Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O-])=O)[CH2:5][C:4]=2[S:3][CH:2]=1.[N:13]([CH2:16][CH2:17][CH2:18][C:19]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:23](C(=S)N)[N:22]=[C:21]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[S:20]1)=[N+]=[N-].BrC1C(=O)CCN(C(OC(C)(C)C)=O)C1.CCN(C(C)C)C(C)C>C(O)C>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[C:21]1[S:20][C:19]([CH2:18][CH2:17][CH2:16][NH2:13])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:23]([C:2]2[S:3][C:4]3[CH2:5][N:6]([CH3:10])[CH2:7][CH2:8][C:9]=3[N:1]=2)[N:22]=1
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Reactant: O=C([O-])N1CCc2ncsc2C1
Agent: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN)c3ccccc3)sc2C1
Reaction time: 8 h

Procedure:
Preparation of tert-butyl 24243-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate: To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.300 g, 0.717 mmol) in 10 mL of ethanol was added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (0.239 g, 0.860 mmol) followed by DIEA (0.25 mL, 1.43 mmol). The mixture was allowed to stir overnight at reflux, then treated with tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (100 mg) and stirred at reflux for a further 3 hours. The cooled mixture was partitioned between a saturated NaHCO3 solution (30 mL) and EtOAc (30 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a bright yellow foam, 0.313 g, 73%.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1C(CCl)=[N:46][C:47]([Cl:50])=[CH:48][CH:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:44]([Cl:43])=[CH:49][CH:48]=[C:47]([Cl:50])[N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: ClCc1nc(Cl)ccc1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3nc(Cl)ccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,6-dichloro-2-(chloromethyl)pyridine and isolated as light-yellow gum. MS(m/c): 442.3 (MH+).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.O.[CH:23](O)=[O:24]>>[CH:23]([O:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[CH:14]([CH2:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH:8]=[CH:9][C:10]2=[O:11])[CH2:19]1)=[O:24]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=CO
Solvent: O
Product: C[C@]12CC[C@H](OC=O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]12
Temperature: 60 °C

Procedure:
Following the procedure described by Ringold (H. J. Ringold, et al., J. Am. Chem. Soc. 78, 816, 1956), dehydroepiandrosterone (2.88 g, 10 mmol) dissolved in 85% formic acid (100 mL) is heated at 60° C. for 1 h. After cooling, the mixture is poured into iced water and after 16 h, crystals are filtered and dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:18])[C@@H:12]3[C@H:15]([OH:17])[CH3:16])[C:9]=2[C:19]([O:21][CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:20])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:39](Cl)(=[O:41])[CH3:40]>ClCCl>[C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:18])[C@@H:12]3[C@H:15]([OH:17])[CH3:16])[C:9]=2[C:19]([O:21][CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:20])=[CH:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ccc(N)cc3)C[C@H]12
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Temperature: 0 °C

Procedure:
A mixture of [(2,2-dimethylpropanoyl)oxy]methyl (5R,6S)-3-(4-aminophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate prepared by example 26, diisopropylethylamine and dichloromethane was cooled at 0° C., and thereto was dropped acetyl chloride. After stirring, the reaction mixture was poured into ice water. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution in the order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography, to give [(2,2-dimethylpropanoyl)oxymethyl (5R,6S)-3-[4-(acetylamino)phenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:6])[CH2:4][F:5].[OH-].[K+].[CH2:9]1[O:11][CH2:10]1>>[F:1][CH2:2][CH:3]([CH2:4][F:5])[O:6][CH2:9][CH2:10][OH:11]
Reactant: OC(CF)CF
Reactant: C1CO1
Agent: [K+]
Agent: [OH-]
Product: OCCOC(CF)CF
Reaction time: 12 h
Yield: 38 %

Procedure:
112 g (1.0 mol) of 1,3-difluoro-2-propanol and 3 g of potassium hydroxide are initially introduced and 50 ml of ethylene oxide are condensed in a V4A autoclave (volume : 300 ml) at -78° C. The reaction mixture is then shaken for 12 hours at +80° C. to +90° C. (initial pressure about 9000 hPa). After depressurizing and venting unreacted ethylene oxide, the residual contents of the autoclave are fractionally distilled in a water jet vacuum. 59 g (38 % of theory) of 2-(2-fluoro-1-fluoromethyl-ethoxy)-ethanol are obtained as a main fraction of boiling range 98° C. to 105° C./24 hPa.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH3:26])[N:18]=2)[CH2:13][CH2:12]1)=[O:10].CO>[Pd].C1COCC1>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[O:10])[CH2:16][CH2:15]2)=[N:18][C:19]=1[CH3:26]
Reactant: Cc1nc(N2CCN(C(=O)c3c(F)cccc3F)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(N2CCN(C(=O)c3c(F)cccc3F)CC2)ccc1N
Temperature: 26 °C
Reaction time: 0.5 h

Procedure:
Charge (2,6-difluoro-phenyl)-[4-(6-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone (1.00 equiv, 1.44 moles, 520.00 g), methanol (197.66 moles, 8.00 L, 6.33 kg), and THF wetted 5% palladium on carbon (75.00 g) to a three gallon autoclave. Hydrogenate the reaction at 50 psi at room temperature while maintaining a temperature below 30° C. After 0.5 hours, cool to 26° C., and maintain for 2 hours. Filter and concentrate under reduced pressure. Filter to obtain solids, rinse with methanol then heptanes. An additional filtration yields a second batch of [4-(5-amino-6-methyl-pyridin-2-yl)-piperazin-1-yl]-(2,6-difluoro-phenyl)-methanone. Dry under reduced pressure at 45° C. (445 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: C1COCCN1
Product: O=C(c1ccc2cc(O)ccc2c1)N1CCOCC1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and morpholine (commercially available) according to the procedure described for Example A. MS (m/e): 256.0 (MH−, 100%)
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[S:14][C:13]=2[C:12]([N:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:11][CH:10]=1>CN(C=O)C.C(Cl)Cl>[Br:1][C:31]1[CH:32]=[CH:33][C:34]2[N:22]([C:12]3[C:13]4[S:14][C:15]5[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=5[C:17]=4[CH:9]=[CH:10][CH:11]=3)[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3
Reactant: c1ccc2c(c1)sc1c(-n3c4ccccc4c4ccccc43)cccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
N-bromosuccinimide (0.31 g, 1.74 mmol) in 5 mL DMF was added slowly to 9-(dibenzo[b,d]thiophen-4-yl)-9H-carbazole (0.6 g, 1.72 mmol) in 50 mL of DCM at 0° C. The reaction was allowed to warm to room temp and stirred overnight. The reaction mixture was extracted with DCM and dried over MgSO4 and the solvent was evaporated. The residue was purified by column chromatography using DCM:hexane (1:4, v/v) as the eluent to obtain 0.45 g of product.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:27]([N:34]1[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:36]=[C:35]1[CH2:49][CH3:50])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N1C(C(OCC)=O)=C(C(OCC)=O)NC1(C)Br)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:27]([N:34]1[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:36]=[C:35]1[CH:49]([Br:1])[CH3:50])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(CC)n(Cc2ccccc2)c1C(=O)OCC
Agent: CCOC(=O)C1=C(C(=O)OCC)N(Cc2ccccc2)C(C)(Br)N1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(C(C)Br)n(Cc2ccccc2)c1C(=O)OCC
Yield: 97.8 %

Procedure:
3.08 g of N-bromosuccinimide and 0.51 g of benzoyl peroxide were added to a solution of 5.19 g of diethyl 1-benzyl-2-ethylimidazole-4,5-dicarboxylate [prepared as described in step (i) above] in 100 ml of carbon tetrachloride, and the resulting mixture was heated under reflux for 1 hour. Following a procedure similar to that described in Preparation 42(ii), 6.29 g of the title compound were obtained as a syrup from the resulting reaction solution.
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[OH:22])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.[CH3:23][OH:24]>>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:2]1([O:24][CH3:23])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: CO
Reactant: COc1ccc(O)c(C2(Cl)Sc3ccccc3N(C)C2=O)c1
Product: COc1ccc(O)c(C2(OC)Sc3ccccc3N(C)C2=O)c1
Yield: 85.3 %

Procedure:
A mixture of 2-chloro-3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (14.0 g, compound No. 3) and methanol (200 ml) is stirred for 2 hours at room temperature, and the separated crystals are collected by filtration to give 11.8 g (85.3%) of the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CS(C)=O.O>[O:18]1[CH2:19][CH2:20][N:15]([C:6]2[N:5]=[C:4]([NH2:8])[CH:3]=[CH:2][CH:7]=2)[CH2:16][CH2:17]1
Reactant: Nc1cc(Cl)ccn1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cccc(N2CCOCC2)n1
Temperature: 190 °C
Reaction time: 10 h
Yield: 47.4 %

Procedure:
A mixture containing 4-chloro-2-aminopyridine (164; 26 g, 0.20 mol), K2CO3 (0.40 mol) and morpholine (48; 0.6 mol) in DMSO (150 mL) was stirred at 190° C. for 10 h. Upon cooling to room temperature, the reaction mixture was diluted with water (300 mL) and the resulting mixture was extracted with ethyl acetate (4×150 mL). The combined organic layers were washed with water (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:ethyl acetate=10:1) to afford 6-morpholinopyridin-2-amine 165 (17 g, 47%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH:22](Br)[CH:23]=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[N:3]3[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]3=[N:1][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: Nc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3ccc(Br)cn23)CC1

Procedure:
The title compound was prepared from 2-amino-5-bromopyridine and 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)-piperidine (from Example 292, Step C) according to the general procedure described in Example 235, Step A.
Reaction SMILES: [C:1]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:27][CH:28]([CH3:34])[CH2:29][C:30]([NH:32]O)=[NH:31]>CN(C=O)C.O>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1([C:12]2[O:14][N:32]=[C:30]([CH2:29][CH:28]([OH:27])[CH3:34])[N:31]=2)[CH2:10][CH2:11]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(O)CC(=N)NO
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of N-boc-amino-cyclopropanecarboxylic acid (500 mg, 2.49 mmol) in 2 mL of DMF at 0° C. was added carbonyldiimidazole (403 mg, 2.49 mmol). The reaction mixture was stirred at room temperature for 30 min, and 3,N-dihydroxy-butyramidine (480 mg, 4.06 mmol) was added as a solution in 2 mL of DMF. The pale yellow, faintly cloudy reaction mixture was stirred at room temperature for 30 min and then heated at 100° C. for 15 h. After cooling to room temperature, the reaction mixture was diluted with 15 mL of water and extracted with 50 mL of ethyl acetate. The organics were washed with 2×15 mL of water and 15 mL of brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by flash chromatography on silica gel (0-8% MeOH/CH2Cl2) to afford 242 mg (34%) of {1-[3-(2-hydroxy-propyl)-1,2,4-oxadiazol-5-yl]-cyclopropyl}-carbamic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:18](Br)([CH3:20])[CH3:19]>>[CH:18]([N:15]1[CH2:16][CH2:17][N:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:14]1)([CH3:20])[CH3:19]
Reactant: CC(C)Br
Reactant: Fc1cc(N2CCNCC2)cc(C(F)(F)F)c1
Product: CC(C)N1CCN(c2cc(F)cc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine and isopropylbromide, the title compound was recovered by the procedure described in Example 2; MS m/z (rel. intensity, 70 eV) 290 (M+, 30), 275 (bp), 190 (20), 84 (23), 56 (64).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)=[O:10].[CH3:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[N:22]=1.[BH4-].[Na+]>O1CCCC1.CO>[NH2:17][C:13]1[CH:12]=[C:11]([CH:9]([OH:10])[CH2:8][N:34]2[CH2:35][CH2:36][N:31]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:28]=3[CH:29]=[CH:30][C:21]([CH3:20])=[N:22]4)[CH2:32][CH2:33]2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc2c(N3CCNCC3)cccc2n1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CCN(CC(O)c4cccc(N)c4)CC3)cccc2n1
Reaction time: 1 h
Yield: 55 %

Procedure:
Sodium carbonate (1.5 eq) and 2-bromo-1-(3-nitrophenyl)ethanone (1.5 eq) were added to a stirred solution of 2-methyl-5-(1-piperazinyl)quinoline (D3) (1 eq) in tetrahydrofuran at room temperature under an inert atmosphere, and the reaction was left under stirring for 1 h. The solution was then diluted with MeOH, NaBH4 (2 eq) was added and the reaction was left under stirring for 1 h. The solvent was removed under reduced pressure. The crude material was purified on SPE cartridge (SCX) using as eluant a gradient from MeOH to MeOH:CH2Cl2 (1:1) and then 2M NH3 in MeOH affording an intermediate which was reduced following a similar procedure to D6 to give the title compound in 55% yield.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([C:29]1[N:37]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:13][N:8]([C:6]([N:4]3[CH2:5][CH:2]([OH:1])[CH2:3]3)=[O:7])[CH2:9]2)[O:25][N:28]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: NC(Cc1ccccc1)=NO
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cc3ccccc3)no2)C1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 44.4 mg (0.295 mmol) of N′-hydroxy-2-phenylethanimidamide were reacted according to the General Method 1. Yield: 40.0 mg (29% of theory).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:35]5[CH2:40][CH2:39][S:38][CH2:37][CH2:36]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: C1CSCCN1
Product: Nc1ncnn2c(-c3ccc(CN4CCSCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 6 %

Procedure:
Using a procedure similar to that of Example 282, step 2, with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and thiomorpholine as starting materials, 19 mg (6%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.60 (d, 2 H), 2.6 (t, 8 H); ES-MS m/z 532.07 [M+H]+, HPLC RT (min) 2.34.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([Si:27]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[N:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1)([CH3:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:30]2[CH:31]=[CH:32][N:28]([Si:27]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:24]([CH3:25])[CH3:26])[CH:29]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c1
Temperature: 120 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (100 mg, 0.225 mmol) in DME (5 mL) is added 1-triisopropylsilylpyrrole-3-boronic acid (120 mg, 0.450 mmol), Pd(PPh3)4 (27 mg, 0.023 mmol) and 0.5 mL of Na2CO3 (2M aqueous solution) and the mixture is heated in a microwave apparatus at 120° C. for 5 min. The mixture is concentrated under reduced pressure and the residue purified by reverse phase MPLC using a gradient of 10-50% MeCN/water as eluent to afford the title compound: (M−1)−=538.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:49]=[CH:48][C:39]([C:40]([NH:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])=[O:41])=[CH:38][C:37]=1[O:50][CH3:51]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:49]=[CH:48][C:39]([C:40]([NH:42][CH2:43][CH2:44][N:45]([CH3:46])[CH3:47])=[O:41])=[CH:38][C:37]=4[O:50][CH3:51])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NCCN(C)C)ccc1N
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 72 %

Procedure:
A mixture of 0.0642 g (0.194 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0542 g (0.29 mmole) of toluenesulfonic acid monohydrate, 0.0451 g (0.194 mmole) of 4-amino-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 16 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (85:15:1) to give 0.0743 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide (I-253) as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[Cl:9][C:10]1[C:15](Cl)=[N:14][CH:13]=[CH:12][N:11]=1>CN(C)C=O>[Cl:9][C:10]1[C:15]([N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])=[N:14][CH:13]=[CH:12][N:11]=1
Reactant: Clc1nccnc1Cl
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1c1nccnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
Sodium hydride (60% in mineral oil, 67 mg, 1.62 mmol) was added to a solution of pyrrolidinone (0.12 ml, 1.54 mmol) in dry dimethylformamide (5 ml) under argon at 0° C. The mixture was allowed to warm to room temperature over 1.5 hours. A solution of 2,3-dichloropyrazine (D46, Step 2) (250 mg, 1.69 mmol) in dry dimethylformamide (2 ml) was added and the mixture stirred at room temperature under argon for 2 hours. The mixture was poured onto water (30 ml) and was extracted with ethyl acetate (×3). The ethyl acetate extracts were combined, washed with brine, dried under magnesium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:pentane (1:1) to afford the title compound (0.10 g); MS (ES+) m/e 198 [M+H]+.