Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si](C)(C)C.C([BH3-])#N.[Na+].[CH:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:21]3[S:22][C:23]([CH3:66])=[CH:24][C:25]=3[O:26][C@@H:27]3[CH2:32][C@H:31]([CH2:33][O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C@@H:30]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C@H:29]([O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C@H:28]3[O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1.C(Cl)Cl>C(#N)C>[CH:10]1([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][C:21]3[S:22][C:23]([CH3:66])=[CH:24][C:25]=3[O:26][C@@H:27]3[CH2:32][C@H:31]([CH2:33][O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C@@H:30]([O:42][CH2:43][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C@H:29]([O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C@H:28]3[O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:17][CH:18]=2)[CH2:11][CH2:12]1
Reactant: Cc1cc(O[C@@H]2C[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(C(=O)c2ccc(C3CC3)cc2)s1
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc(O[C@@H]2C[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(Cc2ccc(C3CC3)cc2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
In a nitrogen stream, chlorotrimethylsilane (0.46 mL, 3.56 mmol) and sodium cyanoborohydride (230 mg, 3.65 mmol) were added to an solution of (4-cyclopropylphenyl)-[5-methyl-3-((1R,2S,3S,4R,5R)-2,3,4-trisbenzyloxy-5-benzyloxymethylcyclohexyloxy)thiophen-2-yl]methanone (237 mg, 0.30 mmol) in acetonitrile (5 mL) under cooling with ice and the reaction mixture was stirred at 0° C. for one hour. Methylene chloride was added thereto and the mixture was subjected to Celite filtration, and the solvent of the filtrate was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (135 mg, 58%).
Reaction SMILES: CC1(C)COC([C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:40]3[CH:45]=[CH:44]C=[CH:42][CH:41]=3)([O:30][CH2:31][CH2:32][O:33]C3CCCCO3)[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][O:23]C4CCCCO4)[CH:15]=3)=[CH:9][CH:8]=2)=N1.[OH-].[Na+].CCO.[C:52]([OH:55])(=[O:54])[CH3:53]>>[OH:33][CH2:32][CH2:31][O:30][C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][OH:23])[CH:15]=1)([C:10]1[CH:9]=[CH:8][CH:7]=[CH:12][CH:11]=1)[C:40]1[CH:45]=[CH:44][C:53]([C:52]([OH:55])=[O:54])=[CH:42][CH:41]=1
Reactant: CC1(C)COC(c2ccc(C(OCCOC3CCCCO3)(c3ccccc3)c3cccc(OCCOC4CCCCO4)c3)cc2)=N1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(OCCO)(c2ccccc2)c2cccc(OCCO)c2)cc1

Procedure:
A solution of 4 (360 mg) in 3 mL of 80% aqueous acetic acid was heated at 75° C. for 12 h. Then the solution was evaporated and the residue obtained was refluxed with 20% NaOH/EtOH (1:1, v/v, 3 mL) for 2 h. The solvent was removed and 10 mL of ice cooled water was added to the residue and the aqueous solution was acidified with 1N HCl. The precipitated yellow solid was filtered and washed several times with water and dried under high vacuum. Yield: 270 mg (100%, quantitative).
Reaction SMILES: [Cl:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[CH:16]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][C:17]=1[OH:26]>>[ClH:1].[C:14]([C:11]1[CH:12]=[CH:13][C:8]([CH:2]([O:26][C:17]2[CH:18]=[CH:19][C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=3[CH:16]=2)[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])=[CH:9][CH:10]=1)#[N:15]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: CN(C)CCC(Cl)c1ccc(C#N)cc1
Product: CN(C)CCC(Oc1ccc2c(c1)CCCC2)c1ccc(C#N)cc1
Product: Cl

Procedure:
(Compound 25) was subsequently prepared by treating (compound 26) with 5,6,7,8-tetrahydro-2-naphthol as described for the preparation of (compound 3). Reflux time 2 days. M.p. 132° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccccc3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2cc(-c3ccccc3)no2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A mixture of methyl 4-(3-phenyl-5-isoxazolyl)benzoate (1.70 g), 1 M aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (30 ml) and methanol (30 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (10 ml) was added. The crystals were collected by filtration and recrystallized from N,N-dimethylformamide-water to give 4-(3-phenyl-5-isoxazolyl)benzoic acid (1.56 g, yield 97%) as colorless crystals. melting point: >300° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:6]2.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:6]2
Reactant: COC(=O)C1Cc2ccc(OC)cc2C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C1Cc2ccc(O)cc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 5-methoxy-2,3-dihydro-1h-indene-2-carboxylate (696) (2.35 g, 11.4 mmol) in anhydrous dichloromethane (40 mL) cooled to −78° C. was added boron tribromide (1.5 eq.). The reaction was allowed to stir at −78° C. for 30 minutes, 0° C. for 2 hours, and at room temperature overnight. The reaction mixture was cooled to 0° C. and quenched slowly with methanol. After stirring for 15 minutes a saturated sodium bicarbonate solution was added slowly to the mixture and allowed to stir at 0° C. for 30 minutes. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford methyl 5-hydroxy-2,3-dihydro-1H-indene-2-carboxylate (697).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH:17]2[NH:1][C:2]3[CH:7]=[C:6]([Cl:8])[C:5]([S:9](=[O:11])(=[O:12])[NH2:10])=[CH:4][C:3]=3[S:13](=[O:15])(=[O:14])[NH:16]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Product: NS(=O)(=O)c1cc2c(cc1Cl)NC(c1ccccc1)NS2(=O)=O

Procedure:
2-Amino-4-chloro-5-sulfamoylbenzenesulfonamide was transformed by Method G (using benzaldehyde). M.p. 235–238° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10](C=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)Br.[OH-:19].[K+].[O:21]1[CH2:26][CH2:25][O:24][CH2:23]C1.CO>CO>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([CH:25]([O:24][CH3:23])[C:26]([OH:21])=[O:19])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccn(Cc2ccccc2)n1
Reactant: C1COCCO1
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: BrC(Br)Br
Product: COC(C(=O)O)c1ccn(Cc2ccccc2)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Benzyl-1H-pyrazole-3-carbaldehyde (1.55 g, CAS 321405-31-6) and bromoform (0.94 ml) were dissolved under an argon atmosphere in dioxane/MeOH 1:1 (40 ml) and cooled to 0° C. A solution of KOH (2.31 g) in MeOH (20 ml) were added over a period of 20 min. The reaction was warmed to r.t. and stirred overnight. The reaction mixture was concentrated to one third of the volume, then taken up in water and washed with EtOAc. The aqueous layer was brought ot pH 1 with HCl, then extracted with EtOAc. The organic layer was washed with brine and concentrated to give crude (RS)-(1-benzyl-1H-pyrazol-3-yl)-methoxy-acetic acid (1.41 g). Yellow oil. MS 245.1 ([M−H]−)
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[NH2+:12].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[Cl:26][CH:27]([Cl:32])[C:28](OC)=O.C(=O)([O-])[O-].[K+].[K+]>CCO>[Cl:26][CH:27]([Cl:32])[C:28]1[N:12]=[C:3]2[CH:4]=[CH:5][C:6]3[C:11]([N:2]2[N:1]=1)=[CH:10][CH:9]=[CH:8][N:7]=3
Reactant: Nn1c(=[NH2+])ccc2ncccc21
Reactant: COC(=O)C(Cl)Cl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: ClC(Cl)c1nc2ccc3ncccc3n2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
A suspension of 1-amino-1,5-naphthyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate (crude product from the previous step, 3.0 mmol), methyl 2,2-dichloroacetate (0.86 g, 6.0 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in EtOH (30 mL) was stirred at 80° C. for 16 h. After cooled to room temperature, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluting with 2% v/v MeOH in DCM) to give the title compound as a purple solid (300 mg, yield 39%). ESI MS: m/z 253, 255 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8](=[NH:16])[CH:9](OCC)OCC)=[CH:4][CH:3]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:18]=[C:17]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[N:7][C:8]([NH2:16])=[CH:9]2
Reactant: CCOC(OCC)C(=N)NCc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2cc(Br)ccc2cn1
Yield: 40.1 %

Procedure:
N-(4-bromobenzyl)-2,2-diethoxyacetimidamide (1.53 g, 4.85 mmol) in sulfuric acid (4 mL, 95-98%) was heated at 40 C for 14 h. The mixture was neutralized with 1M NaOH to pH 7 and the resulting suspension was filtered. The residue was purified by silica gel chromatography with 20-55% ethyl acetate in hexanes. The desired fractions were concentrated to give a brownish yellow solid (0.434 g, 40%). LCMS:R.T.=1.62; [M+2]+=225.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[O:27]=[C:28]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][C:30](=[O:39])[N:29]1[CH2:40][CH2:41][CH2:42][CH2:43][NH2:44]>ClCCl>[O:27]=[C:28]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][C:30](=[O:39])[N:29]1[CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1C(=O)C=C(c2ccccc2)C1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)C=C(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
2.7 g (17.8 mmol) 3-(3-pyridyl)-acrylic acid and 1.8 g (17.8 mmol) TEA are suspended in 50 ml abs. dichloromethane and cooled to ca. 0° C. under moisture exclusion. 3.1 g (17.8 mmol) 88% HOBT and 3.4 g (17.8 mmol) EDC are added and the mixture is stirred for 30 min under ice cooling. 5.0 g (17.8 mmol) 4-(2,5-dioxo-3-phenyl-2,5-dihydropyrrol-1-yl)-butylamine hydrochloride are dissolved in 30 ml abs. dichloromethane and added dropwise under ice cooling. The mixture is stirred overnight at RT without further cooling. Subsequently, the batch is washed with 25 ml 1M NaOH and with 50 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The resinous residue is chromatography pre-purified over silica gel with CHCl3/CH3OH (95/5) and further purified by flash chromatography with CHCl3/CH3OH (95/5). After withdraw of the solvent, this is crystallized from acetic acid ethyl ester: Colorless crystals with MP. 141–143° C.; Yield 0.6 g (9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[CH:5][C:4]=1[NH2:16].CS([C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1)=O.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[CH:5][C:4]=1[NH:16][C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1
Reactant: COc1cc(N2CCN(C)CC2)ncc1N
Reactant: CS(=O)c1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cc(N2CCN(C)CC2)ncc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Temperature: 85 °C
Yield: 76.9 %

Procedure:
4-Methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-amine (8a; 1.22 g, 5.49 mmol), tert-butyl (3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (52; 1.40 g, 3.50 mmol) were treated with tert-butanol (20 mL) and DIEA (1.53 mL, 8.74 mmol) and heated to 85° C. overnight (20 h) in a 250 mL round-bottomed flask with a reflux condenser. The reaction mixture was concentrated on the rotovap and the crude solid was suspended in Et2O and filtered affording the crude tert-butyl (3-(24(4-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (8b; 1.50 g, 2.69 mmol, 77% yield) as a brownish-yellow amorphous solid. m/z (ESI, +ve ion) 559.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.48 (1H, br. s.), 8.65 (1H, br. s.), 8.54 (1H, s), 7.86 (1H, d, J=9.4 Hz), 7.82 (1H, s), 7.43 (1H, d, J=8.0 Hz), 7.37 (2H, br. s.), 6.81 (1H, br. s.), 6.38 (1H, d, J=9.4 Hz), 6.29 (1H, br. s.), 3.73 (3H, s), 3.45 (4H, br. s.), 2.40 (4H, br. s.), 2.24 (3H, s), 1.47 (9H, s).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:19])[CH2:8]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:20]([CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:19])[CH2:8]1)=[N+:21]=[N-:22]
Reactant: CS(=O)(=O)OCC1CCN(c2ccccc2)C(=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1CCN(c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2-oxo-1-phenylpiperidin-4yl)methyl methanesulfonate (0.37 g, 1.3 mmol) was dissolved in dimethylsulfoxide (6 mL), treated with sodium azide (0.18 g, 2.8 mmol, 2.1 equiv) and placed into a preheated oil bath at 60° C. for 18 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate (50 mL) and washed twice with water (50 mL) and brine (50 mL). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:30]([CH3:32])[CH3:31])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2Br)[N:8]=1)=[O:6].[C:33]1(B(O)O)[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=1.C(OC(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=C(OC)C=CC=2C2C=CC=CC=2)N=1)=O)(C)(C)C>>[OH:1][CH2:2][CH2:3][N:4]([CH:30]([CH3:32])[CH3:31])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=2)[N:8]=1)=[O:6]
Reactant: OB(O)C1=CCCCC1
Reactant: CC(C)N(CCO)C(=O)c1nc(Cc2ccccc2Br)nc(O)c1OCc1ccccc1
Agent: COc1ccc(-c2ccccc2)c(Cc2nc(O)c(OCc3ccccc3)c(C(=O)OC(C)(C)C)n2)c1
Product: CC(C)N(CCO)C(=O)c1nc(Cc2ccccc2C2=CCCCC2)nc(O)c1OCc1ccccc1
Yield: 41.9 %

Procedure:
5-Benzyloxy-2-(2-cyclohex-1-enyl-benzyl)-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (155) (210 mg, 41.9%) as a colorless sticky liquid was synthesized from 5-benzyloxy-2-(2-bromobenzyl)-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (151) (500 mg, 0.999 mmol) and cyclohexene boronic acid (188.84 mg, 1.49 mmol) following the procedure as described for 5-benzyloxy-6-hydroxy-2-(4-methoxy-biphenyl-2-ylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (139).
Reaction SMILES: CS([CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[C:10]2[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=2[S:8]1)(=O)=O.[CH3:36][NH2:37]>O1CCCC1>[CH3:36][NH:37][CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:31])[C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:19][CH:20]=2)[C:10]2[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=2[S:8]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2C=CC(CCS(C)(=O)=O)Sc3ccccc32)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc2S1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Compound 13 as prepared in Example 10 (0.045 g, 0.08 mM) and methylamine (40% solution in water; 1 ml) in tetrahydrofuran (4 ml) was heated in a sealed tube with stirring in an 80° C. oil bath for 16 hours. The mixture was cooled to room temperature, evaporated to dryness, diluted with water (30 ml) and extracted with ethyl acetate (2×35 ml). The combined ethyl acetate extracts were dried (MgSO4) and evaporated in vacuo to give a crude mixture. Purification by chromatography (EM silica Gel 60; 10% EtOAc in CH2Cl2) gave the product as a white solid. m/z (MH+)460.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:10][C:11]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:10][C:11]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)CCc1oc(Sc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1oc(Sc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
A mixture of methyl 3-[2-(4-hydroxyphenylthio)-4-phenyl-5-oxazolyl]propionate (450 mg), 4-chloromethyl-5-methyl-2-phenyloxazole (263 mg), potassium carbonate (351 mg) and N,N-dimethylformamide (5 ml) was stirred at 50° C. for 3 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-oxazolyl]propionate (609 mg, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][CH:6]=1.C(O)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:19][CH3:20]>>[CH3:3][O:4][C:5]1[N:10]=[N:9][C:8]([C:11](=[O:13])[CH:19]([CH3:20])[C:18]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC
Reactant: COC(=O)c1ccc(OC)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)C(=O)c1ccc(OC)nn1
Yield: 52.5 %

Procedure:
Ethyl 3-(6-methoxypyridazin-3-yl)-2-methyl-3-oxopropionate is prepared by the fractional addition, over a period of 20 minutes, of sodium hydride (19.2 g) (50% in mineral oil) to a solution of methyl 6-methoxypyridazine-3-carboxylate (50 g) in ethyl propionate (220 g) at a temperature of about 98° C. The reaction mixture is maintained under reflux for a further 30 minutes. It is subsequently cooled to a temperature of about 20° C., and ethanol (10 cc) is added with care, followed by distilled water (800 cc). The aqueous phase is removed, washed by decantation with diisopropyl ether (3 × 250 cc), pure acetic acid (250 cc) is added (pH = 5-6) and the aqueous phase is washed again with ethyl acetate (3 × 150 cc). The organic phase are combined, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (30 mm Hg) to give ethyl 3-(6-methoxypyridazin-3-yl)-2-methyl-3-oxopropionate (37.2 g) in the form of a yellow oil.
Reaction SMILES: C(O)=O.[Cl:4][C:5]1[C:13]([CH3:14])=[N:12][C:11]2[N:7]([N:8]=[C:9]3[CH2:17][N:16]([C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][C@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:19])[CH2:15][C:10]3=2)[C:6]=1[CH3:33].[O:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:4][C:5]1[C:13]([CH3:14])=[N:12][C:11]2[N:7]([N:8]=[C:9]3[CH2:17][N:16]([C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][C@H:28]4[CH2:32][CH2:31][N:30]([CH:37]5[CH2:38][CH2:39][O:34][CH2:35][CH2:36]5)[CH2:29]4)=[O:19])[CH2:15][C:10]3=2)[C:6]=1[CH3:33]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@H]1CCNC1)C3
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=CO
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@H]1CCN(C2CCOCC2)C1)C3
Yield: 55.6 %

Procedure:
A mixture of Example 83 (150 mg; 0.35 mmol; 1 eq.), tetrahydropyran-4-one (52 mg; 0.52 mmol; 1.5 eq.) and sodium triacetoxyborohydride (74 mg; 0.35 mmol; 1 eq.) in DCE (4 mL) was stirred at 50° C. for 16 hours. The reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to EA/MeOH/TEA, 90/10/2) afforded the title compound (100 mg, 56%) as white foam. 1H NMR (DMSO-d6) δ 7.41-7.30 (m, 1H), 6.99 (dd, J=11.5, 2.2 Hz, 1H), 6.87 (td, J=8.4, 2.3 Hz, 1H), 5.04-4.94 (m, 1H), 4.84-4.78 (m, 2H), 4.73-4.45 (m, 2H), 3.75-3.58 (m, 2H), 3.21-3.05 (m, 2H), 2.84 (s, 1.5H), 2.81 (s, 1.5H), 2.79-2.63 (m, 3H), 2.62 (s, 1.5H), 2.56 (s, 1.5H), 2.35-2.14 (m, 2H), 2.14-2.00 (m, 1H), 1.80-1.67 (m, 1H), 1.62-1.50 (m, 2H), 1.30-1.02 (m, 2H). HPLC (max plot) 94.2%, Rt 2.83 min. UPLC/MS: (MS+) 514.6 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:36][CH3:37])=[C:7]([CH:25]=[C:26]([N:28]2[CH:33]=[CH:32][C:31](=[O:34])[NH:30][C:29]2=[O:35])[CH:27]=1)/[CH:8]=[CH:9]/[C:10]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13])([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.[OH-].[Na+]>[C:1]([C:5]1[C:6]([O:36][CH3:37])=[C:7]([CH:25]=[C:26]([N:28]2[CH:33]=[CH:32][C:31](=[O:34])[NH:30][C:29]2=[O:35])[CH:27]=1)/[CH:8]=[CH:9]/[C:10]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])=[CH:16][C:11]=1[C:12]([OH:14])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-n2ccc(=O)[nH]c2=O)cc(C(C)(C)C)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2C(=O)O)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Yield: 99.2 %

Procedure:
A solution of the product from Example 25 (55 mg, 0.104 mmol) in THF (1 ml) and 1N aq. NaOH (1 ml) was stirred in the dark at room temperature for 1.5 h. 1N aqueous HCl was added until pH 3, and the resulting mixture was extracted with EtOAc (2×2 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (53 mg, 99%). 1H NMR (300 MHz, DMSO-d6) δ 13.22 (br s, 1 H) 11.40 (d, J=2.21 Hz, 1 H) 10.02 (s, 1 H) 7.72-7.91 (m, 3 H) 7.68 (d, J=2.57 Hz, 1H) 7.49 (d, J=2.57 Hz, 1 H) 7.42 (dd, J=8.64, 2.39 Hz, 1 H) 7.21 (d, J=2.57 Hz, 1 H) 7.16 (d, J=16.18 Hz, 1 H) 5.64 (dd, J=7.72, 2.21 Hz, 1 H) 3.79 (s, 3 H) 3.04 (s, 3 H) 1.38 (s, 9 H).