Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31].CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC>C(Cl)Cl>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[C:27]([F:26])([F:37])[F:38])[CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(NC2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 36 %

Procedure:
A mixture of 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) (0.100 g, 0.275 mmol), 2-(trifluoromethyl)benzoyl chloride (0.049 ml, 0.330 mmol) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (0.600 g, 1.376 mmol) in DCM (2 ml) was stirred at rt for 17 h. The mixture was filtered, evaporated to dryness and the residue was purified by preparative HPLC to give the title compound (0.053 g, 36%). 1H NMR (500 MHz CDCl3): δ 7.68 (t, 1H), 7.61-7.42 (m, 6 h), 7.26 (d, 1H), 7.18 (d, 1H), 5.21 (d, 1H), 4.61-4.46 (m, 1 h), 3.24-3.10 (m, 2H), 2.54-2.38 (m, 2H), 1.88-1.78 (m, 1H), 1.76-1.48 (10H), 1.44-1.32 (m, 1H), 1.26-1.10 (m, 1H); 13C NMR (125 MHz CDCl3): δ 167.4, 167.3, 159.8, 159.7, 134.8, 133.9, 133.8, 132.5, 132.3, 131.9, 131.7, 130.4, 130.2, 129.5, 129.0, 128.9, 127.3, 127.0, 126.9, 125.3, 125.1, 107.8, 107.5, 61.9, 50.3, 50.1, 45.7, 45.5, 41.2, 40.3, 40.1, 32.5, 32.1, 31.9, 31.8, 27.8; Mass Spectrum: M−H+ 534
Reaction SMILES: [N:1]1[O:2][C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#N)=[CH:12][CH:11]=2)=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[OH2:19].[OH-:20].[Na+]>C(O)C>[N:1]1[O:2][C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:20])=[O:19])=[CH:12][CH:11]=2)=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N#CCc1ccc(-c2onc3ccccc23)cc1
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1ccc(-c2onc3ccccc23)cc1
Yield: 54 %

Procedure:
A solution of 3.6 g (0.015 mole) of 4-(2,1-benzisoxazol-3-yl)benzeneacetonitrile in 75 ml of ethanol and 10 ml of 20% sodium hydroxide was heated at reflux under a nitrogen atmosphere overnight. The dark solution was cooled and poured into 600 ml of water. The solution was filtered and the filtrate was treated with charcoal. The mixture was filtered through Celite and the filtrate pH was adjusted to 7. The mixture was again filtered and the filtrate was made acidic with concentrated hydrochloric acid. The solid which precipitated was collected by filtration, washed with water, dried, and recrystallized from 2-propanol to yield 2.1 g (54%) of tan powder, m.p. 179°-181° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O:34]C)=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([C@H:36]([CH3:39])[CH2:37][CH3:38])[O:11][N:10]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([C@H:36]([CH3:39])[CH2:37][CH3:38])[O:11][N:10]=1
Reactant: CC[C@@H](C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)OC)ccc3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H](C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To a solution of methyl 6-{4-[({3-(2,6-dichlorophenyl)-5-[(1R)-1-methylpropyl]-4-isoxazolyl}methyl)oxy]phenyl}-2-quinolinecarboxylate (50 mg, 0.089 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.13 mL, 0.13 mmol). The solution was heated in a microwave reactor at 80° C. for 10 minutes and then 1 N hydrochloric acid (0.13 mL, 0.13 mmol) was added. The solution was concentrated and the residue was taken up with ethyl acetate and water. The layers were separated and the organic layer was dried over magnesium sulfate and concentrated to afford 6-{4-[({3-(2,6-dichlorophenyl)-5-[(1R)-1-methylpropyl]-4-isoxazolyl}methyl)oxy]phenyl}-2-quinolinecarboxylic acid (45 mg, 92%). 1H-NMR (400 MHz, DMSO-d6) δ 13.37 (br s, 1H), 8.53 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.18-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.63-7.51 (m, 3H), 6.99 (d, J=9 Hz, 2H), 4.88 (app q, J=12 Hz, 2H), 3.31-3.22 (m, 1H), 1.73-1.66 (m, 2H), 3.32 (d, J=7 Hz, 3H), 0.83 (t, J=7 Hz, 3H). HRMS (ESI) C30H24Cl2N2O4 calculated: 547.1186 (M+H)+, found: 547.1186 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[C:4]2=[CH:14][S:15][CH:16]=[C:3]12.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>N1C=CC=CC=1>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:18])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Solvent: c1ccncc1
Product: CN1c2ccccc2NC(=S)c2cscc21
Reaction time: 18 h

Procedure:
A mixture of 0.4 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 0.5 g. of phosphorus pentasulfide in 5 ml. of dry pyridine is stirred and heated under reflux for 4 hours. The reaction mixture is concentrated to dryness and the residue is stirred with 10 ml. of 1N sodium carbonate solution for 18 hours. The precipitate is collected, washed with water and recrystallized from methanol to give gold crystals, m.p. 203°-204° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16].BrC[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[CH3:29]N(C=O)C>>[C:24]([CH:23]([CH3:22])[CH2:29][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16])([O:26][CH2:27][CH3:28])=[O:25]
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccccc1O
Reactant: CN(C)C=O
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)COc1ccccc1-c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A dispersion of 780 mg (17.7 mmol) of 60% sodium hydride in mineral oil and 10 ml of DMF is treated, dropwise, with a solution of 2.00 g (8.8 mmol) of 5-(2-hydroxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridine carbonitrile in 20 ml of DMF. The reaction is stirred 30 min at RT, then cooled in an ice bath and 1.72 g (8.8 mmol) of ethyl 4-bromobutyrate in 10 ml of DMF is added dropwise. The reaction is allowed to slowly come to RT and stirred overnight under N2. The mixture is then concentrated under vacuum, the residue taken up in 80 ml of water, and extracted with EtOAc (2×25 ml). The aqueous phase is acidified to pH=5 with 10% HCl and extracted with EtOAc (4×80 ml). The EtOAc extracts are dried (MgSO4) and the solvent removed to leave an orange oil. This oil is crystallized from EtOAc-hexane to give 1.61 g of 5-(2-carboethoxypropyloxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile as a light yellow solid, m.p. 167°-170° C. Yield, 54%. 1H-NMR (d6 -DMSO): 1.18 (t,3H); 1.88 (m,2H); 2.10 (s, 3H); 2.37 (t, 2H); 3.97 (q,2H); 7.00 (t,2H); 7.10 (d,1H); 7.20 (d,1H); 7.40 (t,1H); 7.97 (s,1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21](=O)[CH3:22].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:28][O:27][C:25]([CH2:24][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH:21]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:22])=[C:13]([Cl:12])[CH:14]=1)=[O:26]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)c(Cl)c1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)c(Cl)c1
Yield: 9.7 %

Procedure:
Following a procedure similar to that described in Example 6, but using 5.15 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 10.3 g of methyl 3-chloro-4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 19), 200 ml of benzene, 100 ml of absolute methanol and 6 g of sodium cyanoborohydride, 1.2 g of the title compound were obtained as crystals, melting at 83°-103° C. (after recrystallization from a mixture of ethyl acetate and hexane).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:8]2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.[OH:25][C:26]1([C:32]([OH:34])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[CH3:35][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:35][O:33][C:32]([C:26]1([OH:25])[CH2:31][CH2:30][N:29]([C:4]2[N:3]=[CH:2][N:10]=[C:9]3[C:5]=2[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:8]3[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:28][CH2:27]1)=[O:34]
Reactant: O=C(O)C1(O)CCNCC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3cnc(Cl)nc32)cc1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C1(O)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reaction time: 1 h

Procedure:
Chloro-9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purine I-(4A-7)c (59 mg, 0.16 mmol) and 4-hydroxy-piperidine-4-carboxylic acid (22 mg, 0.14 mmol) were coupled by the general method of Example 19. The crude product (ESI MS (M+1) 484) was dissolved in 1:1 methanol/benzene (0.6 ml) and then treated with trimethylsilyldiazomethane (2 M in hexanes, 0.17 ml, 0.34 mmol). After stirring for 1 hour the reaction was concentrated under a stream of nitrogen and then purified by preparative TLC using 4% methanol in methylene chloride to give title compound 23A-1 (31 mg, 44%). An ether/methylene chloride solution of the material was treated with excess 1 M HCl in ether, concentrated under a stream of nitrogen, and then triturated from ether to give the hydrochloride salt of compound 23A-1 (27 mg, 36% overall) as a light tan solid: +ESI MS (M+1) 498.1; 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 7.62–7.59 (m, 1H), 7.51–7.40 (m, 5H), 7.34 (d, J=8.7 Hz, 2H), 3.90 (v br s, 2H), 3.75 (s, 3H), 2.25 (td, J=13.1, 4.1 Hz, 2H), 1.97 (br d, J=12.4 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](OCC)C.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[CH3:23][O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of the compound (1.15 g) obtained in Example 63, diethyl ether (6 ml) and methanol (14 ml), a solution of trimethylsilyldiazomethane in n-hexane (2.0 M, 7.4 ml) was added and the resulting mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to give the titled compound quantitatively.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:7]=1
Reactant: Oc1cnc(Br)cn1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1cc(Br)ncc1=O
Reaction time: 0.25 h

Procedure:
5-Bromopyrazin-2-ol (1.209 g, 6.91 mmol) was dissolved in DMF (10.0 mL) and sodium hydride (60% in mineral, 530 mg, 13.25 mmol) was added. The reaction flask was put in a water bath and stirred under argon for 15 minutes, and then (2-bromoethoxy)(tert-butyl)dimethylsilane (1.69 mL, 7.93 mmol) was added as a solution in DMF (4.7 mL total volume), followed by a ˜0.5 mL rinse with DMF. The reaction was stirred under argon at room temperature for 2 days. It was then quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The organic extracts were combined, washed with water (4×50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The material was taken on crude to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Clc1ccn2c(I)cnc2c1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Yield: 97 %

Procedure:
To a round bottomed flask add 7-chloro-3-iodo-imidazo[1,2-a]pyridine (3.0 g, 0.011 mol), add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.6 g, 1.1 equiv.), potassium carbonate (4.5 g, 3 equiv.), dioxane (40 mL), and water (20 mL). Deoxygenate this mixture thoroughly with N2 then add dichlorobis(triphenylphosphine)palladium (II) (0.23 g, 0.03 equiv.) and reflux the reaction overnight under N2. Concentrate the reaction to dryness and slurry in DCM. Filter this slurry thru Celite® and wash with DCM. Concentrate the filtrate then purify by silica plug (EtOAc to 5% MeOH: DCM to 10% MeOH: DCM) to give a pale grey solid (2.6 g, 100%). MS (ES), m/z 244 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[OH:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>CN(C)C=O>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:18][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:20][CH:21]=1
Reactant: CC(C)CCCC(C)CCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCC(C)CCCC(C)C)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
Under an argon atmosphere, potassium carbonate (12.5 g, 90.3 mmol) was suspended in anhydrous N,N-dimethylformamide (100 ml), 1-bromo-3,7-dimethyloctane (13.3 g, 60.1 mmol) and methyl (4-hydroxy)benzoate (8.74 g, 57.4 mmol) were added, and the mixture was stirred at 70° C. for 16 hr. The reaction mixture was filtered to remove potassium carbonate. Water (50 ml) was added and the mixture was extracted with hexane (250 ml). The extract was washed successively with 1.0 mol/l aqueous hydrochloric acid solution (100 ml), aqueous sodium hydrogen carbonate solution (100 ml) and saturated brine (100 ml). The obtained organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (16.1 g, 95.7%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]3[C:19]=2[CH3:20])=[CH:4][C:3]=1[OH:21].[CH3:22][N:23]=[C:24]=[O:25].C(OCC)(=O)C>O1CCCC1.CO>[CH3:20][C:19]1[N:13]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]2=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:24]([NH:23][CH3:22])=[O:25])=[C:3]([OH:21])[CH:4]=1
Reactant: CN=C=O
Reactant: Cc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)Nc1ccc(CCc2nc3cc(C)ccn3c2C)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (2.5 g) and methyl isocyanate (0.6 ml) in tetrahydrofuran (25 ml) and methanol (2.5 ml) was stirred for 1 hour at ambient temperature. To the reaction mixture was added ethyl acetate (30 ml) and the precipitate was collected by filtration. The precipitate was washed with ethyl acetate and dried to give 3,7-dimethyl-2-[2-{3-hydroxy-4-(3-methylureido)phenyl}ethyl]imidazo[1,2-a]pyridine (2.92 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH:11]=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
To a solution of Intermediate AW (N-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (50 mg, 0.1 mmol)) in THF at −78° C. under N2 was added DIBAL-H (0.5 ml, 0.5 mmol). The reaction mixture was stirred for 30 min. and was allowed to warm up to 0° C. The reaction was diluted with ethyl acetate (5 mL) and quenched with aqueous saturated Rochelle's salt (5 ml). The reaction mixture was stirred for 10 min at 0° C. and then warmed to rt. The organic layer was collected and washed with aqueous Rochelle's salt (2×), dried (Na2SO4) and concentrated. The crude concentrate was purified via column chromatography (5:95, v/v MeOH—CH2Cl2) to afford 25 mg of the title compound (yield 49%). 1H-NMR (DMSO-d6) δ9.32 (s, 1H), 8.96 (d, J=3 Hz, 1H), 8.63 (d, J=5 Hz, 1H), 7.90 (s, 1H), 7.58 (d, J=7 Hz, 2H), 7.50 to 7.32 (m, 3H), 5.0 (t, J=5 Hz, 1H), 4.79 (d, J=5 Hz, 2H), 4.30 (s, 3H), 3.16 (s, 2H) ppm; MS [M+H]+=505.1; LCMS RT=2.66 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1>C(OCC)(=O)C.C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(N)cc2F)CC1
Yield: 92.6 %

Procedure:
A solution of 1-(2-fluoro-4-nitrophenyl)-4-methylpiperazine (5.00 g, 20.9 mmol) (from Step A above) and 10% palladium-on-carbon (0.20 g, 0.2 mmol) in ethyl acetate (100 mL) and ethanol (50 mL) was hydrogenated at 50 psi in a Parr shaker for 4 h. The mixture was filtered through Celite™. The Celite™ was washed with ethyl acetate (50 mL) and the solvent was evaporated to give 3-fluoro-4-(4-methyl-1-piperazinyl)benzenamine as a white solid (4.05 g, 93%, mp 89–91° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#N)=[CH:4][CH:3]=1.[OH-:18].[Na+].[OH2:20].Cl>C(O)CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]([OH:20])=[O:18])=[CH:4][CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: N#Cc1ccccc1CCc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: OCCO
Product: O=C(O)c1ccccc1CCc1ccc(F)cc1

Procedure:
A mixture of 2-[2-(4-fluorophenyl)ethyl]benzonitrile (8.03 g, 35.6 mmol, 1 equiv) and aq. NaOH (10N; 16 mL, 160 mmol, 4.5 equiv) in ethylene glycol (100 mL) was heated to 190 C for 69 h. After allowing the reaction mixture to cool, H2O (300 mL) was added, followed by 12N HCl (16 mL). This mixture was extracted with CHCl3 (1×100 mL) and the organic layer was then washed with H2O (2×50 mL). The organic layer was dried (anh. Na2SO4) and rotary evaporated (90° C.). This provided 7.44 g (85.4%) of a light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:20][CH2:21][C:22]#[N:23])[CH2:9][CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.S(C)C.CO>C1COCC1>[NH2:23][CH2:22][CH2:21][O:20][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16]
Reactant: CN(CCC(OCC#N)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CN(CCC(OCCN)c1cccc(Cl)c1)C(=O)OC(C)(C)C

Procedure:
A solution of tert-butyl 3-(3-chlorophenyl)-3-(cyanomethoxy)propyl(methyl)carbamate (3 g, 8.9 mmol) in THF (50 mL) was heated to reflux and BH3.Me2S was added drop wise. The reaction mixture was heated to reflux overnight. MeOH was added to the mixture at −15° C. The solution was removed in vacuo to give the crude product, which was used for the next step without purification.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.CCCCCC.[CH3:33][O:34][C:35]1[C:40]([CH:41]=O)=[CH:39][N:38]=[C:37]2[N:43]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:44]=[CH:45][C:36]=12>C1COCC1>[CH3:33][O:34][C:35]1[C:40]([CH:41]=[CH2:2])=[CH:39][N:38]=[C:37]2[N:43]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:44]=[CH:45][C:36]=12
Reactant: COc1c(C=O)cnc2c1ccn2COCC[Si](C)(C)C
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1cnc2c(ccn2COCC[Si](C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
To a solution methyltriphenylphosphonium iodide (782 mg, 1.93 mmol) in dried THF (5 mL) was added 2.5 M n-BuLi in Hexane (0.74 mL, 1.85 mmol) at −78° C. After 10 minutes, 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (493 mg, 1.61 mmol) was added to the reaction mixture. The reaction mixture was warmed to room temperature spontaneously. After 2 hours, the reaction mixture was quenched with water and was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (5% to 15% Ethyl acetate/Hexane) as a solvent to afford title compound (371 mg, 76% yield). 1H NMR (600 MHz, CDCl3) δ 8.40 (s, 1H), 7.27 (d, J=3.6 Hz, 1H), 7.07 (dd, J=11.4, 18 Hz, 1H), 6.78 (d, J=3.6 Hz, 1H), 5.78 (d, J=18 Hz, 1H), 5.70 (s, 2H), 5.30 (d, J=11.4 Hz, 1H), 4.38 (s, 3H), 3.60 (t, J=8.4 Hz, 2H), 0.97 (t, J=8.4 Hz, 2H), 0 (s, 9H). MS m/z: 305 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:12](=O)C(Cl)=C(Cl)[C:15](=O)[C:16]=1Cl.Cl.CC(C=C)=O>CCO.O1CCCC1>[ClH:10].[C:6]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[CH:12][CH:11]=[C:16]2[CH3:15])#[N:7]
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: N#Cc1ccc(N)cc1
Agent: C=CC(C)=O
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccnc2ccc(C#N)cc12
Temperature: 75 °C
Reaction time: 0.06 h
Yield: 82.55 %

Procedure:
Add 95% ethanol (EtOH) (270 L, 9 vol.), 4-aminobenzonitrile (30.0 kg, 1 equiv) and 2,3,5,6-tetrachloro-2,5-cyclohexadiene-1,4-dione, (66.81 kg 1.07 equiv) to a 200 gallon reaction vessel equipped with nitrogen purge, condenser, thermocouple, and overhead agitation. Stir for 2-5 min, then add concentrated hydrochloric acid (HCl) (62.56 L, 3.0 equiv), then heat to 75° C. Dilute methyl vinylketone (33.06 L, 1.5 equiv) in 95% EtOH (30 L, 1 vol.) then add slowly to reaction mixture over 30 min. Monitor for reaction completion by high performance liquid chromatography (HPLC). Add tetrahydrofuran (THF) (11 vol., 330 L), at 75° C., then stir for 1 hour at 60° C. Cool to room temperature and stir for 1 additional hour. Filter on agitated filter/dryer, then rinse with THF (240 L, 8 volumes). Dry overnight under vacuum at 70° C. to give the title compound (42.9 kg, 82.55%).