Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[C:24]([CH3:25])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:27](=[O:29])[CH3:28]>>[C:27]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)=[C:24]([CH3:25])[C:19]=1[OH:18])(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(O)c(C)c1O
Reactant: N#Cc1ccc(Sc2cccc(CO)c2)nc1
Product: CC(=O)c1ccc(OCc2cccc(Sc3ccc(C#N)cn3)c2)c(C)c1O
Yield: 127.6 %

Procedure:
Using the method of Preparation 166 using 6-(3-(hydroxymethyl)phenylthio) nicotinonitrile (1.46 g, 6.02 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (1.00 g, 6.02 mmol) affords the title compound (3.00 g). MS (APCI-neg) m/z (rel intensity): 389 (M−H, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([N+:11]([O-])=O)[CH:10]=[C:4]2[CH2:3]1>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[CH:10]=[C:4]2[CH2:3]1
Reactant: CN1CCn2nc([N+](=O)[O-])cc2C1
Solvent: CCO
Product: CN1CCn2nc(N)cc2C1
Reaction time: 2 h
Yield: 988.6 %

Procedure:
A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 5-methyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 101k (4.00 g, 2.20 mmol) in ethanol (160 mL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 99% yield of 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (101l) (3.31 g) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 5.34 (s, 1H), 3.98 (t, 2H, J=5.4 Hz), 3.52 (s, 3H), 2.84 (t, 2H, J=5.7 Hz), 2.45 (s, 3H); MS (ESI+) m/z 153.1 (M+H).
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][CH2:7][C:8]([O:10]CC1C=CC=CC=1)=[O:9])[CH2:4][F:5].O.[OH-].[Li+]>C1COCC1.O>[F:1][CH2:2][CH:3]([O:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:4][F:5]
Reactant: O=C(COC(CF)CF)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COC(CF)CF
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
Benzyl 2-(1,3-difluoropropan-2-yloxy)acetate (0.91 g, 3.73 mmol) was dissolved in THF (14 mL)/water (7 mL) mixture and treated with lithium hydroxide monohydrate (0.469 g, 11.18 mmol) and allowed to stir for 16 hours at room temperature. The mixture was concentrated, redissolved in water and extracted with ethyl acetate. The aqueous phase was treated with 2M HCl and NaCl then extracted with ethyl acetate (3×). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the title product (0.388 g, 67% yield).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=[O:18].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O>CC#N.O>[OH:18][CH2:2][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)=[O:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)c1nn(CC(=O)O)c2ccccc12
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C(O)Cn1nc(C(=O)CO)c2ccccc21
Temperature: 90 °C

Procedure:
The title compound was prepared in a similar manner as described by N. Yoshikawa et al., J. Org. Chem., 2002, 67, 2556-2565: A mixture of 2-(3-acetyl-1H-indazol-1-yl)acetic acid (100 mg, 0.46 mmol), TFA (0.71 mL, 0.92 mmol) and bis-(trifluoroacetoxy)-iodobenzene (394 mg, 0.92 mmol) in CH3CN (4 mL) and water (0.6 mL) was heated to reflux (90° C.) for 16 h. Solvents were evaporated and the crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give after lyophilization of the purified fractions the title compound. MS (LC-MS): 233 [M+H]+; tR (HPLC conditions k): 2.41 min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[CH:21]=O)[C:11]3=[O:23])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:38]1([NH2:41])[CH2:40][CH2:39]1.C(O)(=O)C>C(Cl)(Cl)Cl.CO>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[CH2:21][NH:41][CH:38]4[CH2:40][CH2:39]4)[C:11]3=[O:23])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC1CC1
Reactant: O=Cc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1CNC1CC1
Yield: 11.5 %

Procedure:
3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde (I-177b: 100 mg, 0.3083 mmol) was reacted with NaBH(OAc)3 (98 mg, 0.4624 mmol), Cyclopropylamine (0.032 mL, 0.462 mmol) and acetic acid (5 mL) at room temperature for 12 hours to afford the crude product. The reaction was monitored by TLC (5% methanol in chloroform). Purification by column chromatography on silica gel (2% methanol in chloroform) followed by preparative HPLC afforded 13 mg of the product (11.6% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[K+].C[Si]([C:34]([F:37])([F:36])[F:35])(C)C>CN(C)C=O.[Cu]Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl[Cu]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(C(F)(F)F)c23)C1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A solution of Intermediate 1a (200 mg) prepared in Example 1-1, Step A in N,N-dimethylformamide (5 ml) was added with potassium fluoride (30.8 mg, Aldrich), trimethylsilyltrifluoromethane (0.196 ml, Aldrich), and copper(I) chloride (65.2 mg, Wako Pure Chemical Industries), and the mixture was stirred at 60° C. for 15 hours. The reaction mixture was cooled to room temperature, and then the insoluble solids were removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the residue was separated and purified by HPLC to obtain the title compound (16.3 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([O:31]C)=[O:30])[CH:25]=[CH:26][CH:27]=2)[N:19]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=2)[N:19]=1
Reactant: COC(=O)Cc1cccc(OCc2csc(CCc3nc(-c4ccccc4)oc3C)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCc1nc(COc2cccc(CC(=O)O)c2)cs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a mixture of methyl 2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetate (0.31 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the precipitated crystals were collected by filtration and air-dried to give crystals (0.23 g, 77%) of 2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 153-154° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([C:19]4([C:22]#[N:23])[CH2:21][CH2:20]4)=[O:18])[CH2:12]3)=[C:8]([C:24]([NH2:26])=[O:25])[CH:7]=[N:6][N:5]2[CH:27]=1.C1(C(C#N)C(O)=O)CC1.C(=O)([O-])[O-].[K+].[K+].[CH3:43][C:44]1[CH:45]=[N:46][NH:47][CH:48]=1.CN[C@H]1CCCC[C@@H]1NC>[Cu](I)I.O1CCOCC1>[C:22]([C:19]1([C:17]([N:13]2[CH2:14][C@H:15]([CH3:16])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:27]=[C:2]([N:46]5[CH:45]=[C:44]([CH3:43])[CH:48]=[N:47]5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:24]([NH2:26])=[O:25])[CH2:12]2)=[O:18])[CH2:20][CH2:21]1)#[N:23]
Reactant: Cc1cn[nH]c1
Reactant: C[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: I[Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: N#CC(C(=O)O)C1CC1
Solvent: C1COCCO1
Product: Cc1cnn(-c2cc3c(N[C@@H]4CN(C(=O)C5(C#N)CC5)C[C@@H]4C)c(C(N)=O)cnn3c2)c1
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 34.2 %

Procedure:
The title compound was prepared from 20 mg (0.046 mmol) of 6-bromo-4-((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (prepared from the product of Step 1 of Example 158 using the methods previously described in Step 1 of Example 191 by replacing cyanoacetic acid with cyclopropylcyanoacetic acid), potassium carbonate (32.0 mg, 0.232 mmol), 4-methyl-1H-pyrazole (15.2 mg, 0.18 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (13.2 mg, 0.09 mmol) and dioxane (0.30 mL). The resulting mixture was sparged with argon for ˜5 min. then copper iodide (17.7 mg, 0.09 mmol) was added and the mixture was heated at 100° C. for 3 h. After cooling to rt, the mixture was purified by preparative LC/MS using the following conditions: (column: Waters XBridge C18, 19×250 mm, 5-μm particles; guard column: Waters XBridge C18, 19×10 mm, 5-μm particles; mobile phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; gradient: 10-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 6.8 mg of the title compound. Analytical LCMS (method H) retention time=1.98 min. (MH+ 433.2). 1H NMR (500 MHz, METHANOL-d4, appeared as rotomers) δ 8.39-8.32 (m, 1H), 8.14 (s, 1H), 8.07 (dd, J=12.4, 1.5 Hz, 1H), 7.98 (d, J=7.4 Hz, 1H), 7.69-7.64 (m, 1H), 7.34-7.24 (m, 1H), 5.20-5.00 (m, 2H), 4.55-4.41 (m, 3H), 4.13-3.90 (m, 3H), 3.04-2.80 (m, 1H), 2.34 (s, 3H), 1.99-1.65 (m, 4H), 1.49-1.38 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[C:8]([C:25]#[N:26])=[N:7]1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C@H:45]1[CH2:50][OH:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:27]=[CH:28][C:29]([C:31]([F:33])([F:34])[F:32])=[CH:30][C:3]=3[C:2]([F:1])([F:35])[F:36])[N:7]=[C:8]4[C:25]#[N:26])[C:17](=[O:24])[N:18]=2)[CH2:46][C@H:45]1[CH2:50][OH:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C#N)nn3Cc2ccc(C(F)(F)F)cc2C(F)(F)F)S1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(C#N)nn4Cc3ccc(C(F)(F)F)cc3C(F)(F)F)S2)C[C@H]1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-cyano-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrile and 2-(S)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15]N(C)C>O.CN(C)C=O>[CH3:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:1]#[N:2]
Reactant: COc1ccc2[nH]cc(CN(C)C)c2c1C
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2[nH]cc(CC#N)c2c1C
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a solution of potassium cyanide (0.74 g) in 20 mL water was added a solution of (5-methoxy-4-methyl-1H-indol-3-ylmethyl)dimethylamine (0.5 g) in 20 mL of N,N-dimethylformamide. The solution was heated to reflux for 40 min, cooled to rt, and 40 mL of ice water was added. The aqueous layer was extracted with three portions of toluene, and the combined toluene layers were washed with water and brine. The solvent was removed in vacuo and the product purified by column chromatography dichloromethane) as the mobile phase to yield (5-methoxy-4-methyl-1H-indol-3-yl)-acetonitrile (0.40 g).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[C:34]([S:36][CH3:37])[CH:33]=[C:32]([F:38])[C:31]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:45]([C:43]3[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:31]4[C:30]([F:29])=[CH:35][C:34]([S:36][CH3:37])=[CH:33][C:32]=4[F:38])[N:44]=3)=[O:46])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CSc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (12.0 mg, 0.031 mmol), 6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylic acid (11.0 mg, 0.037 mmol), HATU (29.2 mg, 0.077 mmol) in DMF (0.07 mL) and DIPEA (11.9 mg, 0.092 mmol) was stirred at room temperature for 16 h. The reaction mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a colorless gum (6.3 mg, 30%). LCMS calc. for C33H37F3N5O5S (M+H)+: m/z=672.2. Found: 672.2.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])([CH:12]2[CH2:17][CH2:16][C:15](=COC)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:29]([OH:31])=O.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([CH:6]1[CH2:7][CH2:8][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])([C:12]2([CH:29]=[O:31])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCC(c2cccc(F)c2F)(C2CCC(=COC)CC2)CC1
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2cccc(F)c2F)(C2(C=O)CCCCC2)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The compound (39) (8.1 g), formic acid (87%; 9.5 g) and toluene (100 ml) were mixed, and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to 30° C., and then water (100 ml) and toluene (200 ml) were added thereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, giving a white solid. This residue was dissolved in toluene (50 ml). The solution was added to a mixture of sodium hydroxide (95%; 0.5 g) and Solmix A-11 (32 ml) which had been cooled to 7° C., and the solution obtained was stirred at 10° C. for 2 hours. Then, an aqueous 2N-sodium hydroxide solution (16 ml) was added thereto, and the mixture was stirred at 5° C. for 2 hours. The reaction mixture obtained was poured into a mixture of water (200 ml) and toluene (200 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue obtained was concentrated, purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder and dried, giving 7.5 g of 1-[4-pentyl-(2,3-difluorophenyl)cyclohexyl]-cyclohexanecarboaldehyde (40). The yield based on the compound (39) was 97.1%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:14]3[N:15]=[C:16]([NH2:18])[N:17]=[C:13]3[CH:12]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:10]=2)[CH2:4][CH2:3]1.[S:25]([N:35]=[C:36]=[O:37])([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].CO>CN(C=O)C>[S:25]([NH:35][C:36]([NH:18][C:16]1[N:17]=[C:13]2[CH:12]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:10]=[C:9]([NH:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[N:14]2[N:15]=1)=[O:37])([C:28]1[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=1)(=[O:26])=[O:27]
Reactant: CN1CCC(Nc2cc(-c3cccnc3)cc3nc(N)nn23)CC1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2nc3cc(-c4cccnc4)cc(NC4CCN(C)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of the product of Step 1 (376 mg, 1.16 mmol) in DMF (4 mL) was treated with TosNCO (0.25 g, 1.3 mmol), then microwaved at 60° C. for 5 min. After stirring at room temperature for 18 h, MeOH (5 mL) was added and the resulting precipitate was collected by filtration and dried in vacuo to yield 1-tosyl-3-[5-(1-methyl-piperidin-4-ylamino)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20]O)[CH:17]=[CH:18][CH:19]=2)=[C:8]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:7]=1>C(Cl)Cl>[Cl:3][CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][C:9]1[C:8]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:7][C:6]([NH2:5])=[N:11][C:10]=1[CH3:12]
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CCl)c1
Reaction time: 1 h

Procedure:
Thionyl chloride (0.17 mL) was added to a stirred solution of the product from step (iv) (0.60 g) in DCM (10 mL) at rt. The mixture was stirred for 1 h and the solvent evaporated under reduced pressure to give the subtitle compound as a yellow oil 0.62 g that was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:27][CH3:28]>CN(C)C=O>[CH2:27]([C:9]1[O:10][C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=2[C:8]=1[C:11]([OH:13])=[O:12])[CH3:28]
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1oc2c(c1C(=O)O)C(=O)CCC2
Temperature: 60 °C
Yield: 86.9 %

Procedure:
To a stirred mixture of 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (640 g, 3.55 mol), potassium carbonate (1.7 kg, 10.65 mol) and cesium carbonate (100 g, 0.32 mol) in N,N-dimethylformamide (9.0 L) is added iodoethane (1250 g, 8.01 mol). The mixture is heated at 60° C. for 2 h. After cooling to ambient temperature, the mixture is filtered, the solid is rinsed with ethyl acetate, and the filtrate concentrated in vacuo. Water (2 L) is added then extracted with ethyl acetate (2×2 L); the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (642 g). A mixture of this ester (640 g, 3.07 mol) and ammonium acetate (426 g, 5.53 mol) in N,N-dimethylformamide (320 mL) is heated to 100° C. for 2 h. The reaction mixture is concentrated in vacuo, ice water (2.5 L) is added, and extracted with dichloromethane (2×3 L); the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate (357 g). A mixture of this ester (170 g, 0.82 mol) in ethyl alcohol (250 mL) and a solution of sodium hydroxide (165 g, 4.1 mol) in water (1 L) is heated at reflux for 1 h, then cooled in an ice water bath. Concentrated hydrochloric acid (350 mL) is added dropwise, the precipitate collected by filtration, rinsed with ice water (3×), and dried in a vacuum oven at 75° C. to afford 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate (125 g). m.p. 269°-270° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:16])[C:7]=2[CH:17]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:30])C.Cl>O>[O:16]=[C:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:15][C:6]2[CH:5]=[CH:4][C:3]([CH:2]=[O:30])=[CH:17][C:7]1=2
Reactant: CC(=O)O
Reactant: O=c1c2cc(CBr)ccc2oc2ncccc12
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: O=Cc1ccc2oc3ncccc3c(=O)c2c1

Procedure:
A mixture of 50 g of 7-bromomethyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine, 48.4 g of hexamethylenetetramine, 167 ml of water and 167 ml of acetic acid is stirred under reflux for 3 hours. To the reaction mixture is added 100 ml of concentrated hydrochloric acid, and the whole mixture is refluxed for 20 minutes. The reaction mixture is diluted with 200 ml of water, and cooled. The crystalline precipitate is filtered off, washed with water, dried, and then recrystallized from dimethylformamide to give 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carbaldehyde melting at 233-235°C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH2:16][C:17]2([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:20][CH2:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.O1CCO[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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>[F:27][C:26]1[C:21]([C:17]2([CH2:16][N:8]([C:5]3[N:6]=[N:7][C:2]([CH:29]=[CH2:30])=[CH:3][CH:4]=3)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:20][CH2:19][CH2:18]2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(Cl)nn1
Reactant: C1COCCO1
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: [K+]
Solvent: CCOC(C)=O
Product: C=Cc1ccc(N(CC2(c3ncccc3F)CCC2)C(=O)OC(C)(C)C)nn1
Temperature: 110 °C
Yield: 86 %

Procedure:
t-Butyl 6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (2.5 g, 6.36 mmol), triethenylboroxin pyridine complex (1.0 g, 4.13 mmol), Pd(PPh3)4 (0.3 g, 0.25 mmol), nitrogen-sparged dioxane (13.2 mL) and aq. 2 N K2CO3 (0.9 mL) were combined and heated to 110° C. for 25 min. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography provided a light yellow oil (2.1 g, 86%), (m/z [M+H]=385.2).