Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:32]3[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3cc(F)cc(F)c3)C2=O)cc1
Yield: 82 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3,5-difluorophenyl boronic acid instead of phenyl boronic acid to obtain the title compound (82%).
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[C:30]2[NH:37][NH2:38]>>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:37]([C:30]5[C:29]6[C:34](=[CH:35][CH:36]=[C:27]([F:26])[CH:28]=6)[N:33]=[CH:32][CH:31]=5)[N:38]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: NNc1ccnc2ccc(F)cc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Product: O=c1ccn(-c2ccc3c(c2)OC(F)(F)O3)nc1-c1ccnn1-c1ccnc2ccc(F)cc12

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and (6-fluoro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=464.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])=[CH:22][CH:21]=2)=[CH:4][C:5]2[N:9]=[C:8]([S:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[NH:7][C:6]=2[CH:19]=1>C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[C:3]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])=[CH:24][CH:25]=2)=[CH:4][C:5]2[N:9]=[C:8]([S:10][CH2:11][C:12]([OH:14])=[O:13])[NH:7][C:6]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(-c3ccc(-c4ccccc4O)cc3)c(Cl)cc2[nH]1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CSc1nc2cc(-c3ccc(-c4ccccc4O)cc3)c(Cl)cc2[nH]1

Procedure:
A solution of tert-butyl 2-(6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1H-benzo[d]imidazol-2-ylthio)acetate in TFA (0.9 mL) and water (0.1 mL) was stirred at room temperature for 2 h and concentrated. The resultant solid was purified with HPLC to afford the desired product. LCMS: calculated for C21H15ClN2O3S 410.05, observed m/e 411.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9])[O:12][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1
Reactant: O=[N+]([O-])c1c(F)cc(O)cc1Cl
Reactant: Cc1ccc(CCl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(COc2cc(F)c([N+](=O)[O-])c(Cl)c2)nc1
Temperature: 75 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
To a mixture of 3-chloro-5-fluoro-4-nitrophenol (2.6 g, 13 mmol), cesium carbonate (8.7 g, 27 mmol), and 2-(chloromethyl)-5-methylpyridine hydrochloride (2.4 g, 13 mmol) was added DMF (88 mL) and the resulting mixture was heated to 75° Celsius for 19 h. The mixture was cooled to RT and then stirred for an additional 20 h. The resulting mixture was then partitioned between sat. NaHCO3 and EtOAc. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to dryness. The resulting residue was purified using FCC to afford the title compound (2.93 g, 74%). MS (ESI): mass calcd. for C13H10ClFN2O3, 296.04; m/z found, 297.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J=1.4, 0.7, 1H), 7.55 (dd, J=7.9, 1.6, 1H), 7.32 (d, J=7.9, 1H), 6.93 (dd, J=2.5, 1.8, 1H), 6.79 (dd, J=11.1, 2.6, 1H), 5.19 (s, 2H), 2.37 (s, 3H).
Reaction SMILES: CN([Si](C)(C)C)C(=O)C(F)(F)F.FC(F)(F)C(O)=O.[NH2:20][C:21]1[CH:22]=[C:23]([OH:28])[C:24](=[CH:26][CH:27]=1)[OH:25].Cl[C:30]([NH:32][NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:31].CO>C(#N)C.ClCCl.CCOCC>[OH:28][C:23]1[CH:22]=[C:21]([NH:20][C:30]([NH:32][NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[O:31])[CH:27]=[CH:26][C:24]=1[OH:25]
Reactant: Nc1ccc(O)c(O)c1
Reactant: O=C(Cl)NNC(=O)OCc1ccccc1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: O=C(NNC(=O)OCc1ccccc1)Nc1ccc(O)c(O)c1
Reaction time: 0.5 h

Procedure:
15.64 ml (80.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added to a suspension of 4.80 g (20.0 mmol) of 4-aminocatechol trifluoroacetate in 80 ml of dry acetonitrile. After stirring for 30 minutes, the dark solution was evaporated in vacuo and the dark residue was redissolved in 25 ml of dichloromethane. A solution of 4.56 g (20.0 mmol) of 2-(chlorocarbonyl)hydrazinecarboxylic acid, phenylmethyl ester in 50 ml of dichloromethane was slowly dropped in with stirring at 10° C. (40 minutes), and stirring was continued for 2 hours at room temperature. After evaporation in vacuo, the residue was taken up in a few ml of methanol and stirred until it became crystalline. The suspension was dluted with ether, and the precipitate was collected by suction; yield: 6.09 g, melting point 204° C., dec.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]([Cl:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1CCCCC1.C(OCC)(=O)C>[CH:8]1([C:7]2[CH:2]=[CH:3][C:4]([CH:14]([Cl:16])[CH3:15])=[CH:5][CH:6]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(Cl)c1ccc(C2CCCCC2)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(Cl)c1ccc(C2CCCCC2)cc1

Procedure:
1-(3'-Chloro-4'-cyclohexyl-phenyl)-1-chloro-ethane, an oil, Rf -value 0.8 on carrier A with cyclohexane/ethyl acetate =4/1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:26])[N:15]4[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:28][OH:29].C([O-])([O-])=O.[Na+].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:26])[N:15]4[CH2:24][CH2:23][C:22](=[N:28][OH:29])[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CCC(=NO)CC2
Reaction time: 8 h

Procedure:
3-((3-fluorophenyl)ethynyl)-6,7,9,10-tetrahydroazepino[2,1-b]quinazoline-8,12-dione (0.1, 0.29 mmol, 1 equiv) was combined with hydroxylamine hydrochloride (40 mg, 0.58 mmol, 2 equiv) and aqueous Na2CO3 (0.5 mL) in a mixture of MeOH (10 mL) and water (1 mL). The mixture was stirred overnight. Then the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was purified by silica gel chromatography. MS (ESI): 362 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 8.15-8.13 (d, J=7.80 Hz, 1H), 7.76 (s, 1H) 7.64-7.59 (d, J=8.10 Hz, 1H), 7.52-7.48 (m, 3H), 7.36-7.33 (m, 1H), 4.46-4.35 (m, 2H), 3.15-3.08 (m, 2H), 2.84-2.73 (m, 2H), 2.59-2.55 (m, 2H). mGluR5 PAM EC50: +++. Fold shift at 10 μM: ++.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[O:17]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]1>>[O:17]1[CH:21]=[CH:20][C:19]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:18]1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccoc1
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccoc2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 3-furaldehyde gave the title compound as a yellow solid m.p.:130° C.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:5].[N:22]#[C:23][NH2:24].C(OCC)C>C(O)C>[ClH:1].[CH3:2][CH:3]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:23]([NH2:24])=[NH:22])=[CH:19][CH:20]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:5]
Reactant: N#CN
Reactant: Cc1ccc(OC(=O)C(C)Cc2ccc(N)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(OC(=O)C(C)Cc2ccc(NC(=N)N)cc2)cc1

Procedure:
In 200 ml of ethanol were dissolved 21.8 g of the p-methylphenyl α-methyl-β-(p-aminophenyl)-propionate hydrochloride obtained and 4.2 of cyanamide, and the resulting solution was subjected to reaction at 70° C. for 5 hours. After the reaction, the solvent was removed by distillation under reduced pressure, to obtain an oily product. A mixture of ethanol and diethyl ether was added thereto and the solution was cooled, upon which crystals precipitated. The crystals were collected by filtration and recrystallized from an ethanol-diethyl ether mixture, to obtain p-methylphenyl α-methyl-β-(p-guanidinophenyl)propionate hydrochloride in the form of colorless crystals. Yield: 17.4 g (70%); melting point: 146°-148° C.; IR (cm-1): 3500-2550, 1748, 1653, 1631; MS: M+ =m/e 312 (M.W. -HCl).
Reaction SMILES: [C:1]1([C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=O)[S:5][CH:4]=[CH:3][CH:2]=1.O.NN.[OH-].[K+]>C(O)COCCO>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[CH2:6][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CCCC(=O)c1cccs1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)CCCCc1cccs1
Temperature: 120 °C

Procedure:
4-(2-thenoyl)butyric acid (9.2 g) was dissolved in 60 ml of diethylene glycol and 30 ml of hydrazine hydrate added. After heating the mixture to 120° C. gradual addition of potassium hydroxide (13.6 g) was begun. Low boiling components were distilled out of the reaction mixture until the reaction mixture temperature reached 210° C. After cooling to room temperature water was added to the reaction mixture followed by 6N hydrochloric acid. This mixture was extracted with benzene, the benzene dried over sodium sulfate, filtered through a pad of charcoal, and concentrated under vacuum. A solid residue was obtained after trituration with ligroine, cooling and scratching. Yield 5.5 g. N.M.R. (CDCl3)δ1.76 (m, 4H), 2.42 (m, 2H), 2.88 (m, 2H), 6.80 (m, 1H), 6.90 (m, 1H), 7.12 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[C:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20]O>[Ni]>[NH2:14][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH:9]=1)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]2
Reactant: CO
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(C(=O)[O-])c2[nH]1
Agent: [Ni]
Product: COC(=O)c1cc(N)cc2cc(C(C)(C)C)[nH]c12
Yield: 68 %

Procedure:
A solution of 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (2.0 g, 7.2 mmol) and Raney Nickel (200 mg) in CH3OH (50 mL) was stirred for 5 h at the room temperature under H2 atmosphere. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate (1.2 g, 68%) 1H NMR (CDCl3, 400 MHz) δ 9.34 (brs, 1H), 7.24 (d, J=1.6 Hz, 1H), 7.10 (s, 1H), 6.12 (d, J=1.6 Hz, 1H), 3.88 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:35])[N:25]([CH2:32][CH:33]=[CH2:34])[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28]C2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[CH2:32]([N:25]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:24](=[O:35])[C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:22]=[C:21]([Cl:23])[CH:20]=1)[CH:33]=[CH2:34]
Reactant: C=CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCC1
Reaction time: 2 h

Procedure:
A solution of {2-[3-(allyl-cyclohexyl-carbamoyl)-5-chloro-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.032 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.027 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: C[O-].[Na+].CN(C)C([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:12]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[C:11]([CH3:29])[NH:10][C:9]1=O)=O.Cl.C[S:34](C)=O>CO>[CH3:29][C:11]1[NH:10][C:9](=[S:34])[NH:8][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:12]=1[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N(C(=O)N(C)C)C(=O)N1
Reactant: CS(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)NC(=S)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium methoxide in methanol (1.6 ml, 7.5 mmol, 2 eq) was added to a solution of isomer B [described in Example 20, part B] of 1,2,3,4-tetrahydro-6-methyl-4-(3-nitrophenyl)-2-thioxo-3,5-pyrimidinecarboxylic acid, 5-(1-methylethyl)ester, 3-[(S)-5-methoxycarbonyl)-3-pyrrolidinyl]ester (2.04 g, 3.7 mmol) in methanol (18 ml). The reaction was allowed to stir at room temperature. After 16 hours, the pH was adjusted to 2 with ethereal hydrochloric acid and the mixture was cooled to 0° C. for six hours. The resulting solid was collected by filtration. Three further crops were collected from the mother liquors, which when combined afforded 1.12 g (89%). [α]D =+85° (c=0.5, dimethylsulfoxide).
Reaction SMILES: [CH3:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([NH:17][CH2:18][C:19](O)=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[NH:17][CH2:18][C:19](=[O:20])[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[CH3:1])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1c(N)cccc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1NC(=O)CNC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a mixture of 2-methyl-3-chloroaniline (14.16 g, 100 mmol, 1 equiv), Boc-glycine (17.52 g, 1 equiv), BOP reagent (48.6 g, 1.1 equiv) in 50 mL of DMF was added TEA (42 mL, 3 equiv). After overnight, standard aqueous workup followed by flash chromatography gave 20 g of [(3-chloro-2-methyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester, which was treated with ˜300 mL of 4N HCl in dioxane overnight to afford 2-amino-N-(3-chloro-2-methyl-phenyl)-acetamide (74).
Reaction SMILES: C(Cl)CCl.Cl.[CH3:6][C:7]1([CH3:23])[C:16](=[O:17])[NH:15][C:14]2[N:13]=[CH:12][C:11](/[CH:18]=[CH:19]/[C:20]([OH:22])=O)=[CH:10][C:9]=2[CH2:8]1.C1C=CC2N(O)N=NC=2C=1.[CH3:34][NH:35][CH2:36][C:37]1[O:38][C:39]2[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=2[C:41]=1[CH3:42].C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH3:23][C:7]1([CH3:6])[C:16](=[O:17])[NH:15][C:14]2[N:13]=[CH:12][C:11](/[CH:18]=[CH:19]/[C:20]([N:35]([CH3:34])[CH2:36][C:37]3[O:38][C:39]4[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=4[C:41]=3[CH3:42])=[O:22])=[CH:10][C:9]=2[CH2:8]1
Reactant: CNCc1oc2ccccc2c1C
Reactant: CC1(C)Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CC(C)(C)C(=O)N3)oc2ccccc12
Temperature: 40 °C
Reaction time: 23 h

Procedure:
EDC (102 mg, 0.53 mmol) was added to a suspension of (E)-3-(6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (125 mg, 0.44 mmol), HOBt (66 mg, 0.49 mmol), N-methyl(3-methylbenzofuran-2-yl)methanamine (92 mg, 0.49 mmol) and (i-Pr)2EtN (0.37 mL, 2.2 mmol) in DMF (5 mL). The mixture was allowed to stir for 23 h at 40° C. The mixture was cooled to room temperature and diluted with water (20 mL) at 0° C. to yield a brown precipitate, which was collected by suction filtration. The solid was then triturated with diethyl ether to obtain an off-white solid product. Yield: 137 mg (81%); 1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.59-7.19 (m, 6H), 4.91 (s, 2H), 3.09 (s, 3H), 2.81 (s, 2H), 2.28 (s, 3H), 1.09 (s, 6H); ESI MS m/z 404 [C24H25N3O3+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:51]([O:55][C:56]([NH:58][CH2:59][C:60]([NH:62][CH2:63][C:64](O)=[O:65])=[O:61])=[O:57])([CH3:54])([CH3:53])[CH3:52]>O1CCCC1>[C:51]([O:55][C:56]([NH:58][CH2:59][C:60]([NH:62][CH2:63][C:64]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:65])=[O:61])=[O:57])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Yield: 56 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-glycyl-glycine. Yield 56%. [α]D =+8.5° (c=0.82, tetrahydrofuran).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[O:16][C@@H:15]([CH2:18][N:19]=[N+]=[N-])[CH2:14][CH2:13]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[O:16][C@@H:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2
Reactant: [N-]=[N+]=NC[C@H]1CCc2cccc(-c3ccccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CCc2cccc(-c3ccccc3Cl)c2O1
Reaction time: 72 h

Procedure:
To a solution of {[(2R)-8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}azide (0.14 g, 0.47 mmol) in tetrahydrofuran (7.8 mL) and water (0.8 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.36 g, 1.08 mmol) and the mixture gently shaken for 3 days. The brown suspension was then filtered through celite, the filter cake washed with diethyl ether (10 mL) and the combined filtrates dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. The crude product was purified by reverse phase HPLC using a solvent gradient of 5 to 95% acetonitrile in water containing 0.1% trifluoroacetic acid. The fractions containing product were concentrated under reduced pressure to remove acetonitrile and the aqueous phase basified by the addition of sodium carbonate and then extracted with ethyl acetate (100 mL). The separated organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford {[(2R)-8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amine as a yellow syrup. The product was dissolved in diethyl ether (1 mL) and a solution of hydrogen chloride (1.0 M in diethyl ether, 0.25 mL, 0.25 mmol) was added followed by 2-propanol (2 drops). The resulting white precipitate was filtered and the solid product triturated with diethyl ether (3×3 mL) to afford 36 mg (25%) of {[(2R)-8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amine hydrochloride as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:1][C:2]2[CH:18]=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: CN(C)C(=O)CN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CN(C)C(=O)CN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2CC1

Procedure:
2-{7-[5-Chloro-4-((1R,2R)-2-methanesulfonylamino-cyclohexylamino)-pyrimidin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-N,N-dimethyl-acetamide was prepared from 2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a yellow foam (88 mg, 39%). LCMS (m/e) 550 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.93 (s, 1H), 7.30-7.22 (m, 2H), 7.05 (d, 1H, J=8.0 Hz), 6.85 (s, 1H), 5.56-5.35 (m, 2H), 3.93-3.82 (m, 1H), 3.31 (s, 2H), 3.31-3.20 (m, 1H), 3.15 (s, 3H), 3.09 (s, 3H), 2.97-2.87 (m, 4H), 2.81 (s, 3H), 2.77-2.67 (m, 4H), 2.27-2.17 (m, 2H), 1.89-1.79 (m, 2H), 1.45-1.32 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:25][C:24]2[CH:23]=[C:22]([OH:26])[CH:21]=[CH:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][C@@H:17]2[F:27])([CH3:15])[CH:13]([OH:28])[CH2:12][CH2:11]1.[I-:29].[Na+]>C(C(C)=O)C.C(OCC)(=O)C>[F:27][C@H:17]1[CH2:16][C@@:14]2([CH3:15])[C@@H:10]([CH2:11][CH2:12][CH:13]2[OH:28])[C@H:9]2[C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[CH:23][C:24]=1[CH2:25][C@H:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:29]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCl)[C@H]3[C@@H]1CCC2O
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCI)[C@H]3[C@@H]1CCC2O
Temperature: 90 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
599 mg of 7α-(6-chlorohexyl)-11β-fluor-estra-1,3,5(10)-triene-3,17-diol is dissolved in 10 ml of ethylmethylketone, mixed with 675 mg of sodium iodide and stirred overnight at a bath temperature of 90° C. For working-up, the reaction mixture is cooled to room temperature, taken up in ethyl acetate, extracted once with 10% sodium thiosulfate solution, washed with common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 691 mg of 11β-fluor-7α-(6-iodohexyl)-estra-1,3,5(10)-triene-3,17-diol is obtained as a crude product, which is used without further purification in the next stage.