Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:19][C:18]2[CH:20]=[CH:21][C:13]([CH:12]=[O:11])=[CH:14][C:15]=2[O:16][CH3:17])[CH:3]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Yield: 87.3 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.60 g, 3.9 mmol), vanillin (0.59 g, 3.9 mmol) and cesium carbonate (1.26 g, 3.9 mmol) were heated with stirring in dry DMF (4 ml) at 50° C. for 22 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, 10% aqueous sodium carbonate (2×), water (2×), brine, and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(4-formyl-2-methoxy-phenoxy)-benzonitrile (0.98 g, 88%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:41]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>O1CCCC1.O>[F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][N:5]([S:47]([N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)(=[O:49])=[O:48])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)N1CCCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)N2CCCCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 121 mg) at room temperature and the mixture was stirred for 15 min. 15-Crown-5 (664 mg) was added dropwise, and the mixture was stirred for 5 min. Piperidine-1-sulfonyl chloride (240 mg) was added, and the mixture was further stirred for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:4→1:1) to give the title compound as a colorless oil (yield 210 mg, 45%).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl[CH2:16][CH2:17][CH2:18][OH:19]>COCCOC>[C:7]([NH:6][C:5]1[CH:10]=[CH:11][C:2]([S:1][CH2:16][CH2:17][CH2:18][OH:19])=[CH:3][CH:4]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: OCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1ccc(SCCCO)cc1
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A mixture of 16.7 g (0.1 mole) of p-mercaptoacetanilide, 4 g of sodium hydroxide, 40 ml of water, 40 ml of 1,2-dimethoxyethane, and 0.39 g (0.11 mole) of 3-chloropropanol is heated in a steam bath with stirring for 30 minutes. Two liquid phases are formed, and TLC indicates that the reaction is substantially complete. The mixture is distilled in vacuo to remove 1,2-dimethoxyethane, and the oily mixture which separates is triturated with cold water until it solidifies. The crude product is recrystallized from ethanol to obtain a by-product: the disulfide derived from the starting mercapto compound. The ethanol filtrate is concentrated, and the residue is triturated with ether-hexane to obtain 15.7 g of the desired product. Recrystallization from ethyl acetate-hexane gives 11.8 g of 3-(p-acetamidophenylthio)propanol which shows the correct IR and NMR spectra.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[O:15][CH3:16])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>C(O)C.[Fe]>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[O:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1OC
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: CCOC(=O)Nc1ccc(N)cc1OC
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
(2-Methoxy-4-nitrophenyl)-carbamic acid ethyl ester (2.20 g) was dissolved in ethanol (220 mL). Aqueous hydrochloric acid (26 mL, 6 M) and iron powder (4.74 g) were added, and the mixture was stirred at 65° C. for 15 minutes. After cooling to room temperature, the mixture was neutralised with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 mL). The organic phase was washed with water (2×100 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was dissolved in ethanol (100 mL), and the above procedure was repeated using aqueous hydrochloric acid (26 mL, 6M) and iron powder (3.7 g), to yield the title compound as a dark oil (1.80 g, 93%). 1H NMR (DMSO-d6): 1.19 (t, 3H), 3.67 (s, 3H), 4.01 (q, 2H), 4.97 (s, 2H), 6.08 (dd, 1H), 6.23 (d, 1H), 6.97 (br. s, 1H), 7.92 (br. s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.Cl.[NH2:31][N:32]1[CH2:39][CH:38]2[CH:34]([CH2:35][CH2:36][CH2:37]2)[CH2:33]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:31][N:32]3[CH2:39][CH:38]4[CH2:37][CH2:36][CH2:35][CH:34]4[CH2:33]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: NN1CC2CCCC2C1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NN3CC4CCCC4C3)n2)cc1
Yield: 67 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and 3-Amino-3-azabicyclo-[3,3,0]octane hydrochloride salt (19 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (34 mg, 67% yield.) MS/ES+: m/z=440.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Sm+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C([C@@H]1COC(=O)N1[C:39]([C@H:41]1[C@H:45]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=2[F:53])[CH2:44][N:43]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:42]1)=[O:40])C1C=CC=CC=1.[CH3:61][OH:62]>C1CCCCC1>[CH2:54]([N:43]1[CH2:44][C@@H:45]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=2[F:53])[C@H:41]([C:39]([O:62][CH3:61])=[O:40])[CH2:42]1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1F
Reactant: CO
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sm+3]
Solvent: C1CCCCC1
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1F
Reaction time: 24 h

Procedure:
Samarium triflate (6.32 g, 10 mmol) was added to a stirred solution of (4R)-4-benzyl-3-{[(3S,4R)-1-benzyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-1,3-oxazolidin-2-one, from preparation 29 (63 g, 130 mmol) in methanol (350 mL) at room temperature. The reaction mixture was stirred for 24 hours and the solvent was removed in vacuo. Dichloromethane (290 mL) was added followed by saturated sodium hydrogen carbonate solution (140 mL) and the mixture stirred for 15 minutes. The resulting precipitate was filtered and washed with dichloromethane (250 mL) and water (25 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2×40 mL). The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. The residue was suspended in warm cyclohexane (300 mL) and shaken till formation of a solid occurred. The mixture was allowed to stand at room temperature for 24 hours. The solid was filtered and washed with cold cyclohexane (150 mL). The filtrate was concentrated in vacuo to afford the desired compound, 38 g (87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([NH:20][C@H:21]([C:23]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27](=[O:35])[C:26]4=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]4[N:24]=3)[CH3:22])[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Li+].Cl>C(O)C.O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C@H:21]([C:23]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27](=[O:35])[C:26]4=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]4[N:24]=3)[CH3:22])[N:12]=[CH:11][N:10]=2)=[CH:40][CH:41]=1
Reactant: CCOC(=O)c1c(NCc2ccc(OC)cc2)ncnc1N[C@@H](C)c1nn2ccc(C)c2c(=O)n1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CNc2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2C(=O)O)cc1
Temperature: 50 °C
Yield: 111.9 %

Procedure:
(S)-Ethyl 4-((4-methoxybenzyl)amino)-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboxylate (281 mg, 0.51 mmol) was dissolved in 2 mL ethanol and 3 mL tetrahydrofuran. Lithium hydroxide (213 mg, 50.8 mmol) in 3 mL water was added and the mixture was heated at 50° C. overnight. Further lithium hydroxide (213 mg, 50.8 mmol) in 3 mL water was added and the reaction mixture heated at 50° C. for 4 h more. The reaction mixture was diluted with water and acidified to pH 5 with hydrochloric acid 5N. The aqueous phase was extracted with ethyl acetate and the organics were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to give 300 mg (99% yield) of the title compound as a white solid. Purity 90%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:24]([O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30])[CH3:25]>>[CH2:24]([O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:30])[CH3:25]
Reactant: CCOc1ccccc1C(=O)Nc1ccc(C(=O)OC)c(N)c1
Reactant: CCOc1ccccc1C(=O)Cl
Product: CCOc1ccccc1C(=O)Nc1ccc(C(=O)OC)c(NC(=O)c2ccccc2OCC)c1

Procedure:
By the procedure similar to that described in Example 21, methyl 2-amino-4-(2'-ethoxybenzamido)-benzoate and 2-ethoxybenzoylchloride were reacted and treated to obtain crystals. Recrystallization from acetone gave methyl 2,4-bis(2'-ethoxybenzamido)-benzoate having a melting point between 199° - 200°C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl[C:56]([O:58][CH3:59])=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:56]([O:58][CH3:59])=[O:57])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and methyl chloroformate as the starting materials in 60% yield. LCMS for C25H27ClN7O4 (M+H)+: m/z=524.1.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35]C)=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].CO.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:44])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 87 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide and methanolic hydrochloric acid, methanol, and ammonium carbonate. Yield: 87% of theory, C27H28N6O3 (484.6); Rf value: 0.11 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=485; (M+2H)++=243; (M+H+Na)++=254.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[C:5]([F:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[O:12]=[C:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1>>[F:11][C:4]1[CH:3]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:14][C:13]2=[O:12])[CH:7]=[C:6]([CH2:8][OH:9])[C:5]=1[F:10]
Reactant: OCc1cc(Br)cc(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(F)c(CO)c2)C(=O)C1

Procedure:
tert-butyl 4-(3,4-difluoro-5-(hydroxymethyl)phenyl)-3-oxopiperazine-1-carboxylate was prepared following the procedure in Example 27 (Step ii) using (5-bromo-2,3-difluorophenyl)methanol and tert-butyl 3-oxopiperazine-1-carboxylate.
Reaction SMILES: C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.[Li].C([O:29][CH2:30][CH2:31][CH2:32][C@H:33]([CH3:43])[CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])C1C=CC=CC=1.[NH4+].[Cl-]>C1COCC1>[Si:36]([O:35][CH2:34][C@@H:33]([CH3:43])[CH2:32][CH2:31][CH2:30][OH:29])([C:39]([CH3:41])([CH3:42])[CH3:40])([CH3:38])[CH3:37]
Reactant: C[C@@H](CCCOCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 97 %

Procedure:
With stirring, 4,4′-di-tert-butyl biphenyl (3.6 g) under an Argon atmosphere is added at 0° C. to a suspension of lithium (30% in mineral oil) in THF (30 ml). Stirring is continued for 2 h at r.t. The resulting deep green solution is added dropwise to a solution of (S)-1-benzyloxy-5-(ter-butyldimethylsilyloxy)-4-methyl-pentane 5 (673 mg, 2.09 mmol) in 10 ml of THF at −78° C., until the colour of the mixture remains green (or until tic analysis shows completion of the reaction, respectively). Saturated aqueous NH4Cl solution (10 ml) is added with stirring. The organic phase is separated and the aqueous layer is extracted with diethyl ether (3×50 ml). The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by flash column chromatography (pentane/diethyl ether 5:1) affords (S)-5-(tert-butyldimethylsilyloxy)-4-methyl-pentan-1-ol 6(471 mg, 97%) as a colourless oil. 13C-NMR (100 MHz, CDCl3): δ=68.29; 63.36; 35.57; 30.24; 29.25; 25.98; 18.38; 16.77; −5.34
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:26](=[O:27])[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][C@@H:3]2[CH2:6][NH:7][CH2:8][C@H:2]12.[CH:28](=O)[CH3:29].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+]>[CH2:28]([N:7]1[CH2:6][C@@H:3]2[C@@H:2]([N:1]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[C:26](=[O:27])[CH:25]=[CH:24][CH:23]=[N:22]5)=[CH:17][CH:16]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:8]1)[CH3:29]
Reactant: CC=O
Reactant: O=c1cccnn1-c1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product from Example 85B (0.050 g, 0.140 mmol) and acetaldehyde (10.0 μL, 0.140 mmol) were combined in 5 mL of dichloroethane containing 3 drops of HOAc and stirred at ambient temperature for 10 minutes. Sodium triacetoxyborohydride (0.039 g, 0.182 mmol) was added and the mixture was stirred for 3 hours. The mixture was diluted with 20 mL of aqueous NaHCO3 and extracted three times with 25 mL of 5% n-propanol in CHCl3 and the combined extracts were dried over Na2SO4, filtered, and absorbed on silica gel. The crude material was chromatographed, eluting with 1% aqueous NH4OH in EtOAc/MeOH (9:1), to provide the title compound, 1H NMR (300 MHz, CDCl3) δ ppm 7.91 (d, J=2.0 Hz, 1H), 7.63 (s, 4H), 7.50 (d, J=8.5 Hz, 2H), 7.23 (d, J=3.7 Hz, 1H), 7.07 (d, J=9.2 Hz, 1H), 6.65 (d, J=8.8 Hz, 2H), 4.11-4.25 (m, 1H), 3.47-3.60 (m, 1H), 3.24-3.39 (m, 1H), 2.88-3.05 (m, 1H), 2.78 (dd, J=9.5, 6.4 Hz, 1H), 2.56-2.70 (m, 2H), 2.35-2.56 (m, 3H), 2.10-2.25 (m, 1H), 1.85-2.02 (m, 1H), 1.26 (s, 1H), 1.09 (t, J=7.1 Hz, 2H). MS (ESI+) m/z 387 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN(C)C=O>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: CN1CCNCC1
Reactant: Nc1ccnc(Cl)n1
Solvent: CN(C)C=O
Product: CN1CCN(c2nccc(N)n2)CC1
Temperature: 220 °C
Yield: 67 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol) and 1-methylpiperazine (771 μl, 6.95 mmol) in N,N-dimethylformamide (DMF) (3 ml) was heated to 220° C. via a microwave reactor for 60 min. The reaction was purified by RP-HPLC to yield 2-(4-methyl-1-piperazinyl)-4-pyrimidinamine (300 mg, 1.552 mmol, 67% yield). MS (ES+) m/z 194.2 (MH+).
Reaction SMILES: C(OC([NH:8][C:9](=[NH:39])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C@@H:17]([C:21]2[CH:26]=[C:25]([O:27][CH2:28][CH3:29])[CH:24]=[C:23]([O:30][CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[C:22]=2[F:38])[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)=O)(C)(C)C>O.C(O)=O>[C:9]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C@@H:17]([C:21]2[CH:26]=[C:25]([O:27][CH2:28][CH3:29])[CH:24]=[C:23]([O:30][CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[C:22]=2[F:38])[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)(=[NH:8])[NH2:39]
Reactant: CCOc1cc(OC2CCN(C)CC2)c(F)c([C@H](Nc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)C(=O)O)c1
Solvent: O
Solvent: O=CO
Product: CCOc1cc(OC2CCN(C)CC2)c(F)c([C@H](Nc2ccc(C(=N)N)cc2)C(=O)O)c1
Temperature: 0 °C
Yield: 72.1 %

Procedure:
A solution of 5.1 g (S)-[4-(tert-butoxycarbonylamino-imino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-acetic acid in 102 ml water/formic acid 1:1 was heated to 40° C. for 2.5 hrs. The solvents were evaporated in vacuo, the residue dissolved in water and the solution evaporated again (repeated twice). The residue was dissolved in methanol and 7N methanolic ammonia was added until pH=9, wereby a precipitate was formed. The mixture was cooled to 0° C., the solid isolated by suction filtration and dried. Afterwards it was suspended in water and the pH adjusted to 9 wiTh conc. ammonia. Suction filtration and drying gave 3 g (S)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-acetic acid. White solid. Mp.: 269° C. MS: 445 ([M+H]+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[N:18]([CH2:19][CH2:20][NH2:21])[CH:13]([CH2:14][CH2:15]2)[CH:12]=1.Br[C:23]1[CH:24]=[C:25]([O:33][CH3:34])[CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:34][O:33][C:25]1[CH:26]=[C:27]2[C:32](=[C:23]([NH:21][CH2:20][CH2:19][N:18]3[CH:16]4[CH2:15][CH2:14][CH:13]3[CH:12]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=3)[CH2:17]4)[CH:24]=1)[N:31]=[CH:30][CH:29]=[CH:28]2
Reactant: COc1cc(Br)c2ncccc2c1
Reactant: NCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(NCCN2C3C=C(c4ccc5ccccc5c4)CC2CC3)c2ncccc2c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A mixture of 0.17 g, (0.61 mmol) 2-[3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]ethylamine, 0.13 g (0.55 mmol) 8-bromo-6-methoxyquinoline, 30 mg (0.03 mmol) Pd2(dba)3, 20 mg (0.08 mmol) 2-(di-t-butylphosphino)biphenyl and 10 mL PhMe is stirred at 23° C. for 16 h. The reaction mixture is poured into 100 mL of H2O and extracted 3×50 mL EtOAc. The combined organics are washed with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered, and the volatiles are evaporated. The crude product is subjected to flash chromatography on SiO2, eluting with EtOAc to EtOAc/2M NH3 in MeOH (40/1), to give the title compound as an off-white solid. This solid is dissolved in 4 mL of absolute EtOH and treated with 0.01 g (0.14 mmol) (CO2H)2 to give 0.07 g (0.13 mmol, a 23% yield) of the oxalate salt of the title compound as a dark green solid: mp: 179-182 C; MS (ES) m/z 436 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(Cl)(Cl)([Cl:23])=O.N>C(Cl)(Cl)Cl>[Cl:23][CH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2oc(-c3ccccc3)c(C)[n+]2[O-])cc1
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc(CCl)c(-c3ccccc3)o2)cc1
Temperature: 0 °C

Procedure:
6.4 g of 4-methyl-5-phenyl-2-p-tolyloxazole 3-oxide are dissolved in 50 ml of chloroform, 2.4 ml of phosphorus oxychloride are added and the mixture is, under reflux, heated at the boil for 30 minutes. The reaction mixture is cooled to 0° C., the pH is made slightly alkaline using ammonia and the mixture is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are washed with water and dried over MgSO4, and the solvent then removed under reduced pressure. This gives 5.4 g of 4-chloromethyl-5-phenyl-2-p-tolyloxazole as a yellow solid. C17H14CINO (283.76), MS (ESI)=284 (M+H+), Rf(n-heptane:ethyl acetate)=7:1)=0.41