Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[CH2:4]([OH:9])[CH2:5][C@@H:6]([OH:8])[CH3:7].[C:10]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].[Cl-].[NH4+]>C(N(CC)CC)C>[Si:14]([O:9][CH2:4][CH2:5][C@@H:6]([OH:8])[CH3:7])([C:10]([CH3:13])([CH3:12])[CH3:11])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@H](O)CCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice cooling, to a dichloromethane solution (20.0 ml) of (S)-1,3-butanediol (519 mg) were added triethylamine (1.04 ml) and tert-butylchlorodiphenylsilane (1.63 ml), followed by stirring at room temperature overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford (2S)-4-{[tert-butyl(diphenyl)silyl]oxy}butan-2-ol (1.69 g).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>CS(O)(=O)=O>[Cl:14][C:12]1[CH:13]=[C:2]([Cl:1])[C:3]2[O:4][CH2:5][CH2:6][C:7](=[O:9])[C:10]=2[CH:11]=1
Reactant: O=C(O)CCOc1ccc(Cl)cc1Cl
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: O=C1CCOc2c(Cl)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
3-(2,4-Dichlorophenoxy)propionic acid (52.36 g, 0.223 mol) is added portion-wise to a mixture of phosphorus pentoxide (70.98 g, 0.490 mol) in methanesulfonic acid (Eatoh's reagent) under nitrogen. The reaction mixture is stirred at room temperature for 4 hours, poured into water and filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven to give the title product as an off-white solid (45.88 g, mp 86°-87° C.).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[CH2:12][N:13]([CH3:15])[CH3:14].[CH2:16]([Br:19])[C:17]#C.[CH3:20]O>>[Br-:19].[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[CH2:12][N+:13]([CH3:20])([CH3:15])[CH2:14][C:16]#[CH:17]
Reactant: C#CCBr
Reactant: CC1=C(/C=C/CN(C)C)C(C)(C)CCC1
Reactant: CO
Product: C#CC[N+](C)(C)C/C=C/C1=C(C)CCCC1(C)C
Product: [Br-]

Procedure:
A solution of [3-(2,6,6-trimethyl-1-cyclohexenyl)-2(trans)-propenyl]dimethylamine (2.0 g) and propargylbromide (2.0 g) in methanol (20 cc) was refluxed for 1 hour, and concentrated. To the residue was added water, and the aqueous solution was washed with ether and extracted with chloroform. The chloroform layer was dried and concentrated to dryness to give an oil (2.9 g) of [3-(2,6,6-trimethyl-1-cyclohexenyl)-2(trans)-propenyl]dimethylpropargylammonium bromide.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>>[C:1]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCCC2)cc1
Yield: 82.4 %

Procedure:
2.00 g (7.2 mmol) of trityl chloride was treated with 0.51 g (7.2 mmol) pyrrolidine and 0.72 g (7.2 mmol) triethylamine according to General Method C in Example 6 to give 1.86 g (82%) of 1-tritylpyrrolidine (T7), mp: 126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N(CC)CC)C.[CH3:33][O:34][CH:35]=[CH:36][C:37](Cl)=[O:38]>C1C=CC=CC=1>[CH3:33][O:34][CH:35]=[CH:36][C:37]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:38]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc(N)cc3)CC2)cc1OC
Reactant: COC=CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC=CC(=O)Nc1ccc(N2CCN(C(=O)c3ccc(OC)c(OC)c3)CC2)cc1
Yield: 72.9 %

Procedure:
A solution of 11 g of p-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]aniline in 100 ml of benzene was added 4.56 ml of triethylamine and refluxed while adding dropwise a solution of 3.94 g of β-methoxyacryloyl chloride in 20 ml of benzene. After completion of addition, the mixture was refluxed for 1 hour. After completion of reaction, the reaction mixture was washed with water and dried. The solvent was distilled off and the residue was purified through silica gel column chromatography to give 10 g of N-(β-methoxyacryloyl)-p-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]aniline.
Reaction SMILES: [K].[CH:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.[Cu](Cl)Cl>[C:4]1([CH3:9])[CH:5]=[CH:6][C:7]([O:8][C:11]2[CH:16]=[CH:15][C:14]([O:8][C:7]3[CH:2]=[CH:3][C:4]([CH3:9])=[CH:5][CH:6]=3)=[CH:13][CH:12]=2)=[CH:2][CH:3]=1
Reactant: Cc1ccc(O)cc1
Reactant: Brc1ccc(Br)cc1
Agent: Cl[Cu]Cl
Agent: [K]
Solvent: Cc1ccccc1
Product: Cc1ccc(Oc2ccc(Oc3ccc(C)cc3)cc2)cc1

Procedure:
A three-necked flask equipped with a distilling receiver and a magnetic stirrer was charged with 32.4 g (0.30 moles) of p-cresol, and 16.8 g (0.30 moles) of potassium hydroxide was added into the flask while stirring the resultant reaction mixture at a temperature of 150° C. to provide a potassium salt of p-cresol. To the resultant p-cresol potassium salt melt were gradually mixed 100 ml of toluene, and the resultant reaction mixture was subjected to azeotropic distillation to remove water from the reaction mixture. After 50 ml of toluene were distilled away, the remaining reaction mixture was mixed with a solution of 23.6 g (0.10 moles) of p-dibromobenzene dissolved in 10 ml of hot toluene, and then with a catalyst consisting of 2.0 g of anhydrous copper chloride (II), and the resultant reaction mixture was refluxed for 8 hours while stirring.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH3:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2>CCOCC>[CH3:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:1](=[O:5])[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc2[nH]ccc2c1
Solvent: CCOCC
Product: Cc1ccc2[nH]cc(C(=O)C(=O)Cl)c2c1

Procedure:
Oxalyl chloride (0.76 ml) was slowly added to a stirred solution of 1 g of 5-methylindole in 20 ml of anhydrous ether at 0° C. The precipitate which formed was filtered off and dried at 80° C. to give 5-methyl-3-indolylglyoxylyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[C:26]([CH3:28])[C:6]([O:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[C:10]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[N:9]=2)=[C:5]([CH3:29])[CH:4]=1)#[N:2]>O1CCCC1.[Pd]>[NH2:14][C:13]1[C:8]([O:7][C:6]2[C:26]([CH3:28])=[CH:27][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH3:29])=[N:9][C:10]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[N:11][CH:12]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)ncc1N
Yield: 84.2 %

Procedure:
A mixture of 4-[[4-(4-cyano-2,6-dimethylphenoxy)-5-nitro-2-pyrimidinyl]amino]benzonitrile (0.0005 mol) in tetrahydrofuran (20 ml) was hydrogenated overnight with Pd/C 10% (0.100 g) as a catalyst. After uptake of H2 (3 equiv; 0.0015 mol), the catalyst was filtered off and the filtrate was concentrated by rotary evaporation and dried in vacuo over 16 hours at 40° C., yielding 0.15 g of 4-[[5-amino-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile (84%); mp. >300° C. (comp. 50).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1)[CH2:2][CH3:3].[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20](Cl)=[O:21])[CH:15]=1.[OH-].[Na+]>ClCCl>[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][CH:4]2[CH2:1][CH2:2][CH3:3])=[O:21])[CH:15]=1
Reactant: CCCC1Cc2ccccc2N1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCC1Cc2ccccc2N1C(=O)c1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.76 g (4.7 mmol) 2-propyl-2,3-dihydro-1H-indole in 15 mL dichloromethane was added to 0.88 g (5.0 mmol) 6-chloro-pyrimidine-4-carboxylic acid chloride in 15 mL dichloromethane at 0° C. and then 4.7 mL (4.7 mmol) of a 1M sodium hydroxide solution were added dropwise. The reaction mixture was stirred for 30 min at 0° C. and then for 1 h at RT. The organic phase was separated off and evaporated down. The residue was purified on silica gel.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[Cl:27])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4ccccc4Cl)cc3)cc2s1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.15 g, 0.31 mmol) and 2-chlorophenyl boronic acid (0.059 g, 0.38 mmol) to afford 0.074 g (51%). MS (m/z): calcd for C2H25ClN4OS (M+H)+: 466.0; found: 466.2.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([N:20]1[C:28]3[C:23](=[N:24][CH:25]=[C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:27]=3)[C:22]3([CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:21]1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH3:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([N:20]1[C:28]3[C:23](=[N:24][CH:25]=[C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH:27]=3)[C:22]3([CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH2:21]1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][N:16]([C:42]([NH:41][CH3:40])=[O:43])[CH2:15][CH2:14]1)=[N:7]2
Reactant: CN=C=O
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Solvent: ClCCl
Product: CNC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(N3CC4(CCOCC4)c4ncc(N5CCOCC5)cc43)c2C)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1′-(5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinolin-4-yl)-6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (50 mg, 0.093 mmol) was dissolved in DCM (5.0 mL), and treated with methylisocyanate (5.50 μL, 0.093 mmol) and the reaction was stirred at rt for 2.5 h. After this time the reaction was concentrated to dryness and the residue was purified using an SCX column (compound loaded in MeOH and using 2M ammonia in MeOH as eluent) to give 4-(5,7-difluoro-3-methyl-4-(6′-morpholino-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]-1′(2′H)-yl)quinolin-2-yl)-N-methylpiperazine-1-carboxamide. 1H NMR (400 MHz, chloroform-d) δ ppm 7.55 (1H, d, J=2.3 Hz), 7.34 (1H, dt, J=9.8, 1.3 Hz), 6.75 (1H, ddd, J=11.8, 9.0, 2.4 Hz), 5.65 (1H, d, J=2.3 Hz), 4.69 (1H, q, J=4.2 Hz), 4.03-4.20 (2H, m), 3.80-3.97 (2H, m), 3.68-3.80 (4H, m), 3.48-3.67 (6H, m), 3.27-3.48 (4H, m), 2.90-3.04 (4H, m), 2.85 (3H, d, J=4.5 Hz), 2.19-2.39 (5H, m), 1.78 (1H, d, J=13.5 Hz), 1.69 (1H, d, J=13.5 Hz). Mass Spectrum (ESI) m/e=594.4 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[N:4]1[CH3:13].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[N:4]1[CH3:13])(=[O:24])=[O:23]
Reactant: CN1C(=O)[C@@H]2CCCN2C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)[C@@H]2CCCN2C[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 74.8 %

Procedure:
(3S,8aS)-3-(Hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (505 mg, 2.74 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.8 mL, 5.75 mmol) was added at 0° C. followed by dropwise addition of methanesulfonyl chloride (0.45 mL, 5.81 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford [(3S,8aS)-2-methyl-1-oxooctahydropyrrolo[1,2-a]pyrazin-3-yl]methyl methanesulfonate as an orange oil (538 mg, 2.05 mmol, 75% yield). 4-[(3,4-Dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-ol hydrochloride (469 mg, 1.20 mmol) was dissolved in dimethylformamide (1 mL) and potassium carbonate (828 mg, 6.00 mmol) was added followed by [(3S,8aS)-2-methyl-1-oxooctahydropyrrolo[1,2-a]pyrazin-3-yl]methyl methanesulfonate (538 mg, 2.05 mmol) in dimethylformamide (1 mL). The mixture was stirred at 70° C. for 34 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil which was purified by column chromatography (6-8% methanol in dichloromethane) to afford a yellow foam (300 mg, 0.577 mmol, 48% yield). The yellow foam (100 mg) was purified further by column chromatography (ethyl acetate-ethanol 1:1) to afford (3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1 (2H)-one as a yellow solid (60 mg). 1H NMR (400 MHz, CDCl3): 8.71 (s, 1H), 8.52 (dd, 1H), 7.36-7.32 (m, 2H), 7.01 (s, 1H), 4.49 (dd, 1H), 4.34 (dd, 1H), 4.03 (s, 3H), 3.90-3.84 (m, 1H), 3.47 (t, 1H), 3.13 (s, 3H), 3.05 (dd, 1H), 2.95 (dd, 1H), 2.93-2.83 (m, 2H), 2.29-2.19 (m, 1H), 2.03-1.84 (m, 2H), 1.83-1.70 (m, 1H); MS (EI) for C24H24N5O3FCl2: 520 (MH+).
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1.[NH2:36][C:37]1[CH:52]=[CH:51][C:40]2[N:41]([CH2:49][CH3:50])[CH2:42][C:43]([CH2:47][OH:48])([OH:46])[CH2:44][O:45][C:39]=2[CH:38]=1>C(O)(C)C>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:36][C:37]2[CH:52]=[CH:51][C:40]3[N:41]([CH2:49][CH3:50])[CH2:42][C:43]([OH:46])([CH2:47][OH:48])[CH2:44][O:45][C:39]=3[CH:38]=2)=[N:18][CH:19]=1
Reactant: CCN1CC(O)(CO)COc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CC(O)(CO)COc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc21

Procedure:
10-Camphorsulfonic acid (107 mg, 0.462 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (132 mg, 0.420 mmol), and 3-Amino-9-ethyl-7-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ol (0.100 g, 0.420 mmol) in Isopropyl alcohol (3.0 mL) and the mixture was irradiated in a CEM microwave (120° C., 40 min). The reaction mixture was then purified by HPLC and lyophilized to afford 2-[5-Chloro-2-(9-ethyl-7-hydroxy-7-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide as a black lyophilate (2 mg, 1%). LCMS: 517.32 (M+H); HNMR (CD3CN): 9.70 (s, 1H), 8.03 (s, 1H), 7.43 (m, 3H), 7.10 (s, 1H), 7.00 (s, 1H), 6.84 (d, J=8.84 Hz, 1H), 6.66 (d, J=8.60 Hz, 1H), 4.02 (q, J=6.80 Hz, 2H), 3.87 (s, 1H), 3.51 (s, 1H), 3.32 (m, 4H), 3.13 (s, 2H), 2.81 (s, 5H), 1.12 (t, J=7.08 Hz, 3H).
Reaction SMILES: N1CCCN=C1C1C=CC([C:13]2[O:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[NH:25][CH2:26][CH2:27][CH2:28][N:29]=4)=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=CC=1.[CH:30]1C(C2NC3C=C(C(N)=N)C=CC=3C=2)=CC=C(C(N)=N)C=1.CN1CCN(C2C=CC3NC(C4C=[CH:69][C:70]5[NH:75][C:74]([C:76]6[CH:77]=[CH:78][C:79](O)=[CH:80][CH:81]=6)=[N:73][C:71]=5[CH:72]=4)=NC=3C=2)CC1>>[NH:25]1[CH2:30][CH2:26][CH2:27][CH2:28][N:29]=[C:24]1[C:21]1[CH:20]=[CH:19][C:18]([C:15]2[O:14][C:13]([C:79]3[CH:80]=[CH:81][C:76]([C:74]4[NH:73][CH2:71][CH2:72][CH2:69][CH2:70][N:75]=4)=[CH:77][CH:78]=3)=[CH:17][CH:16]=2)=[CH:23][CH:22]=1
Reactant: CN1CCN(c2ccc3[nH]c(-c4ccc5[nH]c(-c6ccc(O)cc6)nc5c4)nc3c2)CC1
Reactant: c1cc(-c2ccc(-c3ccc(C4=NCCCN4)cc3)o2)ccc1C1=NCCCN1
Reactant: N=C(N)c1ccc(-c2cc3ccc(C(=N)N)cc3[nH]2)cc1
Product: c1cc(-c2ccc(-c3ccc(C4=NCCCCN4)cc3)o2)ccc1C1=NCCCCN1

Procedure:
2,5-bis[4-(1,4,5,6-tetrahydropyrimidin-2-yl)phenyl] furan (DB103), in comparison to the compounds DAPI and Hoechst 33258.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:15].[C:24]1([P:30](Cl)(Cl)=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCCCCC.C(OCC)C.C1CCCCC1>[C:24]1([P:30]2(=[O:31])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][N:16]2[CH2:14][CH3:15])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNCc1ccccc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CCN1Cc2ccccc2P1(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (8 g, 0.125 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature at 0° C., a solution of N-ethylbenzylamine (8.1 g, 0.06 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 3 hours at 26° C. and then cooled to -71° C. using a solid carbon dioxide-acetone bath. A solution of phenylphosphonic dichloride (12.5 g, 0.064 mol) in 30 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to -20° C. When the reaction temperature began to decrease, the solid carbon dioxide-acetone bath was removed and the reaction mixture was stirred for 2 hours. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 12 ml. of acetic acid. After stirring for 10 minutes, the cyclohexane was removed on a rotary evaporator, and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield an orange oil. This oil was distilled at 170° C. and 0.2 torr, yielding a yellow oil which was then slurried in diethyl ether to yield a white solid. The white solid was purified on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was slurried in ether to yield 1-phenyl-2-ethyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as a crystalline precipitate. A second crop was obtained from the ether filtrate and the combined product yield was recrystallized from methylcyclohexane to yield 1-phenyl-2-ethyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.3 g, 8% yield) as white crystals having a melting point of 94°-95° C. and the following analysis:
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>O>[N+:18]([C:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCCCc2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCCCc2c1cccc2[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6,7,8,9-Tetrahydro-5H-benzo[a]cyclohepten-5-one (18.5 g, 11.5 mmol) was mechanically stirred at −15° C. and treated with concentrated sulfuric acid (41 mL) over 5 minutes, stirred 10 minutes, treated dropwise over 10 minutes with a mixture of fuming nitric acid (9 mL) and concentrated sulfuric acid (14 mL), stirred at −15° C. for 15 minutes and poured carefully onto a mixture of ice (200 g) and water (200 mL). The resulting solid was collected by filtration, washed with water (100 mL, 2×), dried and recrystallized from ethanol (200 mL). The resulting solid was removed by filtration and the filtrate was suspended on silica gel and purified on silica gel eluting with ethyl acetate:hexanes 12:88 to provide the desired product.
Reaction SMILES: [C:1]([C:3](=[C:9](SC)[S:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[NH:14]([C:16]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:19]=[C:18]([C:34]([F:37])([F:36])[F:35])[N:17]=1)[NH2:15]>CO>[NH2:2][C:1]1[N:14]([C:16]2[C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:19]=[C:18]([C:34]([F:37])([F:36])[F:35])[N:17]=2)[N:15]=[C:9]([S:10][CH3:11])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: NNc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Solvent: CO
Product: CCOC(=O)c1c(SC)nn(-c2nc(C(F)(F)F)nc(-c3ccccc3)c2-c2ccccc2)c1N

Procedure:
Ethyl 2-cyano-3,3-bis(methylthio)acrylate (0.3 g, 1.36 mmol) was heated with 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.15 g, 0.45 mmol) in methanol (6 ml) overnight at 60-65° C. The solid that separated out from the reaction mixture was filtered and washed with isopropylalcohol (5 ml), to furnish the required compound. 1H-NMR (DMSO-d6) δ: 1.22-1.25 (t, 3H), 3.16 (s, 3H), 4.11-4.17 (q, 2H), 4.36 (br, 2H, D2O exchangeable), 7.12 (d, 2H), 7.25-7.35 (m, 7H), 7.69 (d, 1H); MS m/z: 500.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCS(=O)(=O)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CCS(=O)(=O)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
860 mg (1.65 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)propanoate (racemate) in 16.6 ml of dichloromethane and 4.77 ml (61.9 mmol) of TFA were reacted according to General Method 6A. Yield: 1.18 g (purity 72%, quant.)