Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:25])[C:12]2[CH:13]=[C:14]([CH2:23]C)[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+].[CH2:29](O)C>>[CH2:25]([N:11]([C:12]1[CH:13]=[C:14]([CH3:23])[C:15]2[O:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:16]=2[CH:22]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:26])=[CH:10][CH:9]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc(N(C)c2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCN(c1ccc(C(=O)O)cc1)c1cc(C)c2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 4-[methyl-(7-ethyl-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 21, 0.095 g, 0.27 mmol) in 10 mL of ethanol was treated with 2 mL (10 mmol) of 5M sodium hydroxide solution and the reaction mixture was stirred overnight at room temperature, and at 55° C. for 2 hours. The volatiles were removed by distillation in vacuo and the residue was neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound (0.070 g, 80%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.92 (d, 2H, J=9.0 Hz), 6.83 (d, 1H, J=2.1 Hz), 6.80 (d, 1H, J=2.1 Hz), 6.65 (d, 2H, J=9.0 Hz), 4.30 (s, 2H), 3.34 (s, 3H), 2.64 (q, 2H, J=7.6 Hz), 1.35(s, 6H), 1.23 (t, 3H, J=7.6 Hz).
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:14]([N:16]2[CH:20]([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[N:46]1[CH:51]=[CH:50][CH:49]=[N:48][C:47]=1[NH2:52]>CN(C)C=O>[CH:7]1([CH2:12][C@H:13]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:14]([N:16]2[C@H:20]([C:21]([NH:52][C:47]3[N:48]=[CH:49][CH:50]=[CH:51][N:46]=3)=[O:23])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C=CCOC(=O)N1CCC(C(=O)O)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Reactant: Nc1ncccn1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CC[C@@H](C(=O)Nc2ncccn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 23.8 %

Procedure:
1-Methylimidazole (38.1 μl, 0.478 mmol) was added into the solution of 2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidinecarboxylic acid (115 mg, 0.239 mmol) in N,N-dimethylformamide (DMF) (1.6 ml). The resulting solution was cooled to 0° C., and then mesyl chloride (19.41 μl, 0.251 mmol) was added dropwise at 0° C. To the reaction mixture was added 2-pyrimidinamine (34.1 mg, 0.358 mmol). After stirring for 3.5 hrs at ambient temperature, the reaction solution was purified by RP-HPLC to yield 2-propen-1-yl (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-3-[(2-pyrimidinylamino)carbonyl]-1-pyrazolidinecarboxylate (32 mg, 0.057 mmol, 24% yield). MS (ES+) m/z 559.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6](O)=O)=[C:4]([F:12])[CH:3]=1.[NH:13]([C:15](=[S:17])[NH2:16])[NH2:14].O=P(Cl)(Cl)Cl>>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]2[S:17][C:15]([NH2:16])=[N:13][N:14]=2)=[C:4]([F:12])[CH:3]=1
Reactant: NNC(N)=S
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(-c2c(F)cc(Br)cc2F)s1
Temperature: 78 °C
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
A stirred mixture of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol) and hydrazinecarbothioamide (2.88 g, 31.6 mmol) was cooled under nitrogen in an ice bath. POCl3 (5.9 mL, 63.3 mmol) was added drop-wise and the reaction was stirred at ice bath temperature for 15 minutes then heated at 78° C. for 3 hours. The reaction mixture was cooled in an ice bath then quenched by addition of ice water (150 mL). The resulting solid was sonicated for 30 minutes to give a free stirring suspension which was left to slurry at room temperature for 72 hours. The solid was collected by vacuum filtration, rinsed with water, and re-suspended in saturated NaHCO3(aq) (150 mL). This suspension was stirred at room temperature for 18 hours then the solid was collected by vacuum filtration, rinsed with water, and dried in a vacuum oven for 24 hours to give the title compound (5.174 g, 84% yield) which was used in the next step without further purification. LC-MS: Rt 0.99 min; MS m/z 294.2 [M+2]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (d, J=8.08 Hz, 2H), 7.57 (s, 2H).
Reaction SMILES: [C:1]([CH2:8][CH2:9][CH2:10][NH:11][NH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1F)[C:24]#[N:25]>CN(C=O)C>[C:1]([CH2:8][CH2:9][CH2:10][N:11]([NH2:12])[C:28]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[Cl:20])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CCCNN
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CCCN(N)c1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3.49 g (20 mmol) 3-Boc-amino-propylamine in 5 ml DMF are combined with 2.75 ml (25 mmol) NMM. After the addition of 3.11 g (20 mmol) 3-chloro-4-fluoro-benzonitrile the mixture is stirred for 3.5 hours at ambient temperature under a nitrogen atmosphere, heated to 105° C. for 20 minutes and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac. The residue is further reacted without any more purification.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.CCOC(C)=O>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 52.6 %

Procedure:
Under nitrogen dissolve 1-benzhydrylazetan-3-ol (5 g, 20.9 mmol), imidazole (3.5 g, 52.25 mmol) in anhydrous DMF (25 mL). Cool solution in an ice bath, add slowly tert-butyldimethylsilyl chloride (50 wt. % solution in toluene, 6.3 g, 41.8 mmol). Stir at RT for 22 h. Dilute with EtOAc and wash with saturated aqueous sodium bicarbonate solution. Separate organic layer, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 EtOAc:hexanes) to give the title compound (3.89 g, 53%).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[C:13]([I:19])[C:14](I)=[CH:15][CH:16]=2)[C:11](=[O:20])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:14]2[C:13]([I:19])=[C:12]3[C:17](=[CH:16][CH:15]=2)[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][NH:10][C:11]3=[O:20])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: O=c1[nH]nc(Cc2ccccc2)c2ccc(I)c(I)c12
Product: CC(=O)Nc1ccc(-c2ccc3c(Cc4ccccc4)n[nH]c(=O)c3c2I)cc1

Procedure:
1-Benzyl-5,6-diiodo-phthalazin-4-one (Indian J. Chem. 16B, 1978, 301-304) is reacted analogously to Example 1/f. with 1 equivalent of 4-acetamidophenyl-boronic acid. The title compound is obtained in pure form by chromatography on silica gel.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]([CH3:29])[C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2.Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:32]([CH2:31][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]([CH3:29])[C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2)#[N:33]
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2cc(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (0.90 g, 2.32 mmol), prepared in step-4 of Example 31, bromoacetonitrile (0.194 mL, 2.79 mmol) and potassium carbonate (1.6 g, 11.6 mmol) in 10 mL DMF was stirred under nitrogen at room temperature for 24 h (overnight). The reaction was diluted with ethyl acetate and extracted five times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-benzofuran-3-carboxylic acid (6-cyanomethoxy-naphthalen-2ylmethyl)-methyl-amide (0.94 g, 95%) as a brown oil, MS m/z: 427 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([CH:25]=O)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:17][C:3]1[C:2]([NH:1][CH2:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)=[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:6]=[C:5]([Cl:16])[N:4]=1
Reactant: C[C@H]1CC[C@H](C=O)CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1NC[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (3-amino-2,6-dichloropyridin-4-yl)carbamate (353 g, 1.27 mol) and trans-4-methylcyclohexanecarbaldehyde (160 g, 1.27 mol) in DCM (8.0 L) and acetic acid (2 ml) was added sodium triacetoxyborohydride (807.7 g, 3.81 mol) at 0° C. The mixture was stirred for 15 min, and then warmed to room temperature. The mixture was stirred for 15 h at room temperature and then quenched with water (10 L). The mixture was filtered, the filtrate was separated, and the organic layer was concentrated under reduced pressure to give crude product. The crude product was purified over a silica gel column, eluting with EtOAc: petroleum ether (0-1:10), to give tert-butyl (2,6-dichloro-3-(((trans-4-methylcyclohexyl)methyl)amino)pyridin-4-yl)carbamate.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([NH:15][C:16]([NH2:18])=[S:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>C(OCC)(=O)C>[N:15]1[C:5]2[C:14]3[C:9]([CH:8]=[CH:7][C:6]=2[S:17][C:16]=1[NH2:18])=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: NC(=S)Nc1cccc2ccccc12
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1nc2c(ccc3ccccc32)s1
Temperature: 25 °C
Yield: 74 %

Procedure:
To 160 ml thionyl chloride 64.0 g (0.32 mol) of 1-(1-naphthyl)-2-thiourea was added portionwise while the temperature of the reaction mixture was kept at 30°-40° (internal temperature). After the addition was completed, an additional 80 ml of thionyl chloride was added and the mixture was heated at 50°-55° for 4 hours. It was cooled to room temperature and diluted with 400 ml of ethyl acetate and filtered. The filtrate in 400 ml of water was basified with concentrated ammonium hydroxide and the aqueous suspension was extracted with ethyl acetate (3×200 ml). The combined ethyl acetate solutions were dried (MgSO4) and the solvent was removed under reduced pressure to give 46.6 g (74%) of naphtho[1,2-d]thiazol-2-amine, mp 186°-188°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([N-]C(C)C)(C)C.[Li+].[CH3:17][S:18]SC.S(=O)(=O)(O)O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:18][CH3:17])[C:3]=1[F:8]
Reactant: Fc1ccccc1Br
Reactant: CSSC
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1cccc(Br)c1F
Yield: 50 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (2.0 g, 11.4 mmol) in dry tetrahydrofuran (50 ml) under nitrogen, at −78° C. was added lithium diisopropylamide (2.5 M in hexane, 6.28 ml, 15.4 mmol). The mixture was stirred for 5 minutes after which dimethyldisulfide (0.92 ml, 15.4 mmol) was added and the stirring was continued at −78° C. for an additional hour. The reaction mixture was brought to ambient temperature and aqueous sulfuric acid (10%, 50 ml) was added. The phases were separated and the aqueous phase extracted with ethylacetate (3×100 ml). The combined organic phases was dried (MgSO4) and evaporated to dryness to give an oil. The residue was purified by flash column chromatography (isooctane) to give the title compound (1.26 g). MS m/z (relative intensity, 70 eV) 222 (M+, bp), 220 (M+, 91), 189 (24), 187 (25), 126 (97).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=2)=[C:12]([CH3:24])[CH:11]=1)=[O:8])=[O:5].[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([NH:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=2)=[C:12]([CH3:24])[CH:11]=1)=[O:8])=[O:5])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: Cc1cc(NC(=O)NC(=O)c2ccccc2N)ccc1Oc1ncc(Br)cn1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1C(=O)NC(=O)Nc1ccc(Oc2ncc(Br)cn2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.3 g of N-(2-aminobenzoyl)-N'-[4-(5-bromo-2-pyrimidinyloxy)-3-methylphenyl]urea (Compound No. 27 as described hereinafter) as prepared in accordance with Preparation Example 3, was added to 30 ml of pyridine, and 0.25 ml of acetyl chloride was dropwise added thereto under cooling with ice. The mixture was stirred at room temperature for 2 hours and 30 minutes. Then, pyridine was distilled off, and the residue was purified by silica gel column chromatography (developing solvent; methylene chloride:ethyl acetate=7:3) to obtain 1.18 g of the desired product (melting point: 186°-191° C.) (Compound No. 49 as described hereinafter).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[O:28]CC=C)[CH2:11][CH2:10]2)=[CH:7][C:6](=[O:32])[N:5]([CH3:33])[C:4]1=[O:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO.[Pd]>[CH3:2][N:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[OH:28])[CH2:11][CH2:10]2)=[CH:7][C:6](=[O:32])[N:5]([CH3:33])[C:4]1=[O:34]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1OCCCN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Cn1c(N2CCN(CCCOc3ccc([N+](=O)[O-])cc3O)CC2)cc(=O)n(C)c1=O
Yield: 78.8 %

Procedure:
0.6 g of 1,3-dimethyl-6-{4-[3-(2-allyloxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 161--free form) was dissolved in 10 ml of methanol, followed by the addition of 0.1 g of 10% Pd/activated carbon, 0.1 g of p-toluenesulfonic acid monohydrate and 2 ml of water. The resultant mixture was heated for 15 hours under stirring and reflux. After allowing the reaction mixture to cool down, insoluble matters were filtered off and the filtrate was concentrated. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol=50/1, by volume), thereby thereby obtaining 0.4 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]2[NH:8][CH:9]=[C:10]([CH2:11][CH:12]([NH2:16])[C:13]([OH:15])=[O:14])[C:3]=2[CH:2]=1.[CH:17](OC(=O)C)=[O:18]>>[CH:17]([NH:16][C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][C:10]1[C:3]2[C:4](=[CH:5][C:6]([Cl:7])=[CH:1][CH:2]=2)[NH:8][CH:9]=1)=[O:18]
Reactant: CC(=O)OC=O
Reactant: NC(Cc1c[nH]c2cc(Cl)ccc12)C(=O)O
Product: O=CN[C@@H](Cc1c[nH]c2cc(Cl)ccc12)C(=O)O

Procedure:
15 g(628 mM) of dl-6-chlorotryptophan was treated with 15 ml of acetic-formic anhydride. An exothermic reaction ensued, accompanied by solidification of the reaction slurry. Excess solvents were distilled off under vacuum and the resultant solids, after first leaching with dilute acid, were recrystallized from ethyl acetate to yield 12.45 g, 74%, of product, m.p. 181°-3° dec.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)[CH:10]=2)=[C:4]([CH3:25])[CH:3]=1.[C:26]([O:29][CH2:30][CH2:31]Br)(=[O:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:26]([O:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH:21]=[O:22])=[CH:23][CH:24]=3)[CH:10]=2)=[C:6]([CH3:8])[CH:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OCCBr
Reactant: Cc1cc(O)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1cc(C)c(-c2cccc(COc3ccc(C=O)cc3)c2)c(C)c1
Temperature: 60 °C
Reaction time: 21 h

Procedure:
A mixture of 4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]benzaldehyde, 2-bromoethyl acetate, cesium carbonate and DMF was stirred at 60° C. for 21 hours to obtain 2-({3′-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)ethyl acetate.
Reaction SMILES: [CH3:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].I[CH2:14][C@@H:15]1[CH2:19][N:18]([C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:17](=[O:28])[CH2:16]1.O>CS(C)=O>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:1])([CH2:14][C@H:15]1[CH2:16][C:17](=[O:28])[N:18]([C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[CH2:19]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](CI)CC1=O
Reactant: COC(=O)C(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)(C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1)C(=O)OC
Yield: 67.1 %

Procedure:
To dimethyl methylmalonate (1.06 g, 7.29 mmol) in DMSO (7 mL) at room temperature was added NaH (291 mg of a 60% dispersion in oil). After the effervescence had ceased the lactam 85 (2 g, 7.29 mol) in DMSO (5 mL) was added. After 1 hour water was added and the aqueous solution extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (1:1 hexane/acetone) of the residue gave the product as an oil (1.7 g, 81%). MS n/z 348 (M+H, 100%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.O>C(#N)C>[F:14][C:7]([F:6])([F:13])[C:8]([NH:5][CH2:4][CH2:3][NH:2][CH3:1])=[O:10]
Reactant: CNCCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CNCCNC(=O)C(F)(F)F
Reaction time: 8 h
Yield: 142.6 %

Procedure:
A solution of N-methylethylenediamine (27.0 g, 364 mmol) and ethyl trifluoroacetate (96.6 mL, 812 mmol) in a mixture of ACN (350 mL) and water (7.8 mL, 436 mmol) was refluxed with stirring overnight. Solvents were evaporated in vacuo. The residue was re-evaporated with i-PrOH (3×100 mL), followed by heat-cool crystallization from DCM (500 mL). Formed crystals were filtered, washed with DCM and dried in vacuo to provide compound A (88.3 g, 85%) as white solid powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:24][C:17]1[CH:16]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:14]=[C:13]([F:12])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cc(Cl)cc(Cl)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 20.4 %

Procedure:
3,5-Dichlorobenzeneboronic acid (30.7 mg, 0.16 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (13 mg, 20%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20]([OH:22])=O)[C:6]2=[O:17].[C:34](N1C=CN=C1)([N:36]1C=CN=[CH:37]1)=O.CNC.O>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20](=[O:22])[N:36]([CH3:37])[CH3:34])[C:6]2=[O:17]
Reactant: CCOc1cc([C@@H](CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution of (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid (0.62 g, 1.3 mmol) in tetrahydrofurane (5 ml) was added carbonyldiimidazole (0.3 g, 2 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added THF solution of dimethylamine (2 M, 1.3 ml, 2.6 mmol). The resulted mixture was stirred at room temperature for 4 hrs. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and to the resulted mixture was added ethyl acetate (30 ml). The mixture was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulted oil was stirred with ether (5 ml) for 2 hrs and filtered to give (1R)-cyclopropanecarboxylic acid {7-chloro-2-[2-dimethylcarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.5 g, 77%): mp 163-165° C.; 1HNMR (CDCl3): δ 0.86-0.89 (m, 2H, c-CH2), 1.08-1.11 (m, 2H, c-CH2), 1.46 (t, J=7.5 Hz, 3H, OCH2CH3), 1.65-1.68 (m, 1H, c-CH), 2.93 (s, 3H, NCH3), 3.04 (dd, J=5, 16 Hz, 1H, CHH), 3.12 (s, 3H, NCH3), 3.56 (dd, J=5, 16 Hz, 1H, CHH), 3.86 (s, 3H, OCH3), 4.10 (q, J=7.5 Hz, 2H, OCH2CH3), 4.25 (d, J=17 Hz, 1H, NCHH), 4.60 (d, J=17 Hz, 1H, NCHH), 5.58-5.64 (m, 1H, CHN), 6.83-6.97 (m, 3H, Ar), 7.35 (d, J=9 Hz, 1H, Ar), 8.41 (d, J=9 Hz, 1H, Ar), 10.51 (s, 1H, NH); 13C NMR (CDCl3): 8.9, 15.4, 16.8, 36.2, 36.6, 38.0, 48.6, 54.3, 56.6, 65.2, 112.1, 113.1, 119.8, 120.0, 120.1, 122.3, 132.2, 133.2, 137.3, 139.9, 149.2, 149.8, 169.4, 170.1, 173.2; Anal. Calcd. for C26H30ClN3O5: C, 62.46; H, 6.05; N, 8.40. Found: C, 62.43; H, 5.42; N, 8.51.