Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][Mg]Br>C1COCC1>[OH:2][CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])[CH3:17]
Reactant: C[Mg]Br
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: CC(O)c1cnccc1-c1cccc(C#N)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg) in THF (2 mL) at −78° C. was added 3.0 M methylmagnesium bromide in THF (0.144 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-[3-(1-hydroxy-ethyl)-pyridin-4-yl]-benzonitrile as a white foam.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([O:18][C:19]1[C:20](=O)[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:27][CH:26]=2)=[N:23][CH:24]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)(O)[O-].[Na+]>ClCCl>[F:7][C:20]1[C:19]([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:24][N:23]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:27][CH:26]=2)[N:21]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(OCCCCCCCC)c(=O)[nH]2)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ncc(OCCCCCCCC)c(F)n2)cc1
Reaction time: 8 h

Procedure:
A solution of 0.7 ml of diethylaminosulfurtrifluoride (DAST) in 10 ml of dichloromethane is added in the course of 10 minutes, at 0° C., to a suspension of 2.1 g of 5-octyloxy-2-(4-octyloxyphenyl)pyrimidin-4-one (prepared, for example, in accordance with Boller et al., Z. Naturf. 33b, 433 (1978)) in 30 ml of dichloromethane. After 8 h at 40° C., aqueous sodium bicarbonate solution is added. After chromatography and recrystallization from acetonitrile, the organic phase yields 0.7 g of colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].[Cl:11][S:12](O)(=[O:14])=[O:13]>ClCCl>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CN(C)Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,N-Dimethyl benzylamine (7 ml) was dissolved in 40 ml of dichloromethane and chlorosulfonic acid (12 ml) was slowly added at 0° C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice to give solids, which was collected by filtration. 2.63 g of the titled compound was obtained. Additional crops (1.34 g) was obtained from the dichloromethane extraction of the filtrate.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[F:14][C:15]([F:31])([F:30])[C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.CCN(C(C)C)C(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([N:20]2[CH2:21][CH:16]([C:15]([F:31])([F:30])[F:14])[CH2:17][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:19]2)=[C:3]2[CH2:13][CH2:12][CH2:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CC(C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.34 g, 1.7 mmol), cis-tert-butyl [5-(trifluoromethyl)piperidin-3-yl]carbamate (0.50 g, 1.9 mmol) in isopropyl alcohol (1.0 g) and DIPEA (1.0 mL, 5.7 mmol) was stirred at 110° C. for 2 h. The solution was allowed to cool to room temperature, then the mixture was concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus (40 g column, eluting with 0 to 70% EtOAc in hexanes) to give the sub-title compound as a pale yellow powder (0.37 g, 50%). LCMS calc. for C19H26F3N4O4 (M+H)+ m/z=431.2. found: 431.0. The material was subjected to chiral HPLC (Phenomenex Lux® Cellulose 4 column, 21, 2×250 mm, 5 micron particle size; Mobile phase: 7% EtOH in hexanes; Flow rate: 18 mL/min. isocratic; Column loading: 10 mg/injection; Run time: 24 minutes) to give two separated enantiomers of the sub-title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]2[CH:12]([CH:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][CH2:16]2)[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](Cl)=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30].[OH-].[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[CH:17]2[CH:12]([CH:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][CH2:16]2)[N:11]([C:32](=[O:33])[CH2:31][C:26]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:24]([Cl:23])[CH:25]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: c1ccc(CN2CCNC3C(N4CCCC4)CCCC32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccc2)C2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(4aRS,5SR,8aRS)-1-Benzyl-5-(pyrrolidin-1-yl)perhydroquinoxaline (325 mg, 1.09 mmol) was dissolved in absolute CH2Cl2 (35 ml). 2-(3,4-Dichlorophenyl)acetyl chloride (291 mg, 1.3 mmol) was added dropwise and the mixture was stirred at room temperature. After 30 minutes, 2 N NaOH (35 ml) was added and the mixture was stirred vigorously for 2 hours. The aqueous phase was separated off. The organic phase was extracted by shaking three times with HCl (1 N). The aqueous phase was then brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. The product was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=O)[CH3:5].[Br:8][C:9]1[CH:16]=[CH:15]C(CBr)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:8][C:9]1[CH:16]=[CH:15][C:5]([CH2:4][CH2:3][C:2](=[O:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)CCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of 2,4-pentanedione (200 mg, 206 μL, 2 mmol), the 4-bromobenzyl bromide (2 mmol), and anhydrous potassium carbonate (276 mg, 2 mmol) in methanol (10 mL) was heated at reflux temperature for 16 h. The mixture was then cooled to room temperature, methanol was removed under reduced pressure, and the resulting residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted further with ethyl acetate (3×10 mL). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, and then the solvent was removed under pressure. The resulting oil was chromatographed on a silica gel column using hexanes-ethyl acetate as mobile phase to give 4-(4-bromophenyl)-2-butanone as a clear liquid (302 mg, 67%): Rf=0.38 (hexanes-ethyl acetate 3:1 v/v); 1H NMR (400 MHz, CDCl3): δ 2.15 (s, 3H), 2.75 (t, J=7.2 Hz, 2H), 2.86 (t, J=7.2 Hz, 2H), 7.07 (d, J=8 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 29.2, 30.2, 44.9, 120.0, 130.2, 131.7, 140.2, 207.4; HRMS (ESI) Calcd. for C10H11BrONa: 248.9891 [M+Na+]. Found: 248.9880.
Reaction SMILES: [I-:1].[K+].Br[C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:10]=3[O:11][CH2:12][C:6]=2[CH:5]=1.O.C(OCC)(=O)C>CN(C)P(=O)(N(C)C)N(C)C.[Cu]I>[OH:17][C:15]1[CH:14]=[CH:13][C:10]2[O:11][CH2:12][C:6]3[CH:5]=[C:4]([I:1])[CH:20]=[CH:19][C:7]=3[C:8](=[O:18])[C:9]=2[CH:16]=1
Reactant: [I-]
Reactant: O=C1c2ccc(Br)cc2COc2ccc(O)cc21
Agent: [Cu]I
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C1c2ccc(I)cc2COc2ccc(O)cc21
Temperature: 160 °C
Reaction time: 4 h
Yield: 37.3 %

Procedure:
10.35 g of copper (I) iodide and 26.9 g of potassium iodide were added to 3.3 g of 8-bromo-2-hydroxy-11-oxo-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 27 dissolved in 33 ml of hexamethylphosphoric acid triamide and the mixture was stirred under nitrogen stream at 160° C. for 4 hours. After 300 ml of water and 400 ml of ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The residue obtained by removing the solvent was washed with chloroform to obtain 1.42 g of the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:25])=O)=[N:21][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[CH:60][C:59]=2[C:65]([F:68])([F:67])[F:66])[CH2:53][CH2:52]1)=[O:50].Cl>CN(C=O)C.O>[F:64][C:62]1[CH:61]=[CH:60][C:59]([C:65]([F:67])([F:66])[F:68])=[C:58]([CH:63]=1)[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:22][N:21]=2)=[O:25])[CH2:52][CH2:53]1)=[O:69]
Reactant: O=C(O)c1ccc(Nc2ccccc2)cn1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1ccc(Nc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
DIPEA (90 mg, 0.12 mL, 0.7 mmol) was added drop wise to 5-(phenyl-amino)-pyridine-2-carboxylic acid (50 mg, 0.23 mmol) in DMF (5 mL). EDCI (111 mg, 0.58 mmol) and HOBT (37 mg, 0.28 mmol) were added consecutively and, after 10 minutes, 2-amino-1-[4-(2-trifluoromethyl-5-fluoro-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (125 mg, 0.28 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 55 mg (44% yield) of 5-phenylamino-pyridine-2-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 99.28%. 1H-NMR (DMSO-d6): δ 8.9 (s, 1H), 8.5 (t, 1H), 7.9 (m, 2H), 7.6 (d, 3H), 7.4 (t, 2H), 7.2 (d, 2H), 7.0 (t, 1H), 4.2 (d, 2H), 3.6 (m, 5H), 3.2 (m, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Sn](C)(C)C)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncccn1
Reactant: C[Sn](C)(C)c1nn(Cc2ccccc2)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: c1ccc(Cn2nc(-c3ncccn3)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
200 mg of 1-benzyl-3-trimethylstannylindazole (crude product, 70% according to GC), 35 mg of 2-chloropyrimidine (0.30 mmol) and 29 mg (0.025 mmol) of Pd(PPh3)4 in 2.5 ml of toluene were heated under reflux overnight in an argon atmosphere. The mixture was cooled to room temperature, saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and freed from the solvent on a rotary evaporator. Purification was carried out by chromatography over aluminium oxide using cyclohexane/ethyl acetate as the eluent (gradient from 10:1 to 1:1).
Reaction SMILES: [Br-].[Mg+2].[Br-].[Cl:4][C:5]1[C:6]([F:26])=[C:7]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24]C)=[C:19]([CH:22]=[O:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1>N1C=CC=CC=1.O>[Cl:4][C:5]1[C:6]([F:26])=[C:7]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([CH:22]=[O:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Agent: [Br-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O
Temperature: 130 °C
Yield: 100.6 %

Procedure:
Solid anhydrous magnesium bromide (3.66 g, 19.9 mmol) was carefully added to a stirred solution of 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazoline-6-carbaldehyde (2.0 g, 6.04 mmol) in pyridine (30 ml) at room temperature. The resulting suspension was heated at 130° C. for 16 hours, cooled to room temperature and concentrated to dryness to give a yellow solid. This was suspended in water (100 ml), collected by filtration and washed several times with water. The resulting yellow solid was dried to a constant weight in a vacuum oven at 40° C. to give 4-[(3-chloro-2-fluorophenyl)amino]-7-hydroxyquinazoline-6-carbaldehyde, (1.93 g, 100%); Mass Spectrum: (M+H)+ 318.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([N:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:24])[C:18]=3[C:17]3=[N:25][O:26][C:27]([CH3:28])=[C:16]3[C:15]2=[O:29])[CH2:11][CH:10]([CH2:30][N:31]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([N:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:24])[C:18]=3[C:17]3=[N:25][O:26][C:27]([CH3:28])=[C:16]3[C:15]2=[O:29])[CH2:11][CH:10]([CH2:30][NH2:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1onc2c1c(=O)n(C1CC(CN=[N+]=[N-])CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1onc2c1c(=O)n(C1CC(CN)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Yield: 66 %

Procedure:
Hydrogenate 3-azidomethyl-5-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.65 g, 1.4 mmol) in THF (7.5 mL) and EtOH (50 mL) with 5% Pd/C (0.132 g, at 50 psi and room temperature for 24 H. Filter through celite and concentrate to dryness. Dissolve in CHCl3. Wash 2× with sat. aq NaHCO3, wash with brine, dry over Na2SO4, filter and concentrate to dryness to afford the title compound (413 mg, 66%) as a tan foam as a mixture of cis isomers. MS(IS) 447.1 (M+); TLC (10% MeOH/CHCl3) Rf=0.14.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[H-].[Na+].Br[CH:15]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][N:21]2[S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:16]>CN(C=O)C>[S:26]([N:21]1[C:22]2[C:18](=[C:17]([CH:15]([N:2]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:1]3=[O:11])[CH3:16])[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1)([C:29]1[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=1)(=[O:27])=[O:28]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)Br)cccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)N4C(=O)c5ccccc5C4=O)cccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 112.5 %

Procedure:
To a solution of isoindoline-1,3-dione (3.83 g, 20.0 mmol), in dry DMF (70 mL) at 0° C. under argon was added NaH (1.04 g, 26 mmol). The resultant mixture was stirred at RT for 30 min. A solution of 284 (9.8 g, 26 mmol) in dry DMF (30 mL) was added and the mixture was stirred at RT for 4 h. The mixture was concentrated in vacuo and purified by SiO2 chromatography to afford 10 g (86%) of 2-(1-(1-tosyl-1H-indol-4-yl)ethyl)isoindoline-1,3-dione (286) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 7.87-7.81 (m, 8H), 7.48 (d, J=7.6 Hz, 1H), 7.38-7.33 (m, 3H), 6.82 (d, J=3.6 Hz, 1H), 5.77-5.74 (m, 1H), 2.29 (s, 3H), 1.84 (d, J=6.8 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:13]([C:31](=[O:34])[NH:32][OH:33])[CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[OH:33][NH:32][C:31]([CH:13]1[CH2:12][N:11]([C:9](=[O:10])[CH2:8][NH2:7])[CH2:16][CH2:15][N:14]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:34]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2C(=O)NO)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)CN)CC2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 0.157 g (0.31 mmol) of the product of Example 229, {2-[4-(4-but-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazin-1-yl]-2-oxo-ethyl}carbamic acid tert-butyl ester, in 4.0 mL of methylene chloride was added 1.0 mL of trifluoroacetic acid. The resulting solution was stirred at room temperature for 1 h and then reduced to dryness. The resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to furnish 0.121 g (95%) of 4-aminoacetyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid hydroxyamide as a yellow solid. Electrospray Mass Spec: 411.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:20])=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1F.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[OH-].[Na+].C(O)(=O)C>CN1CCCC1=O.O>[F:1][C:2]1[C:3]([NH2:20])=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[N:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1
Reactant: CN1CCNCC1
Reactant: CC1Cc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: CC1Cc2c(N3CCN(C)CC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Temperature: 50 °C

Procedure:
8,9-Difluoro-7-amino-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (2 g) and N-methylpiperazine (4 ml) are suspended in N-methylpyrrolidone (20 ml), and the mixture is heated at 110°-120° C. on an oil bath for 3 hours. After the reaction, the reaction mixture is distilled under reduced pressure, and to the residue is added ethyl acetate. The resulting crystals are separated by filtration and thereto is added water (80 ml), which is regulated to pH 2 with 6N hydrochloric acid, and the mixture is heated at 50° C. and then filtered. The filtrate is concentrated to dryness, and the residue is recrystallized from ethanol-water to give yellow cubic crystals. The crystals are again suspended in water (10 ml) and is dissolved by regulating to pH 12 with a 10% aqueous sodium hydroxide solution and then is regulated to pH 8 with acetic acid. The precipitated crystals are separated by filtration, washed with water and dried to give 8-fluoro-2-methyl-9-(4-methyl-1-piperazinyl)-7-amino-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline- 5-carboxylic acid (1.4 g) as yellow cubic crystals. m.p. 240°-243° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:24])[N:9]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:25](I)[CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:24])[N:9]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:10](=[O:14])[N:11]2[CH2:25][CH2:26][CH3:27])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCI
Reactant: N#Cc1ccc(Cn2c(=O)[nH]c3cc([N+](=O)[O-])ccc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCn1c(=O)n(Cc2ccc(C#N)cc2)c(=O)c2ccc([N+](=O)[O-])cc21

Procedure:
Prepared analogously to Example 1c from 4-[(7-nitro-1,4-dihydro-2H-quinazolin-2,4-dion-3-yl)-methyl]-benzonitrile, propyl iodide and potassium carbonate in dimethyl sulphoxide.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[O:20][CH2:21][CH:22]([F:24])[F:23])[CH2:5][CH2:4]1.[CH3:28][C:29]1[C:42]([N:43]=[C:44]=S)=[C:41]([CH3:46])[CH:40]=[CH:39][C:30]=1[CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].CC(C)N=C=NC(C)C>>[F:1][C:2]([F:26])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([O:20][CH2:21][CH:22]([F:23])[F:24])=[CH:13][C:14]3[N:18]([CH3:19])[C:44]([NH:43][C:42]4[C:41]([CH3:46])=[CH:40][CH:39]=[C:30]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]=4[CH3:28])=[N:17][C:15]=3[CH:16]=2)=[O:25])[CH2:5][CH2:4]1
Reactant: CNc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1N=C=S
Agent: CC(C)N=C=NC(C)C
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1Nc1nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc2n1C

Procedure:
The title compound is prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-(2,2-difluoro-ethoxy)-4-methylamino-5-amino-benzoic acid amide and N-(2,4-dimethyl-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide with DIC in analogy to examples 7b/7c.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].CCN(C(C)C)C(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1I
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-iodo-3-methyl aniline (200 mg, 0.86 mmol) and iPr2NEt (0.19 mL, 0.95 mmol) in CH2Cl2 (10 mL) was added 3-(trifluoromethyl)benzoyl chloride (0.133 mL, 0.90 mmol). The mixture was allowed to stir at room temperature for 0.5 h at which time it was diluted with CH2Cl2 (20 mL). The organic layer was washed with aq. HCl (10 mL, 1 M), 9% aq. Na2CO3 (10 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[C:8]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][C@@H:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[OH:20].CI>CCCCCC>[CH3:3][O:20][CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CN(C)C=O
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCCCCC
Product: CCCCCCC(CC=CCCCCCCCC(=O)OCC)OC
Temperature: 40 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a 1-l flask equipped with a stirrer, a dropping funnel and a condenser, 24 g (0.6 mol) of 60% sodium hydride, 500 ml of dimethylformamide were charged, followed by the dropwise addition of a solution of 163.3 g (0.5 mol) of ethyl ricinoleate in 142 g (1.0 mol) of methyl iodide over one hour while stirring at 40° C. under an N2 atmosphere. After the completion of the dropwise addition, stirring was conducted at 40° for further 6 hours. To the reaction mixture so obtained, hexane was added. The resulting mixture was then washed with an aqueous solution of ammonium chloride and an aqueous solution of sodium thiosulfate, followed by concentration under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby 155.8 g of ethyl 12-methoxy-9-octadecenoate were obtained (yield: 92%).