Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[C:6]1([CH:12]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:13]2[N:14]=[N:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li]CCCC.[CH:41]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([CH3:52])[CH3:51])[C:45]=1[N:53]=[C:54]=[O:55])([CH3:43])[CH3:42]>O>[CH3:43][CH:41]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([CH3:51])[CH3:52])[C:45]=1[NH:53][C:54](=[O:55])[C:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:13]1[N:14]=[N:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:17]=1)[CH3:42]
Reactant: CCCCCCCCCCCCn1nnc(C(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCn1nnc(C(C(=O)Nc2c(C(C)C)cccc2C(C)C)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To a THF solution (30 mL) of 5-(diphenylmethyl)-2-dodecyl-2H-tetrazole (1.0 g, 0.0025 mol) at -30° C. under a nitrogen atmosphere with stirring was added n-BuLi (1.62 mL, 1.6M in hexanes, 0.0026 mol). The resulting deep-red solution was stirred for 30 minutes before a THF solution (10 mL) of 2,6-diisopropylphenylisocyanate (0.53 mL, 0.0024 mol) was added dropwise over 10 minutes. The resulting yellow solution was allowed to warm to room temperature over 24 hours. Water (10 mL) was then added and the solution partitioned between ethyl acetate and water. The organic extract was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo to yield a yellow oil which was flash chromatographed (5% EtOAc-Hex as eluant, SiO2) to yield 1.16 g of the title product as a clear oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([C:20]([F:23])([F:22])[F:21])[CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.[N:24]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25]1.C1(S(N)(=O)=O)CC1>>[N:24]1([S:28]([NH:31][C:9](=[O:10])[C:8]2[CH:12]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([O:14][CH2:15][C:16]3([C:20]([F:21])([F:23])[F:22])[CH2:17][CH2:18][CH2:19]3)=[CH:6][C:7]=2[F:13])(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCC2)cc1F
Agent: NS(=O)(=O)C1CC1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCC2)cc1F

Procedure:
Following the procedure as described in Example 218 step 5 and making variations as required to replace trans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)benzoic acid and to replace azetidine-1-sulfonamide with cyclopropanesulfonamide, the title compound was obtained as colorless solid (0.09 g, 47%): 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 7.17-7.09 (m, 2H), 4.34 (s, 2H), 3.12-3.04 (m, 1H), 2.38-2.27 (m, 2H), 2.19-2.09 (m, 3H), 2.03-1.94 (m, 2H), 1.14-1.10 (m, 4H), 0.90-0.84 (m, 2H), 0.70-0.64 (m, 2H); MS (ES+) m/z 436.1 (M+1); MS (ES−) m/z 434.2 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12](OC)(=[O:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14]>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:14])=[CH:5][CH:4]=1
Reactant: COC(=O)C(O)c1ccccc1
Reactant: COc1ccc(CCN)cc1
Solvent: CCOCC
Product: COc1ccc(CCNC(=O)C(O)c2ccccc2)cc1
Reaction time: 16 h

Procedure:
A mixture of 20.0 g. (0.133 mol) of 4-methoxyphenylethylamine and 22.0 g. (0.133 mol) of methyl mandelate is heated at about 90° C. with stirring under nitrogen for 16 hours. The reaction mixture is taken up in ether and the product crystallized, giving N-[2-(4-methoxyphenyl)ethyl]mandelamide, m.p. 86°-88° C.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.C(O[C:15](=O)[CH3:16])(=O)C>>[CH:4]1[CH:5]=[CH:6][C:15](/[CH:16]=[C:2]2/[C:3]([C:4]3[C:9]([O:1]/2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:10])=[CH:2][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1COc2ccccc21
Product: O=C1/C(=C/c2ccccc2)Oc2ccccc21
Temperature: 100 °C

Procedure:
The compounds of this invention are prepared as shown in the following reaction scheme: ##STR2## in which R1 and R2 are as defined in formula I. Thus, as shown above, a 3-coumaranone is reacted with an appropriately substituted benzaldehyde and acetic anhydride by heating at a temperature up to about 100° C. for from 1 to 3 hours. The reaction mixture is treated with ice, extracted with a nonreactive organic solvent such as ether and the product from the extract is heated at reflux for about one hour with a mineral acid, such as hydrochloric acid, an alkanol such as methanol or ethanol, and water. Cooling gives the substituted aurone product.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=O)[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH:6]([OH:60])[CH2:5][C:4]1=[O:61])[CH3:2].[CH2:62]([NH2:69])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C([BH3-])#N.[Na+]>C(O)(C)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:69][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH:6]([OH:60])[CH2:5][C:4]1=[O:61])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(Oc4ccccc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NCc4ccccc4)C(Oc4ccccc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-phenoxy-4"-oxocyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry isopropyl alcohol (3 ml) is added benzyl amine (87 mg). The mixture is stirred at r.t. for 30 minutes, and cooled to -78° C. To this solution is added a solution of sodium cyanoborohydride (6.7 mg) in isopropyl alcohol (0.5 ml). The reaction is stirred at -78° C. and poured into ice water. Extraction with ethyl acetate, followed by purification gives the title compound as a mixture of epimers at C-4".
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[OH-].[NH4+:12]>>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: [NH4+]
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C

Procedure:
5-Chloro-2-thiophenesulfonyl chloride (4 g, 18.4 mmole) was added to ammonium hydroxide (100 ml of conc. aqueous solution). This mixture was stirred at room temperature and concentrated under vacuum. The precipitate was filtered and washed with hexanes and water to produce 1.94 g of solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[N:10][C:9]2[C:4]1=[N:5][C:6]([NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1)=[N:7][C:8]=2[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[CH3:2].O.NN>CO.[Ni]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:8]2[N:7]=[C:6]([NH:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([OH:29])[CH2:27][CH2:28]3)[N:5]=[C:4]3[C:9]=2[N:10]=[CH:11][N:3]3[CH2:1][CH3:2])=[CH:14][CH:15]=1
Reactant: CCn1cnc2c(Nc3ccc([N+](=O)[O-])cc3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CCn1cnc2c(Nc3ccc(N)cc3)nc(N[C@H]3CC[C@H](O)CC3)nc21

Procedure:
A flask is charged with 12.15 g (30.57 mmol) of trans-4-[9-ethyl-6-(4-nitro-phenylamino)-9H-purin-2-yl-amino]-cyclohexanol in 1.15 l of methanol and kept under argon. At 40° C. Raney-Nickel is added slowly, followed by dropwise addition of 15.04 ml (50.06 mmol) of hydrazine monohydrate. After completion the reaction mixture is filtered, the filtrate concentrated and the crude product is purified by chromatography to obtain trans-4-[6-(4-amino-phenyl-amino)-9-ethyl-9H-purin-2-yl-amino]-cyclohexanol (74% yield); ESI-MS: 368 (M+H)+; tRet (HPLC) 7.48 min (method: same system as in method d, gradient 5®40% acetonitrile in 7,5 min.+12 min. 40% acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[C:5]([NH:7][C:8]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:9]=1[C:10]([O:12]C(C)(C)C)=[O:11])=[O:6]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[C:5]([NH:7][C:8]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1cc(Cl)cc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(CCc2ccccc2)ccc1C(=O)O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(3,5-dichlorobenzamido)-4-phenethylbenzoate and stirred ad room temperature for 2 hours. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 62 mg of 2-(3,5-dichlorobenzamido)-4-phenethylbenzoic acid as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[O:21][C:22]([CH3:25])=[N:23][N:24]=3)[CH:17]=[CH:16][C:15]=2[CH3:26])=[CH:10][CH:9]=1)=[O:7].I[CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([CH2:32][CH3:33])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[O:21][C:22]([CH3:25])=[N:23][N:24]=3)[CH:17]=[CH:16][C:15]=2[CH3:26])=[CH:12][CH:13]=1)=[O:7]
Reactant: CCI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4Cl)cc3)c2)o1
Product: CCN(Cc1ccccc1Cl)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-(2-Chlorobenzyl)-N-ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(2-chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.77,(1H, b), 7.58-7.32,(9H, m), 4.76-4.60,(2H, m), 3.42-3.27,(2H, b), 2.56,(3H, s), 2.32-2.28,(3H, m), 1.08,(3H, b). LCMS; retention time 3.66 min, MH+ 446/448.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[CH2:40]([O:42][C:43]([CH:45]1[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]1)=[O:44])[CH3:41]>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:47]3[CH2:48][CH2:49][CH2:50][CH:45]([C:43]([O:42][CH2:40][CH3:41])=[O:44])[CH2:46]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(c2nc3c(c(-c4ccccc4C)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)C1
Yield: 78 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 3-(ethoxycarbonyl)piperidine (28.3 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-2-[3-(ethoxycarbonyl)piperidine-1-yl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (76.0 mg, 78%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:40]=[C:41]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH:42]=1)[NH2:39].Cl[C:50]1[C:59]2[C:54](=[CH:55][C:56]([F:61])=[CH:57][C:58]=2[F:60])[N:53]=[C:52]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=2)[C:51]=1[CH3:68].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:35][C:36]1[CH:37]=[C:38]([NH:39][C:50]2[C:59]3[C:54](=[CH:55][C:56]([F:61])=[CH:57][C:58]=3[F:60])[N:53]=[C:52]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=3)[C:51]=2[CH3:68])[CH:40]=[C:41]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH:42]=1
Reactant: Nc1cc(Cl)cc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Cl)cc(N2CCOCC2)c1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.026 g, 0.055 mmol), 3-chloro-5-morpholinoaniline (0.088 g, 0.41 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.1 g, 0.34 mmol) and Pd2dba3 (0.013 g, 0.014 mmol) in toluene (3.40 mL) was added sodium t-butoxide (0.083 g, 0.860 mmol). The reaction mixture was heated to 120° C. and stirred for 45 min. The reaction was then cooled to rt and diluted with water (25 mL). The mixture was extracted with EtOAc (2×10 mL) and DCM (1×10 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% EtOAc in hexane) to give the desired product N-(3-chloro-5-(4-morpholinyl)phenyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.72 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 7.85-7.92 (1H, dt, J=7.9, 1.8 Hz), 7.79-7.85 (1H, d, J=7.9 Hz), 7.67 (1H, br. s), 7.38 (1H, ddd, J=7.5, 4.8, 1.2 Hz), 7.02 (2H, ddd, J=13.7, 8.6, 2.5 Hz), 6.49-6.54 (1H, m), 6.36 (1H, m), 6.27 (1H, m), 3.79-3.90 (4H, m), 3.09-3.23 (4H, m), 2.17 (3H, s). Mass Spectrum (ESI) m/e=467.2 (M+1).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[C:9](O)=O)=O.C(OC(=O)C)(=O)C.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[C:20]#[CH:21]>>[CH2:24]([O:23][C:19]([C:20]1[CH:9]=[CH:4][N:3]2[CH2:8][CH2:7][O:6][CH2:5][C:21]=12)=[O:22])[CH3:25]
Reactant: C#CC(=O)OCC
Reactant: O=CN1CCOCC1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn2c1COCC2
Temperature: 120 °C
Yield: 37 %

Procedure:
To a mixture of 4-formyl-morpholine-3-carboxylic acid (Comp. No. 1) (43 g, 0.295 mol) and acetic anhydride (410 g, 4 mol) was added ethyl propiolate (190 g, 1.94 mol). The resulting mixture was heated slowly to 120° C., which was accompanied by gas evolution. After heating for 2 h at 120° C., the resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with up to 25% ethyl acetate in heptane) to give 21.4 g (37%) of pure 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester. LC/MS (method 4): Rt=1.10 min; m/z=196.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: BrCCOc1ccccc1
Reactant: Oc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ncccc1OCCOc1ccccc1
Temperature: 100 °C
Yield: 73.3 %

Procedure:
A mixture of 2-chloro-3-hydroxypyridine (3.0 g, 23.1 mmol), β-bromophenetole (4.66 g, 23.2 mmol), and K2CO3 (8.0 g, 57.9 mmol) in DMF (50 mL) was heated at 100° C. for 1.5 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and H2O. The organic phase was dried (MgSO4), filtered, and the solvent evaporated. The solid residue was triturated with a small amount of ether and dried (65° C., 1 mmHg) to afford 4.23 g (74%) of the title product as white crystals: mp 77-78° C. Anal. (C13H12ClNO2) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.Br[C:33]1[CH:34]=[C:35]([S:39]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])(=[O:41])=[O:40])[CH:36]=[N:37][CH:38]=1>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.CN(C=O)C>[CH2:45]([N:42]([CH2:43][CH3:44])[S:39]([C:35]1[CH:34]=[C:33]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)[CH:38]=[N:37][CH:36]=1)(=[O:40])=[O:41])[CH3:46]
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Reactant: CCN(CC)S(=O)(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCN(CC)S(=O)(=O)c1cncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg) was placed in a microwave vial with Pd(PPh3)4 (10 mg) and 5-bromo-N,N-diethyl-3-pyridinesulfonamide (29 mg) was added. DMF (2 ml) was added and the reaction was heated under microwave irradiation for 15 min at 120° C. The reaction was evaporated to dryness and the residue was dissolved in IPA (2 ml) and 2M NaOH (aq) (1 ml). The reaction was stirred at RT for 3 h then evaporated to dryness. The residue was purified by MDAP (method E). The residue obtained was further purified on silica, eluting with 0-100% EtOAc/cyclohexane over 15 min followed by 0-20% MeOH/DCM, to give the title compound (13 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[SH:12][CH2:13][CH2:14][C:15]([N:17]([CH3:29])[C:18]1[S:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:22]=1)=[O:16].C(OCC)(=O)C>ClCCCl>[C:8](=[O:10])([S:12][CH2:13][CH2:14][C:15]([N:17]([CH3:29])[C:18]1[S:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:22]=1)=[O:16])[CH3:9]
Reactant: CN(C(=O)CCS)c1nnc(-c2cccnc2)s1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCCC(=O)N(C)c1nnc(-c2cccnc2)s1
Temperature: 23 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
Triethylamine (12 μL, 0.086 mmol, 1.2 equiv) and acetyl chloride (6 μL, 0.08 mmol, 1 equiv) were sequentially added to a stirred solution of 3-mercapto-N-methyl-N-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanamide (20 mg, 0.071 mmol, 1.0 equiv) in 1,2-dichloroethane (1.4 mL) at 23° C. The resulting pale yellow solution was stirred at 23° C. for 16 h. The reaction mixture was directly subjected to silica gel column chromatography (ethyl acetate) to afford the title compound as a white powder (23 mg, 99%): mp 133-135° C.; 1H NMR (300 MHz, CDCl3) δ 9.14 (d, J=2 Hz, 1H), 8.69 (dd, J=5, 2 Hz, 1H), 8.27 (dt, J=8, 2 Hz, 1H), 7.42 (dd, J=8, 5 Hz, 1H), 3.82 (s, 3H), 3.26 (t, J=7 Hz, 2H), 3.03 (t, J=7 Hz, 2H), 2.36 (s, 3H); ESIMS m/z 323 ([M+H]+).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH:13]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])C.Cl>O1CCOCC1>[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:3])([O:11][CH2:12][CH:13]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10]
Reactant: CCOC(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Agent: Cl
Solvent: C1COCCO1
Product: O=CCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 98000 %

Procedure:
To a stirring solution of N-Fmoc-4-amino-butyraldehyde diethyl acetal (0.050 mmol) in 1,4-dioxane (100 mL) was added aq. HCl (100 ml, 1:1 v/v, H2O:conc. HCl) and the reaction progress was monitored by MS. Upon completion, the organic solvent was removed by rotary evaporation, and the aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with 5% NaHCO3 (2×75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated to dryness to yield the desired N-Fmoc-4-amino-butyraldehyde (15.35 g, 0.049 mol, 90.0% yield), which was carried through to the next step without further purification: MS m/e [M+Na]+ calcd 332.1, found 332.0.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:12]=[C:11]([N:13]3[C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:16]=4[N:15]=[CH:14]3)[S:10][C:9]=2[C:22]([O:24]C)=O)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH3:32]>CO>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:12]=[C:11]([N:13]3[C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:16]=4[N:15]=[CH:14]3)[S:10][C:9]=2[C:22]([NH2:32])=[O:24])=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccc(F)cc1C(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccc(F)cc1C(F)(F)F

Procedure:
In a similar manner as described for example 38, 92.1 mg of methyl 3-{[4-fluoro-2-(trifluoromethyl)benzyl]oxy}-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 15 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH2:29]([C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1)[CH3:30].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH2:29][CH3:30])[CH:32]=1)[CH3:28]
Reactant: CCc1cccc(O)c1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2cccc(CC)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 3-ethylphenol (0.34 g), 8 M potassium hydroxide solution (0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.54 g, 62%).