Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[C:4]=2[C:5]([OH:8])=[N:6][CH:7]=1.[C:20]([Cu])#[N:21].Cl>CN(C=O)C.CN1C(=O)CCC1>[OH:8][C:5]1[C:4]2[C:9]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:10]=3[S:11][C:3]=2[C:2]([C:20]#[N:21])=[CH:7][N:6]=1
Reactant: N#C[Cu]
Reactant: Oc1ncc(Br)c2sc3cc(C(F)(F)F)ccc3c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(O)c2c1sc1cc(C(F)(F)F)ccc12
Temperature: 150 °C

Procedure:
A solution of 4-bromo-7-(trifluoromethyl)[1]benzothieno[3,2-c]pyridin-1-ol in a 4:1 mixture of DMF/NMP (0.9 M) in the presence of CuCN (2.5 equiv) was heated in a microwave reactor at 150° C. for 25 min. The reaction was poured into 0.1 N HCl and the title product filtered as a solid.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[N:10]=[C:9]2[S:11][C:12]([SH:14])=[N:13][C:8]2=[CH:7][CH:6]=1.Br[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([OH:19])=[O:18]>C(N(CC)CC)C>[Cl:4][C:5]1[N:10]=[C:9]2[S:11][C:12]([S:14][CH:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([OH:19])=[O:18])=[N:13][C:8]2=[CH:7][CH:6]=1
Reactant: Sc1nc2ccc(Cl)nc2s1
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Sc1nc2ccc(Cl)nc2s1)c1ccccc1
Yield: 74.3 %

Procedure:
A methylene chloride solution of 4.05 g (0.02 m) 5-chloro-2-mercaptothiazolo[5,4-b]pyridine, 4.30 g (0.02 m) α-bromophenylacetic acid and 4.0 g (0.04 m) triethylamine is heated to gentle reflux overnight. The methylene chloride solution is extracted twice with a dilute hydrochloric acid solution and once with water and then dried over anhydrous MgSO4. After the solvent is removed, the residual solid is recrystallized from acetonitrile. 5.0 g (74% yield) of title compound, melting at 175°-7° C., is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH:14]=[CH:13]N=C1)=[S:9].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1CCN.C(OCC)(=O)C>CN(C)C=O>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:13][CH2:14][NH:10][C:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[S:9]
Reactant: NCCc1ccccc1Cl
Reactant: S=C(Nc1ccccn1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCc1ccccc1Cl)Nc1ccccn1
Temperature: 25 °C
Yield: 14.4 %

Procedure:
A solution of 1-[(2-pyridyl)thiocarbamoyl] imidazole (1.02 g, 5.0 mmol) and 2-(2-chlorophenyl)ethylamine (0.81 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant oil was purified by chromatography on silica gel to provide 0.21 g (14%) of the titled product as a yellow solid:
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:7]=1[CH2:8][N:9]([CH3:14])[C:10](=[O:13])[CH:11]=[CH2:12])[CH:2]([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.Br[C:31]1[CH:42]=[N:41][C:34]2[NH:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][C:33]=2[CH:32]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:5][C:6]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:7]=1[CH2:8][N:9]([CH3:14])[C:10](=[O:13])/[CH:11]=[CH:12]/[C:31]1[CH:42]=[N:41][C:34]2[NH:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][C:33]=2[CH:32]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: C=CC(=O)N(C)Cc1cccc(OC)c1OCC(C)C
Reactant: O=C1CNCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCC(=O)N3)c1OCC(C)C
Yield: 21.3 %

Procedure:
A solution of N-(2-isobutoxy-3-methoxybenzyl)-N-methylacrylamide (0.387 g, 1.40 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. Then treated with diisopropylethylamine (0.39 mL, 2.25 mmol) and 7-bromo-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.07 mmol). The solution was deoxygenated with Ar for 20 min. Then Pd(OAc)2 (0.024 g, 0.10 mmol) and P(o-tol)3 (0.065 g, 0.21 mmol) were added and the solution deoxygenated with Ar for 20 min. The solution was heated to reflux for 18 h, then allowed to cool. The solution was diluted with H2O (30 mL) and was washed with EtOAc (3×50 mL). The organics were washed with brine (2×100 mL), dried over Na2SO4, filtered and concentrated to an orange-brown semi-solid. Purification by column chromatography (silica gel, CH2Cl2 to CH2Cl2/MeOH, 100 to 95:5) gave the title compound (0.10 g, 23%) as an yellow-orange solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.08-10.06 (m, 1H), 8.44-8.39 (m, 1H), 8.02-7.95 (m, 1H), 7.53-7.48 (m, 1H), 7.30-7.25 (m, 1H), 7.04-6.93 (m, 2H), 6.66-6.41 (m, 1H), 4.79-4.64 (m, 2H), 3.91-3.87 (m, 2H), 3.79 (s, 3H), 3.71-3.61 (m, 4H), 3.11-2.87 (m, 4H), 2.03-1.99 (m, 1H), 1.00-0.97 (m, 6H); MS (ESI) m/e 439 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([N:10]2[C:14](=[O:15])[C:13]3[CH2:16][CH2:17][CH2:18][CH2:19][C:12]=3[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[Cl:1][C:2]1[C:7]([CH2:8][Br:23])=[CH:6][C:5]([N:10]2[C:14](=[O:15])[C:13]3[CH2:16][CH2:17][CH2:18][CH2:19][C:12]=3[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(CO)c(Cl)cc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(CBr)c(Cl)cc1F
Reaction time: 8 h

Procedure:
To a stirred solution of 3.0 g (0.0097 mole) of of N-(4-chloro-2-fluoro-5-hydroxymethylphenyl)-3,4,5,6-tetrahydrophthalimide, prepared by the method of Example 4, and 6.4 g (0.0194 mole) of carbon tetrabromide in 30 ml of diethyl ether was added portionwise 5.1 g (0.0194 mole) of triphenylphosphine. This mixture was stirred overnight and was then filtered to remove the solid which had formed, and the solvent was evaporated under reduced pressure. The residue was passed through a column of silica gel. Appropriate fractions were combined, and the solvent was evaporated yielding 1.1 g of N-(4-chloro-2-fluoro-5-bromomethylphenyl)-3,4,5,6tetrahydrophthalimide as a white solid, m .p. 126°-128° C. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]#[N:14])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Cl.[NH2:16][OH:17].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[OH:17]/[N:16]=[C:13](\[N:10]1[CH2:11][CH2:12][N:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:8][CH2:9]1)/[NH2:14]
Reactant: N#CN1CCN(C2CCOCC2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N/C(=N/O)N1CCN(C2CCOCC2)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
A mixture of 4-(tetrahydro-2H-pyran-4-yl)piperazine-1-carbonitrile (632 mg, 3.24 mmol), Ethanol (10 mL), hydroxylamine hydrochloric acid (257 mg, 3.70 mmol) and Na2CO3 (785 mg, 7.40 mmol) was heated to 80° C. After 1.5 h, the solids were filtered off and the filtrate concentrated in vacuo. The residue was dissolved into a minimum amount of methanol and treated with 5 mL of 1 M of HCl/Ether and diluted by acetone. Resulting solids were collected and dried in vacuo to afford the title compound (566 mg, 1.879 mmol, 76% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=11.88 (br. s., 4H), 11.20 (br. s., 1H), 10.17 (br. s., 1H), 8.26 (br. s., 2H), 4.09-3.87 (m, 5H), 3.69-3.49 (m, 4H), 3.42 (br. s., 1H), 3.26 (t, J=11.5 Hz, 2H), 3.17-2.98 (m, 2H), 2.00 (d, J=11.1 Hz, 2H), 1.83-1.64 (m, 2H); LC/MS (m/z) ES+ (ELSD)=229.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N+:13]([O-:15])=[O:14])[C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].[NH2:16][CH2:17][CH2:18][OH:19]>O>[OH:19][CH2:18][CH2:17][NH:16][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=1[CH2:9][CH2:10][OH:11]
Reactant: O=[N+]([O-])c1cc2c(c([N+](=O)[O-])c1)OCC2
Reactant: NCCO
Solvent: O
Product: O=[N+]([O-])c1cc(CCO)c(NCCO)c([N+](=O)[O-])c1

Procedure:
0.29 Mole (60.9 g) of 2,3-dihydro-5,7-dinitrobenzofuran is added in small portions at room temperature to 122 ml of 2-aminoethanol. After the addition is complete, the reaction medium is brought for 15 minutes to 95° C. 500 ml of water are added; after the mixture is cooled, the expected product is drained, and this, after being made into a paste in water and recrystallized from 75 ml of 96° strength ethanol, melts at 115° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][CH2:13][CH3:14])=[N:6][C:5]=2[O:4][N:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:15]([N:8]1[C:9](=[O:11])[C:10]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[N:6]=[C:7]1[CH2:12][CH2:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1nc2onc(C)c2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc2onc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A suspension of 3-methyl-6-propyl-5H-isoxazolo[5,4-d]pyrimidin-4-one (method 17) (1.698 g, 8.8 mmol), benzylbromide (1.5 g, 8.8 mmol), potassium carbonate (2.43 g, 17.6 mmol) in 10 ml DMF was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc (50 ml×3), the combined organic phases were dried, concentrated, purified by flash column chromatography (elute: hexane-EtOAc=5:1). 1.69 g (68%) of the title compound was obtained as white solid. 1H NMR (DMSO-d6): 0.80 (t, 3H), 1.61 (m, 2H), 2.43 (s, 3H), 2.73 (t, 2H), 5.35 (s, 2H), 7.12-7.35 (m, 5H).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][NH:9][CH2:10][C@@H:11]([CH3:24])[CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1.COC(=O)C.[Cl:46]C1C(C(F)(F)F)=CC=CC=1C=O.Cl.CCOCC>CCOCC>[ClH:46].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:9]([CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:10][C@@H:11]([CH3:24])[CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[CH:35][CH:34]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: C[C@H](CNCC(c1ccccc1)c1ccccc1)COc1cccc(CC(=O)O)c1
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: COC(C)=O
Product: COc1ccc(CN(CC(c2ccccc2)c2ccccc2)C[C@@H](C)COc2cccc(CC(=O)O)c2)cc1

Procedure:
Following the procedure of Example 7(d) except (R)-2-(3-{3-[(2,2-diphenylethyl)amino]2-methyl-propoxy}phenyl)acetic acid and 4-methoxybenzaldehyde were used instead of (R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)acetic acid methyl ester and 2-chloro-3-trifluoromethylbenzaldehyde in step (d) the corresponding carboxylic acid was obtained. The resulting amine/carboxylic acid was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give the title compound as a white solid, 94 mg (97%). MS (ESI) 524.4 (M+H+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2].Br[CH2:42][CH:43]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH3:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OC(=O)C)C>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:44][CH:43]([O:45][Si:46]([C:49]([CH3:51])([CH3:50])[CH3:52])([CH3:47])[CH3:48])[CH3:42])=[CH:33][CH:34]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Reactant: CC(CBr)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(C)O[Si](C)(C)C(C)(C)C)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 60 °C
Reaction time: 14 h
Yield: 54.3 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (500 mg, 0.86 mmol) in dry DMF (10 mL), was added (1-bromopropan-2-yloxy)(tert-butyl)dimethylsilane (327 mg, 1.3 mmol) and cesium carbonate (847 mg, 2.6 mmol). The reaction mixture was was stirred at 60° C. for 14 h. After completion of reaction, as confirmed by TLC, the reaction mixture was diluted with ethylacetate (150 mL) and washed with water (3×10 mL). The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:8 Ethyl acetate:Pet. Ether) to afford title compound (350 mg, 53.8%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:20]O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]3[N:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(Cl)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: FC(F)(F)c1ccc2cc(-c3cccc(Cl)c3)nn2c1
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a suspension of 1-(3-chlorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (17 g, 54 mmol) in DME (170 ml) at −5° C. was added dropwise methanesulfonyl chloride (4.5 m, 6.0 mmol) and the mixture stirred for 15 mins. Triethylamine (16.5 ml, 120 mmol) in DME (7 ml) was then added dropwise over 15 min. After the addition was complete, the mixture was then warmed to 35° C. for 45 minutes. This was then cooled and filtered, washing with DME (20 ml). To the filtrate was added iron (II) chloride (75 mg) and the mixture heated to 70° C. for 1 hour and then allowed to cool. The reaction was concentrated to half the original volume and water (100 ml) was added. The resulting solid was removed by filtration, washed with water and dried. The solid was dissolved in ethyl acetate and washed with water and brine and then dried over magnesium sulfate. Filtering and evaporation to dryness under vacuum afforded 14.6 g (91%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:23])[CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])(=O)=O>C(Cl)Cl>[Si:39]([O:23][C@@H:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C[C@H]1CCCN(C[C@@H](O)c2ccc(C#N)cc2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C#N)cc2)C1
Reaction time: 2 h
Yield: 98 %

Procedure:
To a mixture of (18C)-isomer A, ethyl 2-((R)-1-((S)-2-(4-cyanophenyl)-2-hydroxyethyl)piperidin-3-yl)acetate (6.00 g, 18.96 mmol) and DIPEA (5.96 ml, 34.1 mmol) in DCM (63 mL) was added tert-butyldimethylsilyl trifluoromethane-sulfonate (5.67 ml, 24.65 mmol) slowly. The reaction was monitored with HPLC and the reaction was complete in 2 hours. The reaction mixture (a light brown solution) was quenched with water, the aqueous layer was extracted twice with DCM. The organic phase was combined, dried with Na2SO4, filtered, and concentrated. The crude material was purified with on a silica gel cartridge (330 g silica, 10-30% EtOAc/hexanes gradient) to give ethyl 2-((R)-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidin-3-yl)acetate (8 g, 18.58 mmol, 98% yield).
Reaction SMILES: C[CH2:2][O:3]C(C1N(C(OC(C)(C)C)=O)C2=NC=C(OC(=O)C3C=CC=CC=3)C=C2C=1)=O.[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([CH2:52][CH3:53])=[C:44](Br)[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([CH2:52][CH3:53])=[C:44]([CH:2]=[O:3])[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)cnc2n1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Product: CCc1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 15, intermediate c) from (4R,9aR)-7-bromo-6-ethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH3:29])=[C:25]([Cl:28])[C:26]=3[Cl:27])=[O:21])[CH2:15][CH2:14]2)[S:6][C:7]=1[C:8]([O:10]CC)=[O:9].[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>>[Cl:27][C:26]1[C:25]([Cl:28])=[C:24]([CH3:29])[NH:23][C:22]=1[C:20]([NH:19][CH:16]1[CH2:15][CH2:14][N:13]([C:5]2[S:6][C:7]([C:8]([OH:10])=[O:9])=[C:3]([CH2:2][NH:1][C:33]([NH:32][CH2:30][CH3:31])=[O:34])[N:4]=2)[CH2:18][CH2:17]1)=[O:21]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN
Reactant: CCN=C=O
Product: CCNC(=O)NCc1nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)sc1C(=O)O

Procedure:
The title compound was prepared in a manner analogous to Example 250 from ethyl 4-(aminomethyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 246) and ethyl isocyanate.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:4]2=[CH:3][CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I:23]I.Cl>C1COCC1>[I:23][C:6]1[N:5]2[N:1]=[CH:2][CH:3]=[C:4]2[C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: II
Reactant: O=C(O)c1cccn2nccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(I)n2nccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a stirred suspension of pyrazolo[1,5-a]pyridine-4-carboxylic acid (29 g, 179 mmol) in anhydrous THF (1000 mL) cooled at 0° C. was added lithium hexamethyldisilazide solution (1M in THF, 200 mL, 200 mmol). After the mixture was stirred at 0° C. for 30 min, additional LHMDS solution (1M in THF, 320 mL, 320 mmol) was added at −4° C. After the mixture was stirred for 10 min, iodine (55 g, 215 mmol) was added in portions. The reaction mixture was stirred at −4° C. for 1.5 h, at rt for 1 h, and then cooled to 0° C. Aqueous HCl (5N, 40 mL) and NaS2O3 solution (10 g in 40 mL of H2O) were added. The mixture was stirred at 0° C. for 30 min, and then concentrated under reduced pressure. The residual mixture was mixed with sat. NaHCO3 solution (100 mL), ethyl ether (150 mL), and H2O (130 mL). The ether solution was separated and extracted with H2O (50 mL). The combined aqueous solutions were washed with ethyl ether (150 mL), acidified to pH=1 with saturated aqueous solution of KHSO4, heated in a steam bath, and then cooled. The solid was filtered, washed with H2O, and then dried to give compound 777C (50 g, 97%) as a yellow solid. HPLC: 100% at 2.88 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 289 [M+H]+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(N(C(C)C)CC)(C)C.[CH:19]1([C:22]2[CH:26]=[C:25]([NH2:27])[NH:24][N:23]=2)[CH2:21][CH2:20]1>C1COCC1.C(O)(C)C>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:27][C:25]2[NH:24][N:23]=[C:22]([CH:19]3[CH2:21][CH2:20]3)[CH:26]=2)[N:7]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cyanuric chloride (5 g, 27.1 mmol) in THF (40 mL) were added diisopropylethylamine (7.1 mL, 40.6 mmol) and 3-cyclopropyl-1H-pyrazol-5-amine (4.0 g, 32.5 mmol) in isopropyl alcohol (40 mL) at 0° C. over 30 minutes. The reaction mixture was stirred at room temperature overnight. The crude reaction solution was used for the next step without purification. A small amount was purified by Biotage (0-50% EtOAc/Hexane, 1 L). 1H NMR (DMSO, 400 MHz) δ 11.33 (s, NH), 6.19 (s, 1H), 3.83 (br s, NH), 1.88-1.95 (m, 1H), 0.93-0.96 (m, 2H), 0.68-0.70 (m, 2H). LC/MS [M+H]+: 271/273; Ret time (Method F): 3.00 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:20])[C:13]2[N:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:2].[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:21]([O-:23])=[O:22])=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:20])[C:13]2[N:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:2]
Reactant: CCOc1ccccc1-c1nc2cccnc2c(=O)[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOc1ccc([N+](=O)[O-])cc1-c1nc2cccnc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A stirred solution of 2-(2-ethoxyphenyl)pyrido(3,2-d)pyrimidin-4(3H)-one (Preparation 10; 1.4 g, 0.0052 mol) in concentrated sulphuric acid (11 ml) at 0° C., was treated dropwise with concentrated nitric acid (0.4 ml). The reaction mixture was allowed to warm to ambient temperature, stirred for a further 18 hours, then added dropwise to ice/water (70 g). The resulting precipitate was collected by filtration, dried under vacuum and then crystallized from acetonitrile to give the title compound as a pale yellow solid (0.22 g, 86%), m.p. 251-254° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: Cn1cnc(-c2ccc(C#N)cc2)c1Cl
Reactant: Sc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1

Procedure:
4-(5-Chloro-1-methyl-1H-imidazol-4-yl)benzonitrile (1 g), 4-chlorobenzenethiol (797 mg), and 1.3 ml of triethylamine in 20 mL of DMF were heated in a microwave tube at 180° C. for 90 min. The reaction mixture was purified by reverse phase HPLC with MS detector to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.21 (d, 2H), 7.83 (s, 1H), 7.66 (d, 2H), 7.45 (d, 2H), 6.98 (d, 2H), 3.63 (s, 3H). LCMS: [M+1]=326.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([C:13]2[CH:22]=[C:21]([CH3:23])[C:16]3[NH:17][C:18](=[O:20])[O:19][C:15]=3[CH:14]=2)=[O:12])[CH:5]=1.I[CH3:25]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([C:13]2[CH:22]=[C:21]([CH3:23])[C:16]3[N:17]([CH3:25])[C:18](=[O:20])[O:19][C:15]=3[CH:14]=2)=[O:12])[CH:5]=1
Reactant: CI
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
59 mg (1.4 mmol) sodium hydride (55%, suspension in mineral oil) were added at RT to 0.37 g (1.2 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 5.0 mL DMF. The reaction mixture was stirred for 30 min at RT. Then 0.10 mL (1.60 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. Then another 0.10 mL (1.60 mmol) iodomethane were added and the mixture was stirred overnight at RT. The reaction mixture was diluted with ice water and the precipitate formed was suction filtered. The residue was washed with water and dried i. vac.