Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@@H:21]([O:23][CH3:24])[CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][C@@H:21]([O:23][CH3:24])[CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@@H](OC)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1C[C@H](Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2F)[C@@H](c2ccnn2C)C1
Yield: 88.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4S*)-4-methoxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (60.0 mg, 0.0975 mmol) prepared in Example 120d, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (40.0 mg, 88%) as a colorless solid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:12]1[CH2:38][CH2:37][CH2:36][C:14]2([O:18][CH2:17][CH:16]([C:19]3[CH:24]=[C:23]([N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[C:30]([F:33])([F:32])[F:31])[CH:22]=[CH:21][C:20]=3[O:34][CH3:35])[CH2:15]2)[CH2:13]1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].O>C(O)C>[OH:5][CH:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][N:12]1[CH2:38][CH2:37][CH2:36][C:14]2([O:18][CH2:17][CH:16]([C:19]3[CH:24]=[C:23]([N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[C:30]([F:32])([F:33])[F:31])[CH:22]=[CH:21][C:20]=3[O:34][CH3:35])[CH2:15]2)[CH2:13]1
Reactant: COc1ccc(-n2ccnc2C(F)(F)F)cc1C1COC2(CCCN(CC(=O)c3ccccc3)C2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-n2ccnc2C(F)(F)F)cc1C1COC2(CCCN(CC(O)c3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
Sodium borohydride (12 mg, 0.32 mmol) was added to a solution of (±)-(3R*, 5R*)-7-phenacyl-3-(2-methoxy-5-(2-trifluoromethyl-1H-imidazol-1-yl)phenyl)-1-oxa-7-azaspiro[4,5]decane (105.9 mg, 0.212 mmol) in ethanol (2 ml) and the mixture stirred at room temperature for 4 hours. The mixture was poured into water (50 ml) and extracted with ethyl acetate (2×20 ml). The extracts were washed with brine (20 ml), combined, dried (MgSO4) and concentrated. The residue was purified by flash chromatography, eluting with 5% then 7.5% methanol in dichloromethane to give (±)-(3R*, 5R*, 12S*/R*)-7-(2-hydroxy-2-phenylehtyl)-3-(2-methoxy-5-(2-trifluoromethyl-1H-imidazol-1-yl)phenyl)-1-oxa-7-azaspiro[4,5]decane (86.0 mg, 81%). The free base was dissolved in ether and treated with oxalic acid (15.7 mg) in ether. The resulting precipitate was collected under suction, washed with ether and dried in vacuo to afford the title compound (75.1 mg); (Found: C, 58.89; H, 5.11; N, 6.87. C27H30F3N3O3. C2H2O4 requires C, 58.88; H, 5.45; N, 7.10%; δH (360 MHz, D2O) 1.72-2.37 (6H, m), 3.11 (2H, m), 3.34-3.96 (10H, m), 4.27 (1H, m), 5.25 (1H, m), 7.13 (1H, d, J 9.3 Hz, 3'-H), 7.22 (1H, br s, imidazole H), 7.36 (3H, m, ArH), 7.47 (5H, m, ArH); m/z (ES+) 502 ([M+H]+).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[OH:27][CH2:26][C:25]([NH:24][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:14]=1[F:13])([CH3:29])[CH3:28]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
WSC HCl (7.68 g, 40 mmol) was added to a mixture of 2,4-difluorobenzoic acid (6.32 g, 40 mmol), 2-amino-2-methyl-1-propanol (3.56 g, 40 mmol) and HOBt (5.40 g, 40 mmol) in methylene chloride (150 ml), and stirred at room temperature for 3 hours. The reaction mixture was concentrated, diluted with ethyl acetate and washed with saturated aqueous NaHCO3, 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively, dried over MgSO4 and concentrated under a reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate 3/1) to give the title compound (6.20 g; 68%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:4]=1[Cl:27].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>CN(C)C=O.C(OCC)(=O)C>[Cl:27][C:4]1[CH:5]=[C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][N:32]1[C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]2[C:28]1=[O:38]
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CC(c2ccc(CBr)c(Cl)c2)=NO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl

Procedure:
To a solution of 34.1 g of 3-(4-bromomethyl-3-chlorophenyl)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 200 mL of N,N-dimethylformamide, 12.6 g of potassium phthalimide was added and the resultant mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was diluted with 350 mL of ethyl acetate and the diluted reaction mixture was washed with water (80 mL×3). Subsequently, the washed reaction mixture was dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:3) to obtain 24.3 g of the objective substance as a light yellow resinoid.
Reaction SMILES: [CH:1]([C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:11][CH:10]=1)=[O:2].S([CH2:36][N+:37]#[C-:38])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CO>[O:2]1[C:1]([C:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])=[CH:11][CH:10]=2)=[CH:38][N:37]=[CH:36]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(Nc1ccc(C2=C(c3cnco3)CCCC2)cc1)c1c(F)cccc1F
Yield: 65 %

Procedure:
The solution of Compound 100 (60 mg, 0.17 mmol), tosylmethylisocyanide (38 mg, 0.19 mmol) and K2CO3 (50 mg, 0.36 mmol) in MeOH (5 mL) were heated at 90° C. for 40 min before it was filtered and concentrated. The residue was dissolved in EtOAc (10 mL) and H2O (10 mL). The organic phase was collected, dried and concentrated. Column chromatography afforded Compound 23 (47, 65%). 1H NMR (300 MHz, CDCl3) δ 7.64-7.59 (m, 4H), 7.46-7.40 (m, 1H), 7.12 (d, J=8.7 Hz, 2H), 7.01 (t, J=8.1 Hz, 2H), 6.21 (s, 1H), 2.49-2.40 (m, 4H), 1.84-1.76 (m, 4H);
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20][CH2:19]3)=[O:17])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>C(#N)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=2)[C:3]([N:9]2[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH2:14]2)=[N:4][CH:5]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CN1CCCN(C(=O)CC2CCN(c3ncc(Br)cc3N)CC2)CC1
Solvent: CC#N
Product: CN1CCCN(C(=O)CC2CCN(c3ncc(Br)cc3NC(=O)c3cccc(Cl)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of 0.350 g (0.853 mmol) of 2-(3′-amino-5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-1-(4-methyl-[1,4]diazepan-1-yl)-ethanone in acetonitrile (50 mL) is added 0.15 g (0.853 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred overnight at room temperature during which time a solid precipitates from solution. The formed solid is collected by filtration, washed with cold diethyl ether and dried on the filter pad to provide 0.308 g (66.0%) of N-{5′-bromo-4-[2-(4-methyl-[1,4]diazepan-1-yl)-2-oxo-ethyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl}-3-chloro-benzamide in N,N-dimethylformamide as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[N:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([N:20]3[CH:28]([OH:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[N:17]2)=[CH:12][CH:11]=1.[CH3:31][CH:32]([CH3:38])[CH2:33][CH2:34][C:35](Cl)=[O:36].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:31][CH:32]([CH3:38])[CH2:33][CH2:34][C:35]([O:30][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28](=[O:29])[N:20]1[C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[N:19][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)[N:17]=1)=[O:36]
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CC(C)CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)CCC(C)C)nc2n1
Yield: 30.2 %

Procedure:
Triethylamine (27 cc) is added to a solution, maintained at a temperature in the region of 20° C., of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (12.3 g) in methylene chloride (200 cc). 4-Methylpentanoyl chloride (10.8 g) and 4-dimethylaminopyridine (50 mg) are then introduced dropwise in the course of 20 minutes, and the reaction mixture is then heated for 19 hours under reflux. The suspension obtained in poured into water (800 cc) and the solid obtained is separated by filtration and removed. The organic phase is separated after settling has occurred, washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is purified by chromatography on silica gel (0.063-0.2 mm; 150 g) contained in a column 2.7 cm in diameter (eluant: methylene chloride), eluting 50-cc fractions. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After the solid obtained has been recrystallized in acetonitrile, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-methylpentanoate (4.9 g), m.p. 133° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18].S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[Cl:27][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:5]=1)[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cc1OCc1nc(-c2ccccc2)oc1C
Solvent: Cc1ccccc1
Product: COc1ccc(CCl)cc1OCc1nc(-c2ccccc2)oc1C
Yield: 75 %

Procedure:
A mixture of 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (3.22 g), thionyl chloride (0.73 ml) and toluene (50 ml) was refluxed for 1 hour. After the reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 4-(5-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (2.59 g, yield 75%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 129–130° C.
Reaction SMILES: ClC1C=CC(NC2C=C[CH:12]=[C:11]([C:15]3O[C:18]([C:20]4[CH:24]=[CH:23]SC=4)=[N:17][CH:16]=3)N=2)=NC=1.Cl[C:26]1[O:27][C:28]([C:31]2[N:36]=[C:35]([NH:37][C:38]3[CH:43]=[N:42][CH:41]=[CH:40][N:39]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:29][N:30]=1.N1C2C(=CC(B(O)O)=CC=2)C=C1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.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>[NH:17]1[C:16]2[C:24](=[CH:23][C:12]([C:26]3[O:27][C:28]([C:31]4[N:36]=[C:35]([NH:37][C:38]5[CH:43]=[N:42][CH:41]=[CH:40][N:39]=5)[CH:34]=[CH:33][CH:32]=4)=[CH:29][N:30]=3)=[CH:11][CH:15]=2)[CH:20]=[CH:18]1
Reactant: Clc1ncc(-c2cccc(Nc3cnccn3)n2)o1
Reactant: Clc1ccc(Nc2cccc(-c3cnc(-c4ccsc4)o3)n2)nc1
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: OB(O)c1ccc2[nH]ccc2c1
Solvent: O
Solvent: C1CCOC1
Product: c1cc(Nc2cnccn2)nc(-c2cnc(-c3ccc4[nH]ccc4c3)o2)c1

Procedure:
Prepared as for (5-chloro-pyridin-2-yl)-[6-(2-thiophen-3-yl-oxazol-5-yl)-pyridin-2-yl]-amine from [6-(2-chloro-oxazol-5-yl)-pyridin-2-yl]-pyrazin-2-yl-amine, indole-5-boronic acid, Pd(PPh3)4 and K2CO3 in THF/water to afford the title compound as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.08 (s, 1H), 9.28 (s, 1H), 8.38 (s, 1H), 8.30-8.25 (m, 1H), 8.16 (d, J=2.6 Hz, 1H), 7.93-7.81 (m, 2H), 7.79 (s, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.51-7.42 (m, 2H), 6.62 (s, 1H). (ESI+) m/z 338 (M+H)+. Retention time=1.81 mins (method 1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:30])[C:10]=1[C:11](=[O:29])[NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[C:20]([N:22]3[CH2:26][CH2:25][CH:24]([O:27][CH3:28])[CH2:23]3)[N:21]=2)[CH:18]=1)=[O:5])C.CN1C(C(=O)NC2C=CC3N(N=C(N4CCOCC4)N=3)C=2)=C(C(O)=O)C=N1>>[CH3:28][O:27][CH:24]1[CH2:25][CH2:26][N:22]([C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:11]([C:10]4[N:9]([CH3:30])[N:8]=[CH:7][C:6]=4[C:4]([OH:5])=[O:3])=[O:29])=[CH:18][N:17]3[N:19]=2)[CH2:23]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCC(OC)C3)nn2c1
Agent: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Product: COC1CCN(c2nc3ccc(NC(=O)c4c(C(=O)O)cnn4C)cn3n2)C1

Procedure:
Using 5-[2-(3-Methoxy-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, this compound was prepared following the same method as for the synthesis of 1-Methyl-5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid. Off white solid (690 mg, 82%). MS: m/z=386 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[C:8]([NH2:16])=[CH:9][C:10]3[O:14][CH2:13][O:12][C:11]=3[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23](COCC[Si](C)(C)C)[CH:24]=1)#[N:19]>>[C:1]1([C:7]2[C:8]([NH:16][C:33]([C:22]3[NH:21][C:20]([C:18]#[N:19])=[CH:24][N:23]=3)=[O:34])=[CH:9][C:10]3[O:14][CH2:13][O:12][C:11]=3[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1cc2c(cc1C1=CCCCC1)OCO2
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: N#Cc1cnc(C(=O)Nc2cc3c(cc2C2=CCCCC2)OCO3)[nH]1

Procedure:
The title compound was prepared by coupling 6-cyclohex-1-enyl-benzo[1,3]dioxol-5-ylamine (prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (prepared in Example 11, step (d)) according to the procedure in Example 42, step (c) followed by SEM deprotection according to the procedure in Example 11, step (g). 1H-NMR (DMSO-d6, 400 MHz): δ 14.23 (s, 1H), 9.67 (s, 1H), 8.31 (s, 1H), 7.48 (s, 1H), 6.78 (s, 1H), 6.01 (s, 2H), 5.69 (s, 1H), 2.20-2.05 (m, 4H), 1.71-1.57 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C18H16N4O3, 337.1 (M+H), found 337.0.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2N=N1.[CH3:23][C:24]1[C:25]2[N:26]([CH:30]=[C:31]([C:33](O)=[O:34])[N:32]=2)[CH:27]=[CH:28][CH:29]=1.NC1C=CC=CC=1>ClCCl.O.C(N(CC)CC)C>[CH3:23][C:24]1[C:25]2[N:26]([CH:30]=[C:31]([C:33]([NH:14][C:18]3[CH:17]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:34])[N:32]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccn2cc(C(=O)O)nc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: Nc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccn2cc(C(=O)Nc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.9 %

Procedure:
1.67 ml of triethylamine, 1.53 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.08 g of 1-hydroxybenzotriazole are added to a solution of 0.176 g of 8-methylimidazo[1,2-a]pyridine-2-carboxylic acid in 12 ml of dichloromethane. The reaction mixture is stirred at ambient temperature for 20 minutes. 0.090 ml of aniline is added. The reaction mixture is stirred at ambient temperature for 4 hours. 60 ml of dichloromethane and 30 ml of water are added. After separation by settling, the organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. After purifying by flash chromatography (silica, eluent dichloromethane/ethyl acetate 98/02 by volume), 0.193 g of 8-methyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide is obtained in the form of a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:19]2[CH:18]=[C:17](C(OCC)=O)[O:16][C:15]=2[C:14]2[CH:13]=[CH:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=2[CH:4]=1)=[O:2].C1COCC1.Cl>O>[CH:18]1[C:19]2[C:3]([CH:1]=[O:2])=[CH:4][C:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[CH:12]=[CH:13][C:14]=3[C:15]=2[O:16][CH:17]=1
Reactant: CCOC(=O)c1cc2c(C=O)cc3c4ccccc4ccc3c2o1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc2c3ccccc3ccc2c2occc12
Yield: 37 %

Procedure:
To a RB flask equipped with a magnetic stirring bar, condenser, and N2 inlet line with bubbler was added ethyl 11-formyl-phenanthro[1,2-b]furan-2-carboxylate (15A, 2.5 g, 7.8 mmol), 1NaOH solution (25 mL), THF (50 mL) and H2O (25 mL). The mixture was refluxed for 2 h until it became homogeneous. The mixture was acidified with 1N HCl and the solvent removed by rotary evaporaton. The crude solid was then heated to 150° with copper powder (0.9 g) and quinoline and (Aldrich, 25 mL) for 1 h. The reaction mixture was cooled and the quinoline removed under vacuum to give a crude dark green solid. After chromatography and cyrstallization (CH2Cl2 /hexane) 0.71 g (37% yield) of phenanthro[1,2-b]furan-11-carbaldehyde, mp 145°-150°, (C,H).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[NH2:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[NH2:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-amino-5-(3-methyl-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH3:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[OH:17][C:16]1[C:15]([OH:19])=[N:1][C:2]2[C:3](=[CH:4][CH:5]=[C:6]3[N:7]([CH3:11])[N:8]=[N:9][C:10]3=2)[N:12]=1
Reactant: Cn1nnc2c(N)c(N)ccc21
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cn1nnc2c3nc(O)c(O)nc3ccc21
Yield: 90.8 %

Procedure:
A solution of 4,5-diamino-1-methylbenzotriazole (1.2 g, 7.4 mmol) and oxalic acid dihydrate (1.2 g, 9.6 mmol) in 40 ml of 4M hydrochloric acid was refluxed on an oil bath for 2 h and allowed to cool. The resulting precipitate was collected by filtration and washed with water and ethanol to give 1.46 g (91%) of the title compound; m.p.>300° C.; IR (KBr): 1700 cm-1 ; 1H-NMR (DMSO-d6): 4.32 (s, 3H, CH3), 7.33 (d, J=9 Hz), 1H, ArH), 7.55 (d, J=9 Hz, 1H, ArH), 12.03 (broad s, 1H, OH), 12.67 (broad s, 1H, OH).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 50.2 %

Procedure:
Following procedures essentially as described in Example 90, 3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (50 mg, 0.168 mmol) and 1-propanesulfonyl chloride (144 mg, 1.01 mmol) affords 34 mg (50%) of the title compound as a white foam. MS (ES) 426 M+Na), 402 (M−H); HPLC shows 99% purity.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][C:10]=1[Br:18])([CH3:8])[CH3:7].[Cl-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:18][C:10]1[C:9]([CH:6]([CH3:7])[CH3:8])=[CH:14][C:13]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)c1ccc(C(C)C)c(Br)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cc(S(=O)(=O)Cl)c(C(C)C)cc1Br
Reaction time: 0.5 h

Procedure:
4-Bromo-2,5-diisopropylbenzene sulfonyl chloride was prepared as follows: Chlorosulfonic acid, 154 g, was added over 15 minutes to 80 g of 2,5-diisopropylbromobenzene in 200 ml of carbon tetrachloride. The reactants were stirred for 30 minutes longer and then poured onto a mixture of ice and saturated sodium chloride solution. The organic layer was washed with cold water and dried over magnesium sulfate. Removal of the solvent gave 105 g of crystalline product. Recrystallization from n-hexane gave pure 4-bromo-2,5-diisopropylbenzene sulfonyl chloride, which softened at 77°C and melted at 80.5°-83°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[CH3:11][NH:12][NH2:13]>C(OCC)C>[CH3:1][O:2][C:3](=[O:4])/[C:5](/[N:12]([CH3:11])[NH2:13])=[CH:6]\[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CNN
Solvent: CCOCC
Product: COC(=O)/C=C(\C(=O)OC)N(C)N
Temperature: -20 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of dimethylacetylene dicarboxylate (50.0 g, 344.8 mmol) in diethylether (1 L) under argon at 0° C. was added a solution of methylhydrazine (18.52 mL, 344.8 mL) in diethylether (100 mL) and the resulting mixture stirred for 2 h. The precipitate was filtered off, dissolved in ethanol (300 mL) at 50° C. and then the solution cooled to −20° C. whereupon the solid was filtered off and dried to afford the title compound (46.8 g, 72%) as a light yellow solid. MS: m/e=189.3 [M+H]+.