Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH2:4]([CH:6]([C:9]1[C:10]2[N:11]([C:16]([C:20]3[CH:24]=[CH:23][O:22][C:21]=3[CH3:25])=[C:17]([CH3:19])[N:18]=2)[N:12]=[C:13]([CH3:15])[CH:14]=1)[CH2:7][CH3:8])[CH3:5].[Br:26]N1C(=O)CCC1=O>O>[Br:26][C:23]1[O:22][C:21]([CH3:25])=[C:20]([C:16]2[N:11]3[N:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH:6]([CH2:7][CH3:8])[CH2:4][CH3:5])[C:10]3=[N:18][C:17]=2[CH3:19])[CH:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3ccoc3C)c(C)nc12
Solvent: ClCCl
Solvent: O
Product: CCC(CC)c1cc(C)nn2c(-c3cc(Br)oc3C)c(C)nc12
Yield: 70 %

Procedure:
A CH2Cl2 solution (2 mL) of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(2-methyl-furan-3-yl)-imidazo[1,2-b]pyridazine (42.3 mg, 0.14 mmol) under a CaSO4 drying tube is treated with N-bromosuccinimide (27.6 mg, 0.16 mg). After 30 minutes the reaction mixture is poured into H2O (25 mL) and extracted into CH2Cl2 (2×25 mL). The combined organic extracts are washed with sat. NaCl, dried over Na2SO4, filtered, and concentrated. The crude product is purified by chromatography using hexane-ethyl acetate gradient (100% hexane to 12% ethyl acetate in hexane) to elute the title product (36.9 mg, 70% yield) as a white solid. ES-MS (m/z): calc'd for C18H22BrN3O: 375.1. found 376.3 (M+H). 1H NMR (400 mHz, CDCl3): δ 6.67 (s, 1H), 6.50 (s, 1H), 3.33 (m, 1H), 2.53 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 1.90-1.73 (m, 4H), 0.86 (t, J=7.3 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16]OS(C)(=O)=O)=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=3)=[N:10]2)=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=3)=[N:10]2)=[CH:30][CH:31]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)ccc1F
Product: Cc1cc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)ccc1F
Yield: 71.8 %

Procedure:
Following the procedure of Example 1(10), 2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 71.8%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([O:24][C:25]([NH:27][C:28]1[N:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][N:29]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25](=[O:26])[NH:27][C:28]1[N:33]=[CH:32][C:31]([C:34](=[O:35])[NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)=[CH:30][N:29]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)cn1
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)cn1

Procedure:
(5-{[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-pyrimidin-2-yl)-carbamic acid tert-butyl ester was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-tert-butoxycarbonylamino-pyrimidine-5-carboxylic acid (prepared by BOC protection of ethyl 2-amino-5-pyrimidine carboxylate [prepared as described by P. Schenone, et al., J. Heterocyclic Chem., 27:295–305(1990)] using di-tert-butyl dicarbonate and 4-dimethylaminopyridine in acetonitrile, followed by saponification with sodium hydroxide and neutralization with dilute aqueous HCl) as described in EXAMPLE 1, Step 2:
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:1]([CH2:8][C:9]([O:11][CH2:12][CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(COc1ccccc1)OCCO

Procedure:
A 2-liter, 3-neck, round-bottom flask was equipped with a heating jacket, thermocouple and Dean-Stark apparatus for water removal. The flask was charged with 152 g (1.0 mole) phenoxyacetic acid, 62 g (1.0 mole) ethylene glycol, 22 g p-toluenesulfonic acid, 260 ml mixed xylenes and swept with nitrogen and sealed under a nitrogen balloon. The flask contents were heated to a pot temperature of 150° C. for 1/2 hour wherein 23 ml of water were collected and the reaction system cooled. Volatiles were removed at 110° C. in 4 mm of Hg vacuum to give a waxy white solid, IR shows formation of ester and disappearance of acid carbonyl, and mass spectrometry shows the molecular weight of 196.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: NCC1CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)cnc1NCC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
A mixture of 5-bromo-2-chloro-3-nitropyridine (Step B, 5.0 g, 21.1 mmol), cyclopropanemethylamine (2.8 mL, 31.7 mmol) and N,N-diisopropylethylamine (5.5 mL, 31.7 mmol) in ethanol (20 mL) was stirred at room temperature for 24 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate as eluent) to afford the title compound (5.5 g, 96%) as a yellow solid.
Reaction SMILES: C([C:8]1[C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[O:11][C:10](=[O:27])[CH:9]=1)[N:18]([C:22](=[O:24])[CH3:23])[C@@H:17]([CH3:25])[CH2:16][C@H:15]3[NH2:26])C1C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:22]([N:18]1[C:19]2[C:14](=[C:13]3[CH:8]=[CH:9][C:10](=[O:27])[O:11][C:12]3=[CH:21][CH:20]=2)[C@H:15]([NH:26][C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:16][C@@H:17]1[CH3:25])(=[O:24])[CH3:23]
Reactant: CC(=O)N1c2ccc3oc(=O)cc(Cc4ccccc4)c3c2[C@H](N)C[C@@H]1C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccc3oc(=O)ccc3c2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.1 %

Procedure:
[Step 5] 22 mg of the cis-benzyl-7-acetyl-10-amino-8-methyl-7,8,9,10-tetrahydro-3H-pyrano[3,2-f]-quinolin-3-one and 19 mg of 4-chlorophenylboronic acid were dissolved in 10 mL of dichloromethane followed by adding 29 mg of divalent copper acetate and 34 μL of triethylamine and stirring for 18 hours at room temperature in the presence of air. Following completion of the reaction, the solution was filtered with celite and water was added followed by extracting three times with ethyl acetate. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:1) to obtain 7 mg of the target compound in the form of a yellow solid (23%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[OH-].[Na+].O1CCOCC1.Cl[CH:21]([F:23])[F:22]>O>[Br:1][C:2]1[C:3]([O:11][CH:21]([F:23])[F:22])=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)Cl
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(Br)c1OC(F)F
Temperature: 80 °C
Reaction time: 11 h
Yield: 33.4 %

Procedure:
Into a 200-ml four-necked flask provided with a reflux condenser, a stirrer and a thermometer were fed 4.36 g (0.02 mol) of 2-bromo-6-nitrophenol, 16.7 g (0.1 mol) of 24% sodium hydroxide, 20 ml of 1,4-dioxane and 7 ml of water. The mixture was heated to 80° C. The mixture was stirred at that temperature for 11 hours with heating while chlorodifluoromethane (flon 22) was blown thereinto from a bomb. The reaction mixture was cooled and then subjected to extraction two times each using 20 ml of ether. The ether layer was washed with 20 ml of 12% sodium hydroxide and then with the same volume of water. Then, the ether layer was dried over anhydrous sodium sulfate and then subjected to distillation to obtain 1.79 g of 3-bromo-2-difluoromethoxynitrobenzene (yield: 33.4%, purity: 98.8%). To the sodium hydroxide washing was added hydrochloric acid to make the washing acidic, and the resulting precipitate was subjected to extraction with ether, to recover 2.2 g of unreacted 2-bromo-6-nitrophenol (recovery ratio: 50%).
Reaction SMILES: I[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Ic1sc2ccccc2c1Oc1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(-c2sc3ccccc3c2Oc2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a solution of 2-iodo-3-(4-benzyloxyphenoxy)benzo[b]thiophene (5.00 g, 11.0 mmol) in 50 mL of toluene under N2 were added 3-methoxyphenylboronic acid (2.00 g, 13.0 mmol), (Ph3P)4Pd (0.75 g, 0.66 mmol), and 18.0 mL of 2.0N Na2CO3 solution. The resulting mixture was heated to reflux for 2 h. Upon cooling to room temperature, the reaction was diluted with EtOAc and extracted several times with 0.1N NaOH. The organic was then dried (Na2SO4) and concentrated in vacuo to an oil. Chromatography (SiO2, 0-10% Et2O/hexanes) provided 4.8 g (99%) of 2-(3-methoxyphenyl)-3-(4-benzyloxyphenoxy)benzo[b]thiophene as a brown oil.
Reaction SMILES: C[C:2]1([C:13]([O-])=[O:14])[NH:7][C:6]([C:8]([O:10][CH2:11]C)=[O:9])=[CH:5][CH:4]=[CH:3]1.[BH4-].[Na+].Cl>CO.C(Cl)Cl>[OH:14][CH2:13][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=CC=CC(C)(C(=O)[O-])N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 108.8 %

Procedure:
To a solution of 2-ethyl 6-methylpyridine-2,6-dicarboxylate (3.0 g, 14.3 mmol) in MeOH (20 mL) and CH2Cl2 (10 mL) was added slowly NaBH4 (1.95 g, 51.6 mmol) in several portions at −40° C. After 10 min, the reaction mixture was stirred at rt for 1 h. To the reaction mixture was added 5 mL of 1 N HCl and the mixture was stirred for 20 min. The solvents were removed in vacuo and the residue was diluted with CHCl3 and saturated aqueous NaHCO3 solution (20 mL). The organic layer was separated, dried over MgSO4, filtered and the filtrate solution was concentrated in vacuo to give the desired compound (2.6 g, 54%) as a white solid. 1H NMR (DMSO-d6) δ 8.02 (t, J=8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 4.62 (d, J=8.0 Hz, 2H), 3.88 (s, 3H). MS (ESI): 168.1 (M+H)+.
Reaction SMILES: O[Li].O.SCC(O)=O.[CH2:9]([O:16][N:17]([C@H:30]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:33]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:32][CH2:31]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C.O>[CH2:9]([O:16][NH:17][C@H:30]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[C@H:33]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:32][CH2:31]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CN1C(=O)OC(C)(C)C
Agent: O=C(O)CS
Agent: [Li]O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
LiOH.H2O (95 g, 2.3 mol) and 2-mercaptoacetic acid (124 g, 1.3 mol) were added to a solution of (2S,5R)-1-tert-butyl 2-ethyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)piperidine-1,2-dicarboxylate (251 g, 0.45 mol) in DMF (1200 mL). The reaction mixture was then stirred at 20° C. overnight. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layer was washed with brine (3×), concentrated in vacuum and purified by silica gel column chromatography (3;1 petroleum ether/EtOAc) to afford (2S,5R)-1-tert-butyl 2-ethyl 5-((benzyloxy)amino)piperidine-1,2-dicarboxylate (122.9 g, 85%) as a yellow solid.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[N+:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-])=[O:6].C1N2CCN(CC2)C1>C(O)C>[OH:4][CH2:1][C:2]1[O:6][N:5]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1
Reactant: C#CCO
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)c1cc(CO)on1
Temperature: 80 °C
Yield: 80.9 %

Procedure:
To a mixture of propargyl alcohol (1.0 mL; 16.76 mmol) and ethyl 2-nitroacetate (3.79 mL; 33.52 mmol) in ethanol (23.5 mL) in an Ace pressure tube was added 1,4-diazobicyclo[2.2.2]octane (DABCO, 0.194 g; 1.68 mmol). The tube was heated at 80° C. for 72 h. After cooling, the mixture was evaporated to dryness and the residue was purified by flash chromatography on silica gel (eluent: 0 to 6% methanol in dichloromethane) to yield 2.32 g (81%) of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 4-(2-aminoethyl) morpholine (42 mg, 0.32 mmol). The title compound was obtained as a solid (49 mg, 38% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.83 (1H, m), 8.43 (1H, s), 4.02 (4H, m), 3.31 (2H, m), 2.45 (2H, m), 2.38 (4H, m). MS m/z: 463.06, 465.05 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]3[O:18][C:19]([CH3:31])=[C:20]([CH2:22][C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH3:30])=O)[N:21]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:18][C:19]([CH3:31])=[C:20]([CH2:22][CH2:23][N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH3:30])[N:21]=3)=[CH:15][N:16]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)nc1CC(=O)N1CCC[C@H]1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)nc1CCN1CCC[C@H]1C
Reaction time: 4 h

Procedure:
To a stirring solution of 2-{2-[6-(4-Methanesulfonyl-phenyl)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-1-(2-(R)-methyl-pyrrolidin-1-yl)-ethanone (See Intermediate 21) (1.0 mmol) in tetrahydrofuran (0.10M) in a 0° C. ice bath, slowly add 1M lithium aluminum hydride in tetrahydrofuran (2.0 mmol). Remove the ice bath and stir for four hours. After this time, perform a Fieser and Fieser work up by adding water (1 mL per gram of LAH used) followed by 5N sodium hydroxide (1 mL per gram of LAH used) and then water again (3 mL per gram of LAH used). Stir this for 18 hours and then filter the reaction through Celite®. Wash the filtrate with dichloromethane while extracting with 1N hydrochloric acid. Basify the aqueous layer with 2N sodium hydroxide and extract with dichloromethane. Concentrate the organic layer and purify via radial chromatography eluting with 2M ammonia in methanol and dichloromethane. MS (m/e): 426.2 (M+1)
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=[C:22]2B1OC(C)(C)C(C)(C)O1>O1CCOCC1.C([O-])(O)=O.[Na+].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]>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=[C:22]2[C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)c2cccc(Cl)c21
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cc(-c2ncc3c(n2)N2CCOCC2CN3)c2cccc(Cl)c21

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 50 mg, 0.221 mmol), tert-butyl 7-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (125 mg, 0.331 mmol) and PdCl2(dppf) (12.91 mg, 0.018 mmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][N:33]3COCC[Si](C)(C)C)=[CH:29][CH:28]=2)[CH:23]=[C:24]([F:26])[CH:25]=1.C(OCC)(=O)C>O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][NH:33]3)=[CH:29][CH:28]=2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3cc(F)cc(F)c3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3cc(F)cc(F)c3)ccc12
Temperature: 66 °C
Yield: 43.7 %

Procedure:
14 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.1 g of N-[6-(3,5-difluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 18 hours. The heating is then stopped and 100 cm3 of ethyl acetate are added. This mixture is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with cyclohexane/ethyl acetate (60/40 by volume) and collecting 35 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 2×5 cm3 of diisopropyl ether. This mixture is filtered through a sinter funnel and dried under reduced pressure (90 Pa; 50° C.) to give 340 mg of N-[6-(3,5-difluorophenyl)-1H-indazol-3-yl]butanamide in the form of a white solid melting at 260° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:34])[N:17]([C:21]2[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].[CH2:35]([NH2:37])[CH3:36]>O>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:37][CH2:35][CH3:36])([CH3:13])[CH3:12])[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Reactant: CCN
Solvent: O
Product: CCNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O

Procedure:
The title compound was prepared from 3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 198e) and 70% ethylamine in water using the method of example 167f.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][P:5]([CH3:12])(=[O:11])[O:6]CC(C)C>Cl>[NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][P:5]([CH3:12])(=[O:6])[OH:11]
Reactant: CC(C)COP(C)(=O)C[C@@H](O)CN
Agent: Cl
Product: CP(=O)(O)C[C@@H](O)CN
Temperature: 25 °C

Procedure:
A solution of 1.1 g of isobutyl P-[3-amino-2(S)-hydroxy-propyl]-P-methyl-phosphinate in 20 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 12 hours. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure, and co-evaporated four times with 25 ml of water. The crude material is dissolved in water, washed with ether and the aqueous layer is treated with activated charcoal. The solution is filtered hot, the filtrate is concentrated under reduced pressure, the residue dissolved in 20 ml of ethanol and treated with 1 ml of propylene oxide. The mixture is stirred until the precipitated solid is free of halogen. The solid is then filtered and recrystallised from methanol/acetone give P-[3-amino-2(S)-hydroxypropyl]-P- methyl-phosphinic acid, m.p. 221°-222.5°, 31P-NMR spectrum: δ=+38.9 ppm (D2O), [α]D25 =-6.0° (c=0.887% in H2O).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.CCN=C=NCCCN(C)C.[OH:31][C:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH:35]3[CH2:42][C:43](O)=[O:44])[CH2:33]1)[CH2:39]2>C(Cl)Cl>[OH:31][C:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH:35]3[CH2:42][C:43]([N:12]3[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]3)=[O:44])[CH2:33]1)[CH2:39]2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1C2CC3CC1CC(O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC1CC(O)(C4)C3)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Triethylamine 0.38 ml was added to a methylene chloride 15 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.44 g, and stirred at 0° C. for 30 min. WSC 0.53 g and 5-hydroxy-2-adamantyl acetic acid 0.44 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 14.5 hours. The reaction mixture was washed with saturated sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(5-hydroxy-2-adamantyl acetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 95.5 mg and refluxed under heating for 1.5 hours. The reaction mixture was cooled, then added water, and removed the insoluble material by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform: methanol=150:1) to obtain the product. Yield: 556 mg (Yield 79%)
Reaction SMILES: [C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH2:17][C:18]1C=CC=CC=1)=[N:5][CH3:6])#[N:2].[CH3:24]NC(N)=N>>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH:17]([CH3:18])[CH3:24])=[N:5][CH3:6])#[N:2]
Reactant: CNC(=N)N
Reactant: CN=C(NC#N)NCCNCc1nc[nH]c1Cc1ccccc1
Product: CN=C(NC#N)NCCNCc1nc[nH]c1C(C)C

Procedure:
N-cyano-N'-[2-((5-benzyl-4-imidazolyl)methylamino)ethyl]-N"-methylguanidine p N-cyano-N'-[2-((5-bromo-4-imidazolyl)methylamine ethyl]-N"methylguanidine