Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([CH3:22])=[CH2:21]>CN(C=O)C.O>[CH3:21][C:20](=[CH2:19])[CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=C(C)CBr
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)COc1cccc(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Methyl 3-hydroxybenzoate (1 g, 6.57 mmol) was dissolved in DMF (10 ml) to give a colorless solution. To the solution potassium carbonate (1.089 g, 7.88 mmol) and 3-Bromo-2-methylpropene (0.729 ml, 7.23 mmol) were added. The reaction mixture was heated to 90° C. and stirred for 1 h. After cooling the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and evaporated under vacuum to afford the title compound (1.180 mg)
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5](Cl)=[N:4][CH:3]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5]([NH:21][CH2:17][CH2:18][CH2:19][CH3:20])=[N:4][CH:3]=1
Reactant: CCCCN
Reactant: Fc1ccc2[nH]c3c(Br)cnc(Cl)c3c2c1
Product: CCCCNc1ncc(Br)c2[nH]c3ccc(F)cc3c12
Temperature: 100 °C

Procedure:
4-Bromo-1-chloro-8-fluoro-5H-pyrido[4,3-b]indole (150 mg, 0.501 mmol) was suspended in n-butylamine (36.1 mg, 0.501 mmol) and heated to 100° C. for 48 hr. After cooling to ambient temperature, the crude reaction mixture was loaded directly onto silica gel for purification (EtOAc/hexanes). The intermediate was processed according to the general procedures outlined in Example 1 Steps E and F to provide the title compound.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[N:8]=[CH:7][C:6]([Br:13])=[CH:5]2.[OH-:14].[Na+]>P(=O)(O)(O)O>[Br:13][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([OH:14])=[CH:11][C:10]=2[Br:12]
Reactant: [OH-]
Reactant: Nc1cc(Br)c2ncc(Br)cc2c1
Agent: O=P(O)(O)O
Agent: [Na+]
Product: Oc1cc(Br)c2ncc(Br)cc2c1
Temperature: 180 °C

Procedure:
6-Amino-3,8-dibromoquinoline (0.15 g) was suspended in phosphoric acid (75%, 11 ml) and heated in a sealed glass tube at 180° C. for 72 hours. The mixture was allowed to cool to ambient temperature, diluted with ice (50 ml) and taken to pH 2 with aqueous sodium hydroxide (4M). The brown suspension that formed was extracted with ethyl acetate (twice), dried over magnesium sulphate then evaporated under reduced pressure to give 3,8-dibromo-6-hydroxyquinoline (M+—H 300, 2×Br) as a dark red solid that was used in the next stage without further purification, 1H NMR (d6 DMSO) δ: 7.14(1H, d); 7.60(1H, d); 8.52(1H, d); 8.71(1H, d).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4]C[CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl.[OH-].[Na+]>>[O:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][CH:11]1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(c1)OCC(N1CCNCC1)O2

Procedure:
33.0 g of the salt: 1-(1,4-benzodioxan-2-ylmethyl)piperazine.2 HCl was converted to the free base form by treating with aqueous NaOH. The free base was extracted into methylene chloride and the extract dried over Na2SO4. Evaporation of the solvent yielded 24.4 g of 1-(1,4-benzodioxan-2-yl)piperazine.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@@H:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@@H:11]2[O:15][C:14]3=[N:16][C:8](=[O:9])[CH:7]=[CH:6][N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(OC[C@H]2CN=C(N)O2)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(OC[C@H]2Cn3ccc(=O)nc3O2)cc1

Procedure:
The title compound was prepared from (R)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine employing the procedures as set forth in Step 3 of Example 1. [α]D25 +52.20 (c 0.5, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N:10]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl>Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:10])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a mixture of 4-bromo-2-fluoroaniline (5.0 g) in concentrated hydrochloric acid (25 mL) was added a mixture of sodium nitrite (1.9 g) in water (2.5 mL) at −20° C., and the mixture was stirred at 0° C. for 30 min. The reaction mixture was added dropwise to a mixture of tin chloride (19 g) in concentrated hydrochloric acid (25 mL) at −20° C., and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, and washed with diethyl ether. The obtained solid was neutralized with 10% aqueous potassium carbonate solution, and ethyl acetate was added. The insoluble material was removed by filtration, the filtrate was extracted with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.4 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[F:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[C:30]([O:33][CH3:34])=[N:31][CH:32]=[C:27]([F:26])[CH:28]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ncc(F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: COCCOC
Product: COc1ncc(F)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Temperature: 80 °C
Yield: 30.6 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.1 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.1 g, 0.39 mmol), tetrakis(triphenylphosphine)palladium (0) (17 mg, 0.015 mmol), and 2 M sodium carbonate (0.3 mL, 0.6 mmol) and the reaction mixture was heated to 80° C. overnight. The crude material was purified by silica gel chromatography (eluting with 0-35% ethyl acetate in hexanes) to yield the product (42 mg, 31%). ESI-MS m/z calc. 457.4. found 458.3 (M+1)+. Retention time 2.20 minutes.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:17])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[Li+].S([O-])(O)(=O)=O.[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[C:21]([O:20][C:18]([N:16]([C@H:4]([CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[C:3]([OH:25])=[O:2])[CH3:17])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
(2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid methylester (15.0 g; 43.73 mmol) was dissolved in dioxane (150 ml) and cooled on an icebath. Water (115 ml) and lithium hydroxide (1.15 g; 48.10 mmol) were added. The reaction mixture was stirred 4 hours at room temperature. Ethyl acetate (300 ml) and water (200 ml) were added. Sodium hydrogensulfate (3%) was added until acidic reaction (pH=2.5). The organic phase was washed with water (200 ml) and dried (Magnesium sulfate). The solvent was removed in vacuo to afford 13.5 g of (2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid.
Reaction SMILES: [C:1]([C:3]1[C:8]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[CH:11]=[CH:10]2)=[CH:7][C:6]([NH2:16])=[C:5]([NH2:17])[CH:4]=1)#[N:2].[C:18](O)(=[O:22])[C:19](O)=[O:20].Cl>>[C:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[N:9]1[CH:14]=[CH:13][C:12](=[O:15])[CH:11]=[CH:10]1)[NH:16][C:19](=[O:20])[C:18](=[O:22])[NH:17]2)#[N:2]
Reactant: N#Cc1cc(N)c(N)cc1-n1ccc(=O)cc1
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: N#Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1-n1ccc(=O)cc1
Yield: 66 %

Procedure:
First, a mixture containing 246 mg of 4-cyano-5-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine, 294 mg of oxalic acid, and 5 ml of 2N hydrochloric acid was refluxed by heating in an oil bath for 2 hours. The mixture was cooled and precipitated crystals were filtered. Then, 284 g of the crude crystals thus obtained were further recrystallized with 2N hydrochloric acid to give 201 mg of 6-cyano-7-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8](C)([O-])[CH3:9].[K+].C(Br)C=C.C1(=O)CCCCC1>>[CH2:9]([CH:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[O:6])[CH:8]=[CH2:7]
Reactant: O=C1CCCC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=C1CCCCC1
Solvent: C=CCBr
Product: C=CCC1CCCC1=O

Procedure:
Ex-30a) Cyclopentanone is treated with potassium-t-butoxide and then with allyl bromide in the same manner and in the same proportions as described for cyclohexanone in Example 6a, yielding 2-allylcyclopentanone.
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[C:4]1[C:5](=[O:35])[NH:6][C:7](=[O:34])[N:8]([C@H:10]2[O:14][C@H:13]([CH2:15][O:16][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[O:12][CH2:11]2)[CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC#N>[Br:1]/[CH:2]=[CH:3]/[C:4]1[C:5](=[O:35])[NH:6][C:7](=[O:34])[N:8]([C@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[O:12][CH2:11]2)[CH:9]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1OC[C@@H](n2cc(/C=C/Br)c(=O)[nH]c2=O)O1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: O=c1[nH]c(=O)n([C@@H]2CO[C@@H](CO)O2)cc1/C=C/Br
Yield: 89.9 %

Procedure:
A solution of 26 (140 mg, 0.251 mmol) in CH3CN (10 mL) was treated with tetra-n-butylammoniumfluorid (I M solution in THF) (0.3 mL, 0.3 mmol) at rt for 1 h. After concentration of the mixture, the residue was purified by silica gel column chromatography (CHCl3:MeOH, 20:1) to give 28 (72 mg, 90%) as a white solid: mp 75-78° C.; [α]D−2.8 (c 0.4, MeOH); UV (MeOH) λmax 250.0 (ε 13900), 292.0 nm (ε 10600) (pH 7), 249.5 (ε 14400), 291.5 nm (ε 10800) (pH 2), 254.0 (ε 14100), 284.0 nm (sh) (pH 11).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C:17]=2Cl)[C:15]#[N:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].COC(=O)CC1C=CC(OC)=C(Br)C=1.COC1C=C(C2C=NC=C(C=2[NH:51][C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[NH:57][CH:56]=[CH:55]3)C#N)C=CC=1OC.NC1C=C2C(=CC=1)NC=C2>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C:17]=2[NH:51][C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[NH:57][CH:56]=[CH:55]3)[C:15]#[N:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2cncc(C#N)c2Nc2ccc3[nH]ccc3c2)cc1OC
Reactant: COc1ccc(-c2cncc(C#N)c2Cl)cc1Br
Agent: COC(=O)Cc1ccc(OC)c(Br)c1
Agent: Nc1ccc2[nH]ccc2c1
Product: COc1ccc(-c2cncc(C#N)c2Nc2ccc3[nH]ccc3c2)cc1Br

Procedure:
Following procedures analogous to those described in Example 1, 5-(3-bromo-4-methoxyphenyl)-4-chloronicotinonitrile was prepared from methyl(3-bromo-4-methoxyphenyl)acetate. Following procedures analogous to those described above for preparing compound 101 (Example 1), 5-(3-bromo-4-methoxyphenyl)-4-chloronicotinonitrile was treated with 5-aminoindole to produce 5-(3-bromo-4-methoxyphenyl)-4-(1H-indol-5-ylamino)nicotinonitrile 188. MS: 419.2 (M+H); melting range: 148-150° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8](C(OC)=O)=[CH:7][C:5]=2[N:6]=1.[C:15]([O:18][CH2:19]C)(=[O:17])C>>[NH2:1][C:2]1[S:3][C:4]2[C:10]([C:15]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc2sc(N)nc2c1
Product: COC(=O)c1cccc2nc(N)sc12
Temperature: 30 °C

Procedure:
8.4 g of methyl 3-thioureido-benzoate are suspended in 120 ml of chlorobenzene, 2.2 ml of bromine in 30 ml of chlorobenzene are added at 0° C. in the course of 1 hour, while stirring as thoroughly as possible, and the mixture is then stirred to room temperature. It is then kept at 70° C. for 4 hours and subsequently cooled, a little diethyl ether is added and the precipitate is filtered off, mixed thoroughly with 70 ml of aqueous sodium bicarbonate solution, filtered off again and washed with water. 7.7 g (88%) of crude product of melting point 231-232° C. result. HPLC analysis shows a content of more than 83% of the pure title compound, in addition to 8-18% of isomeric methyl 2-amino-benzothiazole-5-carboxylate. Suspension in and brief heating at 70° C. with ethyl acetate, cooling to 30° C. and filtration give the pure title compound of melting point >250° C.
Reaction SMILES: [NH2:1][C:2]1[N:32]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:14]=[CH:15][C:16]=3[CH3:17])=[CH:9][N:4]2[N:3]=1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[C:11]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([NH:1][C:37](=[O:36])[CH2:38][OH:39])[N:32]=3)[CH:9]=2)[CH:12]=1)=[O:31])([CH3:28])[CH3:27])#[N:30]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CO)nn2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.8 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (203 mg, 0.477 mmol) in pyridine (10 mL) was added 2-chloro-2-oxoethyl acetate (103 μL, 0.954 mmol), and the mixture was stirred at room temperature for 17 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 mL). Potassium carbonate (132 mg, 0.954 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hr. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL, 2×10 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue. The obtained precipitate was collected by filtration and dried to give the title compound (182 mg, 79%) as a colorless powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])[N:3]=1.[NH2:24][C@@H:25]1[CH2:30][C@@H:29]([OH:31])[C@H:28]([CH3:32])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:32][C@@H:28]1[CH2:27][CH2:26][C@H:25]([NH:24][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:3]=2)[CH2:30][C@H:29]1[OH:31]
Reactant: FC(F)(F)c1ccncc1CNc1ncc(C(F)(F)F)c(Cl)n1
Reactant: C[C@@H]1CC[C@H](N)C[C@H]1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](Nc2nc(NCc3cnccc3C(F)(F)F)ncc2C(F)(F)F)C[C@H]1O
Temperature: 60 °C
Yield: 47.3 %

Procedure:
4-Chloro-5-(trifluoromethyl)-N-((4-(trifluoromethyl)pyridin-3-yl)methyl)pyrimidin-2-amine (1.0 equiv.) was placed in a sealable flask with (1R,2R,5S)-5-amino-2-methylcyclohexanol (1.1 equiv.), DIEA (2.0 equiv.), and THF (0.1 M). The flask was purged with nitrogen and sealed. The reaction mixture was heated to 60° C. for 18 h. Standard work-up, afforded (1R,2R,5S)-2-methyl-5-(5-(trifluoromethyl)-2-((4-(trifluoromethyl)pyridin-3-yl)methylamino)pyrimidin-4-ylamino)cyclohexanol (47.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.65-8.76 (m, 2H) 8.01-8.14 (m, 1H) 7.71 (d, J=5.08 Hz, 1H) 5.74 (br. s., 1H) 4.67-4.80 (m, 1H) 4.57-4.67 (m, 1H) 4.54 (br. s., 1H) 4.39 (d, J=4.30 Hz, 1H) 4.14 (br. s., 1H) 3.21-3.31 (m, 1H) 1.78 (br. s., 1H) 1.54 (br. s., 1H) 1.41 (br. s., 1H) 1.33 (br. s., 1H) 1.10-1.24 (m, 1H) 0.96 (br. s., 1H) 0.81-0.89 (m, 2H). MS (ESI) m/z 450.2 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].N1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C.[Cl-].[NH4+].[OH-].[Na+]>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1ccccc1CN
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1CNC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
45 mL 2,4-dichlorobenzoyl chloride was added dropwise over 1.5 hours into a solution of 50 ml 2-methoxybenzylamine and 123 ml pyridine in N,N-dimethylformamide (400 mL) at 5 to 10° C., followed by stirring at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, saturated aqueous ammonium chloride solution and 1N aqueous sodium hydroxide solution. The organic layer was washed with 1N aqueous sodium hydroxide solution, 1 N hydrochloric acid (×2), saturated aqueous ammonium chloride solution (×2) and brine, dried over anhydrous sodium sulfate and concentrated. The residue was suspended in diisopropyl ether (300 mL) and diethyl ether (500 mL). The solid was collected by filtration and washed with diethyl ether, to give 81.1 g of N1-(2-methoxybenzyl)-2,4-dichlorobenzamide as a pale yellow solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.ClCCl.[N:22]1([C:28]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=2[NH2:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O>[N:22]1([C:28]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][C:29]=2[NH:30][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)ccc2N2CCCCC2)cc1
Reaction time: 60 h

Procedure:
p-Toluenesulfonyl chloride (233 g, 1.22 mmol, commercially available product) and triethylamine (254 μl, 1.83 mmol) were sequentially added at room temperature to a dichloromethane (5 ml) solution of 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (149 mg, 0.610 mmol), obtained as described in Referential Example 1-2. The resulting mixture was stirred for 60 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=10/1). Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]-p-toluenesulfonamide (GIF-0622) (243 mg, quant) was yielded as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:21])=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1
Reactant: NN1CCOCC1
Reactant: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Product: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 66 %

Procedure:
As described for example 67, 6-((1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (78 mg, 0.24 mmol), was converted, using 4-aminomorpholine instead of isopropylamine, to the title compound (65 mg, 66%) which was obtained as an off white foam. MS: m/e=413.4 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([OH:17])=O>C(Cl)Cl>[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:7]=1[CH2:13][CH2:14][C:15]2=[O:17]
Reactant: O=C(O)CCc1ccc(F)cc1F
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1CCc2c(F)cc(F)cc21
Yield: 79.6 %

Procedure:
Thionyl chloride (54.6 g) was added dropwise at 40° C. to a solution of 3-(2,4-di-fluorophenyl)propionic acid (57 g) in methylene chloride (200 ml). After reaction was complete, excess thionyl chloride and the solvent were removed by distillation. The oily residue was added dropwise at 40° C. to a suspension of aluminium chloride (88.5 g) in methylene chloride (200 ml). The reaction mixture was added to dilute hydrochloric acid after 18 hours at 40° C. The aqueous phase was separated off and extracted once with methylene chloride (250 ml). The combined organic phases were freed from the solvent and then distilled in vacuo. 41 g of a colorless solid were obtained (m.p.: 103° C.).
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[C:14]([S:17][CH3:18])=[N:13][N:12]=2)=[CH:7][CH:6]=1.[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:32]=[C:28]([C:29]([NH2:31])=[O:30])[C:27]([OH:33])=[CH:26][CH:25]=1.O>CS(C)=O>[C:29]([C:28]1[CH:32]=[C:24]([CH:25]=[CH:26][C:27]=1[OH:33])[O:23][CH2:22][CH2:21][NH:20][CH2:19][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[C:14]([S:17][CH3:18])=[N:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:30])[NH2:31]
Reactant: CSc1nnc(-c2ccc(OCC3CO3)cc2)n1C
Reactant: NCCOc1ccc(O)c(C(N)=O)c1
Solvent: CS(C)=O
Solvent: O
Product: CSc1nnc(-c2ccc(OCC(O)CNCCOc3ccc(O)c(C(N)=O)c3)cc2)n1C

Procedure:
Analogously to Example 12, 19.5 g of 3-[4-(2,3-epoxypropoxy)-phenyl]-4-methyl-5-methylthio-4H-1,2,4-triazole are reacted with 11.0 g of 5-(2-aminoethoxy)-salicylamide in 70 ml of dimethyl sulphoxide. The resin-like crude product that is obtained on mixing with water is extracted by boiling with dioxan, the dioxan solution is concentrated by evaporation and the residue is recrystallised from methanol. 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(4-methyl-5-methylthio-4H-1,2,4-triazol-3-yl)-phenoxy]-2-propanol having a melting point of 123°-125° is obtained.