Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4]Cl.[OH-:6].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:4]([O:6][CH2:4][CH:2]1[O:3][CH2:1]1)[CH:2]1[O:3][CH2:1]1
Reactant: [OH-]
Reactant: ClC[C@H]1CO1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: C(OCC1CO1)C1CO1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2.01 g of R-(-)-epichlorohydrin and 16 mg of benzyl triethyl ammonium chloride (the latter two compounds were the same ones as used in Preparation 1) were mixed and heated to 70° C. To the mixture was dropwise added 650 mg of 24% by weight sodium hydroxide aqueous solution. The resultant was stirred for 2 hours at 70° C., and cooled to room temperature. The mixture was extracted trice with chloroform, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was recrystallized from hexane to obtain 380 mg of an S isomer of glycidyl ether of the following formula: ##STR42## mp: 65° C. [α]D25 : +1.90° (C=0.46, CH2Cl2)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:42][CH3:43])=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([O:42][CH3:43])=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: COc1ccc(N)c2c1CN(C)C2=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(OC)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-4-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 205A). MS (ES+): m/z 610.25 (100) [MH+]; HPLC: tR=1.10 min (UPLC, purity).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=C[C:5]2[C:6](=[O:10])[O:7][C:8](=O)[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[C:18]([O:21][CH2:22]C)(=[O:20])[CH3:19]>CO>[CH3:12][C:2]1[CH:1]=[C:19]([C:18]([O:21][CH3:22])=[O:20])[C:5](=[CH:4][CH:3]=1)[C:6]([O:7][CH3:8])=[O:10]
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(C)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3.00 g of 5-methyl-2-benzofuran-1,3-dione was suspended in 30 mL of methanol, to which 0.2 mL of sulfuric acid was added at room temperature, and this suspension was stirred for 2.5 hours while heating it under reflux. The reaction mixture was cooled to room temperature, and poured into ice water followed by addition of ethyl acetate, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and then the solvent was distilled out under reduced pressure to yield 2.95 g of dimethyl 4-methylphthalate as light yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[OH:7][N:8]=[C:9]([C:11]1[C:15]([NH:16]CCCOC)=[N:14][O:13][N:12]=1)N>>[NH2:16][C:15]1[C:11]([C:9](=[N:8][OH:7])[NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[N:12][O:13][N:14]=1
Reactant: COCCCN
Reactant: COCCCNc1nonc1C(N)=NO
Product: COCCCNC(=NO)c1nonc1N
Yield: 93 %

Procedure:
The desired compound was prepared according to the procedure of Example 1, step C, using 3-methoxy-1-propanamine as the starting material in 93% yield. LCMS for C7H14N5O3 (M+H)+: m/z=216.1. Step B: N′-Hydroxy-4-[(3-methoxypropyl)amino]-1,2,5-oxadiazole-3-carboximidamide
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.[NH2:15][NH2:16].O>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[NH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(Br)cc2)=NN1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
4-(4-Bromo-phenyl)-4-oxo-butyric acid (Aldrich, 25.0 g, 97.3 mmol) was treated with NH2NH2—H2O (Aldrich, 55%, 9.1 mL, 156 mmol) in EtOH (Aldrich, 100 mL) at refluxing for 2 h. It was cooled down to ambient temperature and the white solid was filtered off to give the title compound (24.2 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 2.50-2.76 (m, 2H), 2.85-3.09 (m, 2H), 7.43-7.71 (m, 4H), 8.55 (s, 1H) ppm. MS (DCl/NH3) m/z 253 (M+H)+, 255 (M+H)+, 270 (M+NH4)+, 272 (M+NH4)+.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.I[CH2:15][C@H:16]1[O:20][C@@H:19]([N:21]2[CH:28]=[C:27]([F:29])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[C@H:18]([OH:30])[C@@H:17]1[OH:31].CO>C1(C)C=CC=CC=1>[F:29][C:27]1[C:25](=[O:26])[NH:24][C:22](=[O:23])[N:21]([CH:28]=1)[C@@H:19]1[O:20][C@H:16]([CH3:15])[C@@H:17]([OH:31])[C@H:18]1[OH:30]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2O)cc1F
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O

Procedure:
When the reduction is carried out by using tributyltin hydride, the reaction takes place by dissolving 5′-deoxy-5′-iodo-5-fluorouridine in an alcohol, for example methanol, the reducing agent being added as a solution in an organic solvent, for example in toluene, and the mixture is heated at reflux in the presence of α,α′-azoisobutyro nitrile in catalytic amount. After 1÷3 hours the reduction is complete and, after evaporation of the solvent, the 5′-deoxy-5-fluorouridine thus obtained is recovered according to conventional methods.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Cl[S:16](O)(=O)=O.C(Cl)(=O)C(Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>C(Cl)Cl.CN(C)C=O.Cl>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:4]2[CH:3]=[CH:2][C:1]([SH:16])=[CH:6][CH:5]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Sc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
A solution of 4-bromodiphenyl ether (50 g, 200.7 mmol) in methylene chloride (118 mL) was cooled to 0° C. and chlorosulfonic acid (14.7 mL, 220.8 mmol) was added dropwise over a 20 minute period. The solution was stirred an additional 10 minutes, warmed to room temperature and stirred an additional 1 hour. To this mixture was added oxalyl chloride (23.6 mL, 270.9 mmol), followed by N,N-dimethylformamide (1.5 mL) as a catalyst, and the mixture refluxed for 2 hours. The mixture was cooled to room temperature, and additional oxalyl chloride (23.6 mL, 270.9 mmol) was added, the mixture refluxed for 3 hours, cooled to room temperature and stirred 12 hours more. The solution was concentrated to an oil, azeotroped several times using methylene chloride and put under high vacuum (1 torr) for several hours until the mixture had completely solidified. This mixture was immediately dissolved in methylene chloride (160 mL) which was added dropwise to a solution of triphenylphosphine (157.0 g, 602 mmol) in methylene chloride (160 mL) containing N,N-dimethylformamide (4 mL, 52.2 mmol). The mixture was stirred 2 hours, diluted with 1M aqueous hydrochloric acid (300 mL) and stirred for 1 hour. The aqueous layer was separated, extracted with methylene chloride (200 mL), and the organic layers were combined, washed with 200 mL of brine, dried (MgSO4) and concentrated in vacuo. The resulting solid was further purified through trituration with 750 mL of hexane. The solid was then dissolved in 750 mL of diethyl ether, extracted with 2M aqueous sodium hydroxide (2×350 mL), and the basic aqueous layer back extracted using diethyl ether (2×400 mL). The aqueous layer was adjusted to pH 2, extracted with diethyl ether (3×200 mL) and the combined organic layers dried (MgSO4) and concentrated to afford 4-(4-bromophenoxy)thiophenol (45.6 g, 81%). 1HNMR (CDCl3) δ 3.43 (s, 1H), 6.86 (d, J=8.9 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.9 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH2:23][O:24][C:25]3[C:34]4[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=4)[N:28]=[CH:27][CH:26]=3)=[N:21][N:22]=2)[N:19]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].O>>[CH3:36][O:35][C:31]1[CH:30]=[C:29]2[C:34]([C:25]([O:24][CH2:23][C:20]3[N:18]4[N:19]=[C:14]([C:6]5[CH:5]=[CH:4][C:3]([N:2]([CH3:12])[CH3:1])=[N:8][CH:7]=5)[CH:15]=[CH:16][C:17]4=[N:22][N:21]=3)=[CH:26][CH:27]=[N:28]2)=[CH:33][CH:32]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(N(C)C)nc5)nn34)ccnc2c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A 48 mL tube was charged with 6-(dimethylamino)pyridin-3-ylboronic acid (0.109 g, 0.658 mmol), 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.150 g, 0.439 mmol), and DMF (3.00 ml, 38.6 mmol), and stirred for 10 minutes. A solution of potassium carbonate (0.182 g, 1.32 mmol) and water (0.696 ml, 38.6 mmol) was added, followed by PdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol). The tube was flushed with argon, sealed, and heated in a 80° C. oil bath for 5 hours. The mixture was concentrated, and the residue was triturated with water to give a brown solid which was purified by MPLC using a 40 g column, eluting with 1-5% MeOH/DCM over 40 minutes to give 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine as a dark green solid. MS (ESI pos. ion) m/z: 428 (MH+). Calc'd exact mass for C23H18FN5O2: 427.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][C:20]1[N:25]=[C:24]([C:26]#[N:27])[C:23]([C:28](OC)=[O:29])=[C:22]([NH:32][C:33]2[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=2)[N:21]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CCOCC.CCOC(C)=O>[O:29]=[C:28]1[C:23]2[C:22]([NH:32][C:33]3[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=3)=[N:21][C:20]([NH:19][C@@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]3[NH:12][C:10](=[O:11])[O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[N:25][C:24]=2[C:26]2([CH2:2][CH2:1]2)[NH:27]1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1c(C#N)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc3c2C(=O)NC32CC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Ethylmagnesium bromide (0.069 mL, 0.208 mmol) was added at RT to a solution of methyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-cyano-6-(m-tolylamino)pyrimidine-5-carboxylate (50 mg, 0.104 mmol) and tetraisopropylorthotitanate (0.091 mL, 0.312 mmol) in Et2O (5 mL). The reaction mixture was stirred at RT for 20 h and was subsequently diluted with EtOAc. The organic phase was washed with saturated aq NaHCO3, brine and water, was dried then concentrated to give a pink residue, which was purified by reverse phase preparative HPLC. The fractions were collected and concentrated to a residue, which was used in next step. [M+H] calc'd for C26H34N6O3, 479. found, 479.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1ccc(C2=CCC(=O)CC2)cc1
Product: COc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compounds were prepared as white solids from the hydrogenation of 4-(4-methoxy-phenyl)-cyclohex-3-enone (as prepared in the previous step) followed by reductive amination of the corresponding ketone with N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedures described in Step C of Example 5 and Step C of Example 4.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[CH3:7][O:8][N:9]([CH3:13])[C:10](Cl)=[O:11]>C(#N)C.CCOCC>[CH3:7][O:8][N:9]([CH3:13])[C:10]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)=[O:11]
Reactant: CON(C)C(=O)Cl
Reactant: Cn1cncn1
Solvent: CCOCC
Solvent: CC#N
Product: CON(C)C(=O)c1ncnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 1-methyl-1H-1,2,4-triazole (3.15 mL, 55.56 mmol) and methoxy(methyl)carbamic chloride (7.55 g, 61.11 mmol) in acetonitrile (60 mL) was cooled in an ice water bath before addition of TEA (8.52 mL, 61.11 mmol). The mixture was allowed to slowly warm to room temperature and was then stirred overnight. The material was diluted with ether and solids were filtered and rinsed well with ether. The filtrate was concentrated and the residue was taken up in ether. Insoluble solids were filtered off and rinsed well with additional ether. The filtrate was concentrated to give and oil that was chromatographed on silica gel (100% CH2Cl2 followed by gradient elution to 40% EtOAc in CH2Cl2) to afford product as an oil that slowly solidified. 6.13 g (65% yield).
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].S(O)(O)(=O)=O.CS[C:17](=[NH:19])[NH2:18]>[OH-].[Na+].O>[OH:1][N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[C:17]([NH2:19])=[NH:18]
Reactant: CSC(=N)N
Reactant: O=P(O)(O)CCCNO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N=C(N)N(O)CCCP(=O)(O)O
Reaction time: 8 h
Yield: 47.1 %

Procedure:
A mixture of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g.) in 1N aqueous sodium hydroxide solution (10 ml.) and S-methylisothiourea sulfate (1.40 g.) in water (5 ml.) was heated to reflux for 1.5 hours and allowed to stand overnight at ambient temperature to give crystalline precipitates, which was collected by filtration and washed with water and then with ethanol to give 3-(1-hydroxyguanidino)propylphosphonic acid (690 mg.), mp: 244°-247° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:7]([CH2:19][O:20][CH3:21])=[CH:6]2.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[H-].[Na+].[I-].[Na+]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:14][CH:13]=1)[C:7]([CH2:19][O:20][CH3:21])=[CH:6]2
Reactant: ClCCCN1CCCC1
Reactant: COCc1cc2cc(OC)ccc2n1-c1ccc(O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cc2cc(OC)ccc2n1-c1ccc(OCCCN2CCCC2)cc1
Temperature: 70 °C
Yield: 40 %

Procedure:
4-(5-Methoxy-2-methoxymethylindol-1-yl)phenol (0.43 mmol) was dissolved in N,N-dimethylformamide under N2. 1-(3-Chloropropyl)pyrrolidine (74 mg, 0.5 mmol), sodium hydride (20 mg, 60% wt dispersion in mineral oil, 0.5 mmol) and sodium iodide (75 mg, 0.5 mmol) were added, and the mixture was heated at 70° C. for 2 hours. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated. Purification by semi-prep LC-MS gave the desired product, 67.4 mg (40% yield, 2 steps). LC-MS (C24H30N2O3 calc'd 394) m/z 395 (M+H); 1H NMR (300 MHz, CDCl3) d 7.34-7.29 (m, 2H), 7.09 (d, J=2.4 Hz, 1H), 7.04-6.98 (m, 3H), 6.82 (d, J=2.4 Hz, 1H), 6.58 (s, 1H), 4.37 (s, 2H), 4.10 (t, J=6.3 Hz, 2H), 2H), 3.86 (s, 3H), 3.28 (s, 3H), 2.69-2.64 (m, 2H), 2.58-2.54 (m, 4H), 2.11-2.01 (m, 2H), 1.83-1.79 (m, 4H).
Reaction SMILES: [H-].[Na+].[CH2:3]=[C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][N:5]1[C:19](=[O:21])[CH3:20].CN(C=[O:26])C>>[C:19]([N:5]1[CH2:6][C:7]2[C:8](=[O:26])[C:9]3[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=3[NH:15][C:16]=2[C:4]1=[CH2:3])(=[O:21])[CH3:20]
Reactant: CN(C)C=O
Reactant: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(C)=O
Agent: [H-]
Agent: [Na+]
Product: C=C1c2[nH]c3ccc(OC)cc3c(=O)c2CN1C(C)=O
Reaction time: 8 h

Procedure:
NaH (1.5 eq; 60% suspension in oil) is added to a solution of 1-methylene-2-acetyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (1 g; 3.9 mmol) in DMF (5 ml). The mixture is stirred under an oxygen atmosphere overnight. The DMF is then distilled off under reduced pressure. The crude product is washed successively with ethyl acetate, methanol and then ether. After drying, 2-acetyl-7-methoxy-3-methylene-9-oxo-1,3,4,9-tetrahydropyrrolo[3,4-b]quinoline is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11](O)[CH3:12]>S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CCO
Reactant: Cc1cnc(C(=O)O)cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cnc(C)cn1
Temperature: 78 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
The reaction is carried out, under nitrogen, in a 1 L×4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor is charged with 5-methylpyrazinecarboxylic acid (100 g), ethanol (300 g) and sulfuric acid (2 g). The contents are refluxed for eight hours at 78° C. The reaction mixture is cooled to ambient temperature and sodium bicarbonate (4 g) is added. About 75% of the solvent is removed under reduced pressure and the resulting suspension is allowed to stand overnight. The solids are filtered and washed with cold methanol (2×80 g). Drying under oven (25 inches of Hg) yielded 101.25 g (84%) of 5-methyl-2-pyrazinecarboxylic acid, ethyl ester.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH2:12]O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Br)(Br)[Br:15].O>C(OC(C)C)(C)C>[Br:15][CH2:12]/[CH:11]=[CH:10]/[C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(/C=C/CO)cc1
Reactant: BrP(Br)Br
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC(C)c1ccc(/C=C/CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.4 %

Procedure:
To a solution of (E)-3-(4-isopropylphenyl)-2-propen-1-ol (10.5 g, 59.6 mmol) in isopropyl ether (100 ml) was added under ice cooling phosphorus tribromide (10.7 g, 39.7 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted with isopropyl ether. The organic layer was washed with water and an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 10.2 g (72% yield) of the oily title compound.
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH2:4][CH2:5][C:6]([CH3:9])([OH:8])[CH3:7])[CH3:3].[CH:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:12]([CH:15]1[O:10][C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:7])[O:8]1)([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)C=O
Reactant: CC(C)(O)CCC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C)(C)OC(C(C)(C)C)O1
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 730 g (5 mol) of 2,5-dimethylhexane-2,5-diol, 3 g of p-toluenesulfonic acid, 430 g (5 mol) of pivalaldehyde and 1 l of toluene was refluxed for 4 hours (h) during which the water of reaction produced (90 ml) was removed. The reaction mixture was then cooled down to room temperature (RT) and stirred up with 10 ml of 25% strength aqueous sodium hydroxide solution, the phases were separated, the organic phase was washed with a little water until neutral, and the toluene was then removed at 50°-60° C. The residue obtained was fractionated under reduced pressure affording 909 g (4.25 mol) of 2-tert.-butyl-4,4,7,7,-tetramethyl-1,3-dioxacycloheptane (boiling point 54° C./0.2 mbar). This corresponds to a yield of 85% of theory.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[C:8]=2[F:13])[N:3]=1.[CH3:15][O:16][C:17]([C:20]1[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[F:13][C:8]1[C:7]([F:14])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([CH3:12])[C:2]([O:26][C:25]1[C:20]([C:17]([O:16][CH3:15])([CH3:18])[CH3:19])=[N:21][CH:22]=[CH:23][CH:24]=1)=[N:3]2
Reactant: Cc1nc2c(F)c(F)ccc2nc1Cl
Reactant: COC(C)(C)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(C)(C)c1ncccc1Oc1nc2ccc(F)c(F)c2nc1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
0.17 g of 2-chloro-5,6-difluoro-3-methylquinoxaline were dissolved in 2 mL of N-methylpyrrolidone. 0.13 g of 2-(1-methoxy-1-methyl-ethyl)-pyridin-3-ol and 0.11 g of potassium carbonate were added thereto followed by stirring for 3 hours at 100° C. Subsequently, the reaction solution was purified by silica gel column chromatography to obtain 0.24 g of 5,6-difluoro-2-[2-(1-methoxy-1-methyl-ethyl)-pyridin-3-yloxy]-3-methyl-quinoxaline.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>CC(C)=O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:20])=[CH:14][CH:13]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccc(OC)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 3.39 g. sodium in 200 ml. dry acetone, 20 g. valeramidine hydrochloride and 21.9 g. 4-methoxyphenyl isocyanate in 100 ml. dry acetone, there ws obtained after recrystallization from ethyl alcohol 15.5 g. of the hydrochloride of 1-(4-methoxyphenyl)-3-(pentanimidoyl)urea; m.p. 143.5°-145°C.
Reaction SMILES: [NH:1]([C:8]1[CH:12]([N:13]2[CH:17]=[C:16]([NH2:18])[C:15]([CH3:19])=[N:14]2)[C:11](=[O:20])[N:10]([C:21]2[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=2[Cl:29])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](Cl)(=[O:44])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C(OCC)(=O)C>C(#N)C>[NH:1]([C:8]1[CH:12]([N:13]2[CH:17]=[C:16]([NH:18][C:30](=[O:44])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:15]([CH3:19])=[N:14]2)[C:11](=[O:20])[N:10]([C:21]2[C:22]([Cl:29])=[CH:23][C:24]([Cl:28])=[CH:25][C:26]=2[Cl:27])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(C2C(=O)N(c3c(Cl)cc(Cl)cc3Cl)N=C2Nc2ccccc2)cc1N
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCC(=O)Nc1cn(C2C(=O)N(c3c(Cl)cc(Cl)cc3Cl)N=C2Nc2ccccc2)nc1C

Procedure:
The 4-(4-amino-3-methyl-1-pyrazolyl)-3-anilino-1-(2,4,6-trichlorophenyl)-5-oxo-2-pyrazoline obtained in Step 2 was suspended in 100 ml of acetonitrile and stirred with heating. To the solution, 9 g of tetradecanoylchloride was added and the mixture was refluxed for 2 hours. To the reaction mixture, 500 ml of ethyl acetate was added and the mixture was washed several times with water. The oil layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from a solvent mixture of acetonitrile and benzene, 8 g of Coupler (23) was obtained. The melting point of the coupler was 123° to 131° C.