Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:10][S:11][C:12]1[CH:19]=[CH:18][C:15](C=O)=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([N:2]2[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])=[CH:14][CH:13]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: COC(=O)CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSc1ccc(N2CCCC2=O)cc1
Reaction time: 8 h
Yield: 105.7 %

Procedure:
3 g of methyl 4-aminobutyrate hydrochloride and 2.8 ml of triethylamine were added to a chloroform solution of 2 g of 4-(methylthio)benzaldehyde, and 8.4 g of sodium triacetoxyborohydride was added to it, and stirred overnight. Aqueous sodium hydrogencarbonate solution was added to it, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography to obtain 2.88 g of 1-[4-(methylthio)phenyl]pyrrolidin-2-one as a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].[CH2:27]([C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39](O)[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[CH2:28][CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.N1C=CC=CC=1.CN(C)C=O>[CH2:27]([C:30]1[CH:31]=[CH:32][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39]([O:25][C:24]([C@H:21]3[CH2:20][CH2:19][C@H:18]([C@H:15]4[CH2:16][CH2:17][C@H:12]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14]4)[CH2:23][CH2:22]3)=[O:26])[CH2:38][CH2:37]2)=[CH:34][CH:35]=1)[CH2:28][CH3:29]
Reactant: CCCc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O[C@H]3CC[C@H](c4ccc(CCC)cc4)CC3)CC2)CC1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A solution of 0.902 ml of dimethylformamide in 20 ml of acetonitrile was placed at -20° C. while gassing with argon in a sulphonation flask fitted with a mechanical stirrer, serum cap, thermometer and dropping funnel and treated within 2 minutes with 0.338 ml of oxalyl chloride. After completion of the addition, the mixture was stirred at -20° C. for a further 20 minutes and then 1.0 g of trans-4-(trans-4-pentylcyclohexyl)cyclohexanecarboxylic acid was introduced into the resulting white suspension via a solid substance addition tube. The mixture was subsequently stirred at -20° C. for 30 minutes and then treated dropwise at -20° C. within 10 minutes with a solution of 1.97 g of trans-4-(p-propylphenyl)cyclohexanol and 0.9 ml of pyridine in 20 ml of acetonitrile. The mixture was stirred for a further 15 hours while slowly warming to room temperature, then poured into 200 ml of cold 2N sodium carbonate solution and extracted three times with 200 ml of methylene chloride each time. The organic phases were washed once with 100 ml of 2N sodium carbonate solution and twice with 200 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (2.6 g) on 140 g of silica gel using toluene/hexane (volume ratio 1:1) gave 757 mg (44%) of trans-4-(trans-4-pentylcyclohexyl)cyclohexanecarboxylic acid trans-4-(p-propylphenyl)cyclohexyl ester as colourless crystals. A single recrystallization from acetone yielded analytically-pure product of m.p. (C-S) 63.3° C., phase transition S-N 241.5° C., cl.p. (N-I) 285.5° C.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[CH:7]=[C:8]([C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:27]([O:29][C:30](=[O:39])[CH2:31][N:32]1[C:36](=[O:37])[CH2:35][NH:34][C:33]1=[S:38])[CH3:28].N1CCCCC1>ClCCl>[CH2:27]([O:29][C:30](=[O:39])[CH2:31][N:32]1[C:36](=[O:37])/[C:35](=[CH:17]/[C:15]2[O:16][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=3)=[CH:13][CH:14]=2)/[NH:34][C:33]1=[S:38])[CH3:28]
Reactant: CCOC(=O)CN1C(=O)CNC1=S
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(C=O)o2)c1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(/C=C3\NC(=S)N(CC(=O)OCC)C3=O)o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(3-(Tributylstannyl)phenyl)furan-2-carbaldehyde (10 mg, 0.022 mmol) synthesized by the same method as in Example 4 and ethyl-2-(5-oxo-2-thioxoimidazolidin-1-yl)acetate (4.4 mg, 0.022 mmol) synthesized by the same method as in Example 2 were dissolved in dichloromethane (3 mL), piperidine (5 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give labeling precursor 2 in a yield of 11 mg (74.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[N:13]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:12]=2)[CH:3]=1.[N-:48]=[C:49]=[O:50].[K+]>O.C(O)(=O)C>[CH3:39][C:36]1[CH:37]=[CH:38][N:25]2[C:26]=1[C:27](=[O:35])[N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]([C@@H:21]([NH:20][C:18]1[C:19]3[C:11]([C:4]4[CH:3]=[C:2]([NH:1][C:49]([NH2:48])=[O:50])[CH:10]=[C:9]5[C:5]=4[CH:6]=[CH:7][NH:8]5)=[CH:12][N:13]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[C:14]=3[N:15]=[CH:16][N:17]=1)[CH3:22])=[N:24]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NC(N)=O)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 72.6 %

Procedure:
To a suspension of (S)-2-(1-((5-(6-amino-1H-indol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) in 403 μl water and 208 μl acetic acid was added potassium isocyanate (17 mg, 0.21 mmol) according to the method described in Preparation 181. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 40 mg (75% yield) of the title compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]=[N+:9]=[N-:10])=[N+:2]=[N-:3].[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([NH:3][N:2]=[N:1][CH2:4][CH2:5][CH2:6][CH2:7][N:8]=[N:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: [N-]=[N+]=NCCCCN=[N+]=[N-]
Solvent: C1CCOC1
Product: c1ccc(CNN=NCCCCN=NNCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
A solution of 1.40 g (10 mmoles) of 1,4-diazidobutane, in 10 ml. of THF and chilled to -45° C., was treated dropwise with 15 ml of 2.0M benzylmagnesium chloride in THF (30 mmoles). The reaction mixture was magnetically stirred overnight at room temperature. The solvent was removed under vacuum and the residue was dissolved in 200 ml. of diethylether and washed with 30 ml. of ammonium buffer (50 g. ammonium chloride, 178 ml. of 10% ammonium hydroxide and 272 ml. of water), followed by 2×30 ml of water. The solution was dried over sodium sulfate and concentrated on a rotary evaporator and dried under high vacuum at room temperature. The crude product was recrystallized from diethylether in the -20° freezer to produce 2.6 g. of white crystals m.p. 71°-74° C. The nmr and mass spectra were fully consistent with the structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[N:18]1([CH2:27][C:28](O)=[O:29])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=[CH:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:28](=[O:29])[CH2:27][N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=[CH:19]2)[CH2:14][CH2:13]1
Reactant: O=C(O)Cn1ccc2cccnc21
Reactant: FC(F)(F)c1ccc(N2CCNCC2)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cn1ccc2cccnc21)N1CCN(c2ccc(C(F)(F)F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
1-(2-Bromo-4-trifluoromethyl-phenyl)-piperazine (225 mg, 0.73 mmol), pyrrolo[2,3-b]pyridin-1-yl-acetic acid (154 mg, 0.87 mmol), TBTU (304 mg, 0.95 mmol) and triethylamine (304 μl, 2.18 mmol) are combined in dichloromethane (3 mL). The resulting reaction is allowed to stir at ambient temperature for 2 h. Water is added and the mixture is extracted with EtOAc. The organic layer is washed with water, brine, dried (Na2SO4) and concentrated. The crude product is purified using biotage chromatography eluting with 0-50% EtOAc/hexane. Removal of the solvent provides 1-[4-(2-bromo-4-trifluoromethyl-phenyl)-piperazin-1-yl]-2-pyrrolo[2,3-b]pyridin-1-yl-ethanone as a colorless foam (268 mg, 79%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH:8]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)[C:15](O)=[O:16])([CH3:10])[CH3:9]>>[CH:8]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)[C:15]([NH:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)=[O:16])([CH3:10])[CH3:9]
Reactant: Nc1ncc(Br)s1
Reactant: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)O)c1
Product: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)Nc2ncc(Br)s2)c1
Yield: 81.9 %

Procedure:
3-Isopropyloxy-5-phenoxy-N-(5-bromothiazol-2-yl)-benzamide (1.1 g, 82%) was prepared from 5-bromo-2-aminothiazole (830 mg, 4.6 mmol) and 3-isopropyloxy-5-phenoxybenzoic acid (835 mg, 3.1 mmol) following the general procedure A.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>CN(C=O)C.CC(OC)(C)C>[Si:47]([O:46][CH2:45][CH2:44][N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:33][CH2:34][CH2:35][CH3:36])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CCCCN(CCCC)C(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To a stirred solution of 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (190 mg, 0.40 mmol) in dry DMF (5 mL) was added K2CO3 (160 mg, 1.16 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (92 mg, 0.38 mmol) at 0° C. The mixture was allowed to warm to room temperature and heated at 50° C. for 24 h. The reaction mixture was cooled to 0° C., diluted with MTBE and quenched with water. The organic layer was separated and the aqueous layer was extracted with MTBE (3×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to provide crude product. The crude material was purified by flash chromatography (gradient 10 to 30% ethylacetate/hexane) to provide the title compound (144 mg, 54%). 1H NMR (CD3OD) 8.66 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.0, 2.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.38-7.29 (m, 5H), 5.20 (s, 2H), 3.99 (s, 3H), 3.83-3.82 (m, 2H), 3.77 (t, J=5.0 Hz, 2H), 3.70 (t, J=5.0 Hz, 2H), 3.49 (br s, 2H), 1.70-1.55 (m, 4H), 1.45-1.26 (m, 4H), 1.05-0.85 (m, 6H), 0.83 (s, 9H), 0.03 (s, 6H); MS(ESI+) m/z 650.2 (M+H)+.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]=[CH2:8].[F:9][Si:10](F)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[CH2:5]([Si:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[F:9])[CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCBr
Reactant: F[Si](F)(c1ccccc1)c1ccccc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: C=CCC[Si](F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
In a two-neck flask equipped with a condenser was placed magnesium (3.46 g, 142 mmol) and a crystal of iodine. The flask was warmed with heat gun until iodine had sublimed. A solution of 4-bromo-1-butene (9.62 g, 71.3 mmol) in ether (100 mL) was added dropwise in 30 min and the resulting mixture refluxed for 2 h. This Grignard solution was cooled to rt and added over 30 min via cannula to a second flask containing 24 (15.7 g, 71.3 mmol) in ether (100 mL) at rt. After stirring overnight at rt under argon, the reaction mixture was quenched with water (20 mL) and the organic layer isolated. The aqueous layer was extracted twice with 50-mL portions of ether. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Distillation (134° C., 1.5 mm Hg) provided pure 31 as a colorless oil (15.2 g, 83%): 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=7.8 Hz, 4H), 7.50-7.39 (m, 6H), 5.97-5.83 (m, 1H), 5.02 (dd, J=17.1, 1.7 Hz, 1H), 4.94 (dd, J=10.2, 1.7 Hz, IH), 2.28-2.20 (m, 2H), 1.38-1.30 (m, 2H); 13C NMR (75 MHz, CDCl3) δ140.9, 135.9, 134.1, 129.7, 127.8, 113.1, 26.9, 14.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:27]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=O)C.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:3])[C:7]=2[OH:27])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:15]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2cccc(OC)c2)c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Cn2cc(Cl)c3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)c1

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(3-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 415 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][S:11][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:12].[C:13]([O:16][CH2:17][CH2:18]Br)(=[O:15])[CH3:14]>>[NH2:12][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][N:8]([CH2:18][CH2:17][O:16][C:13](=[O:15])[CH3:14])[CH2:7][C:6]=2[CH:1]=1
Reactant: Nc1ccc2c(c1)CNCCS2
Reactant: CC(=O)OCCBr
Product: CC(=O)OCCN1CCSc2ccc(N)cc2C1
Yield: 85.1 %

Procedure:
Following the procedure of 521a, 6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.28 g, 0.0015 mol) and 2-bromoethyl acetate (0.40 g, 0.0023 mol) were reacted to give acetic acid 2-(2-amino-6,7-dihydro-9H-5-thia-8-aza-benzocyclohepten-8-yl)-ethyl ester (0.34 g, 83%) as an oil. LC/MS (ESI+): 266 (M).
Reaction SMILES: C(O[C:6]([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([N:19]1[CH2:27][CH:26]2[CH:21]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][CH2:24][C:25]2=[O:28])[CH2:20]1)=[O:18])C)=O)(C)(C)C.[ClH:41].C(OC(C)C)(C)C>O1CCOCC1>[ClH:41].[CH3:6][NH:8][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([N:19]1[CH2:27][CH:26]2[CH:21]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:23][CH2:24][C:25]2=[O:28])[CH2:20]1)=[O:18]
Reactant: CN(C(=O)OC(C)(C)C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: CNc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1

Procedure:
(3aRS,7aRS)-2-{[2-(N-tert-Butoxycarbonyl-N-methylamino)phenyl]acetyl}-7,7-diphenylperhydro-4-isoindolone (2.8 g) is treated with a 5.7N solution (30 cc) of hydrochloric acid in dry dioxane at 20° C. for 4 hours. Isopropyl ether (100 cc) is added and the solid is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-2-[(2-methylaminophenyl)acetyl]-7,7-diphenylperhydro-4-isoindolone hydrochloride (2.1 g) is obtained in the form of a white solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](N1CC(O)(CCC)C1)(C1C=CC=CC=1)[C:25]1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][C:16]([O:19][S:20]([CH3:23])(=[O:21])=[O:22])([CH2:18][CH2:24][CH3:25])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Product: CCCC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
1-Benzhydryl-3-methanesulphonyloxy-3-propylazetidine was prepared under the conditions described for 1-benzhydryl-3-methanesulphonyloxy-3-methylazetidine in Patent Application EP 406,112, but starting with 2.4 g of 1-benzhydryl-3-hydroxy-3-propylazetidine. 2.4 g of 1-Benzhydryl-3-methanesulphonyloxy-3-propylazetidine are obtained in the form of a colorless solid, melting point 70° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:20][N:21](C=O)C>[NH4+].[OH-].[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:2]1[CH:3]=[C:4]([C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)[CH:5]=[O:6])#[N:21]
Reactant: COc1ccc(COc2ccc(Br)cc2C=O)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [NH4+]
Product: COc1ccc(COc2ccc(C#N)cc2C=O)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 3-bromo-6-((4-methoxybenzyl)oxy)benzaldehyde (4 g), Zn(CN)2 (1 g) and Pd(PPh3)4 (4.32 g) in 40 mL DMF was stirred at 90° C. for 3 hours, cooled to ambient temperature and diluted with 100 mL 50% NH4OH. The aqueous layer was extracted with ethyl acetate (3×). The organic layer was dried, concentrated and purified on silica gel column (ethyl acetate/hexane, 1:4) to afford 2.8 g of 3-cyano-6-((4-methoxybenzyl)oxy)benzaldehyde as a yellow solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][C:6]=1[NH2:7])([CH3:3])[CH3:2].Cl.[C:22](=N)(OC)[CH3:23].C(=O)([O-])O.[Na+]>CO>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[C:9]1[CH:10]=[CH:11][C:5]2[N:4]([CH:1]([CH3:3])[CH3:2])[C:22]([CH3:23])=[N:7][C:6]=2[CH:8]=1
Reactant: CC(C)Nc1ccc(-c2nc3ccccc3o2)cc1N
Reactant: COC(C)=N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C(C)C
Yield: 100 %

Procedure:
To a methanol (5 mL) solution of 2-(2-isopropylaminoanilin-5-yl)benzoxazole (see Working Example 80-2) (180 mg, 0.673 mmol) was added methyl acetimidate hydrochloride (111 mg, 1.01 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with ethyl acetate. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were purified by silica gel column chromatography to yield the title compound (196 mg, quant.) as white crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[NH2:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][NH:26]2)=[CH:22][CH:21]=1>C(O)C>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[N:25][NH:26]4)=[CH:22][CH:21]=3)=[C:3]([C:17]#[N:18])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13])[CH3:16]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OC
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4cn[nH]c4c3)c2cc1OC
Yield: 80 %

Procedure:
A mixture of 500 mg (1.90 mmol) 4-chloro-7-ethoxy-6-methoxy-quinoline-3-carbonitrile, 30 ml ethanol, and 304 mg (2.28 mmol) 6-aminoindazole was heated to reflux under N2. Removed heat at 4 hours and made basic with saturated sodium bicarbonate. Stripped solvents, slurried residue with hexane, collected solids and dried. Washed with water and dried in vacuo, giving 546 mg of tan solid: mass spectrum (electrospray m/e): M+H=359.9.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([N:27]4[CH:31]=[C:30]([CH2:32][OH:33])[CH:29]=[N:28]4)[C@@H:24]([OH:34])[C@H:23]3[OH:35])=[C:15]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:14]=2)[CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([N:27]4[CH:31]=[C:30]([CH2:32][OH:33])[CH:29]=[N:28]4)[C@@H:24]([OH:34])[C@H:23]3[OH:35])=[C:15]([NH:36][CH2:37][CH:38]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:14]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C

Procedure:
{(R)-1-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (first step a) is dissolved in methanol (2 ml). (4 M) HCl in 1,4-dioxane (15 ml) is added and the reaction mixture is stirred at room temperature over night. The compound is purified by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water—0.1% HCl). The compound is partitioned between DCM and saturated NaHCO3(aq). The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. MS (ES+) m/e 596.38 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[N:7]=[C:8](O)[C:9]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[S:12][C:10]=2[N:11]=1.O=P(Cl)(Cl)[Cl:23]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[N:7]=[C:8]([Cl:23])[C:9]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[S:12][C:10]=2[N:11]=1
Reactant: COC(=O)CCc1nc(O)c2c3c(sc2n1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)CCc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 47 %

Procedure:
A solution of 3-(4-hydroxy-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl)-propionic acid methyl ester (2 g, 0.0068 mol) in POCl3 (10 ml) was refluxed for 2 hrs. After consumption of starting material, excess of POCl3 was distilled off. The reaction mixture was quenched with ice and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography on 60-120 silica using ethyl acetate (30%) in hexane as eluant to give 1 g (47%) of 3-(4-chloro-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl)-propionic acid methyl ester. 1H NMR (400 MHz, DMSO) δ ppm=1.83 (m, 4H), 2.8 (m, 4H), 2.98 (m, 2H), 3.2 (t, 2H), 3.57 (s, 3H). LC-MS: [M+H]=311.1.