Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:7]([O:8][CH3:9])[C:4]=1[O:5][CH3:6].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][C:12]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1OC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(OC)c1OC
Yield: 78.7 %

Procedure:
Pyrogallol trimethyl ether (5.1 g) was suspended in CCl4 (60 mL) and N-bromosuccinimide (6.5 g, 1.2 eq.) was added. The reaction mixture was heated at reflux for 20 hours. The succinimide was collected and the filtrate concentrated in vacuo to a brown oil. The oil was separated by gravity column chromatography (hexane-ethyl acetate, 19: 1) and yielded the title compound as a yellow oil (5.9 g, 78%): EIMS m/z 234 ((M+ —CH3, 81Br), 232 (M+ —CH3, 79Br), 107, 95, 69, 58, 44; 1H NMR (CDCl3, 300 MHZ) δ 7.21 (1H, d, J=9.0 Hz, H6), 6.58 (1H, d, J=9.0 Hz, H5), 3.91 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.85 (3H, s, OCH3).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3](=[O:14])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1>CO.Cl.[Pd]>[NH2:13][CH2:12][C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3](=[O:14])[C:2]([CH3:15])([CH3:1])[CH3:16])=[CH:7][CH:8]=1
Reactant: CC(C)(C)C(=O)COc1ccc(C#N)cn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)C(=O)COc1ccc(CN)cn1
Yield: 55.7 %

Procedure:
Bubble nitrogen into a solution of 6-(3,3-dimethyl-2-oxo-butoxy)-pyridine-3-carbonitrile (400 mg, 1.8 mmol) in methanol (36 mL) with 3 drops of concentrated HCl for 10 min. Add 10% Pd/C (Degussa type E101, 80 mg) and submit the mixture to hydrogenation at atmospheric pressure overnight. Filter the reaction mixture over Celite®. Concentrate the filtrate in vacuo and purify by SCX chromatography to obtain the title compound (223 mg, 55%). MS (ES+) m/z: 223 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[CH:9]=2)=[O:4].[C:25]([Cu])#[N:26].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(I)c2cc(Oc3ccccc3F)ccc2c1O
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3F)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
7-(2-Fluoro-phenoxy)-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.23 mmol) and CuCN (41 mg, 0.46 mmol) were suspended in DMF (1.0 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 75 mg. 1H NMR (CDCl3, 200 MHz): δ=12.27 (s, 1H), 8.45 (d, 1H, J=9.0 Hz), 7.63-7.57 (m, 1H), 7.50-7.48 (m, 1H), 7.29-7.20 (m, 4H), 4.11 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=[O:19]>C(OCC)(=O)C>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=[O:19]
Reactant: O=C(CBr)c1ccco1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccco2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromoacetylfuran (prepared according to the method of S. Kajigaeshi et al., Bull. Chem. Soc. Jpn., 1987, 60, 1159-1160). tlc: Rf=0.4 (33% ethyl acetate in hexanes)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:68]=[CH:67][C:53]2[NH:54][C:55]([C@@H:57]([NH2:66])[CH2:58][O:59][C:60]([O:62][CH:63]([CH3:65])[CH3:64])=[O:61])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:66][C@H:57]([C:55]1[NH:54][C:53]2[CH:67]=[CH:68][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][O:59][C:60]([O:62][CH:63]([CH3:65])[CH3:64])=[O:61])=[O:7]
Reactant: CC(C)OC(=O)OC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)OC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 40 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine and (R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-isopropoxycarbonyloxyethylamine in tetrahydrofuran. Yield: 40%; C25H24Cl2N4O5 (531.394); mass spectrum: (M+H)+=531/533/535 (chlorine isotope).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>>[C:11]([C:9]1[CH:10]=[C:4]([NH:1][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:5]([NH:6][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1)#[N:12]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccc(C#N)cc2NC(=O)c2ccc(OC)cc2)cc1

Procedure:
Using the procedures described in Example 93, Part A and Example 96, Part B, 2-nitro-4-cyanoaniline (31 mmol) and 4-anisoyl chloride yielded 500 mg (21%, three steps) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[NH2:18][C:19](=[N:31]O)[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[F:30]>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:10][N:31]=[C:19]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=3[F:30])[N:18]=2)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)c1ccc(C(N)=NO)c(F)c1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(C)c3)n2)c(F)c1

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 3 (113.1 mg; 0.50 mmol; 1 eq.) and Intermediate 2 (106.1 mg; 0.50 mmol; 1 eq.). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a off-white solid. LC/MS (Method A): 403.0 (M+H)+. HPLC (Method A) Rt 6.20 min (Purity: 96.8%).
Reaction SMILES: [C:1](N1C2C(=NC=CC=2)N=N1)(=[O:3])[CH3:2].[OH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=1.[OH-].[Na+]>C1COCC1.Cl>[C:1]([O:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][OH:13])=[CH:18][C:19]=1[O:24][CH3:25])(=[O:3])[CH3:2]
Reactant: COc1cc(OCCO)ccc1O
Reactant: CC(=O)n1nnc2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OCCO)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-acetyl-1H-1,2,3-triazolo[4,5-b]pyridine (0.248 g, 1.532 mmol) in dry THF (6.13 mL) was added to a solution of 4-(2-hydroxyethoxy)-2-methoxyphenol (0,2821 g, 1.532 mmol) in 1N aq. NaOH (1.532 mL, 1.532 mmol) at 25° C. The reaction was stirred at 25° C. for 3 h. The reaction was diluted with 1IN HCl (20 mL) and extracted with Et2O (3×20 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 50% EtOAc in hexanes over 360 mL, gradient to 100% EtOAc over 2034 mL) to afford 4-(2-hydroxyethoxy)-2-methoxyphenyl acetate. Rf=0.28 (50% EtOAc/hexanes). LCMS calc.=249.1; found=249.0 (M+Na)+. 1H NMR (500 MHz, CHCl3): δ 6.87 (d, J=8.7 Hz, 1 H); 6.52 (d, J=2.7 Hz, 1 H); 6.38 (dd, J=8.7, 2.7 Hz, 1 H); 3.96 (t, J=4.7 Hz, 2 H); 3.84 (t, J=4.7 Hz, 2 H); 3.71 (s, 3 H); 2.97 (s, 1 H); 2.24 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH2:12]Br)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14](=[S:19])([O:16]CC)[NH2:15].CC(N(C)C)=O>C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[NH:15][C:14](=[O:16])[S:19][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Reactant: CCOC(N)=S
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NOC)c1csc(=O)[nH]1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (7.6 g.), O-ethyl thiocarbamate (3.0 g.) and dimethylacetamide (5 ml.) was stirred for 3 hours at 50° C. Ethyl acetate (50 ml.) was added to the reaction mixture and the resulting mixture was washed with water and with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ethyl acetate was distilled off to give crystalline residue. The residue was washed with diisopropyl ether to give ethyl 2-methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetate (syn isomer) (2.35 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]=[C:13]2[C:18](=[O:19])OC(C)(C)OC2=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O(C1C=CC=CC=1)C1C=CC=CC=1>CCCCCC>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:11]=[CH:12][CH:13]=[C:18]2[OH:19]
Reactant: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2nccc(O)c2cc1OC
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
5-((3,4-Dimethoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (16.1 g, 52 mmol) was added to a pre-heated 1000 mL round-bottom flask containing 1-phenoxy benzene (100 mL) at 230° C. The reaction was stirred for 5 min, and then cooled to 120° C. n-Hexane (100 mL) was added to the solution to allow the product to precipitate out from the reaction solution. The mixture was further stirred at rt overnight. The solid was collected and crystallized in a solution of EtOAc/n-hexane (50 mL, v/v=10/1) to afford the title compound as a brown solid (10.2 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:29][C:28]=1[C:38](O)=[O:39]>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:38]([C:28]4[N:29]=[C:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[O:31][C:27]=4[CH3:26])=[O:39])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C)cn3)cc2C1=O
Yield: 64 %

Procedure:
The compound of example 654 was prepared analogous to the compound of example 640 by reaction of compound of example 392 with 5-methyl-2-phenyloxazole-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([NH:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:43][CH2:44][CH3:45].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=[C:5]([C:7]([N:46]([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:42][CH2:43][CH2:44][CH3:45])=[O:9])[N:6]=1
Reactant: CCCCNCCCC
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CCCC)C(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a stirred solution of 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (2.4 g, 7.47 mmol) in dry DMF (40 mL) was added HATU (4.26 g, 11.2 mmol), dibutylamine (1.15 g, 8.9 mmol) and diisopropyl ethylamine (2.84 g, 22.4 mmol) successively at 0° C. The reaction mixture was allowed to warm to room temperature over 30 minutes and stirring was continued for 16 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo to give crude compound. The crude material was purified by flash chromatography (gradient from 20 to 30% EtOAc/hexanes) to provide the title compound (2.81 g, 87%). 1H NMR (CDCl3) δ 7.68 (s, 1H), 5.28 (s, 2H), 3.89 (t, J=8.0 Hz, 2H), 3.56 (t, J=8.0 Hz, 2H), 3.44 (t, J=8.0 Hz, 2H), 1.57-1.65 (m, 4H), 1.25-1.45 (m, 4H), 0.91-0.95 (m, 8H), 0.01 (s, 9H); MS(ESI+) m/z 434.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]3C=CC=C[C:21]3=2)[CH:16]=[C:15]1[CH3:27])[CH3:13]>>[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:7]([C:3]2[C:2]([C:10]([OH:9])=[O:11])=[N:1][CH:6]=[CH:5][N:4]=2)=[O:8])=[C:15]1[CH3:27])[CH3:13]
Reactant: CCn1c(C)cc2ccc3ccccc3c21
Reactant: O=C1OC(=O)c2nccnc21
Product: CCn1c(C)c(C(=O)c2nccnc2C(=O)O)c2ccccc21
Yield: 16.2 %

Procedure:
The appropriate keto-acid is prepared as follows. A mixture of about 6 grams of 2,3-pyrazinedicarboxylic anhydride and about 10.5 grams of 1-ethyl-2-methyl-1H-benz[g]indole is heated on a steam bath for about 24 hours. The mixture is extracted with toluene. About 2 grams of (1-ethyl-2-methylindol-3-yl)-(2-carboxypyrazin-3-yl)ketone is obtained having a melting point of 212°-213° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][O:36][C:35]([CH3:40])([CH3:39])[CH2:34]1>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][O:36][C:35]([CH3:40])([CH3:39])[CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1(C)CC(CBr)CCO1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC(C)(C)C3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A mixture of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (223 mg) and potassium carbonate (264 mg) in dry DMF (2 mL) were heated at 60° C. under nitrogen with stirring for 1 h. 4-(Bromomethyl)-2,2-dimethyltetrahydro-2H-pyran (158 mg) was added and the reaction was stirred for 16 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give a brown oil. The crude material was purified by normal phase chromatography (ISCO) using 5-20% methanol/EtOAc as eluent to give a pale oil (181 mg). The material was re-purified by normal phase chromatography (ISCO) using 0-15% methanol/EtOAc as eluent to give the title compound (161 mg).
Reaction SMILES: [OH:1][PH:2]([CH2:4][CH:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[O:3].C(N(C(C)C)CC)(C)C.Br[CH2:34][CH:35]=[CH:36][CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48]>ClCCl>[O:48]=[C:39]1[C:40]2[C:41](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42](=[O:43])[N:38]1[CH2:37][CH:36]=[CH:35][CH2:34][P:2]([CH2:4][CH:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])([OH:1])=[O:3]
Reactant: O=C1c2ccccc2C(=O)N1CC=CCBr
Reactant: O=C(OCc1ccccc1)C(CCc1ccccc1)C[PH](=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C(CCc1ccccc1)CP(=O)(O)CC=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Dichloromethane (30 mL) was added to (+)-benzyl 2-((hydroxyphosphinyl)methyl)-4-phenylbutanoate (8.10 g, 24.4 mmol) and 4Å molecular sieves (5.0 g). Diisopropylethylamine (4.70 mL, 3.49 g, 27.0 mmol) was added over 5 min. After cooling the reaction mixture in an ice bath, O,N-bis(trimethylsilyl)acetamide (17.7 mL, 14.6 g, 71.6 mmol) was added in one portion, followed in 10 min by N-(4-bromo-2-butenyl)phthalimide (8.80 g, 31.4 mmol). The mixture was allowed to slowly warm to room temperature and stirred for 20 h before being filtered. The sieve particles were rinsed with ethyl acetate (100 mL) and the filtrate was washed with 2N aqueous hydrochloric acid (2×50 mL) and saturated aqueous sodium chloride (25 mL). The aqueous layers were extracted in succession with ethyl acetate (50 mL). The organic layers were dried (sodium sulfate), decanted, and evaporated to give 15.66 g of almost colorless syrup containing benzyl 2-(((4-(1,3-dihydro-1,3-dioxo-2M-isoindol-2-yl)-2-butenyl)hydroxyphosphinyl)methyl)-4-phenylbutanoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]2[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])=[N:7][C:2]([NH:23][C:24]2[CH:37]=[CH:36][C:27]3[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:33])([CH3:34])[C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CN(CCC#N)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CN(CCC#N)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
Title compound was prepared from 3-{[2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenyl]-methyl-amino}-propionitrile and 8 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in an analogous manner to Example 1221d. Title compound isolated as a white lyophilate (67 mg, 53%). 99% purity, LCMS (510.19 M+H), 1H-NMR (CDCl3, 400 MHz) δ 12.00 (s, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.42-7.37 (m, 3H), 7.02-6.97 (m, 2H), 6.66 (d, J=9.0 Hz, 1H), 3.28 (t, J=6.4 Hz, 2H), 2.73 (s, 3H), 2.53 (t, J=6.6 Hz, 2H), 2.36 (t, J=6.8 Hz, 2H), 2.06 (t, J=6.9 Hz, 2H), 1.27 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:31]([I:32])=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33].CO[CH:36](OC)[N:37]([CH3:39])[CH3:38]>C1(C)C=CC=CC=1>[C:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:12]1[C@@H:11]2[C@H:15]([C@H:7]([CH2:6][C:5]3[CH:30]=[C:31]([I:32])[C:2]([N:1]=[CH:36][N:37]([CH3:39])[CH3:38])=[C:3]([F:33])[CH:4]=3)[CH2:8][S:9](=[O:28])(=[O:29])[CH2:10]2)[O:14][C:13]1=[O:16])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(I)c4)CS(=O)(=O)C[C@@H]32)c1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1c(F)cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1I
Temperature: 150 °C

Procedure:
To a suspension of (3aR,7S,7aS)-7-(4-amino-3-fluoro-5-iodo-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (2.0 g, 3.2 mmol) in toluene (20 mL) was added N,N-dimethylformamid-dimethylacetal (1.18 g, 9.6 mmol) and the reaction mixture was heated in the microwave oven for 0.5 h at 150° C. After evaporation the residue was purified by chromatography (CombiFlash, 40 g silica gel, hexane-EtOAc 10:1 to EtOAc) to yield the title compound as beige crystals: TLC (hexane-EtOAc 1:1) Rf=0.39; HPLC RtA=1.92 min; ESIMS [M+H]+=641; 1H NMR (400 MHz, CDCl3): δ 7.58 (d, 1H), 7.35 (m, 3H), 7.09 (d, 1H), 6.82 (dd, 1H), 4.54 (d, 1H), 4.33 (d, 1H), 3.83 (dt, 1H), 3.76 (t, 1H), 3.1 (m, 2H), 3.08 (s, 3H), 3.02 (s, 3H), 2.83 (t, 1H), 2.74 (dd, 1H), 2.58 (m, 2H), 1.31 (s, 9H).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([F:15])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:18][CH2:19][C@H:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:15][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH3:14])([CH3:13])[C:4]3[CH:3]=[CH:2][N:18]([CH2:19][C@H:20]([OH:22])[CH3:21])[C:5]=32)=[CH:10][CH:9]=1
Reactant: C[C@@H](O)CN
Reactant: CC1(C)c2ccc(F)cc2C(=O)C1CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)Cn1ccc2c1-c1cc(F)ccc1C2(C)C
Reaction time: 0.75 h
Yield: 55.9 %

Procedure:
A solution of 3.04 g of (RS)-2-(2-oxoethyl)-6-fluoro-3,3-dimethyl-1-indanone and 110 mg of p-toluenesulfonic acid in 100 ml of anhydrous toluene was heated on a water separator. A solution of 4.14 g of (R)-1-amino-2-propanol in 40 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 2.0 g (56%) of (R)-1-(7-fluoro-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:8][C:9]([CH3:13])=[N+:10]([O-:12])[CH:11]=1)([OH:3])=[O:2].[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:17][O:2][C:1]([CH2:4][O:5][C:6]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:8][C:9]([CH3:13])=[N+:10]([O-:12])[CH:11]=1)=[O:3]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc([N+](=O)[O-])c(OCC(=O)O)c[n+]1[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 59.7 %

Procedure:
The carboxylic acid (c) (8.4 g) in DMF (100 ml) was treated with potassium carbonate (7.6 g) and iodomethane (2.8 ml) and stirred for 3 days. After evaporation of solvent, water (200 ml) was added and the solid filtered off and dried under vacuum to give the product (5.32 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH2:11])[C:9]=1[Cl:10])[C:5]#[N:6].CCN(C(C)C)C(C)C.Br[CH2:22][CH2:23][OH:24]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:11][CH2:22][CH2:23][OH:24])[C:9]=1[Cl:10])[C:5]#[N:6]
Reactant: OCCBr
Reactant: N#Cc1cc(N)c(Cl)c(N)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(N)c(Cl)c(NCCO)c1
Temperature: 100 °C
Yield: 29.7 %

Procedure:
To a solution of 3,5-diamino-4-chlorobenzonitrile (200 mg, 1.193 mmol) in DMF (2 mL) was added Hunig's base (2.501 mL, 14.32 mmol) followed by 2-bromoethanol (0.506 mL, 7.16 mmol). The resulting solution was heated at 100° C. for 10 h. LC-MS indicated ca. 30% conversion. It was passed through a pad of celite, rinsed with EtOAc. After concentration, purification via silica gel chromatography (0-70% EtOAc in Hexanes, 24 g) gave 3-amino-4-chloro-5-((2-hydroxyethyl)amino)benzonitrile (75 mg) as an orange oil.