Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@H:40]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:41][O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].[C:66]([OH:72])(=[O:71])[CH2:67][CH2:68][CH:69]=O.C([BH3-])#N.[Na+].Cl>C(OC(N[C@H](C(N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(OC(C)(C)C)=O)=O)C(C)C)=O)C1C=CC=CC=1>[C:66]([CH2:67][CH2:68][CH2:69][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@H:40]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:41][O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:72])=[O:71]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: Cl
Agent: [BH3-]C#N
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 100 °C

Procedure:
24 mg (26 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate and 33.7 μl of a 15% aqueous succinaldehydic acid solution (52 μmol) were dissolved in 953 μl of a 1:1-dioxane/water mixture and heated to 100° C. for 1 h. After brief cooling, 1.80 mg (29 μmol) of sodium cyanoborohydride were added. The reaction mixture was adjusted to pH 3 by adding 0.1 N hydrochloric acid and the mixture was heated to 100° C. for a further 2 h. After again adding the same amounts of succinaldehydic acid solution, sodium cyanoborohydride and hydrochloric acid, the mixture was heated once again to 100° C. for 2 h. The reaction mixture was then separated directly into its components by means of preparative HPLC. 15.2 mg (65% of theory) of the title compound were thus obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:7][C:8]=1[Cl:9])#[N:2].[C:14]([N:16]=[C:17]([NH2:19])[NH2:18])#[N:15].[OH-].[K+]>COCCOCCOC.O>[NH2:15][C:14]1[N:16]=[C:17]([NH2:19])[N:18]=[C:1]([C:3]2[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:11])[F:12])[CH:4]=2)[N:2]=1
Reactant: N#CN=C(N)N
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Product: Nc1nc(N)nc(-c2cc(C(F)(F)F)ccc2Cl)n1

Procedure:
4.0 g of 3-cyano-4-chlorobenzotrifluoride (90°-102° C./29 mm Hg), 2.0 g of dicyanodiamide and 1.0 g of caustic potash are refluxed in 10 ml of diglyme for 3 hours. After cooling, the mixture is diluted with water and the separated crystals are recrystallized from methanol. Melting point: 210°-212° C.; yield: 3.8 g.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([OH:8])=O.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][C@H:27]([CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl.O>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([C:6](=[O:8])[C:5]2[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=2)[C@H:27]([CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1ccc(CN2CCN[C@H](Cc3c[nH]c4ccccc34)C2)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.8 %

Procedure:
To a mixture of 3,5-bis(trifluoromethyl)benzoic acid (1.15 g) and (3R)-1-benzyl-3-(1H-indol-3-yl-methyl)piperazine (1.61 g) in dichloromethane (80 ml) was added triethylamine (1.55 ml) at room temperature under nitrogen atmosphere. 2-Chloro-1-methylpyridinium iodide (1.37 g) was added, and the mixture was stirred at room temperature for 2.5 hours. The resulting mixture was poured into water (20 ml). The organic layer was washed successively with 0.5N hydrochloric acid, water, aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After evaporation under reduced pressure, the residue was chromatographed on silica gel with toluene - ethyl acetate (4:1) as an eluent to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.87 g) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)CC)C.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:56][C@H:57]1[CH2:60][N:59]([C:61]([NH:63][S:64]([NH:67][NH:68][C:69]([NH:71][C:72]2[CH:77]=[CH:76][C:75]([OH:78])=[C:74]([OH:79])[CH:73]=2)=[O:70])(=[O:66])=[O:65])=[O:62])[C:58]1=[O:80].C(OCC)(=O)C.Cl>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][C:13]([CH3:14])([CH3:15])[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:8]([NH:56][CH:57]2[CH2:60][N:59]([C:61]([NH:63][S:64]([NH:67][NH:68][C:69]([NH:71][C:72]3[CH:77]=[CH:76][C:75]([OH:78])=[C:74]([OH:79])[CH:73]=3)=[O:70])(=[O:66])=[O:65])=[O:62])[C:58]2=[O:80])=[O:10])[N:6]=1
Reactant: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)Nc2ccc(O)c(O)c2)C1=O
Agent: Cl
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(ON=C(C(=O)NC1CN(C(=O)NS(=O)(=O)NNC(=O)Nc2ccc(O)c(O)c2)C1=O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Into a -30° C. cold mixture of 0.66 g (1.5 mmol) of (Z)-2-amino-α-[[1-(diphenylmethoxycarbonyl)-1-methylethoxy]imino]-4-thiazoleacetic acid in 13 ml of dry dimethylformamide, 0.63 ml (4.5 mmol) of triethylamine was dropped, followed by 0.33 ml (1.5 mmol) of diphenylchlorophosphate. After stirring at -30° C. for 1 hour, 0.42 ml (3.0 mmol) of triethylamine was dropped in, followed by the addition of 0.80 g (1.5 mmol) of (S)-3-amino-1-[[[[2-[[(3,4-dihydroxyphenyl)amino]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxoazetidine. The mixture was stirred for 2 hours at -10° C. and an additional 2 hours at 0° C. The solvent was removed in vacuo and the residue was taken up in a few ml of ethyl acetate and ice water. The pH of the mixture was corrected to pH=2 the addition of dilute hydrochloric acid. The insoluble material was collected by suction1) and stirred with a few ml of ethyl acetate until it became crystalline; yield after drying in vacuo: 0.31 g. This material was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[F:19][C:20]([F:24])([F:23])[CH2:21][NH2:22]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-N-(2,2,2-trifluoro-ethyl) -isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.30 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of 2,2,2-trifluoro-ethylamine. LC/MS [6.73 min; 440 (M+1)]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].[CH3:17][NH:18][CH2:19][CH2:20][CH3:21].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([N:18]([CH3:17])[CH2:19][CH2:20][CH3:21])=[O:10])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Reactant: CCCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
Mix 5-hydroxymethyl-isophthalic acid monoethyl ester (3.3 g, 14.7 mmol), N-methyl propylamine (1.5 mL, 14.7 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.8 g, 14.7 mmol), and 1-hydroxybenzotriazole hydrate (2.0 g, 14.7 mmol) in dichloromethane (40 mL) and DMF (4 mL). Stir at room temperature for 3 h. Concentrate and redissolve in ethyl acetate (150 mL). Wash with aqueous sodium bicarbonate solution, aqueous ammonium chloride solution, water, saturated aqueous sodium chloride, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (2.5 g, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:22][C:23]([CH3:25])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:23]([CH3:25])[CH3:22])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc(CNCc2ccc([N+](=O)[O-])cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N(Cc1ccc([N+](=O)[O-])cc1)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of bis(4-nitrobenzyl)amine (50 mg, 0.174 mmol) and acetone (51.1 μL, 0.696 mmol) in methanol (752 μL)/acetic acid (39.6 μL)/CH2Cl2 (79 μL) was stirred at room temperature for 1 hour. The reaction was cooled to 0° C. and sodium cyanoborohydride (32.8 mg, 0.522 mmol) was added. The mixture was stirred at 0° C. for 1 hour, and allowed to warm to rt and stirred overnight. The reaction was concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 50% EtOAc/hexane) afforded the title product (42.8 mg, 75%). MS (ESI) m/z 329.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)(=O)C.[CH3:17][N:18]([CH:20]=O)[CH3:19]>O>[F:1][C:2]([F:11])([F:12])[C:3]([C:4](=[CH:17][N:18]([CH3:20])[CH3:19])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:10]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of ethyl trifluoroacetoacetate (4.6 g, 0.025 mol) and acetic acid (3.0 g, 0.05 mol) at room temperature, DMF diusopropyl acetal (8.75 g, 0.05 mol) was added dropwise at a rate which maintained the reaction temperature below 35° C. After stirring the mixture at ambient temperature for 2 hours to complete the reaction (TLC), it was poured into water and extracted with ether. The ether extract was washed with water, brine solution, then dried (MgSO4), and concentrated. The residual yellow oil was column-chromatographed on silica gel (Hexanes:Ethyl acetate/7:3) to give ethyl 2-trifluoroacetyl-3-(N,N-dimethylamino)-2-propenoate (Compound 2; Rf=0.3) as the main product; 4.5 g (75%).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2)([O-])=O>C(OCC)(=O)C.CO>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([O:6][C:5]3[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=3[NH2:1])=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc2[nH]ncc2c1
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
Under a hydrogen atmosphere at atmospheric pressure, a solution of the 5-(2-nitrophenoxy)-1H-indazole (56.7 mg, 0.222 mmol) obtained in Example 352 in a mixture of ethyl acetate (3 ml) and methanol (3 ml) was stirred at room temperature for 1.5 hours. The solution was filtered and then the filtrate was concentrated to obtain 2-(1H-indazol-5-yloxy)aniline (34.5 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[NH:20][C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](I)[CH3:33]>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[N:20]([CH2:32][CH3:33])[C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCn1c(SC)nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
Under argon gas, 7-[4-(4-chlorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (2.46 g) was dissolved in anhydrous DME (72.5 ml)anhydrous DMF (72.5 ml) and, under ice-cooling, 60% sodium hydride-oil (255 mg) was added in two installments. The mixture was stirred for 30 minutes sand ethyl iodide (1.09 g) was added. Then, the mixture was further stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography [silica gel; dichloromethane→methanol: dichloromethane (1:49)] to provide the title compound (1.04 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]([CH3:36])([CH3:35])[CH:28]=1)(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]([CH3:36])([CH3:35])[CH:28]=2)=[C:6]([CH3:19])[CH:5]=1
Reactant: CC1(C)C=C(OS(=O)(=O)C(F)(F)F)CC(C)(C)C1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Product: COC(=O)c1ccc(C2=CC(C)(C)CC(C)(C)C2)c(C)c1
Yield: 75.2 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Example 28, Step A (0.500 g, 1.81 mmol) and 3,3,5,5-tetramethyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.621 g, 2.17 mmol) were reacted by the procedure described in Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 5% ethyl acetate in hexane, afforded the title compound (0.390 g) as a light yellow oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[CH2:26]([O:33][C:34]1[C:41]([O:42][CH3:43])=[CH:40][C:37]([CH:38]=[O:39])=[C:36]([F:44])[CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>O1CCCC1>[CH2:26]([O:33][C:34]1[C:41]([O:42][CH3:43])=[CH:40][C:37]([CH:38]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)[OH:39])=[C:36]([F:44])[CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(C=O)c(F)cc1OCc1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1OCc1ccccc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (68, 620 mg, 1.5 mmol, prepared as described in Example 22) was dissolved in tetrahydrofuran (15 mL) at −20° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 840 μL) was added to the reaction. The reaction was stirred for 1.5 hours, during which the temperature rose to 5° C. The reaction was cooled to −20° C. 4-Benzyloxy-2-fluoro-5-methoxy-benzaldehyde (83, 250 mg, 0.9606 mmol) in tetrahydrofuran (5.0 mL) was added to the reaction. The reaction was stirred for 2.5 hours during which time the temperature rose to 5° C. The reaction was poured into water. The mixture was extracted with ethyl acetate. The organic layer was dried over an hydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2-25% ethyl acetate in hexane to provide compound as a white solid (84, 501 mg, 63%). MS (ESI) [M+H+]+=535.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[C:21]1([CH2:27][CH2:28][CH:29]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][N:14]([CH2:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Reactant: O=CCCc1ccccc1
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(CCCc1ccccc1)CC2

Procedure:
The title compound (142 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and 3-phenyl-propionaldehyde as in Example 35. MS (ESI): exact mass calculated for C25H30FN3, 391.24; found, m/z 392.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.45-7.41 (m, 2H), 7.35-7.26 (m, 6H), 7.22-7.19 (m, 1H), 4.46 (m, 1H), 3.79-3.76 (m, 1H), 3.67-3.63 (m, 1H), 3.46-3.43 (m, 1H), 3.35-3.29 (m, 5H), 2.90-2.87 (m, 1H), 2.83-2.73 (m, 3H), 2.19-2.12 (m, 2H), 1.44 (t, J=6.7 Hz, 6H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)OCC(C)C.CN1CCOCC1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>O1CCCC1.CN(C)C=O.O>[C:1]1([C:7]#[C:8][C:9]([NH:27][C:28]2[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=2)[O:31][C:32]2[CH:33]=[CH:34][C:35]3[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]4[CH2:46][CH2:45]4)=[O:43])[N:40]=3)[N:37]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)C#Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(C#Cc1ccccc1)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a solution of 3-phenylprop-2-ynoic acid (85 mg, 0.581 mmol) in tetrahydrofuran (3 mL) were added isobutyl chlorocarbonate (76 μL, 0.581 mmol) and 4-methylmorpholine (80 μL, 0.727 mmol) under ice-cooling, a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.484 mmol) in N,N-dimethylformamide (3 mL) was further added thereto, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the precipitated solid was filtrated and washed with water to give the title compound (188 mg, 89%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15](O)=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[N:11][N:10]=[N:9]1.C(Cl)(=O)C(Cl)=O.[CH3:30][NH:31][C:32]([NH2:34])=[O:33].N1C=CC=CC=1.Cl>FC1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:34][C:32]([NH:31][CH3:30])=[O:33])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[N:11][N:10]=[N:9]1
Reactant: CNC(N)=O
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: Fc1ccccc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
A solution of 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionic acid (303 mg, 0.9 mmol) in fluorobenzene (1 mL) and NN-dimethylformamide (3 μL) at 25° C. was treated dropwise with oxalyl chloride (97 μL, 1.09 mmol) over 2-3 min. The clear solution was stirred at 25° C. for 1 h and then treated with methyl urea (201 mg, 2.72 mmol). The resulting suspension was heated at 70° C. (bath temperature) for 10 min and then treated with pyridine (146.6 μL, 1.81 mmol). The reaction mixture was then stirred at 70° C. for 20 h. The reaction mixture was then cooled to 25° C. and diluted with ethyl acetate (30 mL) and a 3N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded 1-{2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionyl}-3-methyl-urea (110 mg, 31%) as a white solid: mp 185-186° C. EI-HRMS m/e calcd for C18H23ClN6O2 (M+H)+ 391.1649, found 391.1659.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[CH2:20][CH3:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=2)[CH2:20][CH3:21])[C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1
Reactant: CCC(Br)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Product: CCC(c1ccc(OC(F)(F)F)cc1)N1C(=O)C(C)CC1c1c(OC)cccc1OC

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with 1-(1-bromopropyl)-4-(trifluoromethoxy)-benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.00 min.; [M+H]+: 438.28 g/mol.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[C:19]=1[CH3:26]>ClCCl>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[C:19]=3[CH3:26])=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Cc1c(N)ccc(O)c1C
Solvent: ClCCl
Product: Cc1c(O)ccc(NC(=O)c2cc(NC3CCCCC3)ncn2)c1C

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-2,3-xylenol (TCI), the title compound was obtained as a white solid after trituration in dichloromethane.