Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>ClCCl>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
To an ice-cooled solution of 3-aminopyridine (6 g, 63.8 mmol) and triethylamine (9.72 mL, 70.2 mmol) in 124 mL of dichloromethane under argon, was carefully added pivaloyl chloride (7.92 mL, 64.4 mmol) in 16 mL of dichloromethane. After the addition was completed, the reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for 18 hours. The mixture was washed with water, 4% aqueous sodium bicarbonate, brine, dried over sodium sulphate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, using hexane/ethyl acetate (85:15) as eluent, to yield the title compound (8.5 g, 75%) as a white solid.
Reaction SMILES: C[C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([O:18]CC2C=CC=CC=2)=[CH:16][C:15]([CH3:26])=[CH:14][N:13]=1.[ClH:27]>>[ClH:27].[ClH:27].[CH3:2][C:3]1[NH:4][CH:5]=[N:6][C:7]=1[S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([OH:18])=[CH:16][C:15]([CH3:26])=[CH:14][N:13]=1
Reactant: Cc1cnc(NCCSCc2nc[nH]c2C)c(OCc2ccccc2)c1
Agent: Cl
Product: Cc1cnc(NCCSc2nc[nH]c2C)c(O)c1
Yield: 38 %

Procedure:
2-[2-(5-Methyl-4-imidazolyl-methylthio)ethylamino]-3-benzyloxy-5-methylpyridine (1.29 g, 3.5 mmole) was heated for 1 hour at 60° with conc. hydrochloric acid (excess). This mixture was then evaporated to dryness under reduced pressure and the residue was recrystallised from methanol and ethyl acetate to yield 2-[2-(5-methyl-4-imidazolylthio)ethylamino]-3-hydroxy-5-methylpyridine dihydrochloride (470 mg, 38% yield, mp 214°-216°).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br)([O-:24])=[O:23]>CN(C)C=O.C(OCC)(=O)C.O>[OH:1][CH2:2][CH:3]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[N+:22]([O-:24])=[O:23])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(CO)N(Cc1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.3 %

Procedure:
To a solution of methyl 3-hydroxy-2-(4-methoxybenzenesulfonylamino)-propionate (15.0 g 51.85 mmol) in N,N-dimethylformamide (125 ml), cooled in an ice bath, was added, portionwise, NaH (2.29 g 57.03 mmol, 60% in oil). The mixture was stirred at 0° C. for 20 minutes and then a solution of 2-nitrobenzyl bromide (12.32 g 57.03 mmol) in dry N,N-dimethylformamide (25 ml) was added, dropwise. The solution was stirred at room temperature for 48 hours and diluted with ethyl acetate (500 ml) and water. The organic layer was separated and the aqueous layer extracted with additional f ethyl acetate (250 ml). The combined organic layers were washed with water (200 ml), 1N sodium bicarbonate (200 ml), saturated sodium chloride (200 ml) and dried over sodium sulfate The solvent was removed in vacuo and the residual solid was triturated with ethyl acetate, cooled and filtered to give 13.5 g (61%) of white crystals, mp 127-129° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([CH3:11])[C:3]=1[C:12](O)=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:11][C:4]1[C:5]([F:10])=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[C:3]=1[CH2:12][OH:13]
Reactant: Cc1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1c(F)c(F)c(F)c(F)c1CO
Yield: 42.9 %

Procedure:
3,4,5,6-tetrafluoro-2-toluic acid (500 mg) was dissolved in dry diethyl ether (5.0 ml) added dropwise to a suspension of lithium aluminium hydride (100 mg) in dry ether (10 ml) under an argon atmosphere at the ambient temperature. When the addition was complete and the effervescence had subsided the mixture was heated at the reflux temperature for a period of 1 hour. After allowing the mixture to cool to the ambient temperature water (10 ml) was cautiously added and the resultant mixture extracted with diethyl ether (2×20 ml), the extracts washed with water and dried over anhydrous magnesium sulphate. After filtration the filtrate was concentrated by evaporation of the solvent. The residual low melting solid was recrystallised from petroleum ether (boiling range 40°-60° C.) to yield 2-methyl-3,4,5,6-tetrafluorobenzyl alcohol (200 mg). N.m.r. (1H(ppm)CDCl3): 2.18(s,1H); 2.32(t,3H); 4.86(s,2H).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].OC(C(F)(F)F)=O.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=4)=[O:43])=[CH:37][CH:36]=3)[N:24]=1)[CH2:16]2.C(N(CC)CC)C.Cl[C:59]([O:61][CH3:62])=[O:60]>ClCCl.O1CCCC1>[CH:19]12[O:22][CH:15]([CH2:21][CH2:20]1)[CH2:16][N:17]([C:23]1[N:24]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:43])[NH:44][C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[CH:39][CH:40]=3)[N:26]=[C:27]([N:29]3[CH2:34][CH2:33][N:32]([C:59]([O:61][CH3:62])=[O:60])[CH2:31][CH2:30]3)[N:28]=1)[CH2:18]2.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COC(=O)Cl
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (75 mg) in dichloromethane (2 mL), tetrahydrofuran (2 mL), and triethylamine (1 mL) was treated with methyl chloroformate (0.10 mL). The mixture was concentrated to dryness and purified on RP-HPLC to give the title compound as its TFA salt. MS (ES+) 546.3 (M+H)+
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12]2[C:13]3[CH2:21][NH:20][CH2:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH3:10])=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28](F)=[C:29]([CH:32]=1)[C:30]#[N:31].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N:20]2[CH2:19][CH2:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C@@H:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][CH:5]=4)[CH3:10])[C:13]=3[CH2:21]2)=[C:29]([CH:32]=1)[C:30]#[N:31]
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: C[C@@H](Nc1ncnc2c1CNCC2)c1ccc(C(F)(F)F)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1ncnc2c1CN(c1ccc(Cl)cc1C#N)CC2)c1ccc(C(F)(F)F)nc1
Yield: 52 %

Procedure:
A mixture of (R)—N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (500 mg, 1.55 mmol), 5-chloro-2-fluorobenzonitrile (360 mg, 2.3 mmol), N,N-diisopropylethylamine (540 mL, 3.1 mmol), and acetonitrile (3.0 mL) was subjected to microwave irradiation at 180° C. for 2 h. Then more 5-chloro-2-fluorobenzonitrile (360 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for another 2 h. After that an additional 5-chloro-2-fluorobenzonitrile (360 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for an additional 2 h. After cooling the mixture was concentrated in vacuo and the residue was purified by silica gel column (0-100% EtOAc/hexane) and the obtained solid was washed with ether to yield an off-white solid (370 mg, 51%).
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]2[CH3:47])[N:25]=1.[OH:48][CH2:49][CH2:50][NH:51][C:52]([NH:54][C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[CH:57][CH:56]=1)=[O:53]>>[F:36][C:34]1[CH:33]=[CH:32][C:31]([S:37]([CH3:40])(=[O:39])=[O:38])=[C:30]([C:28]2[N:27]=[C:26]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]3[CH3:47])[N:25]=[C:24]([C:58]3[CH:59]=[CH:60][C:55]([NH:54][C:52]([NH:51][CH2:50][CH2:49][OH:48])=[O:53])=[CH:56][CH:57]=3)[CH:29]=2)[CH:35]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2)OC1(C)C
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCO)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Yield: 24 %

Procedure:
Method as described for intermediate 5 using (S)-4-(4-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-2-yl)-3-methylmorpholine (intermediate 16) and 1-(2-hydroxyethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 18). Material was purified by prep HPLC (low pH) to afford a brown solid. Further purification was achieved using flash chromatography (20-100% EtOAc in petroleum ether (40:60) to afford a light brown solid (60 mg, 24%).
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[O:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=3[C:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH:28]=3)[CH2:15][CH2:14][O:13][C:12]=2[CH:40]=1)(=O)=[O:6].[N:49]1[CH:54]=[CH:53][N:52]=[CH:51][C:50]=1[NH2:55].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(O)(C(F)(F)F)=O.C1COCC1>[N:49]1[CH:54]=[CH:53][N:52]=[CH:51][C:50]=1[NH:55][S:5]([C:8]1[CH:9]=[CH:10][C:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:18]=3[C:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH:28]=3)[CH2:15][CH2:14][O:13][C:12]=2[CH:40]=1)(=[O:6])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Oc4c(F)c(F)c(F)c(F)c4F)ccc32)CC1
Reactant: Nc1cnccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cnccn1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1C1=CCNCC1
Reaction time: 0.33 h
Yield: 49.1 %

Procedure:
A round-bottom flask was charged with tert-butyl 4-(2-(7-((perfluorophenoxy)sulfonyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE AA, 37.7 mg, 0.053 mmol), pyrazin-2-amine (7.61 mg, 0.080 mmol, TCI America, Portland, Oreg.), and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (112 μL, 0.112 mmol) was added dropwise over 30 s to give a light-yellow solution. After 20 min, the flask was lowered into an ice bath. After another 30 min, TFA (3 drops) was added via syringe, and the mixture was concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 20 min, the mixture was concentrated, and the residue was dissolved in MeOH and loaded onto a 500 mg SCX-2 ion exchange column. The column was eluted with MeOH then with 2N ammonia in methanol. The basic fraction was concentrated. The residue was further purified by chromatography on silica gel (12 g column, 10% MeOH/DCM, then 20% of a 2N ammonia in methanol solution dissolved in DCM) to give N-(pyrazin-2-yl)-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (13.49 mg, 0.026 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (s, 1 H), 8.02 (s, 1 H), 7.86 (br. s., 1 H), 7.72 (dd, J=1.7, 8.6 Hz, 2 H), 7.59 (d, J=1.9 Hz, 1 H), 7.54 (d, J=8.1 Hz, 1 H), 6.43 (d, J=8.5 Hz, 1 H), 5.87 (br. s., 1 H), 4.27 (br. s., 2 H), 3.61-3.53 (m, J=6.1 Hz, 5 H), 3.09 (br. s., 2 H), 2.39-2.30 (m, 1 H). m/z (ESI) 518.4 (M+H)+.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([CH2:31][C@H:32]4[CH2:37][CH2:36][C@H:35]([CH3:38])[CH2:34][CH2:33]4)[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][C@H:20]4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:18][C:14]=3[CH:13]=[C:12]([C:39]([O:41]C)=O)[N:11]=2)[CH:7]=[N:8][CH:9]=1>CO.ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([CH2:31][C@H:32]4[CH2:33][CH2:34][C@H:35]([CH3:38])[CH2:36][CH2:37]4)[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][C@H:20]4[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:18][C:14]=3[CH:13]=[C:12]([C:39]([NH:1][NH2:2])=[O:41])[N:11]=2)[CH:7]=[N:8][CH:9]=1
Reactant: NN
Reactant: COC(=O)c1cc2nc(N3CCOC[C@H]3c3ccccc3)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C(=O)NN)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydrazine (9.2 mL, 293 mmol) was added to methyl 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylate (4.11 g, 7.33 mmol) dissolved in methanol (36.6 mL), and the solution was stirred at room temperature for 30 minutes. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbohydrazide. MS ESI calc'd. for C30H34ClN7O2 [M+H]+ 560. found 560.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C1CC(N2CCOCC2)CCN1

Procedure:
41.59 g (0.16 Mol) 4-[1-(phenylmethyl)-4-piperidinyl]-morpholine (N) are dissolved in 400 mL methanol, combined with 5.2 g palladium on activated charcoal (10%) and hydrogenated for 18 hours at ambient temperature with 50 psi hydrogen. The catalyst is filtered off and the filtrate is evaporated down. A colourless oil remains, which crystallises after a short time.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=1)=[O:5])[CH3:2].[CH2:18](O)[C:19]([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)CO
Reactant: CCOC(=O)Cn1nc(C(=O)OCC)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1nc(C(=O)OCC)cc1OCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To an ice cold mixture of 50 mg (0.21 mmol) of 1-Ethoxycarbonylmethyl-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester in 2 mL of tetrahydrofuran was added 49 mg (0.25 mmol) of neopentyl alcohol, 108 mg (0.41 mmol) of triphenylphosphine, followed by 0.081 mL (0.41 mmol) of diisopropyl azodicarboxylate (DIAD) and the mixture was allowed to warm up to rt and stirred at rt overnight. The reaction mixture was then concentrated and the residue was chromatographed on silica gel (3:1 hexane:ethyl acetate) to give 46 mg (70%) of 5-(2,2-dimethyl-propoxy)-1-ethoxycarbonylmethyl-1H-pyrazole-3-carboxylic acid ethyl ester LC-MS calcd. for C15H24N2O5 [M++H]: 313.2; found: 313.2.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[CH2:5].C(=O)(O)[O-].[Na+].C1C(=O)N([Br:33])C(=O)C1.[Na]>C1COCC1>[Br:33][CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(O[Si](C)(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Dissolve the title compound from Step A above (6.0 g, 20 mmol) in THF (120 mL), cool to 0° C. and add sodium bicarbonate. To the resulting suspension was added NBS and the mixture stirred for 1.5 h. TLC showed no starting material left. Poured reaction into sat'd aqueous sodium buicarbonate solution (200 mL) and extracted with ether (2×200 mL). The organics were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The resulting product (6.4 g, 99%) was used without further purification for the next reaction. ESI-MS calculated for C12H20BrNO3: Exact Mass: 305.06. Found: 305.15 (M)+ and 307.09 (M+2)+.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:19]([N:21]1[CH2:32][CH2:31][CH2:30][C@H:22]1[C:23]([NH:25][CH2:26][C:27]([NH2:29])=[O:28])=[O:24])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:18])[NH2:17])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].Cl.C(ON[C@H](C(N[C@H](C(N1CCC[C@H]1C(NCC(N)=O)=O)=O)CCCNC(=N)N)=O)C(=C=O)C(C)C)C1C=CC=CC=1.[N+](C1C=CC([O:84][C:85](=O)[C@@H:86]([CH2:98][C:99]2[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=2)[NH:87][C:88]([O:90][CH2:91][C:92]2[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=2)=[O:89])=CC=1)([O-])=O>CN(C)C=O>[ClH:1].[CH2:91]([O:90][C:88]([NH:87][C@@H:86]([C:85]([NH:2][C@H:3]([C:8]([NH:10][C@H:11]([C:19]([N:21]1[CH2:32][CH2:31][CH2:30][C@H:22]1[C:23]([NH:25][CH2:26][C:27]([NH2:29])=[O:28])=[O:24])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:18])=[O:9])[CH2:4][CH:5]([CH3:6])[CH3:7])=[O:84])[CH2:98][C:99]1[CH:100]=[CH:101][CH:102]=[CH:103][CH:104]=1)=[O:89])[C:92]1[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=1
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: CC(C)C(=C=O)[C@H](NOCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reaction time: 24 h

Procedure:
The L-leucyl-L-arginyl-L-prolyl-glycinamide hydrochloride obtained from de-protection of 6.43 g. of Nα -benzyloxy-carbonyl-L-leucyl-L-arginyl-L-prolyl-glycinamide hydrochloride, 4.3 g. of Nα -benzyloxycarbonyl-D-phenylalanine p-nitrophenyl ester (prepared as for the L-isomer, J. Org. Chem. 27, 3409 (1962)) and 30 ml. of dimethylformamide is stirred until solution is complete. The solution is allowed to stand at 25° C. for 24 hours, filtered from a small amount of fine solid and again allowed to stand at 25° C. for 24 hours. The solution is evaporated to dryness at 40° C. under reduced pressure. The residue is dissolved in methanol (40 ml.) and ethyl acetate (30 ml.) and dropped into 300 ml. of stirred dry diethyl ether. The granular solid which precipitates is separated by decanting and the precipitation is repeated. The solid is separated and dried at 45° C. under reduced pressure to give 6.5 g. of product suitable for use but showing by ultraviolet absorption 0.37% of p-nitrophenol; [α]D23 -54.6° (c 1.0, methanol); ultraviolet in methanol λmax 257 E11 5.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.BrC1C=CN=CC=1OC.CC1(C)C(C)(C)OB(C2CCC3(OCCO3)CC=2)O1.[NH:44]1[CH2:47][CH:46]([NH:48][C:49](=[O:66])[CH2:50][NH:51][C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([C:62]([F:65])([F:64])[F:63])[CH:60]=3)[N:55]=[CH:54][N:53]=2)[CH2:45]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][CH:12]([N:44]2[CH2:45][CH:46]([NH:48][C:49](=[O:66])[CH2:50][NH:51][C:52]3[C:61]4[C:56](=[CH:57][CH:58]=[C:59]([C:62]([F:63])([F:65])[F:64])[CH:60]=4)[N:55]=[CH:54][N:53]=3)[CH2:47]2)[CH2:11][CH2:10]1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: COc1cnccc1C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: COc1cnccc1Br
Product: COc1cnccc1C1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of 4-(3-methoxypyridin-4-yl)cyclohexanone (prepared by the reaction of 4-bromo-3-methoxypyridine with 8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene using the sequence described in Example 1 Step A-C) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:24]=[CH:25][C:26]([C:29]([OH:31])=O)=[N:27][CH:28]=1)=[O:21].[CH2:32]1[C:40]2[C:35](=[CH:36]C=CC=2)[CH2:34][N:33]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:34][CH:35]([CH3:36])[CH2:40][CH2:32][NH:33][C:29]([C:26]1[N:27]=[CH:28][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:21])=[N:24][CH:25]=1)=[O:31]
Reactant: O=C(O)c1cnc(NC(=O)N2Cc3ccccc3C2)cn1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)c1cnc(NC(=O)N2Cc3ccccc3C2)cn1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-methylbutan-1-amine for 3-phenylpropan-1-amine and 5-(isoindoline-2-carboxamido)pyrazine-2-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6, Temp=90° C.) δ ppm 9.34 (bs, 1H), 9.17 (d, J=1.4 Hz, 1H), 8.82 (d, J=1.4 Hz, 1H), 8.30-8.23 (m, 1H), 7.36-7.26 (m, 4H), 4.86 (bs, 4H), 3.37-3.30 (m, 2H), 1.69-1.58 (m, 1H), 1.50-1.44 (m, 2H), 0.92 (d, J=6.5 Hz, 6H); MS (ESI(+)) m/e 354 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:12]3([S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])=[CH:22][CH:23]=2)=[CH:28][CH:29]=1
Reactant: Clc1ccc(-c2ccc(CBr)cc2)cc1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4ccc(Cl)cc4)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4′-bromomethyl-4-chlorobiphenyl in N,N-dimethylformamide. Trituration with diethyl ether provided an off-white solid. 1H NMR: δ 7.99 (s, 1H), 7.93 (dm, J=9.0 Hz, 2H), 7.45-7.49 (m, 4H), 7.38-7.41 (m, 2H), 7.23-7.26 (m, 2H), 7.06 (dm, J=9.0 Hz, 2H), 3.97, (A of AB, J=13.7 Hz, 1H), 3.92 (s, 3H), 3.39 (B of AB, J=13.7 Hz, 1H). MS (m/e): 486.0 & 488.0 (M−H)−Cl isotopes. Anal: Calc for C23H18ClNO5S2.C3H7NO: 55.66% C, 4.49% H, 4.99% N; Found: 55.57% C, 4.41% H, 4.85% N. MP: 197-200° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([Cl:13])=[O:9]
Reactant: Cc1ccsc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: Cc1ccsc1C(=O)Cl
Yield: 100.3 %

Procedure:
In 100 ml of benzene was suspended 3.00 g (21.1 mmol) of 3-methyl-2-thiophenecarboxylic acid, oxalyl chloride [7.36 ml (84.4 mmol)] was added and the mixture was refluxed for 2 hours. After cooling, the solvent was distilled off to obtain 3.40 g of 3-methylthenoyl chloride (yield: quant.). To a solution of 1.50 g (6.23 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.61 ml (18.7 mmol) of triethylamine in 60 ml of methylene chloride, 1.20 ml (7.48 mmol) of the 3-methylthenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 1.54 g of the desired compound (yield: 84.5%, pale yellow powder).