Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Si:13]([O:20][CH2:21]/[CH:22]=[N:23]/[S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Si:13]([O:20][CH2:21][C@@H:22]([NH:23][S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Brc1cccnc1
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[S@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1cccnc1
Yield: 22.4 %

Procedure:
To a solution of toluene (50 mL) cooled to −78° C. was added 2.5 M butyllithium in hexanes (6.31 mL, 15.1 mmol) and the reaction mixture was stirred until the temperature returned to −78° C. 3-Bromopyridine (1.88 g, 11.9 mmol) in toluene (5 mL) was added to the reaction mixture a rate such that the temperature never went above −65° C., and then the reaction was stirred at −78° C. for 1 hour. (S,E)-N-(2-(tert-Butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (3.00 g, 10.8 mmol) in toluene (1 mL) was added to the reaction mixture at a rate such that the temperature did not exceed −70° C., and then the reaction was stirred at −78° C. for 2 hours. To the −78° C. solution was added brine and the mixture partitioned between ETOAc/water. The organic layer was washed with brine, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (15-80% EtOAc in DCM) to provide (S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.862 g, 22% yield) as a yellow oil.
Reaction SMILES: N1CCCCC1.[CH3:7][N:8]([CH2:10][CH:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:21](=[O:51])[C@H:22]([NH:33]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)[CH2:12]1)[CH3:9]>CO>[NH2:33][C@H:22]([CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)[C:21]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH:11]([CH2:10][N:8]([CH3:9])[CH3:7])[CH2:12]1)=[O:51]
Reactant: CN(C)CC1Cc2ccccc2N(C(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)OCC2c3ccccc3-c3ccccc32)C1
Solvent: C1CCNCC1
Solvent: CO
Product: CN(C)CC1Cc2ccccc2N(C(=O)[C@H](N)Cc2c[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
Piperidine (0.66 ml) was added to a methanol (10 ml) solution of 3-(R,S)-(N,N-dimethylamino)methyl-1-[2-(R)-(9-fluorenylmethoxy)carbonylamino-3-(indol-3-yl)propanoyl]-1,2,3,4-tetrahydroquinoline (0.797 g) at room temperature. The reaction mixture was stirred at room temperature for 18 hours, then concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/methanol=10/1) to obtain the entitled compound (0.382 g).
Reaction SMILES: C[Si]([N-:5][Si:6]([CH3:9])([CH3:8])[CH3:7])(C)C.[Li+].[CH3:11][Si:12]([CH3:18])([CH3:17])[C:13]#[C:14][CH:15]=O.C[Si](Cl)(C)C>>[CH3:9][Si:6]([CH3:7])([CH3:8])[N:5]=[CH:15][C:14]#[C:13][Si:12]([CH3:18])([CH3:17])[CH3:11]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[Si](C)(C)C#CC=O
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Product: C[Si](C)(C)C#CC=N[Si](C)(C)C
Reaction time: 1 h

Procedure:
Lithium bis(trimethylsilyl)amide is placed in a reaction vessel to which 3-(trimethylsilyl)-2-propynal of step 1 is added in an aprotic solvent. During the addition of 3-(trimethylsilyl)-2-propynal the pot temperature should be maintained between -40° to -20° C. to ensure stability of the intermediate imine. To the resulting solution is added trimethylsilyl chloride and the resulting mixture stirred at a temperature ranging from -40° to -20° C. for 1 hour. This reaction step yields N,3-bis(trimethylsilyl)-2-propyn-1-imine which is not isolated from the vessel but is confirmed by GC. To the reaction vessel is now added t-butyl acetate and a catalytic amount of lithium bis(trimethylsilyl)amide. The reaction mixture is allowed to stir for 2 h at a temperature ranging from -40° to -20° C. to give (±)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate which is isolated after an aqueous ammonium chloride quench and used in the next step. In order to insure complete cleavage of the nitrogen-silicon bond the stir time for this phase should not be less than 30 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Br:50][C:51]1[CH:56]=[CH:55][C:54](O)=[CH:53][CH:52]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:17][C:54]2[CH:55]=[CH:56][C:51]([Br:50])=[CH:52][CH:53]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCC(O)c1ccc(C(=O)OC)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-heptyl)-benzoic acid methyl ester (1800 mg, 7.2 mmol) in toluene (72 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 2725 mg, 10.8 mmol) at 0° C., followed by the additions of tributylphosphine (2.69 mL, 10.8 mmol) and 4-bromo-phenol (1503 mg, 8.64 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid methyl ester. 1900 mg of the ester product is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 2 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (2 mL), and extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid (1800 mg).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 43 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate. Yield: 43% of theory, C35H42N6O5 (626.8) Rf value: 0.40 (silica gel; dichloromethane/ethanol=19:1) ##EQU68##
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=2)[CH2:10][CH2:9]1)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>ClCCl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[Br:17][C:13]1[CH:12]=[C:11]([C:8]2([NH2:7])[CH2:9][CH2:10]2)[CH:16]=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccnc(Br)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccnc(Br)c2)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of [1-(2-bromo-pyridin-4-yl)-cyclopropyl]-carbamic acid tert-butyl ester (0.160 g, 0.511 mmol) in dichloromethane (3 mL) is added trifluoroacetic acid (1.0 mL, 13 mmol) at room temperature. After 18 hours, the reaction mixture is concentrated in vacuo to yield crude title compound (ES+ m/z 213.49, 215.40) as an oil, which is used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:18][C@H:19]([C:21]([OH:23])=O)[CH3:20])[CH2:7][S:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[C:24]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)([CH3:27])([CH3:26])[CH3:25].CCOC(OC(OCC)=O)=O>C(N(CC)CC)C>[C:24]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:21](=[O:23])[C@H:19]([CH3:20])[NH:18][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][S:8][CH2:9][CH2:10][S:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)[C@H](CSCCSc1ccccc1)N[C@@H](C)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CSCCSc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
Using 3 g of s-isomer of N-[(R)-l-ethoxycarbonyl-2-(2-phenylthioethylthio)ethyl]-alanine prepare in Reference Example 46, 1.58 of (S)-proline t-butyl ester, 1.67 g of DEPC and 1.3 ml of triethylamine and following the general procedure of Example 7, the β-isomer of the title compound was prepared as a colorless oil. Yield 3.41 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:15][C:16]1[CH:21]=[C:20](O)[CH:19]=[C:18]([OH:23])[CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCCCCC>[OH:15][C:16]1[C:21]2[C:12](=[O:14])[C:3]3[CH:4]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]4=[CH:11][C:2]=3[NH:1][C:20]=2[CH:19]=[C:18]([OH:23])[CH:17]=1
Reactant: Nc1cc2ccccc2cc1C(=O)O
Reactant: Oc1cc(O)cc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCCO
Product: O=c1c2cc3ccccc3cc2[nH]c2cc(O)cc(O)c12
Reaction time: 48 h

Procedure:
To a solution of 5 g of 3-amino-2-naphthalenecarboxylic acid in 50 ml of heptan-1-ol there are added 3.5 g of 1,3,5-trihydroxybenzene and 62.5 mg of para-toluenesulphonic acid. The mixture is stirred for 48 hours under reflux using a Dean-Stark apparatus, and the reaction mixture is then concentrated in vacuo. The residue is chromatographed over silica gel (eluant: cyclohexane/acetone: 90/10). The isolated product is crystallised from a cyclohexane/acetone mixture, allowing 5.2 g of the expected product to be obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH3:11])=[CH:4][C:3]=1[N+:13]([O-])=O.CC(O)C.Cl.[H][H]>[Pd].CO>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH2:13])[CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CCCCc1ccc(C)c(N)c1

Procedure:
A mixture of 34 parts of 1-(4-methyl-3-nitrophenyl)1-butanone, 24 parts of 2-propanol saturated with hydrochloric acid and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. Water is added to the residue and the whole is alkalized with ammonium hydroxide. The product is extracted with 2,2'-oxybispropane. The extract is dried, filtered and evaporated, yielding 25.5 parts of 5-butyl-2-methylbenzenamine as a residue.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8](=[O:16])[C:7]2[N:17]([CH3:20])[N:18]=[CH:19][C:6]1=2)[CH3:4].[CH3:21][S:22]CCl>CN(C)C=O.[Cl-].[Na+].O>[CH3:20][N:17]1[C:7]2[C:8](=[O:16])[C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][C:14]=3[N:5]([CH2:3][CH2:4][S:22][CH3:21])[C:6]=2[CH:19]=[N:18]1
Reactant: CSCCl
Reactant: CCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a suspension of sodium hydride (60-72% in mineral oil, 225 mg, 5.6 mmol), which was washed with hexane and dried in vacuo, in N,N-dimethylformamide (40 ml) was added a solution of 1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 47, step 2, 0.80 g, 3.75 mmol) in N,N-dimethylformamide at 0° C. The mixture was stirred at 0° C. for 10 min and at room temperature for 2 h. Chloromethyl methyl sulfide (0.87 ml, 7.5 mmol) was added at 0° C. and the mixture was stirred at room temperature for 10.5 h. Further more, sodium hydride (60-72% in mineral oil, 68 mg, 2.8 mmol) and chloromethyl methyl sulfide (0.87 ml, 7.5 mmol) were added. After 2 h, the mixture was heated at 50° C. for 15.5 h. The mixture was poured into brine (50 ml) and extracted with ethyl acetate (50 ml×2). The organic extracts were dried over magnesium sulfate and concentrated. Purification by column chromatography on silica gel eluting with ethyl acetate/hexane (1:1) gave 0.46 g (43%) of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH:11]=[CH2:12])[C:5]([O:7]C)=O)(=O)[CH3:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>O>[CH2:9]([C:4]1[C:5](=[O:7])[N:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][C:1]=1[CH3:2])[CH2:10][CH:11]=[CH2:12]
Reactant: Nc1ccccn1
Reactant: C=CCCC(C(C)=O)C(=O)OC
Solvent: O
Product: C=CCCc1c(C)nc2ccccn2c1=O

Procedure:
Heat a mixture of 5.7 g of methyl 2-acetyl-5-hexenoate, 3.15 g of 2-aminopyridine and 0.65 g of polyphosphoric acid at 160° C. for 2 hours. Then add, in the cold state, 30 ml of water and extract the mixture using dichloromethane. The residue obtained after evaporating off the solvent is purified by chromatography on silica gel, using a mixture of dichloromethane/methanol: 98/2 as eluant.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[C:28](=[O:30])=[O:29]>C(OCC)C.O>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:28]([OH:30])=[O:29])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnccc1C(=O)O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Pyridin-3-yl-carbamic acid tert-butyl ester (6.20 g) was dissolved in anhydrous diethyl ether (260 mL), cooled to −78° C. and N,N,N′,N′-tetramethylethylendiamine (14.4 mL) was added. A solution of n-butyl lithium (1.6 M in hexane, 60 mL) was added slowly over a time period of 10 minutes. After the addition of the reagent was completed, the reaction mixture was allowed to warm to −10° C. and stirred at this temperature for 2 hours. The reaction mixture was then re-cooled to −78° C. and slowly poured on a stirred mixture of dry ice in diethyl ether. After stirring for 30 minutes, water was added to the reaction mixture and the layers were separated after complete dissolution of solid materials. The aqueous layer was washed 2× with diethyl ether and the pH-value of the aqueous layer was adjusted to 5-6. The organic layer was extracted 2× with MTB-ether. The combined organic layer was washed with a small amount of brine, dried over MgSO4 and concentrated in vacuum. The residue was washed with hexane to remove oily by-products and dried in vacuum to afford 1.19 g of the title compound as beige solid. The aqueous washing was concentrated on a rotary evaporator to approx. 50 mL, inorganic salts were filtered off and MTB-ether was added to the mother liquor. 6N hydrochloric acid was slowly added into the well-stirred mixture until the pH-value was adjusted to −3. The layers were separated, the aqueous layer was washed 2× with MTB-ether and 2× with chloroform. The combined organic layer was dried over MgSO4 and dried in vacuum to give another 2.03 g of beige solid. Together, the first organic extract and 3.22 g of the title compound of the formula
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:3]=12.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN1C(=O)CCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:3]=23)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1c[nH]c2nccc(F)c12
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2nccc(N3CCN(Cc4ccccc4)CC3)c12
Temperature: 80 °C
Yield: 75.9 %

Procedure:
4-Fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (0.300 g, 1.66 mmol) and 1-benzylpiperazine (0.350 g, 1.99 mmol) were placed in NMP (3 mL) and heated to 80° C. in a microwave for 30 minutes. The reaction was then poured into water and extracted with MTBE. The organic fractions were dried, filtered, and concentrated. The crude residue was slurried in minimal DCM, and then triturated with hexane to give 4-(4-benzylpiperazin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine (0.425 g, 76.1% yield).
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:23][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:3][N:4]=[C:5]2[CH2:10]1)=[O:12]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)nnc2C1
Reactant: C1COCCN1
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2N2CCOCC2)C1
Temperature: 110 °C

Procedure:
3-Bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.075 g, 0.183 mmol, e.g. see Example 1 for methods of preparation) was treated with morpholine (1.5 mL) and heated in a microwave reactor at 110° C. for a total of 7 hours. The solvent was evaporated under reduced vacuum and the residue was purified by mass-directed automated (preparative) HPLC (MDAP) and triturated with isohexane to afford 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-morpholinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.012 g) as white solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])=[CH:20][CH:19]=1)[C:6](=[O:16])[CH2:7][CH2:8][C:9]([C:12]([O:14]C)=[O:13])([CH3:11])[CH3:10])[CH2:2][CH2:3][CH3:4].C([Sn]([N:45]=[N+:46]=[N-:47])(CCCC)CCCC)CCC>CC1C=CC=CC=1C>[CH2:1]([N:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[NH:31][N:47]=[N:46][N:45]=2)=[CH:20][CH:19]=1)[C:6](=[O:16])[CH2:7][CH2:8][C:9]([C:12]([OH:14])=[O:13])([CH3:11])[CH3:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CCC(C)(C)C(=O)OC
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)CCC(C)(C)C(=O)O

Procedure:
A solution of 5.5 g (11.3 mmol) of 4-methoxycarbonyl-4-methyl-pentanoic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide and 4.9 g (14.2 mmol) of tributyltin azide in 50 ml of o-xylene is reacted and worked up analogously to Example 2 to yield 4-carboxy-4-methyl-pentanoic acid N-butyl-N-[2'-(1H-tetrazol-5-yl)biphenyl4-ylmethyl]-amide in the form of a beige-coloured foam that has an Rf value of 0.34 [toluene/isopropanol/glacial acetic acid (170:30:2)].
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:55]3[CH2:60][CH2:59][O:58][CH2:57][CH2:56]3)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCOCC5)c4)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and morpholine (29 μL, 0.33 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. Additional morpholine (29 μL, 0.33 mmol) was added and the mixture subsequently stirred at 60° C. in a sealed tube for 24 h. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (25 mg, 50%). LCMS (Method 5): Rt 3.66 min, m/z 748.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.0 Hz), 1.27 (9H, s), 1.46-1.56 (2H, m), 1.61-1.73 (2H, m), 1.75-1.98 (4H, m), 1.99-2.19 (2H, m), 2.42 (4H, t, J=4.0 Hz), 2.67 (2H, t, J=8.0 Hz), 2.86-2.95 (1H, m), 3.12-3.20 (1H, m, obscured by water), —3.30 (1H, m, obscured by water), 3.53 (4H, t, J=8.0 Hz), 4.12 (2H, t, J=8.0 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.33 (1H, s), 6.95-6.99 (1H, m), 7.07-7.13 (3H, m), 7.19 (1H, dd, J=8.0 Hz, 4.0 Hz), 7.25-7.43 (5H, m), 7.64 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=4.0 Hz), 8.13 (1H, s), 8.21 (0.5H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([N:14]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:16][CH2:15]1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32]I.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([N:14]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=2)[CH2:16][CH2:15]1)[CH2:12][O:13][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1[C@H](CO)CCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H](CCOCc1ccccc1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reaction time: 3 h

Procedure:
0.40 g (0.92 mmol) of the above prepared 4-((S)-3-benzyloxy-1-hydroxymethyl-propyl)-1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one and 0.29 ml (4.58 mmol) of methyl iodide were dissolved in 1.6 ml of DMF. After cooling (0° C.), 0.048 g (1.10 mmol) of NaH (55% dispersion in oil) was added. The reaction was stirred for 3 h at this temperature, then poured onto crashed ice/aq. 10% KHSO4 solution and extracted with Et2O (3×). The organic layers were washed with aq. 10% KHSO4 solution and aq. 10% NaCl solution, dried over Na2SO4, evaporated and purified by flash silica gel column (n-heptane:EtOAc 1:1) to yield 0.42 g (quantitative) of the title compound as light yellow oil. MS: 451.2 (MH+, 1Cl).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([N:27]4[CH:31]([CH3:32])[CH2:30][O:29][C:28]4=[O:33])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1.Cl[CH2:35][O:36][CH3:37]>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([N:14]([CH2:35][O:36][CH3:37])[C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([N:27]4[CH:31]([CH3:32])[CH2:30][O:29][C:28]4=[O:33])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COCCl
Reactant: CC1COC(=O)N1c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cccc(Cl)c1)c1nccc(-c2ccnc(N3C(=O)OCC3C)c2)n1
Reaction time: 5 h

Procedure:
Potassium t-butoxide (0.235 g, 2.1 mmol) is added at room temperature to a solution of 3-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-4-methyl-oxazolidin-2-one (0.5 g, 1.3 mmol). After stirring the mixture for 10 minutes chloromethylmethylether (0.17 g, 2.1 mmol) in THF (3 ml) is added. The mixture is stirred for additional 5 hours at this temperature. Dilution with ethyl acetate, washing with brine, drying over magnesium sulfate, filtering and evaporation of the solvent gives the title compound in form of a slightly colored oil; 1H-NMR (DMSO): 8.70 (s, 1H); 8.51 (d, 1H); 8.48 (d, 1H); 7.68 (d, 1H); 7.47–7.23 (m, 5H); 5.39 (s,2H); 4.87–4.74 (m,1H); 4.50 (dd, 1H); 4.08 (dd,1H); 3.25 (s,3H); 1.33 (d,3H).