Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].C(N(CC)CC)C.CC(C)([O-])C.[K+]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.C1COCC1.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2=[O:17])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: O=C(Cl)CCCCBr
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCCN1c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
See Example 75a. 2-Amino-5-nitro-pyridine (2.0 g, 14.3 mmol), 5-bromo-pentanoyl chloride (2.86 g, 14.3 mmol), triethylamine (2.39 g, 17.2 mmol), catalytic DMAP were heated at reflux in toluene (70 mL) 22 h. The reaction was allowed to cool to RT, concentrated and the resulting oil portioned between EtOAc and water. The organic layer was separated, washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate produced an oil which was dissolved in THF (140 mL). Potassium tert-Butoxide (1.68 g, 15.0 mmol) was added portion-wise and the reaction stirred at RT for 2h. Water was then added, and the reaction extracted with EtOAc. The organics were then washed with brine and dried over MgSO4. Purification of the crude material by mplc revealed the product as an orange solid. MS: APCI (AP+): 222.1 (M)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:6]=[CH:7][CH:8]=1)#[CH:2]>C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=1
Reactant: C#Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Solvent: CCO
Product: C#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of 2.00 g (6.36 mmol) 4-[(3-ethynylphenyl)amino]-6-nitro-3-quinoline-carbonitrile, 100 ml ethanol, and 7.19 g (31.8 mmol) SnCl2 dihydrate was heated to reflux under N2. Removed heat at 3.5 hours and added ice water. Made basic with sodium bicarbonate and stirred for 2 hours. Extracted with chloroform, stirred organic layer with Darco, dried with sodium sulfate, filtered, stripped solvent, and dried in vacuo, giving 1.737 g of yellow-brown solid: mass spectrum (electrospray m/e): M+H=285.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:18]1([C:21]#[C:22][C:23]2[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=2)[CH2:20][CH2:19]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:22]#[C:21][CH:18]4[CH2:20][CH2:19]4)=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ccc(C#CC2CC2)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#CC4CC4)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-cyclopropylethynyl-pyridine-2-carboxylic acid (CAS 1174322-62-3; WO2009091016) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=411.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:22])[C:10]3[CH:16]=[C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-:23].[Na+].Cl>O.O1CCCC1.CO>[Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:22])[C:10]3[CH:16]=[C:15]([CH:17]([CH3:21])[C:18]([OH:23])=[O:19])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1c(Cl)cccc1S2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1c(Cl)cccc1S2
Yield: 47.4 %

Procedure:
A mixture of 200 mg of 2-(9-chloro-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 3 g of sodium hydroxide, 25 ml of water, 30 ml of methanol and 2 ml of tetrahydrofuran was refluxed for 14 hours. After the completion of the reaction, the solvent was removed by distillation to obtain a residue, to which was added water, and the mixture was acidified with with 10% hydrochloric acid and then extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain crystals, which were chromatographed over silica gel and eluted with chloroform. The thus obtained product was recrystallized from ethyl acetate to give 95 mg (yield: 48%) of 2-(9-chloro-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as light yellow crystals having a melting point of 163°-164° C.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]1=[O:19]>C1COCC1.[NH4+].[Cl-].[Zn]>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[CH2:2][C:3]1=[O:19]
Reactant: C[Si](C)(C)CCOCN1C(=O)C(Br)(Br)c2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reaction time: 3 h

Procedure:
Zinc (100 g, 1.54 mol) was added to a solution of 3,3-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one from Step B (65 g, 0.154 mol) in THF (880 mL) and saturated aqueous NH4Cl (220 mL). After 3 h, the reaction was filtered and concentrated in vacuo. The residue was partitioned between EtOAc (500 mL) and H2O (500 mL), which resulted in the formation of a white precipitate. Both layers were filtered through a Celite pad and the layers were separated. The aqueous layer was further extracted with EtOAc (2×200 mL) and the combined organic layers were washed with H2O (100 mL), dried over MgSO4, filtered, and concentrated. The crude product was filtered through a plug of silica gel, eluting with EtOAc:CH2Cl2—10:90, and the eluant was concentrated under reduced pressure to provide the title compound. MS: m/z=265 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.C(O[Cl:15])(C)(C)C>C(Cl)Cl>[Cl:15][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: CC(C)(C)OCl
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(Cl)c1
Yield: 31.3 %

Procedure:
Methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was dissolved in 50 ml. of methylene chloride. The solution, stirred under nitrogen, was cooled in an ice-water bath while t-butylhypochlorite (1.95 g., 18 mmoles) in 25 ml. of methylene chloride was added dropwise. The reaction was stirred for 1 hour at room temperature, filtered and evaporated to an oil. The oil was chromatographed (100 g. of silica gel with ethyl acetate-1/hexane-7 as eluant). The column elution was monitored by thin layer chromatography (silica gel plates with chloroform-8/ethyl acetate-2 as eluant). Cuts containing pure product (Rf 0.4) were combined and evaporated to yield crystalline methyl 5-chloropyrrole-3-carboxylate (900 mg., m.p. 92°-95° C., m/e 159/161).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]([CH3:15])=O.CC([O-])(C)C.[K+].Cl>CS(C)=O>[Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][C:13]([CH3:15])=[CH:12]2
Reactant: CC(C)=O
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc2c([N+](=O)[O-])c(Cl)ccc2[nH]1
Reaction time: 1.5 h

Procedure:
4-Chloro-3-nitroaniline (10.0 g, 57.9 mmol) is dissolved in DMSO (130 ml). Acetone (8.52 ml, 115.9 mmol) and potassium tert-butylate (13.0 g, 115.9 mmol) are added. The temperature is kept below 30° C. by the use of an ice bath. After 90 minutes at RT, TLC analysis indicated complete conversion of the starting material. The reaction mixture is poured on water, acidified with aqueous 2M HCl, and then extracted with EtOAc. The organic layer is washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated. Purification by FCC (CH2Cl2) affords a slightly brownish solid, which by 1H-NMR analysis is an approximately 1:1 mixture of the desired title compound and the corresponding de-chlorinated derivative. Careful purification by preparative HPLC affords the title compound. 1H NMR (DMSO, 400 MHz) δ 2.50 (s, 3H), 6.40 (s, 1H), 7.26 (d, J=9.0 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 11.8 (s, 1H); ES-MS: 209 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:9])[CH:4]=2)[CH:14]=1
Reactant: Oc1ccc(Br)c(F)c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(COc2ccc(Br)c(F)c2)c1
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-3-fluorophenol (18.34 g, 96 mmol), 3-bromomethylbenzoic acid methyl ester (20 g, 87.3 mmol), potassium carbonate (13.3 g, 96 mmol), and acetone (300 mL) was heated to reflux overnight, followed by cooling to room temperature and filtered. The filtrate was evaporated. The solid was washed with water and cold MeOH to give 3-(4-bromo-3-fluoro-phenoxymethyl)-benzoic acid methyl ester, 28 g (72%). LC-MS (ES) calculated for C15H12BrFO3, 338; obsd 339 [M+H]+.
Reaction SMILES: [F-].[Cs+].[CH:3](/B(O)O)=[CH:4]/[CH3:5].[F:9][C:10]([F:32])([F:31])[C:11]([C:20]1[CH:25]=[C:24]([CH2:26][CH2:27][CH3:28])[C:23]([OH:29])=[C:22](I)[CH:21]=1)([O:16][CH2:17][O:18][CH3:19])[C:12]([F:15])([F:14])[F:13]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:9][C:10]([F:32])([F:31])[C:11]([C:20]1[CH:25]=[C:24]([CH2:26][CH2:27][CH3:28])[C:23]([OH:29])=[C:22](/[CH:3]=[CH:4]\[CH3:5])[CH:21]=1)([O:16][CH2:17][O:18][CH3:19])[C:12]([F:15])([F:14])[F:13]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(I)c1O
Reactant: C/C=C\B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: C/C=C\c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(CCC)c1O
Reaction time: 8 h
Yield: 181.5 %

Procedure:
Cesium fluoride (1.24 g), cis-propenylboronic acid (1.54 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.49 g) were added to a mixed solution of 4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-iodo-6-propylphenol (2.83 g, 5.99 mmol) in toluene (60 mL) in an argon atmosphere at room temperature, followed by stirring overnight. After completion of the reaction, the reaction solution was extracted with ethyl acetate-water, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 4.20 g of the title compound (yield: 85%) as a brown solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[C:6]([O:27][CH2:28][CH3:29])=[C:7]([CH:13]2[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:14]2)[C:8]([CH3:12])=[C:9]([Cl:11])[CH:10]=1)[CH3:4].Br[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][NH:35]2.CCN(C(C)C)C(C)C>C(O)C.C([O-])(O)=O.[Na+]>[Cl:11][C:9]1[C:8]([CH3:12])=[C:7]([CH:13]2[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:14]2)[C:6]([O:27][CH2:28][CH3:29])=[C:5]([CH:3]([NH:2][C:31]2[N:39]=[CH:38][N:37]=[C:36]3[C:32]=2[N:33]=[CH:34][NH:35]3)[CH3:4])[CH:10]=1
Reactant: CCOc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Reactant: Brc1ncnc2[nH]cnc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 100 °C

Procedure:
Benzyl 3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate (65 mg, 0.13 mmol, second peak from chiral separation in previous step) was treated with 4.0 M HCl in dioxane (0.4 mL, 2 mmol) in methylene chloride (0.4 mL, 6 mmol) at room temperature for 2 hours. The reaction mixture was evaporated to dryness to give benzyl 3-[3-[1-aminoethyl]-5-chloro-2-ethoxy-6-methylphenyl]azetidine-1-carboxylate hydrochloride. LCMS calculated for C22H28ClN2O3 (M+H)+: m/z=4012. found: 403.1. A mixture of the above HCl salt, 6-bromo-9H-purine (31 mg, 0.16 mmol) and DIPEA (0.11 mL, 0.65 mmol) in ethanol (1 mL) was heated at 100° C. overnight. The mixture was diluted with sat. NaHCO3 solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (83 mg). LCMS calculated for C27H30ClN6O3 (M+H)+: m/z=521.2. found: 521.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8].[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:20]2[CH2:21][CH2:22][N:17]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])[CH2:18][CH2:19]2)=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: CC(C)CCCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (4-methylpentyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (36% yield). m.p. 43-45° C. 1H NMR (300 MHz, CDCl3) δ 7.71, 7.66-7.52, 7.34, 6.96, 4.06-3.98, 3.87-3.68, 3.63, 3.53, 3.19, 3.25, 3.09, 1.65-1.58, 1.36-1.33, 1.26-1.12, 0.85. 13C NMR (75 MHz, CDCl3) δ 167.6, 166.9, 166.2, 159.0, 158.9, 149.5, 149.4, 134.4, 132.4, 129.5, 129.2, 127.2, 126.9, 126.8, 112.6, 112.5, 51.4, 48.8, 46.4, 44.7, 44.4, 41.3, 37.8, 34.8, 34.0, 29.7, 29.0, 28.7, 27.1, 26.7, 22.5, 22.3, 14.0, 13.9. MS (ES+) m/z 464.2 (M+1), 486.2 (M+Na).
Reaction SMILES: B(Br)(Br)Br.ClCCl.C[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=2)=[CH:12][CH:11]=1>O>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=2)=[CH:12][CH:11]=1
Reactant: CCCCCc1ccc(-c2ccc(OC)cc2)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCCc1ccc(-c2ccc(O)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A solution of boron tribromide (3.2 cm3) and dichloromethane (30 cm3) was added dropwise to a solution of 2-(4-methoxyphenyl)-5-pentylthiophene (10.0 g) and dichloromethane (70 cm3) at 0° C. under an atmosphere of nitrogen. The reaction solution was stirred overnight at room temperature and water (100 cm3) added. The organic layer was separated off and the aqueous layer extracted with dichloromethane (2×100 cm3). The combined organic layers were washed with brine (2×100 cm3) and then dried (MgSO4), filtered and evaporated down. The residue was purified by column chromatography on silica gel using a 4:1 hexane/dichloromethane mixture as eluent and recrystallisation from hexane to yield 7.7 g of g 2-(4-hydroxyphenyl)-5-pentylthiophene, K 100-102° C., I.
Reaction SMILES: C[Si](C)(C)[Br:3].[CH3:6][CH:7]([CH2:9][C@@H:10]1[N:19]2[C:20]([C@@:22]([NH:27][C:28]([C@@H:30]3[CH:45]=[C:44]4[C@@H:33]([CH2:34][C:35]5[C:39]6[C:40]4=[CH:41][CH:42]=[CH:43][C:38]=6[NH:37][CH:36]=5)[N:32]([CH3:46])[CH2:31]3)=[O:29])([CH:24]([CH3:26])[CH3:25])[O:23][C@@:18]2([OH:47])[C@H:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:11]1=[O:12])=[O:21])[CH3:8].CC(C[C@@H]1N2C([C@@](NC([C@@H]3C=C4[C@@H](CC5C6C(=CC=CC=64)NC=5)N(C)C3)=O)(C)O[C@@]2(O)[C@H]2N(CCC2)C1=O)=O)C.CC(C[C@@H]1N2C([C@@](NC([C@@H]3C=C4[C@H](CC5C6C(=CC=CC=64)NC=5)N(C)C3)=O)(C(C)C)O[C@@]2(O)[C@H]2N(CCC2)C1=O)=O)C.N>CS(C)=O>[CH3:8][CH:7]([CH2:9][C@@H:10]1[N:19]2[C:20]([C@@:22]([NH:27][C:28]([C@@H:30]3[CH:45]=[C:44]4[C@@H:33]([CH2:34][C:35]5[C:39]6[C:38](=[CH:43][CH:42]=[CH:41][C:40]=64)[NH:37][C:36]=5[Br:3])[N:32]([CH3:46])[CH2:31]3)=[O:29])([CH:24]([CH3:25])[CH3:26])[O:23][C@@:18]2([OH:47])[C@H:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:11]1=[O:12])=[O:21])[CH3:6]
Reactant: C[Si](C)(C)Br
Reactant: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Agent: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C)(NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)C(=O)N12
Agent: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@@H]4N(C)C3)(C(C)C)C(=O)N12
Agent: N
Solvent: CS(C)=O
Product: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]c(Br)c(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
9.1 ml of trimethylbromosilane are added to 1000 ml of anhydrous dimethylsulfoxide and the solution is stirred at room temperature for 15 minutes, then 10 g of a base mixture of α-ergocryptine and ergosine are added, which contains 64.2% of α-ergocryptine base, 28.46% of ergosine base, 2.78% of α-ergocryptinine base and 1.96% of ergosinine base. After stirring for 20 minutes, the mixture is poured into 5 liters of ice-water and the pH is made alkaline up to a value of 8 to 9 by adding aqueous ammonia. The mixture is extracted 3 times with 500 ml of dichloromethane each, the organic phases are combined and washed 3 times with 200 ml of 10% sodium chloride solution each. The dichloromethane phase is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified on a Kieselgel column by using ethyl acetate as eluant to give the title compound in a yield of 6.3 g (0.00967 mole, 87%) (as calculated for the starting base mixture), m.p.: 218° C.; as well as 2.9 g (0.0046 mole, 89%) of 2-bromoergosine, m.p.: 183°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:14]C(=O)C(F)(F)F.Cl>CO>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Temperature: 80 °C
Yield: 84.3 %

Procedure:
A stirred suspension of 5-Bromo-3-nitro-2-(2,2,2-trifluoro-acetylamino)-benzoic acid methyl ester (8 g, 21.56 mmol) in methanol (150 ml) was treated with hydrochloric acid (6M, 75 ml) and heated at 80° C. for 16 h. After cooling to ambient temperature, the yellow solid was collected by filtration and washed with cold water and dried in vacuo to give 2-Amino-5-bromo-3-nitro-benzoic acid methyl ester (5.0 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:16]=[C:15]([CH:17]=O)[CH:14]=[C:13]2[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1COCC1.[O:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)[CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH:16]=[C:15]([CH2:17][NH:46][C:45]3[CH:47]=[CH:48][C:42]([N:39]4[CH2:38][CH2:37][O:36][CH2:41][CH2:40]4)=[CH:43][CH:44]=3)[CH:14]=[C:13]2[C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(CNc3ccc(N4CCOCC4)cc3)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-p-methoxyphenylsulfonyl-2-(3,4,5-trimethoxyphenyl)pyrrole-4-carbaldehyde (50 mg, 0.12 mmol, Example 94a) in THF (1 ml) acetic acid (21 mg, 3 equiv.), 4-morpholinoaniline (21 mg, 1.05 equiv.) and NaBH(OAc)3 (61 mg, 2.5 equiv.) are added. The reaction mixture is stirred at room temperature for 16 h, and diluted with aqueous 1 M Na2CO3 solution and ethyl acetate. The organic layer is dried (MgSO4) and purified by flash chromatography and preparative HPLC. RT (program 2) 3.52. MS: 593.7.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]([CH3:15])[N:9]=[CH:10][C:11]=2[N+:12]([O-])=O)=[O:6])[CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:12][C:11]1[CH:10]=[N:9][N:8]([CH3:15])[C:7]=1[C:5]([N:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6]
Reactant: Cn1ncc([N+](=O)[O-])c1C(=O)N1CCC1
Agent: [Pd]
Solvent: CCO
Product: Cn1ncc(N)c1C(=O)N1CCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of azetidin-1-yl-(2-methyl-4-nitro-2H-pyrazol-3-yl)methanone (268 mg, 1.28 mmol) in ethanol (4.5 ml) was added Pd/C 10% (72 mg, 67.7 μmol) and the reaction mixture was stirred at r.t. under a hydrogen atmosphere for 6 h. The reaction mixture was filtered and concentrated in vacuo and the off-white solid was used without further purification in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](Cl)[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]>NCCCCN>[C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:16][CH2:15][CH2:17][CH2:18][CH2:19][NH2:20])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Agent: NCCCCN
Product: NCCCCNc1cc(-c2ccnc(Nc3cccc(C(=O)O)c3)n2)ccn1
Temperature: 110 °C
Yield: 148 %

Procedure:
A mixture of N-[3-carboxy-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (99 mg, 0.30 mmol) in 1,4-diaminobutane (1.5 mL) is heated to 110° C. overnight, cooled to room temperature and concentrated. The residue is dissolved in water and neutralized with 10% hydrochloric acid. The reaction mixture is purified by preparative HPLC to give N-[3-carboxy-phenyl]-4-[2-(4-amino-butyl-amino)-4-pyridyl]-2-pyrimidineamine (84 mg); ESI-MS (m/z): 379 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24]C)=[O:23])[CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:4])(C)C.CCOCC.C([O-])(O)=O.[Na+].C(Cl)(OCC1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=O>C(Cl)Cl.C(O)(C(F)(F)F)=O.O.O1CCOCC1>[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=1)([O:5][CH2:1][CH:4]1[C:45]2[C:46](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:47]2[C:52]1=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:7]
Reactant: COC(=O)Cc1cccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)Cc1cccc(OC[C@@H]2CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of the above (S)-3-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxyphenyl acetic acid in CH2Cl2 (10 mL) and TFA (10 mL) was stirred for 1 hr at room temp. Et2O was added to the mixture and allowed to stand. Upper layer was removed by decantation to give an oil. A mixture of this oil in water (100 mL), dioxane (30 mL) and NaHCO3 (6.0 g) was added Fmoc-Cl (2.86 g, 11.1 mmol) and the mixture was stirred for 20 hr at room temp. The mixture was extracted with Et2O (×2), and the aqueous layer was acidified by the addition of 1 N HCl. The mixture was extracted with EtOAc. The extract was washed with water, brine, dried over MgSO4 and concentrated in vacuo to afford 5.08 g (81%) (S)-3-(1-Fmoc-2-pyrrolidinyl)methoxyphenylacetic acid as a viscous oil.