Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:19]([C:20]2[NH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)=[CH:23][N:24]=2)[CH2:18][C:13]2(OCC[O:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:12][C:13](=[O:14])[CH2:18][CH:19]1[C:20]1[NH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=2)=[CH:23][N:24]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CC2(CC1c1ncc(-c3ccc(Br)cc3)[nH]1)OCCO2)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)NC(C(=O)N1CC(=O)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 60 °C
Reaction time: 72 h
Yield: 44.6 %

Procedure:
(1-{8-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-1,4-dioxa-7-aza-spiro[4.4]nonane-7-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (230.0 mg, 0.453 mmol) was dissolved in acetone (10 mL) and water (0.2 mL) and p-TsO.H2O (53 mg, 0.278 mmol) were added. The reaction was heated at 60° C. for 20 hours, after which additional p-TsOH.H2O (53 mg, 0.278 mmol) was added heating at 60° C. was continued. After three days, all volatiles were removed in vacuo. The crude material was taken into EtOAc and was washed with aqueous sodium bicarbonate solution and dried over sodium sulfate. Filtration and evaporation of solvents in vacuo gives the crude product. The crude material was purified via silica gel chromatography (eluent: EtOAc containing 10% MeOH/hexanes) to yield the product (93.9 mg, 0.202 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:16][C:17]1[N:18]=[CH:19][C:20]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]3[CH:29]=[C:30]([NH:34]C(=O)OC(C)(C)C)[CH:31]=[CH:32][CH:33]=3)[C:21]=2[N:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C:30]1[CH:29]=[C:28]([N:23]2[C:21]3[N:22]=[C:17]([NH:16][C:4]4[CH:5]=[CH:6][C:7]([N:9]5[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]5)=[CH:8][C:3]=4[O:2][CH3:1])[N:18]=[CH:19][C:20]=3[CH:26]=[CH:25][C:24]2=[O:27])[CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
The crude 1a from above was treated with DCM (20 mL) and TFA (20 mL) and stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure (rotary evaporator) and purified on a silica gel column (1-20% 2M NH3/MeOH in DCM) affording 8-(3-aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b) (470 mg, 1.03 mmol, 79% yield) as a brown amorphous solid. m/z (ESI, +ve ion) 458.0 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.67 (1H, s), 7.88 (1H, d, J=9.4 Hz), 7.63 (1H, d, J=8.2 Hz), 7.32 (1H, t, J=8.0 Hz), 6.91 (1H, dd, J=8.1, 1.5 Hz), 6.59-6.65 (2H, m), 6.53-6.59 (1H, m), 6.46-6.52 (1H, m), 6.24 (1H, br. s.), 3.88 (3H, s), 3.21 (4H, br. s.), 2.84 (4H, br. s.), 2.53 (3H, s).
Reaction SMILES: [BrH:1].[CH2:2]([C:4]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:5]=1N)[CH3:3].[Br-].[Na+].N(OCCC(C)C)=O>ClC1C=CC=CC=1Cl>[Br:1][C:5]1[C:4]([CH2:2][CH3:3])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=1[CH2:12][CH3:13]
Reactant: Br
Reactant: CCc1cc(C)cc(CC)c1N
Agent: CC(C)CCON=O
Agent: [Br-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: CCc1cc(C)cc(CC)c1Br
Temperature: 50 °C

Procedure:
Gaseous hydrogen bromide (1.05 equiv.) is fed into a mixture of 2,6-diethyl-4-methylaniline (1.00 equiv.) and sodium bromide (0.10 equiv.) in o-dichlorobenzene. The resulting salt suspension is cooled to 50° C. Isoamyl nitrite (1.05 equiv.) and additional gaseous hydrogen bromide (0.3 equiv.) are fed subsurface simultaneously at 50-55° C. over a 2-hour period to afford 1-bromo-2,6-diethyl-4-methylbenzene as a yellow to light brown solution. The reaction mass is neutralized with 25% caustic solution (ca. 0.3 equiv.). The bottom aqueous phase is separated off. Isoamyl alcohol and o-dichlorobenzene are sequentially stripped off to produce the crude 2,6-diethyl-4-methylbromobenzene material with an assay of 90% and an isolated yield of 87-90%. The product can be further purified by vacuum distillation at 95° C./5 mmHg to give an assay of 97-99%.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH:20]=[CH:21][CH2:22]Br>>[C:1]1([N:7]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:19][CH:20]=[CH:21][CH2:22][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Reactant: BrCC=CCBr
Product: C(=CCN(c1ccccc1)c1cccc2ccccc12)CN(c1ccccc1)c1cccc2ccccc12
Temperature: 70 °C
Yield: 17.5 %

Procedure:
A mixture of N-phenyl-1-naphthylamine (63 g, 0.29 mol) and 1.4-dibromobut-2-ene (12 g, 0.056 mol) is heated to 70° C. for three days. The resulting reaction mass is allowed to cool and is then extracted with 3×100 ml of hot hexane. The combined hexane extracts are concentrated in vacuo to an oil which is chromatographed (silica gel. 95/5 cyclohexane/diethyl ether) to give an oil. Said oil is then crystallized from ether to give 4.8 g (17.5% yield) of the title compound as a tan solid melting at 140°-142° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15]C)=[O:14])=[N:5]1)(=O)C.[OH-].[Na+].O>Cl>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[N:5]1
Reactant: COC(=O)c1nn(C(C)=O)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1n[nH]c2ccccc12
Temperature: 65 °C
Reaction time: 6.5 h
Yield: 108.5 %

Procedure:
To methyl 1-acetylindazole-3-carboxylate (22.3 g, 0.10 mol) were added sodium hydroxide (8.18 g, 0.20 mol) and water (640 ml) and the resulting mixture was stirred at 60 to 70° C. for 6.5 hours. The reaction mixture was poured in concentrated HCl (30 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give indazole-3-carboxylic acid (17.6 g, 100%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[CH2:1]([NH:8][C:9]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(NC(=O)NCc3ccccc3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 35 °C

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to 35° C. for 16 hours, benzyl isocyanate was reacted with 4-amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline to give the title compound; NMR Spectrum: (DMSOd6): 1.3-1.5 (m, 2H), 1.8-1.9 (m, 4H), 1.95 (t, 1H), 2.2 (s, 3H), 2.8 (br d, 2H), 3.9 (br s, 3H), 4.0 (br d, 2H), 4.5 (br d, 2H), 7.2-7.3 (m, 2H), 7.3-7.4 (m, 4H), 8.0 (br s, 1H), 8.55 (br s, 1H), 10.2-10.5 (br s, 1H), 10.4 (t, 1H); Mass Spectrum: M+H+ 436.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:8][C:9]([F:13])([F:12])[CH:10]=[CH2:11]>C1(C)C=CC=CC=1>[CH3:7][O:6][C:4](=[O:5])[CH2:3][CH2:2][S:1][CH2:11][CH2:10][C:9]([F:13])([F:12])[F:8]
Reactant: COC(=O)CCS
Reactant: C=CC(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)CCSCCC(F)(F)F
Temperature: 20 °C
Yield: 94 %

Procedure:
A 100 mL stainless steel Parr reactor was charged with methyl 3-mercaptopropionate (4.15 g, 34.5 mmol), toluene (30.3 g), and 2,2′-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70, 0.531 g, 1.72 mmol) and the reactor was cooled with a dry ice/acetone bath, purged with nitrogen, and pressure checked. 3,3,3-Trifluoropropene (3.40 g, 35.4 mmol) was added via transfer cylinder and the reaction was allowed to warm to 20° C. After 23 hours the reaction was heated to 50° C. for 1 hour to decompose any remaining V-70 initiator. The reaction was allowed to cool to room temperature. The solution was concentrated to provide the title compound (7.01 g, 66%, 70.3 wt % linear isomer by GC internal standard assay, 4.93 g active, 66%, 24:1 linear:branched by GC, 18:1 linear:branched by fluorine NMR).
Reaction SMILES: Br[CH2:2][C:3]1[NH:4][C:5](=[O:18])[NH:6][C:7]=1[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[ClH:19].Cl.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[ClH:19].[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:7]2[NH:6][C:5](=[O:18])[NH:4][C:3]=2[CH2:2][N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:29][CH2:30]2)=[O:17])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CBr)cc1
Reactant: Cc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CN2CCN(c3ccccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 6.2 g of 4-(bromomethyl)-1,3-dihydro-5-(4-methoxybenzoyl)-2H-imidazol-2-one, 5.0 g of 1-(2-methylphenyl)piperazine dihydrochloride and 5.4 g of potassium carbonate in 100 ml of ethanol is stirred at room temperature for 24 hours. Water is added to the reaction mixture and the precipitate which forms is separated by filtration. The solid is then suspended in 2-propanol, 1 equivalent of hydrochloric acid is added, and the resulting solid is separated and recrystallized from 2-propanol/water to give 1,3-dihydro-4-(4-methoxybenzoyl)-5-[[4-(2-methylphenyl)-1-piperazinyl]methyl]-2H-imidazol-2-one hydrochloride melting at about 223°-225° C. with decomposition.
Reaction SMILES: [OH-].[Li+].[CH2:3]1[CH:14]2[CH:6]([NH:7][C:8]3[C:9]([C:15]([NH:17][C@@H:18]([CH3:24])[C:19]([O:21]CC)=[O:20])=[O:16])=[CH:10][CH:11]=[CH:12][C:13]=32)[CH2:5][CH2:4]1>C1COCC1>[CH2:3]1[CH:14]2[CH:6]([NH:7][C:8]3[C:9]([C:15]([NH:17][C@@H:18]([CH3:24])[C:19]([OH:21])=[O:20])=[O:16])=[CH:10][CH:11]=[CH:12][C:13]=32)[CH2:5][CH2:4]1
Reactant: CCOC(=O)[C@H](C)NC(=O)c1cccc2c1NC1CCCC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1cccc2c1NC1CCCC21)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A 1 M aqueous lithium hydroxide solution (13 mmol, 13 mL) was added to a solution of ethyl (2S)-2-[(1,2,3,3a,4,8b-hexahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoate (6.1 mmol, 1.9 g) in THF (50 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction was concentrated in vacuo and diluted with 0.1 N HCl and ethyl acetate. The phases were separated and the organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a yellow oil (1.6 g, 6.1 mmol, quantitative yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[NH2:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][C:47]([C:49]([N:51]3[CH2:57][C:56]4([CH3:59])[CH2:58][CH:52]3[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55]4)=[O:50])=[CH:48][C:43]=2[N:42]=[CH:41]1>C1COCC1>[CH3:59][C:56]12[CH2:58][CH:52]([N:51]([C:49]([C:47]3[CH:46]=[CH:45][C:44]4[N:40]([CH2:39][CH2:38][NH:37][C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)=[O:8])[CH:41]=[N:42][C:43]=4[CH:48]=3)=[O:50])[CH2:57]1)[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55]2
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc3c(c2)ncn3CCN)C1
Reactant: O=C(O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc3c(c2)ncn3CCNC(=O)c2ccco2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 2-furoic acid (37 mg, 0.33 mmol) in dry THF (2 mL) at room temperature under an inert atmosphere of nitrogen were added HOBt (49 mg, 0.36 mmol) and EDAC (82 mg, 0.43 mmol), and the resulting solution was stirred for 30 min. [1-(2-Aminoethyl)-1H-benzoimidazol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone trifluoroacetate (150 mg, 0.33 mmol) was added to the solution followed by TEA (0.184 mL, 1.32 mmol), and the reaction mixture was stirred for 16 h at room temperature. The volatiles were evaporated in vacuo and the resulting solid was purified by preparative HPLC, dried in vacuo at 50° C. affording 100 mg (70%) of the title compound as a solid. MS-ESI m/z 435; 1H NMR (400 MHz, DMSO-d6) δ 0.88-0.99 (m, 6H), 1.07 (d, 3H), 1.29-1.41 (m, 4H), 1.50-1.52 (m) and 2.10-2.11 (m, 1H), 1.76-1.79 (m, 1H), 3.02 (d), 3.13 (d), 3.32 (d) and 3.47 (d, 2H), 3.69 (t, 2H), 3.87-3.89 (m) and 4.39-4.41 (m, 1H), 4.56 (t, 2H), 6.58 (s, 1H), 6.98 (d, 1H), 7.48 (dd, 1H), 7.77-7.82 (m, 2H), 7.89 (t, 1H), 8.54-8.58 (m, 1H), 9.07 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.S(Cl)([Cl:30])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH2:16][Cl:30])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(CCl)c(C)c23)cc1
Temperature: 0 °C
Yield: 59.5 %

Procedure:
To a cold (ice bath) solution of acetic acid 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (4.00 g, 9.4 mmol) in anhydrous methylene chloride (41 mL) was added sulfuryl chloride (0.76 mL, 10.3 mmol) dropwise over a period of 10 minutes. After stirring 1 hour in the ice bath the reaction was quenched with water (100 mL) and diluted with diethyl ether. After filtering, the layers were separated. Silica gel was added to the organic layer and the solvents were removed. The adsorbate was flash chromatographed (gradient 90/10-80/20 petroleum ether/ethyl acetate) to give the title compound as a white solid (2.57 g, 59%): NMR (DMSO-d6); δ 8.23 (d, J=8 Hz, 1H), 7.71 (dd, J=8,1 Hz, 1H), 7.55-7.43 (m, 4H), 7.33-7.30 (m, 2H), 5.09 (s, 2H), 2.34 (s, 3H), 1.66 (s, 3H).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccccn3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[CH:16]=2)=[N:6]1.Cl[C:19]1[CH:20]=[CH:21][N:22]=[C:23]2[C:28]=1[N:27]=[CH:26][C:25]([O:29][CH3:30])=[CH:24]2>CC(O)C>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([N:2]([CH3:1])[CH2:3][CH2:4][N:5]3[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]4[S:13][CH:14]=[C:15]([CH3:17])[CH:16]=4)=[N:6]3)=[CH:20][CH:21]=[N:22]2)=[N:27][CH:26]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: CNCCn1nc(-c2cc(C)cs2)ccc1=O
Solvent: CC(C)O
Product: COc1cnc2c(N(C)CCn3nc(-c4cc(C)cs4)ccc3=O)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of 2-(2-(methylamino)ethyl)-6-(4-methylthiophen-2-yl)pyridazin-3(2H)-one (275 mg, 1103 μmol) and 8-chloro-3-methoxy-1,5-naphthyridine (193 mg, 993 μmol) in iPrOH (5 mL) was heated to 100° C. for 18 h in an appropriately sealed vial. The mixture was partitioned between CH2Cl2 (30 mL) and 1M NaOH (10 mL), and the organic dried over MgSO4. After concentration under reduced pressure, the organic residue was dissolved in iPrOH (2 mL) and the resulting crystallized solid was washed with iPrOH (2×0.5 mL) then dried under reduced pressure. MS (ESI pos. ion) m/z (MH+): 408. Calc'd exact mass for C21H21N5O2S: 407. 1H NMR (400 MHz, Chloroform-d) δ ppm 2.26 (s, 3 H) 3.22 (s, 3 H) 3.83 (s, 3 H) 4.51 (t, J=5.77 Hz, 2 H) 4.75 (t, J=5.77 Hz, 2 H) 6.55 (d, J=5.52 Hz, 1H) 6.60 (d, J=9.54 Hz, 1 H) 6.91 (s, 1 H) 6.97 (s, 1 H) 7.19 (d, J=9.54 Hz, 1 H) 7.32 (d, J=3.01 Hz, 1 H) 8.32 (d, J=5.52 Hz, 1 H) 8.46 (d, J=2.51 Hz, 1 H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cccnc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (60 mg, 77%), MS (ISP) m/z=312.5 [(M+H)+], mp 252.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available pyridin-3-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3]1)=[CH:11][CH:10]=[CH:9][C:8]=3[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl>[Cl:30][CH2:31][C:32]([N:13]([C:8]1[C:7]2[NH:6][C:5]3[CH2:21][CH2:22][N:2]([CH3:1])[CH2:3][C:4]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:33]
Reactant: O=C(Cl)CCl
Reactant: CN1CCc2[nH]c3c(NCc4ccncc4)cccc3c2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCc2[nH]c3c(N(Cc4ccncc4)C(=O)CCl)cccc3c2C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 189.5 %

Procedure:
2,3,4,5-Tetrahydro-2-methyl-N-((pyridin-4-yl)methyl)-1H-pyrido[4,3-b]indol-6-amine (0.15 g, 0.515 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. Triethylamine (0.145 mL, 1.03 mmol) was added dropwise with constant stirring. 2-Chloroacetylchloride (0.04 mL, 0.515 mmol) was added dropwise at the same temperature and, after addition, allowed to come to RT. The reaction mass was stirred at RT for 20 min. Ice water (3 mL) was then added and the mixture extracted with DCM. The organic layer was washed with saturated bicarbonate solution (3 mL) to obtain 2-chloro-N-(2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-6-yl)-N-((pyridin-4-yl)methyl)acetamide (360 mg). The product (360 mg, 0.978 mmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (46 mg, 1.173 mmol) was added and the reaction mixture was stirred at RT for 20 min. MeOH (2 mL) was added and concentrated under reduced pressure. The product was purified through reverse phase chromatography. Yield: 10.7 mg as freebase. 1H NMR (CD3OD, freebase) d (ppm): 8.45 (d, 2H), 7.40 (d, 2H), 7.10 (d, 1H), 6.90 (t, 1H), 6.56 (d, 1H), 5.30 (s, 2H), 5.06 (s, 2H), 4.0 (s, 2H), 3.20 (t, 2H), 3.0 (t, 2H), 2.76 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH:23]=[CH:24]B(O)O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13](/[CH:24]=[CH:23]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C=CC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(/C=C/C2CCCCC2)nc1
Temperature: 90 °C
Yield: 70.2 %

Procedure:
Combine 3-(tert-butoxycarbonylamino-methyl)-6-chloropyridine (1.42 g, 5.85 mmol), 2-cyclohexylvinyl boronic acid (1.35 g, 8.78 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with DCM (239 mg, 0.293 mmol), and 2M aqueous Na2CO3 (9.65 mL, 19.2 mmol) in 1,4-dioxane (60 mL). Purge the resulting solution with nitrogen for 5 min and heat at 90° C. overnight. Cool the reaction mixture to room temperature and partition the mixture between EtOAc and water. Separate the aqueous phase and extract twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (120 g, pre-packed cartridge) eluting stepwise with hexane/EtOAc (1:0 over 5 min, 49:1 over 5 min, 19:1 over 5 min, 9:1 over 5 min and 85:15 over 5 min; 50 mL/min) to obtain the desired intermediate (1.3 g, 70%). MS (APCI+) m/z: 317 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:27]=[CH:26][C:20]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:19][CH:18]=1>>[C:1]([C:5]1[C:6]([NH:14][C:23](=[O:24])[CH2:22][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:28])([F:29])[F:15])=[CH:27][CH:26]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Product: CC(C)(C)c1c(NC(=O)CCc2ccc(C(F)(F)F)cc2)nn2cccnc12

Procedure:
The product from Example 105B and 4-(trifluoromethyl)hydrocinnamic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.36 (s, 9H), 2.61-2.73 (m, 2H), 3.00 (t, J=7.5 Hz, 2H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 7.78-7.51 (m, 2H), 7.63-7.66 (m, 2H), 8.48 (dd, J=4.1, 1.7 Hz, 1H), 8.91 (dd, J=7.1, 1.7 Hz, 1H), 9.75 (s, 1H); MS (DCI) m/z 391 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[CH:9][C:10]=1[Br:11])[CH:2]=[CH2:3].[C:13]([O-:16])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[Br:11])[O:12][C:5]1[CH:6]=[CH:7][C:8]([CH:13]=[O:16])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1cc(O)ccc1Br
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOc1cc(Oc2ccc(C=O)cc2)ccc1Br
Temperature: 100 °C
Yield: 166.3 %

Procedure:
4-Flurorbenzaldehyde (1.15 mL, 10.76 mmoles) was added to a solution of the product from Example 63B (1.76 g, 7.69 mmoles) and K2CO3 (3.19 g, 23.1 mmoles) in DMF (7.7 mL). The reaction mixture was heated to 100° C. for 14 h and was cooled to room temperature The crude products were diluted with diethyl ether, extracted with sat. NH4Cl, extracted with H2O (2×), rinsed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on a prepacked Biotage colum (hexane to 4:1 hexane:ethyl acetate) on silica gel to provide the title compound (2.13 g, 83%) as a white solid.