Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC[O-].[Na+].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][C:16]1[N:17]([CH2:27][C:28](OC(C)(C)C)=[O:29])[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=1>CO>[NH2:4][C:3](=[NH:5])[NH:2][C:28](=[O:29])[CH2:27][N:17]1[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=[C:16]1[CH2:15][C:11]1[O:10][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)Cn1c(Cc2ccco2)ccc1-c1ccccc1
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(N)NC(=O)Cn1c(Cc2ccco2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a solution of guanidine hydrochloride in anhydrous MeOH (1.5 ml) was added powder NaOEt (80 mg. 1.17 mmol). After 10 min stirring at room temperature, the reaction mixture was treated with tert-butyl [2-(2-furylmethyl)-5-phenyl-1H-pyrrol-1-yl]acetate. After 5 h stirring at 55° C., the reaction mixture was cooled and quenched with H2O (5 ml), diluted with EtOAc (15 ml). The organic layer was separated and the aqueous was extracted with EtOAc (2×15 ml). The combined organic extracts were washed with H2O (15 ml), brine (15 ml), dried (Na2SO4) and concentrated. The crude material was purified by chromatography (silica gel; EtOAc/2M NH3 in MeOH: 97/3) to give the titled compound (73 mg, 57%) as a solid: mp 80-82° C.; MS (−) ES, 321 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])(=O)[CH3:2].[C:27]([NH:35][NH2:36])(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:5]1[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:7][N:8]2[C:4]=1[C:1]([CH3:2])=[N:36][N:35]=[C:27]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1-c1ccccc1F
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4)nnc(C)c3c2-c2ccccc2F)cc1
Temperature: 25 °C

Procedure:
Toluene-4-sulfonic acid 5acetyl-4-(2-fluorophenyl)-1H-pyrazol-3-yl ester (1.0 g, 2.7 mmol; prepared as described in Example 1, steps a to c) was stirred with benzhydrazide (400 mg, 2.9 mmol) in xylene (30 ml) at reflux overnight. The mixture was allowed to cool to room temperature. A solid crystallised out of solution This was separated by filtration, and was recrystallised from ethyl acetate, yielding toluene-4-sulfonic acid 3-(2-fluorophenyl)-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester as a white solid (694 mg). 1H NMR (400 MHz, CDCl3) δ 2.47 (3H, s), 2.52 (3H, s), 7.19 (1H, t, J=8.9 Hz), 7.28 (3H, m), 7.41-7.52 (4H, m), 7.61 (1H, m), 7.79 (2H, d, J=8.3 Hz), 8.25 (2H, d, J=7.5 Hz); MS (ES+) m/e 475 [MH]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].[CH2:28](OC(OCC)CBr)[CH3:29].CN(C)C=O>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:27][CH:28]=[CH:29][N:26]=1
Reactant: CCOC(CBr)OCC
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Solvent: CN(C)C=O
Solvent: O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1nccs1)OCO3
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 80 %

Procedure:
A mixture of 1.00 g (2.60 mmol) of the starting material I, 2.54 g (12.89 mmol) of bromoacetaldehyde diethyl acetal and 10 ml of dimethylformamide was stirred at 80° C. for 40 min. Then the reaction mixture was diluted with water and the crude product obtained was recrystallized from ethanol to yield 0.85 g (80%) of the title compound. Mp.: 145-150° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([S:9][CH2:10][C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15][CH2:14]3)=[O:12])[S:8][C:4]=2[CH:3]=1.[CH3:25][C:26](OC(C)=O)=[O:27].CCN(CC)CC>C(Cl)Cl>[N:13]1([C:11](=[O:12])[CH2:10][S:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([NH:1][C:26](=[O:27])[CH3:25])[CH:24]=[CH:23][C:5]=3[N:6]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccc2nc(SCC(=O)N3CCCc4ccccc43)sc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2nc(SCC(=O)N3CCCc4ccccc43)sc2c1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a 0° C. solution of compound 49 (0.16 g, 0.45 mmol) in dry CH2Cl2 (5 mL) was added Ac2O (0.25 mL, 2.70 mmol) followed by dropwise addition of Et3N (0.25 mL, 1.80 mmol). The reaction was stirred for 2 h under N2. The reaction mixture was diluted with CH2Cl2 (40 mL), washed with saturated NaHCO3 (10 mL), water (2×10 mL), and saturated NaCl (2×10 mL). Dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (EtOAc/hexanes 3:7) to afford 51 as a white solid (154 mg, 86%); MS m/z: 398 (M+H)+. Anal. Calcd. For, C20H19N3O2S2: C, 60.43; H, 4.82; N, 10.57; S, 16.13. Found: C, 60.54; H, 4.91; N, 10.41; S, 15.87.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6])[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Reactant: C1CCNC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C(=O)N2CCCC2)c(Br)c1

Procedure:
100 g (0.388 mol) of 2-bromoterephthalic acid is dissolved in 700 mL of N,N-dimethylformamide and slowly combined with 69.2 g (0.427 mol) of N,N′-carbonyldiimidazole with stirring. After total dissolution, the mixture is stirred for 15 minutes at ambient temperature and then 48.5 mL (0.582 mol) of pyrrolidine and 93.9 mL (0.854 mol) of N-methylmorpholine are slowly added dropwise one after the other. The mixture is stirred for 2.5 days at ambient temperature and then concentrated in vacuo. The residue is combined with distilled water and acidified with 2 molar hydrochloric acid solution. The aqueous phase is extracted with ethyl acetate. The precipitate formed is suction filtered and dried at 40° C. Yield: 29.4 g (25%); Rf value: 0.30 (silica gel; dichloromethane/ethanol=9:1); C12H12BrNO3 (298.14); mass spectrum: (M+H)+=298/300 (bromine isotope).
Reaction SMILES: S1CCS[CH:2]1[C:6]1[NH:20][C:19]2[C:21]3[C:7]=1[CH2:8][C@@H:9]1[C:14]([C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:13][C@H:12]([NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:11][N:10]1[CH3:30].O.S(Cl)(Cl)(=O)=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:2]([C:6]1[NH:20][C:19]2[C:21]3[C:7]=1[CH2:8][C@@H:9]1[C:14]([C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:13][C@H:12]([NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:11][N:10]1[CH3:30])=[O:33]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4[nH]c(C5SCCS5)c(c34)C[C@H]2N(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
Under argon, 1.10 g (2.5 mmol) of 3-[9,10-didehydro-2-(1,3-dithiolan-2-yl)-6-methyl-8α-ergolinyl]-1,1-diethylurea is dissolved in 25 ml of chloroform and combined with 1.9 g of silica gel of a particle size of 0.063-0.2 mm. Under vigorous agitation, 2 ml of distilled water is added dropwise. Subsequently, within a time period of 15 minutes, a solution of 0.5 ml (0.6 mmol) of sulfuryl chloride in 13 ml of chloroform is added dropwise and the mixture is stirred for 2 hours at room temperature. For working-up purposes, 3 g of potassium carbonate is added and the mixture is vigorously agitated for 20 minutes. The precipitate is filtered off and washed with methylene chloride. The precipitate is moistened with ethanol and made into a slurry with 250 ml of saturated sodium chloride solution. This mixture is repeatedly extracted with methylene chloride. The extracts are dried together with the methylene chloride filtrate over magnesium sulfate and concentrated. The crude product is chromatographed under pressure on silica gel with a chloroform/methanol mixture and the main fraction of 448 mg is recrystallized from diisopropyl ether, thus obtaining 225 mg of 3-(9,10-didehydro-2-formyl-6-methyl-8α-ergolinyl)-1,1-diethylurea (25% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[O:20]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][C:31](=[O:32])[C:30]3[CH:29]=[CH:28][C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:35][CH:34]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4ccc(Oc5ccccc5)cc4)ccc3o2)C1

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.034 g, 0.131 mmol), 4-phenoxy-benzoic acid (0.042 g, 0.196 mmol), HATU (0.050 g, 0.131 mmol), polystyrene-bound diisopropylamine (0.327 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (10 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Concentrate the solution in vacuo. Dilute with CH2Cl2, wash with 1.0M NaOH (2×25 mL), dry over Na2SO4, filter, and concentrate in vacuo. Subject the residue to silica gel flash column chromatography on an ISCO Companion (4 g column, eluting with 10% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as a white oil. Dissolve in CH2Cl2 and add n-hexane. Re-concentrate to yield the desired product as a white solid (0.031 g, 52%). mass spectrum (m/e): 457.3 (M+1), 455.3 (M−1). 1H NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 8.01-7.99 (m, 2H), 7.70-7.68 (m, 1H), 7.49-7.42 (m, 2H), 7.35-7.32 (m, 2H), 7.25-7.20 (m, 1H), 7.13-7.07 (m, 4H), 3.52-3.47 (d, J=8.0 Hz, 2H), 3.12 (s, 3H), 2.66-2.55 (m, 1H), 2.55-2.47 (m, 2H), 2.43-2.35 (m, 1H), 2.55-2.47 (m, 2H), 2.43-2.35 (m, 1H), 2.28-2.24 (m, 1H), 2.23 (s, 3H), 1.93-1.83 (m, 1H), 1.49-1.39 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(=O)C(F)(F)F)=[CH:18][C:17]=2[CH2:29][C:30](OC)=[O:31])(=[O:15])=[O:14])=[CH:10][C:5]2[B:6]([OH:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[OH-].[NH3:35]>CO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:13](=[O:14])(=[O:15])[NH:12][C:11]2[C:2]([F:1])=[CH:3][C:4]3[CH2:8][O:7][B:6]([OH:9])[C:5]=3[CH:10]=2)=[C:17]([CH2:29][C:30]([NH2:35])=[O:31])[CH:18]=1
Reactant: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1cc2c(cc1F)COB2O
Reactant: N
Agent: [OH-]
Solvent: CO
Product: NC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1cc2c(cc1F)COB2O
Temperature: 100 °C

Procedure:
To the solution of methyl 2-(2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (480 mg, 1 mmol) in methanol (5 ml), added ammonia hydroxide (2 ml), heated at 100° C. in a sealed tube overnight. The result mixture was concentrated, then dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as yellow solid. MS calcd for (C15H15BN3O5FS): 379.17. MS found (ESI negative): (M−H)−=378.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.64 (s, 1H), 9.20 (bs, 1H), 7.53 (d, J=8 Hz, 1H), 7.34 (s, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.13 (d, J=10.4 Hz, 1H), 7.04 (s, 1H), 6.45 (d, J=2 Hz, 1H), 6.29 (dd, J=8.8 Hz, 1H), 4.82 (s, 2H).
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Br:30])[CH:26]=2)[CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[O:38])[CH:32]=1>O1CCCC1>[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:29][CH2:28][C:27]2[CH2:26][C:25]([CH:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[OH:38])([Br:30])[CH:24]=[CH:23][C:22]=2[CH2:21]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(Br)ccc2C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC2=C(C=CC(Br)(C(O)c3cccnc3)C2)C1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
8.8 ml of a solution of n-butyl lithium in hexane (2.5 mol) was dropped to a solution of 3.25 g of 2-tert.butoxycarbonylamino-6-bromo-1,2,3,4-tetrahydro-naphthaline in 50 ml of absolute tetrahydrofurane cooled to -70° C. and stirring was continued for 1.5 hours at -50° C. Subsequently, 1.1 g of pyridine-3-aldehyde were dropped into the mixture at -70° C. After stirring for one hour, the reaction mixture was poured on ice and extracted with ethyl acetate. The organic Phase was washed with water, dried and evaporated. The obtained residue was recrystallised from cyclohexane/ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([CH:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11]Br)[CH3:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:8]([CH:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)CNc1ccccc1
Temperature: 75 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A mixture of aniline (18.6 parts), 2-ethylhexyl bromide (42.4 parts), anhydrous potassium carbonate (30.3 parts) and dry N,N-dimethylformamide (100 parts) was stirred at 75° C. for 24 hours. The cooled mixture was filtered, diluted with dichloromethane and washed with 2N-hydrochloric acid (100 parts). The organic phase was evaported to leave oil which was triturated with petroleum ether and water to give N-(2-ethylhexyl)aniline (18 parts, 43%).
Reaction SMILES: O=[C:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=32)[C:4](=[O:18])[CH2:3]1.Br.Br[CH2:21][CH2:22][CH2:23][NH2:24].N1C(C)=CC=CC=1C>C(O)CCC>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:9]2[CH:10]3[N:5]([C:4](=[O:18])[C:3]4[CH2:21][CH2:22][CH2:23][NH:24][C:2]=4[CH2:11]3)[CH2:6][CH2:7][C:8]=2[CH:15]=1
Reactant: COc1ccc2c(c1)CCN1C(=O)CC(=O)CC21
Reactant: NCCCBr
Agent: Br
Solvent: Cc1cccc(C)n1
Solvent: CCCCO
Product: COc1ccc2c(c1)CCN1C(=O)C3=C(CC21)NCCC3
Temperature: 10 °C
Yield: 70.3 %

Procedure:
A solution of 27.3 Kg of 2,4-dioxo-9-methoxy-1,2,3,4,6,7-hexahydro-11bH-benzo[a]quinolizine, 19.6 Kg of 3-bromopropylamine hydrobromide and 22.8 Kg of 2,6-lutidine in 70 litres of n-butanol was refluxed for 1 hour. Butanol and excess 2,6-lutidine were removed under reduced pressure, and the solid residue dissolved in 150 litres of methanol at reflux temperature. The temperature was maintained above 70° C. while 150 litres of water was added. The mixture was cooled to 10° C., the precipitate filtered off and washed with 1:1 aqueous methanol. This product was recrystallized from a mixture of 150 Kg of methanol and 175 Kg of water. Drying under vacuum at 80° C. for three days gave 17.9 Kg of (±)-3-methoxy-5,6,9,10,11,12,13,13a-octahydroisoquino[2,1-g][1,6]naphthyridin-8-one, m.p. 202°-205° C.
Reaction SMILES: [C:1](=O)([O:37]C1C=CC=CC=1)[O:2][C:3]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH3:36])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])(=[O:16])=[O:15])[C:4]1=[O:27].[CH3:45][C:46]1[N:51]=[C:50]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH:49]=[CH:48][CH:47]=1>CN(C=O)C>[CH3:45][C:46]1[N:51]=[C:50]([N:52]2[CH2:57][CH2:56][N:55]([C:1]([O:2][C:3]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH2:35][CH3:36])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=4)[N:5]([S:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=4[O:25][CH3:26])(=[O:16])=[O:15])[C:4]3=[O:27])=[O:37])[CH2:54][CH2:53]2)[CH:49]=[CH:48][CH:47]=1
Reactant: CCOc1ccccc1C1(OC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Reactant: Cc1cccc(N2CCNCC2)n1
Solvent: CN(C)C=O
Product: CCOc1ccccc1C1(OC(=O)N2CCN(c3cccc(C)n3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Yield: 89.6 %

Procedure:
0.1 g (0.16 mmol) of intermediate 1d and 115 mg (0.65 mmol) of 1-(6-methylpyridin-2-yl)piperazine were stirred in 3 ml of DMF at 100° C. for 20 minutes. The reaction mixture was then poured into 30 ml of ice-water/K2CO3. The resulting precipitate was isolated and crystallized from a little methanol, resulting 0.1 g of the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.CS(C)=O.[C@H:28]1([NH2:35])[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1>C(OCC)(=O)C>[NH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([NH:35][C:18]2[CH:17]=[C:16]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([NH:8][CH2:9][CH:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[N:4]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:29][CH2:30]1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(Cl)cn1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To 3,5′-dichloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (Intermediate G) (250 mg, 0.702 mmol) was added DMSO (3 ml) and trans-cyclohexane-1,4-diamine (952 mg, 6.32 mmol). The reaction mixture was stirred at 100° C. for 20 hours and the reaction progress was followed by LCMS. The reaction mixture was cooled, diluted with 250 ml ethyl acetate, washed with saturated sodium bicarbonate (1×), water (3×) and concentrated to constant mass, giving 320 mg of product as a free base, which was used without further purification. A portion of the title compound, 25 mg was purified by prep LC and lyapholized to give 17.6 mg of the title compound as a TFA salt. LCMS (m/z): 450.2 (MH+), retention time=0.58 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.16-1.76 (m, 8H) 1.76-1.98 (m, 1H) 2.04-2.27 (m, 4H) 3.06-3.16 (m, 1H) 3.19 (d, J=6.74 Hz, 2H) 3.37 (t, J=11.87 Hz, 2H) 3.62-3.77 (m, 1H) 3.92 (dd, J=11.28, 3.08 Hz, 2H) 6.61 (d, J=8.79 Hz, 1H) 6.73 (s, 1H) 7.50 (d, J=9.08 Hz, 1H) 8.04 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)ccc1C(F)(F)F
Yield: 49.3 %

Procedure:
Reaction of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl -pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (104 mg, 49%). MS (ISP) 423.3 [(M+H)+]; mp 227° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][NH2:11]>CO.C(O)C>[Br:1][C:2]1[C:3]([NH:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CN
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCO
Solvent: CO
Product: CNc1nc(Cl)ncc1Br
Temperature: 25 °C
Yield: 39 %

Procedure:
To a cooled (0° C.) solution of 5-bromo-2,4-dichloropyrimidine (5.0 g, 22 mmol) in methanol (42 mL) was added dropwise a 33 wt % solution of methylamine in ethanol (3.3 mL). The reaction was allowed to warm to room temperature. The reaction was then concentrated. The crude product was purified by column chromatography (0-10% methanol in DCM) to give 5-bromo-2-chloro-N-methylpyrimidin-4-amine (1.8 g, 39%). 1H-NMR (DMSO): δ 8.22 (s, 1H), 7.75 (s, 1H), 2.85 (d, J=3.9, 3H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][N:9]1[C:32](=[O:42])[C@@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:11][CH2:10][N:9]1[C:32](=[O:42])[C@@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:34][C:43](=[O:45])[CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
200 mg 0.348 mmol) of the mixture of (2R*,4S*)-2-benzyl-1-((R)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine diastereomers are reacted with 39 μl (0.417 mmol) of acetic anhydride in analogy to Example 31. The title compound is obtained as mixture of diastereomers (white foam). TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.28, FD-MS: M+ =616.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:12][C:13](C3C=CC=CC=3)=[CH:14][C:15](=[O:17])[CH:16]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>CCOCC>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:12][CH:13]=[CH:14][C:15](=[O:17])[CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=Cc2cc(=O)cc(-c3ccccc3)o2)cc1
Agent: BrB(Br)Br
Solvent: CCOCC
Product: O=c1ccoc(C=Cc2ccc(O)cc2)c1

Procedure:
The ether linkage of 2-[2-(4-methoxyphenyl)ethenyl]-6-phenyl-4H-pyran-4-one was cleaved with boron tribromide as described in Example 47 to give the title product as orange needles (mp 198°-201° C.).
Reaction SMILES: CCCCC.[H-].[Na+].[CH3:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:21]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:20][N:19]=[C:18]([S:26][CH3:27])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29]>C1COCC1>[CH3:29][CH:28]([NH:31][C:32]([NH:25][S:22]([C:21]1[C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=2)=[N:17][C:18]([S:26][CH3:27])=[N:19][CH:20]=1)(=[O:23])=[O:24])=[O:33])[CH3:30]
Reactant: CC(C)N=C=O
Reactant: CSc1ncc(S(N)(=O)=O)c(Nc2cccc(C)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CSc1ncc(S(=O)(=O)NC(=O)NC(C)C)c(Nc2cccc(C)c2)n1
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
Pentane washed sodium hydride (3.99 mmol, 1.05 eq) was suspended in THF (50 mL), and 4-[(3-methylphenyl)amino]-2-(methylthio)-5-pyrimidinesulfonamide (1.18 g, 3.90 mm) was added slowly as a solid. The mixture was stirred for 90 minutes and isopropyl isocyanate (0.39 mL, 3.99 mmol, 1.05 eq) was added. After stirring 45 minutes an additional 0.1 mL of isopropyl isocyanate was added to complete the reaction. The THF was removed under reduced pressure and the residue was dissolved in dilute sodium hydroxide. Acetic acid was added until a pH of 4 and the aqueous solution was extracted with four 50 mL portions of ethyl acetate. The organic portions were combined, dried (Na2SO4), filtered and the solvent removed under reduced pressure to yield 1.61 g of crude solid. The crude solid was crystallized from ethanol and water to yield 1.21 g (3.06 mmoles, 80%) of white crystals, m.p. 160°-160.5° C.