Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([Br:9])[CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[NH2:1][C:2]1[CH:3]=[C:4]([Br:9])[N:5]=[CH:6][C:7]=1/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Nc1cc(Br)ncc1I
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cnc(Br)cc1N
Temperature: 100 °C
Yield: 89.6 %

Procedure:
4-Amino-2-bromo-5-iodopyridine (9.0 g 30.0 mmole) was dissolved in DMF (90 mL) and ethyl acrylate (6.5 mL, 60 mmole), triethylamine (6.1 mL, 43.2 mmole), tri-o-tolylphosphine (728 mg 2.4 mmole) and palladium acetate (270 mg 1.2 mmole) were added. The reaction was placed under nitrogen and heated at 100° C. for 3 hours. The reaction was concentrated in vacuo and diluted with EtOAc (250 mL). Water (100 mL) was added and the biphasic mixture filtered through celite. The filter cake was washed with EtOAc and the organic layers collected. The combined organic layers were washed with water (2×100 mL), brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a gradient of 10-40% EtOAc in DCM to afford the title compound (7.29 g, 89%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12].[CH:17](O[Na])=[O:18]>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[O:18]
Reactant: O=CO[Na]
Reactant: CON(C)C(=O)c1n[nH]c2ccc(I)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1n[nH]c2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.6 %

Procedure:
A mixture of 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (5 g, 15.1 mmol), HCOONa (1.85 g, 30.2 mmol), and PdCl2(PPh3)2 (320 mg, 0.453 mmol) in DMF (20 mL) was put under vacuum, and charged with CO. This process was repeated three times, and the mixture was kept at 110° C. for 6 hr. After cooling to rt, the reaction mixture was diluted with brine and extracted with EtOAc. The organic phases were combined, washed with brine, dried, and concentrated. The crude product was purified by column chromatography to afford 5-formyl-N-methoxy-N-methyl-1H-indazole-3-carboxamide (550 mg, 15.6%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:3]=1[NH:4][CH2:5][CH:6]([OH:13])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:13][CH:6]([CH2:5][NH:4][C:3]2[CH:14]=[C:15]([Cl:19])[C:16]([Cl:18])=[CH:17][C:2]=2[Cl:1])[CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:23][CH:22]=1
Reactant: ClCc1ccc(Br)cc1
Reactant: OC(CNc1cc(Cl)c(Cl)cc1Cl)Cn1ccnc1
Product: Clc1cc(Cl)c(NCC(Cn2ccnc2)OCc2ccc(Br)cc2)cc1Cl

Procedure:
Reaction of 1-[3-(2,4,5-trichloroanilino)-2-hydroxypropyl]-imidazole with p-bromobenzyl chloride yields 1-[2-(4-bromobenzyloxy)-3-(2,4,5-trichloroanilino)-propyl]-imidazole.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[CH2:12]([O:26][C:27]1[O:31][C:30]([C:32]([OH:34])=[O:33])=[CH:29][CH:28]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:12]([O:26][C:27]1[O:31][C:30]([C:32]([O:34][CH2:2][CH2:3][CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)=[O:33])=[CH:29][CH:28]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: BrCCCOC1CCCCO1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCCOC2CCCCO2)o1

Procedure:
The title compound was prepared as in Example 30 starting with 0.335 g (1.5 mmol) of 2-(3-bromopropoxy)tetrahydro-2H-pyran and 0.162 g (0.5 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid. 1H NMR (300 MHz, CDCl3) δ: 7.15 (d, 1H), 5.30 (d, 1H), 4.59-4.62 (m, 1H), 4.40 (app t, 2H), 4.10 (t, 2H), 3.80-3.90 (m, 2H), 3.40-3.60 (m, 2H), 2.05 (p, 2H), 1.20-1.85 (m, 30H), 0.89 (t, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])[N:16]=[C:15]2[CH2:26][CH2:27][S:28][CH2:29][C:14]=12.CCOCC.CCCCC>C(Cl)(Cl)Cl>[Cl:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])[N:16]=[C:15]2[CH2:26][CH2:27][S:28](=[O:9])[CH2:29][C:14]=12
Reactant: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CSCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCCCC
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=S1CCc2nn(-c3ccc(Cl)cc3F)c(Cl)c2C1
Reaction time: 16 h

Procedure:
1.6 parts of 85% m-chloroperbenzoic acid dissolved in 110 parts of chloroform were added dropwise for 1 hour to a stirred solution of 3-chloro-2-(4-chloro-2-fluorophenyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole dissolved in 75 parts of chloroform. The resulting solution was stirred 16 hours, washed 4 times with 40 parts of saturated aqueous NaHCO3, 2 times with water, dried with anhydrous magnesium sulfate, and solvent evaporated under a reduced pressure of 50 to 300 mm Hg. to give a pale yellow oil. The oil, when contacted with a mixture of ether and pentane, gave 1.2 parts of 3-chloro-2-(4-chloro-2-fluorophenyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole-5-oxide as a pale caramel-colored solid, m.p. 119°-122° C. This solid can be recrystallized from a mixture of methylene chloride, ether, and pentane to give m.p. 1221/2°-125° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:26]([NH2:29])([CH3:28])[CH3:27].C(=O)([O-])O.[Na+]>ClCCl>[CH:26]([NH:29][CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:28])[CH3:27]
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Reactant: CC(C)N
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NCCCN(C)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
tert-Butyl (3-hydroxypropyl)methylcarbamate (430 mg, 2.27 mmol) was dissolved in dichloromethane (5 mL), triethylamine (0.633 mL, 4.55 mmol) and methanesulfonyl chloride (0.262 mL, 3.41 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. Isopropylamine (1.3 g, 23 mmol) was further added, and then the mixture was stirred overnight at room temperature. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted with methylene chloride (×3), and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (elution solvents, n-hexane:ethyl acetate=9:1→1:1, v/v) to give the title compound (362 mg; yield, 73%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=2)[NH:26][CH:25]=1)=O)=O)C1C=CC=CC=1>C1COCC1>[NH3:17].[CH3:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:22][C@H:18]1[CH2:19][CH2:20][CH2:21][N:17]1[CH3:15]
Reactant: Cc1ccc2[nH]cc(C(=O)[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Product: N
Yield: 6 %
Yield: 52 %

Procedure:
A solution of LAH (39 mL, 1 M in THF, 39 mmol) was added slowly to a cooled (0° C.) solution of (R)-3-[(N-benzyloxycarbonylpyrrolidin-2-yl)carbonyl]-5-methyl-1H-indole (Example 1b, 9.5 mmol) in THF (100 mL). Once the addition was completed, the reaction mixture was stirred at reflux overnight prior to quenching with sodium sulfate decahydrate. The product was taken into ethyl acetate, filtered to remove the solid residue, and the solvent was removed in vacuo. The product was taken into ethyl acetate, filtered to remove the solid residue, and the solvent was removed in vacuo. Flash chromatography (silica gel, 6% 2M methanolic ammonia in dichloromethane) yielded (R)-5-methyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (52%; yellow oil; HRMS-FAB+ for C15H20N2 : calculated MH+ :229.1705; found MH+ :229.1706).
Reaction SMILES: [CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][CH2:37][CH2:38]Br.C(Cl)Cl>C(C(C)=O)C>[CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:38][CH2:37][O:36][CH3:35])=[CH:25][CH:26]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CCC[C@H](C)NC(=O)Nc1nc2nccc(-c3ccc(O)cc3)n2n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: COCCOc1ccc(-c2ccnc3nc(NC(=O)N[C@@H](C)CCCC(C)C)nn23)cc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
(S)-1-(1,5-dimethylhexyl)-3-[7-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]urea (the compound obtained in Example 255; 30 mg) and potassium carbonate (108 mg) were suspended in methyl ethyl ketone (3 ml). Thereafter, 2-methoxyethyl bromide (327 mg) was added to the obtained suspension, and the obtained mixture was stirred at 80° C. for 10 hours. Thereafter, the reaction solution was cooled to a room temperature, and methylene chloride (5 ml) was then added thereto. The obtained mixture was washed with an aqueous 1 M hydrochloric acid solution (5 ml×3), an aqueous saturated sodium bicarbonate solution (5 ml×2), and distilled water (5 ml×2). The organic layer was concentrated under a reduced pressure, and the obtained residue was purified by reverse phase liquid chromatography (Inertsil PREP-ODS; 20 Φ×250 mm; eluted with water-containing acetonitrile) to obtain the captioned compound (14 mg).
Reaction SMILES: COC1C=CC(C[N:8]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:21])=CC=1.[N+]([O-])([O-])=O.[Ce+3].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[CH3:19][C:16]1([CH3:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:21])[NH:8][C:17]1=[O:18]
Reactant: COc1ccc(CN2C(=O)c3ccccc3C(C)(C)C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+3]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC1(C)C(=O)NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 297 %

Procedure:
The compound (6.0 g) obtained in step (b) just above was dissolved in a mixed solvent (acetonitrile:water 4:1) (40 ml). Diammonium cerium nitrate (26.6 g) was added to the solution. The mixture was stirred at room temperature for 3 hr. The reaction solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=8:2) to give 4,4-dimethyl-4H-isoquinoline-1,3-dione (10.9 g).
Reaction SMILES: FC1C=C(C=CC=1C1C(C2C=CN=CC=2)=CN(C)N=1)OCC1C=CC2C(=CC=CC=2)N=1.[F:32][C:33]1[CH:34]=[C:35]([OH:55])[CH:36]=[CH:37][C:38]=1[C:39]1[C:43]([C:44]2[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=2)=[CH:42][N:41]([CH2:50][C:51]([F:54])([F:53])[F:52])[N:40]=1.Cl[CH2:57][C:58]1[CH:67]=[N:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:59]=1>CC(C)=O>[F:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][C:38]=1[C:39]1[C:43]([C:44]2[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=2)=[CH:42][N:41]([CH2:50][C:51]([F:52])([F:53])[F:54])[N:40]=1)[O:55][CH2:57][C:58]1[CH:67]=[N:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:59]=1
Reactant: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)c(F)c1
Reactant: ClCc1cnc2ccccc2n1
Agent: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2F)n1
Solvent: CC(C)=O
Product: Fc1cc(OCc2cnc3ccccc3n2)ccc1-c1nn(CC(F)(F)F)cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-[3-Fluoro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 3-Fluoro-4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol, 2-Chloromethyl-quinoxaline and acetone as the solvent provided the title compound. 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.46 (m, 2H), 8.15 (m, 1H), 8.09 (m, 1H), 7.81 (m, 3H), 7.43 (t, J=8.7 Hz, 1H), 7.12 (d, J=6.2 Hz, 2H), 6.93 (dd, J=7.9, 2.0 Hz, 1H), 6.81 (dd, J=11.6, 2.5 Hz, 1H), 5.43 (s, 2H), 4.80 (q, J=8.3 Hz, 2H); MS: (M+H m/z=480.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.F[C:25]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:33][C:32]1[C:25]([N:11]2[C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=3[C:9]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)=[N:10]2)=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]
Reactant: N#Cc1cccc(F)c1F
Reactant: COc1nccc2[nH]nc(-c3ccc(N4CCOCC4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cccc1C#N
Yield: 77.4 %

Procedure:
A solution of 4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (355 mg), 2,3-difluorobenzonitrile (180 mg) and potassium carbonate in DMF (5 mL) was stirred at 100° C. for 2.5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was washed with petroleum ether to give the title compound (380 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N=C=N.C1C=CC2N(O)N=NC=2C=1.[Cl:25][C:26]1[CH:27]=[C:28]([N:33]([CH2:45][CH2:46][CH2:47][N:48]2[CH2:55][CH:54]3[CH:50]([CH2:51][NH:52][CH2:53]3)[CH2:49]2)[C:34]([CH:36]2[CH2:41][CH2:40][N:39]([C:42](=[O:44])[CH3:43])[CH2:38][CH2:37]2)=[O:35])[CH:29]=[CH:30][C:31]=1[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:52]1[CH2:53][CH:54]2[CH2:55][N:48]([CH2:47][CH2:46][CH2:45][N:33]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[C:26]([Cl:25])[CH:27]=3)[C:34]([CH:36]3[CH2:37][CH2:38][N:39]([C:42](=[O:44])[CH3:43])[CH2:40][CH2:41]3)=[O:35])[CH2:49][CH:50]2[CH2:51]1)=[O:6]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CC3CNCC3C2)c2ccc(C)c(Cl)c2)CC1
Reactant: Cc1cccc(C(=O)O)c1Br
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(C(=O)N(CCCN2CC3CN(C(=O)c4cccc(C)c4Br)CC3C2)c2ccc(C)c(Cl)c2)CC1
Reaction time: 24 h

Procedure:
A mixture of 2-bromo-3-methyl-benzoic acid (62, 0.016 g, 0.075 mmol), resin-bound carbodiimide (0.078 g, 0.15 mmol) and HOBT (0.012 g, 0.085 mmol) in DCM:DMF (1 mL, 10:1) was shaken for 18 h. A solution of 42b (0.022 g, 0.05 mmol) and DIPEA (0.03 mL, 0.17 mmol) and DCM (1 mL) was added. Shaking was continued for 24 h, the resin filtered and washed with DMF (1 mL) and twice with DCM (1 mL). The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to afford II-244: ms (ES+) m/z 644 (M+H)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([C:9]1[CH:10]=C([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1)C(O)=O)#[N:8].CN(C)C=O>ClCCl>[C:7]([C:9]1[CH:10]=[C:1]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1)[C:2]([Cl:4])=[O:3])#[N:8]
Reactant: N#Cc1cc(C(=O)O)ccc1OCC1CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)Cl)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Oxalyl chloride (0.040 ml, 0.460 mmol) was added to a stirred solution of 3-cyano-4-[(cyclopropylmethyl)oxy]benzoic acid (D24; 50 mg, 0.230 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at room temperature under nitrogen, and the mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo to give the title compound (54.2 mg) which was used in the subsequent step (D49) without purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.CCN(C(C)C)C(C)C.Cl.[C:20]1([CH2:26][CH2:27][C:28]2[N:29]=[C:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[S:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[C:20]1([CH2:26][CH2:27][C:28]2[N:29]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:7](=[O:9])[CH2:6][C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)[CH2:35][CH2:34]3)[S:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Reactant: O=C(O)Cc1ccsc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cc1ccsc1)N1CCC(c2nc(CCc3ccccc3)cs2)CC1
Reaction time: 0.5 h

Procedure:
Thiophen-3-ylacetic acid (156 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred for 30 min. 4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg), prepared according to Process 1.2, is added, and the mixture is stirred for a further 5 min before bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (599 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives 1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}-2-(thiophen-3-yl)ethanone (99 mg).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Br:13][CH2:14][CH2:15]Br.C(N(CC)CC)C>CN(C)C=O>[Br:13][CH2:14][CH2:15][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCCBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
Dissolve 32.6 g of N-hydroxyphthalimide in 240 ml of dimethylformamide and introduce, into this solution, 74 g of 1,2-dibromoethane and then 40 g of triethylamine. Stir the reaction mixture at room temperature for 20 hours and then filter the crystals which have precipitated. Pour the filtrate into 1500 ml of cold water and isolate the white precipitate formed. After washing with water and drying in an oven, the product is obtained, with a 60% yield, which melts at 98° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([OH:38])[CH3:37]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][CH:36]([OH:38])[CH3:37])=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CC(O)CN
Product: CON=C1C[C@@H](C(=O)NCC(C)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (2RS)-1-amino-2-propanol, the title compound was obtained in 82% purity by HPLC. MS(ESI+): m/z=396.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[F:36][C:37]1([F:41])[CH2:40][NH:39][CH2:38]1>C(#N)C>[Cl:24][C:18]1[CH:19]=[C:20]([N:39]2[CH2:40][C:37]([F:41])([F:36])[CH2:38]2)[CH:21]=[CH:22][C:17]=1[S:14]([C@H:12]1[CH2:11][N:10]([C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)[C@H:9]([C:7]([NH:6][C:3]2([C:1]#[N:2])[CH2:5][CH2:4]2)=[O:8])[CH2:13]1)(=[O:16])=[O:15]
Reactant: FC1(F)CNC1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CC(F)(F)C4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 385b) was reacted with 3,3-difluoroazetidine hydrochloride (CAS Reg. No. 288315-03-7) in acetonitrile at 90° C. for 48 h to give the title compound as off-white foam. MS (ESI): m/z=579.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccc(Cl)cc4)C3)nc(N)n2)cc1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3ccc(Cl)cc3)C2)n1
Temperature: 150 °C
Yield: 30.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(4-chlorophenyl)-3-piperidinecarboxamide (190 mg, 0.421 mmol), 3 mL of EtOH, Hunig's base (0.22 mL, 1.26 mmol), and hydrazine anhydrous (0.053 mL, 1.69 mmol) were added, and the yellow mixture was heated at 150° C. for 180 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH at 50° C., EtOAc was used to triturate. When the solution turned slightly cloudy, it was cooled down to room temperature to get pure crystallized light yellow title compound (59 mg). LC-MS (ES) m/z=463 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.45 (m, 1H), 1.64-1.85 (m, 2H), 1.99 (m, 1H), 2.55 (m, 1H), 2.78-3.07 (m, 2H), 4.38-4.82 (m, 2H), 5.37 (s, 2H), 6.10 (s, 2H), 6.64-6.74 (m, 1H), 7.31-7.40 (m, 2H), 7.53-7.76 (m, 4H), 7.97 (s, 1H), 10.18 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])(=O)C.[Na+].[Br:14]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:14][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: COc1ccccn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)cn1
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a suspension of 2-methoxypyridine (10.00 g, 0.09 mol) and sodium acetate (8.27 g, 0.10 mmol) in 30 mL of glacial acetic acid was added a solution of bromine in 20 mL glacial acetic acid while maintaining the reaction temperature below 50° C. After 3 hours, 100 mL of H2O was added and the resulting solution neutralized with cold 2.5 M NaOH. The suspension was extracted with ether (2×200 mL), the combined organics were dried over MgSO4, filtered and evaporated. The crude material was purified on silica gel (eluent: hexane to hexane:ethyl acetate 97:3) and distilled (34-36.5° C./0.05 mm Hg) to give 8.84 g (51.3%) of 5-bromo-2-methoxy-pyridine as a clear colorless liquid.