Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:16]([C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)[N:17]=[CH:18][CH:19]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.S(C1C=CC(C)=CC=1)(O[CH2:34][F:35])(=O)=O>>[F:35][CH2:34][O:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:16]([C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)[N:17]=[CH:18][CH:19]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccn(-c2cccc(O)c2)nc1-c1ccnn1-c1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Product: O=c1ccn(-c2cccc(OCF)c2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 1-(3-Hydroxy-phenyl)-3-(2-naphthalen-1-yl-2H-pyrazol-3-yl)-1H-pyridazin-4-one (example 276) and fluoromethyl tosylate according to the method described in example 290. MS: M=413.1 (M+H)+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@@H:10](CC([O-])=O)[CH2:9]1.C(=O)([O-])[O-:27].[K+].[K+]>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@@H:10]([OH:27])[CH2:9]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CC(=O)[O-])C[C@@H](OC2CCCCO2)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)C[C@@H](OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate (6, 3.5 parts, 9.16 mmol) was dissolved in dry methanol (25 parts). To the solution anhydrous potassium carbonate (0.828 parts, 6 mmol) was added and the mixture was stirred at room temperature for 2 hr. Methanol was removed under vacuum and residue was extracted several times with dichloromethane. Dichloromethane layers were combined and washed with water followed by brine wash. It was dried on anhydrous sodium sulfate. Solvent was removed under vacuum and residue was purified by flash column chromatography to yield 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexan-1-ol (7, yield 3 parts, 96%).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][NH:15][C:16]([C:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=1[CH2:27][CH2:28][CH2:29][CH3:30])=[O:17])[CH:8]=[CH:7]2>CC(O)=O>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH2:14][NH:15][C:16]([C:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=1[CH2:27][CH2:28][CH2:29][CH3:30])=[O:17])=[CH:10]2
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2cc(O)ccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Bromine (210 μL, 4.02 mmol) in 50 mL of glacial HOAc was added under nitrogen dropwise over 2 h to a solution of 2-butyl-benzofuran-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (1.5 g, 4.02 mmol), prepared in step 2 of Example 8, in 300 mL of glacial HOAc at room temperature. After the addition the reaction was stirred at room temperature for 20 h (overnight). The solid formed was collected by filtration and dried under reduced pressure to give 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (1.41 g, 81%) as a light gray solid, mp 192-193° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](Cl)=[O:37])(=[O:28])[CH3:27]>>[C:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:37])(=[O:28])[CH3:27]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OC(C)=O)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-(chlorocarbonyl)phenyl acetate as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([CH2:20][CH2:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:19]=[CH:18][CH:17]=[N:16]1>>[N:15]1([CH2:20][CH2:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH:4]=3)=[O:30])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: O=C(O)c1ccc(S(=O)(=O)CCn2cccn2)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCn2cccn2)cc1

Procedure:
250 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with pyrazole to yield 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-(1H-pyrazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 467.0 (M)+.
Reaction SMILES: C[C:2]1([CH3:18])[O:7][C:6](=[O:8])[CH:5]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C)[C:4](=[O:17])O1.OCC[C:22]#[N:23]>C1(C)C=CC=CC=1>[O:17]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:5]([C:6]([O:7][CH2:2][CH2:18][C:22]#[N:23])=[O:8])[CH2:4]1
Reactant: CCCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Reactant: N#CCCO
Solvent: Cc1ccccc1
Product: N#CCCOC(=O)C1CCCCCCOC1

Procedure:
A mixture of 2,2-dimethyl-5-(1-oxoheptyl)-1,3-dioxane-4,6-dione (29.4 mmol) and 3-hydroxypropionitrile (4.48 g, 63.0 mmol) in 25 mL of dry toluene were heated at reflux temperature for 1 hour. The solvent was removed in vacuo, and the residue was chromatographed on silica gel to give the title compound as a viscous oil, which was used in the next step after spectral characterization.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:13]([CH3:16])=[N:14][NH:15][C:7]=12>C1(C)C(C)=CC=CC=1>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:13]([CH3:16])=[N:14][NH:15][C:7]=12
Reactant: NCCO
Reactant: Cc1cc(Cl)c2[nH]nc(C)c2n1
Solvent: Cc1ccccc1C
Product: Cc1cc(NCCO)c2[nH]nc(C)c2n1
Yield: 66 %

Procedure:
A mixture of ethanolamine (1.0 g, 0.016 mole) and 7-chloro-3,5-dimethyl-1H-pyrazolo[4,3-b]pyridine (1.0 g) in dry xylene (20 ml) was heated under reflux for 48 h. After cooling, the brown oil in the reaction vessel solidified. The solvent was then decanted off and the solid washed several times with xylene. The brown solid was dissolved in aqueous methanol and the pH adjusted to pH 8-9 with 10% sodium carbonate solution. The resulting solid was filtered off, dried and recrystallised from chloroform/methanol to give the title compound as a white solid (0.750 g, 71%), m.p. 225°-230° C. (Found: C, 58.29; H, 6.89; N, 27.06. C10H14N4O requires C, 58.18; H, 6.84; N, 27.17%).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:38])C.[OH-].[Na+].Cl>C(O)C>[CH3:38][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCCCN3CCOCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccccc3)cc(OCCCN3CCOCC3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.28 mmol) was dissolved in ethanol (15 mL), and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 110 mg. HPLC-MS: m/z: 518.1 (M+H); Rt: 1.86 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].[NH2:21][CH2:22][C@@H:23]([C:25]1[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=1)[OH:24]>>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([NH:21][CH2:22][C@H:23]([OH:24])[C:25]3[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(S(=O)(=O)NCCO)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)NCCO)cc3)CC2)ccc1O

Procedure:
The title compound was prepared according to the procedure of Example 1 from 0.12 g (0.4 mmol) of Reference Example 30, N-(2-hydroxyethyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, and 0.12 g (0.5 mmol) of (R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide, yielding 0.22 g of an off-white solid; m.p. 78-81° C.; MS (ES) m/z 529.2 (MH+); HRMS (ES) Calcd. for C22H33N4O7S2 (MH+): 529.1785, Found: 529.1779.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:14])[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].I[CH2:16][CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:14])[C:7]([CH2:16][CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: ICCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCc1cccs1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
Sodium hydride (55%, 18.8 g, 0.43 mol) was suspended in dimethylformamide (200 ml), and methylmalonic acid diethylester (50.0 g, 0.29 mol) was slowly added thereto for 30 minutes in an ice bath, and then the reaction solution was stirred for 30 minutes. To the reaction solution was added 2-(2-iodoethyl)thiophene (75.2 g, 0.32 mol) dissolved in dimethylformamide (200 ml) under-a nitrogen atmosphere for 15 minutes, and then the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was poured into ice-cold 10% hydrochloric acid (500 ml), and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=10:1-5:1) to afford the title compound (53.1 g, 65% yield) as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)=[O:2].CC[N:21]([CH:25]([CH3:27])C)[CH:22]([CH3:24])C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCC1>CN(C=O)C>[N:21]1([C:11]([C:10]2[CH:9]=[C:8]([CH:16]=[CH:15][CH:14]=2)[O:7][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:18][CH:17]=2)=[O:13])[CH2:22][CH2:24][CH2:27][CH2:25]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=Cc1ccc(Oc2cccc(C(=O)O)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1 g (4.1 mmol) of 3-(4-formyl-phenoxy)-benzoic acid were dissolved in 25 ml DMF and combined with 0.86 ml (4.95 mmol) of DIPEA and 1.32 g (4.1 mmol) of TBTU, stirred for 5 min at ambient temperature and then 0.29 g (4.1 mmol) of pyrrolidine were added. The mixture was stirred at ambient temperature, filtered through basic Alox, concentrated by rotary evaporation and purified by chromatography (silica gel column, dichloromethane with gradient of 0-10% methanol).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2OS(C(F)(F)F)(=O)=O)[S:4][C:3]=1[C:19](=[O:21])[NH2:20].[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCOCC1>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:32]2[CH2:33][CH2:34][N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:30][CH2:31]2)[S:4][C:3]=1[C:19]([NH2:20])=[O:21]
Reactant: NC(=O)c1sc2nccc(OS(=O)(=O)C(F)(F)F)c2c1N
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: C1COCCO1
Product: NC(=O)c1sc2nccc(N3CCN(Cc4ccccc4)CC3)c2c1N
Reaction time: 8 h

Procedure:
A mixture of 20 mg trifluoromethanesulfonic acid 3-amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl ester and 50 microL of N-benzylpiperazine in 1 mL of dry dioxane was purged with N2 and capped and left at room temperature overnight. The reaction was diluted with EtOAc, washed four times with water, dried and concentrated to dryness in vacuo. The product was purified on a 2 mm silica gel prep plate, developing and eluting the band with MeOH—CH2Cl2 mixtures and then concentrating to dryness. The product was re-dissolved in 5-10% MeOH—CH2Cl2, filtered to remove silica gel, concentrated, and dried in vacuo at 60° C. overnight to provide 7.9 mg of the title compound as a beige solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:24]C)=[C:15]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:16]=1)=[O:10])=[O:5])C.Cl.N1C=CC=CC=1>O>[C:4]([C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([OH:24])=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:16]=1)=[O:10])([OH:5])=[O:3]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OC
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)CCc1cc(C(=O)c2cccc(C(=O)O)c2)ccc1O
Temperature: 180 °C
Yield: 91.7 %

Procedure:
A mixture of 41.5 g of 5-[3-(ethoxycarbonyl)benzoyl]-2-methoxybenzenepropanoic acid, ethyl ester and 410 g of pyridine hydrochloride were heated at 180° C. for 4 hours. After cooling, water was added to the mixture while hot. As the mixture cooled, the title product precipitated from solution. Filtration of the solids and crystallization from ethanol/water provided 31.1 g of the title product, m.p. 197°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:15](I)=[CH:16][C:9]=23)[CH:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=2)O1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:15]([C:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc(F)cc1-c1ccnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1ccnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Temperature: 80 °C

Procedure:
A mixture of Example 87B (1.600 g, 3.15 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.071 g, 3.46 mmol), tetrakistriphenylphosphine palladium (0.182 g, 0.157 mmol), and aqueous sodium bicarbonate solution (15 mL) in N,N-dimethylformamide (60 mL) was degassed with nitrogen and heated at 80° C. for 3 hours. After cooling, the mixture was quenched with water and brine and extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated, and purified on silica gel using an ISCO Companion flash system eluting with heptane/ethyl acetate (65:35 to 5:5) to afford the title compound. MS (ESI+) m/z 564.1 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].Cl[CH2:4][C:5]1[C:14]2[C:9](=[C:10]([CH3:16])[C:11]([OH:15])=[CH:12][CH:13]=2)[O:8][C:7](=[O:17])[CH:6]=1.Cl>>[OH:15][C:11]1[CH:12]=[CH:13][C:14]2[C:5]([CH2:6][C:7]([OH:17])=[O:1])=[CH:4][O:8][C:9]=2[C:10]=1[CH3:16]
Reactant: [OH-]
Reactant: Cc1c(O)ccc2c(CCl)cc(=O)oc12
Agent: Cl
Agent: [Na+]
Product: Cc1c(O)ccc2c(CC(=O)O)coc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 1M NaOH (89 mL) and 4-(chloromethyl)-7-hydroxy-8-methyl-2H-chromen-2-one (4.0 g) was stirred at 100° C. for 1 h. After cooling, the reaction mixture was acidified with 6N HCl. The precipitate was collected by filtration, and washed with water and hexane to give the title compound (2.62 g). The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The solid was washed with hexane to give the title compound (831.4 mg). Total yield: 3.45 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([NH2:9])=[O:8])[CH3:2].Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:8][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:9]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOc1ccc(C(N)=O)cc1OCC
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1coc(-c2ccc(OCC)c(OCC)c2)n1
Yield: 85 %

Procedure:
Using 10.4 g of 3,4-diethoxybenzamide and 19.5 g of ethyl 3-bromo-2-oxopropionate and following the procedure of Reference Example 5, 12.9 g of white powdery ethyl 2-(3,4-diethoxyphenyl)oxazole-4-carboxylate was obtained.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:26][Si](C(C)(C)C)(C)C)=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:7]1=[O:34].O.[OH-].[Li+]>C1COCC1.O>[OH:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[C:16]([CH2:15][N:8]1[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([CH2:5][CH2:4][C:3]([OH:35])=[O:2])[C:7]1=[O:34])=[CH:17][CH:18]=[CH:19]2
Reactant: COC(=O)CCn1c(=O)n(Cc2cccc3cc(O[Si](C)(C)C(C)(C)C)ccc23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCn1c(=O)n(Cc2cccc3cc(O)ccc23)c2ccccc21
Yield: 10.1 %

Procedure:
To a stirred solution of 3-{3-[6-(tert-Butyl-dimethyl-silanyloxy)-naphthalen-1-ylmethyl]-2-oxo-2,3-dihydro-benzimidazol-1-yl}-propionic acid methyl ester (200 mg, 0.41 mmol) in THF (7 ml) and water (1 ml) was added lithium hydroxide monohydrate (26 mg, 0.61 mmol) at ambient temperature. Upon complete consumption of the starting material the reaction was diluted with water, ethyl acetate and 6N HCl (adjusted to pH=2). The layers were separated and the aqueous phase was extracted once with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated. The remaining residue was diluted with acetonitrile (3 ml) and allowed to stand over night. The resulting precipitated product was collected via filtration, washed with acetonitrile and dried on house vacuum to give 15 mg (10%) of the desired product. LCMS (ESMS): m/z 363.38 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C(OCC)(=O)C.CCCCCC>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]3[O:10][C:9]([CH3:21])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[C:13]=2[CH3:20])=[O:28])=[CH:25][CH:24]=1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccc(F)cc1
Yield: 75 %

Procedure:
By using 3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 75%. Melting point: 232-234° C. (Ethyl acetate-hexane).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[N+:9]([C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[C:14]([S:18]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1Br
Yield: 55 %

Procedure:
3-Nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared in the same manner as described in Example 30 from 5-amino-4-bromo-3-methylisoxazole and 3-nitrobenzenesulfonyl chloride in 55% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 151-153° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21])#[N:16].C1CCN2C(=NCCC2)CC1>CN1CCCC1=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([C:15]#[N:16])[CH:18]=2)=[N:4][N:3]=1
Reactant: N#Cc1ccc2c(Cl)nnc(Cl)c2c1
Reactant: COc1ccc(CN)cc1C#N
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1C#N

Procedure:
1,4-Dichlorophthalazine-6-carbonitrile and 3-cyano-4-methoxybenzylamine were stirred at room temperature in 1-methyl-2-pyrrolidinone in the presence of DBU, whereby 1-chloro-4-[(3-cyano-4-methoxybenzyl)amino]-6-phthalazine carbonitrile was obtained as a less polar product.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([N:7]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:21][NH2:22]>CCO>[Br:17][C:15]1[CH:16]=[C:11]2[C:12]([N:7]3[C:8]([CH2:9][O:10]2)=[N:22][NH:21][C:4](=[O:3])[C@H:5]3[CH3:6])=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@@H](C)N1C(=S)COc2cc(Br)ccc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)ccc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a mixture of (R)-2-(7-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (60 g, 174 mmol) in EtOH (800 mL) was added hydrazine hydrate (98%, 17.4 g, 349 mmol) and the reaction mixture was stirred at ambient temperature overnight. The precipitate was collected by filtration and washed with cold EtOH (3×80 mL) to give (R)-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (32.5 g, 59%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.23 (s, 1H), 7.21 (s, 2H), 4.78 (q, J=6.8 Hz, 1H), 4.68-4.60 (m, 2H), 1.29 (d, J=6.8 Hz, 3H). SFC (Table 1, Method 31) Rt=6.114 min.; [α]D20=−342.08 (C=0.002 g/mL in methanol).