Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=1)C.O[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:26][C:25]2=[O:38].CC(OC(/N=N/C(OC(C)C)=O)=O)C.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][O:17][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[O:28][C:27]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:26][C:25]3=[O:38])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)C(Cc1ccc(C#CCCO)cc1)OC
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: Cc1ccccc1
Product: CO[C@@H](Cc1ccc(C#CCCOc2ccc3oc(-c4ccccc4)cc(=O)c3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(4-Hydroxy-but-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 47, Step A and 6-hydroxyflavone following the standard coupling-hydrolysis procedure A using toluene as solvent and DIAD instead DEAD. MS(ES) for C29H24O6 [M+H]+: 469.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[OH-].[K+].[CH:12]1([SH:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:17][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][N:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: SC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(CSC2CCCC2)cn1
Reaction time: 16 h
Yield: 82 %

Procedure:
Slurry 2-chloro-5-chloromethyl-pyridine (8.1 g, 45 mmol) and potassium hydroxide (10.3 g, 225 mmol) in methanol at 0° C. under nitrogen atmosphere. Add cyclopentyl mercaptan (4.8 mL, 45 mmol), warm the mixture to room temperature and stir for 16 h. Concentrate in vacuo and partition the residue between water (50 mL) and DCM (200 mL). Collect the organic phase, concentrate in vacuo and purify the crude mixture by chromatography on silica gel (330 g) eluting with hexane/EtOAc (49:1 to 4:1 gradient) to obtain the desired intermediate as an oil (8.4 g, 82%). MS (APCI+) m/z: 227 (M)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH2:23]([O:28][C:29]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=1[CH:31]=O)[CH2:24][CH:25]([CH3:27])[CH3:26].[O-]CC.[Na+]>C(O)C>[CH2:23]([O:28][C:29]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=1/[CH:31]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=1)[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: COc1cccc(C=O)c1OCCC(C)C
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCCC(C)C
Yield: 49.3 %

Procedure:
The title compound was prepared by condensation of Intermediate 15 (350 mg, 1.071 mmol) with 2-isopentyloxy-3-methoxybenzaldehyde (334 mg, 1.501 mmol) in the presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to afford 280 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J=6.3 Hz, 6H), 1.45 (q, J=6.6 Hz, 2H), 1.85-1.91 (m, 1H), 3.77 (s, 3H), 3.86 (t, J=6.6 Hz, 2H), 6.86-6.94 (m, 2H), 7.00-7.06 (m, 2H), 7.46-7.51 (m, 5H), 7.99 (d, J=4.8 Hz, 1H), 8.07 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 531.20 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:11][CH:10]([CH3:12])[C:9](=[O:13])[CH:3]([NH:2][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([CH3:14])=[CH:16][CH:17]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(N)C(=O)C(C)C
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g of ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride and 7.4 g of 4-methylbenzoyl chloride are dissolved in 250 ml of dichloromethane, and 13.3 ml of triethylamine are slowly added dropwise at 0° C. The mixture is stirred at room temperature for one hour and then washed with water, the organic phase is separated off and dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 13 g of ethyl 4-methyl-2-(4-methylbenzoylamino)-3-oxopentanoate as an oil. C16H21NO4 (291.35), MS (ESI)=292 (M+H+).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][CH:8]([CH3:10])[CH2:7]1)=O.[OH-].[Na+]>CCO.C(Cl)(Cl)Cl>[CH3:10][CH:8]1[CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)([NH2:5])[CH2:9]1
Reactant: CC1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC1CC(N)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A mixture of 2,2,2-trifluoro-N-(3-methyl-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-12) (3.3 mg, 0.006 mmol) and NaOH (5M in water, 0.30 mL) in EtOH (3 mL) was stirred at 70° C. for 15 hours. The mixture was diluted with CHCl3, washed with water and brine, dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC eluting with 10% MeOH in CHCl3 to give 3-methyl-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine (4-13) as a white form. HRMS (M+H)+: observed=484.2250, calculated=484.2243.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:6]=1)=[NH:4].[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=O)=[CH:28][N:27]=1>>[F:14][C:11]([F:12])([F:13])[C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[N:6]=[C:5]([C:3]2[N:4]=[C:30]([C:29]3[CH:33]=[CH:34][C:26]([NH2:25])=[N:27][CH:28]=3)[O:1][N:2]=2)[N:10]=1
Reactant: N=C(NO)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Reactant: Nc1ccc(C(=O)O)cn1
Product: Nc1ccc(-c2nc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)no2)cn1

Procedure:
The title compound was prepared from N-hydroxy-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxamidine (example C.2) (0.176 g, 0.5 mmol) and commercially available 6-amino-nicotinic acid (0.07 g, 0.5 mmol) according to the general procedure V. Obtained as an off-white solid (0.055 g, 24%). MS (ISP) 453.1 [(M+H)+]; mp 205° C.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>CO>[CH2:19]([NH:20][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NCCCCCCN
Reactant: CCCCCCCCCC1CO1
Solvent: CO
Product: CCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCC
Reaction time: 8 h

Procedure:
A solution of 1-undecene oxide (88.8 g.), hexamethylenediamine (1,6-hexanediamine, 30.3 g.) and methanol (400 ml.) was allowed to stand at 0° C. overnight, then at room temperature over the weekend. The solid was collected and recrystallized from ethanol, affording N,N'-(1,6-hexylene)-bis[2-hydroxyundecylamine] (I: R= CH3 (CH2)8, R' = X= (CH2)6 ; Z= H)(m.p. 122.6°-129.0° C.).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][C:13]3=[N:12][C:4]=1[CH:5]=[N+:6]2[O-].[NH4+:18].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][C:13]3=[N:12][C:4]=1[C:5]([NH2:18])=[N:6]2
Reactant: [O-][n+]1cc2nc3n(c2c2ccccc21)OCC3
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc1n2OCC1
Reaction time: 0.08 h

Procedure:
A solution of 8,9-dihydroisoxazolo[2′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (0.0499 g, 0.220 mmol) in dichloromethane from the previous step was treated with 1.5 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (0.046 g, 0.242 mmol) was carefully added. Rapid stirring was continued for 5 minutes. The reaction mixture was then diluted with more dichloromethane, washed successively with dilute aqueous K2CO3, H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Chromatography (SiO2, 0-15% CMA/CHCl3) gave 0.015 g of 8,9-dihydroisoxazolo[2′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a brown solid, mp greater than 300° C.
Reaction SMILES: CCN(CC)CC.[CH:8]([O:11][C:12]1[CH:17]=[C:16]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:15]([CH3:24])=[CH:14][C:13]=1[NH:25][C:26]1[N:27]=[C:28]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[S:43]([CH:46]([CH3:48])[CH3:47])(=[O:45])=[O:44])[C:29]2[C:34]([CH3:35])=[CH:33][NH:32][C:30]=2[N:31]=1)([CH3:10])[CH3:9].Br[CH2:50][C:51]([NH2:53])=[O:52]>CN(C=O)C>[CH:8]([O:11][C:12]1[C:13]([NH:25][C:26]2[N:27]=[C:28]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S:43]([CH:46]([CH3:48])[CH3:47])(=[O:44])=[O:45])[C:29]3[C:34]([CH3:35])=[CH:33][NH:32][C:30]=3[N:31]=2)=[CH:14][C:15]([CH3:24])=[C:16]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:50][C:51]([NH2:53])=[O:52])[CH2:20][CH2:19]2)[CH:17]=1)([CH3:10])[CH3:9]
Reactant: NC(=O)CBr
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)c[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)c[nH]c3n2)c(OC(C)C)cc1C1CCN(CC(N)=O)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
82 uL of Et3N (0.69 mmol) was added into a solution of 40 mg N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (11) (0.069 mmol) and 28.5 mg 2-bromoacetamide (0.207 mmol) in 1 mL of DMF. The reaction mixture was heated to 100° C. and stirred for 10 minutes under microwave irradiation. After cooling to room temperature, the solvent was removed under vacuum and the residue was redissolved in 1 mL of DMSO and purified by mass-triggered HPLC to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10]CC)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:13]([C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17](Cl)[N:16]=1)[CH3:14]>C(O)C.CCN(CC)CC>[CH2:13]([C:15]1[N:20]=[C:19]([N:5]2[CH2:4][CH2:3][C:2]([CH3:1])([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]2)[CH:18]=[CH:17][N:16]=1)[CH3:14]
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: CCc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1nccc(N2CCC(C)(C(=O)O)CC2)n1
Reaction time: 20 h

Procedure:
1-(2-Ethylpyrimidin-4yl)-4-methyl-piperidine-4-carboxylic acid was prepared on a 3 mmol 4-methyl-4-ethoxycarbonyl-piperidine (as TFA salt) in 7 ml ethanol and 1 ml Et3N treated with a solution of 0.531 g 2-ethyl-4,6-dichloropyrimidine in 4 ml ethanol. After 20 hours at ambient temp. The ethanol was removed and the residue partitioned between water and ethanol, washed with sodium hydrogen carbonate solution and brine. Evaporated to give gum (88.3%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:14])[NH:7][C:8]([CH:11]2[CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:15]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:14])[C:5]([CH:2]([NH:1][C:20]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:21])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CC2)[nH]c1=O
Reactant: O=C(Cl)C1CCCC1
Product: CCC(NC(=O)C1CCCC1)c1nnc(C2CC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 250 mg (1.29 mmol) 6-(1-aminopropyl)-3-cyclopropyl-1,2,4-triazin-5(4H)-one, 170 mg (1.29 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:22]=[CH:21][C:10]([CH:11](CO)[O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[CH:9][C:8]=2[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24](O)C>[C].[Pd]>[CH2:1]([C:7]1[CH:22]=[CH:21][C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:9][C:8]=1[CH3:23])[C:6]1[CH:24]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: CCO
Reactant: Cc1cc(C(CO)OC2CCCCO2)ccc1-c1ccccc1
Agent: [Pd]
Product: Cc1cc(COC2CCCCO2)ccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
2-(4-Phenylhydroxymethyl-3-methylbenzyloxy)tetrahydropyran (2.5 g, 8 millimol) was dissolved in ethanol (20 ml). 5%-palladium carbon was added at a catalytic amount, and stirred at room temperature under hydrogen atmosphere for 6 days. After the insoluble material was distilled away, the filtrate was concentrated, and the residue was separated and purified by using a silica-gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (1.65 g, 5.6 millimol).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1Cl)[C:4]#[N:5].[OH:19]S(O)(=O)=O>O>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([NH:6][CH:3]([CH:2]([CH3:18])[CH3:1])[C:4]([NH2:5])=[O:19])=[CH:8][CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1Cl
Solvent: O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1)C(N)=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 3.63 g (0.015 mol) of the above nitrile, 10 ml of conc. H2SO4 and 0.5 ml of water, under nitrogen, is allowed to stand at room temperature for about 24 hours. The mixture is poured onto about 40 g of ice and extracted with ether. The ether extracts are washed with water and brine, dried over sodium sulfate and solvent removed to give 2-(4-trifluoromethylphenylamino)-3-methylbutyramide (VI; R is hydrogen), which can be recrystallized from ether/hexane, m.p. 93°-94°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][CH:15]2[S:19][C:18](=[O:20])[NH:17][C:16]2=[O:21])=[CH:12][CH:11]=1)[CH3:8].Br[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][CH:15]2[S:19][C:18](=[O:20])[N:17]([CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:16]2=[O:21])=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(CC2SC(=O)N(CCNC(=O)OC(C)(C)C)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (1.40 g, 9.68 mmol) was added to a solution of compound 4 (303 mg, 1.21 mmol) in 4 mL of anhydrous DMF at 0° C. After stifling the reaction mixture for 20 min, a solution of tert-butyl (2-bromoethyl)carbamate (268 mg, 1.21 mmol) in anhydrous DMF (2 mL) was added and then the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched by adding water and then extracted with ethyl acetate. The ethyl acetate layer was washed with 10% NH4Cl aqueous solution followed by water and dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (20% ethyl acetate in hexanes) to afford compound 5 in 53.1% (253 mg) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][O:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:28])=[C:23]([CH:27]=2)[C:24]([OH:26])=O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH:1]1([CH2:6][O:7][NH:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:28])=[C:23]([C:24]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:26])[CH:27]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccc1F
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cc(CNc3ccccc3C(=O)NOCC3CCCC3)ccc2F)CC1

Procedure:
Prepared by a similar procedure as described for the preparation of Example 499, starting from 5-[(2-cyclopentylmethoxycarbamoyl-phenylamino)-methyl]-2-fluoro-benzoic acid (Example 496) and 1-methyl-piperazine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ncc([N+](=O)[O-])c(O)n1
Product: Nc1ncc([N+](=O)[O-])c(Cl)n1

Procedure:
A suspension of 2-amino-4-hydroxy-5-nitropyrimidine (5.0 g, 32.1 mmol) in phosphorous oxychloride (100 mL) was refluxed overnight, and the excess phosphorous oxychloride was evaporated under reduced pressure. The residue was mixed with ice (100 g) in an ice-bath, and the mixture was neutralized with concentrated aqueous sodium carbonate solution. A yellow precipitate was collected by filtration and washed with water: yield, 1.39 g (25%); mp 191°-194° C. dec.; 1H NMR δ8.45 (br s, 2H, NH2, exchange with D2O), 9.03 (s, 1H, H-6); MS (EI) calcd. m/z for C4H3N4O235Cl 173.9944, found 173.9934; calcd. m/z for C4H3N4O237Cl 175.9915, found 175.9916.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[CH:11]([O-])([O-])[O:12]CC.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[OH:10][C:7]1[CH:6]=[C:4]2[O:5][CH2:1][O:2][C:3]2=[CH:9][C:8]=1[CH:11]=[O:12]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCOC([O-])[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=Cc1cc2c(cc1O)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
To a mixture of sesamol (8.28 g), ethyl orthoformate (53.58 g) and benzene (120 ml), powdered anhydrous aluminum chloride (12.0 g) was added, followed by stirring at room temperature for 1 hour. The mixture was then poured into 5% hydrochloric acid (180 ml) and stirred at room temperature for 30 minutes. After the insoluble substance was filtered off, the filtrate was extracted with ether. The ether layer was washed with water and dried (MgSO4), after which the solvent was evaporated off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:8, v/v) to yield 2-hydroxy-4,5-methylenedioxybenzaldehyde (3.48 g, 35%) having a melting point of 128°-129° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:17]1[CH:18]=[N:19][N:20]([CH:22]2[CH2:26][CH2:25][O:24][CH2:23]2)[CH:21]=1>O1CCCC1>[Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:26][CH2:25][O:24][CH2:23]3)[CH:21]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Ic1cnn(C2CCOC2)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2cnn(C3CCOC3)c2)cc1

Procedure:
4-[tert-Butyl(dimethyl)silyl]oxyaniline (0.92 g, 3.48 mmol) and 4-iodo-1-tetrahydrofuran-3-yl-pyrazole (0.78 g, 3.48 mmol) dissolved in anhydrous tetrahydrofuran (20 mL) are stirred for one hour at ambient temperature in the presence of sodium tert-butylate (1.7 mL, 2M solution in THF) and chloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (84 mg, 0.122 mmol). The reaction mixture is filtered over Celite and then evaporated to dryness. The residue is crystallised from a mixture of heptane/ethyl acetate, filtered and washed with heptane and then purified by chromatography over silica gel using dichloromethane and methanol as eluants to yield the expected product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([C:10](=[O:30])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[C:19](=O)[NH:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([C:10]1[O:30][C:19](=[N:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[C:13]2[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cccc(Cl)c1C(=O)Nc1cc(F)cc(F)c1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2c(=Nc2cc(F)cc(F)c2)o1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A 100-mL, three-neck, round bottomed flask equipped with a magnetic stirrer and thermometer was purged with nitrogen and charged with compound 168 (3.30 mmol), anhydrous methylene chloride (25 mL), N,N-diisopropylethylamine (4.60 g, 35.7 mmol) and triphenylphosphine (3.98 g, 15.2 mmol). The reaction mixture was then cooled to 0-5° C. in an ice/water bath. Iodine (3.61 g, 14.2 mmol) was then added portion-wise to the reaction mixture over 1 h. Once the addition was complete, the cooling bath was removed, and the mixture was stirred at room temperature for an additional 30 min. The reaction was then quenched with 10% aqueous potassium carbonate (25 mL), the organic layer separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography of the resulting solid (silica gel, EtOAc/hexanes) gave a 52% yield of compound 169 as a white solid. m.p. 117-118° C.; 1H NMR (DMSO-d6) δ (ppm) 7.72-7.60 (m, 2H), 7.42 (dd, 1H, J=7.6 Hz, 1.3 Hz), 7.31 (d, 1H, J=7.0 Hz), 6.95 (t, 1H, J=9.3 Hz), 6.82 (m, 2H), 4.27 (m, 1H), 1.33 (s, 9H), 1.28 (d, 3H, J=7.2 Hz); m/z=436 (M+H). The reaction described above and compound 169 are shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]([NH2:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>N1C=CC=CC=1.ClC1C=CC=CC=1Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:21]([NH:22][S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=3)(=[O:35])=[O:34])=[N:20][C:19]3[C:14]([N:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1cc(Nc2nc3ccccc3nc2N)cc(OC)c1
Solvent: Clc1ccccc1Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(S(C)(=O)=O)c2)cc(OC)c1
Temperature: 100 °C
Yield: 21 %

Procedure:
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine (50 mg, 0.17 mmol), 3-(methylsulfonyl)benzenesulfonyl chloride (64 mg, 0.26 mmol, commercially available from Matrix) are dissolved in a 1 to 1 mixture of pyridine and 1,2-dichlorobenzene (0.4 ml) and the reaction mixture is heated at 100° C. in the microwave for 20 min. When TLC confirms the total consumption of the starting material, the reaction mixture is cooled down to rt. The precipitate formed is filtered and purified by column chromatography, using CHCl3: MeOH as eluent, to afford 18 mg (21%) of the title compound as a light brown solid. HPLC (max plot) 84%, rt. 4.2 min. LC/MS: (ES+): 515.