Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[Cl:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:12]2[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)n1nc2c(c1-c1ccc(Cl)c(Cl)c1)CCNCC2
Yield: 39.5 %

Procedure:
The title compound (60 mg) was prepared according to Example 189 using 200 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 268 mg of 3,4-dichlorophenylboronic acid. MS (ESI): exact mass calculated for C16H19Cl2N3, 323.10; found, m/z 324.4 [M+H]+, 326.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.72-7.71 (m, 1H), 7.53-7.52 (m, 1H), 7.29-7.27 (m, 1H), 4.64 (br s, 2H), 4.32 (m, 1H), 3.86-3.57 (m, 2H), 3.31-3.08 (m, 2H), 2.84-2.75 (m, 2H), 1.39 (d, J=6.6 Hz, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1.B(Br)(Br)Br>ClCCl>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:11](=[O:15])[O:12][C:13]3[C:8]([CH:9]=2)=[CH:7][CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:14]=3)=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2cc3ccc(CCCO)cc3oc2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1oc2cc(CCCO)ccc2cc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (3.22 mmol) of 7-(3-hydroxypropyl)-3-(4-methoxyphenyl)chromen-2-one (see Ex. 3.1) is initially introduced in 30 ml of dichloromethane, and a solution of 0.4 ml (4.2 mmol) of boron tribromide in 10 ml of dichloromethane is added with ice-cooling. The cooling is removed, and the batch is stirred overnight at room temp. The solution is added to ice-water, acidified using 2 N hydrochloric acid and extracted three times with ethyl acetate. The combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is chromatographed on silica gel with toluene/ethyl acetate (1:1). After first runnings, 3-(4-hydroxyphenyl)-7-(3-hydroxypropyl)chromen-2-one is obtained as colourless solid in a second fraction (Rf=0.3).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[CH:14]=2)[NH:9][CH:8]=1.C(Cl)Cl.B(Br)(Br)Br>O>[S:18]1[CH:19]=[CH:20][C:16]([C:13]2[CH:14]=[C:15]3[C:7]([CH2:6][C:5]4[CH:4]=[C:3]([OH:2])[CH:23]=[CH:22][CH:21]=4)=[CH:8][NH:9][C:10]3=[N:11][CH:12]=2)=[CH:17]1
Reactant: COc1cccc(Cc2c[nH]c3ncc(-c4ccsc4)cc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(Cc2c[nH]c3ncc(-c4ccsc4)cc23)c1
Reaction time: 5 h
Yield: 26.2 %

Procedure:
Into a Round bottom flask was added compound 14 (20.0 mg, 0.0000624 mol) and Methylene chloride (4.0 mL, 0.062 mol) at room temperature. Into the reaction mixture, was added 0.1 mL BBr3 (1.0M in). The reaction mixture was allowed to room temperature for 5 hours. TLC indicated the reaction was not complete. The reaction mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with preparative TLC to give product 15 (5 mg).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH2:5][C:6]([NH:14][C:15](=[O:34])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]34[CH2:33][CH:28]5[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]5)[CH2:25]3)[CH2:31]4)=[CH:20][CH:19]=2)([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9]C)=[O:8].Cl>O1CCOCC1.O>[C:24]12([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:15]([NH:14][C:6]4([C:7]([OH:9])=[O:8])[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:35])=[O:2])[CH2:5]4)=[O:34])=[CH:19][CH:20]=3)[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2
Reactant: COC(=O)C1=CC=CC(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)(C(=O)OC)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)NC1(C(=O)O)C=CC=C(C(=O)O)C1
Yield: 105.3 %

Procedure:
A 3-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-isophthalic acid dimethyl ester (158.9 mg, 0.34 mmol) in 1,4-dioxane/H2O (1:1, 3.5 ml) was treated with LiOHH2O (56.2 mg, 1.34 mmol) at room temperature. The reaction mixture was then acidified with 10% HCl to PH 2, and then partitioned between ethyl acetate and brine. The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:MeOH=5:1) to give 3-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-isophthalic acid as a white solid (161.7 mg, 100% yield).
Reaction SMILES: [CH:1]12[CH2:7][CH:5]([O:6]1)[CH2:4][N:3]([C:8]1[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH:19]3[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]3)[CH:9]=1)[CH2:2]2.F[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:5]12[CH2:7][CH:1]([O:6]1)[CH2:2][N:3]([C:8]1[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH:19]3[CH2:20][CH2:21][CH:22]([NH:25][C:27]4[N:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][CH2:24]3)[CH:9]=1)[CH2:4]2
Reactant: NC1CCC(Oc2cc(N3CC4CC(C3)O4)cc3nccnc23)CC1
Reactant: Fc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: c1cnc(NC2CCC(Oc3cc(N4CC5CC(C4)O5)cc4nccnc34)CC2)nc1
Temperature: 150 °C
Yield: 51.5 %

Procedure:
A mixture of 4-[7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoxalin-5-yl]oxycyclohexanamine (190 mg, 0.5581 mmol), 2-fluoropyrimidine (60 mg, 0.6118 mmol) and DIEA (200 μL, 1.148 mmol) in 2-propanol (2 mL) was heated in a microwave reactor for 20 min at 150° C. The reaction mixture was concentrated, and then purified from 12 g silica gel cartridge with 0-6% MeOH/DCM to yield N-[4-[7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoxalin-5-yl]oxycyclohexyl]pyrimidin-2-amine (120.2 mg, 48.9%) as a yellow solid. Mass+1: 419.23; Retention Time: 0.72; NMR Annotation: 1H NMR (400 MHz, Chloroform-d) δ 8.42 (d, J=1.9 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 8.04 (d, J=4.8 Hz, 2H), 6.65-6.56 (m, 2H), 6.28 (t, J=4.8 Hz, 1H), 4.99 (d, J=8.1 Hz, 1H), 4.60 (d, J=6.5 Hz, 3H), 3.79 (dd, J=8.2, 4.0 Hz, 0H), 3.62-3.38 (m, 4H), 3.17-3.03 (m, 1H), 2.07-1.90 (m, 2H), 1.89-1.59 (m, 7H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([O:34][CH3:35])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[C:17]=23)=[CH:20][C:21]=1[O:34][CH3:35]
Reactant: CN1CCNCC1
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCN(C)CC4)c23)ccc1OCc1cccc(F)c1
Yield: 44 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and N-methylpiperazine to give the title compound in 44% yield; NMR Spectrum: 2.10 (s, 3H), 2.50 (s, 4H), 2.78 (t, 2H), 3.80 (s, 3H), 4.42 (t, 2H), 5.12 (s, 2H), 7.00 (d, 1H), 7.16 (m, 2H), 7.23 (m, 2H), 7.38 (d, 1H), 7.44 (q, 1H), 8.25 (s, 1H), 8.44 (s, 1H); Mass Spectrum: 508 (MH+).
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:11]([C@H:16]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:17][C:18](=[O:20])[CH3:19])[O:12][C:13](=[O:15])[CH3:14])[C:6](=[O:10])[CH:7]=[N+]=[N-])(=[O:3])[CH3:2].[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27]>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[C:26]([O:29][CH2:7][C:6]([C@@H:5]([C@H:11]([C@H:16]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:17][C:18](=[O:20])[CH3:19])[O:12][C:13](=[O:15])[CH3:14])[O:4][C:1](=[O:3])[CH3:2])=[O:10])(=[O:28])[CH3:27]
Reactant: CC(=O)OC[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C(=O)C=[N+]=[N-]
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](COC(C)=O)OC(C)=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 156.9 %

Procedure:
A solution of 10 grams of 1-deoxy-1-diazo-keto-L-fructose tetracetate and 0.01 gram of cupric acetate in 300 ml. of anhydrous acetic acid in a 2 liter flask was heated gently and after the initial violent evolution of gas had subsided, was brought just to the boiling point. The solvent was removed by distillation under reduced pressure, the final portion was removed by distillation with ethanol. The resulting syrup was dissolved in 15 ml. of ethanol, filtered and allowed to crystallize overnight in a refrigerator. This yielded 4 grams of crystals, m.p. 65° C. The syrup obtained from mother liquid was dissolved in 50 ml. of acetic anhydride containing 0.5 gram of zinc chloride (fresh fused), allowed to stand overnight at room temperature and heated 90 minutes at 50° C. Excess acetic anhydride was hydrolyzed by pouring into 200 ml. of ice-water and stirred for 2 hours. The acetylated sugar was extracted from the water with 200 ml. of chloroform. The chloroform solution was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to a syrup. This syrup was crystallized from 10 ml. of ethanol and yielded an additional 3 grams of product.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[C:21]1([CH:27]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:28]2[CH2:31][C:30](=O)[CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.COC(OC)OC>CO>[CH:27]([N:28]1[CH2:31][C:30](=[N:1][CH2:2][C@H:3]([OH:20])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:8][CH:7]=2)[CH2:29]1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: NC[C@H](O)COc1ccc(OCc2ccccc2)cc1
Solvent: COC(OC)OC
Solvent: CO
Product: O[C@@H](CN=C1CN(C(c2ccccc2)c2ccccc2)C1)COc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.6 %

Procedure:
A mixture of (2S)1-Amino-3-(4-benzyloxy-phenoxy)-propan-2-ol (1.64 g, 6 mmol) and 1-(diphenylmethyl)-3-azetidinone (1.19 g, 5 mmol) in methanol (20 ml) was treated with trimethylorthoformate (1.59 g, 15 mmol), and stirred at room temperature for 2 days. The resulting suspension was filtered, and the precipitate washed with 3×5 ml of methanol, and dried in vacuo to give 1.96 g of a white solid. The methanol filtrate was evaporated, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was filtered through a pad of silica gel, and eluted with 2×30 ml of ethyl acetate. The combined filtrate was evaporated, and the residue triturated with a mixture of ether and hexanes to give an additional 0.30 g of product; m.p. 141-142° C.; MS (ES) m/z 748 (MH+); HRMS (El) Calcd. for C32H32N2O3 (M+): 492.2413, Found: 492.2397.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:27]#[C:26][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)=[CH:35][CH:34]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=Cc1ccc(C#Cc2ccc(F)cc2)cc1
Reactant: CCCCCCNc1ccc(F)c(C(=O)OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(F)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Temperature: 50 °C
Yield: 32 %

Procedure:
To a solution of methyl 2-fluoro-5-(hexylamino)benzoate (270 mg; 1.07 mmol) and 4-[(4-fluorophenyl)ethynyl]benzaldehyde (358 mg; 1.60 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) in anhydrous DCE (15 mL) was added sodium triacetoxyborohydride (678 mg; 3.20 mmol) at rt. The reaction mixture was then heated at 50° C. for 14 h. It was then poured into a solution of saturated NaHCO3 and extracted twice with DCM. The combined organic phases were then washed with brine, dried over MgSO4, filtrated and concentrated. The crude brown oil (652 mg) was purified by preparative HPLC using a X-Terra column to give 158 mg (32%) of the title compound as a beige powder. HPLC, Rt: 6.01 min (purity: 96.5%), LC/MS, M+(ESI): 462.2, 1H NMR: (CDCl3) δ: 7.46 (m, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.37 (m, 1H), 7.13 (d, J=7.9 Hz, 2H), 6.94-7.05 (m, 4H), 4.52 (s, 2H), 3.90 (s, 3H), 3.42 (t, J=7.7 Hz, 2H), 1.56 (m, 2H), 1.26 (m, 6H), 0.85 (t, J=6.6 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:9](=[O:22])[CH2:8][CH2:7]2)([O-])=O.O.NN>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)[C:9](=[O:22])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCCC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCC1
Temperature: 25 °C

Procedure:
6-nitro-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (89 mg, 0.293 mmol) in dry methanol (5 mL) was treated with Ra—Ni (˜0.05 g) followed by hydrazine hydrate (92 uL, 2.95 mmol) at room temperature and the resulting mixture was refluxed for 30 minutes. The reaction was cooled to room temperature, filtered through a celite bed, washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5:97.5). Yield: 58 mg of yellow oil (73%). 1H NMR (CDCl3) δ: 6.86 (d, J=8.4 Hz, 1H), 6.55 (dd, J=2.7, 8.4 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 3.94 (m, 2H), 2.81-2.76 (m, 2H), 2.61-2.56 (m, 2H), 2.53-2.49 (m, 6H), 1.87-1.82 (m, 2H), 1.79-1.75 (m, 4H). MS (ESI): 274.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.ClCCl>[F:10][C:11]1[CH:12]=[C:13]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([NH:21][C:2]2[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=2)[CH2:19][CH2:20]1
Reactant: N#Cc1ccc(Cl)nn1
Reactant: NC1CCN(Cc2cc(F)cc(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCN(Cc3cc(F)cc(F)c3)CC2)nn1
Temperature: 120 °C
Reaction time: 0.67 h
Yield: 60.4 %

Procedure:
A mixture of 6-chloro-pyridazine-3-carbonitrile (D4) (1.74 g, 12.46 mmol), 1-(3,5-difluoro-benzyl)-piperidin-4-ylamine (D5) (2.35 g, 10.386 mmol) and diisopropylethylamine (2.71 ml, 15.58 mmol) in acetonitrile (30 ml) was stirred at 120° C. for 40 min., under microwave irradiation (Milestone MW-oven). Dichloromethane, water and a saturated solution of sodium carbonate were then added. The organic layers were filtered over cotton, evaporated in vacuo and the residue was purified by column chromatography (silica gel; 0-1.5% ammonia in methanol (7 M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The residue was precipitated in heptane to yield E15 (2.065 g, 60%) as a solid. C17H17F2N5 requires 329. Found 330 (MH+); mp: 187.9° C.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1([C:11]([N:13]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:16][CH:15]([C:29](O)=[O:30])[CH2:14]2)=[O:12])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[NH2:39][CH2:40][C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:42]>ClCCl.O>[N:5]1([C:11]([N:13]2[CH2:18][CH:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=3)[CH2:16][CH:15]([C:29]([NH:39][CH2:40][C:41](=[O:42])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:30])[CH2:14]2)=[O:12])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: NCC(=O)c1ccccc1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(CNC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1)c1ccccc1

Procedure:
97 mg (0.57 mmol) of thionyl chloride were added to a solution of 200 mg (0.52 mmol) of the compound from Example 49A in 1 ml of dichloromethane. The mixture was stirred under reflux for 1 h. For work-up, the dichloromethane was removed under reduced pressure, and once more dichloromethane was added to the residue and the mixture was concentrated. The residue was initially charged in 5 ml of dichloromethane, and 78 mg (0.78 mmol) of triethylamine and 97 mg (0.57 mmol) of 2-amino-1-phenylethanone were then added. The reaction mixture was stirred at room temperature for 3 h. For work-up, water was added to the mixture, and the organic phase was separated off and washed repeatedly with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate and evaporated to dryness under reduced pressure. Yield: 300 mg (62% of theory, 70% pure)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1c[nH]c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1c[nH]c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-hydroxy-1H-indole-3-carboxylic acid (1.05 g) in N,N-dimethylformamide (11.0 mL) were added sodium carbonate (722 mg) and benzyl bromide (0.775 mL), followed by stirring at room temperature overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain benzyl 6-hydroxy-1H-indole-3-carboxylate (1.04 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:33](=[O:37])[CH2:32]2)=[CH:38][CH:39]=1
Reactant: O=C1CN(CCc2ccc(F)cc2)CCN1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 76.1 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (514 mg, 1.356 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (301 mg, 1.356 mmol) were reacted following the procedure for Example 53 (step b) to provide the title compound (537 mg, 76%) as a white solid: ESI MS m/z 521 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[N:24]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:25]=[O:26]>ClCCl>[C:30]1([CH2:29][CH2:28][CH2:27][NH:24][C:25]([N:13]2[CH2:12][C:11]3([N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][CH2:10]3)[CH2:14]2)=[O:26])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=NCCCc1ccccc1
Reactant: c1ccc(CN2CCC23CNC3)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCc1ccccc1)N1CC2(CCN2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
To a solution of 1-benzyl-1,6-diaza-spiro[3.3]heptane (41 mg, 217 μmol) in dichloromethane (2 mL) was added diisopropyl-ethyl-amine (112 mg, 868 μmol)) followed by (3-isocyanato-propyl)-benzene (84 mg, 521 μmol) and the reaction mixture was allowed to stir at ambient temperature for 16 h. After complete consumption of starting material the reaction mixture was diluted with dichloromethane and was washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. Purification by HPLC afforded the title compound (9 mg, 12%) as an off-white solid. MS m/e: 350 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=O.O.[NH2:13][NH2:14]>C(O)CCC>[NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([NH:13][NH2:14])=[O:10]
Reactant: NN
Reactant: COC(=O)c1scc(C)c1N
Solvent: O
Solvent: CCCCO
Product: Cc1csc(C(=O)NN)c1N

Procedure:
A solution of methyl 3-amino-4-methyl-2-thenoate (25 g) and hydrazine hydrate (20 ml) in butanol (150 ml) was heated under reflux for 18 hours. On cooling the solvent was removed and the residue was recrystallised from toluene to give the title product, m.p. 141-143° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH2:36][C@@H:37]([NH2:39])[CH3:38])[CH:35]=1.CCN(C(C)C)C(C)C>CCO>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH2:36][C@@H:37]([NH:39][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:10][C:11]3[C:12]([N:28]=2)=[CH:13][C:14]2[CH2:15][N:16]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[C:17](=[O:20])[C:18]=2[CH:19]=3)[CH3:38])[CH:35]=1
Reactant: O=C1c2cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc3cc2CN1CCN1CCCC1
Reactant: Cc1ccc(Cl)cc1C[C@H](C)N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)cc1C[C@H](C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN1CCCC1)C3
Yield: 59.7 %

Procedure:
A solution of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (50 mg, 0.126 mmol), (1S)-2-(5-chloro-2-methylphenyl)-1-methylethylamine (30 mg, 0.164 mmol) and DIEA (66 uL, 0.38 mmol) in 2 mL of EtOH was heated at 80° C. for 24 h. Then the solvent was evaporated and the residue was purified by column (silicagel, DCM:MeOH 95:5) to give 2-(4-((1S)-2-(5-cloro-2-methylphenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (41 mg, 59%) as yellow solid. ESI-MS: m/z (MH+) 545.5. 1H NMR (300 MHz, CDCl3): δ 7.96 (d, J=44.8 Hz, 1H), 7.51 (d, J=66.3 Hz, 1H), 7.20 (m, 2H), 7.03 (m, 2H), 5.86 (m, 1H), 4.59 (m, 2H), 3.93 (m, 3H), 2.96-3.13 (m, 8H), 2.32 (s, 3H), 1.91 (m, 4H), 1.38 (d, J=7.35 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:4]2[CH2:3]1.Cl.O1CCOCC1>ClCCl>[CH2:13]1[N:5]2[C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][C:2](=[O:1])[CH2:3][CH:4]2[CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1CC2CNCCN2c2ccccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 1C (1.78 g, 5.61 mmol) in dichloromethane (100 mL) was added 4 M HCl/dioxane (14.02 mL, 56.1 mmol). The solution was stirred for 2-4 hours at room temperature, and title compound was collected by filtration as the hydrochloric acid salt. 1H NMR (500 MHz, pyridine-d5) δ ppm 7.34-7.42 (m, 1 H), 7.24-7.31 (m, 1 H), 7.16-7.23 (m, 1 H), 7.11 (d, J=7.02 Hz, 1 H), 3.92-4.00 (m, 1 H), 3.88 (d, J=11.90 Hz, 1 H), 3.80 (d, J=12.82 Hz, 1 H), 3.64-3.74 (m, 1 H), 3.57 (t, J=11.90 Hz, 1 H), 3.11-3.24 (m, 2 H), 2.64 (dd, J=13.43, 7.02 Hz, 1 H), 2.37 (d, J=12.82 Hz, 1 H); MS (ESI) m/z 217.9 (M+H)+.