Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C@H:14]1[CH2:19][NH:18][C@H:17]([CH3:20])[CH2:16][NH:15]1>ClCCl>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:15]2[CH2:16][C@@H:17]([CH3:20])[NH:18][CH2:19][C@@H:14]2[CH3:13])=[N:3][N:4]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: ClCCl
Product: C[C@@H]1CN(c2nnc(Cl)c3ccccc23)[C@@H](C)CN1
Temperature: 130 °C

Procedure:
1,4-dichlorophthalazine (1.0 g, 5 mmole) and trans-2,5-dimethyl piperazine were combined in a reaction vial and heated to 130° C. for 3 h with stirring. After cooling to room temperature, the solid residue was dissolved in 150 mL of dichloromethane and washed with 1×20 mL of 1:1 saturated NaHCO3 solution:H2O and 1×20 mL of saturated NaCl solution. The organic phase was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (100:5:1 dichloromethane:methanol:triethylamine) afforded 1-chloro-4-(trans-2,5-dimethylpiperazin-1-yl)phthalazine. MS (M+H)+=277.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>ClCCl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[C:2]([NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:31])=[N:3][CH:4]=[N:5]3)=[CH:14][CH:15]=1
Reactant: COc1ccc(Oc2cccc3ncnc(N)c23)cc1
Reactant: COc1cccc(N=C=O)c1
Solvent: ClCCl
Product: COc1ccc(Oc2cccc3ncnc(NC(=O)Nc4cccc(OC)c4)c23)cc1
Yield: 73.9 %

Procedure:
4-Amino-5-(4-methoxyphenoxy)quinazoline (0.35 g, 1.3 mmol) and 3-methoxyphenyl isocyanate (0.23 g, 1.6 mmol) were reacted in 20 ml of dichloromethane according to procedure E to give 1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-methoxyphenyl)urea (0.4 g, 74.1%, m.p. 209-210° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([Cl:6])=[O:5].[Cl-].[C:8]([O:11][CH:12]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[C:24]([I:25])=[C:23]([NH2:26])[C:22]([I:27])=[C:18]([C:19]([OH:21])=[O:20])[C:17]=1[I:28])(=[O:10])[CH3:9]>O1CCOCC1>[Cl-:6].[C:8]([O:11][CH:12]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[C:24]([I:25])=[C:23]([NH:26][C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:22]([I:27])=[C:18]([C:19]([OH:21])=[O:20])[C:17]=1[I:28])(=[O:10])[CH3:9]
Reactant: COCC(=O)Cl
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I)OC(C)=O
Agent: [Cl-]
Solvent: C1COCCO1
Product: COCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 25 °C

Procedure:
24.7 g (150 mmol) of methoxyacetyl chloride is added to a suspension of 73.4 g (100 mmol) of 5-amino-2,4,6-triiodoisophthalic acid-N-(2,3-diacetoxypropyl)-amide-chloride (EP 0308364) in 500 ml of anhydrous dioxane, stirred with exclusion of moisture, at room temperature. The batch is refluxed for several hours, until, according to thin-layer chromatography, feedstock is no longer detectable, then it is concentrated by evaporation, the residue is taken up in dichloromethane and shaken out with saturated aqueous sodium bicarbonate solution. After drying on anhydrous magnesium sulfate, the organic phase is concentrated by evaporation, and the residue is recrystallized from ethyl acetate/tert-butyl methyl ether.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[S:14][CH:15]=[C:16]([CH3:17])[C:12]=2[C:11](=[O:18])O[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1C(=O)N(CC2C=CC=CC=2)C2SC=CC=2C=1O)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([C:25]1[C:9](=[O:19])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]2[S:14][CH:15]=[C:16]([CH3:17])[C:12]=2[C:11]=1[OH:18])=[O:24])[CH3:21]
Reactant: CCOC(=O)c1c(O)c2ccsc2n(Cc2ccccc2)c1=O
Reactant: Cc1csc2c1c(=O)oc(=O)n2Cc1ccccc1
Product: CCOC(=O)c1c(O)c2c(C)csc2n(Cc2ccccc2)c1=O
Yield: 80 %

Procedure:
This compound was prepared from 1-benzyl-5-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (59) by applying the same method described for the preparation of 7-benzyl-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (60). Yield 80%; MP 166° C. 1H-NMR (DMSO-d6): δ 1.32 (t, J=6.8 Hz, 3H), 2.40 (d, J=1.2 Hz, 3H), 4.36 (q, J=6.8 Hz, 2H), 5.22 (s, 2H), 6.84 (d, J=1.2 Hz, 1H), 7.25 (m, 3H), 7.32 (m, 2H), 14.04 (b, 1H) ppm; EIMS m/z 344 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:14]=[C:13]([S:15](=[O:18])(=[O:17])[NH2:16])[S:12][C:11]=3[CH:19]=2)OCC[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:2]([C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([S:15](=[O:18])(=[O:17])[NH2:16])[S:12][C:11]=2[CH:19]=1)(=[O:3])[CH3:1]
Reactant: CC1(c2ccc3cc(S(N)(=O)=O)sc3c2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)c1ccc2cc(S(N)(=O)=O)sc2c1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
The ketal product from Example 37 (4.4 g, 14.7 mmole) and p-toluenesulfonic acid (400 mg) were dissolved in acetone (90 ml). The mixture was stirred overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (200 ml) and 10% saturated NaHCO3 solution (b 100 ml). The organic layer was washed with H2O (2×100 ml) and dried over Na2SO4. The solvent was removed in vacuo and the residue was triturated with hot CHCl3 (100 ml). Upon cooling, 3.4 g (90.6%) of product was obtained, m.p. 154°-155° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=O)(=[O:3])[CH3:2].C(O)C.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(F)c(F)c2c1CCCC2=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(=O)Nc1cc(F)c(F)c2c1CCCC2
Temperature: 25 °C

Procedure:
The compound obtained in (5) above (1 gm) was dissolved into 20 ml of ethanol. To the solution was added 166 mg of sodium borohydride while stirring at room temperature. After stirring for 20 minutes, chloroform and 10% citric acid were added to the reaction mixture. The chloroform layer was extracted and concentrated. To the concentrate were added 20 ml of toluene and a small amount of p-TsOH, followed by heating under reflux for 1 hour. Upon addition of 100 ml of ethyl acetate, the reaction product was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved into a mixed solvent of 20 ml of ethanol, 20 ml of dioxane, and 0.2 ml of acetic acid. The mixture was catalytically hydrogenated with the addition of 200 mg of platinum oxide. The catalyst was removed, the filtrate was concentrated, and ether was added to the concentrate. 0.8 gm of the title compound was obtained by collecting the precipitate by filtration.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3](=[O:14])[CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][NH:9][CH2:10]2)[CH2:6]1.CS(O[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)(=O)=O>CC#N>[CH3:1][C:2]([CH3:16])([CH3:15])[C:3](=[O:14])[CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][N:9]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH2:10]2)[CH2:6]1
Reactant: CS(=O)(=O)OCCc1ccc(C#N)cc1
Reactant: CC(C)(C)C(=O)CN1CC2CNCC(C1)O2
Solvent: CC#N
Product: CC(C)(C)C(=O)CN1CC2CN(CCc3ccc(C#N)cc3)CC(C1)O2
Temperature: 50 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A mixture of 3,3-dimethyl-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-2-butanone (from step (ii) above; 56 mg, 0.25 mmol), TEA (0.35 mL, 2.5 mmol) and MeCN (2 mL) was treated with 4-cyanophenethyl methanesulfonate (see step (iii) above; 84 mg, 0.37 mmol). The resulting mixture was stirred at 50° C. for 24 h. The solvents were removed by evaporation, the crude product was dissolved in DCM and then the solution was added to an ion-exchange solid-phase extraction plug (2 g, CBA (carboxylic acid on silica support)). After 1 h, the plug was washed with DCM (15 mL), after which the product was finally eluted with DCM:MeOH:TEA (90:5:5), to give 84 mg (95%) of the title compound.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4]1=[O:21].C(=O)([O-])[O-].[K+].[K+].[C:28](#[N:31])[CH:29]=[CH2:30]>CS(C)=O>[NH2:2][C:3]1([CH2:30][CH2:29][C:28]#[N:31])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4]1=[O:21]
Reactant: C=CC#N
Reactant: COc1ccc2c(c1)C(N)C(=O)N2c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(N)(CCC#N)C(=O)N2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 60 g of 3-amino-1-(4-fluorophenyl)-2,3-dihydro-5-methoxy-1H-indol-2-one hydrochloride, 43 g of potassium carbonate, 20 ml of acrylonitrile and 200 ml of dimethyl sulfoxide was stirred at room temperature under argon atmosphere for 2 hours. 2 ml of acrylonitrile was added to the mixture, and stirring was continued overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. Precipitated crystals were collected by filtration to afford 46.8 g of 3-[3-amino-1-(4-fluorophenyl)-2,3-dihydro-5-methoxy-2-oxo-1H-indol-3-yl]propanenitrile. Melting point 136° to 138° C. EI-MS (m/z): 325 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27]([OH:29])=O)=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:30][C:31]1[CH:32]=[C:33]([S:37]([NH:40][CH2:41][CH3:42])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>>[CH2:41]([NH:40][S:37]([C:33]1[CH:32]=[C:31]([NH:30][C:27]([C:26]2[CH:25]=[N:24][N:17]3[C:18]([C:20]([F:22])([F:23])[F:21])=[CH:19][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:12])([F:11])[F:13])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:15][C:16]=23)=[O:29])[CH:36]=[CH:35][CH:34]=1)(=[O:39])=[O:38])[CH3:42]
Reactant: CCNS(=O)(=O)c1cccc(N)c1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.11) and 3-amino-N-ethyl-benzenesulfonamide [CAS 56445-08-0] according to general procedure II. Yellow solid. MS (ISP) 600.0 [(M−H)−]; mp 226° C.
Reaction SMILES: C(O[C@H:5]1[C@H:10]([N:11]2[CH2:15][CH2:14][N:13]([CH3:16])[C:12]2=[N:17][C:18]#[N:19])[C:9]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:8]=2[O:7][C:6]1([CH3:27])[CH3:26])(=O)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:18]([N:17]=[C:12]1[N:13]([CH3:16])[CH2:14][CH2:15][N:11]1[C:10]1[C:9]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:8]=2[O:7][C:6]([CH3:27])([CH3:26])[CH:5]=1)#[N:19]
Reactant: CC(=O)O[C@H]1[C@H](N2CCN(C)C2=NC#N)c2cc(C#N)ccc2OC1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CN1CCN(C2=CC(C)(C)Oc3ccc(C#N)cc32)C1=NC#N
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 71.7 %

Procedure:
To a suspension of trans-3-acetoxy-4-(2-cyanoimino-3-methylimidazolidin-1-yl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.45 g) in toluene (9 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 ml), and the reaction mixture was stirred at 100° C. for 2 hours and 40 minutes. The solvent was removed under reduced pressure. The residue was poured into water (30 ml) and then extracted with ethyl acetate (45 ml). The organic layer was washed with brine (30 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give 4-(2-cyanoimino-3-methylimidazolidin-1-yl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.27 g).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:12]3[C:13]([OH:18])=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)C>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:5]3[NH:1][N:2]=[N:3][N:4]=3)[CH:7]=2)[C:13]=1[OH:18])([O-:21])=[O:20]
Reactant: Oc1ccccc1-c1cccc(-c2nnn[nH]2)c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-c2cccc(-c3nnn[nH]3)c2)c1O
Reaction time: 8 h
Yield: 26.7 %

Procedure:
3′-(1H-Tetrazol-5-yl)-biphenyl-2-ol 8d (3.5 g, 14.7 mmol) was dissolved in 145 mL of ethanol under argon atmosphere. Fuming nitric acid (0.565 mL, 13.2 mmol) was added dropwise at 35° C. After the reaction mixture was reacted at room temperature for 1 hour, 150 mL of water was added. After standing overnight, the mixture was filtered. The filter cake was washed with 100 mL of water and dissolved in 500 mL of ethyl acetate and 250 mL of water. The separated organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixture was purified by silica gel column chromatography to obtain the title compound 3-nitro-3′-(1H-tetrazol-5-yl)-biphenyl-2-ol 8e (1 g, yield 27.0%) as a yellow solid.
Reaction SMILES: [CH:1]([C@H:4]1[O:9][CH2:8][C@H:7]([NH2:10])[CH2:6][O:5]1)([CH3:3])[CH3:2].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]2[CH:24]=[N:25][C:26]([OH:29])=[CH:27][CH:28]=2)=[CH:14][N:13]=1.C(N(CCCC)CCCC)CCC>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH:1]([C@H:4]1[O:9][CH2:8][C@H:7]([NH:10][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]3[CH:24]=[N:25][C:26]([OH:29])=[CH:27][CH:28]=3)=[CH:14][N:13]=2)[CH2:6][O:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1OC[C@H](N)CO1
Reactant: Oc1ccc(Cc2cnc(Cl)c3ccccc23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1OC[C@H](Nc2ncc(Cc3ccc(O)nc3)c3ccccc23)CO1

Procedure:
In a sealed glass bottle under N2-atmosphere, 424 mg (2.92 mmol) of trans 2-isopropyl-[1,3]dioxan-5-ylamine, 396 mg (1.46 mmol) of 1-chloro-4-[(6-hydroxy-pyridin-3-yl)methyl]-isoquinoline (contains 1-iodo derivative) and 2 ml of tributylamine are stirred at 150° C. for 48 h. The resulting mixture is diluted with EtOAc and NaHCO3-solution, the aqueous layer is separated and extracted twice with EtOAc. The organic phases are washed with brine, dried (Na2SO4) and concentrated in vaccuo. “Reversed Phase” medium-pressure chromatography (water/acetonitrile/TFA) yields trans 1-(2-isopropyl-[1,3]dioxan-5-ylamino)-4-[(6-hydroxy-pyridin-3-yl)methyl]-isoquinoline; FAB-MS; (M+H)+=286; HPLC(gradient20-100) tRet=8.6.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:36])=[C:5]([C:32]([O:34][CH3:35])=[O:33])[CH:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[N:9]=1.ClC1C=C(C=CC=1)C(OO)=[O:42]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH3:36])=[C:5]([C:32]([O:34][CH3:35])=[O:33])[CH:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:42])=[O:15])[N:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C1=C(C)NC(C)=C(c2nc(CS(=O)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(C)NC(C)=C(c2nc(CS(=O)(=O)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of 550 mg of methyl 1,4-dihydro-2,6-dimethyl-3-(3-benzylsulfinylmethyl-1,2,4-oxadiazol-5-yl)-4-(3-nitrophenyl)pyridine-5-carboxylate in 30 ml of chloroform was added 520 mg of m-chloroperoxybenzoic acid. After stirring at room temperature for 8 hours, the mixture was treated in the same manner as described in Example 117 to give 180 mg of methyl 1,4-dihydro-2,6-dimethyl-3-(3-benzylsulfonylmethyl-1,2,4-oxadiazol-5-yl)-4-(3-nitrophenyl)pyridine-5-carboxylate, m.p. 227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH2:25]([NH:32][C:33]([CH3:38])([CH3:37])[C:34]([NH2:36])=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:33]([CH3:37])([CH3:38])[C:34](=[O:35])[N:36]=[C:21]1[C:10]1[C:9]([CH3:24])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)(NCc1ccccc1)C(N)=O
Product: Cc1c(C2=NC(=O)C(C)(C)N2Cc2ccccc2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 13 was synthesized from 4a (250 mg, 0.66 mmol) and 5h (189 mg, 0.99 mmol) as a white solid (152 mg, 43%) in a manner similar to that described in Example 36. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 1H), 7.31 (d, 2H), 7.26 (m, 5H), 7.20 (dd, 1H), 7.04 (d, 2H), 7.01 (d, 1H), 5.29 (s, 2H), 2.45 (s, 3H), 1.31 (s, 6H); ESMS m/z: 537.1 (M+1).
Reaction SMILES: [OH-].[Na+].O.[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH2:14][C:15]3[C:20]([C:8]2=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.[CH3:21]I>C1C=CC=CC=1>[CH3:21][N:10]1[C:11]2[C:7](=[CH:6][C:5]([CH3:4])=[CH:13][CH:12]=2)[C:8]2[C:20]3[C:15]([CH2:14][C:9]1=2)=[CH:16][CH:17]=[CH:18][CH:19]=3
Reactant: Cc1ccc2[nH]c3c(c2c1)-c1ccccc1C3
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)c1c(n2C)Cc2ccccc2-1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
45 g of NaOH, 60 ml of water, 60 ml of benzene, 0.3 g of trimethyl-cethyl-ammonium bromide, 19.3(0.088 mol) of 2-methyl-5,6-dihydroindeno[2,1-b]indole, prepared in Example 8-bis, and 7.5 ml (0.12 mol) of CH3I were placed in a bulb. The resulting two-phase system was stirred for 2 hours at room temperature and then 10 minutes at reflux. Then the reaction mixture cooled to room temperature and filtered. The obtained precipitate was washed twice with ethanol and finally dried, thus obtaining 18 g of N-methyl-2-methyl-5,6-dihydroindeno[2,1-b]indole (yield=88%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[CH:26](/B(O)O)=[CH:27]\[CH3:28].CCO>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>[F:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:8]([C:7]1[C:2](/[CH:26]=[CH:27]/[CH3:28])=[N:3][C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:5][C:6]=1[CH3:19])=[O:9]
Reactant: C/C=C/B(O)O
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: C/C=C/c1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 110 °C
Yield: 72.7 %

Procedure:
To a solution of 400 mg (1.1 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide in toluene (15 ml) were added 140 mg (1.7 mmol) (E)-prop-1-enylboronic acid, 1.1 g (3.3 mmol) CsCO3 and EtOH (1.5 ml). After degassing with argon for 15 min 370 mg (0.32 mmol) Pd(PPh3)4 were added and the RM was heated to 110° C. for 5 h. Subsequently the RM was filtered through celite and the filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 300 mg (0.8 mmol, 74%) (E)-N-(3-fluorobenzyl)-4-methyl-6-morpholino-2-(prop-1-enyl)-pyridine-3-carboxylic acid amide (example 9). [M+H]+ 370.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26](=[O:27])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1)[CH3:29])([CH3:18])([CH3:19])[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccc(F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccc(F)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4-fluoro-N2-(5-fluoropyridin-2-yl)benzene-1,2-diamine (30 mg, 0.136 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (28 mg, 0.15 mmol), HOAt (20 mg, 0.15 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol) in DCM (5 mL) was stirred at 0° C. for 1 h. Additional (S)-2-tertbutoxycarbonylaminopropionic acid (5 mg), HOAt (4 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (5 mg) were added and stirring continued for 30 min. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was dried and concentrated in vacuo to afford {(S)-1-[4-fluoro-2-(5-fluoropyridin-2-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester as an orange oil. LCMS (Method C): RT 3.51 min [M+H]+ 393.1.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]=[O:18].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:20]([CH3:22])[CH3:21])[CH:12]=[C:11]2[CH:17]=[O:18]
Reactant: CC(C)I
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
Cesium carbonate (545 mg, 1.67 mmol) was added to a stirred room temperature of 5-bromo-1H-indole-3-carbaldehyde (125 mg, 0.56 mmol) in DMF (1.0 mL) and the mixture was stirred at room temperature for 15 minutes. Then 2-iodopropane (0.112 mL, 1.116 mmol) was added and the solution was stirred at 80° C. for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (2×20 mL) and saturated sodium bicarbonate (5 mL), washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (148 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[NH:24][C:23]=2[C:31]([NH2:33])=[O:32])=[CH:18][CH:17]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[NH:24][C:23]=2[C:31]([NH2:33])=[O:32])=[CH:20][CH:21]=1
Reactant: NC(=O)c1[nH]c2cccnc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: NC(=O)c1[nH]c2cccnc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
73 mg of 2-fluoro-5-trifluoromethylphenyl isocyanate are added to a solution of 80 mg of 3-(4-aminophenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in 18 ml of tetrahydrofuran. After stirring for 1 hour, the mixture is concentrated under reduced pressure and the residue is purified by chromatography on a silica column, elution being carried out with a mixture of cyclohexane and ethyl acetate (20/80 by volume) to give 110 mg of 3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrolo[3,2-b]pyridine-2-carboxamide, the characteristics of which are as follows: