Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[N:9]2[CH:10]=[N:11][C:12]3[CH:13]([CH2:17][C:18]([OH:20])=O)[C:14](=[O:16])[CH:15]=[C:7]([C:8]=32)[NH:6][CH2:5][CH2:4][C:3]1=[O:21].[NH2:22][C:23]1[N:28]=[CH:27][C:26]2[CH2:29][C:30]3([CH2:40][C:25]=2[CH:24]=1)[C:38]1[C:33](=[N:34][CH:35]=[CH:36][CH:37]=1)[NH:32][C:31]3=[O:39].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:1][CH:2]1[N:9]2[CH:10]=[N:11][C:12]3[CH:13]([CH2:17][C:18]([NH:22][C:23]4[N:28]=[CH:27][C:26]5[CH2:29][C:30]6([CH2:40][C:25]=5[CH:24]=4)[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:32][C:31]6=[O:39])=[O:20])[C:14](=[O:16])[CH:15]=[C:7]([C:8]=32)[NH:6][CH2:5][CH2:4][C:3]1=[O:21]
Reactant: CC1C(=O)CCNC2=CC(=O)C(CC(=O)O)c3ncn1c32
Reactant: Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1C(=O)CCNC2=CC(=O)C(CC(=O)Nc3cc4c(cn3)CC3(C4)C(=O)Nc4ncccc43)c3ncn1c32
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (8-methyl-2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetic acid (66 mg, 0.23 mmol, described in Intermediate 14), (±)-3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in intermediate 3), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH3:10])=[CH:4][N:3]=1.[C:20]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1)#[N:21].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:28]([C:24]3[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=3)[C:20]#[N:21])[C:29](=[O:30])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:9]([CH3:10])[C:5]2=[CH:4][N:3]=1
Reactant: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)cc1
Reactant: N#Cc1cccc(N=C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Cl)ncc3C2C)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a solution of (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-(4-methoxy-phenyl)-amine (0.10 g; 0.34 mmol) (from Example 1d supra) in toluene (1 mL) was added 3-cyanophenyl isocyanate (66.6 mg; 0.46 mmol) (Aldrich). The mixture was heated in an oil bath at 110° C. for two hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was triturated with hexanes and dried briefly. The solid residue (intermediate urea) was taken up in freshly distilled tetrahydrofuran (1.5 mL), cooled in an ice-brine bath and treated with potassium tert-butoxide (1.0 M in tetrahydrofuran; 370 μL; 0.37 mmol) (Aldrich). After 15 minutes in the cold the reaction was complete by TLC analysis and was filtered through a silica gel pad (0.5 g) and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography (Biotage, 12M, 40:60 ethyl acetate-hexanes) to give (±)-3-[7-chloro-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile as a solid. (Yield 0.13 g; 85.6%).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:17]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:20][C:9]1=2)(=O)=O.[CH2:31]([CH2:33][NH2:34])[OH:32]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[OH:32][CH2:31][CH2:33][NH:34][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:17]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:18][C:19]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[N:20][C:9]1=2
Reactant: CS(=O)(=O)OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCCNCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21

Procedure:
A mixture of 9-(2-methanesulfonyloxyethyl)-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (IX, EXAMPLE 4, 1.3 g) and 15 ml of ethanolamine is heated to reflux for 4 hr, then cooled, and diluted with methylene chloride (100 mL) and aqueous saturated sodium bicarbonate. The phases are separated, and the aqueous phase is extracted again with methylene chloride/chloroform (1/1). The combined extracts are dried over sodium sulfate and concentrate under reduced pressure at 50°-60° to give a solid. The solid is recrystallized from ethyl acetate/hexane at 20°-250 to give the title compound, NMR (CDCl3) 1.5-1.7, 1.9-2.0, 2.84, 3.12, 3.56, 3.63, 3.92, 4.20, 7.10, 7.13-7.30 and 7.80 δ; MS (EI, m/z) 394 (M+), 363, 320 and 307.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH2:44][C@@H:45]([CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:46][C:47]#[N:48].S([O-])(O)(=O)=O.[Na+]>CN(C=O)C.O.C(Cl)CCl>[C:47]([CH2:46][C@@H:45]([NH:44][C:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[N:8][C:9]=2[CH:14]=1)=[O:17])[CH2:49][CH:50]([CH3:52])[CH3:51])#[N:48]
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)C[C@H](N)CC#N
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@H](CC#N)CC(C)C)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of 4.93 g of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid in 50 ml of dry DMF 2.04 g of HOAT, 3.45 g of EDC and 4.35 ml of DIPEA were added at 0° C. After 30 min 3.29 g of (S)-3-Amino-5-methyl-hexanenitrile-hydrochloride and 4.35 ml of DIPEA were added and the reaction was stirred at rt for 4 h. The reaction was then poured into water and the pH was adjusted to 3 by the addition of 2 M aqueous sodium hydrogensulphate solution. The reaction was extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. 5.90 g (90%) of 1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid ((S)-1-cyanomethyl-3-methyl-butyl)-amide were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.[CH2:13](Br)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:6]=[CH:5]2
Reactant: Oc1nccc2cc(Br)ccc12
Reactant: BrCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: O=c1c2ccc(Br)cc2ccn1CCc1ccccc1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
6-Bromo-1-hydroxyisoquinoline (300 mg, 1.34 mmol, 1.0 equiv), tetrabutylammonium bromide (50 mg, 0.13 mmol, 0.10 equiv), and phenethyl bromide (220 uL, 1.6 mmol, 1.2 eq) were combined in toluene (14 mL), treated with 50% aq. NaOH (3 mL) after which the resulting mixture stirred rapidly at ambient temperature. After stirring for an additional 14 hours, the mixture was diluted with MTBE and washed with water, saturated NaHCO3, and brine. The organic phase was dried over Na2SO4. Addition of silica gel, concentration, and purification of the residue using flash silica gel chromatography (gradient of 3-15% ethyl acetate/hexanes) provided 6-bromo-2-phenethyl-isoquinolin-1-one (225 mg, 0.69 mmol, 51%) as a white solid. This isoquinolinone (225 mg, 0.69 mmol) was then converted, via Methods 1 and 2, to compound 3 (95 mg, 47%) and isolated as a white solid. [M-H]-=292.1 m/z. Activity: A
Reaction SMILES: O=O.Cl[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[CH:15][C:14](=[O:18])[C:13]=2[CH:19]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[C:20]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]3[CH:10]=[CH:11][C:12]4[O:17][CH:16]=[CH:15][C:14](=[O:18])[C:13]=4[CH:19]=3)[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1ccoc2ccc(OCCCCCl)cc12
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=O
Product: O=c1ccoc2ccc(OCCCCN3CCN(c4ccccc4)CC3)cc12

Procedure:
The title compound was prepared by the method described above for the compounds of Formula I wherein X is oxygen. Thus, 6-(4-chlorobutoxy)-4H-1-benzopyran-4-one, as prepared above in Preparation 3, (3.79 g; 15 mmol) was reacted with 1-phenylpiperazine (2.59 g; 16 mmol) in the usual way, yielding 3.5 g of 6-[4-(4-phenyl-1-piperazinyl)butoxy]-4H-1-benzopyran-4-one as its dihydrochloride salt, mp 193°-195° C. (See Scheme I.)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[C:6]([I:13])[CH:7]=[C:8]([Cl:12])[C:9]=2[Cl:11])[C:4](=[O:14])[N:3]1C(C)(C1C=CC=CC=1)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[Cl:11][C:9]1[C:8]([Cl:12])=[CH:7][C:6]([I:13])=[C:5]2[C:10]=1[CH2:2][NH:3][C:4]2=[O:14]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(I)cc(Cl)c(Cl)c2C1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: O=C1NCc2c(Cl)c(Cl)cc(I)c21
Yield: 74 %

Procedure:
In a similar manner to Step 4 of Example 16, 3-hydroxy-4,5-dichloro-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (347 mg, 0.750 mmol) was dissolved in nitromethane (14 mL), and the solution was treated with trifluoroacetic acid (0.867 mL, 11.3 mmol) and triethylsilane (0.240 mL, 1.50 mmol), followed by purification by slurry using chloroform to obtain 4,5-dichloro-7-iodoisoindolinone (182 mg, yield 74%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:15]3=[CH:16][C:17]4[O:21][CH2:20][O:19][C:18]=4[CH:22]=[C:14]3[O:13][CH2:12]1)[C:5](=[O:11])[NH:6]2.BrC1C=CC=C2C=1[C:26]1([C:42]3=CC4OCOC=4C=[C:41]3[O:40][CH2:39]1)C(=O)N2CCCCC.O1C=CC(B(O)O)=C1.CN(C)C1N=CC(B(O)O)=CC=1>>[O:40]1[CH:41]=[CH:42][C:26]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:15]4=[CH:16][C:17]5[O:21][CH2:20][O:19][C:18]=5[CH:22]=[C:14]4[O:13][CH2:12]2)[C:5](=[O:11])[NH:6]3)=[CH:39]1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1ccoc1
Product: O=C1Nc2cccc(-c3ccoc3)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4, making variations using 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-furanboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (66%) as a colorless solid: mp 270-272° C.; 1H NMR (300 MHz, CDCl3) δ 7.32 (t, 1H), 7.25 (d, 2H), 6.97 (d, 1H), 6.91 (d, 1H), 6.83 (s, 1H), 6.44 (s, 1H), 6.30 (s, 1H), 6.04 (d, 1H), 5.89 (dd, 2H), 4.68 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 180.4, 156.2, 149.2, 142.9, 142.1, 141.2, 140.4, 131.3, 129.2, 128.5, 125.3, 122.6, 120.6, 111.0, 109.5, 102.9, 101.6, 94.0, 77.2, 59.0; MS (ES+) m/z 348.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:8]=1)[NH2:5].Cl[C:15]1[N:20]=[C:19]([CH:21]2[CH2:23][CH2:22]2)[C:18]([F:24])=[CH:17][N:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:21]1([C:19]2[C:18]([F:24])=[CH:17][N:16]=[C:15]([NH:5][C:4]3[CH:6]=[C:7]([C:9]4[S:13][CH:12]=[N:11][CH:10]=4)[CH:8]=[C:2]([CH3:1])[CH:3]=3)[N:20]=2)[CH2:23][CH2:22]1
Reactant: Cc1cc(N)cc(-c2cncs2)c1
Reactant: Fc1cnc(Cl)nc1C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: Cc1cc(Nc2ncc(F)c(C3CC3)n2)cc(-c2cncs2)c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 91.6 %

Procedure:
3-Methyl-5-(1,3-thiazol-5-yl)aniline (0.250 g, 1.31 mmol), the product of Step 1 (0.227 g, 1.31 mmol), palladium(II) acetate (0.0295 g, 0.131 mmol), xantphos (0.114 g, 0.197 mmol), and cesium carbonate (0.856 g, 2.63 mmol) were added to a dry flask. The flask was degassed with argon and then dioxane (4.4 ml) was added. The reaction'mixture was'degassed with argon for 5 minutes, and then heated to 100° C. After 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc/dichloromethane gradient) to afford 4-cyclopropyl-5-fluoro-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (0.390 g, 1.20 mmol, 91% yield). MS ESI: [M+H]+ m/z 326.8. 1H NMR (500 MHz, DMSO-d6) δ 9.59 (s, 1H); 9.06 (s, 1H); 8.38 (d, J=2.5 Hz, 1H); 8.19 (s, 1H); 7.94 (s, 1H); 7.39 (s, 1H); 7.10 (s, 1H); 2.29 (s, 3H); 2.28-2.23 (m, 1H); 1.18-1.14 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:15])[N:6]2[CH2:11][C:12]([NH2:14])=[O:13].C1C(=O)N([Cl:23])C(=O)C1.O>OS(O)(=O)=O>[Cl:1][C:2]1[C:10]([Cl:23])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:15])[N:6]2[CH2:11][C:12]([NH2:14])=[O:13]
Reactant: NC(=O)CN1C(=O)Cc2c(Cl)cccc21
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: NC(=O)CN1C(=O)Cc2c1ccc(Cl)c2Cl
Reaction time: 2 h

Procedure:
2-(4-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 7 (0.205 g, 0.9 mmol) is dissolved in 90% H2SO4 (1 ml) at room temperature, and NCS (0.12 g, 0.9 mmol) is slowly added with stirring. After 2 hours, the mixture is poured into cold water. The precipitate is collected, washed several times with water and then with Et2O. The crude reaction mixture is purified by column chromatography on silicagel (CH2Cl2/EtOH/NH4OH: 94.5/5/0.5 (v/v)) to afford the 2-(4,5-dichloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 10 as a white solid.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH3:29][O:30][C:31]1[N:36]=[N:35][C:34]([NH2:37])=[C:33]([CH3:38])[C:32]=1[CH3:39].C(N(CC)C(C)C)(C)C>C(#N)CCC>[CH3:29][O:30][C:31]1[C:32]([CH3:39])=[C:33]([CH3:38])[C:34]2[N:35]([C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])[CH2:12][CH2:13][CH2:14]4)=[CH:9][CH:10]=3)[N:37]=2)[N:36]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: COc1nnc(N)c(C)c1C
Solvent: CCCC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)c1C
Temperature: 120 °C
Yield: 28 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example Int-1-A] (391 mg, ˜80% purity, 0.710 mmol, 1.0 eq), 6-methoxy-4,5-dimethylpyridazin-3-amine (that was prepared in a manner analgous to that described for Intermediate Example Int-34, Step 1, 108 mg, 0.710 mmol, 1.0 eq) and N,N-diisopropylethylamine (140 μL, 0.780 mmol, 1.1 eq) in butyronitrile (4.9 mL) was heated for 3 hours at 120° C. On cooling the reaction mixture was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/EtOAc 9/1→hexane/EtOAc 2/3) to give 105 mg (28% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:23][C:24]#[C:25][CH3:26]>>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([S:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:23][C:24]#[C:25][CH3:26])=[CH:19][CH:20]=1)[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:13]
Reactant: CC#CCBr
Reactant: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(Cl)cc1
Product: CC#CCOc1ccc(SC(C(=O)OCC)c2ccc(Cl)cc2)cc1
Yield: 69 %

Procedure:
Ethyl{[4-(2-butynyloxy)phenyl]sulfanyl)(4-chlorophenyl)acetate was prepared according to the general method as outlined in example 1 (step 2), starting from ethyl (4-chlorophenyl)[(4-hydroxyphenyl)sulfanyl]acetate (15.37 g, 47.7 mmol) and 4-bromo-2-butyne (4.26 ml, 48.7 mmol); 12.57 g yellow oil. Yield 69%; MS(EI): 374 (M+H)+
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][C:12]([CH3:20])([CH3:19])[C:11]=2[CH:10]=[C:9]([C:21](Cl)=[O:22])[CH:8]=1.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1>C(COC)OC.[Zn].C([O-])(=O)C.[Cu+2].C([O-])(=O)C.[Zn].[Cu].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:30]([C:29]1[CH:34]=[CH:35][C:26]([CH2:25][C:21]([C:9]2[CH:8]=[C:7]([O:6][CH3:5])[C:16]3[C:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][C:12]([CH3:20])([CH3:19])[C:11]=3[CH:10]=2)=[O:22])=[CH:27][CH:28]=1)([O:32][CH3:33])=[O:31]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1cc(C(=O)Cl)cc2c1C(C)(C)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu+2]
Agent: [Cu]
Solvent: COCCOC
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CC(=O)c2cc(OC)c3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 1.25 h
Yield: 31.7 %

Procedure:
2.1 g of zinc powder and 0.21 g of copper(II) acetate were stirred with 7.3 ml of acetic acid at 20° C., with cooling, for 30 min. The zinc/copper couple was filtered off with suction and washed 2× with dry ether and 1× with dry dimethoxyethane. A solution of 4.5 g (16 mmol) of 5,6,7,8-tetrahydro-4-methoxy-5,5,8,8-tetramethylnaphthalene-2-carbonyl chloride and 3.7 g (16 mmol) of methyl 4-bromomethylbenzoate in 60 ml of dimethoxyethane was added dropwise to a suspension of the zinc/copper couple prepared in this way and of 0.56 g of bis(triphenylphosphine)palladium(II) chloride in 15 ml of dimethoxyethane at room temperature. The mixture was stirred for 75 min and then filtered through Celite, and the filtrate was concentrated. Three recrystallizations of the residue from methanol yielded 2.0 g of the title compound of melting point 143°-144° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:8])([CH3:7])[C:5](=[O:9])[NH:4][C:3]1=[O:10].N([CH2:14][CH2:15][CH2:16][CH2:17]CC)=C=O>>[CH3:1][N:2]1[C:6]([CH3:8])([CH3:7])[C:5](=[O:9])[NH:4][C:3]1=[O:10].[CH2:6]([C:5]([NH2:4])=[O:9])[CH2:7][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCN=C=O
Agent: CN1C(=O)NC(=O)C1(C)C
Product: CCCCCCC(N)=O

Procedure:
1,5,5-Trimethylimidazolidine-2,4-dione (100 mg, 0.70 mmol) and 1-isocyanatohexane (107.4 mg, 0.84 mmol) were reacted in analogy to example 1. Yield: 31.5 mg (17%), M+H+: 270.17.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=1.[CH3:24][O:25][CH2:26][CH2:27][N:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[C:36]([NH2:39])[CH:37]=[CH:38][C:31]=2[CH2:30][CH2:29]1>>[CH3:24][O:25][CH2:26][CH2:27][N:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[C:36]([NH:39][C:2]3[N:7]=[C:6]([NH:8][C:9]4[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=4[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=3)[CH:37]=[CH:38][C:31]=2[CH2:30][CH2:29]1
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cccc(C)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide and 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 195 to afford a white solid (29 mg, 47%). Mp: 73-6° C. LCMS (m/e) 529 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.40 (s, 1H), 8.30 (s, 1H), 7.39 (m, 2H), 7.31 (m, 1H), 7.10 (s, 1H), 6.99 (br s, 1H), 6.84 (br s, 1H), 6.00 (br s, 1H), 3.55 (t, 2H, J=5 Hz), 3.39 (s, 3H), 2.88 (d, J=5 Hz, 3H), 2.90 (m, 2H), 2.74 (t, J=5 Hz, 2H), 2.70-2.63 (m, 6H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:32]3[CH:33]=[CH:34][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:30][CH:31]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: COC(=O)c1ccc(B(O)O)cc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a flask charged with 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 2) (1000 mg, 2.60 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (561 mg, 3.11 mmol), tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.260 mmol) and potassium carbonate (1076 mg, 7.79 mmol) was added DME (20 mL) and water (4.0 mL). The resulting mixture was stirred at 100° C. under nitrogen for 1 h, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water and the layers were separated. The organic phase was dried (MgSO4), concentrated in vacuo and the residue was purified by chromatography (10 g column, MeOH/DCM gradient) to give methyl 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (1002 mg, 2.275 mmol, 88% yield) as an orange foam. LCMS (HpH, 2 min), Rt=1.09 min, MH+=441.