Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[CH:24](=O)[CH2:25][CH:26]([CH3:28])[CH3:27].[BH4-].[Na+]>>[CH3:27][CH:26]([CH3:28])[CH2:25][CH2:24][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1
Reactant: CC(C)CC=O
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)CCN1CCCC(c2ccc(Oc3ccc(C(N)=O)cn3)cc2)C1
Yield: 32.1 %

Procedure:
Using a method similar to Example 324, 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.0252 g, 0.0847 mmol), isovaleraldehyde (0.0165 mL, 0.154 mmol), and sodium borohydride (0.0082 g, 0.217 mmol) provide 0.0100 g (32%) of the title compound as an off-white foam: high resolution mass spectrum (electrospray): m/z calc for C22H30N3O2 368.2338, found 368.2355; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.41-7.36 (m, 2H), 7.17-7.12 (m, 2H), 7.03 (d, 1H, J=8.8 Hz), 3.28-3.19 (m, 2H), 2.96 (tt, 1H, J=3.4, 11.7 Hz), 2.71-2.63 (m, 2H), 2.43-2.28 (m, 2H), 2.06-1.92 (m, 2H), 1.84 (qt, 1H, J=3.9, 13.2 Hz), 1.71-1.51 (m, 4H), 0.99 (d, 6H, J=6.3 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(N(CC)CC)C.[C:17](Cl)(Cl)=[S:18]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:6]=[C:17]=[S:18]
Reactant: S=C(Cl)Cl
Reactant: NCc1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1cccc(CN=C=S)c1
Temperature: -10 °C
Reaction time: 2.75 h
Yield: 51.4 %

Procedure:
A solution of 3-fluorobenzylamine (6.3 g, 0.05 mole) and triethylamine (15.4 ml, 0.11 mole) in 50 ml of tetrahydrofuran was added dropwise to a solution of thiophosgene (4.2 ml, 0.055 mole) in 50 ml of tetrahydrofuran with cooling to -10° C. over a period of twenty minutes. The mixture was stirred at 25° C. for 2.75 hours and filtered. The filtrate was treated with charcoal, then filtered and evaporated to an oil. The oil was diluted with hexane:ethyl acetate (90:10) and purified on a flash silica column eluted with hexane:ethyl acetate (90:10) to yield 4.3 g (51%) of 3-fluorobenzyl isothiocyanate as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[I:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:17]2[CH:18]=[CH:19][C:14]([I:13])=[CH:15][CH:16]=2)[CH:9]=1)=[O:4]
Reactant: Oc1ccc(I)cc1
Reactant: COC(=O)c1cc(CO)c(C)o1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Yield: 63.4 %

Procedure:
A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (1.14 g) in tetrahydrofuran (15 mL) was cooled to 0° C. with stirring and treated with 4-iodophenol (4.6 g), triphenylphosphine (5.5 g) and diisopropylazodicarboxylate (4.2 g). After 10 minutes the cooling bath was removed. After 3 hours the reaction mixture was concentrated in vacuo and taken up in ethyl acetate (100 mL) and washed successively with water (100 mL), 1.0 M aqueous sodium hydroxide solution (100 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:4 by volume) to give compound 20 as a white solid (1.58 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[N:3]=[C:4]4[C:10]([C:11]([C:13]5([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)cc2)CC1

Procedure:
4-{4-[7-(1-Methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester following general procedures as described in these Examples. M+H=504.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)c1ccc(-c2cccs2)cc1
Yield: 95.2 %

Procedure:
Ex-17A: 4′-Bromoacetophenone (3.98 g, 20 mmol) was dissolved in ethylene glycol dimethyl ether and then the solution was degassed with nitrogen for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.31 g, 2 mmol) was added, and the solution was further degassed for 10 minutes. Thiophene-2-boronic acid (3.07 g, 24 mmol) was added followed by the addition of sodium carbonate solution (2 M, 45 mL). The mixture was stirred at reflux under nitrogen overnight. Most of the solvent was removed, and water was added to the remainder. The solid was filtered out and recrystallized from ethanol and water to give 3.85 g of the desired 4′-(thien-2-yl)acetophenone as a solid, 95% yield. 1H-NMR (CDCl3) δ 7.97 (d, J=9 Hz, 2H), 7.70 (d, J=9 Hz, 2H), 7.44 (d, J=4 Hz, 1H), 7.38 (d, J=5 Hz, 1H), 7.11–7.14 (m, 1H), 2.62 (s, 3H). HMRS (EI) calcd. for C12H10OS: 202.0452; found: 202.0454.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][S:18]([C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>CO.[Pd].C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][S:18]([C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc(NS(=O)(=O)c4cccc5ccccc45)cc23)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(NS(=O)(=O)c4cccc5ccccc45)cc23)CC1
Yield: 64.8 %

Procedure:
To a solution of 417 mg (1 mMol) of N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide in 50 ml of methanol are added 100 mg of 5% palladium on carbon. The mixture is hydrogenated at ambient temperature at an initial hydrogen pressure of 3 atmospheres for 20 hours. The reaction mixture is filtered and the filtrate is concentrated at reduced pressure to provide a crude that is suspended in ethyl ether, yielding 272 mg (65%) of N-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide as a solid with m.p.=254–256° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:48])=[C:4]([CH:45]=[CH:46][CH:47]=1)[C:5]([N:7]([C@@H:22]([C:26]1[N:35]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](=[O:43])[C:33]2[C:28](=[CH:29][C:30]([Cl:44])=[CH:31][CH:32]=2)[N:27]=1)[CH2:23][C:24]#[CH:25])[CH2:8][CH2:9][CH2:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O)=[O:6].N#N.NN>CO>[NH2:11][CH2:10][CH2:9][CH2:8][N:7]([C@@H:22]([C:26]1[N:35]([NH:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:34](=[O:43])[C:33]2[C:28](=[CH:29][C:30]([Cl:44])=[CH:31][CH:32]=2)[N:27]=1)[CH2:23][C:24]#[CH:25])[C:5](=[O:6])[C:4]1[CH:45]=[CH:46][CH:47]=[C:2]([Cl:1])[C:3]=1[F:48]
Reactant: C#CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCN1C(=O)c2ccccc2C1=O)C(=O)c1cccc(Cl)c1F
Agent: N#N
Agent: NN
Solvent: CO
Product: C#CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCN)C(=O)c1cccc(Cl)c1F
Temperature: 25 °C
Yield: 77.7 %

Procedure:
To a solution of (R)-3-chloro-N-[1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-2-fluoro-benzamide (1.13 g, 1.65 mmol) in methanol (10 ml) and the solution was purged with N2. To this solution was added hydrazine (110 μl). The mixture was then stirred at room temperature and the reaction progress was monitored by HPLC/MS. The reaction mixture was then filtered and solvent was removed from the filtrate. The residue was purified by flash column to afford N-(3-amino-propyl)-3-chloro-N-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynyl]-2-fluoro-benzamide (708 mg, 91%) as off-white solid, M.p. 101-103° C. LCMS: m/e 552 [M+H]. 1H NMR (CDCl3): δ 8.13 (d, J=8.8 Hz, 1H), 7.83 (s, 1H), 7.45 (dd, J=4.8 and 2.0 Hz, 1H), 7.32 (m, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H), 6.95 (m, 1H), 6.84 (t, J=7.2 Hz, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.48 (d, J=7.2 Hz 1H), 3.62 (m, 1H), 3.48 (m, 1H), 3.28 (br, 1H), 3.14 (m, 1H), 3.02 (br, 1H), 2.59 (m, 2H), 2.30 (br, 1H), 2.02 (t, 2.4 Hz, 1H), 1.36 (m, 2H).
Reaction SMILES: [F:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=2[CH3:18])=[O:8])[CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:50][C:51]1[CH:62]=[CH:61][C:54]2[NH:55][C:56]([C@@H:58]([NH2:60])[CH3:59])=[N:57][C:53]=2[CH:52]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:50][C:51]1[CH:62]=[CH:61][C:54]2[NH:55][C:56]([C@@H:58]([NH:60][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][C:9]([C:7]([N:4]4[CH2:5][CH2:6][CH:2]([F:1])[CH2:3]4)=[O:8])=[C:10]([CH3:18])[CH:11]=3)[CH3:59])=[N:57][C:53]=2[CH:52]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCC(F)C1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCC(F)C1
Yield: 49 %

Procedure:
Prepared analogously to Example 1g from rac.-4-(3-fluoropyrrolidin-1-ylcarbonyl)-3-methylbenzoic acid, TBTU, diisopropylethylamine and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 49%; Rf value: 0.30 (silica gel: dichloromethane/ethanol=9:1); C22H22ClFN4O2 (428.893); mass spectrum: (M+H)+=429/431 (chlorine isotope).
Reaction SMILES: O.[NH2:2][NH2:3].Br[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11]>C(O)C>[CH3:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:2][NH2:3]
Reactant: NN
Reactant: COCCOCCBr
Solvent: O
Solvent: CCO
Product: COCCOCCNN
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
To a solution of hydrazine monohydrate (44.0 mL, 1.00 mol) in ethanol (75 mL) at 0° C. in an ice-water bath was added 1-(2-bromoethoxy)-2-methoxyethane (13.6 mL, 0.100 mol) drop-wise over 20 minutes. The reaction was then allowed to warm to room temperature and stir for 5 minutes and then heated to 40° C. in a preheated oil bath for 12 hours. The reaction was then cooled to room temperature and concentrated to remove the ethanol. The remaining aqueous layer was extracted with methylene chloride (2×100 mL) and diethyl ether (2×100 mL). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated to provide [2-(2-methoxyethoxy)-ethyl]-hydrazine as a light yellow oil (10.29 g, 85%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[Cl:13][C:14]([Cl:38])([Cl:37])[CH2:15][O:16][C:17](=[O:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:27]=1.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:38][C:14]([Cl:13])([Cl:37])[CH2:15][O:16][C:17](=[O:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33]([O:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=2)=[O:34])[CH:27]=1
Reactant: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
(4-Trifluoromethyl-phenyl)-methanol (58 mg, 0.332 mmol) was added to a stirred mixture of 2-(3-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (120 mg, 0.277 mmol), EDC×HCl (80 mg, 0.415 mmol), DMAP (3.4 mg, 0.028 mmol) and DCM (4 mL). The reaction mixture was stirred at rt overnight. More DCM was added and the mixture was washed with 0.25M HCl, the organic phase was dried through a phase separator and concentrated. The crude was submitted to flash chromatography using heptane and EtOAc (90/10) as the eluent to yield the titled compound (105 mg, 64%) as a colourless oil; 1H NMR (400 MHz, CDCl3): δ 3.62 (s, 2H), 4.54 (s, 2H), 4.96 (s, 2H), 5.18 (s, 2H), 7.09-7.15 (m, 1H), 7.18-7.24 (m, 4H), 7.30-7.43 (m, 4H), 7.60 (d, 2H), 8.08 (d, 1H); Mass spectrum: M−H+ 590.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[C:9]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:8]=2)(=[O:3])C.Cl[O-:22]>O1CCOCC1>[CH:15]1([C:9]2[CH:8]=[C:7]3[C:12]([C:13]([OH:14])=[C:4]([C:1]([OH:22])=[O:3])[CH:5]=[N:6]3)=[CH:11][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: [O-]Cl
Reactant: CC(=O)c1cnc2cc(C3CCCCC3)ccc2c1O
Solvent: C1COCCO1
Product: O=C(O)c1cnc2cc(C3CCCCC3)ccc2c1O
Reaction time: 0.75 h

Procedure:
10 g of powdered 3-acetyl-4-hydroxy-7-cyclohexylquinoline are added to a solution of 10 ml of dioxane and 10 g of a freshly prepared hypochlorite solution at room temperature. After 45 minutes, the unconverted acetyl compound is washed out with chloroform. The aqueous solution is acidified with 10% strength hydrochloric acid. The product which precipitates is washed with water and then dried. 7-Cyclohexyl-4-hydroxy-quinoline-3-carboxylic acid of melting point 241°-43°C is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23](C5NN=CC=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[CH3:77][C:78]1[C:82](B2OC(C)(C)C(C)(C)O2)=[CH:81][NH:80][N:79]=1>>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:82]5[C:78]([CH3:77])=[N:79][NH:80][CH:81]=5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Product: Cc1n[nH]cc1-c1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 70 %

Procedure:
Following the procedure of (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with 3-methyl-1H-pyrazole-4-boronic acid pinacol ester to give the title compound as a gum (35 mg, 70%). LCMS (Method G): RT=3.81 min, [M+H]+=548.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][O:13][NH2:14])=[CH:10][CH:9]=1>N1C=CC=CC=1>[S:1]([NH:14][O:13][CH2:12][C:11]1[CH:15]=[CH:16][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)([CH3:4])(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CON)cc1
Solvent: c1ccncc1
Product: COc1ccc(CONS(C)(=O)=O)cc1
Yield: 64.9 %

Procedure:
63.0 g (0.55 mole) of mesyl chloride was added dropwise to a solution of 76.5 g (0.5 mole) of O-(p-methoxybenzyl)-hydroxylamine in 400 ml of pyridine while ice-cooling and stirring. After completion of the addition, the resulting mixture was stirred at room temperature (about 20°-30° C) for 5 hours and then the solvent was removed by distillation. 600 ml of ethyl acetate was added to the resulting residue, and the mixture was washed successively with 1N hydrochloric acid and water. The mixture was then dried and the solvent was distilled off to obtain 75 g (64.8% yield) of N-mesyl-O-(p-methoxybenzyl)hydroxylamine (IV) having a melting point of 114°-116° C.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([CH2:14][CH2:15]O)[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[BrH:17]>>[BrH:17].[Br:17][CH2:15][CH2:14][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[N:8][CH:7]=2)[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: COc1ccc(C2(CCO)CCNC2)cn1
Agent: Br
Product: Oc1ccc(C2(CCBr)CCNC2)cn1
Temperature: 160 °C
Reaction time: 5 h

Procedure:
0.32 g (1.44 mmol) of 2-[3-(6-methoxypyridin-3-yl)pyrrolidin-3-yl]ethanol obtained in stage 4.3, in solution in 7.2 ml of aqueous hydrobromic acid (48% by weight solution), is introduced into a sealed tube. The reaction medium is stirred at 160° C. for 5 hours. This solution is then brought back to ambient temperature and concentrated under reduced pressure. The resulting residue is dissolved in methanol, evaporated twice under reduced pressure and triturated from diethyl ether, to result, after filtration in 0.5 g of the desired compound in the form of a brown gum.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:20])=O.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:20][C:3]1[N:2]([CH3:1])[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[N:4]=1
Reactant: COC(=O)c1ccc2c(=O)n(C)c(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)c1ccc2c(=O)n(C)c(Cl)nc2c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 22.6 %

Procedure:
Into a round bottom flask was added methyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (0.48 g, 2.1 mmol) dissolved in phosphoryl chloride (20.0 mL, 214 mmol). N,N-diethylaniline (0.99 mL, 6.2 mmol) was added followed by phosphorus pentachloride (0.22 g, 1.05 mmol). The reaction mixture was heated to 120° C. and stirred for 1 d. The mixture was then cooled to rt and concentrated. The residue was poured over ice and extracted with DCM (3×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford methyl 2-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.12 g, 23%). LC-MS: (FA) ES+ 253; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=8.4 Hz, 1H), 8.31 (d, J=1.5 Hz, 1H), 8.10 (dd, J=8.4, 1.5 Hz, 1H), 3.98 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [C:1]([CH2:6][C:7]1[O:8][C:9]([SH:12])=[N:10][N:11]=1)(OCC)=[O:2].[NH3:13]>C(O)C>[C:1]([CH2:6][C:7]1[O:8][C:9]([SH:12])=[N:10][N:11]=1)(=[O:2])[NH2:13]
Reactant: CCOC(=O)Cc1nnc(S)o1
Reactant: N
Solvent: CCO
Product: NC(=O)Cc1nnc(S)o1

Procedure:
A solution of 1.88 g (0.01 mol) of 2-carbethoxymethyl-1,3,4-oxadiazol-5-thiol in 25 ml of absolute ethanol is added dropwise at ambient temperature to 100 ml of a saturated solution of anhydrous ammonia in absolute ethanol. When the reaction is complete, as evidenced by thin layer chromatography, the solution is evaporated to dryness. The residue is dissolved in 100 ml of water and the aqueous solution is acidified to pH 2.5 with dilute hydrochloric acid and extracted with ethyl acetate. The extract is dried (MgSO4) and evaporated to dryness to give 2-carbamoylmethyl-1,3,4-oxadiazole-5-thiol.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[C:17]([C:19]([NH:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[O:20])[N:18]=2)=[CH:10][CH:9]=1)(=O)C.[OH-].[Na+]>>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:16]2[NH:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][OH:4])=[CH:13][CH:12]=3)=[N:18][C:17]=2[C:19]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])=[CH:32][CH:31]=1
Reactant: CC(=O)OCCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(F)cc3)[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1nccs1)c1nc(-c2ccc(OCCO)cc2)[nH]c1-c1ccc(F)cc1

Procedure:
2-(4-(2-Acetoxyethyloxy)phenyl)-5-(4-fluorophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide is hydrolyzed with sodium hydroxide to give 5-(4-fluorophenyl)-2-(4-(2-hydroxyethyloxy)-phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: ClCCC1CCNCC1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCCC2CCNCC2)ccc1Cl
Temperature: 80 °C
Reaction time: 20 h
Yield: 56.1 %

Procedure:
4-chloro-3-nitrophenol (2.5 g, 14.4 mmol, 1 eq.) was placed in dimethylformamide (48 mL) with 4-(2-chloro-ethyl)piperidine (8 g, 43.2 mmol, 3 eq.), Cs2CO3 (33 g, 100.8 mmol, 7 eq.), KI (5.3 g, 31.7 mmol, 2.2 eq.). The reaction mixture was heated at 80° C. and stirred for 20 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1% NaOH aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 4-(2-(4-chloro-3-nitrophenoxy)ethyl)piperidine (2.3 g, 56%).
Reaction SMILES: [H-].[Na+].[O:3]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4]1.[CH3:18][CH2:19][OH:20]>>[CH2:19]([O:20][CH2:4][C:5]1([OH:3])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH3:18]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: [H-]
Agent: [Na+]
Product: CCOCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
To anhydrous EtOH (20 mL) was added slowly NaH (124 mg, 52 mmol) at 0° C., and after the addition was complete the mixture was stirred for 1.5 h. Then tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (9B, 45 mmol) was added, and the resulting mixture was stirred at 50° C. for 1 h, when TLC showed that s.m. was consumed. Then the mixture was neutralized with 1N aq. HCl, and concentrated. The residue was purified by prep-TLC to give the desired product 9C as colorless oil (600 mg)1H NMR (METHANOL-d4) δ: 3.78 (d, J=12.6 Hz, 2H), 3.51 (q, J=7.0 Hz, 2H), 3.22-3.29 (m, 2H), 3.15 (br. s., 2H), 1.48-1.60 (m, 4H), 1.43 (s, 9H), 1.18 (t, J=7.0 Hz, 3H).