Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:15]([CH3:16])=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10]C(C)C)=[O:9])=[C:4]([CH3:17])[C:3]=1[NH:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:23]=[CH:22][C:21]=1[F:33].[Li+].[OH-].O>C1COCC1>[F:1][C:2]1[C:15]([CH3:16])=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:17])[C:3]=1[NH:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:23]=[CH:22][C:21]=1[F:33]
Reactant: Cc1cc(OCC(=O)OC(C)C)c(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)O)c(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of isopropyl 2-[4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methyl amino]-2,5-dimethyl-phenoxy]acetate (130 mg, 0.28 mmol, 1.0 eq) in THF (2 mL) was added LiOH (2M aqueous solution, 2 mL, 4 mmol, 14 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Water was added and THF was removed under reduced pressure. The aqueous layer was washed with MTBE and the organic extract was discarded. The aqueous layer was adjusted to pH 3-4 by addition of 3M HCl and then extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude product was recrystallized from CH2Cl2 (1 mL) and petroleum ether (3 mL) to give the target compound as an off-white solid (85 mg, 72%).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:4]#[N:5].[O:21]([CH2:28][CH2:29][NH2:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[O:21]([CH2:28][CH2:29][NH:30][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:4]#[N:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C(F)(F)F)c(C#N)c(NCCOc3ccccc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h

Procedure:
Compound F (300 mg, 1.00 mmol), 2-phenoxyethylamine (261 μl) and sodium hydrogencarbonate (837 mg) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction system was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-phenoxyethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-trifluoromethylnicotinonitrile (80 mg).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][O:4][C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:19]([O-])=O)[CH:18]=[C:13]3[C:12]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[N:11]2)=[CH:7][CH:6]=1>CCO.O.CCOC(C)=O.O.[Fe]>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:19])[CH:18]=[C:13]3[C:12]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[N:11]2)=[CH:27][CH:28]=1
Reactant: COCCOc1nn(Cc2ccc(OC)cc2)c2ncc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COCCOc1nn(Cc2ccc(OC)cc2)c2ncc(N)cc12
Temperature: 85 °C
Reaction time: 5 h
Yield: 91.9 %

Procedure:
Fe (0) (0.251 g, 4.49 mmol) and ammonium chloride (0.600 g, 11.2 mmol) were added to 1-(4-methoxybenzyl)-3-(2-methoxyethoxy)-5-nitro-1H-pyrazolo[3,4-b]pyridine (402 mg, 1.12 mmol) in EtOH (8 mL) and water (3.7 mL). The mixture was stirred at 85° C. for 5 hours. The mixture was diluted with EtOAc-water and filtered through GF/F paper. The filtrate was diluted with aqueous bicarbonate and extracted with EtOAc (3×12 mL), dried over sodium sulfate, decanted and concentrated to provide 1-(4-methoxybenzyl)-3-(2-methoxyethoxy)-1H-pyrazolo[3,4-b]pyridin-5-amine (338 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[C:14]3[C:22](O)=[O:23])[CH:8]=2)=[CH:4][CH:3]=1.Cl.[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)([CH3:28])[CH3:27].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(N(CC)CC)C>[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:22]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[O:23])[CH2:31][CH2:30]1)([CH3:28])[CH3:27]
Reactant: O=C(O)c1cc2ncccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2cc3ncccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reaction time: 16 h

Procedure:
To a suspension of 50 mg 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid, 36 mg 1-isopropyl-piperidin-4-ylamine hydrochloride and 35 mg bis(2-oxo-3-oxazolidinyl)phosphinic chloride in 1 mL dichloromethane, 77 μl triethylamine were added at room temperature and the mixture was stirred for 16 hours. After removing of the solvent under reduced pressure, the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoroacetic acid). The fractions containing the product were evaporated and lyophilized to yield a white residue which was partitioned between 5 mL aqueous 0.1 N sodium hydroxide solution and 5 mL ethyl acetate. The organic layer was washed with additional water and then dried over sodium sulphate. After filtration and removal of the solvent under reduced pressure, a white solid was obtained.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3C(C)=NC(C)=CC=3)O)[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([C:49]2[N:53]([CH3:54])[CH:52]=[N:51][CH:50]=2)=[O:48])=[CH:43][CH:42]=1.C(=O)=O.CC(C)=O>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:47]([C:44]3[CH:43]=[CH:42][C:41]([Cl:40])=[CH:46][CH:45]=3)([C:49]3[N:53]([CH3:54])[CH:52]=[N:51][CH:50]=3)[OH:48])[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 4.6 mL, 11.5 mmol) was added drop-wise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (5.0 g, 11.6 mmol, Intermediate 47: step d) in dry THF (58 mL) in a dry ice-acetone bath. After 1 min, a solution of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (2.6 g, 11.6 mmol, Intermediate 1: step b) in dry THF (58 mL) was added drop-wise via syringe. An additional 10 mL of THF was used to complete the quantitative addition. The reaction mixture was stirred for 5 minutes in the dry ice-acetone bath then placed into an ice-water bath. After 10 minutes, the ice-water bath was removed and the mixture was allowed to warm to ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride and the mixture was partitioned between water and DCM. The layers were separated and the aqueous phase was further extracted with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated. Crude product was purified by flash column chromatography (silica gel, 0-3% MeOH-DCM) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=2.1 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.53 (dd, J=8.8, 2.1 Hz, 1H), 7.51-7.47 (m, 2H), 7.40-7.36 (m, 2H), 7.28-7.32 (m, 4H), 7.23-7.21 (m, 1H), 6.29 (d, J=1.2 Hz, 1H), 5.06 (s, 1H), 4.32 (s, 2H), 4.07 (s, 2H), 3.33 (s, 3H). MS m/e 572.0 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:17])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a mixture of quinoline-6-carboxylic acid (O-1) (2.0 g, 11.5 mmol) in CH2Cl2 (250 mL) was added 3 drops of DMF at 0° C., followed by oxalyl chloride (7.3 g, 57.5 mmol) dropwise. The resulting reaction was stirred at room temperature overnight, and then concentrated to afford the title compound (2.2 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[Cl:9][C:10]1[N:19]=[C:18](Cl)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>O1CCCC1>[ClH:9].[ClH:9].[Cl:9][C:10]1[N:19]=[C:18]([NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CCN(CC)CCN
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: C1CCOC1
Product: CCN(CC)CCNc1nc(Cl)nc2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 169.1 %

Procedure:
To a solution of 43.2 g of 2-diethylaminoethylamine (N,N-diethylethylenediamine) in 400 ml of tetrahydrofuran was added 54 g of 2,4-dichloroquinazoline. The mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated almost to dryness and the residue was suspended in water. The aqueous medium was made alkaline with dilute sodium hydroxide and was extracted several times with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was saturated with anhydrous hydrogen chloride. The solid which precipitated was isolated by filtration and then was recrystallized from ethanol and ether, giving 53.8 g of 2-chloro-4-(2-diethylaminoethylamino)quinazoline dihydrochloride which decomposed at 152°. The following analytical data were obtained:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.BrC1C=C([OH:23])C=CC=1.[C:24]1([CH:30]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[N:31]2[C:39]3[C:34](=[C:35]([O:42][CH3:43])[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=3)[C:33](=[O:44])[C:32]2=[O:45])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[C:46]1([CH:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:31]2[C:39]3[C:34](=[C:35]([O:42][CH3:43])[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=3)[C:33]([OH:44])([C:13]3[C:12]([OH:15])=[CH:11][C:10]4[O:23][CH2:2][CH2:1][O:8][C:9]=4[CH:14]=3)[C:32]2=[O:45])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Oc1cccc(Br)c1
Reactant: COc1cc(OC)c2c(c1)N(C(c1ccccc1)c1ccccc1)C(=O)C2=O
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Product: COc1cc(OC)c2c(c1)N(C(c1ccccc1)c1ccccc1)C(=O)C2(O)c1cc2c(cc1O)OCCO2

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 4-(benzyloxy)phenol to replace 3-bromophenol, and 1-(diphenylmethyl)-4,6-dimethoxy-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,6-dimethoxy-1,3-dihydro-2H-indol-2-one was obtained (50%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.81 (s, 1H), 7.34-7.16 (m, 10H), 6.82 (s, 1H), 6.55 (s, 1H), 6.31 (s, 1H), 6.14 (d, J=1.8 Hz, 1H), 5.64 (d, J=1.8 Hz, 1H), 4.22-4.10 (m, 4H), 3.92 (s, 1H), 3.77 (s, 3H), 3.49 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25].[OH-].[Na+].[Na+].[I-].Cl[CH2:31][C@@H:32]([OH:35])[CH2:33][OH:34]>C(O)(C)C.C(O)=O>[OH:35][C@@H:32]([CH2:33][OH:34])[CH2:31][O:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Reactant: OC[C@H](O)CCl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=CO
Product: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OC[C@@H](O)CO
Temperature: 90 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (8.9 mg, 0.025 mmol) in isopropanol (1 mL) is added 2 N aq. NaOH (100 μL), NaI (1 mg, 0.007 mmol) and (S)-3-chloro-propane-1,2-diol (11.1 mg, 0.1 mmol). The reaction mixture is heated to 90° C. and shaken for 8 h before it is cooled to rt. Formic acid (0.2 mL) is added and the reaction mixture is separated by prep. HPLC to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-benzylamide (3.7 mg) as a colourless lyophilisate. LC-MS: tR=0.94 min, [M+1]+=430.27.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:21]3[CH2:20][CH2:19][CH2:18][C:17]4([CH2:25][CH2:24][CH2:23][CH2:22]4)[C:16]=3[N:15]=[C:14]([NH2:26])[N:13]=2)(=O)=O)=CC=1.Cl.Cl.[NH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[N:34]=1>>[NH2:39][C:35]1[N:34]=[C:33]([NH:32][CH2:31][CH2:30][NH:29][C:12]2[C:21]3[CH2:20][CH2:19][CH2:18][C:17]4([CH2:22][CH2:23][CH2:24][CH2:25]4)[C:16]=3[N:15]=[C:14]([NH2:26])[N:13]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Reactant: NCCNc1ccnc(N)n1
Agent: Cl
Product: Nc1nccc(NCCNc2nc(N)nc3c2CCCC32CCCC2)n1

Procedure:
The product from Example 10D (61 mg, 0.163 mmol) and the product from Example 1E (44 mg, 0.195 mmol) were treated under the conditions of Example 1F to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (dd, J=11.19, 5.43 Hz, 2H) 1.47-1.57 (m, 2H) 1.57-1.69 (m, 4H) 1.69-1.83 (m, 2H) 1.96-2.09 (m, 2H) 2.16 (t, J=5.93 Hz, 2H) 3.33-3.52 (m, 4H) 5.45 (s, 2H) 5.66-5.77 (m, 1H) 5.84 (s, 2H) 6.20 (s, 1H) 6.89 (s, 1H) 7.61 (d, J=5.09 Hz, 1H); MS (ESI+) m/z 355.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13]>CCN(CC)CC.[Cu]I>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=2)[NH:7][N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1n[nH]c2ccc(C#C[Si](C)(C)C)cc12
Temperature: 25 °C

Procedure:
5-Bromo-3-methyl-1H-indazole (1.72 g, 8.2 mmol), PdCl2(PPh)2 (1.14 g, 1.64 mmol), CuI (155 mg, 0.82 mmol) and ethynyltrimethylsilane (3.5 mL, 24.6 mmol) were dissolved in 180 mL Et3N and refluxed over night. The mixture was cooled to room temperature, filtered and evaporated. The residue was taken up in MeOH (100 mL), filtered again and evaporated. The product thus obtained was purified on glass column chromatography (20% EtOAc in hexane). The title compound was obtained as a dark solid. LCMS (API-ES) m/z (%): 229.0 (100%, M++H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[C:4]([C:11]#[N:12])[CH:3]=1.[N+:13]([CH:16]([CH:19]=O)[CH:17]=O)([O-:15])=[O:14].[Na].Cl>C(O)CC>[C:7]([N:6]1[C:2]2=[N:1][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:19]=[C:3]2[C:4]([C:11]#[N:12])=[CH:5]1)([CH3:8])([CH3:9])[CH3:10]
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: CC(C)(C)n1cc(C#N)cc1N
Agent: Cl
Agent: [Na]
Solvent: CCCO
Product: CC(C)(C)n1cc(C#N)c2cc([N+](=O)[O-])cnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a solution of 5.85 g (35.8 mmol) of 5-amino-1-tert-butyl-1H-pyrrole-3-carbonitrile, being prepared as disclosed in Org. Proc. Res. Dev., 7(2), 209-213, 2003, in 120 mL of n-propanol, it was added sodium nitromalonaldehyde (6.02 g, 43.0 mmol) portionwise under stirring at room temperature. The resulting mixture was treated dropwise with 37% hydrochloric acid (4.6 mL, 55.2 mmol) and heated at 100° C. for 2 hours. The reaction mass was concentrated under vacuum to ⅓ of the initial volume and kept at 4° C. for 18 hours. The precipitate was filtered off, washed thoroughly with 15% aqueous ethanol (35 mL), water (5 mL) and finally dried to afford 7.14 g of the title compound as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8](Cl)[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.Cl.[Cl:17][C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[C:18]([Cl:17])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:25][CH2:26]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2c1

Procedure:
The benzoimidazole from step (b) above (210 mg, 0.7 mmol), 1-(3-chloropyridin-2-yl)piperazine hydrochloride (187 mg, 0.8 mmol, Example 3b) and N,N-diisopropylethylamine (0.28 mL, 1.6 mmol, Aldrich) were reacted under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 461 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#[CH:17]>CN(C=O)C>[Cl:10][C:5]1[CH:4]=[C:3]([CH2:2][N:11]2[CH:17]=[C:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])[N:13]=[N:12]2)[CH:8]=[CH:7][C:6]=1[Cl:9]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: [N-]=[N+]=[N-]
Reactant: C#CC(=O)OCC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 4-(bromomethyl)-1,2-dichlorobenzene (2 g, 8.3 mmol), in DMF (30 mL) was added sodium azide (0.65 g, 1.2 eq). The reaction was stirred at 80° C. for 3 hours. The solvent was then evaporated and the residue was dissolved in DCM and washed with water. The organic phase was dried over sodium sulphate and the solvent was evaporated. The crude azido compound was dissolved in ethanol (100 mL) and ethyl 2-propynoate (1 mL, 1.2 eq) was added. The reaction was stirred to reflux for 24 hours. The reaction was not completed and 0.3 mL of ethyl 2-propynoate was added and the reaction was stirred to refleux for more 24 hours. Ethanol was evaporated and the reaction was dissolved in DCM and washed with water, dried over sodium sulphate and concentrated in vacuo. Purification by flash chromatography eluting with DCM and DCM/MeOH 99/1 gave the title compound as a white solid (1.5 g, 60%). LC/MS: m/z 300 (M+H)+. Rt: 3.12 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:6]1[CH:7]=[C:2]([C:30]2[CH:31]=[N:32][CH:33]=[C:28]([F:27])[CH:29]=2)[CH:3]=[CH:4][C:5]=1[F:26])[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1cc(C2(c3cc(Br)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Product: Cc1cc(C2(c3cc(-c4cncc(F)c4)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Yield: 41 %

Procedure:
The title compound was synthesized as described for Example 1 in 41% yield, starting from 1-(5-bromo-2-fluorophenyl)-4-fluoro-1-(2-methylpyridin-4-yl)-1H-isoindol-3-amine (80 mg, 0.19 mmol) and 5-fluoropyridin-3-ylboronic acid (35.4 mg, 0.25 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[C:23]([N:31]=[C:32]=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.I[CH3:35]>CC(C)=O>[C:23]([NH:31][C:32](=[N:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1)[S:33][CH3:35])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Reactant: CI
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(N=C(NC(=O)c3ccccc3)SC)cc2)n1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a heterogeneous brown mixture of 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.260 g, 0.886 mmol) in 2 mL acetone was added benzoyl isothiocyanate (0.136 ml, 0.975 mmol) dropwise via syringe. The mixture became homogeneous and remained brown. After 10 min, a precip formed. After 16 h, iodomethane (0.0554 ml, 0.886 mmol) was added, and the reaction was heated to 80° C. The mixture became homogeneous. After 3 h, further iodomethane (0.0554 ml, 0.886 mmol) was added and after 1 h at 80° C. and 3 days at ambient temperature, the reaction was adsorbed onto 1.7 g SiO2 and dried. The solid was purified by silica gel chromatography, 40 g, 0-10% MeOH/MC, to give 1-benzoyl-2-methyl-3-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)isothiourea which was used without further purification. MS m/z=471 [M+H]+. Calc'd for C25H22N6O2: 470.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:19](=[O:36])[N:20]([C:27]2[O:35][C:31]3=[CH:32][CH:33]=[CH:34][C:30]3=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:19](=[O:36])[N:20]([C:27]2[O:35][C:31]3=[CH:32][CH:33]=[CH:34][C:30]3=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][C:15]([C:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(Br)cc2)cc1
Reactant: OB(O)C1=CCCCC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(C3=CCCCC3)cc2)cc1
Temperature: 130 °C
Yield: 102.1 %

Procedure:
A mixture of 4-[2-(4-benzofuran-2yl-phenylcarbamoyl)-2-(4-bromo-phenyl)-ethyl]-benzoic acid methyl ester (0.4 g, 0.74 mmol), cyclohexen-2-ylboronic acid (0.23 g, 1.85 mmol), PdCl2 (o-tolylphosphine) (75 mg, 0.096 mmol), and Na2CO3 (390 mg, 3.70 mmol) in DME/EtOH/H2O (4:2:1) (17.5 mL) was heated in an oil bath at 130° C. for 2 h, cooled to rt, filtered and washed with EtOAc (20 mL). The solvent was removed under reduced pressure. The crude mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel, eluting with ethyl acetate:hexanes (3:2) to afford 4-[2-(4-benzofuran-2-yl-phenylcarbamoyl)-2-(4-cyclohex-1-enyl-phenyl)-ethyl]-benzoic acid methyl ester as a white solid (0.42 g). 1H NMR (300 MHz, CDCl3): δ 10.23 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.54-7.65 (m, 4H), 7.21-7.34 (m, 8H), 6.10 (bt, 1H), 4.02 (m, 1H), 3.78 (s, 3H), 3.45 (dd, J=8.7, 13.5 Hz, 1H), 3.04 (dd, J=6.6, 13.5 Hz, 1H), 2.25-2.40 (m, 2H), 2.10-2.20 (m, 2H), 1.64-1.72 (m, 2H), 1.54-1.59 (m, 2H); LC-MS m/z=556 [C37H33NO4+H]+; TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate/hexanes (2:1); Rf=0.45.