Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Br:42][C:43]1[CH:44]=[C:45]([NH:50]C)[C:46]([NH2:49])=[CH:47][CH:48]=1>CN(C=O)C>[NH2:50][C:45]1[CH:44]=[C:43]([Br:42])[CH:48]=[CH:47][C:46]=1[NH:49][C:6]([CH:4]1[CH2:3][C:2](=[O:1])[CH2:5]1)=[O:8]
Reactant: CNc1cc(Br)ccc1N
Reactant: O=C1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Br)ccc1NC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.9 %

Procedure:
To a stirred solution of 3-oxocyclobutanecarboxylic acid (1.1 g) in DMF (50 ml) were added HATU (5.7 g) and N,N-diisopropylethylamine (4.2 ml) at 0° C., and the mixture was allowed to warm to room temperature for 30 min. A solution of 4-bromo-N2-methylbenzene-1,2-diamine (2.0 g) in DMF (2 ml) was added, and the resulting mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and diluted with DCM. The mixture was washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (hexane/EtOAc) to afford the title compound (2.7 g) as an off-white solid.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH:13]1([N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)[CH2:15][CH2:14]1.[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:43])[CH:39]=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[CH:13]1([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:1]([NH:43][C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[N:34]=[C:33]([NH:32][C@H:23]3[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25][CH2:24]3)[CH:42]=[CH:41]4)=[O:12])[CH2:18][CH2:17]2)[CH2:15][CH2:14]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: NC1CCN(C2CC2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCN(C2CC2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-cyclopropyl-piperidin-4-ylamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=442.7 (M+H+).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:16][CH2:15]N[CH2:13][CH2:12]1.[CH2:17](O)C>>[S:3]1[C:2]([N:6]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[CH:17][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]1=2
Reactant: Clc1nc2ccccc2s1
Reactant: CCO
Reactant: C1CNCCN1
Product: c1ccc2sc(N3CCNCC3)cc2c1

Procedure:
2-Chlorobenzothiazole (5 g) is heated in ethanol (75 ml) with piperazine (3.05 g) for 20 h. The mixture is partitioned between methylene chloride/ether and aqueous sodium bicarbonate. The organic phase is separated, dried with sodium sulfate and concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].C(=O)([O-])[O-:23].[K+].[K+]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([OH:12])=[O:23]
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [K+]
Product: Cn1nc(C(F)F)c(C(=O)O)c1Oc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared using 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde and 3,4-dichlorophenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[C:7]([CH:15]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH2:23]([NH2:25])[CH3:24].O.C(OCC)(=O)C>O1CCCC1>[CH2:23]([NH:25][CH2:2][C:3]1[CH:4]=[C:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[C:7]([CH:15]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:24]
Reactant: CC(C)(C)OC(=O)c1cc(CBr)cc(C(=O)OC(C)(C)C)c1
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCNCc1cc(C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of di-tert-butyl 5-(bromomethyl)isophthalate (1.00 g) in tetrahydrofuran (10.0 mL) were added a 70% aqueous ethylamine solution (2.21 mL), followed by stirring at room temperature overnight. To the reaction mixture were added water and ethyl acetate, and the organic layer was extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, and subsequently chloroform-methanol) to obtain di-tert-butyl 5-[ethylamino(methyl)]isophthalate (558 mg).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6]Br.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25].CO>O>[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][NH:26][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCN
Reactant: Nc1cc(CBr)cc(S(N)(=O)=O)c1Cc1ccccc1
Agent: Br
Solvent: O
Solvent: CO
Product: CCCCNCc1cc(N)c(Cc2ccccc2)c(S(N)(=O)=O)c1
Reaction time: 24 h

Procedure:
A mixture of 3-amino-4-benzyl-5-sulfamylbenzyl bromide hydrobromide (1.1 g; prepared as described in Example 61), n-butylamine (5.0 ml) and methanol (10 ml) is stirred at 22°-25° C. for 24 hours. The resulting solution is then diluted with water (20 ml) to precipitate crude (3-amino-4-benzyl-5-sulfamylbenzyl)-n-butylamine. After filtration and recrystallization from aqueous ethanol it is obtained with a melting point of 141°-143° C.
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH3:5].[CH2:6]([C:8]1[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([CH3:22])[O:10][N:9]=1)[CH3:7].[OH-].[K+]>O1CCOCC1.C(O)(=O)C>[CH2:6]([C:8]1[C:12]([C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH2:3][N:4]([CH3:1])[CH3:5])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([CH3:22])[O:10][N:9]=1)[CH3:7]
Reactant: CCc1noc(C)c1-c1cc2ccccc2[nH]1
Reactant: CNC
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1CN(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 20.6 ml. (0.24 mole) 37% aqueous formaldehyde, 18 ml. (0.12 mole) 40% aqueous dimethylamine and 80 ml. acetic acid is cooled to 0° and treated by the dropwise addition of 25.5 g. (0.113 mole) 2-(3-ethyl-5-methyl-4-isoxazolyl)-indole in a solution of 45 ml. acetic acid and 125 ml. dioxane. After addition is complete the mixture is stirred for 1 hour at room temperature and poured onto 500 ml. ice-water. The resulting solution is made basic with 20% potassium hydroxide and then extracted with methylene chloride. The methylene chloride is washed with water, brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give a gum that crystallizes to give 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-(dimethylaminomethyl)indole; m.p. 88° to 90° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38]I>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[O:29])[CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:38][CH2:37][O:36][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][O:30]2)=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1
Reactant: ICCOC1CCCCO1
Product: O=C(c1ccc(OCCOCCOCc2ccccc2)cc1)C(CCOC1CCCCO1)c1ccccc1

Procedure:
is prepared by using the method described in the example 4d starting from 1-{4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}-2-phenylethanone (8.4g, 21.5 mmol) and 2-(tetrahydropyran-2-yloxy)ethyl iodide (6.6 g, 25.8 mmol). The product (11.7 g) is used in the next reaction step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH2:35])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(OCC)C>[N+:18]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:35][CH2:34][CH:31]1[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29][CH2:30]1)=[CH:10][CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:7]=2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CNc2c([N+](=O)[O-])cnc3cc(-c4ccccc4)ccc23)CC1
Yield: 94.3 %

Procedure:
4-Chloro-3-nitro-7-phenylquinoline (8.35 g, 29.3 mmol) was treated with 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (7.54 g, 35.2 mmol) according to the method described in Part A of Examples 152–156. The crude solid was triturated with water, isolated by filtration, sonicated with diethyl ether, isolated by filtration, and dried for four hours in a vacuum oven at 40° C. to provide 12.78 g of tert-butyl 4-[(3-nitro-7-phenylquinolin-4-ylamino)methyl]piperidine-1-carboxylate as a yellow solid, mp 153–154° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:5]=[C:4]([CH2:16][CH3:17])[N:3]=1.[NH2:18][NH2:19].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:16]([C:4]1[N:3]=[C:2]([NH:18][NH2:19])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:5]=1)[CH3:17]
Reactant: CCc1nc(Cl)cc(-c2ccccc2OC)n1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCc1nc(NN)cc(-c2ccccc2OC)n1

Procedure:
[2-Ethyl-6-(2-methoxy-phenyl)-pyrimidin-4-yl]-hydrazine was prepared from 4-chloro-2-ethyl-6-(2-methoxy-phenyl)pyrimidine (0.91 g, 3.7 mmol), hydrazine (0.69 mL, 22 mmol), sodium carbonate (0.76 g, 7.1 mmol) and potassium carbonate (0.79 g, 5.5 mmol) in dioxane (10 mL) by a procedure similar to example 3, step 1 yielding 0.77 g (86%) of a white solid.
Reaction SMILES: C([C:4]1([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=O)C.[OH:20]O>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([CH2:12][CH2:11][C:4]1([C:5]([OH:10])=[O:20])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(=O)C1(CCC(=O)OC(C)(C)C)CCCCC1=O
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
To a solution of 2-acetyl-2-[2-(tert-butoxycarbonyl)-ethyl]-cyclohexanone (see Preparations 1 and 2) (2.0 g, 7.45 mmol) and concentrated sulphuric acid (98% w/w, one drop) in toluene (6.0 ml) was added, dropwise, a 30% aqueous solution of hydrogen peroxide (1.05 ml, 9.31 mmol) at room temperature. The mixture was stirred for 68 hours at room temperature, treated with a further quantity of a 30% aqueous solution of hydrogen peroxide (0.4 ml, 3.72 mmol) and stirred for a further 16 hours at room temperature. The mixture was partitioned between toluene (25 ml) and 5% aqueous sodium sulphite solution and the layers separated. The toluene layer was washed with dilute aqueous ammonia solution (25 ml of 0.880 ammonia in 200 ml of distilled water, 4×25 ml). The combined aqueous extracts were washed with toluene (25 ml), acidified to pH 2-3 with 5.0N aqueous hydrochloric acid solution and extracted with toluene (3×25 ml). The combined toluene extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure to give an oil, (1.11 g, 61%). The crude product was crystallized from pentane (7.5 ml/g) to give the title compound as a colorless solid. Rf. 0.28 (silica, hexane/ethyl acetate 2:1). 1H-NMR (300 MHz, CDCl3):=1.45 (s, 9H). 1.45-1.60 (m, 2H), 1.62-1.78 (m, 4H), 1.92-1.99 (m, 2H), 2.11-2.21 (m, 2H), 2.21-2.33 (m, 2H) ppm. Analysis %: Found: C, 64.26; H, 9.27; C13 H22O4 requires: C, 64.44; H, 9.15.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][S:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[Cl:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[CH:7]([S:6][CH2:5][CH2:4][C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[Br:1])[Cl:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)CSCCc1ccccc1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Cl)SCCc1ccccc1Br
Reaction time: 2.5 h
Yield: 97 %

Procedure:
A mixture of methyl 2-((2-bromophenethyl)thio)acetate (4.4 g), 1-chloropyrrolidine-2,5-dione (2 g) and carbon tetrachloride (2.4 g) was stirred on ice-bath for 2.5 hrs, filtrated and evaporated to yield the title compound (4.7 g).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[C-:13]#[N:14].[K+].Cl.[OH2:17]>>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:4](=[O:5])[O:3][CH:2]2[C:13]([NH2:14])=[O:17]
Reactant: [C-]#N
Reactant: O
Reactant: O=C1OC(O)c2cccc(O)c21
Agent: Cl
Agent: [K+]
Product: NC(=O)C1OC(=O)c2c(O)cccc21
Temperature: 25 °C

Procedure:
2.8 g of 3,7-dihydroxy-phthalide (see Examples 105 and 106) are introduced into a solution of 7.5 g of potassium cyanide in 35 ml of water, and 25 ml of concentrated hydrochloric acid are slowly added to the mixture while cooling with ice, so that the internal temperature does not exceed 10° C. The reaction mixture is maintained at room temperature for a further 5 hours and then the crystals are filtered off. Having been washed with water and dried well, the product (m.p. 213°-215° C.) is pure 4-hydroxy-1,3-dihydro-3-oxo-1-isobenzofurancarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23].Cl>O1CCCC1>[CH3:23][CH:22]([N:10]1[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:9]1)[CH3:24]
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Reactant: CC(C)I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)n1nc(-c2cccc(Cl)c2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
To a suspension of 8- (3-chlorophenyl)pyrido [2,3 -d]pyridazin-5-one (0.33 g, 1.28 mmoles) in tetrahydrofuran (50 ml) was added sodium hydride (0.07 g, 1.53 mmoles). The mixture was stirred at room temperature for 30 minutes under an inert atmosphere. 2-Iodopropane (0.64 ml, 6.4 mmoles) was added and the mixture refluxed for 48 hours. The mixture was cooled and acidified by the addition of 50 ml of 1N HCl. The mixture was extracted with ethyl acetate (3×50 ml) and dried over magnesium sulfate. The solution was filtered and the solvent removed to yield the crude product. The product was purified by crystallization (ethyl ether/hexane) yielding 0.15 g of 6-(2-propyl)-8-(3-chlorophenyl)pyrido[2,3-d]pyridazin-5-one (39%), mp 80°-81° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:9]2)=[N:6][CH:7]=1.[OH-].[Na+:24].[ClH:25]>CO.C1COCC1>[Cl-:25].[Na+:24].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: Cl
Reactant: COC(=O)c1cn(-c2ccc(F)cn2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cn(-c2ccc(F)cn2)nc1-c1ccccc1
Product: [Cl-]
Temperature: 50 °C
Reaction time: 18 h
Yield: 146.1 %

Procedure:
To a solution of methyl 1-(5-fluoropyridin-2-yl)-3-phenyl-1H-pyrazole-4-carboxylate (0.55 g, 1.86 mmol) in methanol (9.3 mL) and THF (9.3 mL) was added NaOH (1.0 M in water; 5.59 mL, 5.59 mmol). The mixture was stirred at 50° C. After 18 h, the mixture was cooled to ambient temperature and HCl (6.0 M in water; 0.93 mL, 5.59 mmol) was added. The mixture was concentrated to dryness to give sodium chloride salt of the title compound (0.77 g). MS 284.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C:21]2[N:26]=[CH:25][C:24](Br)=[CH:23][N:22]=2)[C:10]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH:32]=[O:33])C.[CH3:34][OH:35].C(N(CC)CC)C>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>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C:21]2[N:26]=[CH:25][C:24]([C:34]([O:33][CH3:32])=[O:35])=[CH:23][N:22]=2)[C:10]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: CN(C)C=O
Reactant: Cc1c(COc2ncc(Br)cn2)nc2ccccc2c1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(OCc2nc3ccccc3c(OCc3ccccc3)c2C)nc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
4-(Benzyloxy)-2-{[(5-bromopyrimidin-2-yl)oxy]methyl}-3-methylquinoline (1.5 g) was suspended in a mixed solvent (40 mL) of DMF-methanol (1:1), and triethylamine (1 mL) and dichlorobis(triphenylphosphine)palladium(II) (1.2 g) were added thereto, followed by stirring at 100° C. under a carbon monoxide atmosphere (1.0 MPa) for 5 hours. The reaction mixture was allowed to cool to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0˜50/50). The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue which was then warmed to be dissolved. Hexane was added to this solution, followed by stirring at room temperature, and the resulting solid was collected by filtration and dried under vacuum at room temperature to obtain 1.034 g of methyl 2-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}pyrimidine-5-carboxylate as a pale yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][N:10]=[CH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>C(Cl)Cl>[OH:9][N:10]=[C:11]([Br:1])[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(C=NO)cc1
Solvent: ClCCl
Product: N#Cc1ccc(C(Br)=NO)cc1
Temperature: 25 °C

Procedure:
The compound was prepared according to Tanaka et al. Bull. Chem. Soc. Jpn. 1984, 57, 2184. A 0.05 M solution of N-bromosuccinimide (724 mg, 4.07 mmol, 1.20 eq) in CH2Cl2 was added dropwise to a 0° C. solution of 4-(hydroxyiminomethyl)-benzonitrile (496 mg, 3.39 mmol, 1.00 eq) in CH2Cl2 (50 mL). The solution was warmed to room temperature before being volumetrically partitioned between two different reaction vials. Each vial was then concentrated and the crude residues were used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=[O:39])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:29]([C:31]3[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=3)[C:34]#[N:35])[CH2:28][C:27](=[O:39])[NH:22][C:9]=2[CH:10]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: COc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
Prepared from (3-amino-2′-methoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G10) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light green powder (30 mg).
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].Cl[CH2:12][C:13](OCC)=[O:14]>C(OCC)(=O)C.CO>[CH3:10][C:7]1[S:8][CH:9]=[C:5]([CH:2]2[O:1][CH2:12][C:13](=[O:14])[NH:4][CH2:3]2)[N:6]=1
Reactant: Cc1nc(C(O)CN)cs1
Reactant: CCOC(=O)CCl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(C2CNC(=O)CO2)cs1

Procedure:
Prepared analogously to Example S by reaction of 2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with ethyl chloroacetate and purification on a silica gel column using ethyl acetate/methanol=19:1 as eluant.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][C:13]1[CH:17]=[CH:16][N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:14]=1.CO[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1>C1COCC1>[CH3:12][C:13]1[CH:17]=[C:16]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)[N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:14]=1
Reactant: Cc1ccn(C2CCCCO2)n1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-methylpyrazole (3.0 g, 35.4 mmol), 3,4-dihydro-2H-pyrane (4.97 mL, 53.2 mmol) and TFA (0.02 mL, 0.260 mmol) was stirred at 85° C. for 6 h under an argon atmosphere. The RM was cooled to RT and NaH 60% in mineral oil (0.061 g, 1.524 mmol) was and the RM was stirred for 10 min. The RM was purified by bulb-to-bulb distillation to give 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (b.p. 150-170° C., 12 mbar). A solution of n-1.6 M BuLi in n-hexane (3.38 mL, 5.41 mmol) was added dropwise over 10 min to a solution of 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.0 g, 5.41 mmol) in THF (12 mL) at −70° C. under a nitrogen atmosphere and The RM was stirred for 10 min and then treated dropwise with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.898 g, 5.69 mmol) and stirred at −70° C. for 1 h. The RM was allowed to warm to RT, treated with n-hexane and the product was filtered, dissolved in water (10 mL) and acidified to pH 6 with 10% aqueous citric acid. The water was evaporated off under reduced pressure and the aqueous residue extracted with EtOAc, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a yellow resin. UPLC-MS (Condition 3) tR=0.56 min, m/z=211.2 [M+H]+.
Reaction SMILES: C=O.[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[F:13].[C:15](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:15])=[CH:8][C:7]=1[F:13]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(N)cc1F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNc1ccc(C(=O)OC)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Add formaldehyde (0.15 g) to a mixture of 2-fluoro-4-amino benzoic acid methyl ester (0.62 g), acetic acid (2.1 mL) and 1,2 dichloroethane (20 mL). Stir at room temperature overnight. Add sodium triacetoxyborohydride (1.15 g) and stir at room temperature for 2 hours. Quench by pouring the reaction mixture into a mixture of saturated aqueous sodium bicarbonate and ethyl acetate. Separate the layers, wash the organic phase with water, dry the remaining organic phase over sodium sulfate and then concentrate under reduced pressure. The residue is purified by chromatography eluting with ethyl acetate:hexane (1:4) to provide 2-fluoro-4-methylamino benzoic acid methyl ester (0.10 g, 15%) as an oil.