Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:24]3[CH:25]=[CH:26][NH:27][C:23]=3[CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1.C([Li])(C)(C)C.CN(C)[CH:35]=[O:36].[NH4+].[Cl-]>O1CCCC1>[NH:27]1[C:23]2[CH:22]=[CH:21][N:20]=[C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([CH:35]=[O:36])[CH:3]=5)[NH:7][CH:6]=4)[CH2:14][CH2:15]3)[C:24]=2[CH:25]=[CH:26]1
Reactant: Brc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Reaction time: 1 h

Procedure:
A solution at −78° C. of 1.5 mmol of the compound obtained in Step 3 in tetrahydrofuran is treated with 9 mmol of tert-butyllithium (1.8M in hexane). After stirring the mixture for 1 hour, 12 mmol of dimethylformamide are added and the mixture is brought to ambient temperature. After reaction for 4 hours, the solution is hydrolysed by a saturated solution of NH4Cl and then extracted with dichloromethane. After treating the organic phase in conventional manner, chromatography of the residue on silica gel enables the expected product to be isolated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(Oc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, phenol and DBU in DME. EI-MS m/e (%): 278 (M+, 100), 277 ([M—H]+, 22), 250 (68), 249 (89).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)C(C)C)(C)C.[F:13][C:14]1[CH:34]=[CH:33][C:17]([O:18][CH2:19][C:20]2[C:21]([CH2:31][OH:32])=[C:22]([OH:30])[C:23]([C:26](OC)=[O:27])=[N:24][CH:25]=2)=[CH:16][CH:15]=1>CO.CCOC(C)=O>[OH:3][NH:2][C:26]([C:23]1[C:22]([OH:30])=[C:21]([CH2:31][OH:32])[C:20]([CH2:19][O:18][C:17]2[CH:33]=[CH:34][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:25][N:24]=1)=[O:27]
Reactant: NO
Reactant: COC(=O)c1ncc(COc2ccc(F)cc2)c(CO)c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(NO)c1ncc(COc2ccc(F)cc2)c(CO)c1O
Temperature: 70 °C
Yield: 97.3 %

Procedure:
Hydroxylamine hydrochloride (0.045 g, 0.65 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.81 mmol) were added to a solution of methyl 5-((4-fluorophenoxy)methyl)-3-hydroxy-4-(hydroxymethyl)picolinate 28b (0.050 g, 0.16 mmol) in MeOH (3 mL) and heated to 70° C. for 5 h. The crude mixture was diluted with EtOAc and washed with saturated aqueous ammonium chloride solution and brine. The organic extract was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.048 g, 96%): LC-MS (M+H)+ m/z 309.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:15][CH2:16][CH2:17][CH2:18]OS(C)(=O)=O)=[CH:6][C:7]2[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=2[CH:14]=1)[CH3:2].[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)C>[CH2:1]([O:3][C:4]1[C:5]([O:15][CH2:16][CH2:17][CH2:18][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:6][C:7]2[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=2[CH:14]=1)[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOc1cc2ccc(=O)oc2cc1OCCCOS(C)(=O)=O
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: CCO
Product: CCOc1cc2ccc(=O)oc2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 76 %

Procedure:
Method B (40 h at 50° C.); starting materials: 6-ethoxy-7-[3-(methanesulfonyloxy)-propoxy]-2H-1-benzopyran-2-one (see example 71) and 1-phenylpiperazine; yield 76%; fusion point 116° to 117° C. (from isopropanol). Fumarate: method E; yield 94%; fusion point 185° to 187° C. (from ethanol and acetone).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](B1OC(C)(C)C(C)(C)O1)([CH3:29])=[CH2:28]>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([C:27]([CH3:29])=[CH2:28])=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Product: C=C(C)c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C(=O)OC)n1

Procedure:
The product was obtained starting from methyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromopyrazine-2-carboxylate (1.13 g, 2.61 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (672 μl, 3.4 mmol) according to the method described in example A-1, step 1 after extraction with ethyl acetate and purification by silica gel chromatography using a heptane/ethyl acetate gradient as yellow viscous oil (323 mg, 31%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23]([C:27]1[CH:28]=[C:29]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[C:30]([O:53][CH3:54])=[C:31]([NH:33][C:34]([C:36]2[N:37]([CH3:52])[C:38]3[C:43]([CH:44]=2)=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[O:35])[CH:32]=1)([CH3:26])([CH3:25])[CH3:24].O>O1CCCC1.C(OCC)(=O)C>[C:23]([C:27]1[CH:28]=[C:29]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[C:30]([O:53][CH3:54])=[C:31]([NH:33][C:34]([C:36]2[N:37]([CH3:52])[C:38]3[C:43]([CH:44]=2)=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:45][N:46]2[CH2:47][CH2:48][N:49]([C:8]([CH:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[O:10])[CH2:50][CH2:51]2)=[O:35])[CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCNCC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CN1CCCC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)C5CCCN(C)C5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
61 mg 1-methyl-piperidine-3-carboxylic acid are dissolved in 1 ml of tetrahydrofuran, combined with 69 mg carbonyldiimidazole and stirred for 20 minutes at 50° C. The mixture is left to cool to ambient temperature, 150 mg 1-methyl-7-piperazin-1-ylmethyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-amide are added and then the mixture is stirred for 12 hours at ambient temperature. Then a further 122 mg of 1-methyl-piperidine-3-carboxylic acid in 2 ml of tetrahydrofuran are combined with 138 mg carbonyldiimidazole, the mixture is stirred for 20 minutes at 50° C. and this solution is added to the reaction mixture. It is stirred for 2 hours at 50° C., then divided between water and ethyl acetate, the organic phase is washed with saturated aqueous sodium chloride solution, dried with magnesium sulphate and the solvents are eliminated in vacuo. The residue is chromatographed on silica gel with dichloromethane/(methanol/ammonia 9:1) 99:1 to 90:10. The product thus obtained is purified by preparative HPLC (HPLC method 3).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([NH:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36].C(=O)([O-])O.[Na+]>CCCCCC.C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([N:21]([CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=4)[C:35](=[O:37])[CH3:36])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CCNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(CCN(C(C)=O)c2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
Sodium hydride (a 60% dispersion in liquid paraffin, 232.1 mg, 5.80 mmol) was washed twice with hexane and then suspended to N,N-dimethylformamide (25 ml). To this suspension was added under an argon atmosphere 3-(4-isopropylphenyl)-N-[2-(4-methoxyphenyl)ethyl]-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (537.9 mg, 1.18 mmol) and the reaction mixture was stirred at 60° C. for 20 minutes. Then, acetyl chloride (0.5 ml, 7.03 mmol) was added into the reaction mixture and stirred at the same temperature for 1 hour. After the reaction solution was cooled down to room temperature, an aqueous saturated solution of sodium hydrogen carbonate was added to the reaction mixture and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 3:1) to obtain the rotamer 1 (Rf=0.38; hexane-ethyl acetate 3:1) of the title compound (46% yield). Melting point: 134-136° C. (Ethyl acetate-hexane)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>C1COCC1>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A mixture of 0.397 g (1 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2), 0.24 g (1.2 mmol) of tert-butyl 4-amino-1-piperidinecarboxylate, and 0.194 g (1.5 mmol) of DIPEA in 25 mL of THF was stirred at room temperature overnight. Dilution with water and extraction with CH2Cl2, followed by chromatography on silica eluting with CH2Cl2/EtOAc (4:1) gave 0.51 g (91% yield) of tert-butyl 4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate: mp (hexanes/CH2Cl2) 142-145° C.; 1H NMR (CDCl3) (rotamer mixture; ratio ca. 3:2) δ 7.96 and 7.95 (2d, J=8.3 and 7.9 Hz, 1H), 7.54 and 7.52 (2t, JHF=53.6 Hz, 1H), 7.34 (br t, J=8.1 Hz, 1H), 6.81 (t, J=6.9 Hz, 1H), 5.22 and 5.17 (2d, J=7.4 and 7.6 Hz, exchangeable with D2O, 1H), 4.10 (m, 3H), 4.05 (s, 3H), 3.87 (m, 4H), 3.78 (m, 4H), 2.93 (t, J=12.1 Hz, 2H) 2.06 (m, 2H), 1.48 (s, 9H), 1.43 (m, 2H); Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1; N, 20.0. Found: C, 55.6; H, 6.2; N, 20.0%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH2:24])=[N:9]3)=[CH:4][CH:3]=1.C(O)(C)C.[Cl:29]CCl>C(=O)=O>[ClH:29].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH2:24])=[N:9]3)=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: NC1=NC2(c3ccc(F)cc3)CN(c3ncc(F)cn3)CC2CS1
Agent: O=C=O
Solvent: CC(C)O
Product: Cl
Product: NC1=N[C@@]2(c3ccc(F)cc3)CN(c3ncc(F)cn3)C[C@H]2CS1
Yield: 40 %

Procedure:
Racemic 7a-(4-fluorophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine (437 mg, 1.26 mmol) is chirally purified by SFC (Column: Chiralpak AD-H (5u), 2.1×15 cm; eluent: 40% isopropyl alcohol (0.2% isopropylamine) in CO2; flow 70 mL/min at UV 225 nm). The second eluting isomer is dissolved in 15 mL dichloromethane and hydrogen chloride gas is bubbled through the solution for approximately 15 seconds and concentrated to give the title compound as a white solid (194 mg, 40%, >99% ee). ES/MS (m/e) 348 (M+H).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@H:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[K+].C(O)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26]Cl.[C:32](=[S:34])=[S:33]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][S:34][C:32]([N:2]1[C@@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:33]
Reactant: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)c(Cl)c1
Yield: 51 %

Procedure:
In the same manner as described in Example 16, (3R)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (3.24 g), KOH (1.75 g), 70% ethanol (45 ml), carbon disulfide (0.88 ml) and 3,4-dichlorobenzyl chloride (3.52 g) are reacted and treated. The product is purified by silica gel column chromatography (solvent, chloroform:methanol:acetic acid=97:2:1) to give the title compound (3.37 g, 51%), as pale yellow powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:6]=1[CH2:18][C:19]([NH2:21])=[O:20])(=[O:3])[CH3:2].C[O:23][C:24](=O)[C:25]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=O.CC([O-])(C)C.[K+]>C1COCC1>[NH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([C:25]2[C:24](=[O:23])[NH:21][C:19](=[O:20])[C:18]=2[C:6]2[CH:7]=[C:8]([N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]3)[CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])=[CH:28]1
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: CC(=O)Nc1ccc(N2CCN(C)CC2)cc1CC(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(N2CCN(C)CC2)cc1C1=C(c2c[nH]c3ccccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-[2-Acetylamino-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide (145 mg, 0.50 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (183 mg, 0.90 mmol) in dry THF (6.0 mL) is added a solution of 1.0 M t-BuOK in THF (2.0 mL, 2.0 mmol) at 0° C. under argon. The resulting yellow suspension is stirred for 18 h at RT. The now dark red reaction mixture is partitioned between EtOAc (25 mL) and brine (25 mL), and the layers are separated. The pH of the aqueous layer is adjusted to 6 with a sat., aqueous NH4Cl solution. The aqueous layer is extracted with EtOAc (2×25 mL) and the combined organic layers are washed with brine (25 mL), dried over Na2SO4, and concentrated at reduced pressure. The crude product is purified by FCC (EtOAc/AcOH/H2O 5.5:1:1) to afford the title compound as its water soluble acetate salt. Orange solid. 1H NMR (DMSO-de, 400 MHz): δ 1.75 (s, 12H, CH3COO), 2.16 (s, 3H), 2.31-2.38 (m, 4H), 2.92-2.99 (m, 4H), 6.61 (d, J=7.8 Hz, 1H), 6.66 (t, J=7.4 Hz, 1H), 6.75 (d, J=2.5 Hz, 1H), 6.92 (dd, J=9.0 Hz, J=2.7 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.47 (d, J=8.9 Hz, 1H), 7.75 (s, 1H), 8.69 (s, 1H), 11.86 (bs, 1H). ES+-MS: 444 [M+H]+.
Reaction SMILES: Cl[CH2:2][C@H:3]([C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)[OH:4].[OH-].[Na+]>CC(O)C.C1(C)C=CC=CC=1.O>[F:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[O:6][C@@H:5]([C@H:3]1[CH2:2][O:4]1)[CH2:14][CH2:13]2
Reactant: O[C@H](CCl)[C@H]1CCc2cc(F)ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: Fc1ccc2c(c1)CC[C@H]([C@H]1CO1)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound (S*)-2-chloro-1-((R*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol obtained in Example 2 (200 mg, 0.867 mmoles) is dissolved in i-PrOH (1.6 g) under nitrogen and the reaction mixture is cooled to 0° C. On the magnetically stirred mixture is added a 2M aqueous solution of sodium hydroxide (0.9 ml) in 10 min. The mixture is stirred for 1 hour at 0° C., then diluted with toluene (5 ml) and transferred in a separator funnel. The biphasic mixture is further diluted with toluene (5 ml) and demi water (5 ml) and the phases are separated. The organic phase is washed with demi water (10 ml) and concentrated under vacuum to yield (R*)-6-fluoro-3,4-dihydro((R*)-oxiran-2-yl)-2H-chromen as yellow oil (110 mg, 87%, 95% de via GC).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[CH2:20]([O:19][C:17]([CH2:16][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:18])[CH3:21]
Reactant: NCc1ccccn1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Finely powdered potassium carbonate (5.8 g) was suspended in a solution of 2-(aminomethyl)pyridine (3.0 g) and ethyl bromoacetate (3.1 ml) in dimethylformamide (30 ml). The mixture was stirred at room temperature overnight, then poured into ice water. The mixture was extracted with ethyl acetate (50 ml×2) and the organic layer was washed with saturated sodium chloride solution (2 times), dried over magnesium sulfate, and evaporated in vacuo. The residue was purified with a silica gel column chromatography (MeOH:CHCl3 =1:99 as an eluent) to give N-(ethoxycarbonylmethyl)-N-(pyridin-2-ylmethyl)amine (2.30 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.Cl.Cl.[NH2:20][OH:21]>O>[CH3:1][C:2]([CH3:17])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[NH2:4])[CH:3]=[N:20][OH:21]
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Reactant: NO
Agent: Cl
Solvent: O
Product: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NO
Yield: 92 %

Procedure:
The procedure described in Example (1b) is repeated, except that 233.4 g (1 mol) of 3,3-dimethyl-12-isopropyl-1-aza-1,5,9-cyclododecatriene, 100 g of 37% hydrochloric acid, 200 ml of water and 69.5 g (1.0 mol) of hydroxylamine hydrochloride are used. Working up and subsequent distillation yields 245 g (0,92 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal oxime; yield 92% of theory; boiling point 158°-162° C./4 Pa; nD20 =1.4930.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](C)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.[K+].[Cl-].[Mg+2].[Cl-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:17])=[C:6]([C:7](=[O:9])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])[CH:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(Cl)cc1C(=O)O
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
To a stirring solution of 5-chloro-2-methylbenzoic acid (4.85 g, 28.4 mmol) in tetrahydrofuran (30 mL) was added N,N-carbonyldiimidazole (4.87 g, 30.0 mmol, 1.06 equiv). After 30 minutes, the reaction mixture was added to a suspension of potassium ethyl malonate (11.61 g, 68.22 mmol, 2.40 equiv) and magnesium chloride (3.27 g, 34.3 mmol, 1.21 equiv) in tetrahydrofuran (50 mL). The resultant suspension was heated at 50° C. After hours, the reaction mixture was partitioned between ethyl acetate and water. The organic portion was dried over magnesium sulfate, filtered, and concentrated to provide 8.07 g (118%) of ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate which was used without purification. LCMS (ESI) m+H=241.2
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([F:11])=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[Al+3].[Cl-].[Cl-].[Cl-].[Cl-].C(C1NC=C[N+]=1C)C.Cl[C:26](=[O:31])[C:27]([O:29]C)=[O:28]>O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([F:11])=[C:6]2[C:10]([C:26](=[O:31])[C:27]([OH:29])=[O:28])=[CH:9][NH:8][C:7]=12
Reactant: COC(=O)C(=O)Cl
Reactant: Fc1cnc(Br)c2[nH]ccc12
Agent: CCc1[nH]cc[n+]1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(O)C(=O)c1c[nH]c2c(Br)ncc(F)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridine (2.0 g, 9.3 mmol) was added to a mixture of AlCl3 (7.5 g, 55.8 mmol) and ethylmethylimidazolium chloride (2.7 g, 18.6 mmol). Methyl chlorooxoacetate (2.1 mL, 18.6 mmol) was added slowly to the above solution and the mixture was stirred at room temperature for 3 h. Reaction flask was placed in an ice bath and water was slowly added until a white precipitate formed. The solid was collected by filtration and washed with water to afford 2-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (2.4g, 92%). LCMS: m/e 287 (M+H)+, ret time 0.91 min (method 1).
Reaction SMILES: C1(C)C(S(O[C:11]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][CH:19]=[CH:18][C:12]=2[CH:13]([CH3:17])[C:14]([OH:16])=[O:15])(=O)=O)=CC=CC=1.[H][H]>[Ni]>[O:22]([C:21]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: Cc1ccccc1S(=O)(=O)Oc1c(Oc2ccccc2)cccc1C(C)C(=O)O
Agent: [Ni]
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Yield: 89 %

Procedure:
To a solution of 4.1 g. of 2-toluene-sulphonyloxy-3-phenoxy-hydratropic acid in 150 ml. of alcohol 24 g. of a W-6 nickel catalyst are added, and the mixture is hydrogenated at 25° C., under atmospheric pressure until a calculated amount of hydrogen is used up. The catalyst is filtered off, the filtrate is evaporated and the residue is taken up in water and acidified with a 10% aqueous hydrochloric acid solution. The separated oil is extracted with chloroform, the chloroform solution is dried over sodium sulphate and evaporated. 2.1 g. (89%) of 3-phenoxy-hydratropic acid are obtained. Melting point of the corresponding cyclohexylamine salt amounts to 151° C. to 153° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5].O.C(=O)(O)[O-].[C:15](O)(=[O:26])[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>COCCOC.CN(C)C=O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:15]([NH:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:26]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: NC(=O)[C@@H](N)CC(=O)O
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)[C@H](CC(=O)O)NC(=O)c1ccc2ccccc2n1
Yield: 69.1 %

Procedure:
To a solution of 0.50 g (3.78 mmol) of L-isoasparagine in 5.0 mL H2O containing ˜45 mg (1.5 eq) of solid bicarbonate. To this was added a suspension of 1.02 g (3.78 mmol) quinaldic acid, N-hydroxysuccinamide ester in ethylene glycol dimethylether, and the suspension was solubilized by the addition of 10 mL of dimethylformamide. After 3 hours the solution was acidified by the addition of 5% HC1 (aqueous) and the product was filtered and washed with water, dried under vacuum to yield 750 mg (70% yield) of N-(2-quinolinylcarbonyl)-L-isoasparagine.