Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH:2]=1.[H][H]>CCO.C(O)(=O)C.[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH2:2]1
Reactant: [H][H]
Reactant: CCOP(=O)(OCC)c1cccnc1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOP(=O)(OCC)C1CCCNC1

Procedure:
Diethyl pyridin-3-ylphosphonate was dissolved in EtOH-acetic acid, to which platinum oxide was added, for stirring under 3.4 kgf/cm2 hydrogen for 120 hours, to obtain diethyl piperidin-3-ylphosphonate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[N:3]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28]>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:36](=[O:37])[CH2:35][NH:34][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[N:3]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(CO)cc2)nc(N)n1
Solvent: ClCCl
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)CNC(=O)OC(C)(C)C)cc2)nc(N)n1
Reaction time: 6 h

Procedure:
To a stirred suspension of the title compound of Example 44 (0.400 g, 1.08 mmol), N-(tert-butoxycarbonyl)-glycine (0.227 g, 1.29 mmol) and 4-dimethyl-amino-pyridine (0.184 g, 1.51 mmol) in dichloromethane (20 ml) was added 1-[3-(dimethyl-amine)-propyl]-3-ethyl carboduimide (0.282 g, 1.51 mmol). After stirring for 6 hours, the mixture was purified by flash chromatography on silica gel eluting in ethyl acetate-hexane (2:3) to provide tert-butoxycarbonylamino-acetic acid 4-[2-amino-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzyl ester.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([NH:29][C:30]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[O:31])[CH:23]=[CH:22]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([NH:29][C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[O:31])[CH:23]=[CH:22]4)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cc(-c3ccc4cc[nH]c4c3)ccc2c1)c1ccsc1
Temperature: 25 °C
Yield: 22 %

Procedure:
6-bromo-1H-indole (28.8 mg, 0.147 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (109.2 mg, 0.288 mmol), Fibercat palladium catalyst (Johnson-Matthey, 55.5 mg), and K2CO3 (2 M in water, 0.50 ml, 1.0 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.5 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (10 ml; 2×5 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified via HPLC (10%->95% MeCN/water with 0.1% TFA), silica gel (4:1->3:1->2:1->1:1 hexanes/EtOAc) to afford crude product. This crude material was then purified again via HPLC (same conditions as above) to afford title compound (11.9 mg, 22%). MS (ESI pos. ion) m/z: 369 (M+H). Calc'd Exact Mass for C23H16N2OS: 368.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:1]1([C:7]2([C:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[CH2:8][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: O=C(O)C1(c2ccccc2)CC1
Product: O=C(N1CCCC1)C1(c2ccccc2)CC1

Procedure:
The title compound was prepared from 1-phenylcyclopropanecarboxylic acid and pyrrolidine using a similar procedure to that described for Description 8.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH2:17][CH2:18]O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]1(=[O:55])[NH:49][C:48](=[O:50])[C:47]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]12>C1COCC1>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:49]3[C:45](=[O:55])[C:46]4[C:47](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:48]3=[O:50])[CH2:12][CH2:13]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 15 °C

Procedure:
40 g (−118 mmol) 2-[2-(4-diphenylmethyl-piperazin-1-yl)-ethoxy]-ethanol, 31.1 g (119 mmol) triphenylphosphine and 17.3 g (118 mmol) phthalimide are suspended in 200 ml THF and 24.2 ml (119 mmol) are azodicarbonic acid diethyl ester are added dropwise under protective atmosphere and light cooling (to Ca. 15° C.). The mixture is stirred without further cooling for three hours and subsequently, the solvent is removed under vacuum. The residue is taken up in 1N HCl and washed twice each with 50 ml acetic acid ethyl ester respectively. The aqueous phase is neutralized with ca. 50 g sodium hydrogen carbonate and extracted four times each with 125 ml chloroform. The combined chloroform phases are dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (99/1 to 90/10): Yield 11 g (19%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[N:13][C:14]=1[CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl-].[CH3:31][O:32][CH2:33]OCOC.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[N:13][C:12]([C:18]([O:27][CH2:31][O:32][CH3:33])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:20])[F:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nc(C(O)(C(F)(F)F)C(F)(F)F)ccc1OCc1ccccc1
Reactant: COCOCOC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 67.9 %

Procedure:
2-(5-(Benzyloxy)-6-propylpyridin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (537 mg, 1.37 mmol) was dissolved in N,N′-dimethylformamide (2.5 mL) and added with sodium hydride (purity 50%) (79 mg, 1.64 mmol) and methoxymethyl ether chloride (113 μL, 1.50 mmol) under ice-cold conditions The resultant mixture was stirred under ice-cold conditions for 1.5 hours and then further stirred at room temperature for 45 minutes. After completion of the reaction, the reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 3-(benzyloxy)-6-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylpyridine (407 mg, yield 68%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8]#[C:9][CH:10]([OH:13])[CH2:11][CH3:12]>C(N(CC)CC)C.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.CSC.[Cu]Br>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:8]#[C:9][CH:10]([OH:13])[CH2:11][CH3:12])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CC(O)CC
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CSC
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1cccnc1
Temperature: 70 °C
Yield: 100.1 %

Procedure:
To a solution of 3-bromopyridine (12.0 g, 75.6 mmol) and 1-pentyn-3-ol (7.0 mL, 83.2 mmol) in triethylamine (150 mL) were added Pd(PPh3)4 (88 mg, 0.076 mmol) and copper(I) bromide dimethylsulfide (31 mg, 0.15 mmol). The mixture was heated at 70° C. for 5 hr, cooled to room temperature and filtered. The filter cake was washed with EtOAc (30 mL). The combined filtrate was concentrated to give 1-(3-pyridinyl)-1-pentyn-3-ol (12.2 g, 99%) as a dark oil.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:15]([Cl:23])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>N1C=CC=CC=1>[ClH:23].[C:15]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Oc1ccccc1C1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1C1CCCCC1)c1cccnc1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
15 g (85 mmol) of o-cyclohexylphenol and 16.5 g (93 mmol) of nicotinic acid chloride hydrochloride was mixed with 200 ml of dry pyridine and stirred for 24 hours at 30° C. After cooling precipitated pyridine hydrochloride was sucked off and 300 ml of water added. The precipitated raw product was washed with two 200 ml portions of water, dissolved in alcohol and reduced by means of a rotary evaporator. The remaining viscous oil was dissolved in 500 ml of dry ether and hydrochlorinated with HCl gas. Subsequently, the mixture was filtered, washed with ether and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([C:15]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=O)[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[CH3:28][Si:29]([CH3:38])([CH3:37])[CH2:30][CH2:31][O:32][C:33]([NH:35][NH2:36])=[O:34].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:36]([NH:35][C:33]([O:32][CH2:31][CH2:30][Si:29]([CH3:38])([CH3:37])[CH3:28])=[O:34])[C:15]=1[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[O:27])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(=O)c1cccc2ccccc12
Reactant: C[Si](C)(C)CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)n(NC(=O)OCC[Si](C)(C)C)c1-c1cccc2ccccc12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A solution of 2-(Naphthalene-1-carbonyl)-4-oxo-4-phenyl-butyric acid ethyl ester (1 g, 2.77 mmol) in toluene (6.5 mL) was treated with Hydrazinecarboxylic acid 2-trimethylsilanyl-ethyl ester (599 mg, 3.34 mmol) and p-toluene sulfonic acid (33 mg). The resulting solution was heated to reflux, with the azeotropic removal of water (Dean Stark trap), under Ar for 6 h, cooled to rt and concentrated in vacuo to afford 2-Naphthalen-1-yl-5-phenyl-1-(2-trimethylsilanyl-ethoxycarbonylamino)-1H-pyrrole-3-carboxylic acid ethyl ester (1.33 g), which was not purified, but used immediately in the next reaction.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6].[OH-].[Na+].I[CH3:22]>CN(C=O)C>[CH3:22][O:1][CH2:2][C@H:3]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CI
Reactant: Cc1ccc(C(=O)N[C@@H](CO)CC(C)C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC[C@@H](CC(C)C)NC(=O)c1ccc(C)c(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of (R)—N-(1-hydroxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide (1.59 g, 6.39 mmol) (example 71a) in dry DMF (20 mL) was added powdered NaOH (281 mg, 7 mmol) an the solution was stirred at 0° C. for 2 hrs. Iodomethane (1 eq, 6.39 mmol) was added in DMF (10 ml) drop-wise over period of 1 hr. The temperature was kept at 0° C. and the mixture was stirred for 1 hr. The reaction was quenched by adding 300 ml of water. The aqueous layer was extracted with dichloromethane, dried over MgSO4 and evaporated. The residue was purified by flash chromatography on silica-gel (toluene-ethyl acetate; 5-20% gradient) to give 1.23 g (R)—N-(1-methoxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide (73%). 1H NMR (500 MHz, CDCl3): δ 0.94-0.97 (t, 6H), 1.41-1.47 (M, 1H), 1.54-1.60 (m, 1H), 1.64-1.68 (m, 1H), 2.29 (d, 6H), 3.36 (s, 3H), 3.45-3.50 (m, 2H), 4.34-4.39 (m, 1H), 6.23-6.25 (d, 1H), 7.16-7.17 (d, 1H), 7.47-7.49 (dd, 1H), 7.56 (s, 1H). MS (M+H, 264.3)
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:7][CH:6]=2.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:55])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:55][CH2:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:7][CH:6]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2 g, 4.72 mmol), benzoyl peroxide (0.114 g, 0.472 mmol) and NBS (1.093 g, 6.14 mmol) was suspended in carbon tetrachloride (31.5 mL) and heated to reflux for 4 h. Additional benzoyl peroxide (0.571 g, 2.36 mmol) was added, and the mixture was stirred at 100° C. for 24 h. Additional benzoyl peroxide (0.571 g, 2.36 mmol) was added, and the mixture stirred for 3 h. Additional benzoyl peroxide (0.571 g, 2.36 mmol) and NBS (0.250 g, 1.42 mmol) were added, and the mixture was heated for 2.5 h. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to afford methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 502.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)O

Procedure:
Methyl 4-(3-chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxylate (2.26 g), 2N aqueous sodium hydroxide (20 ml), methanol (20 ml) and tetrahydrofuran (20 ml) were stirred together at room temperature for 1 hour. After adding 5N aqueous hydrochloric acid and distilling off 10 ml of the organic solvent, the precipitated solid was filtered out. The solid was washed with a methanol and water mixed solvent to obtain 2.0 g of the target substance as a faint red powder.
Reaction SMILES: [C:1]([C:8]1[CH:20]=[C:19]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][C:17]=3[CH2:18]2)=[CH:10][CH:9]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Cl)Cl.[C:31](#[N:34])[CH:32]=[CH2:33]>CO>[C:31]([CH2:32][CH2:33][C:18]1([CH2:33][CH2:32][C:31]#[N:34])[C:17]2[CH:16]=[C:15]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:14]=[CH:13][C:12]=2[C:11]2[C:19]1=[CH:20][C:8]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][CH:10]=2)#[N:34]
Reactant: C=CC#N
Reactant: CCCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCCC)ccc1-2
Solvent: CO
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc2c(c1)C(CCC#N)(CCC#N)c1cc(C(=O)CCCCC)ccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A 3-neck 250-mL round bottom flask was equipped with a condenser, a nitrogen inlet, an addition funnel, and a magnetic stir bar. The flask was then charged with 14.50 g of 1-(7-hexanoyl-9H-fluoren-2-yl)-hexan-1-one and 80 mL of methylene chloride. TRITON B (0.80 g, 40% methanol solution) was then added, followed by the drop wise addition of acrylonitrile (4.67 g) at a rate that kept the reaction temperature below 35° C. The reaction was then stirred at ambient temperature for three hours. The solvent was then removed under reduced pressure and the resulting solid was crystallized from ethanol to give 12.60 g of the title compound. 1H NMR (CDCl3, 300 MHz) δ 8.11-8.03 (m, 4H), 7.89 (m, 2H), 3.04 (m, 4H), 2.55 (m, 4H), 1.81 (m, 4H), 1.56 (m, 4H), 1.44-1.38 (m, 8H), 0.94 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][C:34](=[O:38])[CH2:33]1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH2:33][C:34]3=[O:38])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]1=2
Reactant: O=C1CN(CCc2ccccn2)CCN1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccn5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 19.6 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (200 mg, 0.528 mmol) and 4-(2-(pyridin-2-yl)ethyl)piperazin-2-one (118 mg, 0.576 mmol) were reacted following the procedure for Example 53 (step b) to provide the title compound (52 mg, 20%) as a white solid: ESI MS m/z 504 [M+H]−.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:29])[CH:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=2)[CH:19]=1)[CH3:17].C(N(CC)CC)C>CC(C)=O>[CH3:13][O:14][C:15](=[O:29])[CH:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:28][C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=2)[CH:19]=1)[CH3:17]
Reactant: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)C(C)c1ccc2cc(OC(=O)COCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
Benzyloxy acetyl chloride (24 gm, 86.95 mmol) was added drop-wise to a mixture of 2-(6-Hydroxynaphthalen-2-yl)-propionic acid methyl ester 6 (20 g, 86.95 mmol) and triethylamine (22.5 g, 222.35 mmol) in acetone (300 ml) and stirred for 2 hrs at room temp. Solids were filtered off, acetone distilled off, and water (100 ml) added. Crude 99 was extracted into chloroform, washed with 5% sodium bicarbonate (2×50 ml), water (2×50 ml), dried over sodium sulphate and distilled. Crude 99 was purified by recrystallising in chloroform:hexane (1:6) to get pure 99 (21 g, 63.9%) as a white powder. M.p: 58-60° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[NH:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:13][C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH:33][C:34](=O)[O:35]C(C)=C.CN1CCCC1>O1CCOCC1.C(OCC)(=O)C>[F:13][C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH:33][C:34]([NH:1][C:2]1[C:3](=[O:12])[NH:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)=[O:35]
Reactant: Nc1cc(C(F)(F)F)c[nH]c1=O
Reactant: C=C(C)OC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)cc1F
Agent: CN1CCCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)c[nH]c4=O)c(F)c3)ccn2)cn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 57.6 %

Procedure:
3-Amino-5-(trifluoromethyl)pyridin-2(1H)-one (44 mg, 0.247 mmol), prop-1-en-2-yl 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamate from Example 21 (85 mg, 0.231 mmol) and N-methylpyrrolidine (7.5 mg, 0.088 mmol) were combined in 1,4-dioxane (0.8 mL). The resultant mixture was heated to 80° C. After 13 h, the mixture was cooled to RT and diluted with ethyl acetate (3 mL). The resultant precipitate was collected by filtration, washed with ethyl acetate and dried in vacuo to provide 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)urea as an off-white solid (65 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.47 (s, 1 H), 9.56 (s, 1 H), 9.35 (s, 1 H), 8.36 (d, J=5.3 Hz, 1 H), 8.25 (br s, 2 H), 8.17 (t, J=9.4 Hz, 1 H), 7.96 (s, 1 H), 7.59 (s, 1 H), 7.25-7.22 (m, 2 H), 7.00 (d, J=8.5 Hz, 1 H), 6.68 (m, 1 H), 3.84 (s 3 H); MS (ESI) m/z: 489.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:29]([N:36]1[C:44]2[CH:43]=[CH:42][C:41]([Cl:45])=[C:40]([NH2:46])[C:39]=2[C:38]([CH2:47][CH3:48])=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:29]([N:36]1[C:44]2[C:39](=[C:40]([NH:46][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[C:41]([Cl:45])=[CH:42][CH:43]=2)[C:38]([CH2:47][CH3:48])=[N:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCc1nn(Cc2ccccc2)c2ccc(Cl)c(N)c12
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nn(Cc2ccccc2)c2ccc(Cl)c(NC(=O)c3cnc4cc(OCCOC)ccn34)c12
Temperature: 25 °C
Yield: 37.5 %

Procedure:
To a magnetically stirred, ice cooled, suspension of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (6.76 mg, 0.0286 mmol) (prepared as in Example 1, steps A-D) in dichloromethane (1 mL) was added N,N-dimethylformamide (1 μL) followed by oxalyl chloride (18.3 μL, 0.0365 mmol; 2M solution in dichloromethane). The mixture was allowed to warm to ambient temperature with occasional venting to allow gases to evolve. After stirring for 30 minutes, 1-benzyl-5-chloro-3-ethyl-1H-indazol-4-amine (8.70 mg, 0.0304 mmol) was added as a solution in dichloromethane (0.5 mL). The mixture was stirred for 60 minutes and then concentrated under reduced pressure. The material was purified using preparative thin layer chromatography on silica, eluting with 5% methanol in dichloromethane to give N-(1-benzyl-5-chloro-3-ethyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (5.4 mg). MS (APCI), positive scan, m/z=504.3 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13].C(OCCO)C>>[CH:8]1([C:6]2[CH:7]=[C:2]([NH:12][NH2:13])[N:3]=[CH:4][N:5]=2)[CH2:10][CH2:9]1
Reactant: NN
Reactant: Clc1cc(C2CC2)ncn1
Solvent: O
Solvent: CCOCCO
Product: NNc1cc(C2CC2)ncn1

Procedure:
1.6 g (6.9 mmol) 4-chloro-6-cyclopropylpyrimidine [FR 1 519 069 (1966); Chem. Abstr. 71, 49965y, 1969] and 3.4 ml (3.5 g, 69.0 mmol) hydrazine hydrate are stirred at a bath temperature of 90° C. for 16 h. Ethylene glycol monoethyl ether is added to the cooled reaction mixture and the mixture is concentrated in vacuo. This operation is repeated once. The residue is then chromatographed over silica gel 60 (mobile phase: acetonitrile/water 8:2).