Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(OC1C=[CH:51][C:50]([NH:53][C:54]2[N:59]=CN=[C:56]([O:60][C:61]3[CH:66]=[CH:65][C:64]([NH:67]C(=O)CC(NC4C=CC(F)=CC=4)=O)=[CH:63][C:62]=3[F:81])[CH:55]=2)=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:59][C:54]1[CH:55]=[C:56]([O:60][C:61]2[CH:66]=[CH:65][C:64]([NH:67][C:8]([C:7]3[C:2](=[O:1])[N:3]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:4]=[CH:5][CH:6]=3)=[O:10])=[CH:63][C:62]=2[F:81])[CH:51]=[CH:50][N:53]=1
Reactant: O=C(O)c1cccn(-c2ccccc2)c1=O
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(NC(=O)c3cccn(-c4ccccc4)c3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (36 mg, 0.17 mmol) and HOBt (18 mg) in DMF (3 mL) at rt was added EDCI.HCl (45 mg, 0.23 mmol) followed by 4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B of Example 24, 36 mg, 0.17 mmol), and the reaction mixture was stirred at rt overnight. Purification of the reaction mixture by preparative HPLC afforded the title compound (32 mg, 36%) as a beige colored solid (TFA salt). 1H NMR (DMSO-d6) δ 13.35 (br s, 1H), 12.11 (s, 1H), 8.52 (dd, 1H, J=7.3, 2.1 Hz), 8.08 (dd, 1H, J=6.6, 2.1 Hz), 8.03 (d, 1H, J=2.3 Hz), 7.89 (d, 1H, J=7.2 Hz), 7.81 (s, 1H), 7.54-7.36 (m, 6H), 6.69-6.63 (m, 2H), 6.08 (d, 1H, J=2.4 Hz), 3.55 (br s, 1H); MS(ESI+) m/z 417.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12](=[O:41])[C@@H:13]2[CH2:17][C@@H:16]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[C:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:20]=3)[CH2:15][N:14]2[C:37]([NH:39][NH2:40])=[O:38])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[CH:42](=O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl>CO.C1COCC1>[CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12](=[O:41])[C@@H:13]2[CH2:17][C@@H:16]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[C:21]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:20]=3)[CH2:15][N:14]2[C:37]([NH:39][NH:40][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:38])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NN)C(=O)OCC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NNCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
To a solution of compound 105 (0.037 mmol) in MeOH:THF (4:1) was added benzaldehyde (0.0448 mmol). The solution was stirred at RT for 18 hrs. Borane-pyridine complex (0.37 mmol) was added followed by HCl (37%, 400 μl). The solution was stirred for 1.5 hrs and then filtrated and concentrated to dryness. The crude material was dissolved in MeOH and purified by Prep LCMS which gave the title compound (0.01 mmol). Purity by HPLC>95%. M+H+650.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Product: CCOC(=O)c1nc(-c2ccccn2)c2snc(-c3ccccc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 3 from 7-bromo-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 2-(tributylstannyl)pyridine: MS (m/z) 378.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][C:7]([CH3:15])([CH3:14])[CH:6]2O.[NH:17]1[CH:21]=[C:20]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[N:19]=[CH:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>C1COCC1>[CH:25]([O:24][C:22]([C:20]1[N:19]([CH:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9](=[O:13])[CH2:8][C:7]2([CH3:15])[CH3:14])[CH:18]=[N:17][CH:21]=1)=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)OC(=O)c1c[nH]cn1
Reactant: COc1ccc2c(c1)C(O)C(C)(C)CC2=O
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(n1cncc1C(=O)OC(C)C)C(C)(C)CC2=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 6-methoxy-4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-naphthalen-1-one (0.75 g, 3.28 mmol), isopropyl 4-imidazolecarboxylate (0.36 g, 2.30 mmol), which can be prepared as described in Example 1, in THF (20 mL) at 0° C. is added triphenylphosphine (0.87 g, 3.28 mmol), followed by dimethyl azodicarboxylate (40% in toluene, 1.2 mL, 3.28 mmol) and the cooling bath is removed. After 16 hours, the mixture is diluted with ethyl acetate and washed twice with half-saturated brine. The mixture is extracted five times with 1M aqueous HCl (20 mL portions). The acidic aqueous phases are then cooled to 0° C., the pH is adjusted to ca. 9 with 2M aqueous NaOH at 0° C. and the aqueous phase is extracted three times with dichloromethane. The combined organic phases are dried over MgSO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (dichloromethane-methanol, 99:1 to 49:1) to give 3-(7-methoxy-2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 357.1 (M+H)+ The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(7-methoxy-2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester 1H NMR (400 MHz, MeOD) δ ppm 1.00 (s, 3 H), 1.23 (s, 3 H), 1.48 (d, J=6.3 Hz, 3 H), 1.50 (d, J=6.3 Hz, 3 H), 2.61 (d, J=17.4 Hz, 1 H), 2.78 (d, J=17.4 Hz, 1 H), 3.89 (s, 3H), 5.34-5.47 (m, 1 H), 6.85 (d, J=2.3 Hz, 1 H), 6.95 (s, 1 H), 7.20 (dd, J=8.6, 2.3 Hz, 1 H), 8.16 (d, J=8.6 Hz, 1 H), 8.40 (s, 1 H), 8.94 (s, 1 H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([N:19]3[CH2:24][CH2:23][C:22]([O:28][P:29](=[O:32])([OH:31])[OH:30])([CH2:25][O:26][CH3:27])[CH2:21][CH2:20]3)=[C:14]([F:33])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].C[O-].[Na+:36]>>[Na+:36].[Na+:36].[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([N:19]3[CH2:24][CH2:23][C:22]([O:28][P:29](=[O:30])([O-:31])[O-:32])([CH2:25][O:26][CH3:27])[CH2:21][CH2:20]3)=[C:14]([F:33])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: COCC1(OP(=O)(O)O)CCN(c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Agent: C[O-]
Agent: [Na+]
Product: COCC1(OP(=O)([O-])[O-])CCN(c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of phosphoric acid mono-(1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl) ester (5.0 g, 0.010 mol) anhydrous methanol (50 ml) at 0-5° C., under argon, was added anhydrous sodium methoxide powder (0.542 g, 0.010 mol). The reaction mixture was stirred at 5-10° C. for 2 hours. The ice-bath was removed and the stirring continued further at 30-35° C. for 1 hour. The reaction mixture was filtered and the filtrate evaporated under reduced pressure. Acetone (25 ml) was added to the residue and triturated. The solvent was decanted. This procedure was repeated twice with acetone (50 ml). Acetone after the third trituration was decanted and the residue dried under reduced pressure to obtain the product as off-white solid, 5.0 g, in 92% yield, Mp>150° C. (dec); MF: C19H24F2K2N3O8P. Aqueous solubility at pH 7 was >200 mg/ml.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH3:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=[O:15].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:13]/[C:14]([C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)=[O:15])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.6 %

Procedure:
To a stirred solution of 4-propoxybenzaldehyde (1.5 ml, 9.5 mmol) and 3,4,5-trimethoxyacetophenone (2.0 g, 9.5 mmol) in methanol (30 ml) was added 50% w/v of aqueous sodium hydroxide (7.6 ml, 0.095 mol). The reaction was stirred for 24 h at room temperature. A precipitate was isolated by filtration, washed with pet:ether and subsequently recrystallised from ethanol to give 0.9 g (27%) of a pale yellow powder. 1H-NMR (CDCl3) δ 7.8 (d, 1H), 7.6 (d, 2H), 7.3 (d, 1H), 7.2 (m, 1H), 6.8 (d, 2H), 3.95 (m, 2H), 3.9 (s×2, 9H), 1.8 (t, 2H), 1.0 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([CH3:25])=[C:15]([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.CN(C)[CH:33]=[O:34].O>O1CCCC1>[CH3:25][C:14]1[S:13][C:12]([C:4]2[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=2)[CH:33]=[O:34])=[N:16][C:15]=1[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CN(C)C=O
Reactant: Cc1sc(-c2cc(Br)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(-c2cc(C=O)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
Under a nitrogen atmosphere at −78° C., to a solution (80 mL) of the compound (7.3 g, 17 mmol) obtained in Example 95a in tetrahydrofuran was added n-butyllithium (1.6M hexane solution, 16 mL, 25 mmol), and the mixture was stirred at the same temperature for 1 hr. Anhydrous N,N-dimethylformamide (2.6 mL, 33 mmol) was added to the reaction mixture, and the mixture was stirred overnight while allowing to spontaneously warm to room temperature from −78° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=80/20) to give the title compound (1.6 g, 24%) as an orange oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[CH:21]=[C:20]4[C:15]([NH:16][C:17](=[O:24])[N:18]([CH3:23])[C:19]4=[O:22])=[N:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:27](I)[CH:28]([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[CH:21]=[C:20]4[C:15]([N:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:24])[N:18]([CH3:23])[C:19]4=[O:22])=[N:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4cccc(F)n4)cc3)cc2c1=O
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Temperature: 140 °C
Yield: 94.1 %

Procedure:
2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (422 mg, 1.2 mmol), isobutyl iodide (276 μL, 2.4 mmol) and potassium carbonate (497 mg, 3.6 mmol) are place in a Biotage microwave vial, and then DMF (6 mL) is added. The mixture is heated in a Biotage microwave instrument at 140° C. for 30 min. The mixture is diluted with water (150 mL), and then extracted with methylene chloride three times. The combined organic phase is evaporated to dryness to give 460 mg of crude product as pale yellow solids, which is used in the next step without further purification. MS (ESI) m/z 408.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.CI.[H-].[Na+].[CH2:14]1[CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:16][O:17][CH2:18][CH2:14][C:15]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Brc1ccc(CCOCCc2ccc(Br)cc2)cc1
Temperature: 25 °C

Procedure:
4-Bromobenzylalcohol(5.0 g, 26.7 mmol) was dissolved in THF (130 ml) and methyl iodide added (6.7 ml, 107.0 mmol). Sodium hydride (1.20 g of 80% dispersion in oil, 40.1 mmol) was added in two portions while stirring at room temperature under nitrogen. After stirring for 2 hours, the solvents were removed in vacuo and the residue partitioned between water and ether. The water was reextracted with ether and the combined organic fractions were then washed with water and brine before drying (Na2SO4) and evaporating in vacuo to give 4-bromobenzylmethyl ether as an orange liquid (5.3 g, 26.4 mmol). δH (250 MHz, CDCl3) 3.39 (3H, s, CH3), 4.40 (2H, s, CH2), 7.21 (2H, d, J 7.5 Hz, Ar--H), 7.48 (2H, d, J 7.5 Hz, Ar--H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[C:14]([C:19]2[N:23]([CH2:24][C:25]([O:27]CC)=[O:26])[N:22]=[CH:21][CH:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:2].[OH-].[Na+]>CO.C1COCC1>[CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[C:14]([C:19]2[N:23]([CH2:24][C:25]([OH:27])=[O:26])[N:22]=[CH:21][CH:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:2]
Reactant: CCOC(=O)Cn1nccc1-c1ncccc1COc1cnc(OC)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccnn2CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To ethyl 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (182 mg, 0.46 mmol, 1 eq.) in a mixture of MeOH/THF (1/5, 12.0 mL) was added NaOH (2N, 2.3 mL, 4.6 mmol, 10 eq.). The mixture was stirred at rt for 2 h, acidified to pH 3, and extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid (135.1 mg, 80%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.71 (d, J=4.7 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.97 (s, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.52 (dd, J=7.9, 4.9 Hz, 1H), 7.13 (s, 1H), 6.56 (d, J=1.7 Hz, 1H), 5.31 (s, 2H), 5.14 (s, 2H), 3.91 (s, 3H). LRMS (M+H+) m/z 369.1.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:17])[NH:5][C:6]2[CH2:14][CH:13]([Cl:15])[CH:12]([Cl:16])[CH2:11][C:7]=2[C:8](=[O:10])[CH:9]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl>[OH:2][C:3]1[C:4](=[O:17])[NH:5][C:6]2[CH2:14][CH:13]([Cl:15])[CH:12]([Cl:16])[CH2:11][C:7]=2[C:8](=[O:10])[CH:9]=1
Reactant: COc1cc(=O)c2c([nH]c1=O)CC(Cl)C(Cl)C2
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=c1cc(O)c(=O)[nH]c2c1CC(Cl)C(Cl)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 3-methoxy-7,8-dichloro-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dione (100 mg, 362 μmol) in dry CH2Cl2 (2 mL, distilled from CaH2) under N2 there was added a solution of BBr3 in CH2Cl2 (1.0 mL, 1M, Aldrich) in one portion over 5 seconds at ft. A greenish yellow precipitate immediately formed. The reaction was allowed to stir under N2 at rt for 45 min. The reaction was added to saturated NaHCO3 (15 mL) and the resulting beige suspension was allowed to stir for 15 min. The suspension was acidified with concentrated HCl (pH 2), allowed to stir for 15 rain at rt, the solid collected by filtration and washed to neutrality with water (6×2 mL). Crystallization from 95% EtOH (dissolved in 75 mL, hot filtered (Whatman #2), concd to 30 mL, allowed to cool to rt) yielded a beige amorphous solid (68 mg, 71%, >98% pure by 1H NMR, pure by C,H,N analysis); mp 246°-248° C. (dec.); 1H NMR (DMSO-d6) δ2.70 (dd, J= 18.2, 5.6 Hz, 1H), 2.91 (dd, J=18.9, 5.4 Hz, 1H), 3.06 (dd, J=18.3, 4.8 Hz, 1H), 3.26 (dd, J=18.8, 4.6 Hz, 1H), 4.57 (m, 2H), 6.34 (s, 1H), 10.46 (s, 1H), 11.11 (s, 1H). Anal. Calcd for: C, 45.83, H, 3.46, N, 5.34. Found: C, 46.02; H, 3.54; N, 5.26.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.[Na].[CH2:19]([N:25]=[C:26]=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(OCC)C>[CH2:19]([NH:25][C:26](=[O:27])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:9][CH2:10]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccn1
Reactant: CCCCCCN=C=O
Agent: [Na]
Solvent: CCOCC
Product: CCCCCCNC(=O)Oc1ccc2c(c1)CCN2Cc1ccccn1
Reaction time: 0.03 h
Yield: 68.2 %

Procedure:
To a solution of 1-(2-pyridylmethyl)indolin-5-ol (20 mg, 88 μmol) in 0.5 mL of diethyl ether was added a piece of sodium (1 mg to 10 mg) at room temperature. After the reaction mixture was stirred at the same temperature for 2 min, n-hexylisocyanate (15 μL, 0.11 mmol, 1.2 equivalent) was added with additional stirring for 5 min to 10 min. After removal of sodium, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 30/70) to obtain the title compound (21.2 mg, 68%) as a slightly brown solid.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=5)[C:38](OC)=[O:39])[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[BH4-].[Li+].O1CCCC1>O>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH2:38][OH:39])[CH:42]=[CH:43][CH:44]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(C(=O)OC)c4)oc3C)c(OC)c2)cs1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(CO)c4)oc3C)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
A mixture of methyl 3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate (212 mg), lithium borohydride (74 mg) and tetrahydrofuran (40 mL) was stirred at room temperature for 12 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4, v/v) to give {3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}methanol (143 mg, yield 62%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 130-132° C.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:9])[CH2:7][NH2:8])[CH2:2]1.C(N(CC)CC)C.S=[C:18]1[CH2:22][S:21][C:20](=[O:23])[NH:19]1>C(O)C>[O:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:9])[CH2:7][NH:8][C:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]=2)[CH2:2]1
Reactant: O=C1NC(=S)CS1
Reactant: NCC(=O)NC1COC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(CNC1=NC(=O)SC1)NC1COC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the crude product (5.7 g) containing N-oxetan-3-ylglycinamide obtained in B) and triethylamine (13.3 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (5.8 g), and the mixture was stirred at room temperature is for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol/dichloromethane) to give the title compound (2.03 g).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][CH:8]([CH3:15])[CH2:9][CH2:10][P+](C)(C)C.[Cl:16][CH2:17][CH2:18][C@H:19]([CH3:22])[CH:20]=O.CN(C)C=O>CCOCC>[Cl:16][CH2:17][CH2:18][C@H:19]([CH3:22])/[CH:20]=[CH:10]\[CH2:9][CH:8]([CH3:15])[CH3:7]
Reactant: C[C@H](C=O)CCCl
Reactant: CC(C)CC[P+](C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C/C=C\[C@@H](C)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
23.5 ml of n-butyllithium (about 2-M in n-hexane) are added dropwise under argon to a suspension of 20.4 g of 3-methylbutyl-trimethylphosphonium bromide in 80 ml of dry ether, a reaction temperature of about 20° being adhered to by slight cooling. Thereafter, the mixture is stirred at room temperature for a further 2 hours. The mixture is cooled to -10° and a solution of 5.4 g of (S)-4-chloro-2-methylbutyraldehyde in 5 ml of dry ether is added thereto. The separated precipitate is stirred for one hour without cooling bath, whereupon 100 ml of dimethylformamide are added dropwise at room temperature. The mixture is stirred at room temperature for 16 hours, hydrolysed on ice and extracted with ether. The ether phase is washed with water, dried and concentrated under reduced pressure. The residue is purified by adsorption on silicagel as well as on neutral aluminium oxide of the activities III and II (elution agent: n-hexane). After distillation under reduced pressure (13 mm Torr/90°), there are obtained 4.13 g (53%) of (S)-cis-1-chloro-3,7-dimethyl-4-octene. [α]D20 = -32.6° (2.15% in chloroform).
Reaction SMILES: FC1C=CC(S(N(S(C2C=CC(N3CC[C@@H](O)C3=O)=CC=2)(=O)=O)C2SC=CN=2)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:57][C:58]1[CH:59]=[C:60]([CH:65]2[O:70][CH2:69][CH2:68][NH:67][CH2:66]2)[CH:61]=[C:62]([Cl:64])[CH:63]=1>>[Cl:64][C:62]1[CH:61]=[C:60]([C@@H:65]2[O:70][CH2:69][CH2:68][NH:67][CH2:66]2)[CH:59]=[C:58]([Cl:57])[CH:63]=1
Reactant: Clc1cc(Cl)cc(C2CNCCO2)c1
Agent: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(F)cc2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Cl)cc([C@H]2CNCCO2)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Synthesized according to General procedure 31, Method A. A stirring suspension of ((R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide (1.07 g, 2.15 mmol), N,N-diisopropylethylamine (1.15 mL, 6.50 mmol), and CH2Cl 2 (10.0 mL), under N2, was cooled to −20° C. Triflic anhydride (545 μL, 3.25 mmol) was added dropwise over 10 minutes. The suspension was stirred at −20° C. for 1 hour. A solution of (S)-2-(3,5-dichlorophenyl)morpholine (500 mg, 2.15 mmol) [this enantiomer of 2-(3,5-dichlorophenyl)morpholine was obtained by preparative SFC separation of its racemic mixture: Chiralpak AD-H column (2×15 cm), 50% ethanol (0.1% DEA)/CO2, 50 mL/min)] and CH2Cl2 (2.0 mL) was added dropwise over 5 minutes. The mixture was stirred at −20° C. for 1.5 hours. Morpholine (375 μL, 4.30 mmol) was added dropwise over 5 minutes. The mixture was stirred at −20° C. for 2 hours. The solution was allowed to warm to room temperature and concentrated to dryness under reduced pressure. The residue was purified via silica gel chromatography using 2% MeOH in CH2Cl2 to obtain the desired lactam as a white solid (814 mg, 1.48 mmol, 69% yield). 1H-NMR (400 MHz, DMSO) δ 7.85-7.78 (m, 4H), 7.54 (t, J=1.9 Hz, 1H), 7.42 (d, J=1.8 Hz, 2H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 4.53 (dd, J=1.9, 9.9 Hz, 1H), 3.97 (d, J=9.9 Hz, 1H), 3.80-3.65 (m, 4H), 3.01-2.89 (m, 2H), 2.70-2.65 (m, 1H), 2.51-2.45 (m, 1H), 2.27-2.22 (m, 1H), 2.12-2.07 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=553.3; tR=1.44 min. SFC (Chiralpak AS-H, (0.46×25 cm), 55% methanol (1% DEA)/CO2, 3 mL/min): tR=6.8 min.