Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:42])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:36]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: O[C@H]1CCCC[C@@H]1c1ccccc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 600 mg, 1.35 mmol) and (1S*,2R*)-2-phenylcyclohexanol (240 mg, 1.36 mmol) in DMSO (6.0 mL), sodium hydride (63%; 100 mg, 2.63 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed twice with water (200 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=4:1) to yield the title compound (270 mg, 33%) as a colorless oil.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C(O[C:26]1([CH:36]=[CH:35][CH:34]=[CH:33][CH2:32]1)[CH:27]=[N:28][C:29](=O)[CH3:30])C>O>[CH3:30][C:29]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:10])[N:9]=[C:27]([C:26]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:28]=1
Reactant: Cc1ccccc1NN
Reactant: CCOC1(C=NC(C)=O)C=CC=CC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccccc1-n1nc(-c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Next, 9.1 g of o-tolyl hydrazine hydrochloride and 100 mL of carbon tetrachloride were put into a 300-mL three-neck flask, 12 mL of triethylamine (Et3N) was added dropwise to the mixture little by little, and the mixture was stirred at room temperature for 1 hour. After a predetermined time elapsed, 10 g of N-(1-ethoxybenzylidene)acetamide was added, and the mixture was stirred at room temperature for 19 hours. Then, water was added to this reacted solution and the aqueous layer was subjected to extraction with chloroform. The obtained solution of the extract and the organic layer were combined and washed with saturated saline, and anhydrous magnesium sulfate was added to the organic layer for drying. The obtained mixture was gravity-filtered, and the filtrate was concentrated to give an oily substance. The obtained oily substance was purified by silica gel column chromatography. As the developing solvent, dichloromethane was used. The obtained fraction was concentrated, so that 5-methyl-1-(2-methylphenyl)-3-phenyl-1H-1,2,4-triazole (abbreviation: HMp3tz1-mp) was obtained (a red oily substance, 64% yield). The synthesis scheme of Step 2 is shown in (B-2) below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=4)=[O:24])[NH:12][C@H:11]3[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:5]2=[CH:4][CH:3]=1.C[CH2:42][N:43]=[C:44]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CNC>>[CH3:42][N:43]([CH3:44])[C:30]([C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:35][C:36]([CH3:37])([CH3:38])[CH3:39])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:40])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])=[CH:34][CH:33]=1)=[O:31]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Product: CN(C)C(=O)c1ccc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1

Procedure:
In a manner similar to the method described in Example 22, rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzoic acid (30 mg, 0.051 mmol) was reacted with EDCI (19 mg, 0.1 mmol), HOBt (14 mg, 0.1 mmol), and dimethylamine (0.1 mL, O2 mmol) at 60° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-dimethylcarbamoyl-phenyl)-amide as a light yellow solid (Yield, 10 mg, 32%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([NH:29][NH:30][CH:31]([CH3:33])[CH3:32])=[O:28])=[CH:25][CH:24]=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>CN(C=O)C.CCOC(C)=O>[OH:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([NH:29][N:30]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:9]=2)[CH:31]([CH3:32])[CH3:33])=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)NNC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccc(O)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.696 mmol), 4-hydroxy-N′-isopropylbenzohydrazide (202.81 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (40% EtOAc) and dried so that ivory (E)-tert-butyl 3-(3-(2-(4-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (102.5 mg, 31.8%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][CH2:12][C:13]([O:15]CCCC)=[O:14])([CH3:10])([CH3:9])[CH3:8]>CO.O>[C:7]([O:11][CH2:12][C:13]([OH:15])=[O:14])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCCCOC(=O)COC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OCC(=O)O
Temperature: 0 °C

Procedure:
To 100 ml of a 50:50 (v/v) methanol/water solution containing 14.35 g of potassium carbonate, was added n-butyl 2-tert-butoxyacetate (6.50 g, 0.0346 mol). The mixture was heated at reflux for 17 hours and the volatiles removed on a flash evaporator. The remaining solution was cooled to approximately 0° C. and acidified to pH 3-4 with cold 50% aqueous hydrogen chloride. The product was extracted with ether, the ether extract washed with brine and dried over magnesium sulfate, then concentrated in vacuo to give the title compound as a yellow liquid.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:3]Cl.[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][NH:16][CH2:15]1.C([O-])([O-])=O.[Na+].[Na+]>O>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH:2]([CH3:1])[CH2:3][N:16]2[CH2:15][C@H:14]([CH3:13])[O:19][C@H:18]([CH3:20])[CH2:17]2)=[CH:7][CH:8]=1
Reactant: CC(CCl)Cc1ccc(Br)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(Cc1ccc(Br)cc1)CN1C[C@@H](C)O[C@@H](C)C1

Procedure:
15 parts of 2-methyl-3-(4-bromophenyl)-propyl chloride and 28 parts of cis-2,6-dimethylmorpholine were stirred at 150° C. for 8 hours. The reaction mixture was cooled, poured into 100 parts of water, brought to pH 9-10 with saturated aqueous Na2CO3 solution and extracted with methylene chloride. The organic phase was dried and concentrated and the residue was distilled to give, at a boiling point of 100°-102° C./0.01 mbar, 15.8 parts of 4-[3-(4-bromophenyl)-2-methylpropyl]-cis-2,6-dimethylmorpholine of nD22 1.5265.
Reaction SMILES: C(=O)C.[CH3:4][C:5]1[N:6]=[C:7]([C:23](=O)[CH3:24])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([CH3:22])([CH3:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=1.[BH3-]C#[N:28].[Na+].CCO.[ClH:33]>O1CCOCC1>[ClH:33].[ClH:33].[CH3:4][C:5]1[N:6]=[C:7]([CH:23]([NH2:28])[CH3:24])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([CH3:22])([CH3:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=1
Reactant: CC(=O)c1nc(C)c(-c2ccnc(C(C)(C)C(F)(F)F)c2)s1
Reactant: [BH3-]C#N
Agent: CC=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1nc(C(C)N)sc1-c1ccnc(C(C)(C)C(F)(F)F)c1
Reaction time: 1 h

Procedure:
1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanone ethanone (1.6 g, 4.87 mmol), NH4OAc (5.6 g, 73.1 mmol), and NaBH3CN (1.2 g, 19.5 mmol) were taken up in 40 mL 200 proof EtOH, and heated at 130 C for 10 minutes in a sealed tube. The mixture was concentrated to remove the EtOH. Crude was taken up in 50 ml water+50 mL EtOAc. 6N NaOH was added until aqueous pH was ˜9. Separated layers, and extracted aqueous with EtOAc (50 ml). The combined organic layer was washed with 60 mL brine and dried with Na2SO4. Filtered and concentrated with reduced pressure to give 1.58 g crude tan oil. This material was taken up in 20 mL dioxane. 2.2 eq HCl (4N in dioxane) was added, and stirred 1 h. Yellow ppt was formed. The suspension was concentrated in vacuo to give 1.97 g 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanamine dihydrochloride salt as a yellow-green solid, which was carried forward without further purification. Major product Anal. RP-HPLC tR=1.23 min. MS m/z 330.1 (M+H)+.
Reaction SMILES: [ClH:1].CCOC(C)=O.[N:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:10][CH:9]=1.[H][H]>[Pt]=O.C(O)C>[ClH:1].[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/c2ccncc2)CC1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCC2CCNCC2)CC1

Procedure:
A 4 M hydrogen chloride/EtOAc solution (0.88 ml) and platinum oxide (100 mg) were added to an ethanol (25 ml) solution of tert-butyl 4-[(E)-2-pyridin-4-ylvinyl]piperidine-1-carboxylate (1.02 g), followed by stirring in the presence of hydrogen (3.5 atm) for 24 hours. This was purged with argon, diluted with methanol, filtered through Celite, and concentrated under reduced pressure. The solid precipitated was washed with EtOAc/hexane, and dried under reduced pressure to obtain tert-butyl 4-(2-piperidin-4-ylethyl)piperidine-1-carboxylate hydrochloride (850 mg) as a white solid.
Reaction SMILES: [O:1]=[C:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Br:9]Br>C(Cl)Cl.CCOC(C)=O>[Br:9][CH:7]([CH3:8])[C:2](=[O:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: BrBr
Reactant: CCC(=O)C(=O)OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of methyl 2-oxobutanoate (6.92 g, 59.6 mmol) in DCM (60 mL) at 0° C. was added bromine (3.10 mL, 60.3 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h, diluted with EtOAc, washed with saturated NaHCO3 (2×), water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The product, methyl 3-bromo-2-oxobutanoate, (8.26 g, 42.4 mmol, 71% yield) was used in the next step without further purification.
Reaction SMILES: [Cl-].[Na+].[C:3]([O:6][CH2:7]C)(=[O:5])C.[O:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH3:7][O:6][CH2:3][O:5][C@H:12]([CH:11]=[CH2:10])[CH2:13][OH:9]
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Na+]
Product: C=C[C@H](CO)OCOC

Procedure:
Example 8-(2) (11.3 g) in tetrahydrofuran (220 mL), and the mixture was stirred at room temperature for two hours. Saturated aqueous sodium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. Ethyl acetate was added to the aqueous layer, and the organic layer was separated again. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (4.15 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[NH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:13][C:12]([F:15])([F:14])[C:4]1[N:3]=[C:2]([NH:16][NH2:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: FC(F)(F)c1nc(Cl)c2ccccc2n1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: NNc1nc(C(F)(F)F)nc2ccccc12
Yield: 56.1 %

Procedure:
To a solution of 4-chloro-2-(trifluoromethyl)quinazoline (2.0 g, 8.6 mmol) and hydrazine (0.27 mL, 8.6 mmol) in 20 mL of tetrahydrofuran was added 1.8 g (13 mmol) of potassium carbonate. The resultant suspension was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. After filtration, the organics were concentrated in vacuo to yield a yellow solid that was recrystallized in ethyl acetate:hexanes. 1.1 g (56%) of yellow needle-like crystals were isolated.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:27][CH2:28][C:29]#[N:30])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:23][CH2:24][C:25]#[N:26])[CH2:19][CH2:20][C:21]#[N:22])#[N:2].[H][H]>O1CCOCC1>[NH2:26][CH2:25][CH2:24][CH2:23][N:18]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:1][NH2:2])[CH2:27][CH2:28][CH2:29][NH2:30]
Reactant: N#CCCN(CCC#N)CCCCCCCCCCCCN(CCC#N)CCC#N
Reactant: [H][H]
Solvent: C1COCCO1
Product: NCCCN(CCCN)CCCCCCCCCCCCN(CCCN)CCCN
Yield: 97.8 %

Procedure:
5.00 g of N,N,N′,N′-tetrakis(2-cyanoethyl)dodecamethylenediamine, 0.50 g of Raney Co and 50 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 8.0 MPa at 170° C. for 2 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 5.08 g of the title compound as a pale red oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.ClC(N(C)C)=C(C)C.[CH2:23]([C@@H:30]1[CH2:35][C@@H:34]([N:36]([CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[CH:46][CH:45]=2)[C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])[CH2:33][CH2:32][NH:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.N>C(Cl)Cl.CO>[CH2:23]([C@@H:30]1[CH2:35][C@@H:34]([N:36]([CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[CH:46][CH:45]=2)[C:37](=[O:42])[C:38]([F:40])([F:41])[F:39])[CH2:33][CH2:32][N:31]1[C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)Cc1ccc2ccccc2c1
Agent: CC(C)=C(Cl)N(C)C
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: O=C(Cc1ccc2ccccc2c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
105 mg (0.561 mmol) of 2-naphtylacetic acid are reacted in analogy to Example 6 first 92 μl (0.655 mmol) of 1-chloro-N,N,2-trimethyl-1-propen-1-amine and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 130 μl (0.936 mmol) of triethylamine to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.56, FD-MS: M+ =595.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[N:6][CH:7]=1
Reactant: COc1nc(Br)cnc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1

Procedure:
Prepared by method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine and benzenesulphonyl chloride
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([CH3:32])[C:30]#[CH:31].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:30]([C:29]#[CH:32])[CH3:31])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][N:15]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: C#CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(C)Oc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
First, 150 mg of 3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-357) was dissolved in 0.90 ml of N,N-dimethylformamide, to which 92 mg of potassium carbonate and 65 mg of 3-bromo-1-butyne were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 159 mg (yield, 92%) of 3-{2,4-dichloro-5-(3-butyn-2-yloxy)phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-371).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:11])[C:6]=1[C:7](OC)=[O:8].Cl[C:13]1[N:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1>>[CH3:11][C:5]1[C:6]2[C:7](=[O:8])[N:18]3[CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][C:13]3=[N:1][C:2]=2[S:3][CH:4]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: COC(=O)c1c(C)csc1N
Product: COC(=O)c1ccc2nc3scc(C)c3c(=O)n2c1

Procedure:
A mixture of 11.27 g (0.066 mol) of 2-amino-4-methyl-3-thiophenecarboxylic acid, methyl ester (Chemische Berichte, Vol. 98, pages 3571-3577, 1965) and 11.3 g (0.066 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader Chemical Company) is heated in a wax bath at 173°-190° C. for 220 minutes under nitrogen. The distillate is collected in a Dean-Stark trap attached to the reaction flask. The mixture is cooled, dissolved in hot methanol, cooled and 0.61 g of 3-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid, methyl ester is collected; mp 208°-209° C. after recrystallization from dichloromethane-methanol.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[S:12]1[CH:16]=[CH:15][C:14]2[CH2:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:13]1=2.Cl>C(Cl)Cl>[S:12]1[C:16]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:15][C:14]2[CH2:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:13]1=2
Reactant: c1ccc2c(c1)CCc1sccc1C2
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1cc2c(s1)CCc1ccccc1C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
11.0 g of succinic acid anhydride are dissolved in 220 cc of anhydrous methylene chloride with heating, the resulting solution is cooled to 20° and 30 g of aluminium chloride are added portionwise. After stirring for 15 minutes at room temperature, a solution of 22.0 g of 9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene in 100 cc of anhydrous methylene chloride is added dropwise within 30 minutes, the resulting mixture is stirred for a further 45 minutes at room temperature and is poured on a mixture of 200 cc of concentrated hydrochloric acid and 200 g of ice. After adding 300 cc of methylene chloride, the entire mixture is heated for 15 minutes on a water bath, is cooled, the methylene chloride is removed and the aqueous phase is further extracted with methylene chloride. The acidic portion is extracted from the combined methylene chloride solutions with 0.5 normal caustic soda, the basic extract is acidified with 5 N hydrochloric acid and extracted with chloroform. The chloroform solutions are washed with water, dried over magnesium sulphate, filtered through active charcoal and evaporated to dryness. The title compound, obtained as solid residue, is recrystallized from dimethyl formamide/acetone. M.P. 202° to 203°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][N:12]=1)[C:5]#[N:6].C(=O)([O-])[O-:20].[K+].[K+].OO.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][N:12]=1)[C:5]([NH2:6])=[O:20]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cn2)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cn2)c(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
Combine 3-bromo-4-(5-formyl-pyridin-2-yloxy)-benzonitrile (1.60 g, 5.28 mmol) and potassium carbonate (365 mg, 2.64 mmol) in DMSO (40 mL). Cool the reaction mixture at 0° C. Add hydrogen peroxide (1.59 mL, 5.28 mmol) dropwise and let the reaction stir at room temperature for 2 h. Pour into water and triturate to a white solid with stirring. Filter the white solid and dry to give (852 mg, 82%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.CCN(CC)CC.Cl.[F:18][CH2:19][CH2:20][NH:21][CH3:22]>CN(C=O)C>[F:18][CH2:19][CH2:20][N:21]([CH3:22])[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: CNCCF
Reactant: Cn1cc(C(=O)O)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCF)C(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol) was combined with DMF (10.0 ml) to give a colorless solution. Et3N (3.3 ml, 23.8 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, 2.8 g, 8.72 mmol) were added and the reaction mixture was stirred at RT for 1 h. 2-Fluoroethyl-methylamine hydrochloride (991 mg, 8.72 mmol) was added and stirring was continued overnight. DMF was removed under HV and the crude product (5.93 g brown oil) was purified by chromatography with a 50 g SiO2—NH2 cartridge (CH2Cl2/MeOH 95:5). The resulting product was dried under HV at RT for 48 h. Yellow oil (1.40 g, 92%); MS: m/z=186.1 [M+H]+.