Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=[C:19]([CH3:29])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:18]=[C:19]([CH3:29])[CH:20]=[C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:22]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(N2CCOCC2)nc(Cl)n1
Product: COc1cc(Nc2nc(C)cc(N3CCOCC3)n2)ccc1-n1cnc(C)c1
Yield: 87 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.30 mmol) and 4-(2-chloro-6-methyl-pyrimidin-4-yl)-morpholine (71 mg, 0.33 mmol) in analogous manner as described in example 90. The crude product was purified by stirring with diethyl ether. It was obtained in 87% yield as a light brown solid. MS ISP (m/e): 381.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.27 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 7.23 (d, 1H), 7.16 (d, 1H), 7.01 (s, 1H), 6.21 (s, 1H), 3.77 (s, 3H), 3.68 (m, 4H), 3.57 (m, 4H), 2.22 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].S(=O)(=O)(O)O.[OH:12][CH2:13][CH:14]([CH2:16]O)[OH:15]>>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]1[O:15][CH:14]([CH2:13][OH:12])[CH2:16][O:1]1
Reactant: OCC(O)CO
Reactant: O=CC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Product: OCC1COC(C(Cl)(Cl)Cl)O1
Reaction time: 10 h

Procedure:
A mixture of 16 g of chloral, 5 g of glycerine and 5 ml of concentrated sulphuric acid is,heated on a water-bath for 10 hours, then the reaction mixture is distilled in vacuo.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:40][CH2:41][CH3:42])([CH3:39])[PH2:37]=[O:38])=[CH:32][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].Cl.[BH4-].[Na+].O.[OH-].[Li+]>C1COCC1.O.CO>[CH2:41]([O:40][C:36]([CH3:39])([PH2:37]=[O:38])[C:33]1[CH:34]=[CH:35][C:30]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH:20]3[CH2:21][CH2:22][CH:23]([OH:24])[CH2:28][CH2:29]3)[C:11]([CH:13]3[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[CH:8]=2)=[CH:31][CH:32]=1)[CH3:42]
Reactant: CCOC(C)([PH2]=O)c1ccc(-c2cc(N(C(=O)C3CCC(C)CC3)C3CCC4(CC3)OCCO4)c(C(=O)OC)s2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)([PH2]=O)c1ccc(-c2cc(N(C(=O)C3CCC(C)CC3)C3CCC(O)CC3)c(C(=O)O)s2)cc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 5.9 %

Procedure:
3-[(1,4-Dioxa-spiro[4.5]dec-8-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-[4-(ethoxy-methyl-phosphinoylmethyl)-phenyl]-thiophene-2-carboxylic acid methyl ester (204 mg, 0.331 mmol, 1 eq.) was weighed into a small flask and dissolved in 3 mL THF. Next, 2 mL of 3.6 N HCl was added and the reaction was stirred at 40° C. for 1.5 hours. The reaction was then cooled to room temperature and diluted with 40 mL water. The solution was then extracted twice with ethyl acetate. The combined ethyl acetate layers were then washed twice with saturated NaHCO3, twice with water, and once with brine, dried over sodium sulfate, filtered and concentrated to afford the crude ketone (176 mg). This material (176 mg, ˜0.307 mmol) was dissolved in 5 mL anhydrous THF and cooled to −25° C. using an acetonitrile/dry ice bath. Sodium borohydride (9 mg, 0.230 mmol, 0.75 eq.) was added as a solid in two portions. The reaction was stirred 1.5 hours at −25° C., then was quenched with 3 mL 2 N HCl and warmed to room temperature. The solution was then extracted twice with ethyl acetate. The combined ethyl acetate layers were washed once with brine, and then dried over sodium sulfate, filtered and concentrated. This crude product (173 mg) was dissolved in 2 mL THF. Stirring was begun and 0.5 mL methanol and a solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol, 2 eq. in 0.5 mL water) were added. The reaction was stirred at 40° C. for 45 minutes whereupon the reaction was stopped by the addition of 0.35 mL 2 N HCl. The reaction was concentrated, then redissolved in methanol and purified by reverse phase preparative HPLC to afford 5-[4-(Ethoxy-methyl-phosphinoylmethyl)-phenyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (11 mg, 6%). MS (m/z) 562.1 [M+H]+ HPLC retention time: 3.152 min (5-95% acetonitrile with 0.05% TFA: water with 0.05% TFA).
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:20]COC)[CH2:16][CH2:17][CH2:18][CH3:19])=[C:11]([F:24])[CH:10]=1)[CH:6]([CH3:8])[CH3:7])(=[O:3])[CH3:2].Cl>C(O)(=O)C>[C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[C:11]([F:24])[CH:10]=1)[CH:6]([CH3:7])[CH3:8])(=[O:3])[CH3:2]
Reactant: CCCCC(OCOC)c1ccc(C(OC(C)=O)C(C)C)cc1F
Agent: Cl
Solvent: CC(=O)O
Product: CCCCC(O)c1ccc(C(OC(C)=O)C(C)C)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A mixture of 1-[3-fluoro-4-[1-(methoxymethoxy)pentyl]phenyl]-2-methylpropyl acetate (110 mg) and 1N hydrochloric acid (0.3 ml) in acetic acid (3 ml) was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The organic solution was washed with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate to give 1-[3-fluoro-4-(1-hydroxypentyl)phenyl]-2-methylpropyl acetate (70 mg) as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[B-](F)(F)(F)[CH:14]=[CH2:15].[K+].C(=O)([O-])[O-].[Na+].[Na+]>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]>[F:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([CH:14]=[CH2:15])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)cccc1Br
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cccc(F)c1C(=O)OC
Temperature: 100 °C
Yield: 76.4 %

Procedure:
To a solution of methyl 2-bromo-6-fluorobenzoate (53 g, 0.228 mol) and potassium trifluoro(vinyl)borate (33.63 g, 0.251 mol) in dioxane and H2O (3:1, 600 mL) was added Pd(dppf)Cl2 (5 g, 6.84 mmol) and sodium carbonate (69 g, 0.684 mol) at RT. The reaction mixture was heated at 100° C. for 12 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo, diluted with water, and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2CO3, filtered, and concentrated. The crude product was purified by column chromatography eluting with a gradient of EtOAc (1-100%) and PE to give the title compound (31.4 g, 76.5%). 1H NMR (400 MHz, CDCl3) δ ppm 7.45-7.36 (m, 2H), 7.03-7.02 (m, 1H), 6.88-6.81 (m, 1H), 5.77-5.73 (m, 1H), 5.41-5.39 (d, J=10.8 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>[Cl-].[Na+].O.O.ClCCl>[CH:1]1([NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:28]3[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]3)=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)NC1CCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NC3CCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
A flask was charged with 4-(3-cyclobutylureido)benzoic acid (51.3 mmol, 12.023 g), triethyl-amine (129 mmol, 18 mL, 13.07 g) and dichloromethane (75 mL) and cooled to 0° C. tert-Butyl piperazine-1-carboxylate (51.3 mmol, 9.56 g) was then added and the reagents were stirred together for 10 minutes at 0° C. before 1-propanephosphonic acid cyclic anhydride (64.2 mmol, 38.0 mL, 40.8 g, 50% solution in ethyl acetate) was slowly added. The reaction mixture was allowed to warm slowly to room temperature. After 5 hours stirring, the reaction was poured into a flask containing water (100 mL) and brine (20 ml). The mixture was then stirred and left to stand overnight. The resulting precipitate was collected by vacuum filtration, washed with cold water and dried under vacuum to yield the title compound as a white powder (19.6 g). MS (ESI) m/z 403.5 [M+H]+
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH2:14][CH:13]([CH2:15]Br)[CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:11]1=[O:24])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].N12CCCN=C1CCCCC2.O>C1(C)C=CC=CC=1>[CH3:1][C:2]([N:10]1[CH2:14][CH:13]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)([CH2:15]2)[C:11]1=[O:24])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(C)(c1ccccc1)N1CC(CBr)C(c2cccc(F)c2)C1=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(c1ccccc1)N1CC2CC2(c2cccc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To 15 ml of toluene were added 0.8 g of 1-(1-methyl-1-phenylethyl)-4-bromomethyl-3-(3-fluorophenyl)pyrrolidine-2-one and 0.4 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the solution was then stirred at room temperature for 2 hours. After water was added to the solution, extraction was made with toluene, and the resultant extract was then dried over anhydrous sodium sulfate. After the solvent was distilled off, silica gel column chromatography was done to obtain 0.45 g of the desired 3-(1-methyl-1-phenylethyl)-1-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-one.
Reaction SMILES: [F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[CH2:17]([O:19][C:20]([CH2:22]P(OCC)(=O)OCC)=[O:21])[CH3:18]>>[F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Product: CCOC(=O)C=Cc1ccc(OCC(F)(F)C(F)F)cc1

Procedure:
Prior-art syntheses of 4-fluoroalkoxycinnamonitriles start, for example, from p-chlorobenzonitrile, which is reacted, in a first reaction step, with 2,2,3,3'tetra-fluoropropanol to give 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile (EP 0 472 392). This reaction has already been described by J. P. Idoux (J. Org. Chem. 48, 3772, 1983). In a second reaction step, 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile is reacted in the presence of metal hydrides, such as diisobutylaluminumhydride, to give the corresponding benzaldehyde (JPS Sho 61-72767). 4-(2,2,3,3-tetrafluoropropoxy)-benzaldehyde subsequently reacts with diethyl ethoxycarbonylmethanephosphonate to give ethyl 4-(2,2,3,3-tetrafluoropropoxy)cinnamate, which is hydrolyzed, in a fourth step, to give free cinnamic acid. The fifth reaction step consists in the formation of the cinnamoyl chloride, which, in a sixth reaction step, reacts with aqueous ammonia to give 4-(2,2,3,3-tetrafluoropropoxy) cinnamamide. In the seventh and last step of the reaction sequence, the abovementioned cinnamamide is reacted in the presence of thionyl chloride or phosphorus pentachloride to give the desired product.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([O:19]CC)=O.C(O)C.O1CCOCC1.O.[NH2:32][NH2:33]>O>[CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([NH:32][NH2:33])=[O:19]
Reactant: NN
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Reaction time: 48 h

Procedure:
A mixture of ethyl anthraquinone-2-carboxylate (4.83 g) 25 ml of ethanol, 50 ml of dioxane and 7 ml of hydrazine hydrate is boiled under argon for 48 hours. It is poured into water and the product is isolated by filtration and dried at 60° C. in a vacuum oven. Crystallization of the crude product (4.05 g) from dimethylformamide/chloroform gives 3.01 g of product with a melting point (m.p.) of 250° C./decomposition.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][CH2:31][O:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[N:19]=2)=[C:9]1[CH3:40])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:31][CH2:30][N:20]2[N:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:41])=[O:5])[C:9]=3[CH3:40])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:29])=[O:28])=[CH:34][CH:35]=1
Reactant: Cc1c(C2=NN(CCOc3ccc(Cl)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(CCOc3ccc(Cl)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
(3-{2-[2-(4-Chloro-phenoxy)-ethyl]-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl}-5-fluoro-2-methyl-indol-1-yl)-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.11 (d, 1H), 7.92 (t, 1H), 7.83 (t, 1H), 7.46 (m, 2H), 7.24 (m, 2H), 6.95 (m, 4H), 4.52 (s, 2H), 4.39 (t, 2H), 4.27 (t, 2H), 2.20 (s, 3H) ppm. MS calculated for C26H21FClN3O5S—H: 540, observed: 540.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10](CC3C=CC=CC=3)[N:11]=[CH:12][C:5]=12)=[N+]=[N-].[ClH:20].CO.[H][H]>CO.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[ClH:20].[ClH:20].[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][N:11]=[CH:12][C:5]=12
Reactant: [H][H]
Reactant: [N-]=[N+]=Nc1ccnc2c1cnn2Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [C+4]
Solvent: CO
Product: Nc1ccnc2[nH]ncc12

Procedure:
A solution (40 ml) of 4-azido-1-benzyl-1H-pyrazolo[3,4-b]pyridine (2.7 g), 10% palladium hydroxide carbon (1.0 g) and 15% hydrochloric acid-methanol (1 ml) in methanol was stirred in an autoclave at initial hydrogen pressure of 10 atm and at 40°-50° C. for 5 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give crystals. Recrystallization from methanol-ethyl acetate gave 1.9 g of 4-amino-1H-pyrazolo[3,4-b]pyridine dihydrochloride.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][CH3:22])[CH2:16]3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)(Cl)Cl>[CH:11]1[C:12]2[CH:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([N:21]([C:30](=[O:32])[CH3:31])[CH3:22])[CH2:16]3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNC1CCCN(C2c3ccccc3Oc3ccccc32)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)C1CCCN(C2c3ccccc3Oc3ccccc32)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1.0 g. of 1-(9-xanthenyl)-3-methylaminopiperidine and 2.0 g. of triethylamine in 25 ml. of dry chloroform is treated at 0°C. with 0.5 g. of acetic anhydride in 2 ml. of dry chloroform. The mixture is refluxed with stirring for two hours and then poured into ice water. The chloroform layer is washed with water, dried over potassium carbonate, and the solvent is removed in vacuo to give 1-(9-xanthenyl)-3-(N-acetyl-N-methylamino)-piperidine.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([O:22]C(C)C)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[OH-]>C1COCC1.O>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
In a 5 L, 3-neck round-bottom flask, (Z)-isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate (130 g, 1.0 eq.) was dissolved in THF (1.3 L). A solution of LiOH (69.3 g, 5.0 eq.) in water (1.3 L) was added dropwise to the solution and the reaction mixture was stirred at RT for 4 h before being quenched with 400 mL ice-water slurry and made acidic (pH=2-3) with dilute aqueous HCl. The mixture was extracted with EtOAc (3×1 L) and the combined organic layers were washed with aqueous saturated sodium chloride solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 110 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (yield: 94%), (cis content=90.0%, trans content=8.2% by LCMS).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=3[F:28])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:7][CH3:8].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CC1N(C(N(C)C)=O)C1>CCCCCC.C1COCC1>[CH2:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:23]([F:27])[C:22]=3[F:28])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[CH2:7][CH3:8]
Reactant: CCCCCBr
Reactant: CCCc1ccc(-c2ccc(-c3cccc(F)c3F)cc2)cc1
Agent: CC1CN1C(=O)N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCc1ccc(-c2ccc(-c3ccc(CCC)cc3)cc2)c(F)c1F
Temperature: -100 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium (0.1 mol) in 65 ml of hexane is added to a mixture of 4"-propyl-2,3-difluoro-p-terphenyl (0.1 mol), potassium t-butylate (0.1 mol) and 200 ml of THF at -100° C. After stirring 5 minutes at -100° C. a mixture of brompentane (0.1 mol) and N,N-dimethylpropylene urea (0.1 mol, DMPU) is added. After warming-up to -30° C. and usual work-up 4"-propyl-4-pentyl-2,3-difluoro-p-terphenyl is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1.ClC1C(C)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:27][NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][C:20]([OH:19])=[CH:21][CH:22]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Agent: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: ClCCl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Yield: 49.6 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 3a) (503 mg, 1.9 mmol) was coupled with 4-hydroxy-benzohydrazide (285 mg, 1.9 mmol) similarly to the procedure described for the preparation of intermediate 1b. Trituration with hot methylene chloride provided the title compound as a white solid (380 mg, 62%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.68 (br s, 1H), 9.30 (br s, 1H), 7.85 (AA′XX′, J=8.7 Hz, 2H), 7.52 (d, J=8.7 Hz, 1H), 6.91 (AA′XX′, J=8.8 Hz, 2H), 6.71 (d, J=8.6 Hz, 1H), 5.59 (d, J=7.1 Hz, 1H), 4.84 (br s, 1H), 4.20 (m, 1H), 4.09 (m, 1H), 2.34 (s, 3H), 1.37 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C1C=CC=CC=1>[CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([Cl:24])=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Yield: 103.4 %

Procedure:
4.0 g (1.31×10-2 mol) of p-dodecyloxybenzoic acid was dissolved in 15 ml of benzene, and 2.79 g (1.31×10-2 mol) of PCl5 was slowly added thereto under stirring at room temperature. Thereafter, 3 hours of heat-refluxing was effected, followed by distilling-off the solvent to obtain 4.4 g of p-dodecyloxybenzoic acid chloride.
Reaction SMILES: CC1(C)OC(=O)[C:5](=[CH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:4](=O)[O:3]1.[F:20][C:21]([F:38])([F:37])[C:22]1[CH:23]=[C:24]([NH:28]/[C:29](/[CH3:36])=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:25]=[CH:26][CH:27]=1>COCCOCCOC.O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH:9]2[CH2:5][C:4](=[O:3])[N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:37])([F:38])[F:20])[CH:23]=3)[C:29]([CH3:36])=[C:30]2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:11][CH:12]=1)#[N:15]
Reactant: CC1(C)OC(=O)C(=Cc2ccc(C#N)cc2)C(=O)O1
Reactant: CCOC(=O)/C=C(\C)Nc1cccc(C(F)(F)F)c1
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)CC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
4-[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl]benzonitrile (Example 18A; 200 mg, 0.77 mmol) and ethyl (2E)-3-{[3-(trifluoromethyl)phenyl]amino}-2-butenoate (212.4 mg, 0.77 mmol) are dissolved in 1-methoxy-2-(2-methoxyethoxy)ethane (3 ml). The solution is stirred at reflux temperature overnight. The reaction mixture is cooled to room temperature and diluted with water (5 ml). After extraction with toluene (2×5 ml), it is dried with anhydrous sodium sulphate, filtered, and the solvent is removed in vacuo. The product is purified via preparative HPLC.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:26]2[NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:25]=2[C:24]([O:33][CH3:34])=[CH:23][CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:26]3[NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:25]=3[C:24]([O:33][CH3:34])=[CH:23][CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1ccc(N)c2c1CCCC(=O)N2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(OC)c3c2NC(=O)CCC3)ncc1Cl

Procedure:
Analogous to the procedure described in Example 1, the reaction of 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 9-amino-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one gave 2-[5-chloro-2-(6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-9-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide, upon purification by flash chromatography (Dichloromethane: MeOH 97:3) followed by PLC (hexane:EtOAc 1:1), as solid (6%): 1H NMR (400 MHz, CD3OD) δ8.3 (br s, 1H), 7.60 (dd, J=7.70 Hz, 1.44 Hz, 1H), 7.26 (d, J=8.78 Hz, 1H), 7.06 (m, 1H), 7.04 (m, 1H), 6.93 (d, J=8.83 Hz, 1H), 3.89 (s, 3H), 2.90 (s, 3H), 2.82 (m, 2H0, 2.06 (m, 4H); MS (m/e) 467, 468 (M+H);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1([N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:20]2=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)CC1(Nc2ccccc2N)CCCCC1
Solvent: C1CCOC1
Product: COC(=O)CC1(n2c(=O)[nH]c3ccccc32)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
A mixture of [1-(2-amino-phenylamino)-cyclohexyl]-acetic acid methyl ester (205 mg, 0.79 mmol) in THF (5 mL) was added 1,1′-carbonyldiimidazole (180 mg, 1.11 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The resulting residue was purified by CombiFlash with 50% EtOAc in Hexane as the eluent to afford the desired [1-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-cyclohexyl]-acetic acid methyl ester (194 mg, 86%).