Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][CH2:14][C@H:15]([OH:26])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1)=[O:17])[CH3:12].Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=3)[N:35]=[CH:36][C:29]=12>C1COCC1.CCOC(C)=O>[Cl:43][C:42]1[C:37]([N:34]2[C:30]3[N:31]=[CH:32][N:33]=[C:28]([O:26][C@@H:15]([CH2:14][O:13][CH2:11][CH3:12])[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=4)=[O:17])[C:29]=3[CH:36]=[N:35]2)=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(C)cn1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (3.26 mL, 3.26 mmol) was added dropwise to a stirred solution of (S)-3-ethoxy-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate G1) (730 mg, 3.26 mmol) in anhydrous THF (15 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (866 mg, 3.26 mmol) in dry THF (3 mL) added dropwise over 1 minute and the reaction heated to 50° C. for 3hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography eluting with EtOAc to afford (2S)-2-[1-(3-chloropyridin-2-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxy-N-(5-methylpyridin-2-yl)propanamide (930 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 1.20 (3H, t), 2.29 (3H, s), 3.59-3.67 (2H, m), 4.06-4.17 (2H, m), 6.06-6.08 (1H, m), 7.47 (1H, dd), 7.53 (1H, dd), 8.00 (1H, dd), 8.09-8.10 (1H, m), 8.13 (1H, d), 8.48 (1H, s), 8.62 (1H, dd), 8.63 (1H, s), 8.65 (1H, s); m/z (ESI+) (M+H)+=454.3; HPLC tR=1.97 min.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([NH2:14])[NH:12][N:13]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[C:24]([CH:28]=1)[C:25]([NH:14][C:11]1[NH:12][N:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:15])([F:1])[F:16])[CH:4]=2)[N:10]=1)=[O:26]
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of 5-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3-amine (100 mg, 0.44 mmol, 1.00 equiv) in tetrahydrofuran (1 mL) was added sodium hydride (35 mg, 0.88 mmol, 2.00 equiv, 60%) followed by the dropwise addition of a solution of 5-chloro-2-nitrobenzoyl chloride (96.49 mg, 0.44 mmol, 1.00 equiv) in tetrahydrofuran (1 mL) and the resulting solution was stirred for 2 h at room temperature. The mixture was diluted with 50 mL of ethyl acetate, washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 120 mg (67%) of a yellow solid.
Reaction SMILES: C(OC[C:11](=[CH:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O-:14])=O)(=O)C1C=CC=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH:16]1[C:17]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12](=[O:14])[CH:11]=[CH:15]1
Reactant: O=C([O-])C(=CNc1ccccc1)COC(=O)c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc[nH]c2ccccc12
Reaction time: 0.25 h
Yield: 110.6 %

Procedure:
Diphenyl ether (500 ml) was heated to reflux, ethyl 2-isobutyryl-3-(2-(benzoyloxymethyl)phenylaminoacrylate (29.3 g, 74.1 mmol) added, and heating continued for 15 minutes. The bulk of the diphenyl ether was removed by vacuum distillation, and the residue chromatographed (silica gal, 1%-2.5% methanol in dichloromethane) and recrystallized from ethyl acetate to give 3-isobutyryl-8-benzoyloxymethyl)-4(1H)-quinolone (11.9 g, 46%), m.p. 158°-160°.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])OCC)#[N:4]>C(O)C.O>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])#[N:4]
Reactant: CCOC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Yield: 75 %

Procedure:
90 ml of a 30% aqueous solution of monomethylamine is added dropwise with cooling by ice to 4.3 g of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-O-ethylisourea dissolved in the mixture of 90 ml of ethanol and 60 ml of water. After reaction at 0° C. overnight, the solution is concentrated under reduced pressure and chromatographed similarly as in Example 1 (iii) to separate a reaction solution. Thus obtained solution is concentrated under reduced pressure and is crystallized from isopropyl alcohol-ether to yield 3.0 g of cimetidine, namely N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (yield: 75.0%)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=O)[N:17]([C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[NH2:29])[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH2:1]([O:8][C:9](=[O:31])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[N:17]([CH2:18][CH2:19][CH3:20])[C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=2[N:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(C(=O)CCCCCNC(=O)OCc1ccccc1)c1cc(C#N)ccc1N
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCn1c(CCCCCNC(=O)OCc2ccccc2)nc2ccc(C#N)cc21
Reaction time: 16 h
Yield: 95.9 %

Procedure:
The compound (317 mg) obtained in Example 48-2 was dissolved in methanol (5.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (2.0 ml) and the whole was stirred for 16 hours. The residue obtained by distilling the solvent off was dissolved in methanol and the solution was neutralized with an anion-exchange resin (Amberlite IRA-410). The resin was filtrated out and the solvent was distilled off, thereby obtaining the subject compound (291 mg) as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](F)[CH:3]=1.[CH3:14][O-:15].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH3:14])[CH:3]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc(F)c(Br)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(Br)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 4-bromo-2,5-difluorobenzoate (i-7c) (0.5 g, 2 mmol) in DMF (5 mL) at 0° C. was added NaOMe (25% in MeOH, 0.45 mL, 2 mmol). The reaction mixture was stirred at 0° C. for 10 min and then at rt for 30 min. The mixture was then brought back to 0° C. and quenched with EtOAc and 1M HCl. The organic layer was separated, and the aqueous phase was extracted with EtOAc, dried over Na2SO4, concentrated and purified by flash chromatography (Pentane/EtOAc=9:1) to give the title compound. LCMS (ESI) calc'd for C9H8BrFO3 [M+H]+: 263. found: 263
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15]/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C@@H:30]1[CH2:32][C@@H:31]1[C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C@@H:30]1[CH2:32][C@@H:31]1[C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:24])[CH2:15]/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:35][CH:34]=1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(-c2ccc(-c3onc(C)c3C(O)C/C=C/c3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-but-3-en-1-ol and (cis)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+].CCOC(C)=O>CC(C)=O>[N:15]([CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4])=[N+:16]=[N-:17]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2-bromo-1-(2-naphthyl)ethanone in acetone was added NaN3 (1 eq.) and the mixture was stirred at RT for 24 h. EtOAc was added (10 vol.) and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with 10% EtOAc/Petroleum ether to obtain the product as a white solid. 1H NMR (300 MHz, CDCl3) δ: 8.39 (1H, s), 8.02-7.82 (4H, m), 7.69-7.50 (2H, m), 4.68 (2H, s). MS (ES) C12H9N3O requires: 211, found: 212 (M+H)+.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]([N:16]([CH:27]([CH3:31])[C:28](=O)[CH3:29])[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH3:8].C[O-].[Na+]>CO>[CH3:6][C:7]([N:16]1[CH:27]([CH3:31])[C:28]([CH3:29])=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:17]1=[O:26])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH3:8]
Reactant: CC(=O)C(C)N(C(=O)Cc1ccccc1F)C(C)(C)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2cccc(Cl)c2)C1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.0 g of N-[1-methyl-1-(3-chlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)-2-(2-fluorophenyl)acetamide and 1.5 g of a 28% methanol solution of sodium methoxide, followed by stirring at room temperature for 5 minutes. After the solvent was distilled off, water was added, followed by extraction with ethyl acetate. After dried over anhydrous sodium sulfate, the solution was concentrated and then subjected to column chromatography to obtain 0.9 g of the desired 1-[1-methyl-1-(3-chlorophenyl)ethyl]-4,5-dimethyl-3-(2-fluorophenyl)-3-pyrroline-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([O:1][CH2:13][CH2:14][CH2:15][Cl:16])[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCCl)cc1C
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 4′-hydroxy-2′-methyl-acetophenone (10.5 g) and 1-bromo-3-chloropropane (7.6 mL) in acetone (70 mL) was treated with potassium carbonate (14.5 g). The mixture was stirred at 50° C. for approximately 18 hours. The reaction mixture was cooled to ambient temperature and partitioned between dichloromethane (200 mL) and water (200 mL). The aqueous layer was washed twice with fresh portions of dichloromethane (200 mL) and brine was used to break any emulsions. The organic fractions were combined, dried over sodium sulfate, and evaporated. The residue was re-dissolved in dichloromethane (100 mL) and washed with 0.5 M sodium hydroxide (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and evaporated to give the title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:12]([Cl:13])=[C:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH:10]=[C:9]([C@H:24]2[C@H:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:28]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:27]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@@H:26]([CH2:54][O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[O:25]2)[C:3]=1[O:4][CH2:5][CH2:6]CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:82]([Cl:86])(Cl)(Cl)Cl>CC#N>[CH2:47]([O:46][C@H:27]1[C@H:28]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@@H:29]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:24]([C:9]2[CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH3:23])=[CH:19][CH:20]=3)[C:12]([Cl:13])=[C:2]([Br:1])[C:3]=2[O:4][CH2:5][CH2:6][CH2:82][Cl:86])[O:25][C@@H:26]1[CH2:54][O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCO)c(Br)c2Cl)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCCl)c(Br)c2Cl)cc1
Temperature: 55 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a suspension of bromide 29 (1.47 g, 1.59 mmol) in CH3CN (25 mL) were added triphenylphosphine (1.1 g, 3.98 mmol) and CCl4 (2.5 mL) at r.t. The mixture was stirred at 55° C. for 3 hours. The reaction mixture was cooled to r.t and concentrated in vacuo. The residue was purified using normal phase column chromatography to provide the desired product 29-1 (1.03 g, 70%).
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:23])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.C(N(CC)C(C)C)(C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[NH2:54][C:55]1[CH:60]=[CH:59][C:58]([CH:61]2[CH2:66][CH2:65][N:64]([CH2:67][C:68]([NH2:70])=[O:69])[CH2:63][CH2:62]2)=[CH:57][C:56]=1[O:71][CH3:72]>CN(C)C=O>[CH3:21][S:18]([N:17]([CH3:22])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[N:4]2[C:5]([CH:6]=[N:7][C:2]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([CH:61]4[CH2:66][CH2:65][N:64]([CH2:67][C:68]([NH2:70])=[O:69])[CH2:63][CH2:62]4)=[CH:57][C:56]=3[O:71][CH3:72])=[N:3]2)=[C:8]([CH3:23])[CH:9]=1)(=[O:20])=[O:19]
Reactant: COc1cc(C2CCN(CC(N)=O)CC2)ccc1N
Reactant: Cc1cc(-c2ccccc2N(C)S(C)(=O)=O)n2nc(O)ncc12
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCN(CC(N)=O)CC2)ccc1Nc1ncc2c(C)cc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into an 8-dram vial, N-[2-(2-Hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (87 mg, 0.26 mmol), N,N-Dimethylformamide (0.948 mL), N,N-Diisopropylethylamine (0.100 mL, 0.576 mmol), and N-Phenylbis(trifluoromethanesulphonimide) (0.112 g, 0.314 mmol) were added. The reaction was stirred at room temperature for 30 minutes. 2-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetamide (0.152 g, 0.576 mmol) was then added. The reaction mixture was heated at 120° C. for 4 hours. The solvent was removed under vacuum overnight. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid. The solid was partitioned with NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 2-[4-(4-{7-[2-(Methanesulfonyl-methyl-amino)-phenyl]-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-phenyl)-piperidin-1-yl]-acetamide as a yellow solid. LCMS (E/I+) 578.16 (M+H). NMR 1H (DMSO-d6)-8.95 (s, 1H), 7.93-7.98 (m, 1H), 7.88 (d, 1H, J=8.18 Hz), 7.61-7.67 (m, 1H), 7.57 (s, 1H), 7.51-7.56 (m, 1H), 7.21 (s, 1H), 7.14 (s, 1H), 6.89 (s, 1H), 6.81 (s, 1H), 6.68 (d, 1H, J=8.51 Hz), 3.84 (s, 3H), 3.05 (s, 3H), 2.85-2.95 (m, 7H), 2.35-2.45 (m, 4H), 2.08-2.28 (m, 2H), 1.64-1.81 (m, 4H).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH2:4][C:5](O)=[O:6])#[N:2].[H][H].B>C1COCC1>[Cl:15][C:10]1[CH:9]=[C:8]([CH:3]([CH2:4][CH2:5][OH:6])[CH2:1][NH2:2])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: N#CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: [H][H]
Agent: B
Solvent: C1CCOC1
Product: NCC(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 67.9 %

Procedure:
350 ml of a 1 molar solution of BH3 in THF are added to a solution of 244 g (1 mol) of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid in 500 ml of THF, cooled to 0° C. When the evolution of hydrogen has ceased, 650 ml of the borane solution are added at 20° C., followed by 1000 ml at 40° C. When the reaction is complete, the excess borane is destroyed by the addition of methanol and the reaction mixture is concentrated to dryness. The concentrate is dissolved in 500 ml of water, acidified with hydrochloric acid and washed twice with 250 ml of toluene. The aqueous phase is rendered alkaline with sodium hydroxide and extracted with twice 400 ml of dichloromethane. The organic phase is washed with water, separated off by decantation, dried over magnesium sulfate and concentrated under vacuum to give 159 g (yield: 68%) of the expected product. Chiral purity by HPLC: 99%.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:14]3[C:19]=1[C:18]([NH2:20])=[N:17][CH:16]=[N:15]3)=[CH:6]2.ClC[C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[NH2:20][C:18]1[C:19]2=[C:11]([C:7]3[CH:8]=[CH:9][C:10]4[C:5]([CH:6]=3)=[N:4][N:3]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:2]=4[NH2:1])[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:23][CH2:22]3)[N:14]2[N:15]=[CH:16][N:17]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 46 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-(3-amino-2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting dimethylcarbamyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 40 mg (46%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) 8 ppm 7.82 (s, 1 H) 7.71 (d, 1 H) 7.23-7.37 (m, 6 H) 6.96 (d, 1 H) 6.57 (s, 1 H) 5.44 (s, 2 H) 3.79 (d, 2 H) 3.41 (dt, 1 H) 3.01 (d, 2 H) 2.86 (s, 6 H) 2.16 (d, 2 H) 1.77 (dt, 2 H). LC-MS [M+H]+=510.2, RT=2.21 min.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.[NH2:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](/[C:22](=[N:25]/[N:26]3[CH2:30][CH2:29][NH:28][C:27]3=[O:31])/[CH3:23])[N:20]=2)[N:15]=[N:14]1
Reactant: NN1CCNC1=O
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Product: C/C(=N\N1CCNC1=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 74 %

Procedure:
The title compound (18.0 mg, 66%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (20.0 mg, 0.06 mmol) and 1-amino-imidazolidin-2-one (28.2 mg, 0.19 mmol) using the same procedure as described in the synthesis of example 72. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.42 (s, 1H), 8.93 (dd, 1H), 8.41 (d, 1H), 8.20 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 7.38 (s, 1H), 6.25 (s, 2H), 3.86 (t, 2H), 3.42 (t, 2H), 2.38 (s, 3H). LCMS (method A): [MH]+=401, tR=2.01 min.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([N:11]2[C@@H:17]([CH3:18])[C@H:16]([NH2:19])[C:15](=[O:20])[NH:14][C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]2=3)=[O:10])=[CH:7][CH:6]=1)(=[O:4])[CH3:3].[C:27]([O:31][C:32]([N:34]([CH3:40])[C@@H:35]([CH3:39])[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:27]([O:31][C:32](=[O:33])[N:34]([C@H:35]([C:36](=[O:37])[NH:19][C@H:16]1[C@H:17]([CH3:18])[N:11]([C:9](=[O:10])[C:8]2[CH:25]=[CH:26][C:5]([C:2](=[O:4])[CH3:3])=[CH:6][CH:7]=2)[C:12]2[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=2[NH:14][C:15]1=[O:20])[CH3:39])[CH3:40])([CH3:28])([CH3:29])[CH3:30]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc(C(=O)N2c3ccccc3NC(=O)[C@@H](N)[C@@H]2C)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(C(=O)N2c3ccccc3NC(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]2C)cc1
Reaction time: 2 h

Procedure:
To a solution of (3S,4S)-5-(4-acetyl-benzoyl)-3-amino-4-methyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one hydrochloride (0.39 g, 1.03 mmol) in N,N-dimethylformamide (6.0 mL) at 0° C. was added (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (0.23 g, 1.13 mmol), N,N-diisopropylethylamine (0.72 mL, 4.12 mmol) and 0-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophosphate (0.43 g, 1.13 mmol), the reaction was stirred for 2 h. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×40 mL). The organic layers were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate (1×20 mL), water (1×25 mL), dried over sodium sulfate, filtered through a plug of silica gel and concentrated in vacuo to give {(S)-1-[(2S,3S)-1-(4-acetyl-benzoyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester which was used in the subsequent step without further purification (0.53 g, 98%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C)C=O.O>[CH2:20]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[CH2:3][CH2:2]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Oc1cccc(C2CCNCC2)c1
Reactant: CCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN1CCC(c2cccc(O)c2)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of 3-(4-piperidinyl)phenol (Preparation 47, 376 mg, 2.12 mmol) in N,N-dimethylformamide (5 ml) was added sodium hydrogen carbonate (267 mg, 3.18 mmol) and 1-bromohexane (0.36 ml, 2.55 mmol). The reaction mixture was heated at 100° C. for 4 h. The reaction mixture was then diluted with water (20 ml) and extracted with diethyl ether (3×10 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an oil which was not purified further (500 mg, 89%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][O:21][CH:20]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:26]1([C:24]([CH:20]2[O:21][CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19]2)=[O:25])[CH2:28][CH2:27]1
Reactant: OC(C1CC1)C1CN(Cc2ccccc2)CCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)C1CN(Cc2ccccc2)CCO1
Reaction time: 0.25 h

Procedure:
A solution of dimethylsulphoxide (0.69 mL, 9.7 mmol, 2.2 eq) in DCM (4.5 mL) is slowly added to a solution of oxalyl chloride (2.43 mL, 4.85 mmol, 1.1 eq) in DCM (2.5 mL) followed by a solution of 76 (1.09 g, 4.41 mmol) in DCM (0.7 mL) under nitrogen at −60° C. After stirring for 15 minutes, triethylamine (3.14 mL, 22.1 mmol, 5 eq) is added and stirring continues for 15 minutes. After addition of water, the layers are separated.