Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(C(C)C)CC)(C)C.N1([C:29]([O:31][C:32]([CH3:61])([CH2:34][CH2:35][CH2:36][O:37][C:38]([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:33])=[O:30])C=CN=C1>CN(C)C=O>[CH3:60][O:59][C:56]1[CH:55]=[CH:54][C:53]([C:38]([C:45]2[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:37][CH2:36][CH2:35][CH2:34][C:32]([CH3:61])([O:31][C:29]([NH:6][C@@H:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[O:14])=[O:30])[CH3:33])=[CH:58][CH:57]=1
Reactant: COc1ccc(C(OCCCC(C)(C)OC(=O)n2ccnc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)CCCOC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution composed of L-phenylalanine methyl ester hydrochloride (1.4 g, 6.1 mmol), diisopropylethylamine (1.1 mL, 6.2 mmol), and N,N-dimethylformamide (40 mL) was added to the solution of Example 1. The reaction was stirred overnight at room temperature. The solvents were evaporated at reduced pressure, and then the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and filtered. The solvents were evaporated once again. Chromatography on silica gel eluting with hexane-ethyl acetate 70:30 afforded purified Cmoc-protected phenylalanine methyl ester. MS (EI+): 626 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=2)=[O:7])[CH3:4].Br[CH2:23][C:24]#[N:25]>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:23][C:24]#[N:25])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=2)=[O:7])[CH3:4]
Reactant: N#CCBr
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC#N)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 60% NaH in mineral oil (115 mg, 2.9 mmol) and 1H-indole-2,6-dicarboxylic acid diethyl ester (500 mg, 1.9 mmol) in DMF (3 mL) was stirred at room temperature for 0.5 h. Then bromo-acetonitrile in DMF (1 mL) was added and the reaction was warmed to 77° C. and kept at this temperature overnight. The reaction was cooled and quenched with ice water. A large amount of precipitate formed which was filtered and rinsed with water, followed by cold ether. The wet cake was dried in the vacuum oven (50° C.) to give 585 mg of 1-cyanomethyl-1H-indole-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])/[CH:4]=[CH:5]\[C@H:6]([CH3:44])[C@H:7]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@@H:8]([CH3:35])[CH2:9][N:10]([C:12](=[O:34])[C@H:13]([CH3:33])[C@@H:14]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:15]([CH3:24])[C@@H:16]([OH:23])[C@@H:17]([CH3:22])/[CH:18]=[CH:19]\[CH:20]=[CH2:21])[CH3:11].ClC(Cl)(Cl)[C:48]([N:50]=C=O)=[O:49]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:45])/[CH:4]=[CH:5]\[C@H:6]([CH3:44])[C@H:7]([O:36][Si:37]([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:38])[CH3:39])[C@@H:8]([CH3:35])[CH2:9][N:10]([C:12](=[O:34])[C@H:13]([CH3:33])[C@@H:14]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:27])[CH3:28])[C@H:15]([CH3:24])[C@@H:16]([O:23][C:48]([NH2:50])=[O:49])[C@@H:17]([CH3:22])/[CH:18]=[CH:19]\[CH:20]=[CH2:21])[CH3:11]
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N(C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)OC
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N(C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of (2Z,4S,5S,6S)-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-[[(2R,3S,4R,5S,6S,7Z)-3-[[(1, 1-dimethylethyl)dimethylsilyl]oxy]-5-hydroxy-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-4,6-dimethyl-2-heptenoic acid methyl ester (1.8 g, 2.7 mmol) in CH2Cl2 (10 mL) at room temperature, is added trichloroacetyl isocyanate (763 mg, 4.05 mmol) in one portion. The mixture is stirred at room temperature for 1 h, and concentrated in vacuo. The residue is dissolved in MeOH (10 mL), and then K2CO3 (0.4 g) is added. After stirring at room temperature for 2 h, the mixture is concentrated in vacuo, then purified by column chromatography with silica gel eluted with hexane/EtOAc (70/30) to give the desired compound (1.77 g, 92.4%) as a colorless glassy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8].[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=2)[CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8])[CH:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CS(=O)(=O)NCc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CS(=O)(=O)NCc1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
5.309 g N-(3-Amino-benzyl)-methanesulfonamide (obtained in Step 2, 26.5 mmol) and 4.739 g 4,6-dichloropyrimidine (31.81 mmol) was dissolved in 120 cm3 of isopropyl-alcohol, 6.93 cm3 N,N-diisopropyl-ethylamine (5.140 g, 39.76 mmol) was added and the mixture was refluxed for four days. The reaction mixture was cooled to room temperature and the precipitated compound was filtered off. The light yellow product was washed well with diethyl-ether and air-dried. 3.612 g N-[3-(6-Chloro-pyrimidin-4-ylamino)-benzyl]-methanesulfonamide was obtained in more than 98% purity and in 44% overall yield. For analitical results and compound identification see Table 1. The compound was used as a starting material in the preparation of Example 2-32 and 75.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:72])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:59]=[C:58]4[C:54]([CH:55]=[C:56]([CH:60]([O:62][Si](C(C)(C)C)(C)C)[CH3:61])[NH:57]4)=[CH:53][CH:52]=3)[CH:46]([O:70][CH3:71])[CH2:45]2)[CH:7]([CH3:73])[CH:6]([OH:74])[CH2:5][C:4]1=[O:75])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:72])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:59]=[C:58]4[C:54]([CH:55]=[C:56]([CH:60]([OH:62])[CH3:61])[NH:57]4)=[CH:53][CH:52]=3)[CH:46]([O:70][CH3:71])[CH2:45]2)[CH:7]([CH3:73])[CH:6]([OH:74])[CH2:5][C:4]1=[O:75])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(C(C)O[Si](C)(C)C(C)(C)C)[nH]c5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(C(C)O)[nH]c5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 2 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-t-butyldimethylsilyloxyethylindol-6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (150 mg) in CH2Cl2 (4 mL.) at rt was added a solution of p-toluene sulfonic acid (20 mg.) in CH3OH (4 mL.). The reaction mixture was stirred for 2 hr., quenched with saturated NaHCO3, then extracted with CH2Cl2. The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1, hexane/acetone) to give 55 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]([F:36])[F:35])(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]([F:36])[F:35])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: C1CCOC1
Product: COc1cn(C(CC(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
150 mg (388 μmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 125 mg (582 μmol) of 2,2-difluoroethyl trifluoromethanesulphonate and 427 μl (427 μmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 3 ml of THF were reacted according to General Method 7B. Purification by column chromatography (24 g silica cartridge, flow rate: 35 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 122 mg (71% of theory)
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([CH3:11])[CH:5]=[CH:6][CH2:7][CH:8]([CH3:10])[CH3:9].[I-:12].[Na+]>CC(CC(C)C)=O.CCOCC>[I:12][CH2:2][CH2:3][C@H:4]([CH3:11])/[CH:5]=[CH:6]\[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)CC=C[C@@H](C)CCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)CC(C)C
Product: CC(C)C/C=C\[C@@H](C)CCI
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A solution of 4.4 g of (S)-1-chloro-3,7-dimethyl-4-octene in 30 ml of isobutyl methyl ketone is stirred at 130° for 37 hours with 7.55 g of sodium iodide. A further 3.75 g of sodium iodide are added thereto and the mixture is stirred further for 4 hours. After cooling to room temperature, the mixture is diluted with ether, washed with water, dried and concentrated under reduced pressure. The residue is pre-purified by adsorption on silicagel (elution agent: n-hexane), pure fractions are combined and distilled at 14 Torr and 130°. These are obtained 5.6 g (83.5%) of (S)-cis-1-iodo-3,7-dimethyl-4-octene as a colourless liquid. [α]D20 = +14.3° (2.21% in CHCl3).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH:22][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)CCCCc1ccccc1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CCCCc1ccccc1

Procedure:
Following General Procedure BB and using 5-phenylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: C[O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9]2[N:18]=[CH:17][C:16]3[CH2:15][CH2:14][C:13]4[C:19]([C:23]([NH2:25])=[O:24])=[N:20][N:21]([CH3:22])[C:12]=4[C:11]=3[N:10]=2)=[CH:5][CH:4]=1.C(Cl)(Cl)Cl>[OH-].[NH4+]>[OH:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9]2[N:18]=[CH:17][C:16]3[CH2:15][CH2:14][C:13]4[C:19]([C:23]([NH2:25])=[O:24])=[N:20][N:21]([CH3:22])[C:12]=4[C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CNc2ncc3c(n2)-c2c(c(C(N)=O)nn2C)CC3)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cn1nc(C(N)=O)c2c1-c1nc(NCc3ccc(O)cc3)ncc1CC2
Yield: 53 %

Procedure:
To a well stirred solution of 8-[(4-methoxybenzyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (242 mg, 0.7 mmol) in chloroform (30 mL) boron tribromide (1M in dichloromethane, 5.12 ml, 5.1 mmol) was added dropwise over a 5 minutes period, at room temperature. The mixture was heated to reflux for 8 hours. A solution of 10% aqueous ammonium hydroxide (30 mL) was added dropwise at 0° C. over a 10 minutes period. A precipitate was formed and, after 2 hours, it was filtered and washed with water and dried at 40° C. under vacuum. There were obtained 130 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1.[C:32](OC)(OC)(OC)[CH2:33][CH3:34]>>[CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][C:26]6[N:29]=[C:32]([CH2:33][CH3:34])[NH:30][C:25]=6[CH:24]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1
Reactant: CCC(OC)(OC)OC
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5ccc(N)c(N)c5)cc4C3)c2C1
Product: CCc1nc2ccc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 18 omitting step 1 and by using 4-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]benzene-1,2-diamine and trimethyl orthopropionate in step 2. 1H NMR (400 MHz, d6-DMSO): 8.69 (s, 1H), 7.94 (s, 1H), 7.84-7.78 (m, 3H), 7.60 (m, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.04 (d, 1H), 5.09 (s, 2H), 4.48 (m, 2H), 4.19 (m, 2H), 3.18 (dd, 2H), 2.70 (t, 2H), 2.54 (s, 2H), 1.58 (t, 2H), 1.45 (t, 3H), 0.85 (s, 6H); MS (EI) for C28H31N5O: 454 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:12](=[O:23])[C:11]=2[C:10]([CH3:24])=[CH:9]1.C1C(=O)N([Br:32])C(=O)C1.O>CN(C=O)C>[Br:32][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:16]2[CH2:15][CH2:14][N:13]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:12](=[O:23])[C:11]=2[C:10]=1[CH3:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn(-c2ccccc2Cl)c2c1C(=O)N(N1CCCCC1)CC2
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2c(n(-c3ccccc3Cl)c1Br)CCN(N1CCCCC1)C2=O
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To as solution of 1-(2-chlorophenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-4-one (0.93 g, 2.70 mmol) in DMF (30 ml) was added NBS (0.50, 2.84 mmol) at 0° C. The reaction mixture was stirred at this temperature for one hour and then water was added. The mixture was extracted with ether (×3). The combined ether extracts were dried (Na2SO4), filtered and concentrated to give 0.92 g (84%) of the title compound after flash chromatography (heptane:EtOAc gradient).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].S(=O)(=O)(O)O>>[CH3:8][C:7](=[CH:6][CH3:5])[CH:12]=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1
Reactant: NNC1=NCCc2ccccc21
Agent: O=S(=O)(O)O
Product: CC=C(C)C=NNC1=NCCc2ccccc21

Procedure:
In a manner similar to that of Example 4, condensation of 1-hydrazino-3,4-dihydroisoquinoline (11.0 g.) and tigladehyde (7.47 g.) and treatment of the product with sulfuric acid gave 1-[2-(2,3-dimethylallylidene)hydrazino]-3,4-dihydroisoquinoline (I: X=CH3CH=C(CH3), X'=Y=Y'=Z=Z'=H) sulfate (5.1 g., m.p. 231°-232° C. with decomposition).
Reaction SMILES: [Na].[NH2:2][C:3]1[N+:8]([O-:9])=[C:7]([CH3:10])[CH:6]=[C:5](Cl)[N:4]=1.[OH-].[Na+].[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17]>>[NH2:2][C:3]1[N+:8]([O-:9])=[C:7]([CH3:10])[CH:6]=[C:5]([O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH3:14])[N:4]=1
Reactant: Cc1cc(Cl)nc(N)[n+]1[O-]
Reactant: CC(C)(C)CO
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: Cc1cc(OCC(C)(C)C)nc(N)[n+]1[O-]
Reaction time: 22 h

Procedure:
0.32 g of sodium is dissolved in 50 ml of 2,2-dimethyl-1-propanol in the heated state. 2 g (0.0125 mole) of 2-amino-4-methyl-6-chloropyrimidine 3-oxide are added and the reaction medium is brought to 105° C. for 22 hours. The mixture, still hot, is poured into 300 ml of 10% aqueous sodium hydroxide solution. The product is extracted with ethyl acetate and the organic phase is dried with sodium sulphate. It is concentrated and a brown oil is obtained. The latter is filtered on silica gel using an elution gradient with ethyl acetate and methanol. After evaporation, a solid crude product is obtained, which is recrystallized in an acetonitrile/water (98:2) mixture.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2c(C)ccc2-c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 90.8 %

Procedure:
A mixture of 1-(4-methylsulfonylphenyl)-1,4-pentanedione (Example 1, Step 2) (335 mg, 1.32 mmol), p-toluidine (156 mg, 1.45 mmol) and p-toluenesulfonic acid (25 mg) in toluene (100 ml) was heated to reflux for 20 hours. The reaction mixture was cooled, filtered and concentrated. The crude solid (560 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 2-methyl-1-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (390 mg, 91%) as a white solid: mp (DSC) 144° C. Anal Calc'd. for C19H19NSO2 : C, 70.13; H, 5.88; N, 4.30; S, 9.85. Found: C, 69.99; H, 6.23; N, 4.18; S, 9.74.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9]I)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH3:18]>CC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][NH:23][C:22]2[CH:24]=[CH:25][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(CI)c(Cl)n1
Reactant: CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A heterogeneous mixture of 2,4-dichloro-5-(iodomethyl)pyrimidine (31.07 g, 107.3 mmol) (from Example 1c supra) and potassium carbonate (74 g, 536.5 mmol) in acetone (535 mL) was treated with 4-ethylaniline (13.3 mL, 107.3 mmol) (Aldrich). The mixture was stirred at room temperature overnight, then diluted with water (500 mL) and extracted with ethyl acetate. The combined organic layers were successively washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The crude mixture was purified by flash chromatography (20% ethyl acetate in hexanes) to give (2,4-dichloro-pyrimidin-5-yl-methyl)-(4-ethyl-phenyl)-amine as a beige solid. (Yield 21.4 g, 70%).
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:35])=O)=[CH:29][CH:28]=2)=[C:23]([CH3:36])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[NH2:38][OH:39].Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[OH:39][NH:38][C:33]([C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:16])([CH3:18])[CH3:17])=[C:8]([CH3:20])[CH:7]=3)[CH2:1][CH3:2])=[CH:22][C:23]=2[CH3:36])=[CH:32][CH:31]=1)=[O:35]
Reactant: NO
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(=O)NO)cc2)c(C)c1
Reaction time: 0.5 h
Yield: 4.5 %

Procedure:
4′-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-carboxylic acid (Example 170-(3); 25.7 mg, 0.053 mmol), hydroxylamine hydrochloride (7.4 mg, 0.106 mmol) and dichloromethane (0.5 mL) were placed in a reaction vessel. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.2 mg, 0.069 mmol) was added at 0° C., and then the mixture was stirred for 30 minutes. Subsequently, diisopropylethylamine (0.0184 mL, 0.106 mmol) and 4-dimethylaminopyridine (1.94 mg, 0.016 mmol) were added and the mixture was stirred at room temperature overnight. 1 N hydrochloric acid aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=10:1) to give the title compound (1.2 mg, 5%).
Reaction SMILES: O[C:2]1[CH:15]=[CH:14][C:13](OC)=[C:12]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]12O[CH2:10][CH2:9][O:8]1.I[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1C(OC)=C[CH:25]=[CH:24]2.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[C:9]1([O:8][C:7]2[C:12]3[C:3](=[CH:2][CH:15]=[CH:14][CH:13]=3)[CH:4]=[CH:5][CH:6]=2)[C:28]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][CH:10]=1
Reactant: COc1cccc2cccc(I)c12
Reactant: COc1ccc(O)c2c1C1(CCC2)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: c1ccc2c(Oc3cccc4ccccc34)cccc2c1
Reaction time: 12 h
Yield: 113.6 %

Procedure:
To a solution of compound 6 (4.72 g, 0.02 mol) and 7 (8.52 g, 0.03 mol) in degassed pyridine (150 mL) were added K2CO3 (2.76 g, 0.02 mol) and Cu20 (286 mg, 0.002 mol). This reaction mixture was heated at reflux for 12 hours under a nitrogen atmosphere. After addition of additional Cu2O (286 mg, 0.002 mol) to the solution, heating was continued for 12 h. Pyridine was removed under reduced pressure and the residue was redissolved in EtOAc (300 mL). It was washed with water (100 mL) and brine (100 mL), dried (Na2SO4), and concentrated in vacuo. Chromatography on SiO2 (hexanes/EtOAc, 2: 1) gave 6.14 g (78%) of compound 9 as an oil. This oil was treated with TsOH (100 mg) in a mixture of acetone/water (7: 1, 50 mL) for 7 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc (300 mL), washed with water (2×100 mL) and brine (100 mL), dried (Na2SO4), and concentrated in vacuo. Chromatography on SiO2 (hexanes/EtOAc, 1: 1) gave 5.44 g (100%) of compound 10 as a colorless solid: Mp 152-153 ° C; IR(neat) 2952, 1696, 1581, 1484, 1387, 1272, 1245, 1183, 1095, 980, 838, 821, 759 cm−1; 1H NMR δ7.59 (dd, 1 H, J =8.2, 0.8 Hz), 7.45 (dd, 1 H, J =8.2, 1.0Hz), 7.37 (q, 2 H, J =7.9Hz), 6.87 (dd, 1 H, J =7.6, 0.8 Hz), 6.81 (dd, 1 H, J =7.6, 0.8 Hz), 6.72 (d, 1 H, J=8.9 Hz), 6.67 (d, 1 H, J =9.1 Hz), 3.84 (s, 3 H),3.74 (s, 3 H), 3.05 (t, 2 H, J=6.2 Hz), 2.67 (t, 2 H, J =6.3 Hz), 2.11 (p, 2 H, J =6.4 Hz); 13C NMR δ197.9, 156.2, 155.4, 152.7, 149.3, 137.6,136.4, 126.7, 126.4, 124.1, 123.1, 121.7, 120.7, 118.8, 115.9, 110.1, 106.1, 56.3, 56.0, 40.9, 24.1, 22.5; MS (EI) m/z (rel intensity) 348 (M+, 100), 319 (7), 305 (10), 291 (14), 261 (8), 218 (7), 189 (12), 174 (24), 158 (45), 127 (34), 115 (29), 101 (10), 77 (15), 63 (8); HRMS (EI) Calcd for C22H20O4 348.1361, found 348.1361.