Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH2:25])=[N:11][C:12]=2[C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH:4]=[N:3][CH:2]=1.[CH3:26][CH2:27][N:28](C(C)C)C(C)C.Br[CH:36]([CH2:40][CH3:41])[C:37](Br)=[O:38].CN>C(Cl)Cl.C1COCC1.CN1C(=O)CCC1>[CH2:27]([NH:28][CH:36]([CH2:40][CH3:41])[C:37]([NH:25][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[C:12]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[N:11]=1)=[O:38])[CH3:26]
Reactant: CCC(Br)C(=O)Br
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(-c2cncnc2)c(C#Cc2ccc3ncccc3c2)n1
Agent: CN
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCNC(CC)C(=O)Nc1ccc(-c2cncnc2)c(C#Cc2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-pyrimidin-5-yl-6-(2-quinolin-6-ylethynyl)pyridin-2-amine G2b (600 mg, 1.86 mmol) is mixed with NMP (10 ml) and DIPEA (1.42 ml, 8.35 mmol). 2-Bromobutanoyl bromide (985 μl, 8.17 mmol) is added dropwise. The mixture stirred for 1 h at RT. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The crude intermediate is mixed with a THF solution of methylamine (2 mol/l, 5 ml, 10 mmol) and stirred at RT for 16 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 250 mg (32%). HPLC-MS: M+H=423; tR=1.25 min (*Method—1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:14]2[CH2:15][CH2:16][CH:11]([CH3:10])[CH2:12][CH2:13]2)[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC1CCNCC1
Solvent: ClCCl
Product: CC1CCN(Cc2cccc(Br)n2)CC1

Procedure:
5] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 4-methylpiperidine (0.4 mL, 3.22 mmol) in dry CH2Cl2 (10 mL) to give 2-bromo-6-[(4-methyl)piperidinylmethyl]pyridine as a white solid. MS m/z: 269.4 (M+H). Calc'd for C12H17BrN2: 269.18.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:16][CH2:17][CH:18]([N:21]2[CH2:25][CH2:24][CH2:2][NH:23][C:22]2=[O:26])[CH2:19][CH2:20]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNC2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 1-(1-t-butoxycarbonylpiperidin-4-yl)imidazolidin-2-one (20 mg, 0.07 mmol) in dichloromethane (2 mL) and the reaction stirred at room temperature overnight. The reaction was concentrated in vacuo to give the title compound as its trifluoroacetic acid salt (12 mg).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:15]1(=[O:22])[CH2:20][CH2:19][CH2:18][C:17](=O)[CH2:16]1.[CH2:23]([O:25][C:26](=[O:31])[CH2:27][C:28](=[NH:30])[NH2:29])[CH3:24]>C(O)C>[CH2:23]([O:25][C:26]([C:27]1[CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[C:15](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]=2[NH:29][C:28]=1[NH2:30])=[O:31])[CH3:24]
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C1CCCC(=O)C1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1ccccc1-c1ccccc1
Yield: 45 %

Procedure:
Upon heating a solution of 6.1 g of biphenyl-2-aldehyde, 3.8 g of cyclohexane-1,3-dione and 5.1 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour, 2-amino-4-(biphenyl-2-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 248°C (ethanol) is obtained. Yield: 45% of theory.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=2)=[O:14])[CH:3]=1.[CH3:24][S:25](C)=O>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([S:25][CH3:24])=[CH:21][CH:22]=2)=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)NCc2ccc(Cl)nc2)cc(N)c1C#N
Reactant: CS(C)=O
Product: CCOc1nc(C(=O)NCc2ccc(SC)nc2)cc(N)c1C#N

Procedure:
A solution of Example 185 (70 mg, 0.21 mmol) and sodium methylthiolate (32 mg, 0.46 mmol) in dimethyl sulfoxide (0.8 mL) was heated to 90° C. for 12 h., extracted with ethyl acetate (5 mL), and washed with H2O (2×5 mL). The organic layer was concentrated in vacuo and purified by silica gel chromatography (50-100% ethyl acetate in hexanes) providing the title compound as an off white solid (42 mg, 58%). 1H NMR (300 MHz, DMSO-d6) δ 8.98-9.15 (m, 1H), 8.32-8.44 (m, 1H), 7.57 (dd, J=8.31, 2.20 Hz, 1H), 7.32 (s, 2H), 7.25 (dd, J=8.31, 0.85 Hz, 1H), 7.06 (s, 1H), 4.49 (q, J=7.12 Hz, 2H), 4.41 (d, J=6.44 Hz, 2H), 2.48 (s, 3H), and 1.31 (t, J=7.12 Hz, 3H); MS (ESI) m/e positive ion 344 [M+H]+; negative ion 342 [M−H]−.
Reaction SMILES: [Br-:1].[Li+].[C:3](=[O:11])([O:7][CH:8](Cl)[CH3:9])[O:4][CH2:5][CH3:6].O>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.ClCCl>[C:3](=[O:11])([O:7][CH:8]([Br:1])[CH3:9])[O:4][CH2:5][CH3:6]
Reactant: CCOC(=O)OC(C)Cl
Reactant: [Br-]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)OC(C)Br
Temperature: 35 °C
Reaction time: 24 h
Yield: 75.9 %

Procedure:
A mixture of lithium bromide (43 g, 0.5 m), ethyl alphachloroethyl carbonate (15.3 g, 0.1 m); water (100 ml), dichloromethane (100 ml) and cetyl trimethyl ammonium bromide (1.5 g) was stirred at ambient temperature for 24 hours. The aqueous layer was removed and replaced by a fresh solution of lithium bromide (26 g, 0.3 m) in water (40 ml) containing cetyl trimethyl ammonium bromide (1 g). After stirring for a further 24 hours during which time the temperature was raised to 35° C., the organic layer was separated, dried and vacuum distilled to afford after repeated fractionation the new compound, ethyl alpha-bromoethyl carbonate (15.0 g, 76% yield) having a boiling point of 90°-92° C. at 35 mms of mercury pressure.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].CS(C)=O.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([NH2:22])=[C:17]([CH3:23])[CH:16]=1>C(O)(=O)C.O>[NH2:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:14](=[O:13])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:16][C:17]=1[CH3:23]
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C(=O)CS(C)(=O)=O)cc(C)c1N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A suspension of 33 g. of dimethylsulfone and 11 g. of sodium hydride (50% dispersion in oil) in 160 ml. of absolute dimethylsulfoxide was stirred at 50° C. under an atmosphere of nitrogen and the exclusion of moisture for 3 hours. Then, 18 g. of 4-amino-3,5-dimethyl-benzoic acid methyl ester were added. The mixture was stirred at 80° C. for 30 minutes and at room temperature for 1 hour and then dissolved in 400 ml. of water. The solution was neutralized with glacial acetic acid. The precipitate which formed was removed by filtration with suction, washed with water, dried and recrystallized from ethyl acetate, whereby there was obtained 4'-amino-3',5'-dimethyl-2-(methylsulfonyl)-acetophenone having a melting point of 179°-180° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].[C:29]([NH:36][CH2:37][CH2:38][NH2:39])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(N(CC)CC)C>ClCCl.CCOC(C)=O>[C:32]([O:31][C:29]([NH:36][CH2:37][CH2:38][NH:39][S:25]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[N:7]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:6]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:27])=[O:26])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)NCCNC(=O)OC(C)(C)C)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 4 Step C (235 mg) was combined with Boc-ethylenediamine (74 μL) and triethylamine (178 μL) in 3 mL of dichloromethane and stirred at room temperature for 1 hour. The reaction was diluted with EtOAc and washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using EtOAc/hexane as mobile phase to give the titled compound. ESI+ MS: 678 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:12])[N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:5]2=[O:18].[Cl:20][C:21]1[C:26]([CH:27]=O)=[C:25]([O:29][CH3:30])[N:24]=[CH:23][CH:22]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][N:24]=[C:25]([O:29][CH3:30])[C:26]=1[C:27]1[NH:11][C:10]2=[CH:9][C:8]3[C:7](=[O:12])[N:6]([CH2:13][CH2:14][N:15]([CH3:16])[CH3:17])[C:5](=[O:18])[C:4]=3[C:3]([CH3:19])=[C:2]2[N:1]=1
Reactant: Cc1c(N)c(N)cc2c1C(=O)N(CCN(C)C)C2=O
Reactant: COc1nccc(Cl)c1C=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1nccc(Cl)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Temperature: 50 °C

Procedure:
A mixture of 5,6-diamino-2-(2-(dimethylamino)ethyl)-4-methylisoindoline-1,3-dione (0.36 g, 1.37 mmol) and 4-chloro-2-methoxynicotinaldehyde (0.26 g, 1.51 mmol) in a mixture of methanol (8 mL) and acetic acid (0.4 mL) was heated at 50° C. for 14 h. After the end of reaction was established by TLC, the reaction mixture was concentrated under vacuum to dryness, and the crude product was subjected to the next step without further purification. Mass (ESI, positive) m/z 414.1 [M+H]+.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)[NH:10][C:11]2[O:12][CH2:13][CH2:14][C@@:15]([CH:38]([F:40])[F:39])([C:17]3[CH:22]=[C:21]([N:23]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH:20]=[CH:19][C:18]=3[F:37])[N:16]=2)=CC=1.FC(F)(F)C(O)=O.Cl.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.O1CCOCC1>[NH2:23][C:21]1[CH:20]=[CH:19][C:18]([F:37])=[C:17]([C@:15]2([CH:38]([F:39])[F:40])[CH2:14][CH2:13][O:12][C:11]([NH2:10])=[N:16]2)[CH:22]=1
Reactant: COc1ccc(C(NC2=N[C@@](c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)(C(F)F)CCO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)CCO1
Temperature: 23 °C
Reaction time: 60 h
Yield: 43.7 %

Procedure:
To a solution of (S)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-4-(difluoromethyl)-4-(5-(diphenylmethyleneamino)-2-fluorophenyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (intermediate E8.1) (525 mg, 723 μmol) in dichloromethane (20 ml) was added at 23° C. trifluoroacetic acid (4.12 g, 2.79 ml, 36.2 mmol) and the mixture was stirred at 23° C. for 1 hour, whereupon 1 M HCl (14.5 ml, 14.5 mmol) and dioxane (40 ml) were added and the mixture was stirred vigorously at 23° C. for 60 hours. Poured into 1 M Na2CO3-solution, extracted with dichloromethane, washed the organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil. The residue was purified by chromatography on 5 g silica gel with dichloromethane/methanol/ammonium hydroxide 110:10:1 to give (S)-4-(5-amino-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (82 mg, 316 μmol, 43.7% yield) as a light brown solid. MS (ISP): m/z=259.9 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[CH3:25][CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30](O)=[O:31]>>[CH3:25][CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:11][CH:12]=1)=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: CCCc1cccc(C)c1C(=O)O
Product: CCCc1cccc(C)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)O

Procedure:
N-[[2-(2-methylethyl)-6-methylphenyl]carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 2-(2-methylethyl)-6-methylbenzoic acid using the general procedures described in example 7 and was obtained as an amorphous white solid. ES-HRMS m/e calcd for C27H31N3O5 (M+Na) 500.2156, found 500.2160.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([NH:40][NH2:41])=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1N=CN([C:59](N2C=NC=C2)=[O:60])C=1>C1COCC1>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]6[O:39][C:59](=[O:60])[NH:41][N:40]=6)=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ncc(-c2ccc(C(=O)NN)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: C1CCOC1
Product: COc1ncc(-c2ccc(-c3n[nH]c(=O)o3)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{5-[4-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(morpholin-4-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzohydrazide (Step A, 108 mg, 0.145 mmol) was dissolved in THF (1.5 mL) and treated with N,N-carbonyldiimidazole (70.5 mg, 0.435 mmol). The reaction was stirred at room temperature overnight. The reaction was purified directly by silica gel chromatography, eluting with a gradient of 25-100% ethyl acetate/hexanes to give the title compound. LCMS (M+H)+: 772.5. 1H NMR (CDCl3, 500 MHz): δ 9.09 (s, 1H), 8.22 (m, 2H), 7.88 (s, 1H), 7.78 (s, 1H), 7.72 (s+d, 3H), 7.48 (d, 1H), 7.35 (d, 1H), 5.63 (d, 1H), 4.75 (d, 1H), 4.33 (m, 1H), 4.01 (m, s, 4H), 3.86 (m, 4H), 3.81 (m, 4H), 2.38 (s, 3H), 0.73 (d, 3H). RTA IC50: 29 nM.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8](O)[C:7]([N+:11]([O-:13])=[O:12])=C(O)[CH:5]=1.O=P(Cl)(Cl)[Cl:17].[CH2:20]([Cl:22])Cl>>[Cl:17][C:8]1[C:7]([N+:11]([O-:13])=[O:12])=[C:20]([Cl:22])[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCl
Reactant: COCc1cc(O)c([N+](=O)[O-])c(O)n1
Product: COCc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C

Procedure:
6-Methoxymethyl-3-nitro-pyridine-2,4-diol (725 mg, 3.63 mmol) is added to a solution of POCl3 (15 mL) at 0° C. The mixture is warmed to room temperature followed by heating at reflux for 5 hours. Excess POCl3 is removed under reduced pressure to yield a light brown oil. The crude oil is dissolved in CH2Cl2 (100 mL) and extracted with water (100 mL), NaHCO3 (100 mL), and brine (100 mL). The organic extract is dried over Na2SO4 and the solvent removed under reduced pressure. The crude product is chromatographed on silica gel eluting with hexanes/EtOAc (4:1) to yield the title compound as a light yellow oil.
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[O:22])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:21])[C@H:12]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])[NH2:13])[CH3:3].[N+](C1C=CC([O:32][C:33](=O)[C@H:34]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=CC=1)([O-])=O>CN(C)C=O>[ClH:1].[CH2:2]([NH:4][C:5](=[O:22])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:21])[C@H:12]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])[NH:13][C:33](=[O:32])[C@H:34]([CH2:46][CH:47]([CH3:48])[CH3:49])[NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH3:3]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
A solution of 18.6 g. of L-arginyl-L-proline N-ethylamide hydrochloride (Ex.1,1) and 7.2 g. of Nα -benzyloxycarbonyl-L-leucine p-nitrophenylester in 30 ml. of dimethylformamide is allowed to stand for four days, warmed to 50° C. for a half hour and evaporated at reduced pressure and 40° C. to yield an oil. A solid product is obtained by chromatography over silica gel, eluting with chloroform with increasing percent of methanol. Fraction selection is made on the basis of analytical thin layer chromatography and the product obtained solid by precipitating from methanol with ethyl acetate and then by dropping a methanol solution into ethyl ether. The solid is dried at 40° C. and reduced pressure; [α]D25 -68.4° (c 1, methanol); ultraviolet in methanol λmax 257 E11 3.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH3:9][O:10][CH2:11][C:12](=O)[CH2:13][C:14](OC)=[O:15]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:14]([OH:15])=[CH:13][C:12]=2[CH2:11][O:10][CH3:9])[N:3]=1
Reactant: Nc1cccc(N)n1
Reactant: COCC(=O)CC(=O)OC
Solvent: CC(=O)O
Product: COCc1cc(O)nc2nc(N)ccc12
Yield: 19.5 %

Procedure:
A mixture of 21.8 g (0.2 mol) of 2,6-diaminopyridine and 29.2 g (0.2 mol) of methyl 4-methoxyacetoacetate in 400 ml of glacial acetic acid is stirred under reflux for 3 hours. After cooling, the precipitate is suction filtered and stirred with 150 ml of cold ethanol. 8 g (20%) of the title compound is obtained; m.p.: >290° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7]([CH2:9][O:21][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:22])[F:23])=[CH:20][CH:19]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: ClCc1nc2cc(Br)ccc2[nH]1
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1

Procedure:
Using the procedure for Step E in Example 1, the title compound was prepared from 5-bromo-2-chloromethyl-1H-benzimidazole (200 mg, 0.816 mmol) and α,α,α-trifluoro-p-cresol (132 mg, 0.816 mmol) and was obtained as an off-white solid (76.2 mg, 25% yield). Calcd. For C21H16F3N3O3S: 371.15 (M+H), Found 371.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][NH:5][CH:6]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)Cl.O>CCOCC>[CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][NH:5][C:6]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1c[nH]cc1C
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]c(C(=O)c2ccccc2)c1C

Procedure:
Ethyl 4-methylpyrrole-3-carboxylate (920 mg., 6 mmoles) was combined with benzoyl chloride (0.7 ml., 6 mmoles), stannic chloride (1.2 ml., 12 mmoles) in 25 ml. of methylene chloride and stirred under nitrogen for 2 hours at room temperature. Water (15 ml.) was added slowly, dissolving the precipitate which had formed. Ether (50 ml.) was then added, and the organic phase separated, back-washed with 20 ml. of water, and evaporated to an oil. The oil was triturated with hexane to yield crystalline product (1.12 g.). Recrystallization from acetone/hexane afforded purified ethyl 4-methyl-5-benzoylpyrrole-3-carboxylate (900 mg., m.p. 127°-129° C.).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])[C:3]([NH:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:22]1([N:25]2[CH2:30][C:29]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[O:28][CH2:27][C:26]2=[O:36])[CH2:24][CH2:23]1>CN(C)C=O.O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH:2]([N:33]2[CH2:34][CH2:35][C:29]3([O:28][CH2:27][C:26](=[O:36])[N:25]([CH:22]4[CH2:23][CH2:24]4)[CH2:30]3)[CH2:31][CH2:32]2)[C:3]([NH:5][CH3:6])=[O:4])=[C:8]([F:14])[CH:9]=1
Reactant: CNC(=O)C(Br)c1ccc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A solution of 2-bromo-2-(4-bromo-2-fluorophenyl)-N-methylacetamide (0.579 mmol) in N,N-dimethylformamide (3 mL) was treated with potassium carbonate (1.715 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.632 mmol). The reaction was allowed to stir at room temperature overnight. The reaction solution was then diluted with water (50 mL) and was extracted three times with dichloromethane. The organic layers were combined and were washed with water three times, twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-6% methanol/dichloromethane) afforded the title compound as a yellow oil (185 mg, 63% yield). MS(ES)+ m/e 454.0/455.9 [M+H]+ (bromide isotope pattern).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]([OH:11])=O)[CH2:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C>[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:63][C:9]([CH:5]4[O:6][CH2:7][CH2:8][N:3]([CH3:2])[CH2:4]4)=[O:11])[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CN1CCOC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCOC(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)C1
Reaction time: 0.08 h

Procedure:
4-Methyl-2-morpholinecarboxylic acid hydrochloride (40 mg, 0.22 mmol) was treated with HATU (84 mg, 0.22 mmol) in DMF (0.250 mL) and DIPEA (0.069 mL, 0.40 mmol). The mixture was shaken for five minutes prior to treatment with 6-(1H-indol-4-yl)-1H-indazol-4-amine (25 mg, 0.1 mmol) in DMF (0.25 mL). Reaction mixture was left to stand at room temperature for 18 hrs. Solvent was removed in vacuo and the product re-dissolved in chloroform (0.3 mL) prior to application on to a pre-conditioned (methanol then chloroform) NH2 cartridge (0.5 g). Product was eluted after 2 hr with ethyl acetate/methanol (1:1, 3 mL), and concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP (Method D) afforded the title compound.
Reaction SMILES: [CH:1]([Si:3]([CH2:10][CH2:11][CH3:12])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])=[CH2:2].[C:13]1([PH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:10]([Si:3]([CH2:1][CH2:2][P:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])[CH2:11][CH3:12]
Reactant: C=C[Si](CCC)(CCC)CCC
Reactant: c1ccc(Pc2ccccc2)cc1
Product: CCC[Si](CCC)(CCC)CCP(c1ccccc1)c1ccccc1

Procedure:
The vinyl tripropyl silane was then reacted with diphenyl phosphine with u.v. initiation for 86 hours in a manner described in the previous example. The conversion was about 95%. The mixture was fractionally distilled to yield the pure product as a clear, colorless, mobile liquid (see Table I.)