH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@@H:9]([NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][O:25]3)=[CH:18][CH:17]=1)[CH2:8][CH2:7]2
Reactant: C=CCc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reactant: CC(C)O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: O=CCc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reaction time: 14 h

Procedure:
A mixture of N-((S)-6-allyl-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (0.50 g), 2-propanol (50 ml) and water (50 ml) was admixed with sodium periodate (0.60 g) and osmium tetroxide (1.3 mg). After stirring vigorously for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and concentrated. The product was thus obtained with the molecular weight of 393.49 (C24H27NO4); MS (ESI): 394 (M+H+).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[Cl:12][CH2:13][C:14](Cl)=[O:15].C>C1C=CC=CC=1>[Cl:12][CH2:13][C:14]([N:6]1[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)CCl
Reaction time: 0.5 h

Procedure:
To a suspension of Example 54A (130 g, 0.72 mol, 1 equivalent) in benzene (3.9 L), chloroacetylchloride (81.1 g, 0.72 mol, 1 equivalent) was added dropwise at 20-25° C. The reaction mixture was refluxed for 5 hours. Then, charcoal (500 mg) was added, and the reaction mixture was hot filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. To this crude material, methyl tert-butyl ether (650 mL) was added, and the mixture was stirred for 30 minutes. The solid was collected by filtration, and the wet cake was dried in a vacuum tray dryer for 5 hours at about 50° C. to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.9-1.96 (m, 1H), 2.08-2.19 (m, 1H), 3.36 (d, 1H, J=14.4 Hz), 3.65 (s, 3H), 3.66 (m, 2H), 4.33 (s, 2H), 4.35 (m, 1H), 5.25 (bs, 1H); MS (ESI) m/z 222 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20](=[O:24])[N:19]([CH3:25])[CH:18]=2)=O)=[C:10]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)(C)(C)C.[C:35](O)(=[O:37])[CH3:36]>>[CH2:27]([N:26]1[C:10]2[CH:9]=[C:8]([NH:7][C:35](=[O:37])[CH3:36])[CH:13]=[CH:12][C:11]=2[N:14]=[C:15]1[C:17]1[CH:22]=[C:21]([CH3:23])[C:20](=[O:24])[N:19]([CH3:25])[CH:18]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(=O)O
Reactant: Cc1cc(C(=O)Nc2ccc(NC(=O)OC(C)(C)C)cc2NCc2ccccc2)cn(C)c1=O
Product: CC(=O)Nc1ccc2nc(-c3cc(C)c(=O)n(C)c3)n(Cc3ccccc3)c2c1
Temperature: 150 °C
Yield: 90 %

Procedure:
{3-Benzylamino-4-[(1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester I-9″ (4.000 g; 8.648 mmol) is suspended in acetic acid (5.190 g; 86 mmol) in a microwave vial and heated in the microwave at 150° C. for 1 h. The reaction mixture is then concentrated under reduced pressure. The residue is added to ice water, precipitation occurs. The precipitate is filtered off and dried under vacuum. The residue is used in the next step without further purification. (Yield: 90%, 3.000 g; 7.763 mmol)
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][NH:22][CH2:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].CN(C)C=O.C(N(CC)C(C)C)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>>[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][N:22]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(S(C)(=O)=O)CC3)cc1
Reaction time: 2 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea hydrochloride (0.1000 g, 0.2310 mmol) in dry N,N-Dimethylformamide (1.60 mL, 20.7 mmol) was added N,N-Diisopropylethylamine (0.161 mL, 0.924 mmol) followed by Methanesulfonyl chloride (0.0268 mL, 0.346 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.69 (s, 1H), 8.19 (d, J=8.7, 2H), 7.49 (d, J=8.8, 2H), 6.18 (t, J=5.5, 1H), 4.23 (dd, J=31.8, 14.8, 2H), 3.97-3.91 (m, 1H), 3.88 (d, J=11.3, 1H), 3.72 (dd, J=11.4, 2.7, 1H), 3.62 (dd, J=10.0, 7.5, 3H), 3.49-3.38 (m, 3H), 3.16-3.08 (m, 2H), 3.03 (s, 3H), 2.99 (t, J=6.3, 2H), 1.22 (d, J=6.6, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+475.2 (M+H)+.