Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:48]=[C:47]([N:49]5[CH2:54][CH2:53][N:52]([CH2:55][C:56]6[CH2:61][CH2:60][C:59]([CH3:63])([CH3:62])[CH2:58][C:57]=6[C:64]6[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=6)[CH2:51][CH2:50]5)[CH:46]=[CH:45][C:21]=4[C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([NH:34][CH2:35][CH:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[C:30]([N+:42]([O-:44])=[O:43])[CH:29]=4)(=[O:27])=[O:26])=[O:23])[C:13]=3[N:12]=[CH:11]2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]3[CH:48]=[C:47]([N:49]4[CH2:50][CH2:51][N:52]([CH2:55][C:56]5[CH2:61][CH2:60][C:59]([CH3:62])([CH3:63])[CH2:58][C:57]=5[C:64]5[CH:65]=[CH:66][C:67]([Cl:70])=[CH:68][CH:69]=5)[CH2:53][CH2:54]4)[CH:46]=[CH:45][C:21]=3[C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([NH:34][CH2:35][CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[C:30]([N+:42]([O-:44])=[O:43])[CH:29]=3)(=[O:27])=[O:26])=[O:23])[C:13]=2[N:12]=[CH:11]1
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2cnc3c(Oc4cc(N5CCN(CC6=C(c7ccc(Cl)cc7)CC(C)(C)CC6)CC5)ccc4C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)cccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4cccc5[nH]cnc45)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 0.5 h

Procedure:
A solution of EXAMPLE 403H (174 mg) and dichloromethane (25 mL) was cooled in an ice bath and 2,2,2-trifluoroacetic acid (25 mL) was added slowly dropwise. The reaction mixture was stirred 30 minutes under nitrogen and the ice bath was removed. The reaction was stirred 18 hours and then concentrated. The crude product was purified by reverse phase chromatography with ammonium acetate buffer in acetonitrile to give the title compound. 1H NMR (400 MHz, pyridine-d5) δ 9.30 (d, 1H), 8.69 (t, 1H), 8.59 (s, 1H), 8.42 (dd, 1H), 7.99 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.26 (m, 1H), 7.18 (m, 1H), 7.06 (d, 2H), 6.94 (d, 1H), 6.72-6.66 (m, 2H), 5.53 (m, 2H), 3.98 (m, 2H), 3.32 (m, 2H), 3.18 (t, 2H), 2.03 (m, 4H), 2.76 (s, 2H), 2.25 (m, 2H), 2.13 (m, 4H), 1.97 (s, 2H), 1.83 (m, 1H), 1.60 (m, 2H), 1.40-1.29 (m, 4H), 0.94 (s, 6H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:20][C:21]1[C:25]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[C:24]([CH3:29])[O:23][N:22]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1noc(C)c1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 95 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), 3,5-dimethylisoxazol-4-ylboronic acid (129 mg, 0.912 mmol), ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (120 mg, 57.7%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:16][C:15]3[CH:14]=[N:13][N:12](COCC[Si](C)(C)C)[C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.COC1C=C(C2SC3C(=NN(COCC[Si](C)(C)C)C=3)C=2)C=CC=1.C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:16][C:15]3[CH:14]=[N:13][NH:12][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cc3c(cnn3COCC[Si](C)(C)C)s2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1cccc(-c2cc3nn(COCC[Si](C)(C)C)cc3s2)c1
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: COc1cccc(-c2cc3[nH]ncc3s2)c1
Temperature: 70 °C
Reaction time: 21.5 h
Yield: 87 %

Procedure:
A portion of this mixture of 5-(3-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-thieno[3,2-c]pyrazole and 5-(3-methoxy-phenyl)-2-(2-trimethylsilanyl-ethoxymethyl)-2H-thieno[3,2-c]pyrazole (4.41 g, 12.2 mmol) and ethylenediamine (2.50 mL, 37.0 mmol) at room temperature under nitrogen was added tetrabutylammonium fluoride (61.0 mL of a 1 M tetrahydrofuran solution, 61.0 mmol) and the resulting solution heated at 70° C. After 21.5 hours, the reaction was cooled to room temperature and the solvent removed in vacuo. Water (150 mL) was added to the residue and the aqueous mixture extracted twice with ethyl acetate (100 mL). The combined extracts were washed with water (75 mL) and brine (75 mL) successively, dried over magnesium sulfate, and concentrated to give 5-(3-methoxy-phenyl)-1H-thieno[3,2-c]pyrazole [2.47 g, 87%, Intermediate (53)] as an off-white solid: TLC Rf 0.45 (silica, ethyl acetate); LC/MS: 231.0 (M+H), RT=3.20 minutes; 1H NMR (300 Mhz, CDCl3) δ 10.65 (br s, 1H), 7.78 (s, 1H), 7.32 (m, 1H), 7.25-7.21 (m, 2H), 7.16 (m, 1H), 6.89 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH2:32]([N:15]1[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:18])[N:13]([C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])[C:14]1=[O:31])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cccc2ccccc12)N1C(=O)N(Cc2ccccc2)C(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (200 mg) was dissolved in DMF (2 mL), benzyl bromide (45 mg) was added, and potassium carbonate (36 mg) was further added. The reaction solution was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. After the solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was recrystallized from IPE to obtain 55 mg of white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=[O:35])[CH2:29][C:30]([O:32]CC)=[O:31])[CH:4]=[N:3]1.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28](=[O:35])[CH2:29][C:30]([OH:32])=[O:31])[CH:4]=[N:3]1
Reactant: CCOC(=O)CC(=O)Nc1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ncc(NC(=O)CC(=O)O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a stirred solution of ethyl 3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropanoate (1.3 g) in tetrahydrofuran (30 ml) was added 1N aqueous sodium hydroxide solution (3.1 ml), and the mixture was stirred at room temperature for 3 hours. Tetrahydrofuran was removed in vacuo and the residue was made acidic with diluted citric acid. The resulting precipitate was collected by filtration and dried under reduced pressure to give 3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropanoic acid (1.22 g).
Reaction SMILES: C(OC(N[C@@H](C(C)C)C(O)=O)=O)(C)(C)C.C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.[NH2:32][C@H:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1.C(OC(=O)NC(C(=O)NC1C2C(=CC=CC=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:75][C:76]([C:78]1([NH:83][C:84]([CH:86]2[CH2:90][CH:89]([O:91][C:92]3[C:101]4[C:96](=[CH:97][C:98]([O:102][CH3:103])=[CH:99][CH:100]=4)[N:95]=[C:94]([C:104]4[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=4)[CH:93]=3)[CH2:88][N:87]2[C:110](=[O:130])[NH:111][CH:112]([C:117](=[O:129])NC2C3C(=CC=CC=3)CC2O)[C:113](C)([CH3:115])[CH3:114])=[O:85])[CH2:80][CH:79]1[CH:81]=[CH2:82])=[O:77])C>>[C@H:33]1([NH:32][C:117]([C@@H:112]([NH:111][C:110]([N:87]2[CH2:88][C@H:89]([O:91][C:92]3[C:101]4[C:96](=[CH:97][C:98]([O:102][CH3:103])=[CH:99][CH:100]=4)[N:95]=[C:94]([C:104]4[CH:105]=[CH:106][CH:107]=[CH:108][CH:109]=4)[CH:93]=3)[CH2:90][C@H:86]2[C:84]([NH:83][C@:78]2([C:76]([OH:77])=[O:75])[CH2:80][C@H:79]2[CH:81]=[CH2:82])=[O:85])=[O:130])[CH:113]([CH3:115])[CH3:114])=[O:129])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Agent: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](C(=O)N[C@@H]1CCc2ccccc21)C(C)C)C(=O)O
Yield: 28 %

Procedure:
(2S)-tert-butoxycarbonylamino-3-methylbutyric acid was attached to the resin as described for the preparation of compound 16 followed by reaction with (1R)-1-aminoindane as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (12.5 mg, 28% yield), Purity by HPLC>90%. M+H+732.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[C:14]([N:18]=[C:19]=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:14]([NH:18][C:19]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)N=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2,6-Dibromopyridine (40 g, 170 mmol) in THF (200 mL) was added dropwise over 1 hr to a cooled (−78 C) solution of n-butyllithium (2.0M in pentane, 85 mL, 170 mmol) in THF (100 mL) under a nitrogen atmosphere. The mixture was allowed to stir for an additional 15 min, then tert-butyl isocyanate was added dropwise over 5 min. The resulting reaction mixture was allowed to warm slowly to room temperature overnight before quenching with saturated ammonium chloride solution (200 mL) and extracting with ethyl acetate (2×100 mL). The combined organics were dried (MgSO4) and evaporated in vacuo to yield the cude product A466.1 (42.4 g) as a dark brown oil which was used immediately without further purification. HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 1.76 min, M+H+=203.08
Reaction SMILES: [Li]CCCC.[C:6]1([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C1C=CC=CN=1)[CH:25]=[O:26]>C1COCC1>[C:6]1([C:12]2[N:13]=[C:14]([CH:25]=[O:26])[O:15][C:16]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C=O)c1ccccn1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
n-BuLi (361 mg, 5.65 mmol) was added to a stirred and cooled (−78° C.) solution of 4,5-diphenyloxazole (500 mg, 2.26 mmol) in dry THF. The stirring was continued for 30 min at −78° C., and N-methyl-N-(pyridin-2-yl)formamide (461 mg, 3.39 mmol) was added. The resulting solution was stirred at −78° C. for 1 h, then quenched with H2O. The mixture was extracted with EtOAc (3×20 mL), and the combined organic extracts were dried (MgSO4) and concentrated. The crude product was purified by column chromatography to afford the desired product 4,5-diphenyloxazole-2-carbaldehyde (372 mg) as an orange oil.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][P:10](=[O:21])([O:16][Si](C)(C)C)[O:11][Si](C)(C)C)(=[O:5])[C:2]([CH3:4])=[CH2:3]>CO>[C:1]([O:6][CH2:7][CH2:8][CH2:9][P:10](=[O:11])([OH:21])[OH:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCCP(=O)(O[Si](C)(C)C)O[Si](C)(C)C
Solvent: CO
Product: C=C(C)C(=O)OCCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Di(trimethylsilyl) 3-methacryloyloxypropylphosphonate (34.0 g; 0.096 moles) was dissolved in methanol (115 ml). The solution was stirred at room temperature for 2 hours. The solvent was vacuum distilled on a rotary evaporator to give 3-methacryloyloxypropyl phosphonic acid as a highly viscous, colorless oil (19.9 g; yield 99%). 1H NMR (DMSO-d6, δ ppm) 1.52-1.66 (m, 2H, CH2—P), 1.74-1.93 (m, 2H, CH2—CH2—P), 1.87 (s, 3H, CH3), 4.12 (t, 2H, CH2—O), 5.66 (s, 1H, CH═), 6.02 (s, 1H, CH═). 31P NMR (DMSO-d6, δ ppm) 27.06.
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[N:24]=[N:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29](O)=[O:30].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH:5][C:6]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([NH:21][C:29]([C:28]3[CH:27]=[C:26]([CH3:32])[N:25]=[N:24][C:23]=3[Cl:22])=[O:30])[CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C1CCN(Cc2cccc(N)c2)CC1
Reactant: Cc1cc(C(=O)O)c(Cl)nn1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cccc(CN3CCC(C(=O)NC(C)(C)C)CC3)c2)c(Cl)nn1

Procedure:
A solution of 1-(3-amino-benzyl)-piperidine-4-carboxylic acid tert-butylamide BB-4 (400 mg, 1.4 mmol) in DCM (15 mL) is treated successively with 3-chloro-6-methyl-pyridazine-4-carboxylic acid (239 mg, 1.4 mmol), EDC (344 mg, 1.8 mmol) and DMAP (25.3 mg, 0.207 mmol) at RT overnight. The reaction mixture is washed twice with sat.aq. NaHCO3 (15 mL). The aqueous phase is extracted twice with DCM (2×10 mL). The combined organic layers are dried over MgSO4 and filtered. The solvent is evaporated under reduced pressure. The residue is purified by prep HPLC E delivering the title compound (53 mg, 36%) as a light brownish powder, LC-MS A: tR=0.60 min; [M+H]+=444.12.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O.[Cl-].[Na+].CN(C)[CH:23]=[O:24]>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:23]=[O:24])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C(C)O)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)Oc1ccc(/C=C/C=O)cc1
Temperature: 0 °C

Procedure:
A solution of 1-(4-isopropyloxy phenyl) ethanol of formula 4 (4.8 g, 27 mmol) in dimethyl formamide (10 ml) is slowly added to phosphorus oxychloride (8 ml) in DMF (12 ml) with stirring at 0° C. The reaction mixture is stirred for 2 hours then allowed attaining room temperature followed by heating on an oil bath for 36 hour at 40° C. After the completion of the reaction as monitored by TLC, contents of the reaction mixture are poured into ice cold water (500 ml), neutralised with dilute alkali solution and saturated by adding sodium chloride. The aqueous portion is extracted with ethyl acetate (3×100 ml), organic layer washed with water, dried over anhydrous sodium sulphate and stripped off the solvent under vacuum to furnish crude product (4.8 g). It was purified by column chromatography over silica gel to yield a semisolid 3-(4-isopropyloxy phenyl)-2E-propenal of formula 3 (80%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19](=O)[CH2:20][C:21](OCC)=[O:22]>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[CH:20]=[C:21]([OH:22])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1Cl
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(Cc3ccccc3Cl)cc2O)c1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 4-(2-chlorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[S:53]1[CH:57]=[CH:56][N:55]=[C:54]1[C:58](Cl)=[O:59]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:58]([C:54]2[S:53][CH:57]=[CH:56][N:55]=2)=[O:59])[CH2:25]1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1nccs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(C(=O)c2nccs2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 1,3-thiazole-2-carbonyl chloride as the starting materials in 66% yield. LCMS for C26H24ClN8O2S (M+H)+: m/z=547.2.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>C1COCC1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:2]([CH3:1])[S:3]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)(=[O:5])=[O:4])=[CH:13][CH:14]=2)([OH:23])[C:19]([F:21])([F:22])[F:20])=[CH:27][CH:26]=1
Reactant: CN(c1ccc(C(=O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CN(c1ccc(C(O)(c2ccc(Cl)cc2)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a solution of 0.2 g of N-methyl-N-(4-trifluoroacetyl-phenyl)-benzenesulfonamide in 10 mL of THF were added 0.7 mL of a 1 M solution 4-chlorophenyl magnesium bromide at −78° C. The resulting mixture was stirred at −78° C. for 4 hr. After this time, the reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 7:1) to give the title compound. 1H-NMR (CDCl3) δ 2.96 (br s, 1 H), 3.17 (s, 3 H), 7.10-7.59 (m, 13 H). Mass Spectrum (CI+) m/e=456 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[N:9][C:8](S(C)=O)=[N:7][C:6]=2[N:5]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:18]=[CH:19][CH:20]=2)[C:4](=[O:26])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[CH3:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([NH:38][C:37]3[CH:36]=[CH:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:40][CH:39]=3)=[N:7][C:6]=2[N:5]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:18]=[CH:19][CH:20]=2)[C:4](=[O:26])[CH:3]=1
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nc32)c1
Temperature: 100 °C
Yield: 19.3 %

Procedure:
A microwave tube was charged with N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 210 mg, 0.57 mmol), 4-(4-methylpiperazino)aniline (136 mg, 0.71 mmol) and DIEA (0.20 mL, 1.14 mmol) in tert-butanol (5.5 mL). The tube was sealed and the mixture was heated to 100° C. for 3 d. The mixture was concentrated and then the brown solid was suspended in Et2O and collected by filtration. The brown solid was washed with Et2O to afford 270 mg of crude material. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0-20% MeOH in DCM. This enriched product was repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were combined and concentrated. A saturated solution of aqueous NaHCO3 was added and the mixture was extracted with 3:1 CHCl3/IPA (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to provide N-(3-(5-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (52 mg, 0.11 mmol, 18% yield) as a yellow solid. m/z (ESI, +ve ion) 496.1 (M+H)+. NMR (400 MHz, DMSO-d6) δ ppm 10.35 (1H, s), 8.82 (1H, s), 7.93 (1H, d, J=8.61 Hz), 7.57-7.56 (1H, m), 7.53 (1H, t, J=8.12 Hz), 7.17-7.19 (2H, m), 6.95-7.02 (1H, m), 6.53-6.56 (1H, m), 6.37-6.48 (1H, m), 6.31 (1H, d, J=0.39 Hz), 6.21-6.28 (1H, m), 5.72-5.80 (1H, m), 2.91-3.02 (4H, m), 2.46 (3H, s), 2.39-2.44 (4H, m) 2.21 (3H, s).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:21]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)=O>>[F:20][C:17]([F:18])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:21][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: N#Cc1ccc(C=O)cc1
Product: N#Cc1ccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-formylbenzonitrile was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,4-diazepan-1-yl]methyl]benzonitrile.