Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23]O)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.CO.C#C>C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=3)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: [Pd]
Agent: C#C
Solvent: CO
Solvent: ClCCl
Product: CCCc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Yield: 3 %

Procedure:
A mixture of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example No. 134 (500 mg) and Pd/C (10%, 100 mg) is dissolved in 80 mL 3:1 CH2Cl2 :MeOH. The reaction mixture is placed under the Parr hydrogenator at 30 psi and monitored by mass spectroscopy for complete reduction of the acetylene. The old palladium catalyst is replaced with fresh palladium catalyst each time the reaction is taken off the Parr. The reaction mixture is filtered over celite to remove the palladium. The filtrate is condensed. The crude solid is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 16.3 mg (3%) of the title compound as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH:17]=[CH2:18])[CH:7]=[CH2:8].[C:20]([O-])(=[O:22])C.[Na+]>CN(C=O)C>[CH2:16]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:10]=1[N:9]([CH2:6][CH:7]=[CH2:8])[CH3:19])[CH:20]=[O:22])[CH:17]=[CH2:18]
Reactant: C=CCc1ccccc1N(C)CC=C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCc1cc(C=O)ccc1N(C)CC=C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To dry DMF (25 ml) is added phosphorous oxychloride (15.4 g, 0.10 mol) at 0°-5° C. with mechanical stirring over 0.5 hours. N,2-Diallyl-N-methylaniline (18.7 g, 0.10 mol) in DMF (10 ml) is added in a slow stream with stirring. The mixture is heated to 100° C. with stirring for two hours. The mixture is cooled, poured into ice water (200 ml) and neutralized by slow addition of saturated sodium acetate (150 ml) with stirring. The mixture is extracted with ether two times. The extracts are washed with aqueous saturated sodium bicarbonate (50 ml), water, and then brine solution, dried over potassium carbonate, and concentrated to a solid. The solid is recrystallized from hexane-ethyl acetate to provide pure 3-allyl-4-(N-allyl-N-methylamino)benzaldehyde.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[OH:11].O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(=S)=S.Br>[Br:1][C:8]1[CH:9]=[C:4]([F:3])[C:5]([OH:11])=[C:6]([F:10])[CH:7]=1
Reactant: BrBr
Reactant: Oc1c(F)cccc1F
Agent: Br
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: S=C=S
Solvent: O
Product: Oc1c(F)cc(Br)cc1F
Reaction time: 16 h
Yield: 23 %

Procedure:
A solution of bromine (1.6 g) in dry carbon disulphide (10 cm3) was added over 5 minutes to a solution of 2,6-difluorophenol (1.3 g) in dry carbon disulphide (10 cm3). To the stirred reaction mixture was added 5 drops of 48% hydrogen bromide solution. The mixture was heated for 2 hours at the reflux temperature, then allowed to stand at the ambient temperature (ca 22° C.) for 16 hours. After a further period of heating (4 hours) the mixture was allowed to stand for 24 hours before being poured into water (20 cm3). To the mixture was added saturated sodium metabisulphite solution (30 cm3). The layers were separated, and the organic phase was washed with saturated sodium hydrogen carbonate solution (20 cm3) and water (20 cm3). The organic layer was dried over anhydrous sodium sulphate then evaporated under reduced pressure to give an oil which solidified. The crude product was distilled in a Kugelrohr apparatus at an oven temperature of 100° C. under reduced pressure (ca 20 mm Hg). The distillate crystallised to give 4-bromo-2,6-difluorophenol as a white solid (0.48 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([SH:10])[C:7]([OH:9])=[O:8].[Cl:11]N1C(=O)CCC1=O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:11][C:5]1[S:1][C:2]([CH:6]([SH:10])[C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1
Reactant: O=C(O)C(S)c1cccs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(S)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of thiophen-2-yl-sulfanyl acetic acid ethy (0.52 g, 2.6 mmol) in 25 mL of CH2Cl2 is added N-chlorosuccinimide (0.35 g, 2.6 mmol). The solution is stirred for 10 minutes. After this time, 1 drop of TFA is added. The solution is stirred for 16 hours. The reaction mixture is then diluted with 25 mL of CH2Cl2. The resulting solution is washed with 1N NaOH and a saturated NaCl solution. The organic layer is dried over MgSO4, filtered and concentrated. The resulting product is obtained as an oil which is determined to contain 45% of the desired product. The oil is then dissolved in 60 mL of 1:1:1 THF:MeOH:H2O. To the solution is added lithium hydroxide monohydrate (1.26 g, 30 mmol). The solution is stirred for 16 hours. After this time, the solution is acidified to pH=3 with 1N HCl. The aqueous solution is washed with H2O and saturated NaCl solution. The solution is extracted with EtOAc/CH2Cl2 (2:1). The organic layer is dried over MgSO4, filtered and concentrated. The resulting crude product is purified by column chromatography eluting with 20% MeOH:Et2O to give the product as a white solid (0.4 g, 1.9 mmol). MS (EI): m/z 208, 210 (M+), Cl pattern.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([Cl:16])=[CH:12][NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:19]([O:23][C:24](=[O:27])[CH2:25][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:18])[CH3:17])[CH:15]=2)[C:11]([Cl:16])=[CH:12]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(Cl)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(Cl)c2ccc(O[Si](C)(C)C(C)(C)C)cc21

Procedure:
In analogy to the procedure described in example 1 b], 6-(tert-butyl-dimethyl-silanyloxy)-3-chloro-1H-indole was reacted with bromo-acetic acid tert-butyl ester in the presence of cesium carbonate in DMF to obtain [6-(tert-butyl-dimethyl-silanyloxy)-3-chloro-indol-1-yl]-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH2:18][CH3:19])([CH3:17])[CH:6]=1)=S.C1(C)C=CC(S(Cl)(=O)=[O:27])=CC=1.Cl>N1C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH2:18][CH3:19])([CH3:17])[CH:6]=1)=[O:27]
Reactant: CCC1(C)C=C(C(=S)NC)c2cc(C#N)ccc2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCC1(C)C=C(C(=O)NC)c2cc(C#N)ccc2O1
Yield: 62.2 %

Procedure:
A mixture of 70 mg of N-methyl-6-cyano-2-ethyl-2-methyl-2H-1-benzopyran-4-carbothioamide, 55 mg of p-toluenesulfonyl chloride, and 5 ml of pyridine was heated at reflux for 6 hours. To the reaction mixture was added 2N hydrochloric acid, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate, and purified by silica gel column chromatography (AcOEt:n-hexane=1:1) and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 41 mg of N-methyl-6-cyano-2-ethyl-2-methyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][C:7]#[N:8].N>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH2:8])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(CC#N)cc1OC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc(CCN)cc1OC

Procedure:
100 kg. of crystalline 3,4-dimethoxy-benzyl cyanide are hydrogenated in 310 1. of a 80 to 96% aqueous ethanol containing 9 to 12% of ammonia in the presence of 24 kg. of Raney-nickel catalyst pre-treated as described in Example 3 at 48°-60° C under a hydrogen overpressure of 8 to 10 atm. The catalyst is filtered off, the filtrate is evaporated and the residue is subjected to fractionation in vacuo. Thus 95,5 kg. of highly pure 3,4-dimethoxy-beta-phenyl-ethylamine are obtained, purity: nearly 100%. The mono-demethylated beta-phenyl-ethylamine derivative impurity is present at most in traces in such a small amount, which can not be detected by thin layer chromatography.
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:36]([O:39][CH2:40][C:41](Cl)=[O:42])(=[O:38])[CH3:37]>ClCCl>[C:36]([O:39][CH2:40][C:41]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7]1)=[O:42])(=[O:38])[CH3:37]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (1.29 g, 3 mmol) was suspended in dichloromethane (25 ml) under nitrogen at ambient temperature. Triethylamine (1.06 g, 10.5 mmol) was added, to give a solution after 15 minutes. The mixture was cooled to 4°, and acetoxyacetyl chloride (410 mg, 3 mmol) was added dropwise. The mixture was stirred for 18 hours at ambient temperature, washed with water (2×20 ml), saturated brine (20 ml), and dried (magnesium sulfate). The residue was purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (1.16 g).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:16]/[CH:17]=[CH:18]\[CH2:19]Cl>ClCCl>[CH:2]([N:1]1[CH2:19][CH:18]=[CH:17][CH2:16]1)([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClC/C=C\CCl
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C1=CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 42.4 %

Procedure:
To a solution of aminodiphenylmethane (9.70 g, 51.46 mmol) in dichloromethane (6 ml) was added cis-1,4-dichloro-2-butene (1.18 g, 9.02 mmol). The mixture was stirred at r.t. 20 hours. The white solid was filtered and washed with dichloromethane. The filtrated was cooled at 0° C. and HCl 37% (2.5 ml) was added carefully and the suspension was stirred overnight. The resulting white solid was filtered and washed with dichloromethane and the filtrated was washed with saturated solution of NaHCO3, water, dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography: silica gel, gradient dichloromethane to dichloromethane:methanol 4% to afforded the product (0.90 g, 43%) as white solid. M.p. 90-91° C.
Reaction SMILES: [C:1]([C:9]1[CH:21]=[C:20]2[N:11]([C:12](=[O:22])[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=32)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)C.O>[OH:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:21]=[C:20]2[N:11]([C:12](=[O:22])[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=32)[N:10]=1
Reactant: O=C(c1ccccc1)c1cc2c3ccccc3[nH]c(=O)n2n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c2ccccc2c2cc(C(O)c3ccccc3)nn12
Reaction time: 0.5 h

Procedure:
1.65 g 80.0057 mole) of 2-benzoylpyrazolo[1,5-c]-quinazolin-5(6H)-one prepared as in part B above is stirred with 880 mg (4 equiv) of sodium borohydride in absolute ethanol (125 ml) at room temperature for 3 hours. The reaction mixture is stripped to dryness and the resulting solid is suspended in water (40 ml), cooled down to 0° and treated dropwise with 1 N HCl 25 ml). The mixture is stirred for 30 minutes, diluted with water (40 ml) and stirred for another 10 minutes. The white precipitates are filtered off, washed well with water and dried overnight in a vacuum oven at 70° C to give 1.6 g of product.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.BrC1C(C)=CC(C)=CC=1C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])[C:33]2=[O:40].[Cl-].[NH4+]>C1COCC1>[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])[C:33]2([C:28]1[C:23]([O:22][CH3:21])=[N:24][CH:25]=[CH:26][CH:27]=1)[OH:40]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccccn1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ncccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A 1.7 M solution of tert-butyllithium in pentane (28.9 ml, 49.1 mmol) was added to THF (100 ml) at −78° C. 2-Bromomesitylene (3.6 ml, 23.4 mmol) was added dropwise and the mixture stirred at −78° C. for 1 h. 2-Methoxypyridine (1.92 ml, 18 mmol) was added at −78° C. and then the mixture was stirred at 0° C. for 1 h and at ambient temperature for 0.5 h. A suspension of 5-chloroisatin (1.27 g, 9.0 mmol) in THF (50 ml) was added dropwise at −78° C. The reaction mixture was allowed to warm to room temperature and then saturated ammonium chloride solution was added. The mixture was extracted three times with ethyl acetate, and the collected extracts were washed with saturated brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by crystallization from dichloromethane yielded 1.1 g of the intermediate.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([OH:6])=[O:5].[CH3:18][C:19](=[CH2:21])[CH3:20].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.C(OCC)C>[NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([O:6][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:5]
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Yield: 78 %

Procedure:
The tert-butyl (S)-3-amino-2-benzyloxycarbonylaminopropionate was prepared as follows. 10 g (42 mmol) of (S)-3-amino-2-benzyloxycarbonylaminopropionic acid were shaken in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of conc. H2SO4 in an autoclave under an N2 pressure of 20 atm for 3 days. Excess isobutylene was blown out and 150 ml of diethyl ether and 150 ml of saturated NaHCO3 solution were added to the remaining solution. The phases were separated and the aqueous phase was extracted 2× using 100 ml of diethyl ether each time. The combined organic phases were washed with 2×100 ml of water and dried over Na2SO4. After removal of the solvent in vacuo, 9.58 g (78%) of tert-butyl (S)-3-amino-2-benzyloxycarbonylaminopropionate were obtained as a pale yellow oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][C:29]([NH2:31])=[O:30]>CCN(CC)CC>[NH2:31][C:29](=[O:30])[CH2:28][N:25]([CH2:24][C:21]1[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[O:23][N:22]=1)[CH3:26]
Reactant: CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: NC(=O)CBr
Solvent: CCN(CC)CC
Product: CN(CC(N)=O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Yield: 104.6 %

Procedure:
Method as for preparation 106 using tert-butyl(3R)-6-cyclohexyl-3-{3-[(methylamino)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 5) (244 mg, 0.67 mmol) and 2-bromoacetamide (95 mg, 0.69 mmol) as starting materials and Et3N as the base to afford the title compound as a colourless oil (296 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH3:22]I>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH3:22])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1ccc2[nH]c(C(=O)OCC)cc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)cc(C(=O)OCC)n2C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Sodium hydride (60%-suspension, 144 mg, 3.6 mmole) was added to a stirred solution of 1H-indole-2,5-dicarboxylic acid diethyl ester 16 (784 mg, 3.0 mmole) in dry DMF (15.0 ml) and kept at ambient temperature for 30 min. To a resulted reaction mixture MeI (280 μl, 4.5 mmol) was added and kept at ambient temperature for 16 hours and evaporated. The residue was suspended in AcOEt (100 ml) and washed with water (2×20 ml), 0.01 M HCl (3×20 ml) and brine (2×100 ml). The organic layer was dried over sodium sulfate and evaporated to give 800 mg (97%) of 1-methyl-indole-2,5-dicarboxylic acid diethyl ester 17 as a yellow oil. 1H-NMR (DMSO-d6): 8.45 (m, 1H, H-4, indole); 8.03 (m, 1H, H-6, indole); 7.40 (m, 11H, H-7, indole); 7.38 (s, 1H, H-3, indole); 4.40 (m, 4H, —OCH2CH3); 4.10 (s, 3H, NCH3, indole); 1.42 (m, 4H, —OCH2CH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:23]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.O.NN>O1CCCC1.C(OCC)(=O)C>[NH2:23][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([OH:8])=[C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1Cl
Temperature: 25 °C
Yield: 75.4 %

Procedure:
5-Chloro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)phenol (0.49 g) was dissolved in tetrahydrofuran (10 mL). To the solution was added hydrazine monohydrate (0.25 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (0.27 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([O-:3])=[O:2].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([Cl:17])=[O:13])([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Nitrophenylacetic acid (15.0 g, 82.8 mmol) was dissolved in 330 mL of dichloromethane. Three drops of DMF were added, followed by dropwise addition of oxalyl chloride (14.4 mL, 165.6 mmol). The reaction was allowed to stir at ambient temperature for 3 hours, at which time the reaction was concentrated under reduced pressure to afford (2-nitrophenyl)acetyl chloride.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[N:30]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[C:31]=[O:32]>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([NH:30][C:31]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:32])[CH:34]=1
Reactant: O=C=Nc1cccnc1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (97 mg, 0.350 mmol, example 9 (step 3), DIEA (61 μL, 0.35 mmol), and 3-iso-cyanatopyridine (42 mg, 0.35 mmol) in DCM (1 mL) was stirred at RT for 16 h. A white precipitate was observed. The reaction mixture was then filtered and the solid was dried in vacuo to give the title compound as a white solid. MS (ESI, positive ion) m/z: 398 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:20][C:19](=O)[C:18]3[C:13](=[CH:14][C:15]([F:31])=[C:16]([O:22][C:23]4[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:30])[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[Li+].[Cl-].O=P(Cl)(Cl)[Cl:36].CCN(C(C)C)C(C)C>C(#N)C>[Cl:36][C:19]1[C:18]2[C:13](=[CH:14][C:15]([F:31])=[C:16]([O:22][C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]2)[N:20]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2nc(Cl)c3cc(Oc4c(C)cccc4C)c(F)cc3n2)c1
Temperature: 25 °C

Procedure:
A mixture of the above 1-[6-(2,6-dimethyl-phenoxy)-7-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (5.0 g, 12 mmol), LiCl (2.5 g, 59 mmol), POCl3 (5.5 ml, 59 mmol), DIEA (10 mL, 59 mmol), and acetonitrile (ACN) (50 mL) was heated to reflux for 6 h. The mixture was allowed to cool to rt and then concentrated. The residue was taken up in a minimal amount of DCM and passed through a pad of silica gel, eluting with 50:50 hexanes/EtOAc. The resulting solution was concentrated to provide the titled compound. (5.2 g, >99%). 1H NMR (500 MHz, DMSO-d6): 9.13 (d, J=0.6 Hz, 1H), 8.23 (d, J=0.6 Hz, 1H), 7.92 (d, J=10.7 Hz, 1H), 7.23-7.19 (m, 3H), 7.07 (d, J=8.6 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 2.19 (s, 6H), 1.40 (t, J=7.1 Hz, 3H).