Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)=[C:4]([F:14])[CH:3]=1.O=S(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]2[C:5]([CH2:9][CH2:10][C:11]2=[O:13])=[C:4]([F:14])[CH:3]=1
Reactant: Cc1cc(CCC(=O)O)c(F)cc1Br
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1c(Br)cc(F)c2c1C(=O)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-bromo-2-fluoro-5-methylphenyl)propanoic acid (EP1795524 A1; 8.4 g) in DCM (200 mL) was added SOCl2 (19.1 g) dropwise at r.t. The mixture was stirred for 2 hours at r.t. The solvent was removed under reduced pressure. AlCl3 (21.4 g) was added to the residue. The brown slurry was heated to 130° C. for 1.5 hours and then cooled to r.t. The residue was dissolved in EA (300 mL) and then washed with water and brine. The organic phase was dried over Na2SO4. The residue obtained after filtration and evaporation was purified by SGC (PE/EA 400:1) to provide the title compound. MS ESI+: m/z=243 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2].CC([O-])(C)C.[K+].Cl[NH2:19]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:19])[CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: NCl
Reactant: CCOC(=O)c1cc(F)c[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(F)cn1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.57 g, 10.0 mmol) in 20 ml DMF is added potassium tert-butylate (2.24 g, 20.0 mmol) under nitrogen. After stirring at room temperature for 90 minutes, the chloroamine solution from above (110 ml, ca. 25 mmol) is added slowly, after which the mixture is stirred for 5 minutes at room temperature. The reaction mixture is partitioned between saturated sodium bisulfite solution and tert-butyl methyl ether. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/dichloromethane as eluent to afford 1-amino-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester as white solid; HPLC/MS 2.21 min (B), [M+H] 173;
Reaction SMILES: [CH2:1]([C:3]1[N:8]2[N:9]=[CH:10][N:11]=[C:7]2[N:6]=[CH:5][CH:4]=1)[CH3:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:12][CH:1]([C:3]1[N:8]2[N:9]=[CH:10][N:11]=[C:7]2[N:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccnc2ncnn12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccnc2ncnn12

Procedure:
A mixture of 7-ethyl-1,2,4-triazolo[1,5-a]pyrimidine (10.5 g), N-bromosuccinimide (12.63 g), dibenzoylperoxide (0.3 g) and tetrachloromethane (270 ml) was heated under reflux for 5 hours with stirring. The mixture was filtered and a crude product was obtained by evaporation of the solvent from the filtrate. This was purified by recrystallisation from tetrachloromethane to give 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine. Yield 10.8 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCCCCCCn1ccc2ccccc21
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A mixture of indole (1) (0.03 mole, 3.51 g), potassium hydroxide (0.03 mole, 1.97 g) powdered in a mortar, and 18-crown-6 ether (0.001 mole, 250 mg) in benzene (20 cm3) is heated under reflux with vigorous stirring for two hours. A solution of octylbromide (2a), (0.04 mole, 7.72 g) in benzene (10 cm3) is added and reflux is maintained for an additional four hours. The reaction is monitored by TLC and the reaction mixture is filtered on Celite. Evaporation of the solvent yields an orange liquid which is purified by distillation in vacuo. The colourless liquid distilled at 154-156° C. and 1.5 mmHg pressure is shown by 1H nmr to be pure 1-octylindole (3a) (4.98 g, 0.0217 mole, 72% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[Cu][C:11]#[N:12].[C-]#N.[Na+].CN(C)C=O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[N:12])=[N:4][C:3]=1[CH3:9]
Reactant: N#C[Cu]
Reactant: Cc1nc(Br)ccc1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1nc(C#N)ccc1Br
Temperature: 95 °C
Reaction time: 48 h
Yield: 66.4 %

Procedure:
A 1-L, three-neck, round-bottom flask equipped with a mechanical stirrer and a nitrogen inlet was charged with 3,6-dibromo-2-methylpyridine (150 g, 0.59 mol), copper (I) cyanide (42.8 g, 0.47 mol) and sodium cyanide (23 g, 0.47 mol). To the mixture was added N,N-dimethylformamide (300 mL). The mixture was heated to 95° C. and stirred for 48 h. The reaction mixture was cooled to ambient temperature and poured into ethanol (3 L) while stirring. The mixture was filtered through a pad of Celite, the filtrate was concentrated under reduced pressure and partitioned between water (3 L) and ethyl acetate (3 L). The organic layer was separated and washed with brine (2×600 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel plug purification (0-5% ethyl acetate in hexanes) to afford the product (61.5 g, 45% yield) as a white solid. In addition, 19.32 g (14%) of the mixture of the starting material and the product was isolated.
Reaction SMILES: O[CH:2]([C:19]1[CH:24]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([O:29][CH2:30][CH3:31])=[C:21]([F:32])[C:20]=1[C:33]([F:36])([F:35])[F:34])[CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.[Na]>C1(C)C=CC=CC=1>[CH2:16]([CH:13]1[CH2:12][CH2:11][CH:10]([CH:7]2[CH2:6][CH2:5][CH:4]([CH:3]=[CH:2][C:19]3[CH:24]=[C:23]([Si:25]([CH3:27])([CH3:26])[CH3:28])[C:22]([O:29][CH2:30][CH3:31])=[C:21]([F:32])[C:20]=3[C:33]([F:35])([F:36])[F:34])[CH2:9][CH2:8]2)[CH2:15][CH2:14]1)[CH2:17][CH3:18]
Reactant: CCCC1CCC(C2CCC(CC(O)c3cc([Si](C)(C)C)c(OCC)c(F)c3C(F)(F)F)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1CCC(C2CCC(C=Cc3cc([Si](C)(C)C)c(OCC)c(F)c3C(F)(F)F)CC2)CC1
Yield: 80.2 %

Procedure:
20.7 g of the crude 1-hydroxy-1-(2-trifluoromethyl-3-fluoro-4-ethoxy-5-trimethylsilylphenyl)-2-(4-(4-propylcyclohexyl)cyclohexyl)ethane obtained in the first step was dissolved in toluene. 0.68 g (3.57 mmol) of p-toluene sulfonic acid monohydrate was added and refluxed under heating for 2 hours while dewatering by using a Dean Stark apparatus. The reaction mixture was poured into 200 ml of an aqueous sodium hydrogen chloride solution and extracted with 200 ml of toluene. The organic layer was washed with 200 ml of water and then with 100 ml of an aqueous saturated sodium chloride solution successively and, after drying over anhydrous magnesium sulfate, it was concentrated under a reduced pressure to obtain 16.03 g of a crude β-(4-(4-propylcyclohexyl)cyclohexyl)-2-trifluoromethyl-3-fluoro-4-ethoxy-5-trimethylsilyl styrene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][C:17]=2[CH2:25][O:26][CH2:27][C:28](Cl)=[O:29])=[CH:10][CH:9]=1.O>ClCCl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][C:17]=2[CH2:25][O:26][CH2:27][C:28]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:29])=[CH:10][CH:9]=1
Reactant: O=C(Cl)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Reactant: C1COCCN1
Solvent: O
Solvent: ClCCl
Product: O=C(COCc1nc2ccccn2c1C#Cc1ccc(F)cc1)N1CCOCC1
Yield: 58 %

Procedure:
0.806 ml (9.25 mmol) of morpholine were solubilised in 4 ml of dichloromethane with magnetic stirring, a solution of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)acetyl chloride in 4 ml of dichloromethane was added and then the mixture was added at r.t. for 1 h before being treated with 10 ml of water. The aqueous phase was extracted with 2×5 ml of dichloromethane. The combined organic phases were washed with 5 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: ethyl acetate 100%). 0.211 g (yield=58%) of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)-1-morpholino ethanone were obtained as a pale yellow solid. LC-MS: m/z=394 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.62 (d, J=6.8 Hz, 1H), 7.74 (dd, J=8.7, 5.5 Hz, 2H), 7.67 (d, J=9.0 Hz, 1H), 7.50-7.39 (m, 1H), 7.33 (t, J=8.9 Hz, 2H), 7.12 (t, J=6.8 Hz, 1H), 4.75 (s, 2H), 4.27 (s, 2H), 3.55-3.46 (m, 4H), 3.39 (s, 4H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[N:24](CC[Si](C)(C)C)[C:23](=[O:34])[CH2:22]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([F:20])([F:18])[F:19])[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:34])[CH2:22]1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCC(F)(F)F)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: [OH-]
Product: O=C1CN(c2ccc(CCC(F)(F)F)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-[2-benzyloxy-4-(3,3,3-trifluoropropyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one analogous to Example 292, steps B and C with the modification that Pd(OH)2 is used as the catalyst in the reduction step: (M−1)−=323.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][C:4]1(C=C)[CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1.CC[O:16][C:17](C)=[O:18]>O>[CH3:13][C:2]([CH3:1])([CH3:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:17]([OH:18])=[O:16])=[CH:8][CH:9]=1
Reactant: CCOC(C)=O
Reactant: C=CC1(CC(C)(C)C)C=CC=CC1
Solvent: O
Product: CC(C)(C)Cc1ccc(C(=O)O)cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 1.74 g (7.76 mmol) of 4-(2,2-dimethylpropyl)-4-ethenylbenzene (from Step A) in 10 mL EtOAc and 10 mL H2O was added 8.30 g (38.8 mmol) of NaIO4 and 1 mg (0.0078 mmol) RuO2. The reaction mixture was heated to 40° C. for 30 min. The reaction mixture was cooled and stirred at rt for 16 hr. To the reaction mixture was added H2O and EtOAc, and layers were separated. The organic layer was dried and concentrated to dryness to provide 776 mg of the title compound: 1H NMR (500 Mhz) δ 0.91 (s, 9H), 2.53 (s, 2H), 7.12 (d, J=8.0, 2H), 7.84 (d, J=8.0, 2H); ESI-MS 193 (M+H); LC-1: 3.2 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C@@H:35]([CH3:38])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C@@H:35]([CH3:38])[CH2:36][OH:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: C[C@H](N)CO
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@@H](C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and (S)-(+)-2-amino-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H33N6O5SF2[(M+H)+] 543.2196, observed 543.2200.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:15][NH2:16]>>[CH3:15][NH:16][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Product: CNc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
1.6 g (7.4 mMol) of methyl 6-chloro-5-nitro-nicotinate (see Bernie et al. in J. Chem. Soc. 1951, 2590) were stirred in 20 ml of 40% aqueous methylamine solution at room temperature for 30 minutes. The reaction mixture was then diluted with ice water, the yellow precipitate formed was filtered off and dried. Yield: 1.2 g (80% of theory), Rf value: 0.66 (silica gel; ethyl acetate/ethanol/glacial acetic acid=90:5:5)
Reaction SMILES: [O:1]=[C:2]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][NH:3]1)=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[C:10]=3[Cl:18].[OH-:19].[K+].Cl>C(O)C.O>[NH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[C:10]([Cl:18])[C:11]([Cl:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[C:2]([OH:19])=[O:1]
Reactant: [OH-]
Reactant: COc1cc2c3c([nH]c2c(Cl)c1Cl)C(=O)NCC3
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc2c(CCN)c(C(=O)O)[nH]c2c(Cl)c1Cl
Yield: 96.9 %

Procedure:
The above lactam was hydrolyzed with base according to the following procedure: 5 g of 1-oxo-6-methoxy-7,8-dichloro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole were dissolved in a mixture of 77 ml of ethanol and 51 ml of water. 13.9 g of potassium hydroxide were added, and the solution was heated to refluxing temperature overnight under a nitrogen atmosphere. The reaction mixture was cooled, and the pH adjusted to about 4 by the addition of 12N aqueous hydrochloric acid. A precipitate formed in the acidic solution, which precipitate was isolated by filtration, and the filter cake washed with water. 5.15 g of 3-(2-aminoethyl)-5-methoxy-6,7-dichloroindol-2-carboxylic acid were obtained. The compound melted at 248°-249° C.
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[OH:22]>C1(C)C=CC=CC=1>[C:3]1([CH2:2][CH2:1][NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[OH:22])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C=NCCc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: Cc1ccccc1
Product: O=C(NCCc1ccccc1)Nc1ccc([N+](=O)[O-])cc1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of phenethyl isocyanate (382 mg, 2.6 mmol) in toluene, 2-amino-5-nitrophenol (400 mg, 2.6 mmol) was added. The reaction mixture was stirred at 80° C. for 24 hours, then cooled to room temperature. The product was purified by precipitation from toluene and filtering (650 mg, 83%). m.p: 188.6-189.4° C.; EI-MS m/z 302 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 2.5 h
Yield: 85.2 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (9.2 g), p-hydroxyacetophenone (7.95 g), potassium carbonate (6.73 g) and N,N-dimethylformamide (DMF) (100 ml) was stirred for 2.5 hours at temperatures ranging from 70° to 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgSO4), then the solvent was distilled off to give 4'-(5-methyl-2-phenyl-4-oxazolylmethoxy)acetophenone (11.6 g, 85%). Recrystallization from ethyl acetate--ether gave colorless prisms, m.p.126°-127° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:22]=[C:21]3[C:13]([C:14]4[C:15](B5OC(C)(C)C(C)(C)O5)=[CH:16][CH:17]=[C:18]([C:23]([NH2:25])=[O:24])[C:19]=4[NH:20]3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.Br[C:36]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:37]=1[CH:38]=[CH:39][CH:40]=[C:41]2[NH2:46].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C>[NH2:46][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:42]=1[CH:43]=[CH:44][CH:45]=[C:36]2[C:15]1[C:14]2[C:13]3[C:21](=[CH:22][C:10]([C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[O:9])=[CH:11][CH:12]=3)[NH:20][C:19]=2[C:18]([C:23]([NH2:25])=[O:24])=[CH:17][CH:16]=1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(B4OC(C)(C)C(C)(C)O4)c23)CC1
Reactant: Nc1cccc2c(Br)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc5c(N)cccc45)c23)CC1
Temperature: 90 °C
Yield: 42 %

Procedure:
Step 2 A mixture of 7-(4-methylpiperazine-1-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide (the crude product prepared according to Step 1, 40 mg, 0.065 mmol), 5-bromonaphthalen-1-amine (21.61 mg, 0.097 mmol), and potassium carbonate (13.45 mg, 0.097 mmol) in toluene (1.5 mL) and ethanol (0.75 mL) was treated with [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) DCM complex (5.3 mg, 0.007 mmol) and purged with argon for ca. 5 min. The mixture was heated at 90° C. for 19 h, then was cooled to rt and concentrated. The residue was purified by preparative HPLC, then was partitioned between EtOAc and NaHCO3 (aq), the aqueous phase was extracted again with EtOAc, and the combined organic phases were dried and concentrated to provide 4-(5-aminonaphthalen-1-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a light yellow solid (13.1 mg, 42%). 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H) 8.22-8.27 (m, 2H) 8.07 (d, J=7.7 Hz, 1H) 7.73 (s, 1H) 7.55 (br. s., 1H) 7.52 (dd, J=8.6, 6.8 Hz, 1H) 7.42 (dd, J=6.9, 1.0 Hz, 1H) 7.09 (d, J=7.7 Hz, 1H) 6.96 (dd, J=8.2, 7.6 Hz, 1H) 6.64-6.70 (m, 2H) 6.49 (d, J=8.3 Hz, 1H) 6.38 (d, J=8.1 Hz, 1H) 5.85 (s, 2H) 3.48-3.59 (m, 4H) 2.17-2.37 (m, 4H) 2.14 (s, 3H). Mass spec m/z 478.10 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:17]=[CH:18][C:19]([C:22]([OH:24])=O)=[N:20][CH:21]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:22]([C:19]2[CH:18]=[N:17][C:16]([O:15][CH2:14][C:9]3[N:10]([CH3:13])[N:11]=[N:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:21][N:20]=2)=[O:24])[CH2:27][CH2:28]1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Reactant: NC1CCOCC1
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1cnc(C(=O)NC2CCOCC2)cn1
Yield: 62 %

Procedure:
As described for example 53c, 5-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (96 mg, 0.29 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (74 mg, 62%) which was obtained as an off white solid. MS: m/e=413.4 [M+H]+.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[C:9](=O)[N:8]([C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([NH2:22])=[O:21])[C:7]2=[O:23]>C1COCC1.CO>[Cl:13][C:12]1[C:4]([Cl:3])=[CH:5][C:6]([C:7]([OH:23])=[O:1])=[C:10]([C:9]2[NH:22][C:20](=[O:21])[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[N:8]=2)[CH:11]=1
Reactant: NC(=O)c1sccc1N1C(=O)c2cc(Cl)c(Cl)cc2C1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(Cl)cc1-c1nc2ccsc2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
3-aminothiophene-2-carboxamide was added to an acetic acid solution of 4,5-dichlorophthalic anhydride and stirred all night heated to reflux to give 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide. 1M NaOH aq was added to THF-MeOH solution of the obtained 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide and stirred for 2.5 hours at 80° C. to give 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid. Sulfuric acid was added to a MeOH-1,4-dioxane solution of the obtained 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid and stirred for three days at 70° C. to give methyl 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoate.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[C:19][Si](C)(C)C)[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[CH:19])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1
Reactant: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)cc(C3CC3)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2

Procedure:
Following general procedure E and using 8-cyclopropyl-6-trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman (Intermediate 33, 0.17 g, 0.68 mmol), methanol and potassium carbonate (0.2 g, 1.47 mmol) the title compound was obtained as an oil (0.064 g, 47%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:16])[C:5]1[C:10]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[I:15])[CH3:2].[CH2:17](N)C#C>>[I:15][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]=1[C:4]([NH:3][CH2:1][C:2]#[CH:17])=[O:16]
Reactant: C#CCN
Reactant: CCNC(=O)c1c(I)cccc1[Si](C)(C)C
Product: C#CCNC(=O)c1c(I)cccc1[Si](C)(C)C
Yield: 85 %

Procedure:
The acid chloride prepared in Example 207 was reacted with propargylamine (3 eq) using General Method E1 to afford the title compound. Purification by recrystallization from hexanes gave 0.48 g of the title compound as an off-white solid in 85% yield. m.p. 109-111° C.
Reaction SMILES: CSC(SC)=[C:4]([C:7]#N)[C:5]#[N:6].CS[C:13](SC)=[C:14]([C:23]#[N:24])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>C(O)C>[O:16]1[C:15]2[CH:14]=[CH:13][CH:7]=[CH:4][C:5]=2[NH:6][C:13]1=[C:14]([C:23]#[N:24])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]
Reactant: CSC(SC)=C(C#N)C(=O)N1CCOCC1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CCO
Product: N#CC(C(=O)N1CCOCC1)=C1Nc2ccccc2O1

Procedure:
The procedure described in Example 1 is repeated using, instead of 3,3-bis(methylthio)-2-cyanoacrylonitrile, an equivalent amount of 3,3-bis(methylthio)-2-cyanoacrylic acid morpholide and holding the mixture under reflux for 24 hours to obtain 2-benzoxazolinylidene-cyanoacetic acid morpholide of melting point 217°-219° C. (from ethanol).
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([OH:22])[C@H:5]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[OH-].[Na+].CO>O1CCOCC1>[C:18]([O:17][C:15]([NH:14][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C@H:4]([OH:22])[C:3]([OH:23])=[O:2])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)[C@@H](O)[C@@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1cccc(F)c1)[C@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
A mixture of (2S,3R)-3-tert-Butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyric acid methyl ester (3.28 g, 10.05 mmol, 1 eq), 4N NaOH (4 mL, 16 mmol, 1.6 eq), MeOH (42 mL) and 1,4-dioxane (63 mL) was stirred at ambient temperature for 1.5 h after which the solvents were evaporated. To the residue was added 10% citric acid (100 mL) followed by extraction with EtOAc (100 mL). The organic layer was washed with H2O (100 mL), brine (50 mL), dried (Na2SO4) and concentrated to give the desired product as a cream colored solid (3.06 g, 97%). 1H NMR (DMSO) 7.33–7.26 (m, 1H), 7.02–6.97 (m, 3H), 6.78 (d, J=5.2, 1H), 3.98 (d, J=5.5, 1H), 3.99–3.86 (m, 2H), 2.77–2.82 (m, 2H), 1.27 (s, 9H).