Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Reaction time: 16 h
Yield: 94.4 %

Procedure:
To a solution of 2.78 g (7.2 mmol) of 4-((S)-2-benzoyloxymethyl-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester in 80 ml of CH2Cl2 was added 5.83 ml of TFA (90% in water) drop by drop. After 16 hours, the reaction mixture was poured into crashed ice; then, the pH was adjusted to 9-10 with sodium carbonate solution and the mixture was extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography [CH2Cl2 (sat. with NH3)/MeOH 1:0 to 9:1] to give 1.96 g (95%) of the title compound as yellow oil. MS: 289.1 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O>C1(C)C=CC=CC=1>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])=[O:7]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: NCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCCCN
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A mixture of 5.05 gm (43.1 mmole) of 5-aminopentanoic acid, 23.3 gm (86.1 mmole) of stearyl alcohol, and 12.0 gm (63.1 mmole) of p-toluenesulfonic acid monohydrate in 200 ml of toluene was heated at reflux, using a Dean-Stark trap to remove water. After 90 minutes, the solution was allowed to cool to 0° C., giving a heavy gelatinous precipitate. The crude ester was collected, washed thoroughly with toluene, triturated with diethyl ether, and dried in vacuo to give 21.1 gm (38.8 mmole) of fluffy white octadecyl 5-aminopentanoate as the tosylate salt. The ester was sufficiently pure according to nmr spectroscopy (in (CD3)2SO) for subsequent use without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[NH:4][CH:3]=1.[C:23]([O:27][C:28]([NH:30][CH2:31][CH2:32][CH:33]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:34](O)=[O:35])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][CH:33]([C:34]([N:14]2[CH2:13][CH2:12][N:11]([C:9]3[C:8]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:7][N:6]=[C:5]4[NH:4][CH:3]=[C:2]([CH3:1])[C:10]=34)[CH2:16][CH2:15]2)=[O:35])[CH2:32][CH2:31][NH:30][C:28](=[O:29])[O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:39][CH:40]=1
Reactant: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Reactant: CC(C)(C)OC(=O)NCCC(Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)C(CCNC(=O)OC(C)(C)C)Cc4ccc(Cl)cc4)CC3)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 12.1 %

Procedure:
3-Methyl-5-phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.137 mmol, see Example 15), 4-(tert-butoxycarbonylamino)-2-(4-chlorobenzyl)butanoic acid (0.0494 g, 0.151 mmol), HOBT-H2O (0.0293 g, 0.192 mmol), and EDCI (0.0341 g, 0.178 mmol) were placed in DCM (3 mL) at room temperature. DIEA (d=0.742; 0.119 mL, 0.684 mmol) was then added, and the reaction was stirred at room temperature for 15 hours. The reaction was then poured into saturated Na2CO3 and extracted with DCM. The combined organic fractions were dried, filtered, concentrated, and purified (500:5 DCM:MeOH) to give tert-butyl 3-(4-chlorobenzyl)-4-(4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-4-oxobutylcarbamate (0.010 g, 12.1% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[CH:13][C:14]#[N:15])[C:7]=2[CH:16]=1.N.C(O)C>C(O)C.[Ni]>[NH2:15][CH2:14]/[CH:13]=[C:8]1\[CH2:9][CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][C:7]\1=2
Reactant: COc1ccc2c(c1)C(=CC#N)CCCC2
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc2c(c1)/C(=C/CN)CCCC2
Temperature: 50 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
To a solution of (2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-9-ylidene)acetonitrile (2.00 g, 9.38 mmol) in ethanol (10 ml) were added a saturated solution of ammonia/ethanol (5 ml) and Raney nickel (W-2, 2 g). The mixture was stirred for 4 hours at 50° C. under hydrogen atmosphere (4 kgf/cm2). The Raney nickel was filtered off, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (chloroform:methanol=9:1 to chloroform:methanol:triethylamine=90:8:2) to give the above-titled compound (1.50 g, yield 74%, oil).
Reaction SMILES: [N:1]([C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH:8]=O)=[C:6]([F:14])[C:5]=1[F:15])=[N+:2]=[N-:3].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.[OH-].[Na+]>CO.O>[N:1]([C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH:8]=[C:19]2[C:20](=[O:23])[C:21](=[CH:8][C:7]3[C:6]([F:14])=[C:5]([F:15])[C:4]([N:1]=[N+:2]=[N-:3])=[C:11]([F:12])[C:10]=3[F:13])[CH2:22][N:17]([CH3:16])[CH2:18]2)=[C:6]([F:14])[C:5]=1[F:15])=[N+:2]=[N-:3]
Reactant: CN1CCC(=O)CC1
Reactant: [N-]=[N+]=Nc1c(F)c(F)c(C=O)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CC(=Cc2c(F)c(F)c(N=[N+]=[N-])c(F)c2F)C(=O)C(=Cc2c(F)c(F)c(N=[N+]=[N-])c(F)c2F)C1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a stirred solution of 4-azido-2,3,5,6-tetrafluorobenzaldehyde (23), 0.140 g, 0.640 mmol) and 1-methylpiperidine-4-one (0.040 mL, 0.32 mmol) in MeOH (1.5 mL), 1N aq. NaOH (0.650 mL, 0.650 mmol) was added dropwise. Yellow suspension resulted within minutes which was stirred at rt for forty-five minutes and diluted with water (3 mL). Yellow solid was collected by vacuum filtration, washed with water until the filtrate was neutral to pH paper. The yellow solid was dried further in vacuo to give 0.139 g (83%) 3,5-bis(4'-azido-2',3',5',6'-tetrafluorophenylmethylene)-1-methyl piperidine-4-one (22) as bright yellow powder; mp 153° C. (violent decomposition). 1HNMR(CDCL3 δ 2.37 (s, 3H), 3.42 (s, 4H), 7.55 (s,2H). ##STR28##
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[N:27]=[C:26]([NH:28][C:29]3[CH:34]=[C:33]([NH:35][C:36]([C:38]4[CH:43]=[CH:42][N:41]=[C:40]([N:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)[CH:39]=4)=[O:37])[CH:32]=[CH:31][C:30]=3[CH3:50])[CH:25]=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:50][C:30]1[CH:31]=[CH:32][C:33]([NH:35][C:36]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:39]=2)=[O:37])=[CH:34][C:29]=1[NH:28][C:26]1[CH:25]=[CH:24][N:23]=[C:22]([O:21][CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)[N:27]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(OC2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(OC2CCNCC2)n1
Yield: 36.9 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 2(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)anilino]pyrimidine (0.212 g) in methylene chloride (5 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The aqueous phase was passed through an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. The product so obtained was triturated under diethyl ether and there was thus obtained the title compound as a solid (0.065 g); NMR Spectrum: (DMSOd6) 1.2 (m, 2H), 1.87 (m, 2H), 2.17 (s, 3H), 2.19 (s, 3H), 2.27 (m, 2H), 2.95 (m, 2H), 3.5 (m, 4H), 3.7 (m, 4H), 4.85 (m, 1H), 6.27 (d, 1H), 7.1 (m, 1H), 7.21 (s, 1H), 7.23 (m, 1H), 7.5 (m, 1H), 7.9 (m, 1H), 8.0 (d, 1H), 8.27 (m, 1H), 9.0 (s, 1H), 10.28 (s, 1H); Mass Spectrum: M+H+ 490.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:6]2[C:5]([C:14]([O:16]C)=[O:15])=[CH:4][C:3]=1[Cl:18].C(Cl)Cl>CO>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:6]2[C:5]([C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[Cl:18]
Reactant: COC(=O)c1cc(Cl)c(N)n2cc(C(C)C)nc12
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1cn2c(N)c(Cl)cc(C(=O)O)c2n1

Procedure:
The title compound was prepared according to the procedure described in the step 4 in EXAMPLE 1 (METHOD A) from methyl 5-amino-6-chloro-2-isopropylimidazo[1,2-a]pyridine-8-carboxylate (EXAMPLE 20, Step 1). Rf value: 0.33 (CH2Cl2:MeOH, 20:1, v/v)
Reaction SMILES: CO[CH:3]([CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])[CH:4]=[CH2:5].[CH3:11][OH:12]>[Pd](Cl)Cl>[CH3:11][O:12][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCC(C=C)OC
Reactant: CO
Agent: Cl[Pd]Cl
Product: C=CCCCC=CCOC

Procedure:
A process for isomerizing 3-methoxy-1,7-octadiene comprising contacting 3-methoxy-1,7-octadiene with methanol and a catalytically effective amount of a catalyst selected from the group consisting of cupric chloride and a mixture of cupric chloride and palladium chloride at a temperature in the range of between about 115° C. and 135° C. and a pressure in the range of between about 75 psig and about 125 psig whereby 8-methoxy-1,6-octadiene is formed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:12]2[O:16]C(C)(C)C(C)(C)[O:13]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O1CCCC1.O.Cl>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([B:12]([OH:16])[OH:13])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)c(F)c2)OC1(C)C
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(B(O)O)cc1F
Reaction time: 2 h
Yield: 42.2 %

Procedure:
Combine 2-(3-fluoro-4-methanesulfonyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (222 mg, 0.74 mmol), NalO4 (474 mg, 2.2 mmol), tetrahydrofuran (THF, 4 mL) and water (1 mL). Stir for 2 hours and add 2M HCl in diethyl ether (0.2 mL). Stir another 12 hours and filter away the solid. Wash the filtrate with brine (10 mL), dry with MgSO4 and evaporate the solvent. Wash the solid with hexane (2×10 mL) and ether (10 mL). Dry the solid under vacuum to obtain 68 mg of the title compound (42%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:22]([C:21]1[CH:25]=[CH:26][N:27]=[CH:28][C:20]=1[NH:19][C:17]([C:15]1[C:14]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:13][CH:12]=[C:11]([CH:8]2[CH2:10][CH2:9]2)[N:16]=1)=[O:18])=[O:23]
Reactant: OCC1CCCN1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C(Nc1cnccc1C(=O)N1CCCC1CO)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 29 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2-hydroxymethylpyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound as off-white solid (29%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:13])([F:14])[C:9]([F:10])([F:11])[F:12])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Product: Cc1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Prepared from 1-methyl-4-(perfluoroethyl)benzene (1.95 g, 9.28 mmol) with sulfuric and nitric acid as described in EP 0418175 (1.45 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH:32]=O>>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:32][C:31]3[CH:34]=[CH:35][C:36]([Cl:37])=[C:29]([Cl:28])[CH:30]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN)CC1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2ccc(Cl)c(Cl)c2)CC1
Yield: 50.7 %

Procedure:
4-Amino-N-(1-(6-aminohexyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2.0 g) as starting compound and 3,4-dichlorobenzaldehyde (0.97 g) were reacted and treated in the same manner as in Example 121 to give 1.42 g of 4-amino-5-chloro-N-((1-(6-(3,4-dichlorobenzylamino)hexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:30]=[CH:29][C:16]2[N:17]([CH2:27][CH3:28])[C:18](=[O:26])[C:19]([CH3:25])([CH3:24])[C:20](=[O:23])[N:21]([CH3:22])[C:15]=2[CH:14]=1.[N+:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41])([O-:33])=[O:32]>ClCCl.O>[CH2:27]([N:17]1[C:18](=[O:26])[C:19]([CH3:24])([CH3:25])[C:20](=[O:23])[N:21]([CH3:22])[C:15]2[CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][S:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N+:31]([O-:33])=[O:32])(=[O:41])=[O:42])[CH:30]=[CH:29][C:16]1=2)[CH3:28]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN)ccc21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Triethylamine (0.8 ml, 5.7 mmol) was added to a dichloromethane solution (50 ml) of 7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.22 g, 3.8 mmol) and ice-cooled. o-Nitrobenzenesulfonyl chloride (1.03 g, 4.2 mmol) was added to the resulting mixture, and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→0:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 1.86 g (yield: 97%) of N-(3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl)-2-nitrobenzenesulfonamide as a white amorphous solid.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][O:11][S:13]([CH3:12])(=[O:15])=[O:14])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CS(=O)(=O)Cl
Reactant: N=C(N)Nc1nc(CO)cs1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCc1csc(NC(=N)N)n1
Yield: 96 %

Procedure:
To a solution of 2-guanidino-4-hydroxymethylthiazole (0.86 g) in pyridine (6 ml) is gradually added methanesulfonyl chloride (0.6 g) under ice cooling, and the resultant mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuum, and the residual oil is chromatographed on a column of silica gel, which is eluted with methanol. The eluate is concentrated in vacuum to give 2-guanidino-4-(methanesulfonyloxymethyl)thiazole (1.2 g) as an oil. The yield is 96%.
Reaction SMILES: [Br-].[Li+].Cl[P:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12]([Mg]Cl)([CH3:15])([CH3:14])[CH3:13].[H+].[B-:19]([F:23])([F:22])([F:21])[F:20]>CCOCC.CCCCCC>[F:20][B-:19]([F:23])([F:22])[F:21].[C:12]([PH+:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Mg]Cl
Reactant: ClP(Cl)c1ccccc1
Agent: F[B-](F)(F)F
Agent: [Br-]
Agent: [H+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)[PH+](c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, 60.6 mg of copper(I)bromide-dimethyl sulphide complex and 51.2 mg of lithium bromide are initially charged under protective gas. 20 ml of hexane, 4 ml of dichlorophenylphosphine and another 19 ml of hexane are subsequently added. The reaction solution is cooled to 0° C. 32.4 ml of a 2 M solution of tert-butylmagnesium chloride in ether are then slowly added dropwise. The mixture is subsequently allowed to slowly adjust to room temperature and is then stirred at room temperature for a further two hours. For workup, the mixture is cautiously admixed with 75 ml of degassed 2 M HBF4. Another 5 ml of 8 M HBF4 are then additionally added and stirred for 15 min. Filtration with suction is then effected and the filter cake is washed with a little cold water. The residue is dried under reduced pressure to constant weight. Yield: 7.9 g (86% of theory) purity >99%.
Reaction SMILES: [CH:1]1([C@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:25]([CH:27]1[CH2:29][CH2:28]1)#[CH:26]>>[CH:1]1([C@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([CH2:26][CH2:25][CH:27]3[CH2:29][CH2:28]3)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: C#CC1CC1
Reactant: C[C@](O)(CNC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1)C1CC1
Product: C[C@](O)(CNC(=O)c1cnc(CCC2CC2)c(-c2ccc(Cl)cc2)n1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 117, using 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide and ethynylcyclopropane as starting materials to yield the product as colorless foam, MS (ISP) 400.1 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][C:34]=1[OH:35])[C:9]([NH:11][NH:12][C:13]([C:15]1[O:16][CH:17]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14])=[O:10].C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][C:34]=1[OH:35])[C:9]([NH:11][NH:12][C:13]([C:15]1[O:16][CH:17]=[C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:14])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 216 h

Procedure:
Acetyl chloride (0.17 ml) was added to a mixture of the compound of Example 42 (0.83 g), ethyldiisopropylamine (1.05 ml) and dioxane (10 ml) at 0° C., allowed to be warmed to 25° C. and stirred for 9 days. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with 1 M hydrochloric acid and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) and recrystallized from ethyl acetate/hexane, thereby giving 0.25 g of the desired compound. Melting point: 233-235° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Cl:24][C:25]1[CH:26]=[C:27]([F:32])[C:28](F)=[N:29][CH:30]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([F:32])[C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:29][CH:30]=1
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Reactant: Fc1cc(Cl)cnc1F
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(Cl)cc4F)cc3n2C)c1
Yield: 69.7 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (15.6 g, 50.0 mmol), 5-chloro-2,3-difluoropyridine (8.22 g, 55.0 mmol), copper iodide (0.95 g, 5.00 mmol), 1,10-phenanthroline (0.90 g, 5.00 mmol), cesium carbonate (48.9 g, 150 mmol) and DMF (200 mL) to obtain the title compound (15.4 g, 70%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([NH:5][C:6]1([CH3:23])[CH:12]([OH:13])[CH2:11][CH2:10][N:9]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH2:8][CH2:7]1)=[O:4].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:20][C:15]1[CH:16]=[N:17][N:18]([CH3:19])[C:14]=1[N:9]1[CH2:10][CH2:11][CH:12]([OH:13])[C:6]([NH:5][C:3](=[O:4])[C:2]([F:25])([F:24])[F:1])([CH3:23])[CH2:7][CH2:8]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(O)C(C)(NC(=O)C(F)(F)F)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cn1ncc(N)c1N1CCC(O)C(C)(NC(=O)C(F)(F)F)CC1
Temperature: 65 °C
Yield: 75.9 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(5-hydroxy-4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide (200 mg, 0.55 mmol) and ammonium formate (700 mg, 2.74 mmol) in MeOH (10 mL) under nitrogen was added 10% palladium on carbon (50 mg, 0.13 mmol). The mixture was heated at 65° C. for 2 hr before being cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between water (10 mL) and DCM (50 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxy-4-methylazepan-4-yl)-2,2,2-trifluoroacetamide as a red gum (140 mg). A solution of PyBOP (330 mg, 0.62 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (160 mg, 0.45 mmol) in DCM (3 mL) was stirred at room temperature for 30 min. A solution of N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxy-4-methylazepan-4-yl)-2,2,2-trifluoroacetamide (140 mg, 0.41 mmol) and DIPEA (140 μL, 0.83 mmol) in DCM (2 mL) was added and the mixture was stirred at room temperature for 18 hr. Additional DCM (50 mL) was added and the mixture washed with water (20 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. The residue was dissolved in a mixture of THF (2 mL), MeOH (2 mL) and water (1 mL) and potassium carbonate (200 mg, 1.44 mmol) was added. The reaction mixture was heated at 60° C. for 18 hr, cooled to room temperature, filtered and concentrated under reduced pressure. The residue was then dissolved in DCM (3 mL) and trifluoroacetic acid (1 mL) added. The mixture was stirred at room temperature for 2 hr, concentrated under reduced pressure and purified via preparative HPLC to give 424 as the monoformate salt as a white solid (5 mg, 2% over three steps). 1H NMR (400 MHz, d4-MeOD) δ 8.56 (s, 1H), 7.57 (s, 1H), 7.53-7.44 (m, 1H), 7.15 (t, J=8.8 Hz, 2H), 3.86-3.72 (m, 5H), 3.45-3.35 (m, 2H), 3.26-3.14 (m, 1H), 2.15-1.90 (m, 4H), 1.46 (s, 3H). LCMS (ES+) m/z 478 (M+1)