Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:11]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:12]=2[CH2:13][N:14]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)([O:9][CH3:10])[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:45](F)(F)C1C=CC(C#N)=CC=1.C1([Mg]Br)CCCCC1.C([Mg]Br)C.CI>>[CH:6]1([C:7]([C:11]2[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:36][C:12]=2[CH2:13][N:14]([CH2:21][C:22]2[CH:23]=[C:24]([C:32]([F:33])([F:35])[F:34])[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=2)[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)([O:9][CH3:10])[CH2:8][CH3:45])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(C)(CC1CCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: Br[Mg]C1CCCCC1
Agent: CC[Mg]Br
Solvent: CI
Product: CCC(OC)(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1

Procedure:
This compound was prepared by an analogous series of reactions to that used for the preparation of N-(2-(1-cyclopentyl-2-methoxypropan-2-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine from 2-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazole-5-yl)amino)methyl)-4-(trifluoromethyl)benzonitrile by the addition of cyclohexylmagnesium bromide followed by ethylmagnesium bromide then alkylation with methyl iodide. LC-MS calc 637.5, found 638.5 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Si:20](OS(C(F)(F)F)(=O)=O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>ClCCl.C(OC(=O)C)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
A mixture of 4-hydroxymethyl-benzoic acid methylester (2 gm) and triethylamine (3.36 mL) in dichloromethane (15 mL) was treated with t-butyldimethylsilyltriflate (4.47 gm) at −78° C. After 30 min the contents were allowed to warm up to the room temperature and continued the stirring for another 30 min. Water (30 mL) and ethylacetate (60 mL) were added to the reaction mixture and the organic layer was washed with 0.3 M KHSO4, water and brine, dried over MgSO4 and filtered. The solvent was evaporated and the residue was subjected to flash chromatography on silica column by eluting with 10% EtOAc/hexane to obtain 4-(t-butyldimethylsilyloxymethyl) benzoic acid methyl ester (3.3 gm, 95% yield).
Reaction SMILES: [C:1]12([C:9]([OH:11])=O)[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.S(Cl)(Cl)=O.[CH:16]([N:19]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])([CH3:18])[CH3:17].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl.CCCCCC.C(OCC)(=O)C.C(N(CC)CC)C>[CH:16]([N:19]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:9]([C:1]12[CH2:2][CH2:3][CH:4]([CH2:5][CH2:6]1)[CH2:7][CH2:8]2)=[O:11])([CH3:18])[CH3:17]
Reactant: COc1ccccc1CCN(CCCCN)C(C)C
Reactant: O=C(O)C12CCC(CC1)CC2
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Product: COc1ccccc1CCN(CCCCNC(=O)C12CCC(CC1)CC2)C(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
Bicyclo[2.2.2]octane-1-carboxylic acid (0.53 g, 3.4 mmol), and thionyl chloride (1 ml, 13 mmol) dissolved in 10 ml toluene, were heated at 80° C. for 3 h. The solvent was partly removed and the residue added dropwise to a solution of 4-{isopropyl-[2-(2-methoxyphenyl)-ethyl]-aminobutylamine (1.2 g, 4.5 mmol) and triethylamine (3 ml, 20 mmol) in 10 ml methylene chloride at 0° C. and stirred for 1 h at room temperature. The mixture was charged on a silica gel column and eluated with hexane/ethyl acetate/triethylamine (16:4:1) to yield 1.1 g (86%) of an oil.
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([C:9]1[CH:10]=[C:11]([N+:18]([O-])=O)[CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)(=[O:8])[CH3:7]>Cl>[C:6]([C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[NH2:18])(=[O:8])[CH3:7]
Reactant: CC(=O)c1cc(C(C)=O)cc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(=O)c1cc(N)cc(C(C)=O)c1
Reaction time: 0.08 h
Yield: 46.7 %

Procedure:
To a stirred solution of tin (II) chloride dihydrate (32.87 grams) in concentrated hydrochloric acid (93 mL) at 50° C. was added 3,5-diacetylnitrobenzene (7.54 grams). The heat was removed immediately and an exotherm occurred. The mixture was stirred for 5 minutes, cooled with an ice bath, and neutralized with saturated potassium carbonate solution. The aqueous phase was extracted with several portions of ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3.01 grams of the title compound. 1H NMR δ 7.77 (s, 1), 7.48 (s, 2), 5.16 (br s, 2), 2.55 (s, 6).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[N:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[CH2:10]2)=[O:4].C(N(CC)CC)C.CCCP(=O)=O.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CN(C1C=CN=CC=1)C.ClCCCl>[F:37][C:38]([F:46])([F:47])[C:39]1[CH:40]=[C:41]([NH:42][C:18]([C:17]2[CH:16]=[C:15]([N:9]3[CH2:10][C:11]4[CH:12]=[N:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=4[CH2:7][CH2:8]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:43]=[CH:44][CH:45]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)O)c1)C2
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
To a mixture of 3-[5-(methoxycarbonyl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]benzoic acid (63 mg, 0.20 mmol), triethylamine (0.084 mL, 0.60 mmol), and catalytic DMAP in 3.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.143 mL, 0.24 mmol). After 5 min at rt, 3-(trifluoromethyl)aniline (0.037 mL, 0.30 mmol) was added and the reaction stirred at rt for 18 hours. The reaction was quenched with aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, dilute aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/EtOAc to give the title compound as a yellow solid (50 mg, 55%). 1H NMR (Acetone-d6) δ: 9.75 (br. s., 1H), 8.89 (s, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.09 (d, J=7.9 Hz, 1H), 7.69 (s, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.37-7.47 (m, 3H), 7.28-7.34 (m, 1H), 4.61 (s, 2H), 3.92 (s, 3H), 3.67-3.73 (m, 2H), 3.37 (t, J=5.9 Hz, 2H).
Reaction SMILES: C([NH:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>[Pd].C(O)C>[F:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH:9]2[NH2:8])=[CH:13][CH:14]=1
Reactant: Fc1ccc2c(c1)C(NCc1ccccc1)CC2
Agent: [Pd]
Solvent: CCO
Product: NC1CCc2ccc(F)cc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
To a high-pressure flask, add 10% palladium on carbon (1.44 g) in ethanol (100 mL). Add a solution of benzyl-(6-fluoroindan-1-yl)-amine (14.44 g, 59.84 mmol) in ethanol (200 mL). Purge the chamber with nitrogen three times, and then with hydrogen three times. Stir vigorously under hydrogen (60 psi) at 50° C. for two hours. Filter the mixture through Celite® 521 and wash the solids with methanol. Concentrate the filtrate in vacuo to give the title compound as a light brown liquid (9.14 g, 100%). MS (ES) m/z=152 [M+1].
Reaction SMILES: COC(=O)[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[C:8]=2[N:9]=1.[OH-].[K+].Cl>C(O)CO.O>[CH3:22][O:21][C:10]1[C:8]2[N:9]=[C:5]([NH2:4])[S:6][C:7]=2[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(-c3ccnc(C)c3)c2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc(-c2ccnc(C)c2)c2sc(N)nc12
Temperature: 100 °C
Yield: 83 %

Procedure:
[4-Methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl]-carbamic acid methyl ester (100 mg, 0.24 mmol) were dissolved in ethyleneglycol (3.0 ml) and treated with potassium hydroxide (528 mg, 1.1 mmol) and heated to 100° C. for 6.5 h. The reaction mixture was cooled to room temperature, diluted with water, neutralized with 1N HCl and extracted four times with ethyl acetate. The organic layers were combined and washed with water and saturated aqueous NaCl. The organic phases were then dried and the solvent removed in vacuo. The product was obtained as a light brown solid (83%). MS: m/e=272 (M+H+).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[N:34]=[CH:35][C:36]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]2)=[O:23])=[CH:37][CH:38]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1ccc(Cl)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccc(Cl)nc1)N1CCN(C2CCC2)CC1
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 2-chloropyridine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (54%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f46) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([NH:20][C:21]3[CH:22]=[C:23]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])[N:24]([CH3:26])[CH:25]=3)=[O:19])[N:15]([CH3:17])[CH:16]=2)=[O:10])[N:6]([CH3:8])[CH:7]=1.[CH:35](N)=[O:36].C(OCC)=O>O>[CH:35]([NH:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([NH:20][C:21]3[CH:22]=[C:23]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])[N:24]([CH3:26])[CH:25]=3)=[O:19])[N:15]([CH3:17])[CH:16]=2)=[O:10])[N:6]([CH3:8])[CH:7]=1)=[O:36]
Reactant: NC=O
Reactant: Cn1cc(NC(=O)c2cc(NC(=O)c3cc(N)cn3C)cn2C)cc1C(=O)NCCC(=O)O
Agent: Cl
Solvent: O
Solvent: CCOC=O
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc(NC=O)cn3C)cn2C)cc1C(=O)NCCC(=O)O
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of the compound obtained in example 1 (4 g), formamide (12 ml) and ethyl formate (12 ml) was stirred at 90° C. for 5 hours. The organic solvent was allowed under vacuum, the brown residue treated with water (100 ml) and the suspension stirred for one hour. The suspension was filtered and the solid washed with cold water (20 ml) yielding, after desiccation under vacuum at 40° C., the title compound (6.8 g; y=90%) as a brown powder.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:21]([O:27][CH2:28]Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)(=O)C>[CH3:23][C:22]([CH3:25])([CH3:24])[C:21]([O:27][CH2:28][N:12]1[C:11]2[N:10]=[CH:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]=2[C:15](=[O:17])[NH:14][C:13]1=[O:18])=[O:26]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.66 g of 7-benzylxanthine was dissolved in 300 ml of N,N-dimethylformamide, and 1.57 g of sodium hydride and 7.7 ml of chloromethyl pivalate were added thereto. The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.66 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH2:3][NH:4][C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16]CC3C=CC=CC=3)[CH:13]=2)[N:8]1[C:24](=[O:36])[C@@H:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH3:27])=[O:6].[H][H]>[Pd].C(OCC)(=O)C>[F:38][C:2]([F:1])([F:37])[CH2:3][NH:4][C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:16])[CH:13]=2)[N:8]1[C:24](=[O:36])[C@@H:25]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:26][CH3:27])=[O:6]
Reactant: [H][H]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)NCC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(O)cc2CC1C(=O)NCC(F)(F)F

Procedure:
A mixture of 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-benzyloxyindoline-2(R/S)-carboxylic acid 2,2,2-trifluoroethylamide (0.9 g, 1.68 mmol) and palladium on activated carbon (0.1 g, 10% wet) in ethyl acetate (20 mL) was hydrogenated under 30 psi hydrogen at room temperature overnight. Then the catalyst was removed by filtration over celite, and the filtrate was evaporated to provide a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[OH-].[K+].[Na].C([Li])CCC.[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH:38]([CH3:40])[CH3:39])[C:30]=2/[CH:41]=[CH:42]/[C:43](N(OC)C)=[O:44])=[CH:25][CH:24]=1.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[CH2:20]([O:19][C:16](=[O:18])[CH2:17][C:43](=[O:44])/[CH:42]=[CH:41]/[C:30]1[N:31]([CH:38]([CH3:39])[CH3:40])[C:32]2[C:37]([C:29]=1[C:26]1[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:21]
Reactant: CCOC(C)=O
Reactant: CON(C)C(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
1.85 ml (12.97 mmol) of diisopropylamine, dried over KOH, in 6 ml of THF, rendered absolute using sodium, are introduced into a thoroughly heated 50 ml three-necked round-bottomed flask, equipped with a magnetic stirrer, thermometer and nitrogen delivery line, and cooled to −50° C. using an ethanol/dry-ice bath. 8.1 ml (12.97 mmol) of butyllithium (1.6M in hexane) are slowly added dropwise so that the internal temperature does not exceed −40° C. Heating to from −5 to 0° C. is carried out slowly, followed by stirring at that temperature for 30 min. Cooling to −65° C. is then carried out and 1.30 ml (12.94 mmol) of ethyl acetate are slowly added dropwise so that the internal temperature does not exceed −60° C. Stirring is subsequently carried out for 40 min. at −65° C. and then 1.20 g (3.28 mmol) of (E)-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-N-methoxy-N-methylacrylamide, dissolved in 5 ml of THF, are added dropwise in the course of 25 min. and stirring is carried out for one hour at that temperature. The temperature is then increased to −5° C. in the course of 15 min. and stirring is carried out for 45 min. 8 ml of saturated ammonium chloride solution are added dropwise over a period of 3 min., in the course of which the temperature rises to 12° C. Stirring is then carried out for 15 min., 10 ml of toluene are added, the phases are separated and the aqueous phase is extracted three times with 20 ml of toluene. The combined organic phases are washed with saturated sodium chloride solution until neutral, dried over magnesium sulfate, filtered and concentrated by evaporation. Purification of the crude product by means of flash chromatography (hexane/ethyl acetate=9:1) yields a viscous orange resin which, according to NMR, is the product in a keto-enol equilibrium of approximately 3:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[F:33][C:24]([F:23])([F:32])[C:25]1[CH:29]=[C:28]([CH2:30][NH:31][C:20]([C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[CH:12][N:11]=2)=[O:22])[O:27][N:26]=1
Reactant: O=C(O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Reactant: NCc1cc(C(F)(F)F)no1
Product: O=C(NCc1cc(C(F)(F)F)no1)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic acid (example AA) and 3-trifluoromethyl-isoxazol-5-methanamine (example BA) as starting materials; MS: 481.0 (M+H)+.
Reaction SMILES: [C:1]12(C3C(=O)NN(C4C=CC=CN=4)C=3C)CC3CC(CC(C3)C1)C2.IC.[C:26]12([C:36]3[C:37](=[O:49])[NH:38][N:39]([C:42]4[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=4)[C:40]=3[CH3:41])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>>[C:26]12([C:36]3[C:37](=[O:49])[N:38]([CH3:1])[N:39]([C:42]4[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=4)[C:40]=3[CH3:41])[CH2:33][CH:32]3[CH2:34][CH:28]([CH2:29][CH:30]([CH2:31]3)[CH2:35]1)[CH2:27]2
Reactant: Cc1c(C23CC4CC(CC(C4)C2)C3)c(=O)[nH]n1-c1ccc(F)cc1
Reactant: Cc1c(C23CC4CC(CC(C4)C2)C3)c(=O)[nH]n1-c1ccccn1
Solvent: CI
Product: Cc1c(C23CC4CC(CC(C4)C2)C3)c(=O)n(C)n1-c1ccc(F)cc1

Procedure:
This compound was obtained in two steps in analogy to example 62 and 61 using 4-fluorophenylhydrazine (example 62) and using iodomethane and 4-adamantan-1-yl-1-(4-fluoro-phenyl)-5-methyl-1,2-dihydro-pyrazol-3-one (example 61) to give 4-adamantan-1-yl-1-(4-fluoro-phenyl)-2,5-dimethyl-1,2-dihydro-pyrazol-3-one as a yellow solid. MS (ESI+): 341.3 [M+H]+).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH2:21][CH3:22].C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:21]([C:3]1[S:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[C:10]=2[C:2]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:22]
Reactant: CCc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1-c1ccccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 12.1 %

Procedure:
Into a 25 ml sealed tube containing a solution of 4-N-[5-bromo-6-ethylthieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (100 mg, 0.26 mmol, 1.00 equiv) in dioxane (5 mL) was added 2-(tributylstannyl)pyridine (96 mg, 0.26 mmol, 1.00 equiv) and Pd(dppf)Cl2 (30 mg, 0.04 mmol, 0.16 equiv) at room temperature under nitrogen. The sealed tube was heated with stirring overnight at 100° C. The reaction mixture was cooled to room temperature and diluted with 20 mL of H2O, extracted with 3×50 mL of ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 49.0% in 27 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the corresponding 4-N-[6-ethyl-5-(pyridin-2-yl) thieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (12 mg) as a light yellow oil. MS (ES, m/z): 382 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.75-8.41 (d, 1H), 7.90 (s, 1H), 7.89-7.84 (m, 1H), 7.46-7.38 (m, 2H), 6.73-6.71 (d, 1H), 3.95-3.89 (m, 1H), 2.89-2.81 (dd, 2, H), 2.29 (s, 6H), 2.25-2.04 (m, 3H), 1.90-1.86 (m, 2H), 1.47-1.38 (m, 2H), 1.32-1.27 (m, 3H), 1.05-1.92 (m, 2H).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:17]([F:18])=[C:16](F)[C:15]([Cl:20])=[C:14]2[C:9]=1[C:10](=[O:33])[C:11]([C:30]([OH:32])=[O:31])=[CH:12][N:13]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH2:29])[N:22]=1.Cl.[OH:35][NH:36][CH:37]1[CH2:40][NH:39][CH2:38]1.CN1CCCC1>C(OCC)C>[NH2:7][C:8]1[C:17]([F:18])=[C:16]([N:39]2[CH2:40][CH:37]([NH:36][OH:35])[CH2:38]2)[C:15]([Cl:20])=[C:14]2[C:9]=1[C:10](=[O:33])[C:11]([C:30]([OH:32])=[O:31])=[CH:12][N:13]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH2:29])[N:22]=1
Reactant: ONC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(N4CC(NO)C4)c(Cl)c32)c(F)cc1F
Temperature: 100 °C
Reaction time: 0.05 h
Yield: 45.6 %

Procedure:
To 300 mg of pyridine were added 120 mg of 5-amino-1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-hydroxyaminoazetidine hydrochloride, and 250 mg of N-methylpyrrolidine, and the mixture was stirred at 100° C. for 3 minutes. After adding 5 ml of diethylether, the mixture was allowed to stand for 1 hour and decanted. 2 ml of ethanol was added and the mixture was stirred. The precipitate was collected by filtration and washed with ethanol and diethylether successively to obtain 64 mg of the title compound as a yellow powder.