Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14](OC)=[O:15])[CH2:4][O:3]1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>ClCCl>[CH:14]([C@H:5]1[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[N:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:15]
Reactant: COC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a cooled solution of 3-tert-butyl 4-methyl (4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (16.5 g, 63.6 mmol) in dry dichloromethane (300 mL) at −78° C., was added a cooled solution of 1.0 M diisobutylaluminium hydride in hexane (127.6 mL, 127.2 mmol) under argon. The rate of addition was adjusted so as to keep the internal temperature below −65° C. and take about 1 hour to complete. The reaction mixture was stirred for an additional 2 hours at −78° C. under argon. The reaction was quenched by slowly adding 60 mL of cold methanol (−78° C.) so as to keep the internal temperature below −65° C. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressure. The residue was distilled at 0.7 mbar to give tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (10 g, 68.5%) as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH2:25][CH3:26])=[C:17]([O:27][CH3:28])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si](C)(C)[N:32]([Si](C)(C)C)[S:33]([CH3:36])(=O)=O>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:32][S:33][CH3:36])[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH2:25][CH3:26])=[C:17]([O:27][CH3:28])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCC#CCOc1ccc(CCNC(=O)C(=O)c2ccc(Cl)c(Cl)c2)cc1OC
Reactant: C[Si](C)(C)N([Si](C)(C)C)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC#CCOc1ccc(CCNC(=O)C(=NSC)c2ccc(Cl)c(Cl)c2)cc1OC
Yield: 70.1 %

Procedure:
To a solution of 1.7 g (3.9 mmol) 2-(3,4-dichloro-phenyl)-N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-2-oxo-acetamide in 32 ml THF, 3.0 g (14.0 mmol) N,N-bis(trimethyl-silyl) methanesulfonamide and 0.1 g (0.32 mmol) tetrabutylammonium bromide (TBAF) are added. The mixture is heated at +70° C. for 7 hours. After cooling, the mixture is diluted with ethyl acetate and washed twice with water. After evaporation of the organic phase the residue is purified by flash-chromatography (ethyl acetate 25, hexanes 75) to give 1.31 g (70%) of the 2-(3,4-dichloro-phenyl)-2-methylthioimino-N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-acetamide. 1H-NMR (300 MHz, CDCl3): 1.15 (t, 3 H, CH2CH3), 2.22 (m, 2 H, CH2CH3), 2.73 (s, 3 H, SCH3), 2.83 (t, 2 H, CH2CH2) 3.59 (t, 2 H, CH2CH2) 3.89 (s, 3 H, OCH3) 4.73 (m, 2 H, OCH2) 6.78 (m, 2 H, CH arom.), 7.02 (m, 1 H, CH arom.), 7.12 (t, 1 H, NH), 7.30 and 7.58 (m, 3 H, CH arom.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[CH:2].[CH3:20][Si:21]([CH2:24][N:25]=[N+:26]=[N-:27])([CH3:23])[CH3:22]>C1C=CC=CC=1.C[C]1[C](C)[C](C)[C](C)[C]1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:5]([CH:4]=[C:3]([C:1]3[N:25]([CH2:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[N:26]=[N:27][CH:2]=3)[CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[N:14][CH:15]=1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: C#Cc1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Agent: Cl[Ru]
Agent: C[C]1[C](C)[C](C)[C](C)[C]1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2cnnn2C[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a degassed solution of methyl 3-ethynyl-5-(5-methylpyridin-2-yl)benzoate (124 mg, 0.493 mmol) in benzene (12 mL) were added trimethylsilylmethylazide (96 mg, 0.740 mmol) and pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride (59 mg, 0.074 mmol) and the mixture heated to 80° C. in a sealed tube. After 16 h, the title compound was showed as the major isomer (10:1 isomeric ratio) in the reaction. The reaction was concentrated and purified by reverse-phase HPLC gave the title compound (120 mg). MS 381.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=[O:4].[NH2:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10]O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:5][C:3]1([C:2]([F:7])([F:6])[F:1])[NH:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][O:4]1
Reactant: NC(CO)c1ccccc1
Reactant: CC(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C(F)(F)F)NC(c2ccccc2)CO1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
55.13 g (492.0 mmol) of 1,1,1-trifluoroacetone in toluene (1.35 l) were admixed with 45 g (328.0 mmol) of rac-2-amino-2-phenylethanol and 8.24 g (32.8 mmol) of pyridinium p-toluenesulphonate. The reaction mixture was boiled under reflux on a water separator for 16 h. The mixture was cooled to 0° C., and the solids formed were filtered off and dried under high vacuum. This gave 68.6 g (77% of theory, purity 85%) of the target compound.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH2:38][O:39][C@@H:40]([CH3:44])[CH2:41][O:42][CH3:43])[C:28]([NH:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29])(C(C)(C)C)(C)C>C1COCC1>[OH:26][C@@H:27]([CH2:38][O:39][C@@H:40]([CH3:44])[CH2:41][O:42][CH3:43])[C:28]([NH:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29]
Reactant: COC[C@H](C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1cnc(C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H](C)OC[C@H](O)C(=O)Nc1cnc(C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (1199 μl, 1.20 mmol) was added to (S)-2-(tert-butyldimethylsilyloxy)-3-((S)-1-methoxypropan-2-yloxy)-N-(5-methylpyrazin-2-yl)propanamide (Intermediate Y2) (230 mg, 0.60 mmol) in THF (3.0 mL) at 20° C. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated and diluted with ethyl acetate (50 mL), and washed sequentially with water (25 mL) and saturated brine (10 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 100% ethyl acetate to afford the product (80 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 1.16 (d, 3H), 2.53 (s, 3H), 3.34-3.45 (m, 5H), 3.66-3.81 (m, 2H), 3.97-4.03 (m, 1H), 4.30 (d, 1H), 4.34-4.39 (m, 1H), 8.13 (d, 1H), 9.30 (s, 1H), 9.41 (d, 1H); m/z (ESI+) (M+H)+=270.29; HPLC tR=0.95 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]#[N:12].[C:14]([C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1)#[N:15].N1C=CC=CC=1.Cl>C(OC)(=O)C.O.CC(O)CC>[C:11]([C:7]1[C:6]2[C:10](=[C:2]([NH:1][S:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:14]#[N:15])[CH:17]=3)(=[O:24])=[O:23])[CH:3]=[CH:4][C:5]=2[CH3:13])[NH:9][CH:8]=1)#[N:12]
Reactant: Cc1ccc(N)c2[nH]cc(C#N)c12
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCC(C)O
Product: Cc1ccc(NS(=O)(=O)c2cccc(C#N)c2)c2[nH]cc(C#N)c12
Temperature: 7 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 5.0 g (29 mmol) of the 7-amino-3-cyano-4-methyl-1H-indole obtained in Example 2A and 6.48 g (32 mmol) of 3-cyanobenzenesulfonyl chloride [CAS No. 56542-67-7] in 150 mL of methyl acetate, were added 75 mL of water and 2.83 mL (35 mmol) of pyridine, followed by stirring for 2 hours and 40 minutes. After adding 0.73 mL (9 mmol) of concentrated hydrochloric acid to the reaction mixture, liquid-liquid separation was performed and the organic layer was washed with a mixture of 75 mL of water and 17.5 mL of ethanol. Activated carbon was added to the organic layer and the mixture was stirred at 45-50° C. for 30 minutes, and then filtered and concentrated. To thus obtained crude crystals were added 96 mL of 2-butanol and 24 mL of water for dissolution at 75° C., and the solution was cooled to 7° C. at approximately 10° C./hr and stirred overnight. The precipitated crystals were collected by filtration and washed twice with 10 mL of 2-butanol to give 8.17 g (wet weight) of crystals of the title compound. The crystals were dried under reduced pressure at 70° C. for 2 hours to give 7.54 g of crystals of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].CC(C)([O-])C.[K+].[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34]>[Pd].O1CCCC1>[CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([O:17][CH2:34][CH2:33][C:32]([O:36][CH3:37])=[O:35])[C:11]([CH3:19])([CH3:18])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: CC1(C)CC(OCc2ccccc2)CC(C)(C)N1O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Product: COC(=O)CCON1C(C)(C)CC(OCc2ccccc2)CC1(C)C
Temperature: 55 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A mixture of 20.0 grams (76 mmol) of 4-benzyloxyl-oxyl-2,2,6,6-tetramethylpiperidine, 10.0 grams of anhydrous magnesium sulfate, 500 mg of 5% palladium on carbon and 150 ml of tetrahydrofuran is hydrogenated on a Parr apparatus (50 psi, ambient temperature). Catalyst and drying agent are removed by filtration and the filtrate is quickly transferred to a flask under a nitrogen atmosphere. To the flask are added 0.85 gram of potassium tert-butoxide, 19.7 grams (229 mmol) of methyl acrylate, and 50 ml of tetrahydrofuran. The reaction mixture is stirred at ambient temperature for three hours and at 55° C. for one hour. The reaction mixture is partitioned between ether (300 ml) and saturated sodium bicarbonate solution (150 ml). The ether layer is washed with water (2×500 ml), washed with saturated aqueous sodium chloride (200 ml), dried over anhydrous magnesium sulfate and concentrated to an oil. The oil is purified by flash chromatography (silica gel; 9:1 hexane:ethyl acetate) to afford 13.0 grams of the title compound as a colorless liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([OH:40])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:40][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Oc1cccc2ccccc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc4ccccc34)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67 mmol), (prepared as described for the starting material in Example 1), potassium carbonate (106 mg, 0.77 mmol) and 1-naphthol (111 mg, 0.77 mmol) in DMF (7.5 ml) was stirred at 100° C. for 5 hours then allowed to cool to ambient temperature. The reaction mixture was treated with 1M aqueous sodium hydroxide solution (40 ml) and stirred at ambient temperature for a few minutes. The reaction mixture was extracted with ethyl acetate and the organic extracts were washed with water. The organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give a solid which was triturated with ether, filtered and dried to give 6-methoxy-7-(3-morpholinopropoxy)-4-(1-naphthyloxy)quinazoline (194 mg, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:22][O:23][CH3:24])([S:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:26].[Na+]>CO.O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:22][O:23][CH3:24])([S:14]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)=[O:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1(Sc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COCC1(S(=O)c2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of N-tert-butoxycarbonyl-4-methoxymethyl-4-(3-tolylsulfanyl)piperidine (0.30 g, 0.85 mmol; Example 107, Step A) and sodium periodate (0.2 g, 0.94 mmol) in a mixture of methanol (6 mL) and water (4 mL) was stirred at room temp. overnight. The reaction mixture was diluted with dichloromethane. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 35% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([CH2:12]C)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].C(C1C=C(C)NC=1C(O)=O)#N>>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([CH3:12])=[CH:8][C:9]=1[C:10]#[N:11])=[O:4]
Reactant: CCc1cc(C#N)c(C(=O)OC)[nH]1
Agent: Cc1cc(C#N)c(C(=O)O)[nH]1
Product: COC(=O)c1[nH]c(C)cc1C#N

Procedure:
The title compound was prepared by a procedure analogous to Intermediate 27 starting from 3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 32).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:24])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[SH:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[N:31]2.C1CCN2C(=NCCC2)CC1.O>C(Cl)(Cl)Cl>[C:12]1([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:3]([OH:24])[CH2:2][S:25][C:26]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:27]=3[CH:28]=[CH:29][CH:30]=[N:31]4)[CH2:6][CH2:7]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Sc1cccc2ncccc12
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: OC(CSc1cccc2ncccc12)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 288 h
Yield: 20.3 %

Procedure:
In 10 ml of chloroform were dissolved 1.2 g of 4-(3-chloro-2-hydroxypropy)-1-diphenylmethylpiperazine prepared in Example 23-(b) and 220 mg of 5-mercaptoquinoline, and 311 mg of DBU was further added thereto. Afterward, the liquid was allowed to stand at room temperature for 12 days. The reaction liquid was poured into 20 ml of water and was then extracted twice with methylene chloride. The resultant organic layer was separated, then dried with an anhydrous Glauber's salt, and was distilled off under reduced pressure. The resultant residue was purified through a silica gel chromatograph (an AcOEt effluent solvent was used) in order to obtain 130 mg of the desired compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([N:26]([CH2:38][P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[S:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[CH:20]=[CH:19]2)=O)(C)(C)C.[OH-].[Na+]>C(Cl)Cl>[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([N:26]([CH2:38][P:39](=[O:46])([O:40][CH2:41][CH3:42])[O:43][CH2:44][CH3:45])[S:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[CH:20]=[CH:19]2
Reactant: CCOP(=O)(CN(c1ccc2cc(NC(=O)OC(C)(C)C)ccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(CN(c1ccc2cc(N)ccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C

Procedure:
1 ml trifluoroacetic acid is pipetted into 130 mg diethyl {[(6-tert.-butoxycarbonylamino-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-methyl}-phosphonate in 3 ml methylene chloride. The reaction mixture is stirred for two and a half hours at ambient temperature, then made alkaline with 1 N sodium hydroxide solution and extracted with methylene chloride. The combined organic phases are washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (40:60 to 0:100).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][O:14]C2C=C(C)C=CC=2N[C:10]1=[O:21].CCN=C=NCCCN(C)C.C(OC(N[C@@H](CO)C(O)=O)=O)(C)(C)C.F[C:48]1[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:51]=[CH:50][C:49]=1[N+:58]([O-])=O>CCOCC.CCCCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:10][O:21][C:48]2[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:51]=[CH:50][C:49]=2[NH:58][C:15]1=[O:14]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1F
Reactant: Cc1ccc2c(c1)OC[C@H](N)C(=O)N2
Agent: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CCCCC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1COc2cc(C(F)(F)F)ccc2NC1=O
Reaction time: 2 h

Procedure:
In a similar manner to that described for the preparation of (S)-3-amino-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate except in Step 3 1.2 eq. EDCI was used and the reaction mixture was stirred for 2 h and in Step 4 the mixture was stirred for 1 h and the material obtained was tritrurated with Et2O/pentane, (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (4.96 g, 24.2 mmol) and 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (5.05 g, 24.2 mmol) were converted to the title compound (1.6 g) as a pale yellow solid.
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-])=O.C1(C2CCC3C(=CC=C(O)C=3)O2)C=CC=CC=1.Cl[C:45]1C=CC(C#N)=C[N:46]=1>>[C:21]1([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([C:45]#[N:46])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Product: N#Cc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
6-(2-Phenylchroman-6-yloxy)nicotinonitrile was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in example 1 (b) using 500 mg of 2-phenylchroman-6-ol and replacing 2-chloro-5-nitropyridine by 337 mg of 6-chloro-nicotinonitrile. The product was purified by column chromatography using heptane-ethyl acetate as an eluant and then crystallised from 2-propanol. 1H NMR (400 MHz, d6-DMSO) δ: 8.65 (d, 1H, J 2.4 Hz), 8.28 (dd, 1H, 8.8, 2.4 Hz), 7.47-7.34 (m, 5H), 7.17 (d, 1H, J 8.8 Hz) 6.96-6.87 (m, 3H), 5.14 (dd, 1H, J 10.1, 2.2 Hz), 2.99 (m, 1H), 2.73 (m, 1H), 2.18 (m, 1H), 2.00 (m, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)=[O:12])[CH:9]=2)[N:4]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[O:46]1[C:50]2[CH:51]=[CH:52][C:53](B(O)O)=[CH:54][C:49]=2[CH2:48][CH2:47]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:46]1[C:50]2[CH:51]=[CH:52][C:53]([C:2]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][C@@H:14]5[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]5)=[O:12])[CH:9]=4)[N:4]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:3]=3)=[CH:54][C:49]=2[CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc3c(c2)c(-c2ccc4c(c2)CCO4)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C

Procedure:
(R)-tert-butyl 3-(3-bromo-1-trityl-1H-indazole-5-carboxamido)piperidine-1-carboxylate (650 mg, 1 mmol) was added to a vial containing 2,3-dihydrobenzofuran-5-ylboronic acid (180 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol). After purging the vial with nitrogen gas, dioxane (3 mL) and 2M sodium carbonate (1.5 mL) was added to the vial respectively. The reaction mixture was stirred and was heated to 80° C. for overnight. Upon completion, the mixture was concentrated under vacuo. Water (10 mL) was added and was extracted using dichloromethane (3×25 mL). The extracts were combined and dried using anhydrous sodium sulfate. The resulting suspension was filtered and concentrated. The crude product was purified using flash chromatography.
Reaction SMILES: [CH2:1]([C@:4]1([C:43]2[CH:48]=[C:47]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:58])=[CH:45][C:44]=2[OH:59])[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:7]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:6]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:69].[Na+].OO>C1COCC1.O>[Cl:58][C:46]1[C:47]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[CH:48][C:43]([C@@:4]2([CH2:1][CH2:2][CH2:3][OH:69])[C@H:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@@H:8]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:7]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:6]([CH2:34][O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:5]2)=[C:44]([OH:59])[CH:45]=1
Reactant: [OH-]
Reactant: C=CC[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(Cc2cc([C@]3(CCCO)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a stirred solution of 34 (200 mg, 0.247 mmol) in dry THF (4 mL) was added 9-BBN in THF (2.0 mL, 0.5 M, 4.1 equiv). The resulting mixture was stirred at ambient temperature for 4 hours and then cooled 0° C. Water (2.5 mL), 1 M aqueous NaOH (0.8 mL) and 30% H2O2 (0.25 mL) were added at 0° C. The mixture was stirred for 1 hour at ambient temperature and 16 hours at 60° C. in a sealed vial. After cooling, the mixture was partitioned between water and EtOAc. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified using preparatory TLC eluting with 18% EtOAc in petroleum ether to give 35 (200 mg, 99% yield). LCMS m/z 828 (M+H), 850 (M+Na).