Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:11])[NH2:10])=[CH:5][CH:4]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:12][C:13]1[S:16][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[N:11]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: Cc1ccc(C(=N)N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
To a solution of 4-methylbenzenecarboximidamide hydrochloride (1.70 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1.5 hours. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.05 g (50.0%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].[C:6](=[S:8])=[S:7].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[CH2:1]([O:3][C:6]([S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:7])[CH3:2]
Reactant: CCO
Reactant: S=C=S
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=S)SCc1ccccc1
Reaction time: 4 h

Procedure:
1 g of Ethanol was dissolved in 50 g of dimethylforamide, 0.44 g of sodium hydride (60% paraffin) was added thereto, and the mixture was stirred for 4 hours. 1.8 mL of carbon disulfide was gradually added thereto, and the mixture was stirred for 12 hours. 1.3 mL of benzylbromide was gradually added to the mixture and the resultant was stirred at room temperature for 12 hours. Then, the reaction was terminated by adding 1 mL of methanol thereto. Ice was added to the resultant, and the resultant was subjected to extraction using ethyl ether and dried using magnesium sulfate to prepare benzyl methoxydithiomate.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[N:10][C:11]([CH3:14])=[N:12][CH:13]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(O)C>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>[CH3:14][C:11]1[N:10]=[CH:9][C:8]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:27])([F:26])[F:15])=[CH:18][CH:19]=2)=[CH:13][N:12]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ncc(Br)cn1
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: CCO
Solvent: COCCOC
Product: Cc1ncc(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of 7.95 g (75 mmol) of sodium carbonate in 15 ml of water was added to a mixture of 2.6 g (15 mmol) of 5-bromo-2-methylpyrimidine [Coll. Czech.Chem. Comm. 14 (1949), 223–235], of 4 g (21 mmol) of 4-(trifluoromethyl)benzeneboronic acid and of 0.52 g (0.45 mmol) of tetrakis(triphenylphosphine)palladium in a mixture of 50 ml of 1,2-dimethoxy-ethane and of 30 ml of ethanol. The reaction mixture was stirred at 80° C. for 2 hours; afterwards, it was concentrated by distilling off the major part of the organic solvents. Subsequently, the residue was extracted with 3 portions of tert.-butyl methyl ether. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and finally evaporated. The residue was chromatographed on silicagel with a mixture of dichloromethane/tert.-butyl methyl ether (9/1 vol./vol.) as eluent. 3 g of the title compound was obtained as greenish solid.
Reaction SMILES: CS[C:3](=[N:8][CH:9]([CH3:11])[CH3:10])[S:4]([O-:7])(=[O:6])=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)=[CH:15][CH:14]=1>C(#N)C>[CH:9]([NH:8][C:3]([S:4]([OH:7])(=[O:6])=[O:5])=[N:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)=[CH:17][CH:18]=1)([CH3:11])[CH3:10]
Reactant: CSC(=NC(C)C)S(=O)(=O)[O-]
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Solvent: CC#N
Product: CC(C)NC(=Nc1ccc(-c2c[nH]cn2)cc1)S(=O)(=O)O
Reaction time: 8 h

Procedure:
A solution of 1-methylthio-1-isopropylimino-methanesulfonate (6.8 g) in acetonitrile (150 ml) was added slowly to a solution of 4-(4-amino phenyl)-1-H-imidazole (5 g) in acetonitrile (250 ml) at room temperature. The reaction mixture was stirred overnight, and the product which crystallized out was collected by filtration to give the crude title compound, which was purified via its maleate in 95% ethanol. M.p. 209° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15].O.[BH4-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:15][CH2:14][CH:13]([O:16][CH3:17])[O:12][CH3:11]
Reactant: COC(CN)OC
Reactant: O=Cc1ccc(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(CNCc1ccc(F)cc1Cl)OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-4-fluorobenzaldehyde (3.17 g, 20 mmol, 1.0 eq.) and aminoacetaldehyde dimethyl acetal (2.18 mL, 20 mmol, 1.0 eq.) in toluene (50 mL) was stirred at 130° C. with concomitant removal of H2O (Dean-Stark) for 2.5 hours. The mixture was concentrated in vacuo and dried under h.v. The residue was dissolved in EtOH (100 mL). The solution was cooled to 0° C. and NaBH4 (1.14 g, 30 mmol, 1.5 eq.) was added portionwise. The cooling bath was removed and the solution was stirred at r.t. for 18 hours. The resulting reaction mixture was quenched with sat. aq. NaHCO3 soln. (150 mL). The mixture was extracted with DCM (3×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO4, and concentrated in vacuo to give (2-chloro-4-fluoro-benzyl)-(2,2-dimethoxy-ethyl)-amine as a yellow oil. The product was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O>C(O)C.N1CCCCC1>[O:10]=[C:2]1[NH:1][C:9]2[C:4](/[C:3]/1=[CH:11]\[C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]3[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(C)(C)OC(=O)Nc1n[nH]c2ccc(C=O)cc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)Nc1n[nH]c2ccc(/C=C3/C(=O)Nc4ccccc43)cc12
Temperature: 80 °C

Procedure:
To a solution of oxindole (13 mg, 0.01 mmol) and tert-butyl 5-formyl-1H-indazol-3-ylcarbamate (25 mg, 0.01 mmol) in ethanol (1 mL) was added piperidine (1 drop). The mixture was heated to 80° C. for 2 h and cooled to rt. The solution was loaded onto a silica gel column and the title compound was eluted with EtOAc/Hex 4:1 as a red solid (14 mg, 37%). 1H NMR (400 MHz, CD3OD) δ 8.14-8.02 (m, 2H), 7.90-7.83 (m, 2H), 7.63 (s, 1H), 7.24 (bs, 1H), 7.00-6.91 (m, 2H), 1.71 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[NH2:11])[C:5]([O-:7])=[O:6].[C:13](C1NC=CN=1)(C1NC=CN=1)=[O:14].O1CCC[CH2:26]1>>[Cl:12][C:9]1[C:10]2[NH:11][C:13](=[O:14])[NH:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:26])=[O:6])[CH:8]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: C1CCOC1
Reactant: Nc1cc(C(=O)[O-])cc(Cl)c1N
Product: COC(=O)c1cc(Cl)c2[nH]c(=O)[nH]c2c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
3,4-diamino-5-chlorobenzoate (from acid preparation 1, 100 mg, 0.50 mmol) and carbonyl diimidazole (89 mg, 0.55 mmol) were combined in tetrahydrofuran (2 mL) and stirred for 16 hours. The reaction solution was heated to 60° C. for 3 hours. To the reaction was added carbonyl diimidazole (81 mg, 0.50 mmol) and the reaction was continued at 60° C. for two hours. The reaction was allowed to cool to room temperature and stirred for 16 hours. A precipitate formed. The mixture was filtered. The filtrate was concentrated in vacuo and the residue was slurried in ethyl acetate. The slurry was filtered on the same filter as the original filtration. The collected solids were washed with a portion on ethyl acetate and then dried under a stream of nitrogen to give methyl 7-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate as a white solid (93 mg, 82%). 1H NMR (400 MHz. DMSO-d6) δ ppm 11.60 (br. s., 1H) 11.16 (s, 1H) 7.55 (d, J=1.37 Hz, 1H) 7.38 (d, J=1.56 Hz, 1H) 3.80 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH2:26][OH:27].C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([CH:26]=[O:27])=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(CO)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of (2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-yl)methanol (5.03 g) and triethylamine (5.7 mL) in DMSO (80 mL) was added sulfur trioxide pyridine complex (4.35 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.37 g) as a colorless oil.
Reaction SMILES: [N:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[NH2:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:26]([O:28][CH2:29][C:30](Cl)=[O:31])[CH3:27]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:26]([O:28][CH2:29][C:30]([NH:18][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[NH:7][N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:31])[CH3:27]
Reactant: Nc1cnc2ccccc2c1NN1CCOCC1
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1cnc2ccccc2c1NN1CCOCC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 97.6 %

Procedure:
A solution of N4-(morpholin-4-yl)quinoline-3,4-diamine (4.06 g, 16.6 mmol) in 50 mL of CH2Cl2 was treated with triethylamine (4.40 mL, 33.2 mmol) and cooled to 0° C. The solution was treated dropwise with ethoxyacetyl chloride (2.40 g, 17.4 mmol) and stirred under an atmosphere of nitrogen. The reaction mixture was allowed to slowly come to room temperature. After 2 d, the reaction mixture was concentrated under reduced pressure to yield a red semi-solid. The material was dissolved in CHCl3 and washed with water, 5% Na2CO3 solution and brine, dried over Na2SO4, filtered and dried to yield 2-ethoxy—N-{4-[(morpholin-4-yl)amino]quinolin-3-yl}acetamide (5.35 g) as a red/orange foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:30]([CH3:33])=[N:31][N:32]=3)[N:18]=[C:19]([N:21]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:22])[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:23]([N:21]([CH3:22])[C:19]1[CH:20]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:16]2[N:17]([C:30]([CH3:33])=[N:31][N:32]=2)[N:18]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nnc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)cc(N(C)Cc3ccccc3)nn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[6-(Benzyl-methyl-amino)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (4.08 g; 9.04 mmol) was dissolved in 20.0 ml of DCM and treated with 5.0 ml TFA. It was stirred at ambient temperature for 1 hour. The solution was concentrated under reduced pressure and the residue taken up in DCM and washed with half concentrated NaHCO3 solution. The organic phase was dried over MgSO4 and concentrated.
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH2:21]([NH2:23])[CH3:22]>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([NH:23][CH2:21][CH3:22])[CH2:19][CH3:20])=[N:10][CH:9]=1
Reactant: CCN
Reactant: CCC(Br)C(=O)Nc1ncc(Cc2ccccc2Cl)s1
Solvent: CN(C)C=O
Product: CCNC(CC)C(=O)Nc1ncc(Cc2ccccc2Cl)s1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing ethylamine (2 M in tetrahydrofuran, 1.00 mL, 2.00 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (19 mg, 0.056, 56%). ESI-MS m/z calc. 337.1. found 338.0 (M+1)+ Retention time 2.08 minutes.
Reaction SMILES: [Cl:1][O-].[Ca+2].Cl[O-].[F:6][C:7]([F:21])([F:20])[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][C:14]2=[O:19]>O.C(O)(=O)C.C(#N)C.O>[Cl:1][C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([O:8][C:7]([F:6])([F:20])[F:21])[CH:10]=1)[O:17][CH2:16][CH2:15][C:14]2=[O:19]
Reactant: O=C1CCOc2c(OC(F)(F)F)cccc21
Reactant: [O-]Cl
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: O=C1CCOc2c(OC(F)(F)F)cc(Cl)cc21
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of calcium hypochlorite (15.4 g, 72.4 mmol) in water:acetic acid (65:5) was added a solution of 8-trifluoromethoxychroman-4-one (4.2 g, 18.1 mmol; from step (iv) above) in acetonitrile (20 mL), whereafter the reaction mixture was stirred overnight. The mixture was diluted with water and extracted with ether (3 times) and EtOAc (once). The combined organic layer was washed with water, dried (Na2SO4) and evaporated, yielding 4.2 g (87%) of the sub-tide compound.
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:17](#[N:20])[CH:18]=[CH2:19].[Cl:21]C1C=CC(Cl)=CC=1C(C1C=CC=CC=1)=O.CCOCC>C(#N)C.Cl.O>[Cl:21][CH:18]([CH2:19][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4](=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:17]#[N:20]
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C=CC#N
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: N#CC(Cl)Cc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9.27 g (0.4 mole) of 2-amino-5-chlorobenzophenone in 250 ml of acetonitrile was added to a mixture of 70 g (0.52 mole) of cupric chloride, 65 g (0.63 mole) of t-butylnitrile, 500 ml of acrylonitrile, and 500 ml of acetonitrile. When the addition was complete stirring at room temperature was continued for 2 hr. The mixture was diluted with 80 ml of 6 N hydrochloric acid and 1500 ml of water, extracted with ether and dried over anhydrous sodium sulfate. The ether solution was concentrated at reduced pressure to give a brown oil, which contained the end product and 2,5-dichlorobenzophenone. Trituration of the oil with a mixture of ether and petroleum ether gave the end product as a tan solid. Recrystallization of a small portion of the end product from a mixture of ether and petroleum ether gave pale yellow needles, mp 69°-71°.
Reaction SMILES: [CH2:1]([O:8]C1C=C2C(C=CN2)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]([NH2:33])=[O:32])[CH:26]=[C:25]2[N:34]=[C:35]=[O:36])C=C>>[CH2:1]([O:8][C:30]1[CH:29]=[C:28]2[C:24]([C:25]([N:34]=[C:35]=[O:36])=[CH:26][N:27]2[C:31]([NH2:33])=[O:32])=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Product: NC(=O)n1cc(N=C=O)c2ccc(OCc3ccccc3)cc21

Procedure:
was prepared from 6-benzyloxyindole using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[OH:11][CH:12]([CH2:23][O:24][CH3:25])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=1)=[O:14].Cl[C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[N:34]=[CH:35][C:28]=12.O>C1COCC1.CCOC(C)=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[N:33]1[C:29]2=[N:30][CH:31]=[N:32][C:27]([O:11][CH:12]([CH2:23][O:24][CH3:25])[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)=[O:14])=[C:28]2[CH:35]=[N:34]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: COCC(O)C(=O)Nc1ccc(C)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCC(Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
LHMDS (1.40 mL, 1.0 M in THF, 1.40 mmol) was added slowly to a stirred solution of 2-hydroxy-3-methoxy-N-(5-methylpyridin-2-yl)propanamide (200 mg, 0.951 mmol) in anhydrous THF (5 mL). The reaction mixture was kept at ambient temperature for 10 minutes, and a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (265 mg, 1.00 mmol) in anhydrous THF (3 mL) was added. The reaction mixture was heated at 50° C. for ½ hrs (another 3 equivalents of LHMDS were added and the reaction heated for 18 hrs at 50° C. in example 49). Water and EtOAc were added, and the two phases were separated. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with DCM/EtOAc:2/1) to give the title compound as a colourless solid (323 mg), 1H NMR (500 MHz, CDCl3) δ 8.67 (br s, 1H), 8.62 (s, 1H), 8.48 (s, 1H), 8.18 (d, 1H), 8.12 (s, 1H), 7.65 (d, 1H), 7.52 (m, 4H), 6.13 (t, 1H), 4.14 (m, 2H), 4.06 (m, 1H), 3.49 (s, 3H), 2.32 (s, 3H), HRMS: calcd for (M+H+) C21H2035ClN6O3: 439.1285. Found: 439.1287.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:19][CH:20]([O:22][CH2:23][CH2:24][F:25])[CH3:21])[CH:10]([C:15]([O:17]C)=[O:16])[C:11]([O:13]C)=[O:12])=O)(C)(C)C.Cl>CO>[NH2:8][CH:9]([CH2:19][CH:20]([O:22][CH2:23][CH2:24][F:25])[CH3:21])[CH:10]([C:15]([OH:17])=[O:16])[C:11]([OH:13])=[O:12].[NH3:8]
Reactant: COC(=O)C(C(=O)OC)C(CC(C)OCCF)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(CC(N)C(C(=O)O)C(=O)O)OCCF
Product: N
Yield: 5 %

Procedure:
100 mg of dimethyl 3-tert-butoxycarbonylamino-4-(2-fluoroethoxy)pentanedicarboxylate (27) were dissolved in 50 ml of MeOH and treated with stirring with 1 ml of HCl (6N). The reaction mixture was heated to reflux for 15-20 min, concentrated to dryness, diluted with 50 ml of water, and the hydrochloride was filtered off and carefully washed with 3×5 ml of water. The amino acid 28 was isolated by means of ion exchange chromatography on a 50 w×8 Dowex column in H+ form (eluent: 5% NH3 aq).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:17](=[O:18])[C:16]2[C:19]3[N:8]([N:9]([CH3:45])[CH2:10][O:11][C:12]=3[C:13]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]5=[O:43])=[CH:29][C:28]=4[F:44])[CH2:23][CH2:22]3)=[C:14]([F:20])[CH:15]=2)[CH:7]=1)=[O:5])C.Cl.C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:40]([NH:39][CH2:38][C@@H:36]1[O:35][C:34](=[O:43])[N:33]([C:30]2[CH:31]=[CH:32][C:27]([N:24]3[CH2:23][CH2:22][N:21]([C:13]4[C:12]5=[C:19]6[C:16]([C:17](=[O:18])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]6[N:9]([CH3:45])[CH2:10][O:11]5)=[CH:15][C:14]=4[F:20])[CH2:26][CH2:25]3)=[C:28]([F:44])[CH:29]=2)[CH2:37]1)(=[O:42])[CH3:41]
Reactant: CCOC(=O)c1cn2c3c(c(N4CCN(c5ccc(N6C[C@H](CNC(C)=O)OC6=O)cc5F)CC4)c(F)cc3c1=O)OCN2C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(c4c(F)cc5c(=O)c(C(=O)O)cn6c5c4OCN6C)CC3)c(F)c2)C(=O)O1

Procedure:
44 mg of 9-(4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid ethyl ester (0.32 mmol) were heated at 80° C. in 2 ml of a 1/1 conc. HCl and acetic acid mixture. The reaction was monitored by HPLC. The HCl/AcOH mixture was evaporated, the residue dissolved in a methanol/dichloromethane 1/1 mixture, treated with triethylamine and evaporated. The deacetylated residue was dissolved in a 1/1 mixture acetic acid and acetic anhydride, and the reaction monitored by HPLC. The solvents were evaporated and the residue was purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].[CH2:32]([N:34]([CH2:49][CH3:50])[CH2:35][CH2:36][N:37]([CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1)[CH3:38])[CH3:33].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH2:49]([N:34]([CH2:32][CH3:33])[CH2:35][CH2:36][N:37]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)=[O:5])=[O:45])=[CH:47][CH:48]=1)[CH3:38])[CH3:50]
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Reactant: CCN(CC)CCN(C)Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCN(C)Cc1ccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Into a 5-mL vial, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 8d (100 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (5 mL), 4-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (74 mg, 0.28 mmol, 1.20 equiv), EDC.HCl (90 mg, 0.47 mmol, 2.00 equiv), and 4-dimethylaminopyridine (43 mg, 0.35 mmol, 1.50 equiv). The resulting solution was stirred overnight at 30° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was washed with 3×10 mL of water and 1×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (150 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 57.8 mg (31%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.684(d, J=9 Hz, 1H), 8.392-8.400(m, 1H), 8.179(s, 1H), 8.047-8.075(m, 3H), 7.991-7.999(m, 1H), 7.589-7.727(m, 5H), 7.078-7.087(m, 1H), 4.007(s, 2H), 3.556-3.615(m, 4H), 3.393-3.436(m, 2H), 3.171-3.263(m, 4H), 3.052-3.095(m, 2H), 2.538-2.560(m, 3H), 1.998(m, 4H), 1.788-1.804(m, 2H), 1.286-1.334(m, 6H). MS (ES, m/z): 676 [M+H]+.