Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([O:8][CH2:9][C@@:10]1([C:24]#[C:25][Si](C)(C)C)[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH:12]=[CH:11]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].CO.O>C(#N)C>[C:24]([C@:10]1([CH2:9][OH:8])[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH:12]=[CH:11]1)#[CH:25]
Reactant: Cc1cn([C@H]2C=C[C@@](C#C[Si](C)(C)C)(COC(=O)OC(C)(C)C)O2)c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: C#C[C@@]1(CO)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
(2R,5R)-5-t-Butoxycarbonyloxymethyl-5-(2-trimethylsilylethynyl)-2-(thymin-1-yl)-2,5-dihydrofuran (35 mg) was added to a glass reactor, and the atmosphere of the reactor was changed to nitrogen. To the reactor, potassium carbonate (72 mg) and methanol (3.5 mL) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was mixed with water and acetonitrile so as to form a uniform solution, and the solution was quantitated (LC). The yielded compound was found to be 4′-ethynyl-2′,3′-didehydro-3′-deoxythymidine (yield: 94%, calculated through quantitation) (internal standard: methyl phthalate). The 1H-NMR data of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:15][C@@H:14]([C:16](O)=[O:17])[C@H:13]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:12]1)(=[O:10])=[O:9].[CH2:28]1[C:30]([NH2:33])([C:31]#[N:32])[CH2:29]1.Cl>>[C:31]([C:30]1([NH:33][C:16]([C@@H:14]2[CH2:15][CH:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:10])=[O:9])[CH2:12][C@H:13]2[CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[O:17])[CH2:28][CH2:29]1)#[N:32]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1COc1ccc(Cl)cc1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2CC(S(=O)(=O)c3ccccc3Cl)C[C@H]2COc2ccc(Cl)cc2)CC1

Procedure:
The title compound was synthesized in analogy to Example 68/69, Step 11, from (1R,2R)-4-(2-Chloro-benzenesulfonyl)-2-(4-chloro-phenoxymethyl)-cyclopentanecarboxylic acid (epimeric mixture) and 1-amino-cyclopropyl cyanic hydrochloride to afford the desired product as a yellow oil. MS (EI): 493.2 (M)+.
Reaction SMILES: O=[C:2]([NH:15]/[N:16]=[C:17]1\[NH:18][C:19](=[O:31])[C:20]2[NH:21][CH:22]=[N:23][C:24]=2[N:25]\1[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[O:31]=[C:19]1[N:18]2[C:2]([CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:15][N:16]=[C:17]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:24]2[N:23]=[CH:22][NH:21][C:20]1=2
Reactant: CCCCCn1/c(=N/NC(=O)CNC(=O)OCc2ccccc2)[nH]c(=O)c2[nH]cnc21
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CNC(=O)OCc3ccccc3)nnc12
Yield: 87.2 %

Procedure:
The solution of benzyl 2-oxo-2-[(2E)-2-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazino]ethylcarbamate (0.60 g, 0.84 mmol) in toluene (30 mL) was refluxed overnight. M+H=410.1. The product was precipitated from the reaction mixture and filtered to give the desired product (300 mg, 87%). LCMS calculated for C20H24N7O3(M+H): 410.2; found: 410.2.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([N:12]2[CH2:19][S:18][CH2:17][C@H:13]2[C:14]([OH:16])=O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([N:12]2[CH2:19][S:18][CH2:17][C@H:13]2[C:14]([CH:21]2[NH:22][CH2:23][CH2:24][S:20]2)=[O:16])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CSCN1
Reactant: O=C(O)[C@@H]1CSCN1C(=O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(C1NCCS1)[C@@H]1CSCN1C(=O)CCCc1ccccc1
Reaction time: 24 h
Yield: 47.6 %

Procedure:
To 20 ml of methylene chloride, 1.4 g of the thus-obtained N-(4-phenylbutanoyl)-L-thioproline were added together with 445 mg of thiazolidine and 1.05 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride [WSC (Water Soluble Carbodiimide).HCl], and the mixture was stirred for 24 hours. The resultant liquid reaction mixture was washed with 1N hydrochloric acid, saturated saline, a saturated aqueous solution of sodium bicarbonate and saturated saline in that order and dried over anhydrous sodium sulfate. Methylene chloride was distilled off, and the resultant oily residue was subjected to column chromatography on silica gel, thereby obtaining 833 mg of the intended N-(4-phenyl-butanoyl)-L-thioprolylthiazolidine as colorless crystals from a chloroform-methanol fraction.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4](O)=[O:5].CSC.B.CO>C1COCC1.COB(OC)OC>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(F)cccc1I
Agent: B
Agent: COB(OC)OC
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: OCc1c(F)cccc1I
Temperature: 22.5 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-fluoro-6-iodobenzoic acid (10 mmol) in THF (6.5 mL) and trimethylborate (3.25 mL) was added borane dimethylsulfide (12 mmol) slowly, maintaining the internal temperature at 20-25° C. Stirring was continued for an additional 16 h at room temperature and then methanol (1.44 mL) was added cautiously. The resulted solution was evaporated in vacuo to offer 2.5 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21](Br)[CH:20]=2)[CH2:13][C:12]3([CH3:28])[CH3:27])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:20]=[C:21]([NH:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32])[CH:22]=[C:23]([F:25])[CH:24]=2)[CH2:13][C:12]3([CH3:28])[CH3:27])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(c2cc(F)cc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cc(F)cc(C2CC(C)(C)c3cc(S(=O)(=O)NC4CCC4)ccc3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A mixture solution of 2-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (150 mg, 0.32 mmol), copper(I) iodide (20 mg, 0.1 mmol), 2-amino-2-methyl-propionic acid (135 mg, 1.3 mmol) and potassium carbonate (140 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyclobutylsulfamoyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-5-fluoro-phenylamino]-2-methyl-propionic acid (79.8 mg, 51.0%) as a white solid: MS (ESI) M+1=490.1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([S:17][CH3:18])(=[S:16])[CH2:14][CH3:15].C(O[C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH3:29])(=O)C>O1CCCC1.CCCCCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[Si:31]([O:30][C@@H:28]([C@@H:24]1[C@@H:23]([C@H:14]([C:13]([S:17][CH3:18])=[S:16])[CH3:15])[NH:26][C:25]1=[O:27])[CH3:29])([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CCC(=S)SC
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CSC(=S)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of diisopropylamine (152 mg) in anhydrous tetrahydrofuran (2 ml) cooled to 0° C. was added a 1.56M solution of n-butyllithium in n-hexane (0.95 ml). After stirring for 30 minutes at 0° C., the solution was cooled to -78° C. and methyl dithiopropionate (120 mg) and a 1M solution of chlorotitanium triisopropoxide in hexane (4.0 ml) were added successively thereto. The mixture was warmed to -40° C. and (3R,4R)-4-acetoxy-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-oxoazetidine (287 mg) was added thereto. The solution was allowed to warm to 0° C., quenched by 1N hydrochrolic acid, and extracted with diethyl ether. The organic layer was washed with brine, dried, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10% diethyl ether-hexane) to afford a mixture (202 mg) of (3S,4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4 -[(1R)-1-[(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine and (3S,4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1S)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine. Recrystallization of the product obtained above from n-hexane gave (3S,4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine as a yellow needle.
Reaction SMILES: [NH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)N.[CH2:17](O)[CH3:18]>>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]3[NH:1][C:5]4[CH2:4][CH2:3][NH:1][CH2:17][C:18]=4[C:4]=3[CH:5]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(Cc2ccc(NN)cc2)CC1
Reactant: CCO
Product: CN1CCN(Cc2ccc3[nH]c4c(c3c2)CNCC4)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-hydrazinobenzyl)-4-methylpiperazine (3.4 g, 13.25 mmol) in ethanol (50 mL) were added piperidone. HCl (2.51 g, 18.55 mmol). The reaction temperature was raised to 90° C. and continued stirring for 2 hrs. The progress of the reaction was monitored by TLC and upon completion of the reaction the mixture was cooled to rt and HCl gas was bubbled through the reaction mixture at 0° C. After the reaction mixture was saturated with HCl, the temperature was raised to 90° C. again and continued stirring for 2 hrs. The ethanolic HCl was removed under reduced pressure and the pH of the reaction mixture was adjusted to 12.0 with 10% NaOH solution. The mixture was partitioned between 20% MeOH:DCM and water (35 mL) and the organic layer was separated, dried over Na2SO4 filtered and the solvent was removed under reduced pressure to give crude residue. Washing with ether gave 8-[(4-methylpiperazin-1-yl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g). 1H NMR (CD3OD, 200 MHz) δ: 7.31 (1H, s), 7.27 (1H, d, J=8.6 Hz), 7.06 (1H, d, J=8.6 Hz), 4.01 (2H, s), 3.60 (2H, s), 3.21 (8H, bm), 2.86 (4H, m), 2.28 (3H, s); m/e=285 (M+1).
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([C:8]12[CH2:15][CH2:14][C:11]([C:16]([O:18]C)=O)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)[CH2:4][CH2:5][CH2:6][CH3:7].O>C(O)CO>[CH2:3]([C:8]12[CH2:15][CH2:14][C:11]([C:16]([NH:1][NH2:2])=[O:18])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NN
Reactant: CCCCCC12CCC(C(=O)OC)(CC1)CC2
Solvent: OCCO
Solvent: O
Product: CCCCCC12CCC(C(=O)NN)(CC1)CC2
Temperature: 25 °C

Procedure:
Hydrazine (anhydrous, 103 mL, 88.7 mmol) was added to a solution of methyl 4-pentylbicyclo[2.2.2]octane-1-carboxylate (2-B) in ethylene glycol (180 mL) and the mixture was stirred under reflux for 17 h. After cooling to room temperature, the mixture was poured into water (1500 mL) and extracted with methylene chloride (3×600 mL). The combined extracts were washed twice with water, brine, dried (MgSO4) and concentrated in vacuo to provide 4-pentylbicyclo[2.2.2]octane-1-carbohydrazide (2-C). 1H NMR (500 MHz, CDCl3): δ 0.90 (t, 3H); 1.21 (m, 8H); 1.43 (m, 6H); 1.74 (m, 6H); 3.85 (broad s, 2H); 6.81 (broad s, 1H) ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[CH:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]3[C:45]([CH:46]=2)=[CH:44][CH:43]=[CH:42][CH:41]=3)O1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:37]4[CH:38]=[N:39][C:40]5[C:45]([CH:46]=4)=[CH:44][CH:43]=[CH:42][CH:41]=5)[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]=3[N:10]=2)[CH2:13][CH2:14]1)=[O:22]
Reactant: CC1(C)OB(c2cnc3ccccc3c2)OC1(C)C
Reactant: CC(O)C(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: C[C@H](O)C(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cnc5ccccc5c4)nc3s2)CC1
Yield: 35.7 %

Procedure:
1-[4-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-piperazin-1-yl]-2-hydroxy-propan-1-one (100 mg) was reacted with 72 mg of 3-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)quinoline via General Procedure A. The product was purified by reverse phase HPLC to yield 43.5 mg of 106. MS (Q1) 520.3 (M)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[S:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)sc3-c3cccc(C)c3)cn2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.75 min; [M+H]+=437.22.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[N:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH:21]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[NH2:39][CH2:40][CH2:41][OH:42]>CN(C)C=O>[CH3:32][O:31][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][NH:39][CH2:40][CH2:41][OH:42])[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)=[N:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH:21]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCCCl
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCCNCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-5,6,6′-trimethyl-[2,2′]bipyridine (compound 465) (35 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (108 mg) and 2-aminoethanol (0.14 ml) were added to the solution, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (24 mg, yield 64%).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[N:5]1)([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ccc(CO)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)n1ccc(C=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To the (1-Isopropyl-1H-pyrazol-3-yl)-methanol from the above reaction was added CH2Cl2 (1.10 L). Dess-Martin periodinane (144 g, 339 mmol) was then added portionwise. The reaction was stirred at room temperature. After 1 h, more Dess-Martin periodinane (16.0 g, 37.7 mmol) was added. The reaction was allowed to stir for 11 h, at which point starting material was no longer detectable by LCMS. The reaction mixture was filtered through celite. The filtrate was then washed with sat. aq. NaHCO3 (3×300 mL) followed by brine (150 mL). The organic was dried over MgSO4, filtered, and concentrated. This crude product was then dry loaded onto the ISCO and eluted with CH2Cl2 to give the purified product (18.8 g, 61%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=2)([CH3:6])[C:3]([NH2:5])=O.Cl>C1COCC1>[CH3:6][C:2]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=2)([CH3:1])[CH2:3][NH2:5]
Reactant: CC(C)(C(N)=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(CN)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
2-Methyl-2-(5-nitro-1H-indol-2-yl)propanamide (200 mg, 0.81 mmol) was suspended in THF (5 ml) and cooled to 0° C. Borane-THF complex solution (1.0 M, 2.4 mL, 2.4 mmol) was added slowly and the mixture was allowed to stir overnight at room temperature. The mixture was cooled to 0° C. and carefully acidified with 3 N HCl. THF was evaporated off, water was added and the mixture washed with ethylacetate. The aqueous layer was made alkaline with 50% NaOH and the mixture was extracted with ethylacetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 2-methyl-2-(5-nitro-1H-indol-2-yl)propan-1-amine (82 mg, 43%).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21](COCC[Si](C)(C)C)[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][O:34][CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OCC2C3C(=O)N(COCC[Si](C)(C)C)N=CC=3NC=2C2C=CC(OC(F)F)=C(OC3CC3)C=2)CCC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][O:34][CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: CCC(CC)OCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(COC3CCC3)c2c1=O
Product: CCC(CC)OCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Yield: 34.6 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 13-(c) except for using 0.26 g (0.46 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(1-ethylpropoxymethyl)-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 65-(b) in place of 3-cyclobutoxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 69 mg of the title compound was obtained as a white solid. (Yield: 35%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH2:15])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[C:37]([NH:44][C@H:45]([C:47](O)=[O:48])C)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH:15][C:47](=[O:48])[CH2:45][NH:44][C:37](=[O:38])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.1 %

Procedure:
To a round bottom flask was added 4-(5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (70 mg, 0.1367 mmol), N-Boc-alanine (24 mg, 0.1367 mmol), EDAC (30 mg, 0.150 mmol), HOBT (20.3 mg, 0.150 mmol) THF (5 ml) and diisopropyl ethyl amine (0.026 ml, 0.150 mmol). The reaction was stirred at rt for 5 hr. After this time the reaction mixture was diluted with EtOAc (25 ml). The resulting solution was washed with water (2×15 ml) and saturated NaCl (15 ml). The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (8 g silica gel) eluting with a gradient of 20%-100% EtOAc/Hex to give product tert-butyl 2-(2-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)hydrazinyl)-2-oxoethylcarbamate as a light yellow solid (54 mg, 60% yield)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([C:38]1[C:39]([N:47]2[CH2:52][CH2:51][CH:50]([N:53]3[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]3)[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43])[CH3:37].Cl.N>C(O)C(F)(F)F.CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH2:36][CH3:37])[C:39]([N:47]4[CH2:48][CH2:49][CH:50]([N:53]5[CH2:54][CH2:55][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:57][CH2:58]5)[CH2:51][CH2:52]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCc1cc(N)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Agent: Cl
Agent: N
Solvent: CO
Solvent: OCC(F)(F)F
Product: CCc1cc(Nc2nccc(-c3c(-c4ccc(OC)c(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 85 °C
Yield: 70.7 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (23.0 g, 46.8 mmol), 5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 206, Step B) (18.6 g, 46.8 mmol) and HCl (4N,1,4-Dioxane, 23.4 mL, 93.6 mmol) in trifluoroethanol (200 mL) was heated in a sealed vessel at 85° C. for 48 h. After cooling to rt, the reaction mixture was treated with an excess of 7N NH3 in MeOH and then subjected to filtration. The filtrate was concentrated onto silica gel and purified by flash chromatography. The chromatographed product was dissolved in DCM and treated with an excess of diethyl ether. The resultant bright yellow precipitate was collected by filtration and then recrystallized from DCM and EtOH to afford the title compound N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide (28.2 g, 67%).