Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Br.Br[CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>C1COCC1.O>[CH2:21]([N:22]([CH2:25][CH3:26])[CH2:23][CH2:24][C:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:20]
Reactant: CCN(CC)CCBr
Reactant: COC(=O)C1CCCC1
Agent: Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCC1(C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To methyl cyclopentanecarboxylate (1 g) in THF (8 ml) at −61° C. is added a solution of 2M LDA (9.8 ml). The mixture is stirred at room temperature for 15 minutes, then 2-bromo-N,N-diethylethanamine hydrobromide (2.04 g) is added at −61° C. The mixture is stirred for 5 minutes at this temperature, then at room temperature. The solution became yellow and was diluted with water (30 ml). The organic phase is extracted twice with a brine solution (30 ml). The pH of the organic phase is adjusted to 4 with 6N HCl. After decantation, the aqueous phase is extracted with CH2Cl2 (20 ml) and the pH of aqueous phase adjusted to 12 with 6 N NaOH. After decantation, the organic phase is dried over MgSO4 and concentrated. The residue is treated with diethyl ether (10 ml) and the white solid is filtrated. Methyl 1-[2-(diethylamino)ethyl]cyclopentanecarboxylate 280 is obtained as a yellow liquid after concentration of the ether solution.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:35]Cl)[N:26]([CH2:27][C:28]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1>CN(C=O)C>[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:35][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[N:26]([CH2:27][C:28]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2CC1(O)CCCCC1
Agent: [K]
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2c2c1nc(CN1C(=O)c3ccccc3C1=O)n2CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.1 %

Procedure:
Potassium phthalimide (2.59 g, 14.0 mmol) was added to a solution of 1-[(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanol (13.3 mmol) in DMF (50 mL). The reaction mixture was stirred at ambient temperature overnight. Additional potassium phthalimide (1.0 g) was added. The reaction mixture was stirred for 5 hours and then concentrated under reduced pressure. The residue was triturated with methanol to provide 6.91 g of crude 2-({4-amino-1-[(1-hydroxycyclohexyl)methyl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)isoindole-1,3-dione as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([CH2:10][S:11][CH:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(O)=[O:8]>CN(C=O)C.O1CCCC1>[CH2:25]1[O:26][C:20]2[C:21](=[CH:22][C:23]3[C:7](=[O:8])[CH2:10][S:11][CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17][C:18]=3[CH:19]=2)[O:24]1
Reactant: COC(=O)C(Cc1ccc2c(c1)OCO2)SCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C1Cc2cc3c(cc2C(=O)CS1)OCO3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.4 %

Procedure:
Oxalyl chloride (14.8 g) and DMF (3 drops) were successively added dropwise to a solution of methyl 2-carboxymethylthio-3-(3,4-methylenedioxyphenyl)propionate (29.0 g) in tetrahydrofuran (THF) (200 ml), followed by stirring for 1.5 hours at room temperature and concentrated under reduced pressure. The residual oil was dissolved in dichloromethane (250 ml). To the solution was added dropwise tin(IV) chloride (SnCl4)(55.6 g) under ice-cooling. The mixture was stirred for an hour under ice-cooing, to which 2NHCl (100 ml) was added dropwise. The dichloromethane layer was separated, washed with water, dried (MgSO4) and distilled off the solvent to give crystals of methyl 7,8-methylenedioxy-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxylate (17.0 g, 63%). Recrystallization from ethyl acetate gave colorless prisms.
Reaction SMILES: N[NH-].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]2[C:13]([O:15][C:16](=[O:17])[C:4]=12)=[O:14].[C:18]([C:21]1[C:30]([C:31](O)=O)=[CH:29]C2C(=CC=CC=2)[N:22]=1)(=[O:20])[NH2:19].N1C=CC=C[CH:35]=1>>[C:18]([C:21]([NH:22][C:16]([C:4]1[C:5]([C:13]([OH:15])=[O:14])=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1)=[O:17])([CH3:35])[CH:30]([CH3:31])[CH3:29])(=[O:20])[NH2:19]
Reactant: NC(=O)c1nc2ccccc2cc1C(=O)O
Reactant: c1ccncc1
Reactant: O=C1OC(=O)c2nc3ccccc3cc21
Agent: [NH-]N
Product: CC(C)C(C)(NC(=O)c1nc2ccccc2cc1C(=O)O)C(N)=O
Temperature: 25 °C

Procedure:
The aminoamide (24.25 mmol) is added over a two hour period to a solution of 2,3-quinolinedicarboxylic anhydride (20.06 mmol) in pyridine (100 mL) while maintaining the reaction mixture at room temperature. The mixture is allowed to stir at room temperature for one-half hour. Analysis of the isomer distribution of the reaction products by high performance liquid chromatography shows an 8.9/1 ratio of the desired 2-carbamoyl-3-quinolinecarboxylic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])[NH2:28].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]2[O:17][N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:26]=2)[CH:12]=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: COc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3ccccc3C)c(OC)c2)n1

Procedure:
Oxalyl chloride (126 μL; 1.49 mmol; 3 eq.), Intermediate 27 (120 mg; 0.5 mmol; 1 eq.), Intermediate 1 (82 mg; 0.5 mmol, 1 eq.) and DIEA (256 μL; 1.49 mmol; 3 eq.) were reacted according to general procedure 2. Purification by precipitation from DCM/n-pentane afforded the title compound as a brown solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:25])[NH2:24])[CH:19]=3)[CH:14]=2)=[O:11])=[CH:7][CH:6]=1.[C@H:26]1([C:35](O)=[O:36])[CH2:31][CH2:30][C@@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]1>>[ClH:1].[C:32]([C@@H:29]1[CH2:30][CH2:31][C@H:26]([C:35]([NH:3][CH2:4][C:5]2[O:9][C:8]([C:10]([O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:24])[NH2:25])[CH:19]=4)[CH:14]=3)=[O:11])=[CH:7][CH:6]=2)=[O:36])[CH2:27][CH2:28]1)([OH:34])=[O:33]
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)o3)ccc2c1
Agent: Cl
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)[C@H]4CC[C@@H](C(=O)O)CC4)o3)ccc2c1

Procedure:
The same procedures as in Example 3 were followed except for using 11.5 g of 6-amidino-2-naphthyl 5-aminomethylfuran-2-carboxylate dihydrochloride and 15.5 g of cis-1,4-cyclohexanedicarboxylic acid, to obtain 5.0 g of the above-mentioned compound in crude form. The crude compound was dissolved in 100 ml of aqueous 90% methanol, 2% aqueous sodium hydrogencarbonate solution was added thereto, and the precipitated carbonate was collected by filtration and washed with water. The washed product was made into solution by addition of 10 ml of DMF and 0.5 ml of hydrochloric acid, and the solution was added dropwise to 150 ml of acetone while stirring and cooling with ice. The white solid thus precipitated was collected by filtration to obtain 1.3 g of the intended product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([OH:18])(=[O:17])[CH2:13]C(O)=O.C([O-])(=O)C.[NH4+:23]>C(O)C>[NH2:23][CH:7]([C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:13][C:12]([OH:18])=[O:17]
Reactant: [NH4+]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.06 mmol of 3-nitrobenzaldehyde, 5.72 g of malonic acid, 8.5 g of ammonium acetate and 40 ml of ethanol are boiled under reflux for 8 hours and stirred at room temperature overnight. The cooled reaction mixture is then filtered with suction, washed with ethanol and ether and dried in air. 3-amino-3-(3-nitrophenyl)propionic acid is obtained. Subsequent N-acylation with phenylacetyl chloride under standard conditions produces 3-(3-nitrophenyl)-3-phenylacetyl-aminopropionic acid. This racemate is dissolved in 40 ml of water, and the solution is adjusted to pH 7.5 with potassium hydroxide. The enzyme penicillin amidase is added and shaken for 3 days. Removal of the enzyme by filtration and the usual workup result in (R)-3-amino-3-(3-nitrophenyl)propionic acid and (S)-3-(3-nitrophenyl)-3-phenylacetylaminopropionic acid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][C:34]3[NH:35][CH:36]=[N:37][C:33]=3[CH:32]=2)O1.B(O)O>>[NH:35]1[C:34]2[CH:38]=[CH:39][C:31]([C:2]3[C:3]4[CH2:16][CH2:15][N:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[C:4]=4[N:5]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:7]=3)=[CH:32][C:33]=2[N:37]=[CH:36]1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Reactant: CC1(C)OB(c2ccc3[nH]cnc3c2)OC1(C)C
Agent: OBO
Product: c1cncc(N2CCc3c(-c4ccc5[nH]cnc5c4)nc(N4CCOCC4)nc32)c1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole as a boronic acid, the desired compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-])=O)=[C:7]([NH:15][CH3:16])[CH:6]=[CH:5]2.C(N(CC)CC)C.Cl.NC1C=CC2C(=CC=CC=2)C=1N.O.O.[C:39]([OH:44])(=O)[C:40](O)=[O:41]>C(O)C.Cl.[Pd]>[CH3:16][N:15]1[C:7]2[CH:6]=[CH:5][C:4]3[CH:3]=[CH:2][CH:11]=[CH:10][C:9]=3[C:8]=2[NH:12][C:40](=[O:41])[C:39]1=[O:44]
Reactant: CNc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Reactant: O=C(O)C(=O)O
Agent: [Pd]
Agent: Cl
Agent: Nc1ccc2ccccc2c1N
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Cn1c(=O)c(=O)[nH]c2c3ccccc3ccc21
Yield: 91.5 %

Procedure:
A suspension of 6-bromo-2-methylamino-1-nitronaphthalene (2.81 g, 10 mmol) and triethylamine (1.40 ml, 10 mmol) in 150 ml of 96% ethanol was hydrogenated at room temperature and atmospheric pressure in the presence of 5% palladium-on-carbon (500 mg) for 1 h. The solution was filtered directly into 50 ml of 4M hydrochloric acid under a nitrogen atmosphere. The acidic filtrate was evaporated to dryness and the solid diaminonaphthalene hydrochloride was refluxed with oxalic acid dihydrate (1.5 g, 11.9 mmol) in 25 ml of 4M hydrochloric acid without further purification. After reflux for 2 h the mixture was cooled, and the solid product was isolated by filtration and washed with water, ethanol and ether to give 2.07 g (92%) of the title compound. M.p. 332.7° C. (ethanol); IR (KBr): 1685 cm-1 ; 1H-NMR (DMSO-d6): 3.60 (s, 3H, CH3), 7.33-7.93 (m, 5H, ArH), 8.37-8.60 (m, 1H, ArH), 12.13 (broad s, 1H, NH); MS m/z: 226 (M+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([O:13]CC)=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.BrC1C=CC=CC=1>CCCCCC>[N:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH:22][C:18]=1[NH:17][C:11]([C:4]1[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=1[OH:16])=[O:13]
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Reactant: Nc1nc2ccccc2[nH]1
Solvent: CCCCCC
Solvent: Brc1ccccc1
Product: Cc1c(Cl)c(O)c(C(=O)Nc2nc3ccccc3[nH]2)c(=O)n1C
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 82.5 %

Procedure:
199 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 98 mg of 2-amino-benzimidazole were added to 2 ml of bromobenzene, then, the mixture was stirred for 9.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, hexane was added to this and the resultant mixture was allowed to stand still. The resulting solid was collected by filtration, and washed with a mixture of t-butyl methyl ether and n-hexane and dried to obtain 202 mg of N-(2-benzimidazolyl)-5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 28) represented by the formula:
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].[F-].[K+].O>CN(C=O)C>[CH:15]([C:14]1[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=1)[O:11][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[O:16]
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1ccc(C#N)c(Cl)n1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C#N)c(Oc2cccc(C=O)c2)n1
Yield: 97.9 %

Procedure:
2-Chloro-6-methylnicotinonitrile (0.50 g, 3.3 mmol), 3-hydroxybenzaldehyde (0.40 g, 3.3 mmol) and potassium fluoride (0.57 g, 9.8 mmol) were heated with stirring in dry DMF (5 mL) at 120° C. for 7 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (4×), water (4×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-formyl-phenoxy)-6-methyl-nicotinonitrile (0.77 g, 97%) as a yellow solid.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[C:27]([F:31])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54](=[O:61])[N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[CH:47][CH:46]=1>CN(C=O)C.O>[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:46]=[CH:47][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54]([N:55]2[CH2:56][CH2:57][N:58]([C:23](=[O:25])[C:22]3[CH:26]=[C:27]([F:31])[C:28]([Cl:30])=[CH:29][C:21]=3[Cl:20])[CH2:59][CH2:60]2)=[O:61])=[CH:49][CH:50]=1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(F)c(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)c(Cl)cc2Cl)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
HOBt (23 mg, 0.17 mmol) and DIPEA (44.8 mg, 0.35 mmol) were added to a stirred solution of 2,4-dichloro-5-fluorobenzoic acid (29 mg, 0.14 mmol) in DMF (1 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (33 mg, 0.17 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (50 mg, 0.14 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered to afford 50 mg (70%) of N-biphenyl-4-yl-3-[4-(2,4-dichloro-5-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 514.11 (M+1)+ 100%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 7H), 7.44 (t, 2H), 7.34 (t, 1H), 7.14 (d, 1H), 3.96 (bs, 2H), 3.72 (m, 4H), 3.54 (d, 2H), 3.34 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([CH3:27])[CH:26]=1)[NH:23][CH2:22][CH2:21]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][CH3:16])=[CH:26][C:25]=3[CH3:27])[CH2:21][CH2:22]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(C)c2c(c1)CCN2
Agent: Cl
Product: CCC(CC)n1cc(Cl)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 164–165° C.; 1H NMR (300 MHz, CDCl3): δ 6.67 (s, 1 H), 6.66 (s, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 4.82–4.80 (m, 1 H), 4.39 (t, J=7.9 Hz, 2 H), 3.79 (s, 3 H), 3.05 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.84–1.73 (m, 2 H), 1.70–1.59 (m, 2 H), 0.89 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C19H25N3O2Cl (M+H)+: 362.1635; found m/z 362.1648.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1([C:14]1[C:15]([S:20][CH3:21])=[N:16][CH:17]=[N:18][CH:19]=1)[OH:13].[H][H].[CH3:25]I>O1CCCC1.O>[CH3:3][C:4]1([CH3:22])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1([C:14]1[C:15]([S:20][CH3:21])=[N:16][CH:17]=[N:18][CH:19]=1)[O:13][CH3:25]
Reactant: CI
Reactant: [H][H]
Reactant: CSc1ncncc1C1(O)c2ccccc2CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1(c2cncnc2SC)c2ccccc2CC1(C)C
Yield: 96.5 %

Procedure:
Sodium hydride (0.16 g of 60 percent in mineral oil, 4.0 mmol) was added with stirring to a solution of 1.0 g (3.5 mmol) of 5-(2,2-dimethyl-1-hydroxyindan-1-yl)-4-(methylthio)pyrimidine in 10 mL of tetrahydrofuran. After the hydrogen evolution and exotherm were complete, 0.43 g (3 mmol) of methyl iodide was added and the mixture was allowed to react overnight at ambient temperature. The mixture was then poured into 20 mL of cold water and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and then with concentrated aqueous sodium hydroxide, was dried over magnesium sulfate, and was concentrated by evaporation under reduced pressure. The oily solid residue was extracted with hexane to remove cold hexane insolubles and then hot hexane insolubles were removed by filtration of a hot hexane solution. The hexane was removed from the filtrate by evaporation under reduced pressure to obtain 0.87 g of the title compound as a white solid melting at 130°-132° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:26][C:27]1[CH:36]=[C:35]([C:37]#[C:38][CH2:39][O:40][CH3:41])[C:30]2[O:31][CH:32](N)[O:33][C:29]=2[CH:28]=1.C[Si]([N-:46][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[O:24]=[S:21]1(=[O:25])[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:46][C:28]4[C:29]5[O:33][CH2:32][O:31][C:30]=5[C:35]([C:37]#[C:38][CH2:39][O:40][CH3:41])=[CH:36][C:27]=4[F:26])=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:19][CH2:20]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COCC#Cc1cc(F)cc2c1OC(N)O2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC#Cc1cc(F)c(Nc2ncnc3cc(OCCCN4CCS(=O)(=O)CC4)c(OC)cc23)c2c1OCO2
Yield: 87 %

Procedure:
This was prepared using the method described in example 4 using 4-chloro-7-[3-(1,1-dioxidothiomorpholin-4-yl)propoxy]-6-methoxyquinazoline (150 mg, 0.39 mmol), 5-fluoro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxolamine (91 mg, 0.41 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 0.82 ml) in DMF (2.5 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (194 mg, 87%) as a colourless solid; NMR Spectrum:DMSOd6) 1.98 (quintet, 2H), 2.66 (t, 2H), 2.92 (m, 4H), 3.21 (m, 4H), 3.36 (s, 3H), 3.94 (s, 3H), 4.20 (t, 2H), 4.37 (s, 2H), 6.16 (s, 2H), 6.91 (d, 1H), 7.23 (s, 1H), 7.81 (s, 1H), 8.36 (s, 1H), 9.52 (s, 1H); Mass Spectrum: M+H+ 573.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.N1C=CN=C1.[Si:23](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:1]([O:8][CH2:9][C@H:10]([OH:13])[CH2:11][O:12][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H](O)COCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OC[C@@H](O)COCc1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.03 h
Yield: 90 %

Procedure:
To a solution of (R)-3-benzyloxypropane-1,2-diol (prepared from (S)-4-benzylymethyl-2,2-dimethyl-1,3-dioxolane (commercially available from FLUKA) by acid hydrolysis using 80% aqueous acetic acid), (8.3 g, 47.2 mmol) in dry THF (70 ml) was added imidazole (6.42 g, 94.4 mmol). After 2 minutes, t-butyldiphenylsilyl chloride (12.28 ml, 47.2 mmol) was added. A white precipitate formed immediately. After 2 hours, the reaction mixture was filtered and the filtrate evaporated. The residue was partitioned between ethyl acetate and water, the organic layer separated, washed with saturated brine, dried (MgSO4), filtered and evaporated to give a colourless oil. Chromatography of the oil on silica gel (dichloromethane as eluant) afforded the title compound as a colourless oil (17.72 g, 90%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5](NCCC)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[N:3]1.[Na]>>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[N:3]1
Reactant: CCCNc1c(-c2cccc(C(F)(F)F)c2)nn(C)c1C(=O)O
Agent: [Na]
Product: Cn1nc(-c2cccc(C(F)(F)F)c2)cc1C(=O)O

Procedure:
1-methyl -3-(3-trifluoromethylphenyl)-4-propylaminopyrazole-5-carboxylic acid, sodium salt
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=O)[C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:4]1[N:5]=[N:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncc(Cl)c1-c1ccncc1
Product: Clc1cnnc(Cl)c1-c1ccncc1
Temperature: 120 °C
Yield: 67 %

Procedure:
A suspension of compound 5-chloro-4-(pyridin-4-yl)pyridazin-3(2H)-one (2.5 g, 12 mmol) in POCl3 (20 mL) was heated at 120° C. for 3 h. After this time, the reaction mixture was cooled to RT. The reaction mixture was concentrated under reduced pressure. The obtained residue was treated with ice-cold saturated aqueous NaHCO3. The formed precipitate was collected by filtration and washed with water to give the title compound, 3,5-dichloro-4-(pyridin-4-yl)pyridazine as an off-white solid (1.8 g, 67%). LC/MS (method A): RT=0.70 min, (M+H)+=226.
Reaction SMILES: F[C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].CO[CH:21](OC)[N:22]([CH3:24])C.[CH:27]1(N)C[CH2:28]1>O1CCCC1>[CH:21]1([N:22]2[C:2]3[C:3](=[CH:12][C:13]([F:18])=[C:14]([F:17])[C:15]=3[F:16])[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:24]2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: NC1CC1
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 108 °C
Yield: 86.5 %

Procedure:
A 12 L stirred flask was charged with 4.8 L of tetrahydrofuran, 1584 g of ethyl 2,3,4,5-tetrafluorobenzoylacetate and 834 ml of dimethylformamide dimethyl acetal. After establishing a nitrogen atmosphere, this mixture was heated to reflux for 1 hour and then stirred at ambient temperature for four hours. The mixture was cooled and maintained at 4°-5° C. while adding 438 ml of cyclopropylamine over a period of 35 minutes. It was then stirred at 3°-5° C. for 1 hour and concentrated in vacuo. The yellow crystalline solid was dissolved in 3.6 L of dimethylformamide and 912 g of powdered potassium carbonate was added with strong stirring. The slurry was then heated on a steam bath for 1 hour (maximum internal temperature was 108° C. for 5 minutes). The hot mixture was poured into 30 L of cold water. Filtration, washing first with 6 L of cold water and then 6 L of cold ethanol followed by drying in vacuo at 50° C. gave 1615 g of product (86.5% yield).