Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[O:31][CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[N:11]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=3[O:31][CH3:32])[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Reactant: COc1c(F)cccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(F)cccc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of (S)-7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamic acid isopropyl ester (1.50 g, 5.29 mmol) and 1-(chloromethyl)-3-fluoro-2-methoxybenzene (1.11 g, 6.35 mmol) in N,N-dimethylformamide (10 mL) is treated with cesium carbonate (2.59 g, 7.94 mmol) at room temperature and stirred overnight under nitrogen. The reaction mixture is diluted with water and ether/hexanes. The white solids that crash out of solution are filtered, rinsed with water, ether, hexanes, and dried under vacuum at 50° C. for 48 h to obtain the title compound as a white solid (2.18 g, 98%). LC-ES/MS m/z 422.2 [M+H]+, TR=4.57 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/I)=[CH:9]/[CH2:10][N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:20]2[CH:21]=[CH:22][S:18][CH:19]=2)=[CH:9]/[CH2:10][N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccsc1
Reactant: CN(C/C=C(\I)c1ccc(Br)cc1)CC(=O)O
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: COCCOC
Product: CN(C/C=C(/c1ccc(Br)cc1)c1ccsc1)CC(=O)O
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
To a solution of (Z)-N-(1-(4-bromophenyl)-1-iodoprop-1-en-3-yl)sarcosine, tbutyl ester D (29.86 g, 64.06 mmol) in dimethoxyethane (300 mL) was added 3-thiopheneboronic acid (9.02 g, 70.47 mmol), Pd(PPh3)4 (3.70 g, 3.20 mmol), and 2M Na2CO3 (300 mL). The reaction was warmed to 90° C. with vigorous mechanical stirring for 4.5 hours. The mixture was cooled, and partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. Column chromatography (2-5% acetone/hexanes) provided (Z)-N-(1-(4-bromophenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine, tbutyl ester E(i) (27.06 g, 78%) as a yellow oil. 1H NMR (300 MHz, CDCl3) 1.43 (s, 9H), 2.36 (s, 3H), 3.14 (s, 2H), 3.28 (d, 2H), 6.16 (7, 1H), 6.86 (d, 1H), 7.12-7.14 (m, 3H), 7.32 (collapsed dd, 1H), 7.41 (d, 2H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:24])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O>CN(C=O)C.O>[CH:1]([O:4][C:5](=[O:24])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:14][C:15]3[C:20]([C:21]=2[Cl:25])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[CH:16]=3)=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2cc(-c3ccc(NC(=O)OC(C)C)cc3)[nH]c2c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Cl)c(-c3ccc(NC(=O)OC(C)C)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To [4-(6-Methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (11.3 g, 34.9 mmol) in DMF (50 mL) was added a solution of N-chlorosuccinimide (5 g, 37.4 mmol) dropwise over 20 minutes and the mixture stirred at room temperature for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and triturated with ether to provide [4-(3-chloro-6-Methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (10.65 g, 85%) as a tan solid.
Reaction SMILES: [CH3:1][Li].C[Si](Cl)(C)C.[Br:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[C:16]([CH:25]=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:15]2[CH3:32])=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC.C1COCC1>[Br:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[C:16]([CH:25]([CH3:1])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:15]2[CH3:32])=[CH:11][CH:10]=1
Reactant: [Li]C
Reactant: CCOC(=O)C=Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 73.1 %

Procedure:
To a 0° C. suspension of cuprous iodide (12.7 g, 67.0 mmol) in 150 mL ether was added CH3Li (1.4M in ether, 96 mL, 134 mmol). The solution was cooled to -78° C. and treated with TMSCl (8.5 mL, 67 mmol) and a solution of the unsaturated ester from Step 3 (6.79 g, 15.8 mmol) in 30 mL of THF. The yellow suspension was allowed to warm to room temperature and was stirred 2.5 h. The reaction mixture was poured into saturated NH4Cl and extracted with EtOAc. The organic extracts were washed with water and brine and dried over Na2SO4. Purification by flash chromatography (20% ethyl acetate/hexanes) provided 5.13 g of the title product as a crystaline solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9](S(C)(=O)=O)[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH3:16])[N:3]=1.[CH2:17]([O:19][C:20]1[CH:25]=[C:24]([C:26]2[N:30]([CH3:31])[CH:29]=[N:28][N:27]=2)[CH:23]=[CH:22][C:21]=1[NH:32]C=O)[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O.O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([NH:32][C:21]3[CH:22]=[CH:23][C:24]([C:26]4[N:30]([CH3:31])[CH:29]=[N:28][N:27]=4)=[CH:25][C:20]=3[O:19][CH2:17][CH3:18])[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH3:16])[N:3]=1
Reactant: Cc1cc2cnc(S(C)(=O)=O)nc2c(Cl)n1
Reactant: CCOc1cc(-c2nncn2C)ccc1NC=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc(-c2nncn2C)ccc1Nc1ncc2cc(C)nc(Cl)c2n1
Temperature: 120 °C
Yield: 27.2 %

Procedure:
To a solution of 8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 178, 31 mg, 0.120 mmol) in DMSO (5 mL) was added N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide (Preparation 150, 35.5 mg, 0.144 mmol) and Cs2CO3 (78 mg, 0.241 mmol). The reaction mixture was heated to 120° C. for 18 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 50-100% EtOAc in cyclohexanes followed by elution through an SCX-2 column using MeOH—1M NH3 in MeOH to afford the title compound (12.9 mg, 27%).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([CH3:17])([CH3:16])[C:13](=[O:15])[CH3:14]>C(Cl)(Cl)Cl>[Br:1][CH2:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3]
Reactant: CC(=O)C(C)(C)Cc1ccc(Cl)cc1Cl
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
13.4 ml (0.26 mol) of bromine are slowly added dropwise to a solution of 64.5 g (0.26 mol) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-2-butanone in 600 ml of chloroform at room temperature. The reaction solution is subsequently stirred at room temperature for 1 hour. It is then concentrated by distilling off the solvent. 84.3 g (100% of theory) of crude 1-bromo-4-(2,4-dichlorophenyl)-3,3-dimethyl-2-butanone are obtained as an oil, which is further reacted directly. ##STR11##
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11](O)[CH3:12])[CH:8]=[CH:9][CH:10]=1.C1(P([N:33]=[N+:34]=[N-:35])(C2C=CC=CC=2)=O)C=CC=CC=1.O>C1(C)C=CC=CC=1>[N:33]([CH:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][C:3]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=1[NH2:1])[CH3:12])=[N+:34]=[N-:35]
Reactant: CC(O)c1cccc(Oc2ccc(Cl)cc2N)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(N=[N+]=[N-])c1cccc(Oc2ccc(Cl)cc2N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the product from Example 170c in toluene (25 mL) was added diphenylphosphoryl azide (1.72 g, 6.23 mmol), followed by 1,8-diazabicyclo[4.3.0]undec-7-ene (0.95 g, 6.2 mmol). The mixture was stirred at 25° C. for 18 h. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The crude product was purified on silica gel, eluting with hexanes/ethyl acetate/methanol (85:17:3) to provide the title compound (700 mg, 50%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH:23]=[CH2:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:23]=[CH:24]/[C:37]2[CH:32]=[CH:33][C:34]([C:42]([F:43])([F:45])[F:44])=[C:35]([C:38]([F:39])([F:41])[F:40])[CH:36]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1C(F)(F)F
Reactant: C=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: FC(F)(F)c1ccc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1C(F)(F)F
Temperature: 140 °C

Procedure:
3,4-bis(Benzyloxy)-6-ethenylpyridazine (Intermediate 78: 0.578 g, 1.816 mmol), cesium carbonate (0.887 g, 2.72 mmol), dichloropalladiumtricyclohexylphosphane (1:2) (0.067 g, 0.091 mmol) and 4-chloro-1,2-bis(trifluoromethyl)benzene (0.542 g, 2.179 mmol) were combined. The reaction vessel was evacuated and purged with nitrogen before toluene (6.05 ml) was added under vacuum and the whole was stirred under nitrogen and heated to 140° C. for 11 hours. Upon quenching with saturated aqueous ammonium chloride, the resulting mixture was diluted with dichloromethane, passed through a phase separator and concentrated in vacuo. The residue was purified by column chromatography eluting (silica, 0-50% ethyl acetate in petrol) to yield crude 3,4-bis(benzyloxy)-6-[(E)-2-[3,4-bis(trifluoromethyl)phenyl]-ethenyl]-pyridazine which was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]1(=[O:16])[CH2:15][CH2:14][CH:13]=[CH:12]1>O1CCOCC1.O.C/C(/O)=C/C(C)=O.C=C.C=C.[Rh].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:13]2[CH2:14][CH2:15][C:11](=[O:16])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=C1C=CCC1
Reactant: OB(O)c1ccc(Br)cc1
Agent: [Rh]
Agent: C=C
Agent: CC(=O)/C=C(/C)O
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC[C@@H](c2ccc(Br)cc2)C1
Yield: 66.8 %

Procedure:
To a mixture of 7.2 g (35.8 mmol) of 4-bromophenylboronic acid, 186 mg (0.72 mmol) of acetylacetonatobis(ethylene)rhodium (I) and 446 mg (0.71 mmol) of (R)-2,2′-bis(diphenylphosphino)-1,1′binaphthyl (BINAP) in 60 mL of dioxane and 6 mL of H2O under nitrogen was added 1.0 mL (11.9 mmol) of 2-cyclopenten-1-one. After refluxing for 5.5 h, the reaction was concentrated. The residue was partitioned between 300 mL of EtOAc and 300 mL of 1 N NaHCO3. After separating phases, the organic layer was washed with 300 mL of brine, dried over Na2SO4 and concentrated. The residue was purified on a 40M Biotage column using 9:1 v/v hexane/EtOAc as the eluant to afford 1.90 g of the title compound as a white solid: 1H NMR δ 1.97 (m, 1H), 2.29-2.37 (m, 2H), 2.43-2.52 (m, 2H), 2.69 (m, 1H), 3.40 (m, 1H), 7.16 (d, J=8.5, 2H), 7.49 (d, J=8.5, 2H).
Reaction SMILES: F[C:2]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=O.S(Cl)(Cl)=O.[NH2:21][NH2:22].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH:7]([NH:6][C:4]1[C:3]2[C:2](=[CH:13][C:12]([N+:14]([O-:16])=[O:15])=[CH:11][CH:10]=2)[NH:22][N:21]=1)([CH3:9])[CH3:8]
Reactant: NN
Reactant: CC(C)NC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Product: CC(C)Nc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
2-Fluoro-N-isopropyl-4-nitro-benzamide (0.204 g, 0.902 mmol) and thionyl chloride (1 mL) were heated to 78° C. and stirred for three hours. The reaction mixture was cooled and concentrated to a white solid. NMP (1 mL), hydrazine (0.28 mL, 8.92 mmol) and powdered K2CO3 were added, and the reation mixture was heated to 90° C. and stirred for two hours. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (EtOAc/hexanes 0-33%) to give 0.075 g of Isopropyl-(6-nitro-1H-indazol-3-yl)-amine, MS (M+H)=249.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][C:13]2[C:12]([NH2:15])=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:2][CH3:3].O[CH2:20][CH:21]([CH2:23]O)O.II.S(=O)(=O)(O)O.[NH4+].[OH-]>>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][CH2:7][C:8]2=[CH:9][CH:10]=[C:11]3[C:12]([N:15]=[CH:23][CH:21]=[CH:20]3)=[C:13]2[CH2:14]1)[CH2:17][CH3:18]
Reactant: CCCN(CCC)C1CCc2cccc(N)c2C1
Reactant: OCC(O)CO
Agent: II
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CCCN(CCC)C1CCc2ccc3cccnc3c2C1
Temperature: 140 °C

Procedure:
A mixture of N7,N7 -dipropyl-5,6,7,8-tetrahydro-1,7-naphthalenediamine (1.95 g, 0.008 mol), described by F.L.-E. Arvidsson et al., World Patent Application 81/03491, published Dec. 10, 1981, glycerol (4.7 mL, 0.064 mol) and iodine (0.05 g) was placed in a 250 mL round bottomed flask. The mixture was stirred at 20°-22° C. and concentrated sulfuric acid (6.5 mL, 0.120 mol) was added dropwise. The reaction soon commenced and the temperature rose to 70° C. and stayed at that point until the addition was complete. The flask was heated to 140° C. in an oil bath for 30 minutes. The reaction proceeded with evolution of SO2 and some iodine vapor. Thereafter, the reaction mixture was cooled to 20°-22° C. and then rendered alkaline by the dropwise addition of concentrated NH4OH. The mixture was extracted with chloroform. Insoluble polymeric material in the extract was removed by filtering the extract through a bed of diatomaceous earth. The filtrate was evaporated to dryness. The residue was taken up in diethyl ether. The solution was passed through a column of magnesium silicate, and the column washed with diethyl ether. The combined eluate was evaporated to give the title compound as a colorless oil. Treatment of the oil with a solution of HCl in diethyl ether, followed by recrystallization of the resulting solid from methanol gave the trihydrochloride salt of the title compound having mp 249°-255° C.; Anal. Calcd for C19H26N2.3HCl; C, 58,40% H, 7.48% N, 7.16%; Found: C, 58.62%, H, 7.22% N, 7.22%; the NMR (CDCl3) of the free base exhibited δ1.04 (t, 3H), 1.06 (t, 3H), 2.05 (m, 6H), 3.25 (m, 8H), 4.22 and 4.40 (m, 1H), 7.65 (d, J=8 Hz, 1H), 7.87 (2d, J=8 Hz, 1H), 7.95 (d, J= 8 Hz, 1H), 8.88 (2d, J=8 Hz, J=1.5 Hz, 1H), 9.19 (2d, J=8 Hz, J=1.5 Hz, 1H), 11.0 (broad, 2H).
Reaction SMILES: [Cl:1][CH:2]1[C:12]([Cl:13])=[CH:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=[O:7]>ClC1C=CC(Cl)=CC=1Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[Cl:13]
Reactant: O=C1OC(=O)C2CC(Cl)C(Cl)=CC12
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Temperature: 190 °C
Yield: 80 %

Procedure:
A mixture of 5.0 grams (22.7 mmol) of 4,5,-dichlorotetrahydrophthalic anhydride and of activated carbon (Darco KB-60, 1.0 gram) was slurried with 10 mL of 1,2,4-trichlorobenzene and heated to 190° C. for 25 h. The reaction mixture was then filtered while hot and the filtrate was allowed to cool to room temperature, at which time the product precipitated out of solution. After the addition of 5 mL of hexanes to ensure complete precipitation, the product was collected and washed with hexanes. Drying in a vacuum dessicator (60° C., 0.25 mm Hg, 24 h) gave 1 (3.9 g, 80% yield, 99.6% purity by GC), mp 185°-16.5° C. (lit mp 187° C.).
Reaction SMILES: [ClH:1].C(OC([CH2:9][NH:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([NH2:34])[N:28]=[C:27]2[C:35]([N:37]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38]1)=[O:36])=[O:13])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[CH3:9][NH:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([NH2:34])[N:28]=[C:27]2[C:35]([N:37]1[CH2:38][C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:45]1)=[O:36])=[O:13]
Reactant: CC(C)(C)OC(=O)CNCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.3 ml of 4N HCl in dioxane are added to 1 g of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4,5-difluorobenzyl (tert-butoxycarbonylmethylamino)acetate in 20 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 1 h, the precipitate is filtered off and rinsed with 3 ml of dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2=[O:13].N1C2C(=CC=CC=2)C(=O)C1=O.[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1I)[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[O:27][CH2:25][CH3:26])[OH:13]
Reactant: CCOc1ccccc1I
Reactant: O=C1Nc2cc(F)c(Cl)cc2C1=O
Agent: O=C1Nc2ccccc2C1=O
Product: CCOc1ccccc1C1(O)C(=O)Nc2cc(F)c(Cl)cc21

Procedure:
The title compound was prepared in analogy to example a.1 using 5-chloro-6-fluoro-isatin as isatin II and ethoxyiodobenzene (to form the Grignard reagent).
Reaction SMILES: OC1C=C2C(=CC=1)N(C)C=C2C[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:21].C[O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][CH:37]=[C:36]2[CH2:42][CH2:43]N(C)C(C)CCCCCC(NC1C=CC(OC)=CC=1)=O>>[OH:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][CH:37]=[C:36]2[CH2:42][CH2:43][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:21]
Reactant: COc1ccc(NC(=O)CCCCCNCCc2cn(C)c3ccc(O)cc23)cc1
Reactant: COc1ccc(NC(=O)CCCCCC(C)N(C)CCc2c[nH]c3ccc(OC)cc23)cc1
Product: COc1ccc(NC(=O)CCCCCNCCCc2c[nH]c3ccc(O)cc23)cc1

Procedure:
6-[[2-(5-hydroxy-1-methyl-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-hexanamide, 7-[[2-(5-methoxy-1H-indol-3-yl)ethyl]methylamino]-N-(4-methoxyphenyl)-octanamide,
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:6][S:7][C:8]([CH2:11]O[Si](C(C)(C)C)(C)C)=[CH:9][CH:10]=1)=[N+:2]=[N-:3].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:40]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[N:1]([CH2:4][C:5]1[S:6][S:7][C:8]([CH2:11][Cl:40])=[CH:9][CH:10]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CN=[N+]=[N-])SS1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=NCC1=CC=C(CCl)SS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a stirred solution of the silyloxyazide 15 (100 mg; 0.31 mmol) in distilled THF (5 mL) was added at room temperature water (6.7 μL), followed by the sequential addition, in one portion, of triphenylphosphine (97 mg; 0.37 mmol) and triphosgene (460 mg; 1.55 mmol). The reaction mixture was shielded from light and stirred at room temperature overnight. The reaction mixture was chromatographed on silica gel, eluting with 10% ethyl acetate in hexane, to afford 27.4 mg (40.4%) of the title chloride 28. 1H NMR (CDCl3) δ6.425 (dd, J=6.4, 6.0 Hz, 2H, C=CH), 4.267 (s, 2H, CH2), 4.004 (s, 2H, CH2); 13C NMR (CDCl3) δ128.538, 28.417, 127.719, 127.582, 54.864, 46.634.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2=[CH:36][CH:37]=[CH:38][NH:39][C:34]2=[CH:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:10][C@H:9]2[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)C1=CC=CNC1=CO2
Reactant: C[C@@H]1CNCCN1c1ccc(Cl)cc1
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: C[C@@H]1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4-chloro-phenyl)-3-(R)-methyl-piperazine (0.2 g, 0.95 mmol) in isopropanol (20 mL) was added 2,6-lutidine (0.11 mL, 0.94 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and then treated with 2-[5-(3-bromo-propylidene)-5,1-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.24 g, 0.63 mmol), added in portions over 2 h. The solution was then stirred at 80° C. for an additional 20 h. The reaction was concentrated in vacuo and purified by flash chromatography (100% dichloromethane to 2% methanol/dichloromethane) to yield the title compound.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:20]([F:23])([F:22])[F:21])([OH:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[CH:11]=1)(C)[CH3:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)(O)[O-].[Na+]>C(OCC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]([CH3:8])[CH2:6][C:5]([OH:19])([C:20]([F:23])([F:22])[F:21])[CH:4]=[O:3])=[CH:11][C:12]=1[O:17][CH3:18]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1ccc(Cl)c(OC)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1cc(C(C)CC(O)(C=O)C(F)(F)F)ccc1Cl
Temperature: 0 °C

Procedure:
5.25 g (14.24 mmol) of (rac.) ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoate is dissolved in 53 ml of diethyl ether and mixed at 0° C. with 405.2 mg (10.68 mmol) of lithium aluminum hydride within 30 minutes. The reaction mixture is stirred for 1¼ more hours at 0° C. For hydrolysis, the mixture is mixed drop by drop with 12.5 ml of saturated sodium bicarbonate solution while being cooled in an ice bath. It is stirred vigorously for 30 minutes while being cooled in an ice bath and for 60 minutes at room temperature. The precipitate is suctioned off and washed with diethyl ether. The filtrate is concentrated by evaporation in a rotary evaporator, and the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 3.29 g (71.2%) of the desired aldehyde, which still contains some starting ester and 54.7 mg of the corresponding diol, is isolated.