Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[OH:40].[CH3:41][N:42]=[C:43]=[O:44].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[CH3:41][NH:42][C:43](=[O:44])[O:40][C:3]1[CH:4]=[C:5]([C@:8]([C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([F:26])[CH:17]=2)([NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(O)c1)c1cccc(C(F)(F)F)c1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1cc([C@@](Cc2ccccc2)(NC(=O)c2cccc(C(F)(F)F)c2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Temperature: 80 °C
Yield: 61 %

Procedure:
A solution of (R)—N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide, prepared as described in Example 264, (15 mg, 0.027 mmol), methylisocyanate (0.01 mL), and Et3N (0.02 mL) in CH2Cl2 (0.3 mL) was heated at 80° C. under microwave irradiation for 10 min. After cooling, the reaction mixture was diluted with EtOAc and the organic layer was washed with H2O, sat. NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO flash chromatography (silica gel, hexanes/EtOAc) to yield (R)-2-fluoro-5-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(3-(trifluoromethyl)-benzamido)-ethyl)phenyl methylcarbamate (Example 272, 11 mg, yield: 61%). LCMS: RT=2.13 min [M+H] 623.3 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:10][CH2:9][C:8]([CH3:11])([CH3:12])[C:7]([NH:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:13]
Reactant: CC(C)(CO)C(=O)NC1CCCC1
Reactant: N#Cc1c(N)cccc1F
Product: CC(C)(COc1cccc(N)c1C#N)C(=O)NC1CCCC1

Procedure:
Prepared as in Example 22b from N-cyclopentyl-3-hydroxy-2,2-dimethylpropanamide (Example 29c) and 2-amino-6-fluorobenzonitrile as a white solid (45%). 1H NR (400 MHz, DMSO-d6) δ 1.19 (s, 6H), 1.40-1.49 (m, 4H), 1.61-1.63 (m, 2H), 1.74-1.79 (m, 2H), 3.95 (s, 2H), 4.03 (m, 1H), 5.98 (s, 2H), 6.19 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H). MS 302 (MH+).
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([CH2:6][OH:7])[NH:3][CH2:2]1.[Cl:8][CH2:9][CH:10]1[CH2:12]O1>>[Cl:8][CH2:9][CH:10]1[O:7][CH2:6][C@@H:4]2[CH2:5][S:1][CH2:2][N:3]2[CH2:12]1
Reactant: OC[C@@H]1CSCN1
Reactant: ClCC1CO1
Product: ClCC1CN2CSC[C@H]2CO1
Temperature: 25 °C
Yield: 2.4 %

Procedure:
A solution of (4R)-1,3-thiazolidin-4-ylmethanol (0.300 g, 2.52 mmol) in 2-(chloromethyl)oxirane (2.0 mL, 25.5 mmol) was heated under nitrogen to 40° C. for 12 h. The solution was then cooled to room temperature and 2-(chloromethyl)oxirane was removed in vacuo. The crude intermediate was cooled in ice, and was taken up in 2.0 mL of concentrated sulfuric acid. The resulting mixture was heated to 200° C. for 0.5 h then poured carefully onto wet ice, which was allowed to melt. The aqueous solution was carefully made basic using solid sodium bicarbonate and the resulting mixture was filtered using water and 10% methanol in ethyl acetate as eluent. The layers were separated and the aqueous layer was extracted with 10% methanol in ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 11.6 mg (2.4% yield) of crude (8aR)-6-(chloromethyl)tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazine as a mixture of diastereomers which was directly taken on to the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[F:10][C:11]1[CH:25]=[CH:24][C:14]2[C:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][O:17][C:13]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[F:10][C:11]1[CH:25]=[CH:24][C:14]2[C:15]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][N:4]4[CH2:8][CH2:7][NH:6][C:5]4=[O:9])[CH2:22][CH2:23]3)=[N:16][O:17][C:13]=2[CH:12]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C1NCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C1NCCN1CCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 61.9 %

Procedure:
21.4 g (0.144 mol) of 1-(2-chloroethyl)imidazolidin-2-one, 23.6 g (0.107 mol) of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine, 92.9 g (0.67 mol) of potassium carbonate, 2.6 g of potassium iodide and 524 ml of methyl isobutyl ketone are placed in a three-necked flask. Refluxing is carried out for one night, and then the reaction mixture is concentrated and taken up in a mixture of water/ethyl acetate. Decanting is carried out, and the organic phase is washed several times with water and then extracted with a normal solution of hydrochloric acid. The acidic phase is then rendered basic with sodium hydroxide solution and extracted with methylene chloride. Drying is carried out over MgSO4. After evaporation, the residue is recrystallised from 80 ml of acetonitrile to yield 22 g of a solid that corresponds to the expected product. M.p.=137°-141° C. (Yield=46%).
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:9][C:8]2=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:9]=[C:8]2[N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: Cc1cc2nc(-n3cc(C(=O)O)cn3)nc(N3CCCC3)c2cc1Oc1c(C)cccc1C

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI/CI): predicted mass C25H25N5O3, 443.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[S:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(C)c(C(=O)OCC)s2)cc1

Procedure:
This compound was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate and 4-n-propylbenzenesulfonyl chloride as described for EXAMPLE 30 with the exception that it was not recrystallized. Yield 315 mg, 85%: 1H NMR (DMSO) δ 7.70 (d, 2H), 7.37 (d, 2H), 4.21 (q, 2H), 2.60 (t, 2H) 2.38 (s, 3H), 1.58 (t, 2H), 1.25 (t, 3H), 0.87 (t, 3H); MS-ES (neg) m/z 367.2.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([OH:16])=O)=[CH:10]2)[CH3:3].Cl.C([N:31]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>O.CN(C)C=O>[CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([NH2:31])=[O:16])=[CH:10]2)[CH3:3]
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 78.5 %

Procedure:
A mixture of 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (1.8 g), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.77 g), 1-hydroxybenzotriazole (1.24 g) and N,N-dimethylformamide (45 mL) was stirred at 50° C. for 25 min. The mixture was cooled to room temperature, and 28% aqueous ammonium hydroxide solution (1.3 mL) was added to the mixture at room temperature. After stirring at room temperature for 16 h, water was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80 to 100/0, volume ratio) to give the title compound (1.41 g, 79%) as a white solid. MS 389 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][NH:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2cccc(Cl)c2)C[C@H](C)O1
Temperature: 130 °C

Procedure:
1-Chloro-3-iodobenzene (3.09 g, 12.96 mmol) was dissolved in 1,4-dioxane (50 mL). To this was added cis-2,6-dimethylmorpholine (1.492 g, 12.96 mmol), caesium carbonate (6.33 g, 19.44 mmol) and BINAP (1.210 g, 1.944 mmol) and the solution was degassed by sonication under argon. To this was added palladium(II) acetate (0.145 g, 0.648 mmol) and the solution was refluxed at 130° C. under argon overnight. Crude LC/MS showed desired product and no starting material so the reaction mixture was filtered through celite, eluting with ethyl acetate. The filtrate was diluted with water and the aqueous phase was separated and re-extracted using ethyl acetate (×3). The combined organic layers were washed with brine, separated, dried over magnesium sulphate, filtered and concentrated under pressure. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by using a Biotage SP4 chromatographic system (65i cartridge, eluted with 0-35% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a yellow oil (1.785 g, 7.51 mmol, 58.0% yield). LC/MS [M+H]+=226/228.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[C:15]2[S:20]([OH:23])(=O)=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>ClCCl>[C:1]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[C:15]2[S:20]([Cl:26])(=[O:23])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1cccc2c(S(=O)(=O)O)cccc12)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1cccc2c(S(=O)(=O)Cl)cccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 5-benzoylamino-napthalene-1-sulfonic acid (1.5 g, 3.51 mmol) in dichloromethane (5 ml), was added thionyl chloride (0.359 ml, 4.92 mmol). The resultant solution was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was quenched by pouring into ice water and extracting with ethyl acetate. The organic extracts were washed with brine, dried over MgSO4 and concentrated to provide the crude intermediate 44 as a yellow oil that was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[F:21][CH:22]([F:43])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]23[NH:42][CH2:41][CH2:40][N:31]2[C:32](=[O:39])[C:33]2[N:34]([CH:36]=[CH:37][CH:38]=2)[CH2:35]3)=[CH:26][CH:25]=1>C(Cl)Cl.N1C=CC=CC=1>[F:43][CH:22]([F:21])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]23[N:42]([C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][CH:5]=4)=[O:9])[CH2:41][CH2:40][N:31]2[C:32](=[O:39])[C:33]2[N:34]([CH:36]=[CH:37][CH:38]=2)[CH2:35]3)=[CH:26][CH:25]=1
Reactant: O=C1c2cccn2CC2(c3ccc(OC(F)F)cc3)NCCN12
Reactant: Cc1nocc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1ccc(OC(F)F)cc1
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To generate the acid chloride, 3-methyl-1,2-oxazole-4-carboxylic acid (95.53 mg, 0.75 mmol) was dissolved in CH2Cl2 (10 mL). Oxalyl chloride (0.22 mL, 2.63 mmol) and a drop of DMF were added at 0° C. The ice bath was removed and the mixture stirred for 1 h before the solvent and the unreacting oxalyl chloride was removed with a stream of nitrogen. The residue was further dried in vacuo. 10a-[4-(difluoromethoxy)phenyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (60 mg, 0.19 mmol) was dissolved in pyridine (4 ml) and the solution added to the previously generated acid chloride in pyridine (1 mL) at 0° C. The ice bath was removed after 15 min and the mixture stirred at room temperature for 18 h. LCMS analysis showed only a trace amount of product. Further 4 equivalent of acid chloride were prepared as described above and added to the reaction mixture. The resultant mixture was then heated at 50° C. until completion (28 h, monitored by LCMS). The resultant suspension was then concentrated in vacuo and the residue partitioned between CH2Cl2 (20 mL) and a saturated aqueous solution of NaHCO3 (10 mL). The organic layers were washed with further a saturated aqueous solution of NaHCO3 (10 mL) and brine (5 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow residue. This residue was purified by flash column chromatography (Biotage SP4, 12 g cartridge, 70-100% EtOAc gradient in n-hexanes) to give 10a-[4-(difluoromethoxy)phenyl]-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one compound (1) as a white solid (42 mg, yield 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:15][CH2:14]3)[N:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: BrCCc1ccccn1
Reactant: Clc1ccc(-c2cc(C3CCNCC3)n(-c3ccccc3)n2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1ccc(-c2cc(C3CCN(CCc4ccccn4)CC3)n(-c3ccccc3)n2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of INTERMEDIATE 5 (30 mg, 0.089 mmol) in dichloromethane (0.4 mL) was added 2-(2-bromoethyl)pyridine (28.4, 0.107 mmol). The mixture was stirred at 60° C. overnight, and then cooled to room temperature. The mixture was diluted with EtOAc, and washed with water. The organic layer was separated, dried and concentrated. The resulting residue was purified by preparative TLC (using 2 M NH3 in MeOH/MeOH/DCM/0.05 mL/5 mL/9.5 mL) to give the title compound. LC-MS m/z 443.17 [M+H]+.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:8]=1[CH:9]=[CH2:1]
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1ccc(C=O)c(Br)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (12.3 g, 33.7 mmol) in anhydrous THF (40 ml) was added n-butyl lithium (1.60 mol/l, hexane solution) (33.7 mmol, 21.1 ml) at 0° C. After 30 minutes at 0° C., to this was added 2-bromo-4-tert-butylbenzaldehyde (4.06 g, 16.8 mmol)(prepared according to J. Med. Chem. 2005, 48, 71-90) in anhydrous THF (10 ml) at 0° C. The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel, eluting with hexane, to afford the title compound (3.27 g, 81%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH3:19])[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([O:10][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=2)=[CH:3][C:4]=1[CH3:19])=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(Br)ccc1NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A suspension of benzyl (4-bromo-2-methylphenyl)carbamate (I51) (1.00 g, 3.12 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (37) (1.16 g, 3.74 mmol), PdCl2(dppf)-DCM complex (310 mg, 0.374 mmol) and potassium carbonate (1.29 g, 9.36 mmol) in DMF (30 mL) was stirred under nitrogen at 80° C. for 16 hours. The volatiles were evaporated under reduced pressure and the residue adsorbed onto silica gel. Chromatography on silica gel (0-30% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I52) (949 mg, 72%) as a yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.83-7.70 (m, 1H), 7.41-7.34 (m, 5H), 7.21 (dd, J=8.5, 1.9 Hz, 1H), 7.16 (d, J=1.8 Hz, 1H), 6.56 (s, 1H), 5.97 (s, 1H), 5.20 (s, 2H), 4.05 (d, J=2.9 Hz, 2H), 3.61 (t, J=5.7 Hz, 2H), 2.48 (d, J=1.5 Hz, 2H), 2.23 (s, 3H), 1.50 (d, J=2.6 Hz, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[N:35]=[C:36]=[O:37].O>CN(C)C=O.C(OCC)(=O)C>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[NH:35][C:36]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:37]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(=O)Nc4ccc(F)cc4F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
After dissolving 4-(1H-indol-5-yloxy)-6,7-dimethoxyquinoline (40 mg, 0.1249 mmol, described in WO9717329) in N,N-dimethylformamide (0.7 ml), sodium hydride (10 mg,) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Difluorophenyl isocyanate (0.018 ml, 0.1561 mmol) was further added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the filtrate was distilled off under reduced pressure. The obtained crystals were suspended in diethyl ether:ethanol=10:1 and diluted with hexane, and then the crystals were filtered out, washed with diethyl ether:ethanol=10:1 and dried by aspiration to obtain the title compound (35 mg, 0.0736 mmol, 58.94%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[C:15]4([CH2:18][CH2:17][CH2:16]4)[CH2:14][N:13]([C:19]([C:21]4([C:24]#[N:25])[CH2:23][CH2:22]4)=[O:20])[CH2:12]3)=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N.ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:24]([C:21]1([C:19]([N:13]2[CH2:12][CH:11]([NH:10][C:9]3[C:4]4[N:5]([CH:29]=[C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:26]([NH2:28])=[O:27])[C:15]3([CH2:18][CH2:17][CH2:16]3)[CH2:14]2)=[O:20])[CH2:22][CH2:23]1)#[N:25]
Reactant: N#CC1(C(=O)N2CC(Nc3c(C(N)=O)cnn4cc(Br)cc34)C3(CCC3)C2)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(-c2cc3c(NC4CN(C(=O)C5(C#N)CC5)CC45CCC5)c(C(N)=O)cnn3c2)cn1
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 54.9 %

Procedure:
A solution of (+/−)-6-bromo-4-((6-(1-cyanocyclopropanecarbonyl)-6-azaspiro[3.4]octan-8-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (15.09 mg, 0.033 mmol) and 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (13.73 mg, 0.066 mmol) in 1,4-dioxane (440 μL) and 2M aq. potassium phosphate (49.5 μL, 0.099 mmol) was degassed for several minutes with N2 gas. 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (2.71 mg, 3.30 μmol) was added and degassing was continued for 1 additional minute. The vial was sealed and the contents were heated @ 110° C. for 1.5 hr. LC/MS and HPLC indicated that no starting material remained (m/e 459.26, no Br pattern, M+H for desired product). After cooling to rt, the reaction was diluted with methanol, filtered and evaporated. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 8.3 mg of the title compound. 1H NMR (500 MHz, METHANOL-d4/CDCl3) δ 8.13 (d, J=8.9 Hz, 1H), 7.83 (d, J=3.5 Hz, 1H), 7.76 (d, J=5.0 Hz, 2H), 7.06-6.90 (m, 1H), 4.80-4.70 (m, 1H), 4.39-4.34 (m, 0.5 H), 4.29-4.10 (m, 1H), 4.05 (dd, J=11.4, 2.5 Hz, 0.5H), 3.94 (s, 3H), 3.91-3.70 (m, 2H), 2.54-1.99 (m, 6H), 1.83-1.38 (m, 4H).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[K+].C(O)C.O>Cl>[C:30]([CH2:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=2)=[CH:21][CH:22]=1)([OH:32])=[O:31]
Reactant: CCCCCCCCCCCCOc1ccc(-c2ccc(CCCCC(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(-c2ccc(CCCCC(=O)O)cc2)cc1
Yield: 90.5 %

Procedure:
19 mmol of the compound from Example 15, 66.7 mmol of KOH, 100 ml of ethanol and 50 ml of water are introduced into a 500 ml single-necked flask fitted with reflux condenser and magnetic stirrer, and the mixture is refluxed for 6 hours. After cooling, the reaction mixture is carefully acidified in concentrated HCl solution and subsequently washed with water until neutral. The solvent is stripped off, and the residue is recrystallized a number of times from glacial acetic acid. The residue is then boiled with methanol and subsequently with ether and filtered off with suction. Yield: 90.5%.