Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[Cl:15].[Cl:16][C:17]1[N:18]=[C:19]([C:24](O)=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>>[Cl:15][C@H:3]1[C@@H:2]([NH:1][C:24]([C:19]2[NH:20][C:21]([CH2:22][CH3:23])=[C:17]([Cl:16])[N:18]=2)=[O:25])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](Cl)C1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2Cl)nc1Cl
Yield: 73.4 %

Procedure:
The same operation as in Example (196b) was performed using tert-butyl cis(±)-4-amino-3-chloropiperidine-1-carboxylate obtained in Example (198a) (134 mg, 0.571 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (99.7 mg, 0.571 mmol), 1-hydroxybenzotriazole hydrate (116 mg, 0.856 mmol), WSC hydrochloride (164 mg, 0.856 mmol) and triethylamine (119 μL, 0.856 mmol), to obtain 164 mg of the title compound (73%) as a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[C:10]([Cl:16])[CH:9]=1)[O:5][CH3:6].[OH-].[K+].O.Cl>C(O)C>[Cl:14][C:12]1[CH:13]=[C:8]([CH:9]=[C:10]([Cl:16])[C:11]=1[Cl:15])[O:7][CH:4]([O:5][CH3:6])[C:3]([OH:17])=[O:2]
Reactant: COC(=O)C(OC)Oc1cc(Cl)c(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(Oc1cc(Cl)c(Cl)c(Cl)c1)C(=O)O
Temperature: 45 °C

Procedure:
A solution of 35.2 g (0.12 mole) methyl-α-(3,4,5-trichlorophenoxy)-α-methoxyacetate in 50 ml ethanol was added slowly to a solution of 9.2 g (0.14 mole) 85% KOH in 150 ml 2B ethanol. The mixture was heated at 45° C for one-half hour, then cooled to room temperature and poured into 300 ml H2O. The pH of the resulting mixture was adjusted to 2 with dilute HCl. An oil separated which was removed by two 150 ml extractions with chloroform. The chloroform extracts were combined, washed with three 150 ml portions of water, and dried over magnesium sulfate. Removal of the solvent in vacuum left 22.9 g (66.8% crude yield) of a solid which was recrystallized from cyclohexane to give α-(3,4,5-trichlorophenoxy)-α-methoxyacetic acid, m.p. 101°-104° C, characterized by infrared spectroscopy. 20.0 g (0.07 mole) of the acid dissolved in 25 ml tetrahydrofuran was added dropwise to 1.9 g (0.08 mole) sodium hydride in 75 ml tetrahydrofuran. One half hour after addition was complete, the solution was evaporated to leave the sodium salt. This was added by portions to a solution of 8.9 g (0.07 mole) oxalyl chloride in 150 ml benzene to give 15.7 g (73.8% yield) of an oil, α-(3,4,5-trichlorophenoxy)-α-methoxyacetyl chloride. Due to its air sensitivity, 5.2 g (0.02 mole) of this compound was immediately dissolved in 25 ml benzene and added slowly to a solution of 1.7 g (0.02 mole) dimethylpropargylamine and 2.1 g (0.02 mole) triethylamine in 100 ml benzene, with stirring while the solution was being cooled to 10° C in an ice bath. After addition was complete the cold bath was removed and the mixture was allowed to come to room temperature. The mixture was then washed first with 100 ml water, followed by two 100 ml portions of 5% sodium carbonate solution. The organic phase was dried over magnesium sulfate, and the solvent was evaporated to give 5.4 g (77.1% yield) of a solid, which was recrystallized from hexane and characterized by infrared and NMR spectroscopy as in N-dimethylpropynyl-α-methoxy-α-(3,4,5-trichlorophenoxy)acetamide, m.p. 76°-80° C.
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH:21](O)([CH3:23])[CH3:22]>>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH:21]([CH3:23])[CH3:22])=[O:2]
Reactant: CC(C)O
Reactant: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)C=Nc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Yield: 78 %

Procedure:
5 g (21.8 mmol) of N-carboxymethylene-4-chloro-anthranilic acid are suspended in 50 ml of isopropanol, and 222 mg (2.3 mmol) of sulfuric acid are added. The mixture is heated under reflux for 8.25 hours. It is then cooled to room temperature and the product which has precipitated out is washed with petroleum ether and dried. 4.6 g (16.9 mmol; 78%) of N-carboisopropoxymethylene-4-chloro-anthranilic acid are obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N+:13]([C:16]1[N:17]=[C:18]2[N:23]([CH:24]=1)[CH2:22][CH2:21][C@H:20]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]3)=[CH:29][CH:28]=1)[O:19]2)([O-:15])=[O:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCCl>[N+:13]([C:16]1[N:17]=[C:18]2[N:23]([CH:24]=1)[CH2:22][CH2:21][C@H:20]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH:36]([NH:8][C:7]4[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=4)[CH2:35][CH2:34]3)=[CH:29][CH:28]=1)[O:19]2)([O-:15])=[O:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(Nc4ccc(OC(F)(F)F)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
4-(Trifluoromethoxy)aniline (1.271 ml) was added to a 1,2-dichloroethane solution (50 ml) of 1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-one (2.5 g). Subsequently, sodium triacetoxyborohydride (1.992 g) and acetic acid (0.538 ml) were added thereto and the mixture was stirred at room temperature for 21 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) and recrystallized from ethyl acetate to afford the title compound as a yellow powder (2.55 g).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15]([C@@H:17]3[CH2:21][C@H:20]([CH:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)[CH2:19][N:18]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:4].[Cl:39]N1C(=O)CCC1=O>C(#N)C.CN(C)C=O>[Cl:39][C:13]1[N:14]=[C:15]([C@@H:17]2[CH2:21][C@H:20]([CH:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]3)[CH2:19][N:18]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:16][C:12]=1[C:9]1[CH:8]=[CH:7][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:11][CH:10]=1
Reactant: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)OC(C)(C)C)[nH]2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)OC(C)(C)C)nc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a solution of the compound prepared in Example 64 (2.41 g, 4.4 mmol) in acetonitrile (50 mL) and N,N-dimethylformamide (20 mL) at 0° C. was added N-chlorosuccinimide (0.62 g, 4.6 mmol). The reaction was warmed to room temperature, stirred under nitrogen overnight then heated between 50-70° C. for 2 h. The reaction was cooled to room temperature, concentrated under reduced pressure and the residue washed with aqueous sodium bicarbonate solution (1×50 mL). The solid residue was suspended in a mixture of ethyl acetate (100 mL) and dichloromethane (100 mL) and sonicated. The solids were collected by filtration to give the title compound (1.39 g) as an off-white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[O:11].[Br:19]Br.O.[OH-].[Na+]>C(O)(=O)C>[Br:19][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)=[O:11]
Reactant: CN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(C(=O)c2[nH]c3ccccc3c2Br)CC1
Reaction time: 7 h

Procedure:
(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 4, 0.222 g) in acetic acid (1 mL) at ambient temperature was treated with bromine (0.05 mL) and stirred for 7 h. The reaction mixture was poured into water and adjusted to basic pH by addition of 1 M sodium hydroxide. The mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane, afforded the title compound (0.154 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](Br)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([N:35]2[C:43]3[C:38](=[CH:39][C:40](B4OC(C)(C)C(C)(C)O4)=[CH:41][CH:42]=3)[CH2:37][CH2:36]2)=[O:34])[CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:40]3[CH:39]=[C:38]4[C:43](=[CH:42][CH:41]=3)[N:35]([C:33](=[O:34])[CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=3)[CH2:36][CH2:37]4)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(N)ncnc32)CC1
Reactant: Cc1cccc(CC(=O)N2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CCN(C(=O)OC(C)(C)C)CC5)c5ncnc(N)c45)ccc32)c1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
To 1,1-dimethylethyl 4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (200 mg, 0.505 mmol), and 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (228 mg, 0.606 mmol) dissolved in 1,4-Dioxane (4 mL) was added saturated aqueous NaHCO3 (2 mL). The mixture was then bubbled with N2 gas for 10 minutes and then Pd(Ph3P)4 (58.3 mg, 0.050 mmol) was added and then bubbled for 5 additional minutes. Then reaction was then capped and heated at 100° C. overnight. The mixture was allowed to cool then diluted with water (10 mL) then extracted with EtOAc (3×20 ml). The organics were combined, washed with brine, dried over MgSo4, filtered and concentrated to isolate a amber color oil. The oil was then purified on a 25 g Biotage SNAP column conditioned with Hexane and eluting with a gradient of 0 to 10% MeOH in DCM for 30 minutes to afford 1,1-dimethylethyl 4-(4-amino-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (230 mg, 80% yield) as a amber color oil. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.13 (s, 1H), 7.45 (s, 1H), 7.32 (s, 1H), 7.20-7.26 (m, 2H), 7.12 (s, 1H), 7.09 (t, J=7.58 Hz, 2H), 4.71-4.83 (m, 1H), 4.20 (t, J=8.46 Hz, 2H), 4.08-4.15 (m, 2H), 3.94 (s, 2H), 3.82 (s, 2H), 3.20 (t, J=8.46 Hz, 2H), 2.95 (br. s., 2H), 2.31 (s, 3H), 1.86-1.97 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>ClCCl>[Br:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(CBr)N1CCOCC1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
A solution of bromoacetyl bromide (3.0 mL, 0.034 mol) in dichloromethane (240 mL) was cooled to −25° C. A solution of morpholine (9.0 mL, 0.10 mol) in dichloromethane (20 mL) was slowly added over a period of one hour. After the addition was complete, the reaction was stirred at −25° C. for 15 minutes and then allowed to warm to ambient temperature. Dichloromethane was added, and the resulting solution was washed sequentially with water, 1N aqueous hydrogen chloride, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure to provide 4-(bromoacetyl)morpholine as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:10]Br>C(OCC)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([Br:10])=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: BrBr
Reactant: Nc1ncccc1C=O
Solvent: CCOCC
Product: Nc1ncc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a stirred solution of 2-aminopyridine-3-carboxaldehyde (10 g, 81.88 mmol) in dry diethyl ether, bromine (5.45 ml, 106.44 mmol) was added drop-wise. The reaction was stirred at ambient temperature for 30 min. The amber solids were filtered and dissolved in ethyl acetate. The ethyl acetate solution was washed with 1 N NaOH and then brine, dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to afford 2-amino-5-bromonicotinaldehyde (14.6 g, 88% yield).
Reaction SMILES: [CH3:1][C:2]([C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14](=[O:15])[C:7]=2[N:6]=1)([CH3:4])[CH3:3]>CO.[Pd]>[CH3:4][C:2]([C:5]1[NH:9][C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:7]=2[N:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1nc2c(=O)ccccc2[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1nc2c([nH]1)CCCCC2=O
Yield: 87.7 %

Procedure:
A solution of Intermediate 63 (1.9 g) in methanol (400 mL) was hydrogenated using the H-Cube (settings: room temp, 1.3 ml/min flow rate) and 10% Pd/C CatCart 30 as the catalyst. The solvent was concentrated under vacuum to give the title compound (1.7 g). LC/MS MH+ 207 Rt 0.75 min (5 minute run).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[CH:12](O)=O>>[NH:1]1[C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=2[N:11]=[CH:12]1
Reactant: O=CO
Reactant: Nc1ccc(C(=O)O)cc1N
Product: O=C(O)c1ccc2nc[nH]c2c1

Procedure:
3,4-diaminobenzoic acid (5 g, 32 mmol) and formic acid (20 ml) were mixed and refluxed overnight. Formic acid was removed on rotavapour and water added to the residue to obtain the solid. Solid was filtered and dried to obtain the title compound quantitatively.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1.C(Cl)Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:12]1([C:18]#[C:19][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(C#Cc2ccccc2)c1

Procedure:
Methyl 3-iodobenzoate, phenylacetylene (1.5 eq.) and Pd(PPh3)2Cl2 (5 mol %) in piperidine (3 eq.) was heated at 70° C. for 30 minutes. The solidified residue was dissolved with CH2Cl2 and water and poured onto HCl 2N. The acidic phase was extracted three times with CH2Cl2. The combined organic layers were washed twice with HCl 2N, once with water and once with brine. The organic layer was then dried over MgSO4 and concentrated. The resulting residue was purified using SiO2 with petroleum spirit/toluene 70:30 to give methyl 3-phenylethynyl-benzoate as a white solid (quantitative yield). NMR 1H (ppm, CDCl3): 8.20 (t, J4=1.7 Hz, 1H), 7.98 (d, J3=7.9 Hz, 1H), 7.69 (d, J3=7.6 Hz, 1H), 7.54-7.50 (m, 2H), 7.42 (t, J3=7.8 Hz, 1H), 7.36-7.31 (m, 3H), 3.92 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][CH:16]1[CH2:20][CH2:19][CH2:18][NH:17]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[CH3:15])=[O:14])[CH:6]=[CH:5]2
Reactant: CC1CCCN1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Product: CC1CCCN1C(=O)c1ccc2cc(O)ccc2c1

Procedure:
The title compound was synthesised from 6-Hydroxy-2-naphtoic acid (commercially available) and 2-methyl-pyrrolidine (commercially available) according to the procedure described for Example A. MS (m/e): 254.1 (MH−, 100%)
Reaction SMILES: [N:1]#[C:2]Br.C[N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:7][CH2:6]1.O>CS(C)=O>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([N:8]2[CH2:7][CH2:6][N:5]([C:2]#[N:1])[CH2:10][CH2:9]2)=[N:12]1
Reactant: CN1CCN(c2n[nH]c3ccccc23)CC1
Reactant: N#CBr
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCN(c2n[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of cyanogen bromide (5.3 g, 0.05 mol), K2 CO3 (7.1 g) and dimethylsulfoxide (40 ml) was added, dropwise, 3-(4-methyl-1-piperazinyl)-1H-indazole (1 1.0 g 0.051 mol) dissolved in dimethylsulfoxide (60 ml). The reaction was stirred at ambient temperature for 1 hour, and then it was poured into water. The aqueous suspension was extracted with ethyl acetate, the ethyl acetate was washed (H2O), dried (MgSO4), and concentrated to afford 7.8 g (67%) of a ye llow solid. This sample was combined with another and recrystallized twice from toluene to afford analytically pure 4-(1H-indazol-3-yl)-1-piperazinecarbonitrile as a white solid, m.p.=12°-122° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[S:14][C:13]([N:15]=[C:16]=[O:17])=[CH:12][CH:11]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:9][C:10]1[S:14][C:13]([NH:15][C:16]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:17])=[CH:12][CH:11]=1
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1ccc(Cl)s1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(Cl)s1
Temperature: 80 °C
Yield: 30.6 %

Procedure:
To a stirred suspension of 2.5 g (22.5 mM) of creatinine in 30 ml of anhydrous DMF was added a solution of 2.87 g (18 mM) of 5-chloro-2-thienyl isocyanate in 15 ml of toluene. The resulting mixture was heated at 80° C. for 3.5 hrs., cooled, and poured into a mixture of 250 ml of water and 50 ml of toluene. The precipitate was collected and recrystallized from ethyl acetate to give 1.5 g of the above urea as a tan solid, m.p. 204°-205° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:3].[H-].[Na+].[CH3:16][O:17][C:18](=O)[O:19]C>CCCCCC.C(OCC)(=O)C>[C:4]1([C:2](=[O:3])[CH2:1][C:18]([O:17][CH3:16])=[O:19])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)OC
Reactant: CC(=O)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)CC(=O)c1cccc2ccccc12
Yield: 3945.4 %

Procedure:
10.2 g(59.9 mmol) of 1-acetonaphthone and 4.8 g(60% in mineral oi, 120 mmol) of sodium hydride were added to 100 mg of dimethylcarbonate and the mixture was refluxed for 24 hours. The solvent was removed under reduced pressure, 100 ml of 1N aqueous HCl solution was added to the residue, and the resulting mixtrue was extracted with 100 ml of ethyl acetate. The organic layer was washed with water(100 ml×3), dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography(eluent: n-hexane/ethyl acetate=90/10, v/v) to give 10.0 g (43.8 mmol, Yield 73%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[H-].[Na+].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[CH3:1][C:2]1([CH3:9])[N:6]([S:22]([C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)(=[O:24])=[O:23])[C:5](=[O:7])[N:4]([S:22]([C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)(=[O:24])=[O:23])[C:3]1=[O:8]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(S(=O)(=O)c2ccc3ccccc3c2)C(=O)N1S(=O)(=O)c1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
5,5-Dimethylimidazolidine-2,4-dione (1.28 g) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (60%, in oil) (0.25 g) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 2-naphthalenesulfonyl chloride (2.38 g) was added at 0° C., and the mixture was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate (150 mL) was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. After drying over anhydrous magnesium sulfate, the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded 597 mg of white crystals.
Reaction SMILES: [N:1]1[N:5]2[C:6](O)=[CH:7][CH:8]=[N:9][C:4]2=[N:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O.[OH-].[Na+]>>[Cl:13][C:6]1[N:5]2[N:1]=[CH:2][N:3]=[C:4]2[N:9]=[CH:8][CH:7]=1
Reactant: Oc1ccnc2ncnn12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccnc2ncnn12
Temperature: 0 °C

Procedure:
5.4 g of [1,2,4]triazolo[1,5-a]pyrimidin-7-ol from the first synthesis step are introduced into 20 ml of phosphorus oxychloride with vigorous stirring. After completion, the mixture is warmed under reflux for a further 1.5 h. For work-up, the cooled batch is stirred in portions into 100 ml of ice-water and subsequently adjusted to pH 12 using conc. NaOH solution. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, and the solvent is removed in vacuo. The 7-chloro-[1,2,4]triazolo[1,5-a]pyrimidine obtained is employed in the following reaction without further purification; m.p. 190° [lit. 186-187° C.];