Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Br:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([O:1][CH:2]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:34][CH:33]=1
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Reactant: Oc1ccc(Br)cc1
Product: COc1ccc(C(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)Oc2ccc(Br)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-bromophenol: ESMS m/e: 564.9 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][C:11]1[N:15]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=[N:13][N:12]=1.[Cl:35][C:36]1[CH:37]=[C:38]([OH:57])[CH:39]=[CH:40][C:41]=1[CH:42]([CH3:56])[C:43]([C:49]1[CH:54]=[CH:53][N:52]=[C:51]([Cl:55])[CH:50]=1)([OH:48])[C:44]([F:47])([F:46])[F:45].O>CN1CCCC1=O>[Cl:55][C:51]1[CH:50]=[C:49]([C:43]([OH:48])([CH:42]([C:41]2[CH:40]=[CH:39][C:38]([O:57][CH2:8][CH2:9][CH2:10][C:11]3[N:15]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:14]=[N:13][N:12]=3)=[CH:37][C:36]=2[Cl:35])[CH3:56])[C:44]([F:47])([F:46])[F:45])[CH:54]=[CH:53][N:52]=1
Reactant: ClCCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(c1ccc(OCCCc2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 60 °C
Yield: 51.5 %

Procedure:
To a suspension of K2CO3 (93 mg), KI (90 mg) in N-methyl-2-pyrrolidone (0.5 mL) were added 5-(3-chloropropyl)-1-(triphenylmethyl)-1H-tetrazole (137 mg, CAS 823797-34-8, preparation see Bosmans et al., WO2005003124 A1, page 23) and 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (99 mg, Example 133). The mixture was heated to 60° C. for 20 hours and TLC confirmed almost complete conversion. The mixture was allowed to cool and poured into water. The aqueous layer was extracted with ethyl acetate and the organic extracts were washed with brine, dried and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (100 mg). MS (neg. ion, m/e)=716.2 ((M−H)−).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:66][C@@H:67]1[CH2:71][NH:70][CH2:69][C@H:68]1[OH:72]>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][C@H:67]5[C@H:68]([OH:72])[CH2:69][NH:70][CH2:71]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N[C@@H]1CNC[C@H]1O
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@@H]2CNC[C@H]2O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.012 g (0.12 mmole) (3R,4R)-4-amino-pyrrolidin-3-ol was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.042 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((3R,4R)-4-hydroxy-pyrrolidin-3-yl)-3-methoxy-benzamide (I-104) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[CH2:24][N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH3:33])=[CH:28][CH:27]=2)[CH2:22][CH2:21][N:20]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:32]([CH3:33])[C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:23]4[CH2:22][CH2:21][N:20]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[C@@H:19]([CH3:18])[CH2:24]4)=[CH:31][CH:30]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Oc2ccc(F)cc2)nc1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid chloride from step 1 was taken up in DCM (3 mL) and added to 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.288 g, 0.904 mmol) in DCM (3 mL). Triethylamine (0.251 mL, 1.808 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with water. The aqueous was extracted with DCM (×2) and the combined organic layers were dried and concentrated. The crude product was purified by column chromatography. Elution with a 0-50% EtOAc/petroleum ether gradient gave the title compound as a colourless oil (0.518 g). δH (CDCl3, 400 MHz) 8.07 (1H, m), 7.65 (1H, dd), 7.24 (2H, d), 7.03 (6H, m), 6.70 (1H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.48 (3H, s), 3.46 (1H, d), 3.34 (1H, d), 3.08 (1H, td), 2.70 (1H, d), 2.50 (1H, d), 2.10 (1H, dd), 2.00 (1H, m), 1.46 (9H, s), 1.20 (3H, d). MS (ES): MH+ 535.3.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>>[C:20]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[CH2:7][O:6][C:5]1[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:4]=1[C:2]#[N:3])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CC(C)(C)C(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared as in Example 176b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride and pivaloyl chloride in 99%. 1H NMR (400 MHz, DMSO-d6) δ 1.16 (s, 9H), 1.91 (m, 3H), 2.13 (m, 1H), 3.70 (m, 2H), 4.35 (m, 3H), 7.81 (dd, J=7.5, 2.1 Hz, 1H), 7.92 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:16]=[CH:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19](Br)=[CH:20][C:11]=3[C:10]=2[CH:9]=1)(C)(C)C.[N:23]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C.C([O-])(=O)C.[K+].CO.C(Cl)Cl.O>[N:23]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:19]3[CH:18]=[N:17][C:12]4[NH:13][C:14]5[CH:15]=[N:16][C:8]([NH2:7])=[CH:9][C:10]=5[C:11]=4[CH:20]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Nc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 140 °C
Yield: 39.6 %

Procedure:
A degassed mixture of tert-butyl-{3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl}-carbamate (105 mg, 0.290 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid (73.7 mg, 0.336 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (17.8 mg, 2.18 μmol, 7.5 mol %) in acetonitrile (1.3 mL) and 1M aqueous potassium acetate (1.3 mL) was heated under microwave irradiation at 140° C. for 30 minutes. The cooled reaction mixture was diluted with 20% MeOH in DCM and water, and filtered to remove the solids. The filtrate layers were separated and the aqueous phase was extracted into 20% MeOH in DCM, and the combined organic phase concentrated in vacuo. The resultant residue was purified by preparative HPLC (0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min) to afford the title compound as a yellow solid (41 mg, 40%). 1H NMR (DMSO-D6, 400 MHz): 11.47 (s, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.18 (s, 1H), 3.48 (s, 2H), 2.38 (m, 4H), 1.57-1.47 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=6.20 min, M+H+=358.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([N:13]([CH3:38])[C@H:14]([C:18]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:11]([N:13]([CH3:38])[C@H:14]([C:18]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:24]=1)=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
To a solution of Boc-Phe(4-Cl)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.45 g, 0.697 mmol) in methylene chloride (4 ml), TFA (3 ml) was added, stirred for 20 min. and evaporated to remove the solvent under reduced pressure. The thus obtained residue was mixed with a saturated aqueous NaHCO3 solution, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=30:1:0.1) to give Phe(4-Cl)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (355 mg, 93%). EI-MS:544 and 546 (M+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[N:5][CH:4]=1.[H-].[Na+].Br[CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1.O>CN(C)C=O.C(OCC)(=O)C>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[CH2:17][N:10]1[C:11]2[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][C:9]1=[O:13]
Reactant: COc1cnc2ccc(=O)[nH]c2c1
Reactant: BrCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cnc2ccc(=O)n(CC3OCCO3)c2c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 0.23 g of 7-methoxy-1,5-naphthyridin-2(1H)-one in 3 mL of N,N-dimethylformamide, 79 mg of 60% sodium hydride was added at room temperature, the temperature was increased to 50° C., and the mixture was stirred for 15 minutes. Thereto was added 0.41 mL of 2-bromomethyl-1,3-dioxolan, the temperature of the reaction mixture was increased to 90 to 100° C., and the reaction mixture was stirred for 3 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=100:0 to 33:67, then gradient elution with chloroform:methanol=100:0 to 90:10 to obtain 0.11 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a light brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]2[N:13]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:14][CH:15]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16]([CH:15]3[CH2:14][N:13]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:10]4[CH2:11][CH2:12][NH:8][CH:9]34)=[CH:17][NH:18]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2NCCC21
Reaction time: 5 h
Yield: 95.5 %

Procedure:
To a solution containing 62 (2.47 g, 5.83 mmol) in DCM (10 mL) was added TFA (5 mL) at 0° C. After 5 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.8 g (95%) of 63 as a white solid which was used without further purification. Mass spectrum, m/z [324.2] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[F:17][C:18]([F:26])([F:25])[C:19]([F:24])([F:23])[C:20](O)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[CH:6][C:5]2[NH:15][C:20]([C:19]([F:24])([F:23])[C:18]([F:26])([F:25])[F:17])=[N:16][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(-c2ccc(F)cc2)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Product: Fc1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)cc1
Yield: 43 %

Procedure:
A solution of 4-chloro-5-(4-fluorophenyl)benzene-1,2-diamine (200 mg, 0.85 mmol) in pentafluoropropanoic acid (2 ml) was stirred for 10 h at 80° C. The reaction was then quenched by the addition of water (100 ml), pH adjusted to 7 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-fluorophenyl)-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (132.4 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[NH2:11][CH2:12][CH2:13][OH:14].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(C(C)C)C(C)C)C>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: NCCO
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCCO)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4-bromopicolinic acid (0.3 g, 1.485 mmol) in DMF (4 mL) were added 2-aminoethanol (0.181 g, 2.97 mmol), HOBt (0.301 g, 2.228 mmol), and EDC (0.456 g, 2.376 mmol), followed by N-ethyl-N-isopropylpropan-2-amine (1.293 mL, 7.43 mmol). The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was diluted with DCM, washed with brine, and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([S:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([S:20][CH2:21][C:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CSc1nc(-c2ccc(Cl)cc2)cs1
Reactant: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CSc1nc(-c2ccc(Cl)cc2)cs1)N1CCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.25 mmol) of [4-(4-chloro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid trifluoroacetic acid salt and 35.6 mg (0.5 mmol) of pyrrolidine. Yield: 51 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.Br[CH2:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(#N)C>[CH2:35]([O:34][C:32]([C:31]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:6][N:7]2[CH:30]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Solvent: CC#N
Product: CCOC(=O)c1cn2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)ccc2n1
Yield: 40.5 %

Procedure:
Compound 22 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.105 g (0.53 mmol) of ethyl 3-bromo-2-oxopropionate in 4 mL of acetonitrile. 0.05 g of the expected product is obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=[O:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH2:19][Br:21])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1cc(Cl)c(CBr)c(C#N)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile (1.00 g, 3.48 mmol), N-bromosuccinimide (0.650 g, 3.65 mmol), and benzoyl peroxide (0.0421 g, 0.174 mmol) in carbon tetrachloride (10 mL) was heated at reflux overnight. After cooling to room temperature, the mixture was diluted with dichloromethane and washed with water. The organic layers were dried over magnesium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to give the desired product (0.57 g, 45%). LCMS calculated for C16H11BrClFNO (M+H)+: m/z=366.0; Found: 366.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:34])(=[N:27][C:28](=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])=[O:26])=[CH:21][CH:20]=1>>[CH:30]([NH:29][C:28]([N:27]=[S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH3:34])=[O:26])=[O:33])([CH3:32])[CH3:31]
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CC(C)NC(=O)N=S(C)(=O)c1ccc(N)cc1
Product: CC(C)NC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1
Yield: 39 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (291.7 mg, 1.08 mmol) with (RS)—S-(4-aminophenyl)-N-(isopropylcarbamoyl)-S-methylsulphoximide (251 mg, 0.98 mmol) according to procedure 5c, the desired product is obtained in 39% yield (186 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.Br[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:10][CH3:11])[C:4](=[O:8])[CH:3]=1
Reactant: Oc1cc(Br)ccn1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1ccc(Br)cc1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 4-bromopyridin-2-ol (100 mg, 0.57 mmol), bromoethane (124 mg, 1.1 mmol) and potassium carbonate (238 mg, 1.7 mmol) in acetone (5 mL) was stirred at 60° C. for 3.0 h. The solution was allowed to cool to room temperature, filtered and the filter cake was washed with acetone (5 mL×2). The filtrate was collected and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE:EA=20:1) to afford the title compound as a white solid LC/MS m/z=402.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.14 (d, 1 H), 6.81 (d, 1 H), 6.33 (dd, 1 H), 3.95 (q, 2 H), 1.34 (t, 3 H).
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C@H:11]2[CH2:13][C@H:12]2[CH2:14][CH2:15][OH:16])[CH2:7][CH2:6]1)=[NH:4].[C:17](Cl)(=O)[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CCOC(C)=O>[CH:18]([C:20]1[O:1][N:2]=[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C@H:11]3[CH2:13][C@H:12]3[CH2:14][CH2:15][OH:16])[CH2:7][CH2:6]2)[N:4]=1)([CH3:19])[CH3:17]
Reactant: N=C(NO)N1CCC([C@H]2C[C@H]2CCO)CC1
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)c1nc(N2CCC([C@H]3C[C@H]3CCO)CC2)no1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
N-hydroxy-4-((1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboximidamide (4.8 g, 21.10 mmol) was dissolved in Pyridine (60 ml) and isobutyryl chloride (18.44 ml, 176 mmol) was added. The mixture was stirred at 80° C. for 3 h and the solvent was evaporated to dryness. The residue was dissolved in MeOH (100 ml) and potassium carbonate (24.32 g, 176 mmol) was added. The mixture was stirred at 50° C. for 2 h. Another potassium carbonate (24.32 g, 176 mmol) was added and the mixture was stirred at 50° C. for another 2 h. The mixture was cooled down and diluted with EtOAc (100 mL), washed with water, sat. NH4Cl, dried over MgSO4, evaporated. The crude material was purified by silica gel column eluting with 20-70% EtOAc in hexane to afford the desired product. LC/MS (m/z): 280 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[NH:4][C:5](=[O:9])[CH2:6][O:7][CH3:8].[CH2:15](Br)[C:16]#[CH:17]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.[OH-].[Na+].C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[N:4]([C:5](=[O:9])[CH2:6][O:7][CH3:8])[CH2:17][C:16]#[CH:15]
Reactant: COCC(=O)Nc1c(C)cccc1C
Reactant: C#CCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#CCN(C(=O)COC)c1c(C)cccc1C
Yield: 716.1 %

Procedure:
30 g (0.155 mol) of 2,6-dimethyl-N-methoxyacetylaniline and 0.3 g of triethyl-benzyl-ammonium chloride were dissolved in a two-phase system mixture of 100 ml of 50% strength sodium hydroxide solution and 250 ml of toluene, and 19 g (0.016 mol) of propargyl bromide were added, whilst stirring vigorously. The mixture was stirred for 4 hours and the toluene phase was separated off, washed several times with water, dried over sodium sulphate and concentrated by distilling off the solvent under a waterpump vacuum. The residue was distilled under a high vacuum. 26.5 g (74% of theory) of 2,6-dimethyl-N-methoxyacetyl-N-propargyl-aniline of boiling point 140°/0.4 mm Hg and of melting point 49°-51° C. were obtained. ##STR178##