Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]1([S:11](Cl)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[CH:1]([NH:4][S:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:13])=[O:12])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of isopropylamine (4.2 g, 70.6 mmol) in methylene chloride (50 mL) at 0-5° C. is added dropwise a solution of benzenesulfonyl chloride (5.0 g, 28.3 mmol) in methylene chloride (10 mL). After stirring the mixture at RT for 2 h, the solvent is removed under reduced pressure and 1N HCl is added to the residue. The mixture is extracted with EtOAc and the organic phase is washed with brine then dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound as a pale yellow oil.
Reaction SMILES: C(Cl)(=O)C.[N:5]1[CH:6]=[CH:7][N:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15]3)[C:9]=12>CO>[N:5]1[CH:6]=[CH:7][N:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15]3)[C:9]=12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2nccn3ccnc23)C1
Solvent: CO
Solvent: CC(=O)Cl
Product: N[C@H]1CCN(c2nccn3ccnc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 432.4 %

Procedure:
To a solution of acetyl chloride (114 mL, 1.6 mol) in 290 mL of MeOH at 0° C. was added a solution of (S)-tert-butyl (1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)carbamate (111.7 g, 0.37 mol) in 450 mL of MeOH. The reaction mixture was stirred at room temperature for 2 h then heated at 60° C. for 30 min. The product was filtered, washed with 200 mL of MeOH and dried in a vacuum oven to afforded (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (101.2 g, 1.6 mol, 100%).
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[C:3]#[CH:4].Br[CH2:8][CH2:9][CH:10]=[O:11].[OH-].[Na+]>CO>[CH3:1][C:2]([NH:6][CH2:8][CH2:9][CH:10]=[O:11])([CH3:5])[C:3]#[CH:4]
Reactant: O=CCCBr
Reactant: C#CC(C)(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CC(C)(C)NCCC=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1,1-Dimethylprop-2-ynylamine (1.0 mole), the diethyl acetal of 3-bromopropionaldehyde (1.0 mole) and methanol (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 6 hours. After this time the reaction mixture is cooled to room temperature and sodium hydroxide (20 grams) is added. The reaction mixture is then stirred for an additional period of about 16 hours. The mixture is then filtered and the filtrate is distilled to yield the desired product the diethyl acetal of 3-(1,1-dimethylprop-2-ynylamino)propionaldehyde.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]=[CH:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2].C(N(CC)CC)C.ClCCl.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]([C:29](=[O:32])[CH2:30][CH3:31])[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CC(C)c1ccccc1N=C1N=CC(C)(C)CS1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCC(=O)N1CC(C)(C)CSC1=Nc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g), triethylamine (0.15 g) and dichloromethane (5 ml) was added dropwise for 5 minutes propionylchloride (0.13 g). The mixture was stirred at room temperature for 2 hours. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-3-propionyl-5,5-dimethyl-1,3-thiazine (0.18 g, yield: 56%) as colorless oil.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][C:21]([C:23]([N:25]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:24])=[CH:22][C:15]=3[N:14]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(N(CC)CC)C.Cl[C:47]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:48].O>C(Cl)Cl>[CH3:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][O:49][C:47](/[N:4]=[C:2](\[NH2:3])/[C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][C:21]([C:23]([N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:24])=[CH:22][C:15]=3[N:14]=2)=[CH:9][CH:10]=1)=[O:48]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Reaction time: 0.5 h

Procedure:
73 gm ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate hydrochloride of Formula (E) in 1460 mL methylene dichloride were stirred 25° C. to 35° C. and cooled to 0° C. to 5° C. To the reaction mixture was treated with 61.1 mL triethylamine at 0° C. to 5° C. and stirred for 30 minutes followed by addition of n-hexyl chloroformate solution (31.35 mL in 365 mL methylene dichloride for 2 hrs. The residue was treated with 730 mL water and extracted with 370 mL methylene dichloride. The methylene dichloride was distilled and the residue was purified using mixture of methylene dichloride and ethanol to afforded amorphous form of dabigatran Etexilate of Formula (F). The amorphous form of dabigatran etexilate of Formula (F) is characterized by x-ray powder diffraction pattern as depicted in FIG. 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]([CH2:25][CH3:26])[NH:22][CH2:21][CH2:20]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=4)[CH:23]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CCC1NCCc2cccc(F)c21
Product: CCC1c2c(F)cccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:12])[CH3:11])[CH2:4][CH2:3]1.[OH-].[K+].NN>C(O)COCCO>[N:5]1([CH2:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:12])[CH3:11])[CH2:4][CH2:3][CH2:2][CH2:7][CH2:6]1
Reactant: CC(O)(CCN1CCC(=O)CC1)c1ccccc1-c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: CC(O)(CCN1CCCCC1)c1ccccc1-c1ccccc1
Reaction time: 4 h

Procedure:
A mixture of 3.23 g of 1-(4-oxopiperidino)-3-p-biphenylyl-butan-3-ol (obtainable from 1-chloro-3-p-biphenylyl-butan-3-ol and 4-piperidone), 1.5 g of KOH, 2.5 ml of 85% hydrazine and 25 ml of diethylene glycol is warmed at 100° for 1 hour. The temperature is raised slowly until the hydrazone is decomposed, and the mixture is boiled for a further 4 hours, cooled and worked up in the customary manner to give 1-piperidino-3-p-biphenylyl-butan-3-ol, m.p. 102° - 104°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:9][C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:11][C:12](=[O:14])[CH:13]=2)[CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(O)(CC)C.[Cl-].[Zn+2].[Cl-]>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[NH:9][C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:11][C:12](=[O:14])[CH:13]=3)[CH:3]=2)[CH2:24][CH2:23]1
Reactant: O=c1cc(-c2ccccn2)[nH]c(-c2cc(Cl)ccn2)c1
Reactant: CN1CCNCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCC(C)(C)O
Product: CN1CCN(c2ccnc(-c3cc(=O)cc(-c4ccccn4)[nH]3)c2)CC1

Procedure:
A mixture of 5.22 g (18.4 mmol) of 4-chloro-1′H-[2,2′;6′,2″]terpyridin-4′-one, 18.36 g (184 mmol, 20.4 ml) of 1-methylpiperazine and 125 mg (0.92 mmol, 0.05 equivalent) of zinc(II) chloride in 80 ml of 2-methyl-2-butanol is boiled under reflux for 30 hours. The mixture is evaporated to dryness on a rotary evaporator. 100 ml of water are added and the mixture is rendered neutral with concentrated hydrochloric acid. Extracting the mixture four times with chloroform and combining and drying (sodium sulfate) the organic extracts gives the crude product which is subsequently recrystallized from acetonitrile. 4-(4-Methyl-piperazin-1-yl)-1′H-[2,2′;6′,2″]terpyridin-4′-one is obtained as a white solid. 1H-NMR (360 MHz, CDCl3): 8.69 (d, 1H, 4.5 Hz); 8.32 (d, 1H, J=5.9 Hz); 7.92-7.74 (m, 2H); 7.37-7.30 (m, 1H); 7.20 (d, 1H, J=2.3 Hz); 7.01 (s, 1H); 6.98 (s, 1H); 6.71-6.63 (m, 1H); 3.45-3.35(tm, 4H); 2.58-2.48 (tm, 4H); 2.32 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([CH3:12])[CH2:7]1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH3:12][N:8]1[CH2:7][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:22]2[CH2:23][CH2:24][N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)[CH2:20][CH2:21]2)[O:10][C:9]1=[O:11]
Reactant: CN1CC(CCCCCl)OC1=O
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CN1CC(CCCCN2CCN(c3ccccn3)CC2)OC1=O

Procedure:
Following the procedure of Example 1, the title compound is prepared from a mixture of 5-(4-chlorobutyl)-3-methyl-2-oxazolidinone (5.0 g, 0.0262 mol), 1-(2-pyridinyl)piperazine (4.56 g, 0.0279 mol) and potassium carbonate (8.5 g, 0.0614 mol) in 1-butanol (50 ml) to obtain 3.4 g (41% yield) of solid. Recrystallization from ethyl acetate/petroleum ether followed by drying in vacuo gave 1.46 g of the title compound, mp 69°-72° C.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][NH:24][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2
Reactant: N#Cc1ccc2c(n1)CCCC2=O
Reactant: COc1ccccc1CCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1CCNC1CCCc2nc(C#N)ccc21
Temperature: 0 °C

Procedure:
41.10 g (0.24 mol) of 5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile were dissolved in 500 ml of toluene, and 35.51 ml (0.25 mol) of 2-(2-methoxyphenyl)ethylamine and 4.54 g (0.024 mol) of p-toluenesulphonic acid monohydrate were added. The reaction solution was then stirred under reflux for 5 hours (using a water separator). Subsequently, the reaction solution was evaporated to dryness and the residue was taken up in 500 ml of ethanol (anhydrous) and, with stirring, cooled to 0° C. A little at a time (careful: reaction mixture foams), 18.06 g (0.48 mol) of sodium borohydride were then added to the reaction solution, and the mixture was stirred overnight. Subsequently, the reaction mixture was concentrated on a rotary evaporator to about 100 ml, and 300 ml of water and 300 ml of ethyl acetate were added. The phases were separated and the aqueous phase was extracted twice with in each case 150 ml of ethyl acetate. The combined organic phases were washed twice with in each case 250 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to a volume of about 150 ml on a rotary evaporator. The solution obtained in this manner was applied to 50 g of silica gel and purified by column chromatography on silica gel (80 g cartridge; flow rate: 75 ml/min; mobile phase: petroleum ether/ethyl acetate 85:15→50:50 over 45 min) This gave 39.03 g (0.10 mol, content 80%, 43% of theory) of the target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.C(O)(=O)C[C:29](CC(O)=O)([C:31](O)=[O:32])[OH:30]>C(O)CO.O>[OH:30][CH2:29][CH2:31][O:32][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)CCc2ccccc2)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: OCCO
Solvent: O
Product: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCO)cc1
Temperature: 120 °C
Reaction time: 27 h

Procedure:
2-Phenyl-ethanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (850 mg) was added to a solution of K-tert. butylate (1.1 g) in ethylene glycol (15 ml). The mixture was stirred at 120° C. for 27 h before it was diluted with water (100 ml), acidified with 10% aq. citric acid (13 ml). The resulting precipitate was collected, washed with water and diethyl ether and dried to give 2-phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (716 mg) as a beige powder. LC-MS: tR=4.44 min, [M+1]+=414.18, [M−1]−=412.13.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[CH3:7][O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:32][CH2:33][CH3:34])[C:13]2[C:22]3[CH:21]=[CH:20][C:19]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:18][C:17]=3[N:16]=[C:15]([NH2:30])[C:14]=2[N:31]=1>C(Cl)(Cl)Cl>[NH2:30][C:15]1[C:14]2[N:31]=[C:11]([CH2:10][CH2:9][O:8][CH3:7])[N:12]([CH2:32][CH2:33][CH3:34])[C:13]=2[C:22]2[CH:21]=[CH:20][C:19]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:26][CH2:25]3)=[CH:18][C:17]=2[N:16]=1
Reactant: CC(C)N=C=O
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Solvent: ClC(Cl)Cl
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCN(C(=O)NC(C)C)CC4)ccc3c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
Isopropyl isocyanate (0.256 mL, 2.61 mmol) was added dropwise to a stirred mixture of 2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine (1.00 g, 2.61 mmol) in chloroform at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 4-12% CMA in chloroform) followed by recrystallization from acetonitrile to afford 0.530 g of 4-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}-N-isopropylpiperidine-1-carboxamide as white crystals, mp 176-179° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH2:29][OH:30])[N:23]=[C:22]2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:36]1[C:40](=[O:41])[CH2:39][CH2:38][C:37]1=[O:42]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][N:36]3[C:40](=[O:41])[CH2:39][CH2:38][C:37]3=[O:42])=[O:27])=[C:24]([CH2:29][OH:30])[N:23]=[C:22]2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CCCCc1nc(CO)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
206 mg of N,N-dicyclohexylcarbodiimide were added to a suspension of 464 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylic acid (prepared as described in Example 4) and 140 mg of N-hydroxysuccinimide in 10 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature for 16 hours. At the end of this time, the material which had precipitated was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 1:15 by volume mixture of methanol and methylene chloride as the eluent, to afford 0.52 g of the title compound as crystals, melting at 107°-109° C.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=1)[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH2:1]([N:3]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23]([CH3:24])=[O:33])[N:18]=1)[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN(c1cccc2c1ccn2-c1ccnc(SC)n1)S(C)(=O)=O
Solvent: ClC(Cl)Cl
Product: CCN(c1cccc2c1ccn2-c1ccnc(S(C)=O)n1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
N-ethyl-N-[1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yl]-methanesulfonamide (0.4 g) in CHCl3 (60 mL) was cooled to 0° C. and MCPBA (0.247 g) added and stirred at 0° C. for 5 h before quenching with 10% sodium thiosulfate solution. The organic layer was separated, dried over sodium sulfate, filtered, concentrated and purified on a column using 100% DCM to 15% MeOH/DCM to yield N-ethyl-N-[1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-indol-4-yl]-methanesulfonamide (0.386 g).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([NH2:8])=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CO>C(Cl)Cl>[F:1][C:2]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]#[N:8]
Reactant: CC(C)(Oc1ccc(F)cc1F)C(N)=O
Solvent: CO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C#N)Oc1ccc(F)cc1F
Temperature: 25 °C

Procedure:
To a solution of Example 51A (0.9 g, 4.0 mmol) in methylene chloride (10 mL) and triethylamine (2.2 mL, 15.8 mmol) was added 2,2,2-trifluoroacetic anhydride (1.6 mL, 11.9 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for three hours before methanol was added to quench the reaction. The reaction mixture was washed with saturated aqueous NaHCO3 solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% methanol/ethyl acetate(1/10) in hexanes) to obtain the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.71 (s, 6H), 7.08-7.18 (m, 1H), 7.36-7.49 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[C:10]=2[F:17])[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C([O-])([O-])=O.[Na+].[Na+].O>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>[F:16][C:11]1[C:10]([F:17])=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1F
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: O
Solvent: COCCOC
Product: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3F)ccn2)cn1
Temperature: 70 °C
Yield: 55.1 %

Procedure:
Nitrogen was bubbled though a solution of 4-(2-chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (2 g, 7.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.6 g, 7.8 mmol) and Na2CO3 (1.65 g, 15.6 mmol) in DME (12 mL)/H2O (4 mL) for 20 min. Pd(PPh3)4 (450 mg, 0.4 mmol), was added and then resulting mixture was degassed in vacuo, blanketed with nitrogen and heated to 70° C. for 16 h. The reaction was concentrated to dryness under reduced pressure. The crude product was suspended in water and extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to give 2,3-difluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine (1.3 g, 55% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.40 (d, J=6.0 Hz, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.26 (s, 1H), 6.96 (t, J=8.8 Hz, 1H), 6.71-6.68 (m, 2H), 5.62 (s, 2H), 3.92 (s, 3H); MS (ESI) m/z: 303.2 [M+H]+.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][CH2:28][CH2:29][NH:30][C:31]([C:33]1[N:34]2[CH:40]=[N:39][CH:38]=[C:35]2[S:36][CH:37]=1)=[O:32]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:39]3[CH:38]=[C:35]4[S:36][CH:37]=[C:33]([C:31](=[O:32])[NH:30][CH2:29][CH2:28][OH:27])[N+:34]4=[CH:40]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: O=C(NCCO)c1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(C(=O)NCCO)[n+]4c3)[C@H](C)[C@H]12
Yield: 13.6 %

Procedure:
The same procedure as in Example 1 was repeated except that 93 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 80 mg of 3-(N-2-hydroxyethyl)carbamoylimidazo[5,1-b]thiazole were used, thereby obtaining 15 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][O:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=1)=[O:19]>>[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[CH2:6][CH2:7][O:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=3[CH:3]=2)[N:27]=1)=[O:19]
Reactant: CCN1C(=O)OCCc2ccc(N)cc21
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)OCCc2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21

Procedure:
Following a procedure analogous to Example 1741e, 3-amino-5-ethyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide were converted to 3-[5-chloro-2-(5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide. TFA salt: 1H NMR (300 MHz, CDCl3) δ 11.42 (s, 1H), 8.35 (d, 1H), 8.22 (s, 1H), 7.80 (s, 1H), 7.41 (s, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 7.04 (s, 1H), 4.80 (bq, 1H), 4.60 (t, 2H), 3.90 (q, 2H), 3.12 (d, 3H), 3.06 (t, 2H), 1.26 (t, 3H); MS (m/e) 473 (M+1).