Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[SH:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Sc1ccncc1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ccncc3)s2)c(C(=O)C2CCCC2)c1
Yield: 25.1 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(pyridin-4-ylsulfanyl)-thiazol-2-yl]-urea (110 mg, 25%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 4-mercaptopyridine (222 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17](OC(C)(C)C)=[O:18])=[C:15]([NH2:24])[N:14]=[C:13]([C:25]3[C:30]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[CH:29][CH:28]=[CH:27][C:26]=3[O:41][CH2:42][CH:43]3[CH2:45][CH2:44]3)[CH:12]=2)=[CH:7][C:6]=1[OH:46])(=[O:3])[CH3:2].[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1COCC1>[NH2:24][C:15]1[C:16]([CH2:17][OH:18])=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([OH:46])[CH:7]=2)[CH:12]=[C:13]([C:25]2[C:30]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)=[CH:29][CH:28]=[CH:27][C:26]=2[O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[N:14]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(-c3ccc(NC(C)=O)c(O)c3)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(-c3ccc(NC(C)=O)c(O)c3)c(CO)c(N)n2)cc1
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
To a cold (0° C.) solution of tert-butyl 4-[4-(acetylamino)-3-hydroxyphenyl]-2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}nicotinate (1.65 g, 2.64 mmol) in THF (25.0 mL) under argon atmosphere was added a solution of sodium bis(2-methoxyethoxy)aluminum hydride (3.7 N in toluene, 4.12 mL, 21.1 mmol) in THF (3 mL) dropwise. After being stirred for 30 minutes, the mixture was quenched with ethyl acetate and poured into saturated aqueous sodium potassium tartarate. The extracted organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 19:1-9:1) to give N-{4-[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]-2-hydroxyphenyl}acetamide (0.48 g, 33%); LC-MS (m/z=556, M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:11]=[CH:12][C:4]=2[O:3]1.[C:22](OC(OC(OC(C)(C)C)=O)=O)(C)([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl>[CH3:1][C@@H:2]1[O:3][C:4]2[CH:12]=[C:11]3[C:10](=[CH:9][C:5]=2[NH:6][C:7]1=[O:8])[C@H:13]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([F:19])([F:21])[F:20])[CH2:24][CH2:22][CH2:23]3
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C[C@H]1Oc2ccc(CNCCCC(F)(F)F)cc2NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1Oc2cc3c(cc2NC1=O)[C@H](NCCCC(F)(F)F)CCC3
Yield: 105.5 %

Procedure:
608 mg (2.014 mmol) of (2R)-methyl-3-oxo-6-(4,4,4-trifluorobutylamino-methyl)-3,4-dihydro-2H-1,4-benzoxazine is stirred with 439.9 mg (2.014 mmol) of di-tert-butyldicarbonate and 303 mg (2.995 mmol) of triethylamine in 15 ml of dichloromethane for four hours at room temperature. The batch is spun in until a dry state is reached, and the residue is put on a column on silica gel (mobile solvent: ethyl acetate/hexane). 727.6 mg (99%) of the desired compound is isolated.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[CH:7][C:6]=2[N:5]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:4]=1)#[CH:2].C(O)C.[H][H]>[Pd].O1CCCC1>[CH2:1]([C:3]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[N:8]=[CH:7][C:6]=2[N:5]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[CH:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: C#Cc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 92.6 %

Procedure:
To 8.56 g (20.4 mmol) of 3-ethynyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 19-(b) were added 300 ml of ethanol and 200 ml of tetrahydrofuran, then, 2.0 g of 5% palladium-active carbon was added to the mixture, and the mixture was stirred under 1 atm hydrogen atmosphere at room temperature for 15 hours. After completion of the reaction, insoluble material was removed from the reaction suspension by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 8.00 g of the title compound as a pale yellowish solid. (Yield: 93%)
Reaction SMILES: [C:1]1(=[C:7]=[CH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C(=O)([O-])[O-].[Ca+2]>[C:1]1(=[CH:7][CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC=C=C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: CCOC(=O)C=CC=C1CCCCC1
Yield: 92 %

Procedure:
Ethyl 4-cyclohexylidene-3-butenoate was reacted at 50°C. for 4 hours in 80 ml of methanol in the presence of 1.5g of calcium carbonate as a catalyst. In the same manner as in the preceding Examples, the resulting reaction mixture was neutralized and subjected to distillation under reduced pressure. Ethyl 4-cyclohexylidene-2-butenoate was obtained in a yield of 92% from a fraction boiling at 111 to 114°C. under 3 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:32])([CH3:31])[CH2:12][C:13]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:14][C:15]2[NH:23][C:22]3[C:17](=[N:18][C:19]([CH:24]=O)=[CH:20][CH:21]=3)[CH:16]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(O)(=O)C.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>ClC(Cl)C.C(OCC)(=O)C.[OH-].[NH4+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:32])([CH3:31])[CH2:12][C:13]([CH2:14][C:15]2[NH:23][C:22]3[C:17](=[N:18][C:19]([CH2:24][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:20][CH:21]=3)[CH:16]=2)([OH:30])[C:26]([F:29])([F:27])[F:28])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: C1COCCN1
Reactant: CC(C)(CC(O)(Cc1cc2nc(C=O)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(CC(O)(Cc1cc2nc(CN3CCOCC3)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
To a solution of the aldehyde of Example 94 (0.050 g, 0.107 mmol) and 0.078 mL of acetic acid in 3.0 mL of dichloroethane was added morpholine (0.233 mL, 2.68 mmol) at 0° C. The reaction was allowed to stir at room temperature for 30 minutes. To this yellow solution was added triacetoxy sodium borohydride (0.057 mg, 0.268 mmol), then continued stirring at room temperature for 14 hours. The reaction mixture was diluted with 10 mL of ethyl acetate and 2 mL of 3% ammonium hydroxide solution. The biphasic system was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with three 20 mL portions of water, brine, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to give yellow oil. This crude material was applied onto a flash column and eluted with 5% MeOH—CH2Cl2, 0.5% NH4OH, to give the title compound (0.018 g, 32.0% yield) as a white foam.
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:30])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)CCC>[CH3:13][O:12][C:9]1[C:8](=[O:14])[N:7]([CH3:15])[C:6]2[N:5]=[CH:4][N:3]=[C:2]([N:16]3[CH2:21][CH2:20][C:19]4([C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][C:22]4=[O:30])[CH2:18][CH2:17]3)[C:11]=2[N:10]=1
Reactant: O=C1Nc2ccccc2C12CCNCC2
Reactant: COc1nc2c(Cl)ncnc2n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1nc2c(N3CCC4(CC3)C(=O)Nc3ccccc34)ncnc2n(C)c1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Into a 100 mL round bottomed flask were placed 4-Chloro-6-methoxy-8-methylpteridin-7(8H)-one (2.00 g, 8.83 mmol, 1 equiv) and spiro[indoline-3,4′-piperidin]-2-one (2.14 g, 10.6 mmol, 1.2 equiv). Anhydrous n-butanol (20 mL) and triethylamine (2.46 mL, 2 equiv) were added and reaction mixture was heated to 80° C. with stirring. The reaction was complete as monitored by LC/MS after 5 hours. The solvent was stripped by rotary evaporation, and the residue rinsed with water (5 mL) to yield a tan precipitate, which was collected by vacuum filtration and rinsed with water to afford the desired product which was used directly without any further purification. 1H NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.39 (s, 1H), 7.49 (d, 1H), 7.20 (d, 1H), 6.97 (t, 1H), 6.87 (t, 1H), 4.53-4.45 (m, 4H), 3.80 (s, 3H), 3.55 (s, 3H), 1.93-1.80 (m, 4H). MS (EI) for C20H20N6O3: 393 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].[Br:7][C:8]1[C:9]([OH:20])=[C:10]([C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:12][C:13]=1[OH:14].I[CH2:22][C:23]1[CH:38]=[CH:37][C:26]([CH2:27][NH:28][C:29]([C:31]2[N:32]=[CH:33][N:34]([CH3:36])[CH:35]=2)=[O:30])=[CH:25][CH:24]=1>CN(C)C=O>[Br:7][C:8]1[C:9]([OH:20])=[C:10]([C:15](=[O:19])[CH:16]([CH3:17])[CH3:18])[CH:11]=[CH:12][C:13]=1[O:14][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:28][C:29]([C:31]2[N:32]=[CH:33][N:34]([CH3:36])[CH:35]=2)=[O:30])=[CH:37][CH:38]=1
Reactant: Cn1cnc(C(=O)NCc2ccc(CI)cc2)c1
Reactant: CC(C)C(=O)c1ccc(O)c(Br)c1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)c1ccc(OCc2ccc(CNC(=O)c3cn(C)cn3)cc2)c(Br)c1O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 16.7 %

Procedure:
Add lithium carbonate (24 mg, 324 μmol) to 1-(3-bromo-2,4-dihydroxy-phenyl)-2-methyl-propan-1-one (70 mg, 270 μmol) and N-(4-(iodomethyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (106 mg, 297 μmol) in anhydrous dimethylformamide (4 mL). Warm the reaction mixture to 50° C. and stir for 1.5 hrs. Add additional N-(4-(iodomethyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (20 mg, 56 μmol) and stir for 1 hr at 50° C. Add additional lithium carbonate (24 mg, 324 μmol) and N-(4-(iodomethyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (20 mg, 56 μmol) and stir overnight at 50° C. Cool the reaction mixture to room temperature and quench with water. Extract the aqueous mixture with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate. Purify the residue by reverse phase HPLC using gradient 90/10 to 20/80 (water/0.1% trifluoroacetic acid)/acetonitrile as eluent to give the title compound (22 mg, 45 μmol). MS (m/z): 487 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 6-bromo-1-indanone (prepared as described by Cornelius, Lyndon A. M. and Combs, Donald W. Synth. Commun. (1994), 24(19), 2777-88) (1.4 g, 6.57 mmol) in 20 mL of methanol was added sodium borohydride (0.087 g, 2.3 mmol) over a period of five minutes at room temperature. The reaction mixture was stirred for two hours at room temperature, concentrated under pressure and partitioned between ethyl acetate (50 mL) and 1N HCl (20 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound as a solid (1.4 g, 99%). 1H NMR (CDCl3): δ 7.45 (s, 1H), 7.3 (d, 1H), 7.0 (d, 1H), 5.2 (t, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.4 (m, 1H), 1.9 (m, 2H).
Reaction SMILES: CO[C:3]([CH:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7](=[O:17])(=[O:16])[N:6]1[CH3:18])=[O:4].[CH3:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([NH2:30])=[CH:27][CH:28]=2)[O:23][C:22](=[O:31])[CH:21]=1>C1(C)C(C)=CC=CC=1>[CH3:18][N:6]1[CH:5]([C:3]([NH:30][C:26]2[CH:27]=[CH:28][C:29]3[C:20]([CH3:19])=[CH:21][C:22](=[O:31])[O:23][C:24]=3[CH:25]=2)=[O:4])[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1(=[O:16])=[O:17]
Reactant: COC(=O)C1C(=O)c2ccccc2S(=O)(=O)N1C
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Solvent: Cc1ccccc1C
Product: Cc1cc(=O)oc2cc(NC(=O)C3C(=O)c4ccccc4S(=O)(=O)N3C)ccc12
Temperature: 170 °C

Procedure:
8.1 g of 2-methyl-3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide and 5.7 g of 4-methyl-7-amino-coumarin are dissolved in 280 ml of xylene and the solution is heated for 21/2 hours in a bath of 170° C. to distill off the methanol formed during the reaction. The reaction mixture is refluxed for a further 5 hours, cooled, and the precipitate is collected by filtration. The precipitate is digested with 100 ml of 2N-hydrochloric acid at elevated temperature, treated with 100 ml of chloroform and extracted. The residue is collected by suction, washed successively with water, ethanol, methylene chloride and diethyl ether, washed, and dried, affording 2-methyl-3,4-dihydro-4-oxo-N-(2-oxo-4-methyl-2H-1-benzopyran-7-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide with a melting point above 285° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.CO[C:12](=O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[C:22]1[O:26][N:25]=[CH:24][CH:23]=1.[NH2:28][CH2:29][CH2:30][NH:31][S:32]([C:35]1[C:36]2[CH:37]=[CH:38][N:39]=[CH:40][C:41]=2[CH:42]=[CH:43][CH:44]=1)(=[O:34])=[O:33]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][NH:28][CH2:29][CH2:30][NH:31][S:32]([C:35]2[C:36]3[CH:37]=[CH:38][N:39]=[CH:40][C:41]=3[CH:42]=[CH:43][CH:44]=2)(=[O:34])=[O:33])=[C:16]([C:22]2[O:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1
Reactant: COC(=O)COc1ccc(Br)cc1-c1ccno1
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Agent: CC(C)C[AlH]CC(C)C
Product: O=S(=O)(NCCNCCOc1ccc(Br)cc1-c1ccno1)c1cccc2cnccc12

Procedure:
By following a similar procedure as described in Example 34, DIBAL-H reduction of (4-bromo-2-isoxazol-5-yl-phenoxy)-acetic acid methyl ester, and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide gives the free amine of the title compound as a white solid. ESIMS: m/z 517 [(M+H)+, 79Br], 519 [(M+H)+, 81Br].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F-].[Cs+].C([Sn](CCCC)(CCCC)[C:26]1[O:27][CH:28]=[CH:29][N:30]=1)CCC.C(=O)(O)[O-].[Na+]>O1CCOCC1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(OCC)(=O)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([C:26]3[O:27][CH:28]=[CH:29][N:30]=3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:13][CH:14]=1
Reactant: COC(=O)c1cc(Br)cc(-c2ccc(C)cn2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2ncco2)c1
Temperature: 90 °C
Yield: 103.9 %

Procedure:
To a degassed solution of methyl 3-bromo-5-(5-methylpyridin-2-yl)benzoate (1.0 g, 3.27 mmol) in 1,4-dioxane (20 mL) was added cesium fluoride (1.49 g, 9.80 mmol), 2-(tributylstannyl)-1,3-oxazole (2.34 g, 6.53 mmol) and Bis(tri-t-butylphosphine) palladium (83 mg, 0.163 mmol). The mixture was heated to 90° C. under nitrogen for 16 h, after which the reaction was cooled to 20° C. Ethyl acetate (200 mL) and saturated sodium bicarbonate solution (200 mL) were added. The organic layer was isolated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was run through silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) to give the title compound (1 g). MS 295.1 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Si:8]([O:15][C@H:16]1[C@H:21]([NH:22]C(=O)OC(C)(C)C)[CH2:20][CH2:19][N:18]([C:30]2[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([NH:38][C:39]3[N:44]=[C:43]([N:45]([CH:55]4[CH2:57][CH2:56]4)CC4C=CC(OC)=CC=4)[C:42]4=[N:58][CH:59]=[C:60]([C:61]#[N:62])[N:41]4[N:40]=3)[C:31]=2[Cl:63])[CH2:17]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C1(OC)C=CC=CC=1>ClCCCl.ClCCl>[NH2:22][C@@H:21]1[CH2:20][CH2:19][N:18]([C:30]2[C:31]([Cl:63])=[C:32]([NH:38][C:39]3[N:44]=[C:43]([NH:45][CH:55]4[CH2:56][CH2:57]4)[C:42]4=[N:58][CH:59]=[C:60]([C:61]#[N:62])[N:41]4[N:40]=3)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=2)[CH2:17][C@H:16]1[O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: COc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N
Temperature: 30 °C
Yield: 60.8 %

Procedure:
TFA (25% in 1,2-dichloroethane, 4 mL, 12.98 mmol) was added to a solution of (+/−)-tert-butyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (270 mg, 0.338 mmol) and anisole (0.148 mL, 1.351 mmol) in 1,2-dichloroethane (2 mL) and the resulting solution was heated at 30° C. overnight The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10), the layers were separated and aqueous layer was extracted with dichloromethane/methanol (4/1) two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 1-7% methanol/dichloromethane to afford (+/−)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (119 mg,) and then 6-16% 2 N ammonia in methanol/dichloromethane to give (+/−)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (8 mg,).
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:24][CH2:25][CH2:26]O>CC(=O)OCC>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:26][CH2:25][Br:24])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: OCCBr
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCBr)o1

Procedure:
The title compound was prepared as described in Example 1 starting from 0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.150 mL (2.1 mmol) of 2-bromoethanol. MS (m/z, ES+): 446.30 (79BrM+1, 100%), 448.30 (81BrM+1, 80%); 1H NMR (400 MHz, DMSO-d6) δ: 7.30 (d, 1H), 5.67 (d, 1H), 4.49 (t, 2H), 4.16 (t, 2H), 3.73 (t, 2H), 1.72 (p, 2H), 1.3-1.45 (m, 2H), 1.25 (s, 20H), 0.85 (t, 3H); EA found for C21H35BrO4: C, 58.93; H, 8.52; calcd: C, 58.47; H, 8.18.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:4]=1.[S:27]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])(=[O:29])[NH2:28]>>[S:27]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:26])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])[CH:34]=[CH:35][CH:36]=1)(=[O:29])(=[O:30])[NH2:28]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethoxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.20) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 526.2 [(M−H)−]; mp 231° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][NH2:13].[CH3:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=O.Cl.[OH-].[Na+]>C(O)C>[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5]/[C:4]/1=[N:12]/[N:13]=[CH:20][C:16]1[N:15]([CH3:14])[CH:19]=[CH:18][N:17]=1
Reactant: Cn1c(=NN)sc2ccccc21
Reactant: Cn1ccnc1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ccnc1C=N/N=c1/sc2ccccc2n1C

Procedure:
As in Example 1, 1.27 g (5.45 mmol) of 2,3-dihydro-3-methyl-2-benzothiazolone hydra-zone hydrochloride and 0.60 g (5.45 mmol) of 1-methyl-2-imidazolecarboxaldehyde in 40 mL of a mixture of HCl and ethanol (1:2) were stirred at room temperature for 30 minutes. The mixture was then rendered slightly alkaline with 2N sodium hydroxide solution. The precipitated product was suction-filtered off, washed with water and dried under vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C.O>[CH2:11]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (283 mg, 2.5 mmol) in dry DMF (5 ml) under an argon atmosphere was added NaH (120 mg, 2.75 mmol) in small portions at 0° C. The reaction mixture was stirred at rt for 1 hour, cooled again to 0° C. before benzyl bromide (300 μl, 2.5 mmol) was added and stirred at rt for 12 h. The mixture was diluted with water, extracted with ethyl acetate and the product was purified by chromatography on silica gel using heptane/ethyl acetate as eluent. The title compound was obtained as light yellow oil (484 mg, 95%). MS ISP (m/e): 226.3 (100) [(M+Na)+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:2]4[N:1]=[CH:6][CH:5]=[CH:4][N:3]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ncccn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ncccn1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 70.2 %

Procedure:
A solution of 2,2,2-trichloroethyl pyrimidin-2-ylcarbamate (200 mg, 0.739 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (181 mg, 0.739 mmol), diisopropylethylamine (0.258 ml, 1.48 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (190 mg, 70.4%) as a solid.