Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C.[C:28]([NH:31][NH2:32])(=[O:30])[CH3:29]>C1(C)C=CC=CC=1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]1[O:30][C:28]([CH3:29])=[N:31][N:32]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1nnc(-c2ccccc2N)o1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of isatoic anhydride (16.3 g, 0.1 mol), p-toluenesulfonic acid (0.2 g, 1.1 mmol), glacial acetic acid (10 ml), acethydrazide (7.4 g, 0.1 mol) and dry toluene (90 ml) was stirred at 120° C. for 4 h, cooledto room temperature and poured into ice water. Toluene (500 ml) was added, and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2×100 ml).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11]O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:24]>C1C=CC=CC=1.O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][Br:24])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Oc2ccc(F)cc2)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: Fc1ccc(Oc2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 192.4 %

Procedure:
4-(4-Fluorophenoxy)benzyl alcohol (1.92 g, 8.80 mmol) and 0.2 ml of pyridine was dissolved in 25 ml of benzene and cooled in cold water. Phosphorus tribromide (1.19 g, 4.40 mmol) in 10 ml of benzene was added dropwise and the reaction was stirred 30 minutes and allowed to warm to room temperature. The solvent was evaporated and the residue was carefully quenched with saturated sodium bicarbonate solution. After dilution with water, the mixture was extracted twice with diethyl ether. The organic extracts were washed with saturated sodium bicarbonate solution and then with brine, dried over MgSO4, and concentrated to afford 2.38 g (96%) of the subtitle compound.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH:23]([CH3:25])[CH3:24])[C:14]([C@H:16]2[CH2:21][CH2:20][C:19]([CH3:22])=[CH:18][CH2:17]2)=[O:15])[CH:6]=1.C(#N)C.FC(F)(F)C(O)=O>O>[CH3:1][C:2]([CH3:26])([CH3:27])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH:23]([CH3:24])[CH3:25])[C:14]([C@@H:16]2[CH2:21][CH2:20][C:19]([CH3:22])=[CH:18][CH2:17]2)=[O:15])[CH:6]=1
Reactant: CC1=CC[C@@H](C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CC1=CC[C@H](C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C(C)C)CC1

Procedure:
The title compound was prepared in a manner similar to Example 5 using acrylic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester (S) in place of acrylic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester (R): MS (m/z): 388.0 [M+H]+; HPLC retention time 4.59 min (2-98% acetonitrile: water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:12][S:13]([CH2:16][C:17]#[N:18])(=[O:15])=[O:14].C([O-])(=O)C.[NH4+]>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:16]([C:17]#[N:18])[S:13]([CH3:12])(=[O:15])=[O:14])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CS(=O)(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)c1ccc(C=C(C#N)S(C)(=O)=O)cc1
Temperature: 0 °C
Yield: 93.2 %

Procedure:
To a solution of p-dimethylaminobenzaldehyde (2.20 g, 15 mmol) dissolved in 30 mL of absolute ethanol was added 1.8 g (15 mmol) of methylsulfonylacetonitrile and 1.2 g (15 mmol) of ammonium acetate. The mixture was heated at reflux under nitrogen for 1 hr and then poured into 150 g of ice water. The precipitated solid was filtered and air dried. The crude material was crystallized from absolute ethanol to give 3.5 g (93%) of (1) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:37]([CH2:39][NH2:40])[OH:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:40][CH2:39][CH2:37][OH:38])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Reactant: NCCO
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCCO)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-{[4-(methylsulfonyl)phenyl]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1 H), 7.81 (d, J=8.2 Hz, 2 H), 7.19 (d, J=8.1 Hz, 2 H), 7.05 (s, 1 H), 6.98-6.95 (m, 4 H), 5.41 (br, 2 H), 4.00 (s, 2 H), 3.78 (t, J=5.2 Hz, 2 H), 3.60 (m, 2 H), 3.01 (s, 3 H); HRMS C26H24FN3O6S (M+H)+ calcd 526.1370, found 526.1434.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].[CH3:25]N(C)C=O>>[CH3:25][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[CH:1]=[CH:19][N:20]([CH3:22])[CH3:21]
Reactant: Cc1c(C(=O)O)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Reactant: COC(OC)N(C)C
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C=CN(C)C
Temperature: 110 °C

Procedure:
2-Methyl-3,5-dinitro-benzoic acid (100 g, 0.442 mol) was dissolved in anhydrous N,N-dimethylformamide (1 M, 400 mL). N,N-Dimethylformamide dimethyl acetal (188 mL, 1.33 mol) was added under an argon atmosphere over 10 min at ambient temperature with stirring. The mixture was heated at 110° C. for 5 hours behind a shield, and cooled at ambient temperature. N,N-Dimethylformamide and the unreacted N,N-dimethylformamide dimethyl acetal were removed under reduced pressure (35° C., c.a. 5 mm Hg). Toluene (˜50 mL) was added and the volatiles removed under vacuum. 2-(2-Dimethylamino-vinyl)-3,5-dinitro-benzoic acid methyl ester, isolated as a dark red solid, was mixed with anhydrous methanol (880 mL) and chlorotrimethylsilane (140 mL, 1.10 mol) was added over 10 min. The solution was heated at reflux (oil bath 67–70° C.) under argon for 20 hours, cooled to ambient temperature, and the volume of the mixture was reduced under vaccuum to approximately 100 mL. The precipitated solid was collected by filtration and washed with cold methanol (100 mL). The dark brown solid was dried under vacuum, triturated with acetone (100 mL), again collected by filtration and washed with diethyl ether (150 mL) to afford Intermediate 2(c) (79 g). The mother liquor from the first precipitation and the various triturations were combined and concentrated. Additional Intermediate 2(c) (21 g) was then recrystallized from cyclohexane/ethyl acetate (9:1) providing a second batch. Again the resulting mother liquor was reduced in vacuo and a third batch of Intermediate 2(c) (4 g) was recrystallized from acetone/H2O (6:4). The combined yield for all three batches of Intermediate 2(c) (104 g) was 75%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37]([N:39]([CH2:44][CH3:45])[CH2:40][CH2:41]CO)[CH3:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:38][CH2:37][N:39]([CH2:44][CH3:45])[CH2:40][CH3:41])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCN(CC)CCCOC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 67.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-(diethylamino)-1-propanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (50 mg, yield 61%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1[C:28](C2C=CC=CC=2)=CS[C:25]=1[C:35](OC)=O.C(OCC)(OCC)OCC.[C@H]1(N)C2C(=CC=CC=2)CCC1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C@H:1]4[C:6]5[C:5](=[CH:28][CH:24]=[CH:25][CH:35]=5)[CH2:4][CH2:3][CH2:2]4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: N[C@@H]1CCCc2ccccc21
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1[C@@H]1CCCc2ccccc21
Yield: 47.6 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), (R)-1,2,3,4-tetrahydronaphthalen-1-amine (0.141 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 73.3 mg (0.20 mmol, 47.6% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([O:28][CH3:29])[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=3)[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.O.[OH-].[Li+]>CO.C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([O:28][CH3:29])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(NCCCN2CCOc3cc(F)ccc32)cc1)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CO[C@@H](Cc1ccc(NCCCN2CCOc3cc(F)ccc32)cc1)C(=O)O
Yield: 69.7 %

Procedure:
(S)-Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate (1.0 g, 1 eq, 2.4 mmol) obtained in example 49, was hydrolyzed using lithium hydroxide monohydrate (151 mg, 1.5 eq, 3.6 mmol) in methanol-THF-water at RT till all the starting material is consumed (4 to 5 h). The reaction mixture was diluted with water, acidified (pH ˜4-5) with dil. HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chromatographed using ethyl acetate and hexanes→methanol and chloroform to afford the title compound (650 mg, yield 70%) as viscous liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].C(N(CC)CC)C.[C:26]([CH2:28][C:29](Cl)=[O:30])#[N:27].C(Cl)[Cl:33]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[C:9]([Cl:33])[S:8][C:7]=1[NH:18][C:29](=[O:30])[CH2:28][C:26]#[N:27])=[O:5])[CH3:2]
Reactant: ClCCl
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)csc1N
Reactant: N#CCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(NC(=O)CC#N)sc(Cl)c1-c1ccc(Br)cc1
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of 2-amino-4-(4-bromophenyl)-thiophene-3-carboxylic acid ethyl ester (1.0 g, 3.1 mmol) and triethylamine (0.64 mL, 4.60 mmol) in methylene chloride (6 mL) was added cyanoacetic acid chloride (6.82 mL, 3.41 mmol, 0.5 M in methylene chloride). The cold bath was removed, and the reaction was stirred for 2 h. Saturated aqueous sodium bicarbonate solution (5 mL) was added to the reaction at room temperature. The layers were separated, and the aqueous was extracted with additional methylene chloride (3×5 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the titled compound as a yellow solid. MS (ESI) m/e 393 (M−H)−, NMR (300 MHz, CDCl3): δ ppm 12.0 (br s, 1H), 7.47 d, 2H), 7.16 (d, 2H), 6.68 (s, 1H), 4.16 (q, 2H), 3.69 (s, 2H), and 100 (t, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(OC([NH:26][C@H:27]1[C@@H:31]([CH3:32])[CH2:30][NH:29][CH2:28]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:26][C@H:27]1[C@@H:31]([CH3:32])[CH2:30][N:29]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:28]1
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@@H](N)[C@@H](C)C3)cc21
Yield: 0.6 %

Procedure:
A mixture of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.0 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.89 g), DBU (0.62 g) and anhydrous acetonitrile (30 ml) was refluxed for 27 hours. Then, the reacting mixture was treated as described in example 33 and recrystallized from chloroform-methanol-concentrated aqueous ammonia (20:20:1) to give the title compound (0.008 g) as white powder, mp 300~° C. (decompd.).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1.Cl>CN(C)C=O>[CH3:18][C:19]1[N:23]=[CH:22][N:21]([C:2]2[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[N:20]=1
Reactant: Cc1nc[nH]n1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2cnc(C(=O)O)cn2)n1
Temperature: 100 °C

Procedure:
A mixture of methyl 5-chloropyrazine-2-carboxylate (0.75 g), K2CO3 (1.8 g) and 3-methyl-1H-1,2,4-triazole (1.2 g) in N,N-dimethylformamide (6 mL) is heated to 100° C. overnight. Analysis of the crude mixture by LCMS shows saponified product. The product is acidified with 1N HCl and the precipitate is filtered and washed with water and diethyl ether to afford the title compound. LC (method 20): tR=1.21 min; Mass spectrum (APCI): m/z=206 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.[OH-].[Na+]>C(Cl)Cl.O>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)=[O:31])=[CH:28][CH:27]=1
Reactant: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)c3ccc(Cl)cc3)CC2)cc1

Procedure:
A solution of 1.0 g (0.0043 mol) of trans-4-(4-dimethylaminomethylphenyl)-cyclohexanol and 0.6 ml of triethylamine in 50 ml of methylene chloride is combined, dropwise, with 0.75 g (0.0043 mol) of 4-chlorobenzoylchloride, with stirring, and refluxed for 3 hours. After cooling, 50 ml of water are added, the mixture is adjusted to pH 12-13 with sodium hydroxide solution, the methylene chloride phase is separated off and the aqueous phase is extracted once more with methylene chloride. The combined organic phases are dried over sodium sulphate and evaporated down in vacuo. The solid residue is purified by column chromatography (aluminium oxide neutral, activity stage III, ICN; petroleum ether/ethyl acetate=40:1). White crystals are obtained with a melting point of 94°-95° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.C1COCC1.C(OCC)(=O)C>[CH3:20][S:21]([O:1][CH2:2][CH:3]([NH:5][C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12])[CH3:4])(=[O:23])=[O:22]
Reactant: CC(CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (2-hydroxy-1-methylethyl)carbamate (2.8 g, 15.98 mmol), triethylamine (4.44 ml, 3.23 mmol) and 4-dimethylaminopyridine (195 mg, 1.59 mmol) were dissolved in 135 ml of THF. Methanesulfonyl chloride (1.3 ml, 16.78 mmol) was added dropwise on an ice bath, and the reaction mixture was stirred for 3 h and warmed to room temperature. Following addition of ethyl acetate and sodium bicarbonate solution, the organic phase was separated off and concentrated. Yield: 3.97 g (98%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O-].[Na+].[CH3:9][C:10]1([CH2:15][CH2:16]CBr)[O:14][CH2:13][CH2:12][O:11]1>CN(C)C=O>[CH3:9][C:10]1([CH:15]([CH3:16])[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[O:11][CH2:12][CH2:13][O:14]1
Reactant: c1c[nH]cn1
Reactant: CC1(CCCBr)OCCO1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cn1ccnc1)C1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
A suspension of 29.0 g of imidazole and 23.1 g of sodium methoxide in 385 ml of dimethylformamide was stirred for 30 minutes and cooled in an ice bath as 85.8 g of 3-(2-methyl-1,3-dioxolan-2-yl)propyl bromide was added dropwise. The resulting mixture was maintained at room temperature for 30 minutes and heated to reflux for 1 hour. The solvent was evaporated in vacuo, the residue diluted with acetone and filtered. The filtrate was concentrated and the residue was distilled to afford 37.9 g (47%) of 1-[2-(2-methyl-1,3-dioxolan-2-yl)propyl]-1H-imidazole as a colorless oil, bp 102°-108° C./0.1 mm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C>C(OC(O)C)C.O>[NH2:20][C:19]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([Cl:9])=[C:7]([Cl:8])[C:2]=2[Cl:1])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1ccc(Cl)c(Cl)c1Cl
Agent: CCOC(C)O
Solvent: O
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Yield: 52.2 %

Procedure:
2,3,4-Trichlorophenylhydrazine (21.15 g) and ethoxymethylenemalononitrile (12.8 g) in ethoxyethanol (100 ml) were heated at reflux for one hour. The solution was then cooled and diluted with water. The sticky solid precipitate thus obtained was crystallized from toluene (48 ml) to give 5-amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (15 g), m.p. 154°-156° C., in the form of off-white crystals.
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12](=O)[CH2:13][CH2:14][N:3]1[C:4]=23.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12](=[N:17][OH:18])[CH2:13][CH2:14][N:3]1[C:4]=23
Reactant: NO
Reactant: O=C1CCN2C(=O)OCc3cccc1c32
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1OCc2cccc3c2N1CCC3=NO

Procedure:
6,7-Dihydro-3,7-dioxo-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (5 g), hydroxylamine hydrochloride (2.1 g) and sodium acetate (7.5 g) were dissolved in a mixed solvent of ethanol-water (5:1) (90 ml) and the mixture was refluxed for 2 hours. After completion of the reaction, the solvent was distilled off and the resulting residue was poured into water. Crystals which precipitated were collected by filtration and dried to give 6,7-dihydro-3-oxo-7-hydroxyimino-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine. The compound was dissolved in acetic acid (150 ml) and platinum oxide (250 mg) was added thereto. The mixture was subjected to catalytic reduction at 50° C. and 4 atmospheres. After completion of the catalytic reduction, catalyst was filtered off and the filtrate was concentrated to give 6,7-dihydro-3-oxo-7-amino-1H,3H,5H-pyrido [3,2,1-ij][3,1]benzoxazine (5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Cl:12])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:13][Mg]Br>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([Cl:12])[C:5]([O:10][CH3:11])=[C:6]([CH:7]([OH:8])[CH3:13])[CH:9]=1
Reactant: C[Mg]Br
Reactant: COc1c(Cl)cc(F)cc1C=O
Solvent: CCOCC
Product: COc1c(Cl)cc(F)cc1C(C)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a stirred solution of 5-Fluoro-2-methoxy-3-chlorobenzaldehyde (2.0 g, 11.0 mmol) in dry diethyl ether (40 mL) at 0° C. was added methylmagnesium bromide of 3.0 M in ether (8.8 mL, 27.12 mmol). The reaction mixture was brought to room temperature and was stirred for 30 min then refluxed for 3 hours. It was then cooled to 0° C. and quenched by adding saturated aqueous NH4Cl. The two liquid layers were separated. The aqueous layer was extracted with ether. The combined organic layers were washed with water, dried, and concentrated to the crude compound which was purified by silica gel column (10-25% ethyl acetate in hexanes) to afford 1-(5-Fluoro-2-methoxy-3-chlorophenyl)ethanol (2.1 g, 98%): 1H NMR (400 MHz, CDCl3): δ 7.12 (dd, 1H), 7.04 (dd, 1H), 5.19 (m, 1H), 3.84 (s, 3H), 2.18 (bs, 1H), 1.43 (d, 3H).
Reaction SMILES: BrCC1C=CNN=1.C(N)CN.[NH:12]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH2:19][CH2:20][NH2:21])=[N:13]1.[C:22]([NH:24][C:25](=[N:28][CH3:29])SC)#[N:23]>>[C:22]([NH:24][C:25]([NH:28][CH3:29])=[N:21][CH2:20][CH2:19][NH:18][CH2:17][C:14]1[CH:15]=[CH:16][NH:12][N:13]=1)#[N:23]
Reactant: CN=C(NC#N)SC
Reactant: NCCNCc1cc[nH]n1
Agent: BrCc1cc[nH]n1
Solvent: NCCN
Product: CNC(=NCCNCc1cc[nH]n1)NC#N

Procedure:
Reacting 3-bromomethylpyrazole with ethylenediamine by the procedure of Example 34 and reacting the resulting N-(3-pyrazolylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(d) gives N-cyano-N'-methyl-N"-[2-(3-pyrazolylmethylamino)ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N'-[2(3-pyrazolylmethylamino)ethyl]guanidine trihydrochloride.
Reaction SMILES: OC1C=CC(C(C)C#N)=CC=1.[N+]([O-])(O)=O.[N+:16]([C:19]1[CH:20]=[C:21]([CH:26]([CH3:29])[C:27]#[N:28])[CH:22]=[CH:23][C:24]=1[OH:25])([O-])=O.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[NH2:16][C:19]1[CH:20]=[C:21]([CH:26]([CH3:29])[C:27]#[N:28])[CH:22]=[CH:23][C:24]=1[OH:25]
Reactant: CC(C#N)c1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(C#N)c1ccc(O)cc1
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C#N)c1ccc(O)c(N)c1

Procedure:
4-Hydroxy-phenyl-propionitrile is nitrated in glacial acetic acid with 65% strength nitric acid at 10°-15° C, in the course of 2 hours, the 3-nitro-4-hydroxyphenyl-propionitrile (melting point = 104° C) is reduced with hydrogen, using 5% strength palladium charcoal as the catalyst, in ethanol at room temperature to give 3-amino-4-hydroxyphenyl-propionitrile (melting point = 125° C) and the amine compound is acetylated in toluene with molar equivalent amounts of acetic anhydride. The 3-acetamino-4-hydroxyphenyl-propionitrile (melting point = 191°-192°) is slowly warmed to 250°-260° and then rapidly heated up to 300°. The melt is cooled to room temperature, the oil is taken up in an alkaline aqueous solution, the pH of which is adjusted to 10, and the water/oil emulsion is extracted by shaking with chloroform. The chloroform solution is separated from the aqueous phase, dried with sodium sulphate and concentrated. The pink-beige needle crystals thus obtained melt at 69°-70° C.