Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Br:16])[C:5]2[O:10][CH2:9][N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28].C(=O)([O-])[O-].[K+].[K+]>CC(O)C.O.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>[Br:16][C:4]1[C:5]2[O:10][CH2:9][N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)[CH:3]=1
Reactant: CC(C)(C)N1COc2c(Br)cc(Br)cc2C1
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)N1COc2c(Br)cc(-c3ccc(Cl)c(C(F)(F)F)c3)cc2C1
Temperature: 72 °C
Yield: 20.1 %

Procedure:
A mixture of 6,8-dibromo-3-(tert-butyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (Intermediate 6) (2.4 g, 6.92 mmol), (4-chloro-3-(trifluoromethyl)phenyl)boronic acid (1.628 g, 7.27 mmol), and potassium carbonate (1.434 g, 10.4 mmol) in 2-propanol (40 mL) and water (8 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (336 mg, 0.29 mmol) was added and the resulting mixture heated at 72° C. for 3 h then the cooled reaction mixture concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give a solid that was re-crystallized from ethyl acetate to give 8-bromo-3-(tert-butyl)-6-(4-chloro-3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.625 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)#[N:25].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:24]#[N:25])[CH:16]=1
Reactant: N#Cc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccccc1Cc1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 26.2 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(2-cyanobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.071 g; 0.203 mmol), 2-cyanophenylboronic acid (0.033 g; 0.226 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.046 g; 0.432 mmol), sodium iodide (0.065 g; 0.432 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.022 g (25%) of the title compound as a white solid.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>C1COCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
Powdered KOH (1.74 g, 30.65 mmol) was added to a vigorously stirred solution of pyridin-2-yl-methanol (2 mL, 20.72 mmol) in THF (100 mL) at 0° C. The reaction mixture was stirred for 15 minutes and tosyl chloride (5.13 g, 26.90 mmol) was then added. The reaction mixture was allowed to warm to RT and stirring was continued overnight. The reaction mixture was quenched with saturated NaHCO3 and the product was extracted with EtOAc (3×50 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo to give a yellow oil. The residue was purified by flash column chromatography using EtOAc: hexane (1:4) to yield the title compound (4.6 g, 85%) as a yellowish solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH3:30][N:31]([C:33]([NH2:35])=[O:34])[NH2:32]>CO>[CH3:30][N:31]([C:33]([NH2:35])=[O:34])/[N:32]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C:11]3([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH2:12][CH2:13]3)=[N:15][N:16]=2)[N:19]=1)\[CH3:24]
Reactant: CC(=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Reactant: CN(N)C(N)=O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\N(C)C(N)=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Yield: 40.9 %

Procedure:
A solution of 1-[3-(1-quinolin-6-yl-cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-ethanone (30 mg, 0.091 mmol), acetic acid (0.1 mL) and 1-methylhydrazinecarboxamide (16.2 mg, 0.18 mmol) in methanol (5 mL) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with DCM, washed with sat. aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel eluting with a CH2Cl2/MeOH gradient to afford the title compound (14.9 mg, 41%) as yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.84 (dd, 1H), 8.30 (d, 1H), 8.22 (d, 1H), 8.13 (d, 1H), 7.94-7.92 (m, 2H), 7.70 (dd, 1H), 7.49 (dd, 1H), 6.64 (s, 2H), 3.21 (s, 3H), 2.16 (s, 3H), 1.78-1.75 (m, 2H), 1.68-1.65 (m, 2H). LCMS (method A): [MH]+=401, tR=4.11 min.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=2)([CH3:3])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:18]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=2)[C:12]([CH:13]=[O:14])=[C:4]1[CH:1]([CH3:3])[CH3:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)c1[nH]c2cc([N+](=O)[O-])ccc2c1C=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1c(C=O)c2ccc([N+](=O)[O-])cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-isopropyl-6-nitro-1H-indole-3-carbaldehyde (Compound 121, 244 mg, 1.05 mmol) in DMF (10 ml) was added benzyl bromide (0.62 ml, 5.26 mmol) and K2CO3 (726 mg, 5.26 mmol). The reaction was stirred at room temperature for 16 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C@@H:17]2[CH2:21][C@H:20]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)[CH2:19][N:18]2C(OCC2C=CC=CC=2)=O)=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])[CH3:3]>C(O)C.[Pd]>[CH3:31][S:28]([N:25]1[CH2:26][CH2:27][N:22]([C@@H:20]2[CH2:19][NH:18][C@H:17]([C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]([O:5][C:2]([CH3:1])([CH3:4])[CH3:3])=[O:7])=[CH:9][CH:10]=3)=[O:16])[CH2:21]2)[CH2:23][CH2:24]1)(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.8 %

Procedure:
To a solution of the compound prepared in Example 5 (2.1 g, 7.4 mmol) in ethanol (100 mL) was added Pd/C (0.40 g, 20% by wt). The reaction was stirred under an atmosphere of hydrogen (50 psi) at room temperature for 6 h. The reaction mixture was filtered through diatomaceous earth and concentrated to give the title compound (1.10 g, 69%) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13].O.[OH-].[Na+]>C(OCC)C>[CH3:7][C:8]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:9][CH2:10][CH2:11][CH:12]([OH:14])[CH3:13]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)O
Temperature: 0 °C
Yield: 94.7 %

Procedure:
To a 3 liter three-neck flask equipped with a dropping funnel, a stirrer and a condenser were added 38 g of lithium aluminum hydride and 700 ml of ethyl ether in a nitrogen gas stream and the mixture was stirred while maintaining at 0 ° C. To this solution was added dropwise 262 g (1.0 mol) of compound (6) as obtained above dissolved in 500 ml of ethyl ether within about 1 hour and the mixture was further reacted under stirring at room temperature for about 13 hours. After the completion of the reaction, 380 ml of water and 380 ml of a 15% aqueous solution of sodium hydroxide were added to the reaction mixture. The white crystals thus formed were separated by filtering through 50 g of Celite, extracted with 500 ml of ethyl ether three times and then concentrated after dehydrating with sodium sulfate anhydride. 251 g of the oily substance thus obtained was purified by silica gel column chromatography (silica gel: 1000 g, developing solvent: hexane:ethyl acetate=2:1 by volume). Thus 250 g (yield: 94.7 %) of the target 6,10,14- trimethyl-5,9,13-pentadecatrien-2-ol, compound (3), was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:20][CH3:21])=O.[Li+].[BH4-]>C1COCC1>[CH2:20]([C:6]1[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:9][C:5]=1[CH2:3][OH:2])[CH3:21]
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1CO
Temperature: 25 °C

Procedure:
To a solution of 4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid methyl ester (4.63 g, 15.47 mmole) in THF (100 mL), is added LiBH4 in one portion at 0° C. The reaction is warmed up to room temperature and stirred for an hour. Additional LiBH4 is added and the reaction is heated at 60° C. for 30 minutes. The excess amount of LiBH4 is destroyed using 6N HCl (50 mL) dropwise at 0° C. The mixture is partitioned between ethyl acetate (300 mL) and brine (300 mL). The organic layer is washed with brine (3×300 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography, eluting with 60% ethyl acetate in hexane and concentrated to provide the titled compound as a white solid. Mass [EI+] 272 (M+H)+.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[C:6]1([S:12][C:13](Br)([F:15])[F:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C>[CH3:1][Si:2]([C:13]([S:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([F:15])[F:14])([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: FC(F)(Br)Sc1ccccc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)C(F)(F)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Into a mixture of 0.22 g (9.2 mmol) Mg turnings, 1.99 g (18.3 mmol) of TMSCl and 20 ml DMF at room temperature, was added 1.1 g (4.6 mmol) bromodifluoromethyl phenyl sulfide (24). The reaction was stirred at room temperature for another 1 h. Excess TMSCl was removed under vacuum (˜10 mmHg). The residue was washed with ice water and then extracted with dichloromethane (20 mL×3). The organic phase was further washed with brine and water successively, and dried over MgSO4. After solvent removal, the crude product was further purified by silica gel chromatography (pentane as eluent) to give 905 mg (85% yield) product 21 as colorless liquid, b.p. 86˜87° C./4 Torr. 1H NMR (500 MHz, CDCl3): δ0.25 (s, 9H); 7.37 (m, 3H); 7.59 (d, 2H). 13C NMR (125 MHz, CDCl3): δ−4.2; 126.3 (t, 3JC-F=4.1 Hz); 128.8; 129.3; 134.0 (t, 1JC-F=300.1 Hz); 136.2. 19F NMR (470 MHz, CDCl3): δ−88.1 (s). 29Si NMR (99 MHz, CDCl3): 7.7 (t, 2JSi-F=31.28 Hz). IR (neat): 3064; 2965; 2904; 1884; 1585; 1475; 1441; 1414; 1307; 1255; 1076; 1025; 962; 884; 850; 825; 744; 703; 690; 631; 607; 496 cm−1. GC-MS (m/z): 232 (M+), 109 (PhS+), 73 (Me3Si+). HRMS (DEI): m/z calculated for C10H14F2SSi (M+) 232.0553, found 232.0545.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=1)=[O:21]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1ccccc1NS(C)(=O)=O
Product: COc1ccc(C(=O)CCCCCBr)cc1NS(C)(=O)=O

Procedure:
Using N-(2-methoxyphenyl)methanesulfonamide (10.0 g) and 6-bromohexanoyl chloride (8.37 ml) according to the same method as that of Reference Example 1, the title compound (9.80 g) was obtained as colorless crystals.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[NH:8][CH2:9][CH2:10][C:4]2=[N:3][N:2]=1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>ClCCl>[CH:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[N:8]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[CH3:15])=[CH:29][CH:28]=3)=[O:26])[CH2:9][CH2:10][C:4]2=[N:3][N:2]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)NCCc1nncn1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3nncn3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5 mmol of 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and then 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then washed with water, aqueous NaHCO3 and brine. The solution is dried (Na2SO4) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel with ethyl acetate-hexane as solvent to give the desired product as a glass.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27](Cl)=[O:28].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[O:7])=[CH:22][CH:23]=1)=[O:28]
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1)c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 144 h
Yield: 240.8 %

Procedure:
A mixture of 300 mg (0.5 mmol) of 5-(4-aminobenzoyl)-5,6-dihydrophenanthridine and 230 mg of (0.55 mmol) of 2,6-dichlorobenzoyl chloride in 1.2 ml of pyridine is heated (100° C.) for 3 hr and then stirred at room temperature for 6 days. To the mixture is added 10 mg of 4-(dimethylamino)pyridine and the mixture stirred for 22 days. To the mixture is added 6 ml of 2N HCl and the solid filtered and washed with 2N HCl, 1N NaOH, H2O to give 0.57 g of solid. The solid is chromatographed on thick layer silica gel plates with hexane ethyl-acetate (1:1) to give 110 mg of solid. Recrystallization from CH2Cl2 -diisopropyl ether to give 73 mg of white crystals, m.p. 230°-235° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]1([CH2:21][OH:22])[CH2:20][O:19][CH2:18]1>C(#N)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:16][C:17]2([CH2:21][OH:22])[CH2:20][O:19][CH2:18]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CC2(CO)COC2)c1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
4-nitro-1H-pyrazole (0.5 g, 4.42 mmol) and K2CO3 (1.22 g, 8.84 mmol) were suspended in acetonitrile (30 mL) in a 2-necked flask under nitrogen and (3-(bromomethyl)oxetan-3-yl)methanol (1.36 g, 7.52 mmol) was added dropwise. The reaction was heated at 60° C. for 16 h and the solution was concentrated to about ⅓ of the volume under vacuum and then partitioned between DCM (50 mL) and water (50 mL). The organics were dried over Na2SO4, filtered and the solvent evaporated to give (3-((4-nitro-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methanol as a transparent oil (0.94 g, quantitative yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]([N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[O:42])=[CH:37][N:36]=4)[CH:29]=3)[C:18]=1[CH2:19][O:20]C(=O)C)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]([N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[O:42])=[CH:37][N:36]=4)[CH:29]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1c(-c2ccnc(Nc3ccc(C(=O)N4CCOCC4)cn3)c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-c4ccnc(Nc5ccc(C(=O)N6CCOCC6)cn5)c4)c3CO)ncc2c1
Reaction time: 2 h

Procedure:
Acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{2-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-pyridin-4-yl}-benzyl ester (200 mg, 0.31 mmol) was dissolved in methanol (10 ml). K2CO3 (86 mg, 0.62 mmol) was added at room temperature, and the mixture was stirred at that temperature for 2 hours. The mixture was poured into water (10 ml), extracted with DCM (100 ml) and then washed with saturated aqueous solution of sodium chloride (100 ml). The combined organic extract was dried over sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:2). The desired product was obtained as a white solid (130 mg, yield 69%). 1H NMR (300 MHz, MeOD): δ 8.36 (d, J=2.6 Hz, 1H), 8.22-8.18 (m, 2H), 7.73 (d, J=1.5 Hz, 2H), 7.65-7.60 (m, 2H), 7.57-7.51 (m, 1H), 7.50-7.46 (m, 1H), 7.38 (d, J=7.6 Hz, 2H), 7.00 (dd, J=5.2, 1.5 Hz, 1H), 4.36 (s, 2H), 3.59 (s, 8H), 1.36 (d, J=5.7 Hz, 9H). LC-MS: 609[M+1]+, tR=1.407 min. HPLC: 97.79% at 214 nm, 99.31% at 254 nm, tR=3.479 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12]C(=O)O)[S:11][C:7]=2[C:6]([CH:16]=[CH2:17])=[CH:5][CH:4]=1.O>C(O)CO>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:16]=[CH2:17])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(OC)c2nc(NC(=O)O)sc12
Solvent: OCCO
Solvent: O
Product: C=Cc1ccc(OC)c2nc(N)sc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
(4-Methoxy-7-vinyl-benzothiazol-2-yl)-carbamic acid methyll ester was dissolved in ethylenglycol/2N KOH (2:1) and stirred at 100° C. for 3 hrs. Then water was added and the mixture was extracted with CH2Cl2, the organic phase was washed with brine and dried over MgSO4. After evaporation the residue was crystallized from CH2Cl2. White crystals (64%); F.p.: 155-159° C.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([NH:5][C:6]1[C:11](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[CH:10][CH:9]=[C:8]([O:21][CH3:22])[N:7]=1)=[O:4].[H][H]>C(O)C.[Pd]>[CH3:23][C:2]([CH3:1])([CH3:24])[C:3]([NH:5][C:6]1[C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[CH:10][CH:9]=[C:8]([O:21][CH3:22])[N:7]=1)=[O:4]
Reactant: CCCCOC(=O)/C=C/c1ccc(OC)nc1NC(=O)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCOC(=O)CCc1ccc(OC)nc1NC(=O)C(C)(C)C
Yield: 98.8 %

Procedure:
A solution of butyl (2E)-3-[2-[(2,2-dimethylpropanoyl)amino]-6-(methyloxy)-3-pyridinyl]-2-propenoate (43.706 g, 131 mmol) in ethanol (450 ml) under argon at rt was treated with palladium on carbon (10% paste) (5.0 g, 47.0 mmol) and then stirred at rt under 1 atmosphere of hydrogen for 90 h. The reaction mixture was then filtered through a thin pad of Kieselguhr, washing the product through with further ethanol (200 ml). The solvent was then evaporated to give product as a yellow solid (43.549 g, 99%).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:7]=[C:6]([OH:19])[CH:5]=1)([CH3:3])[CH3:2].[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)#[N:21]>>[CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:7]=[C:6]([O:19][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(O)nc(-c2cccc([N+](=O)[O-])c2)n1
Reactant: N#Cc1ccc(CBr)cc1
Product: CC(C)c1cc(OCc2ccc(C#N)cc2)nc(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
The title compound was prepared from 6-isopropyl-2-(3-nitro-phenyl)-pyrimidin-4-ol (which was obtained in Intermediate 8) and 4-cyanobenzyl bromide according to Method A; LC retention time 3.71 min; MS: m/z (ESI) 375 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[C:5]([F:20])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:51]=[CH:50][C:33]([C:34](Cl)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)=[CH:32][CH:31]=1>ClCCl>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([C:34]([NH:18][C:10]2[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]3[C:5]([F:20])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)([CH3:19])[N:9]=2)([C:33]2[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:40][CH:39]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2nc(Br)ccc2F)C1(F)F
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
To a solution of (R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (106 mg, 0.301 mmol) and triethylamine (60.9 mg, 0.602 mmol) in dichloromethane (3 ml) was added solid 4,4′-dimethoxytrityl chloride (112 mg, 0.331 mmol) under argon atmosphere. The green solution was stirred at rt for 2 hrs and was then evaporated in vacuo. The crude product was taken up with ethyl acetate and washed with aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered and evaporated. Filtration over silica gel (4.4 g, toluene/ethyl acetate 6:4) afforded the title compound as a blue-gray foam (202 mg, 96%).