Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)=[CH:10][C:7]=2[C:8]#[N:9])[CH2:3][CH2:2]1.Br[C:24]1C=CC(OCC2CCC2)=C(C=1)C#N>>[CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:21])([CH3:22])[O:15]3)=[CH:10][C:7]=2[C:8]#[N:9])[CH2:2][CH2:24][CH2:3]1
Reactant: CC1(C)OB(c2ccc(OCC3CC3)c(C#N)c2)OC1(C)C
Reactant: N#Cc1cc(Br)ccc1OCC1CCC1
Product: CC1(C)OB(c2ccc(OCC3CCC3)c(C#N)c2)OC1(C)C

Procedure:
The preparation succeeds in a similar manner as described above for 2-cyclopropylmethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile with 5-bromo-2-cyclobutylmethoxybenzonitrile (5.0 g, 0.018 mol), giving 3.5 g of the desired product as colourless oil;
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:11])[CH3:10])=[C:5]([Cl:12])[CH:4]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18](B(O)O)[CH:19]=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:5]1[CH:4]=[C:3]([C:16]2[CH:15]=[C:14]([F:13])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH:8]=[CH:7][C:6]=1[CH:9]([NH2:11])[CH3:10]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CC(N)c1ccc(Br)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Product: COc1ccc(F)cc1-c1ccc(C(C)N)c(Cl)c1
Temperature: 190 °C
Yield: 88.9 %

Procedure:
To a stirred solution of 4-bromo-2-chloro-acetophenone (4.66 g, 20 mmol) in methanol (50 ml) under nitrogen atmosphere was added ammonium acetate (29 g, 0.4 mol) and sodium cyanoborohydride (1.21 g, 20 mmol). The reaction mixture was stirred at ambient temperature for 10 days. The solvent was evaporated and the residue partitioned between dichloromethane and aqueous sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was dissolved in diethyl ether and treated with 2M Hydrogen chloride in diethyl ether The resulting precipitate was filtered and dried to give 1-(4-bromo-2-chloro-phenyl)-ethylamine hydrochloride (3.2 g). A mixture of 1-(4-bromo-2-chloro-phenyl)-ethylamine hydrochloride (0.25 g, 1.07 mmol), 5-fluoro-2-methoxyphenyl boronic acid (0.364 g, 2.14 mmol), palladium acetate (0.005 g, 0.021 mmol) in water (4 ml) was heated in a microwave oven at 190° C. for 4 min. The mixture was added to a SCX column (eluted with 1:1 dichloromethane/methanol then 10% 7M ammonia/methanol) and solvent evaporated to give 1-(3-chloro-5′-fluro-2′-methoxy-biphenyl-4-yl)-ethylamine (0.266 g). The title compound was prepared in a similar manner to N-(5′-fluoro-2,2′-dimethoxy-biphenyl-4-ylmethyl)-4-methoxy-benzenesulfonamide (Example 6) using 1-(3-chloro-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine and 2-chloro-4-cyanobenzene sulfonyl chloride instead of 4-methoxybenzene sulfonyl chloride: 1H NMR (400 MHz, DMSO-d6): δ 9.1 (d 1H), 8.1 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.5 (d, 1H), 7.3 (d, 2H), 7.2 (m, 1H), 7-7.18 (m, 2H), 4.9 (m, 1H), 3.8 (s, 3H), 1.4 (d, 3H) ppm. MS (ESI) m/z: value [M+H]+.
Reaction SMILES: FC1C=CC(C)=C2C=1[CH:4]=[C:5]([NH2:13])[N:6]=C2.C(OCC(COCC)C(=N)C(=N)[CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([F:32])[CH:23]=1)C>>[F:32][C:24]1[CH:23]=[C:22]2[C:27]([CH:4]=[C:5]([NH2:13])[N:6]=[CH:21]2)=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=1
Reactant: CCOCC(COCC)C(=N)C(=N)Cc1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(F)c2cc(N)ncc12
Product: Nc1cc2c(C(F)(F)F)cc(F)cc2cn1
Yield: 69.4 %

Procedure:
Scheme O was used for the preparation of 5-fluoro-8-methylisoquinolin-3-amine from 12.0 g of 5-ethoxy-4-(ethoxymethyl)-1-[3-fluoro-5-(trifluoromethyl)phenyl]pentane-2,3-diimine start material to give 5.9 g, yield 69.4%. 1H NMR (400 MHz, DMSO-d6) ppm 6.39 (s, 2H), 6.77 (d, J=1.01 Hz, 1H), 7.91 (dd, J 9.06, 2.52 Hz, 1H), 7.97 (dd, J=8.81, 2.27 Hz, 1H), 8.94 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12](O)[CH3:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:24][CH:12]([C:10]1[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=1)[CH3:13]
Reactant: COc1cc(C(C)O)c2nn(COCC[Si](C)(C)C)cc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1cc(C(C)Br)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-1-(5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (712 mg, 2.21 mmol) and carbon tetrabromide (1.10 g, 3.31 mmol) in tetrahydrofuran (10 mL) at 0° C. was added triphenylphosphine (869 mg, 3.31 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (5% 30% EtOAc/Hex) to give 240 mg (28.2%) as colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.95 (s, 1H), 7.15 (s, 1H), 6.82 (s, 1H), 5.84 (q, J=6.0 Hz, 1H), 5.67 (s, 2H), 3.8 (s, 3H), 3.62 (m, 2H), 2.94(d, J=6.0 Hz, 2H), 0.9 (m, 2H), −0.06 (s, 9H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[O:11][C:10]2[C:12]([Cl:19])=[C:13]([Cl:18])[CH:14]=[C:15]([CH:16]=[O:17])[C:9]=2[O:8][CH2:7]1)(=[O:3])[CH3:2].[Cr](O)(O)(=O)=[O:21]>CC(C)=O>[C:1]([O:4][CH2:5][CH:6]1[O:11][C:10]2[C:12]([Cl:19])=[C:13]([Cl:18])[CH:14]=[C:15]([C:16]([OH:21])=[O:17])[C:9]=2[O:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: O=[Cr](=O)(O)O
Reactant: CC(=O)OCC1COc2c(C=O)cc(Cl)c(Cl)c2O1
Solvent: CC(C)=O
Product: CC(=O)OCC1COc2c(C(=O)O)cc(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a solution of 1.03 g of 2-acetoxymethyl-7,8-dichloro-1,4-benzodioxane-5-carbaldehyde (Ia-a-39) in 70 ml of acetone is added 2 ml of 8N-chromic acid/sulfric acid. The mixture is stirred at room temperature for about 2.5 hours and then filtered after the confirmation by TLC that no starting material is remained. The filtrate is concentrated under reduced pressure to give a residue, which is extracted with dichloromethane. The organic layer is washed with water and evaporated to give 1.004 g (93%) of 2-acetoxymethyl-7,8-dichloro-1,4-benzodioxane-5-carboxylic acid (Ia-a-43: R3 '=Ac), which is recrystallized from dichloromethane/ether to yield crystals, m.p. 144°-145° C.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].Br[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Reactant: BrCCc1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccc3c(c2)CCO3)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)-piperidine (1.09 g), 5-(2-bromoethyl)-2,3dihydrobenzofuran (0.9 g--see Preparation 5), anhydrous potassium carbonate (1.1 g) and acetonitrile (25 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colourless rhombs, yield 0.64 g, m.p. 137-140° C., [α]D25 +13.7° (c, 1.0, CH2Cl2).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[OH-].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19].C(=O)=O>O1CCOCC1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:19][C:18]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:16]([F:15])[CH:17]=1)=[O:4]
Reactant: COc1ccc(N)cc1F
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)c2ccccc2N)cc1F
Temperature: 25 °C
Yield: 38.4 %

Procedure:
To a stirred suspension of isatoic anhydride (1.63 g, 10 mmol) in 15 mL dioxane at room temperature under nitrogen was added powdered sodium hydroxide followed by 3-fluoro-4-methoxyaniline (1.41 g, 10 mmol). The mixture was immersed in a room temperature oil bath and slowly heated to reflux. Carbon dioxide gas evolution was evident. After stirring at reflux for 2 hours, the reaction mixture was cooled to room temperature and inorganics were filtered off with dioxane. The filtrate was concentrated to dryness to a brown solid. The crude product was dissolved in a minimum of hot 95% EtOH and crystals formed upon cooling. The crystals were filtered off and rinsed with a minimum of ice cold 95% EtOH to give a tan solid (1.0 g, 39%). 1H-NMR (400 MHz, CDCl3) δ 7.66 (br s, 1H), 7.50 (dd, 1H), 7.44 (dd, 1H), 7.26 (m, 1H), 7.17 (m, 1H), 6.95 (m, 1H), 6.71 (m, 2H), 5.50 (br s, 2H), 3.89 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(O)C.[ClH:14].C(=O)([O-])[O-].[NH4+:19].[NH4+]>O1CCOCC1>[ClH:14].[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]([NH2:19])=[NH:6]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCO
Product: N=C(N)c1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To 3-fluoro-4-hydroxybenzonitrile (7.56 g, 55.2 mmol) were added ethanol (20 mL) and 4N-Hydrogen chloride in 1,4-Dioxane (100 mL), and the mixture was stirred at room temperature. After 5 days, the mixture was concentrated and dried with a vacuum pump. Then, the mixture was dissolved in ethanol (100 mL), ammonium carbonate (11.0 g, 115 mmol) was added, and the mixture was stirred at room temperature. After 12 hours, the solvent was evaporated, and the residue was dissolved in water (100 mL). The mixture was lyophilized to give the title compound (11.2 g, quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.CN1CCCC1=O.[Cl:29][CH2:30][C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:6]([C:12]#[N:13])=[CH:7][N:8]=[C:9]3[C:4]=2[CH:3]=[C:2]([NH:1][C:31](=[O:32])[CH2:30][Cl:29])[CH:11]=[N:10]3)[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cnc2ncc(N)cc2c1Nc1cccc(Br)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: N#Cc1cnc2ncc(NC(=O)CCl)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Yield: 76.4 %

Procedure:
To a solution of 0.74 g (2.2 mmol) of 6-amino-4-(3-bromo-phenylamino)-[1.8]naphthyridine-3-carbonitrile and 0.7 g (5.44 mmol) of disopropylethyl amine in a 7 ml of N-methylpyrrolidone was added with stirring at 0° C. a solution of 0.29 g (2.6 mmol) of chloroacetyl chloride in 5 ml of tetrahydrofuran over 5 min. After 1 hr at 0° C. the mixture was warmed to room temperature. The mixture was poured into saturated sodium bicarbonate. Solid was collected and air dried. The solid was purified by chromatography on silica gel eluting with ethyl acetate-methanol mixtures giving 0.7 g of the title compound as a tan solid: mass spectrum (electrospray, m/e): M+H 416.1, 418.1.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[CH:36]=[CH:35][C:16]3[N:17]([CH2:31][CH2:32][O:33][CH3:34])[C:18]([NH:20][C:21]4[S:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=5[N:25]=4)=[N:19][C:15]=3[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.[O:37]1CC(O)O[CH2:39][CH:38]1O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:37][CH2:38][CH2:39][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[CH:36]=[CH:35][C:16]3[N:17]([CH2:31][CH2:32][O:33][CH3:34])[C:18]([NH:20][C:21]4[S:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=5[N:25]=4)=[N:19][C:15]=3[CH:14]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCNCC3)ccc21
Reactant: OC1COC(O)CO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCN(CCO)CC3)ccc21
Yield: 34.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid [1-(2-hydroxy-ethyl)piperidin-4-ylmethyl]-amide (45 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid (piperidin-4-ylmethyl)-amide dihydrochloride (136 mg), [1,4]dioxane-2,5-diol (54 mg), and Na(OAc)3BH (95 mg) in DCM (2 mL). LC/MS: m/z 542.7.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[N:11]=[C:12]3[N:18]([CH2:19][C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[CH:25][CH:24]=[CH:23]5)[N:17]=[N:16][C:13]3=[N:14][CH:15]=2)[CH:7]=[N:6]1.[Li+].[OH-].Cl>CO.O>[N:26]1[C:27]2[C:22](=[CH:21][C:20]([CH2:19][N:18]3[C:12]4[C:13](=[N:14][CH:15]=[C:10]([C:8]5[CH:7]=[N:6][N:5]([CH2:4][C:3]([OH:30])=[O:2])[CH:9]=5)[N:11]=4)[N:16]=[N:17]3)=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)Cn1cc(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cn1cc(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
To a solution of [4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-acetic acid methyl ester (242 mgs, 0.60 mmol) in MeOH (4 mL) was added a freshly prepared solution of LiOH (72 mgs, 3.02 mmol) in water (1 mL). The reaction was stirred for 16 hours at ambient temperature. The white suspension was then neutralized to pH 7 with 1 N HCl, and a white solid precipitated out. The solid was filtered, washed with water, and dried under a high vacuum for 16 hours to afford [4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-acetic acid (131 mgs, 56% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[N:24]1([S:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([S:30]([C:33]2[CH:34]=[C:35]([NH:39][C:21]([C:20]3[CH:19]=[N:18][N:11]4[C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[N:9][C:10]=34)=[O:22])[CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)N2CCOCC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 566.1 [(M+H)+]; mp 144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8](=[O:19])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[CH3:18])[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([C:29]([C:31]2[CH:41]=[C:40]([CH3:42])[C:34]3[N:35]([CH3:39])[C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:24]=1.CO>CN(C=O)C>[CH3:39][N:35]1[C:34]2[C:40]([CH3:42])=[CH:41][C:31]([C:29]([C:25]3[N:26]=[CH:27][N:28]=[C:23]([N:15]4[CH2:16][CH2:17][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[CH:20][C:6]=6[NH:7][C:8]5=[O:19])[CH:13]([CH3:18])[CH2:14]4)[CH:24]=3)=[O:30])=[CH:32][C:33]=2[O:37][C:36]1=[O:38]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1C)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1C)C(=O)N2

Procedure:
60 mg (0.21 mmol) 7-methoxy-3-(3-methyl-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 60 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.040 mL (0.29 mmol) TEA were stirred overnight in 1 mL DMF at RT. Then the reaction mixture was combined with 2 mL MeOH, the precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[CH:12]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:13][CH2:14][CH3:15].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]1([CH2:12][CH2:13][CH:14]2[CH2:15][O:9]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CCC2CO2)cc1
Temperature: 25 °C

Procedure:
3-chlorobenzenecarboperoxoic acid (12.1 g, 54.0 mmol) is added in one portion to a solution of 3-buten-1-ylbenzene (7.15 g, 54.1 mmol) in CH2Cl2 at 0° C. followed by warming to 25° C. overnight. Saturated NaHCO3 was added and the mixture separated and the resulting clear oil (8.0 g, quant.) was carried forward without further purification: LC-MS (ES) m/z=149 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:35])([F:34])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:34])([F:33])[F:35])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:28]([F:30])([F:31])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoate (680 mg, 1.27 mmol, 1.00 equiv), water (5 mL), methanol (10 mL), LiOH (153 mg, 6.39 mmol, 5.00 equiv). The resulting solution was stirred for 2 h at 50° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 30 mL of H2O. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 420 mg (65%) of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[CH:34][N:33]=1>>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=2)=[N:33][CH:34]=1)(=[O:40])[CH3:39]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(OC(F)(F)F)cc2)cc1
Reactant: CC(=O)c1ccc(Cl)nc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C(C)=O)cn2)cc1

Procedure:
Similarly prepared from ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate and 2-chloro-5-acetyl-pyridine.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:73])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH2:60][CH2:61][CH2:62][O:63][Si](C(C)(C)C)(C)C)[CH:55]=[CH:54]4)[CH:46]([O:71][CH3:72])[CH2:45]2)[CH:7]([CH3:74])[CH:6]([OH:75])[CH2:5][C:4]1=[O:76])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:73])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH2:60][CH2:61][CH2:62][OH:63])[CH:55]=[CH:54]4)[CH:46]([O:71][CH3:72])[CH2:45]2)[CH:7]([CH3:74])[CH:6]([OH:75])[CH2:5][C:4]1=[O:76])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5c(ccn5CCCO[Si](C)(C)C(C)(C)C)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5c(ccn5CCCO)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(3-t-butyldimethylsilyloxy-propyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (144 mg) in CH2Cl2 (4 mL.) at rt was added a solution of p-toluene sulfonic acid (20 mg.) in CH3OH (4 mL.). The reaction mixture was stirred for 3 hr., quenched with saturated NaHCO3, then extracted with CH2Cl2. The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1, hexane/acetone) to give 81 mg of the title compound. Partial 1H NMR (CDCl3, 200 MHz) d: 7.22 (d, J=9 Hz, 1H); 7.18 (d, J=3 Hz, 1H); 7.07 (d, J=3 Hz, 1H); 6.89 (dd, J=3 Hz and J=9 Hz, 1H); 6.34 (d, J=3 Hz, 1H); 4.20 (t, J=6.5 Hz, 2H); 2.00 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH2:12][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc(C(C)C)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
1-(2,4-Dihydroxy-5-isopropyl-phenyl)-ethanone (1 eq) was dissolved in DMF and potassium carbonate (2.2 eq) then benzyl bromide (2.2 eq) were added. The suspension was heated, with stirring to 150° C., under nitrogen, for 16 hrs. The solution was cooled to room temperature and the mixture was poured into 1MHCl (aq) then extracted in to ethyl acetate. The organic phases were combined and washed again with 1MHCl (aq) then five times with brine solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo, to give a solid, which was purified by diethyl ether hexane (1:1) trituration to give 1-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-ethanone.