Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=2)=[N:4][NH:3]1.C(N(CC)CC)C.C(OC([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[N:36]1([C:19]([C:17]2[N:18]=[C:13]([CH2:12][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2](=[O:1])[NH:3][N:4]=3)[CH:14]=[CH:15][CH:16]=2)=[O:21])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3ccccc23)n1)N1CCNCC1
Reaction time: 18 h
Yield: 59.8 %

Procedure:
A mixture of 6-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-pyridine-2-carboxylic acid (ivb)(0.3 g, 1.1 mmol), triethylamine (0.3 ml, 2.1 mmol), tert-butyl-1-piperazine carboxylate (0.23 g, 1.3 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.5 g, 1.3 mmol) in dimethylformamide (10 ml) was stirred for 18 hours. The reaction mixture was precipitated on the addition of water (50 ml) and air-dried. The white precipitate was dissolved in ethanol (3 ml) and 12 M hydrochloric acid (6 ml) was added to the solution and the reaction was stirred for 30 minutes. The reaction was then concentrated in vacuo, redissolved in water (10 ml) and washed with dichloromethane (2×10 ml). The aqueous layer was basified with ammonium hydroxide and extracted into dichloromethane (2×10 ml). The combined organic layers was dried with MgSO4, filtered and evaporated to yield the expected product (va) as a pink solid (0.23 g, 73%). m/z [M+1]+ 250 (96% purity)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:14])[C:11]#[C:12][CH3:13].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:10]([O:14][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCO
Reactant: Fc1ncnc(F)c1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.31 g of 2-butyn-1-ol and 0.62 ml of N,N-diisopropylethylamine were added to 1 ml of tetrahydrofuran, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.52 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine.
Reaction SMILES: Cl.[Br:2][C:3]1[C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[S:21]>>[Br:2][C:3]1[C:8]([CH2:9][NH:10][C:20]([NH:19][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=2[Cl:11])=[S:21])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: NCc1cccnc1Br
Reactant: S=C=Nc1cccc(Cl)c1Cl
Agent: Cl
Product: S=C(NCc1cccnc1Br)Nc1cccc(Cl)c1Cl
Yield: 55 %

Procedure:
Prepared in 55% yield by treatment of the product of Example 142A with 2,3-dichlorophenylisothiocyanate according to the procedure described for Example 141B. MS (ESI−) m/z 389.9 (M+H)+; 1H NMR (DMSO-d6) δ 4.71 (d, J=4.4 Hz, 2H), 7.37 (dd, J=8.0, 8.0 Hz, 1H), 7.48 (dd, J=7.5, 4.7 Hz, 1H), 7.55 (dd, J=8.1, 1.7 Hz, 1H), 7.58-7.63 (m, 1H), 7.69 (dd, J=7.6, 1.9 Hz, 1H), 8.29 (dd, J=4.7, 2.0 Hz, 1H), 8.44 (br s, 1H), 9.70 (br s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[C:12]2[CH:13]=[C:14]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1.CS(C)=[O:32].N([O-])=O.[Na+].Cl>O.C(O)(=O)C>[OH:32][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[C:12]2[CH:13]=[C:14]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1
Reactant: CS(C)=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4sccc4CBr)c3c2)c1=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4sccc4CO)c3c2)c1=O
Yield: 38.3 %

Procedure:
To a mixture of 3-[3-[3-(bromomethyl)-2-thienyl]-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)uracil(0.840 g, 1.67 mmol), dimethylsulfoxide and sodium nitrite is added glacial acetic acid. The resultant mixture is stirred overnight at 50° C., cooled and acidified with 10% aqueous hydrochloric acid. The mixture is diluted with water and extracted twice with ethyl acetate. The combined organic layers are washed with saturated sodium carbonate, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with diethyl ether-methylene chloride to afford the title compound as an off-white solid (0.290 g, 38.3%, mp 168-169° C.) which is identified by IR and NMR spectral analysis.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([O:17][CH3:18])[CH:8]=1.[C:19](=[O:21])=[O:20].O>C1COCC1>[CH:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:19]([OH:21])=[O:20])=[CH:8][C:9]=1[O:17][CH3:18])([CH3:16])[CH3:15]
Reactant: COc1cc(Br)ccc1OC(C)C
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
Under an atmosphere of nitrogen, tert-butyllithium (2.14 mL of 1.6 M in toluene, 3.42 mmol) was added dropwise to a solution of 4-bromo-1-isopropoxy-2-methoxy-benzene (400 mg, 1.63 mmol) in THF (6 mL) at −78° C. The reaction mixture was allowed to stir for 1 hour at −78° C., then added dropwise to a flask containing CO2 (1.8 g, 40.8 mmol) (solid, dry ice) in THF (2 mL). The reaction mixture was allowed to stir for 30 minutes warming to room temperature. Water (20 mL) was added to the reaction mixture and the volatiles were removed in vacuo. The resultant aqueous layer was acidified with 1N HCl solution to pH 1 and was extracted with ethyl acetate (3×15 mL). The organics were separated and the combined organics were washed with brine solution, dried over sodium sulfate, filtered and concentrated in vacuo to give 4-isopropoxy-3-methoxy-benzoic acid (310 mg, 85%) as a white solid. ESI-MS m/z calc. 210.1. found 211.1 (M+1)+; Retention time: 1.23 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 7.53 (dd, J=8.4, 2.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.7 Hz, 1H), 4.67 (dt, J=12.1, 6.0 Hz, 1H), 3.78 (s, 3H), 1.28 (d, J=6.0 Hz, 6H).
Reaction SMILES: Cl([O-])(=O)(=O)=O.Cl[C:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9](=[N+:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=1.[CH2:20]([N:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[N:25]([CH2:31][CH3:32])[C:23]1=[S:24])[CH3:21].C(N(CC)CC)C>C(O)C>[CH2:31]([N:25]1[C:26](=[O:27])[C:28](=[C:7]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:8]2)[C:29](=[O:30])[N:22]([CH2:20][CH3:21])[C:23]1=[S:24])[CH3:32]
Reactant: CCN1C(=O)CC(=O)N(CC)C1=S
Reactant: CC1(C)CC(Cl)=CC(=[N+]2CCCC2)C1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN1C(=O)C(=C2C=C(N3CCCC3)CC(C)(C)C2)C(=O)N(CC)C1=S

Procedure:
N-(3-Chloro-5,5-dimethylcyclohex-2-en-1-ylidene)-pyrrolidinium perchlorate (3.1 g., 0.01 mol.), 1,3-diethyl-2-thiobarbituric acid (2.0 g., 0.091 mol.) and triethylamine (3.1 ml.) are dissolved in ethanol (15 ml.) and heated at reflux for 10 minutes. After chilling, the crude dye is collected on a filter, rinsed with ethanol and dried. After one recrystallization from methanol, the yield of purified dye is 2.3 g. (64%), m.p. 226°-227°C. This dye is an excellent spectral sensitizer for photographic silver halide emulsions as shown in Table 2 hereinafter.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([OH:16])[CH:9]=1.Cl>CCO>[OH:16][C:10]1[CH:9]=[C:8]([NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(N)cc1O
Reactant: Brc1nccs1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(Nc2nccs2)cc1O
Temperature: 90 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (0.94 mL, 10.4 mmol), 4-amino-2-hydroxybenzonitrile (696 mg, 5.2 mmol) and 37% HCl solution (0.88 mL, 10.4 mmol) in 10% aqueous EtOH solution (20 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 1/1) in 26% yield (293 mg).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)[C:18]1[CH:23]=[CH:22]C=[CH:20][CH:19]=1>C(O)C>[O:1]=[C:2]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Solvent: CCO
Product: O=C(CCc1ccccc1)CC(=O)OCc1ccccc1

Procedure:
Ethyl 3-oxo-5-phenylpentanoate (64.2 g, 0.29 mole) was heated between 190° and 210° C. under nitrogen with benzyl alcohol (28.9 ml, 0.28 mole) for 6 hours, the ethanol formed being distilled out of the reaction mixture. The resulting pale yellow oil was essentially pure product, slightly contaminated by starting materials, n.m.r. δ (CCl4) 7.23 (5H, s), 7.06 (5H, s), 5.03 (2H, s), 3.23 (2H, s) and 2.73 (4H, s).
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[CH:6][NH:5][C:4]=2[CH:3]=[C:2]1[C:9]([O:11]CC)=[O:10].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[O-]CC.[Na+].Cl>CCO>[C:14]1([C:7]2[C:8]3[S:1][C:2]([C:9]([OH:11])=[O:10])=[CH:3][C:4]=3[NH:5][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: CCOC(=O)c1cc2[nH]ccc2s1
Reactant: O=C1CCCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cc2[nH]cc(C3=CCCCC3)c2s1
Yield: 98 %

Procedure:
A solution (0.25 M) of ethyl 4H-thieno[3,2-b]pyrrole-2-carboxylate in EtOH was treated with cyclohexanone (2 eq.) and sodium ethoxide (2.05 eq.) then heated to reflux for 4 h. After cooling down, it was acidified with aqueous HCl (6 N) and the precipitate was filtered and dried, affording the title compound (98%) as a solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.N>O>[N:20]1[CH:21]=[CH:22][C:17]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)=[CH:18][CH:19]=1
Reactant: Clc1ccncc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: N
Solvent: O
Product: COc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 31 %

Procedure:
4-(Piperazin-1-yl)anisole (4.24 g) and 4-chloropyridine hydrochloride (3.35 g) were intimately mixed and heated at 160°-170° C. (bath temperature) for 7 minutes. The solid obtained on cooling was dissolved in water (75 ml) and the solution basified with aqueous ammonia. The solid precipitate was extracted into ethyl acetate and the organic extract washed with water, filtered through phase separating paper (Whatman 1PS) and evaporated. The residue was recrystallised from ethanol to give 4-[4-(4-pyridyl)piperazin-1-yl]anisole (1.84 g) as a solid: m.p. 165°-167° C.; NMR (CDCl3) δ 8.3(2H,d); 6.86(4H,m); 6.71(2H,d); 3.78(3H,s); 3.46(4H,m); 3.2(4H,m).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: COc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(F)cc1
Product: COc1cc(-c2ccc(F)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (61 mg, 79%), MS (ISP) m/z=311.5 [(M+H)+], mp 220° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methoxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 18) (73.8 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23](O)[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[CH:13]=1)([O:8]COC)[C:4]([F:7])([F:6])[F:5].[CH3:33][CH:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2([CH3:50])[NH:47][C:46](=[O:48])[NH:45][C:44]2=[O:49])=[CH:39][CH:38]=1)[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCOC(/N=N/C(OCC)=O)=O>[F:32][C:2]([F:31])([F:1])[C:3]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]([N:45]3[C:44](=[O:49])[C:43]([C:40]4[CH:41]=[CH:42][C:37]([O:36][CH:34]([CH3:33])[CH3:35])=[CH:38][CH:39]=4)([CH3:50])[NH:47][C:46]3=[O:48])[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[CH:13]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(C(C)O)c1
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(C(C)N2C(=O)NC(C)(c3ccc(OC(C)C)cc3)C2=O)c1
Yield: 44.2 %

Procedure:
To a solution of 1-(3-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)phenyl) ethanol (40.0 mg, 85.8 mmol), 5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione (32.0 mg) and triphenylphosphine (56.3 mg) in tetrahydrofuran (5 mL), diethylazodicarboxylate (about 2.2 mol/L toluene solution, 97.5 μL) was added under ice-cold conditions. After completion of the reaction, the reaction solution was concentrated in vacuo. The obtained residue was purified using silica-gel thin-layer chromatography (hexane/ethyl acetate). The obtained compound was added with 2 mol/L hydrogen chloride-ethyl acetate solution (1 mL) at room temperature. After completion of the reaction, the solution was concentrated in vacuo and purified using thin-layer silica-gel column chromatography (hexane/ethyl acetate) and the title compound (37.2 mg, yield 66%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=O)=[CH:10][CH:9]=1>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[CH2:1])=[CH:10][CH:9]=1
Reactant: O=Cc1cccc(Oc2ccc(F)cc2)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=Cc1cccc(Oc2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
To a suspension of potassium tert-butoxide (2.61 g, 23.3 mmol) in ether (100 mL) was added methyltriphenylphosphonium bromide (8.34 g, 23.3 mmol) and the solution was brought to reflux for 15 min. It was then cooled to 0° C. and 3-(4-fluorophenoxy)benzaldehyde (4.80 g, 22.2 mmol) was added. The reaction was stirred for 5 min at 0° C., the cooling bath was withdrawn and the reaction allowed to warm to ambient temperature and stir for 45 min. It was then filtered through Celite and concentrated. The resulting residue was chromatographed (silica gel; hexanes, ether 96:4) to afford 4.09 g (86%) of 3-(4-fluorophenoxy)styrene as a colorless oil.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[N:36]2[CH:40]=[CH:39][C:38]([CH3:41])=[N:37]2)[C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]([NH2:42])[N:18]=1>O1CCOCC1>[NH2:42][C:19]1[N:18]=[C:17]([N:3]2[CH2:4][CH2:5][C:6]3([CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:8][CH2:7]3)[CH2:1][CH2:2]2)[CH:22]=[C:21]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[N:36]2[CH:40]=[CH:39][C:38]([CH3:41])=[N:37]2)[C:25]([F:27])([F:26])[F:28])[N:20]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(Cl)nc(N)n2)C(F)(F)F)n1
Reactant: COC(=O)C1CC2(CCNCC2)CCN1
Solvent: C1COCCO1
Product: COC(=O)C1CC2(CCN1)CCN(c1cc(O[C@H](c3ccc(Cl)cc3-n3ccc(C)n3)C(F)(F)F)nc(N)n1)CC2
Temperature: 100 °C

Procedure:
To a solution of methyl 3,9-diazaspiro[5.5]undecane-10-carboxylate (30 mg, 0.14 mmol) in dioxane (2 mL)/1-PrOH (2 mL) was added 4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-2-amine (92 mg, 0.22 mmol), and the reaction was heated at 100° C. under microwave for 3 h. The reaction was cooled to RT, and concentrated in vacuo. The residue was purified by reversed phase HPLC (MeOH/H2O/0.5% TFA) to provide methyl 9-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylate as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[CH:16]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([O:43][CH3:44])=[C:31]([CH:42]=2)[CH2:32][N:33]([CH2:39][CH2:40][OH:41])C(NCC)=O)[C:23]([Cl:45])=[CH:22][N:21]=1>>[Cl:45][C:23]1[C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([O:43][CH3:44])=[C:31]([CH2:32][NH:33][CH2:39][CH2:40][OH:41])[CH:42]=2)=[N:25][C:20]([NH:1][C:2]2[C:3]([O:17][CH3:18])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH3:15])[C:6]=3[CH:16]=2)=[N:21][CH:22]=1
Reactant: CCNC(=O)N(CCO)Cc1cc(Nc2nc(Cl)ncc2Cl)ccc1OC
Reactant: CCN1CC(=O)N(C)c2cc(N)c(OC)cc2C1
Product: CCN1CC(=O)N(C)c2cc(Nc3ncc(Cl)c(Nc4ccc(OC)c(CNCCO)c4)n3)c(OC)cc2C1

Procedure:
The title compound was prepared from 8-Amino-4-ethyl-7-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and 1-[5-(2,5-Dichloro-pyrimidin-4-ylamino)-2-methoxy-benzyl]-3-ethyl-1-(2-hydroxy-ethyl)-urea in an analogous manner to example 730 (0.010 g, 9%). Mp 65-70° C.; LCMS (m/e) 556 (M); 1H-NMR (DMSO, 400 MHz) δ 8.87 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 7.41 (m, 2H), 7.01 (s, 1H), 6.86-6.84 (d, 1H, J=9.35 Hz), 4.54 (m, 1H), 4.34-4.43 (d, 1H, J=4.04 Hz), 3.86 (s, 3H), 3.78 (s, 4H), 3.68 (s, 2H), 3.45 (s, 4H), 2.97 (s, 2H), 2.80 (s, 2H), 2.63-2.58 (m, 2H), 1.07-1.05 (t, 3H, J=7.07 Hz).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1)(=[O:3])[NH2:2].[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=2)[CH:6]=1
Reactant: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(4,6-dimethylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (75 mg, 165 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.88 g, 1.27 mL, 16.5 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated and then the residue was diluted with dichloromethane and neutralized with NH4OH. Purification by chromatography (silica, 0-100% of a 10:0.5:89.5 methanol:NH4OH:dichloromethane in dichloromethane) followed by further purification by HPLC (C-18, 10-100% water in acetonitrile gradient) gave 6-((1R,2S)-2-aminocyclohexylamino)-4-(4,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide 2,2,2-trifluoroacetate (33 mg, 70.3 μmol, 43%) as a fluffy off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 7.86 (br. s, 1H), 7.40 (br. s, 2H), 6.76 (s, 1H), 6.65 (s, 1H), 4.40 (s., 1H), 3.63 (s, 1H), 2.48 (s, 3H), 1.58-1.86 (m, 8H), 1.46 (m, 2H); MS (EI/CI) m/z: 356.1 [M+H].
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)=[O:3].[Br:18]Br>C(O)(=O)C>[F:17][C:14]([F:15])([F:16])[C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][Br:18])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1
Reactant: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a stirred solution of 3,5-bis(trifluoromethyl)acetophenone (50.0 g, 195.2 mmol) in acetic acid (200 mL) was added dropwise at 90° C. bromine (31.2 g, 195.2 mmol). After the initiation of the reaction (3-4 drops), the oil bath was removed and the mixture was stirred at room temperature for 1 h. To this mixture was added water (50 mL) and the mixture was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate (500 mL) and water (500 mL). The organic layer was separated and washed with saturated sodium hydrogen carbonate (250 mL×2), and saturated sodium chloride (250 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 1-[3,5-bis(trifluoromethyl)phenyl]-2-bromoethanone (57.65 g, 88%) as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[O:12])[CH:5]=1)(=[O:3])[CH3:2].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH:2]=[CH:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[N:9]=[C:8]([CH3:10])[N:7]=2)=[O:12])=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(CNC(=O)c2cc(C(C)=O)nc(C)n2)ccc1F
Reactant: O=Cc1cccnc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C(=O)C=Cc3cccnc3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
To a cold solution of 6-acetyl-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.050 g, 0.158 mmol, Preparation #23) and nicotinaldehyde (0.0168 mg, 0.158 mmol) in DCM (2 mL) was added aluminium chloride (0.02311 g, 0.173 mmol). The reaction mixture was allowed to stir for 15 minutes and added TEA (0.033 mL, 0.236 mmol). The reaction mixture was slowly warmed to RT and stirred for 3 h. The reaction mixture was heated to about 50° C. for 0.5 h then cooled to RT and poured into cold water (20 mL) and the product was extracted with diethyl ether (2×20 mL). The organic layer was washed successively with water (1×20 mL), brine (1×20 mL), dried over sodium sulphate and evaporated to dryness. The residue obtained was purified by preparative TLC eluting with 50% EtOAC/hexane to afford N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(3-(pyridin-3-yl)acryloyl)pyrimidine-4-carboxamide 0.015 g, (23.42%), 1H NMR (400 MHz, DMSO): δ 9.59 (bs, 1H) 9.00 (s, 1H) 8.67 (s, 1H) 8.33-8.17 (m, 3H) 8.00-7.96 (m, 1H) 7.52-7.51 (m, 1H) 7.19-7.17 (m, 2H) 6.92-6.91 (m, 1H) 4.51-4.49 (m, 2H) 3.82 (s, 3H) 2.89 (s, 3H), MS m/z: 407 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][C:7]=1[NH2:8].C1(N)C(F)=C(F)C(F)=C([NH2:22])C=1F.[ClH:25].Cl.Cl>C(O)C>[ClH:25].[ClH:25].[NH2:22][C:2]1[CH:3]=[N:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: CC(C)(C)c1cc(N)c(Br)cn1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)c(N)cn1

Procedure:
Procedure analogous to 4) S18 using 22.9 g (100 mmol) of 3-bromo-4-amino-6-tert-butylpyridine (S40) instead of 29.5 g (100 mmol) of 2-(2-bromo-4-fluorophenyl)-D4-benzimidazole (S9). The crude product is converted into the dihydrochloride by dissolution in 100 ml of ethanol and introduction of gaseous hydrochloric acid. The crystals obtained in this way are filtered off with suction and dried in vacuo. Yield: 13.3 g (56 mmol), 56%. Purity: >95% according to 1H-NMR.