Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@:2]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32](Cl)[C:31]=2[F:38])[CH2:6][O:5][C@H:4]([CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:3]1[CH2:28][OH:29].C([O-])=O.[NH4+]>[Pd].CO>[NH2:1][C@@:2]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:38])[CH2:6][O:5][C@H:4]([CH2:7][O:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:3]1[CH2:28][OH:29]
Reactant: N[C@@]1(c2ccc(F)c(Cl)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: N[C@@]1(c2ccc(F)cc2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
A mixture of ((2S,3R,4S)-4-amino-4-(3-chloro-2,4-difluorophenyl)-2-((trityloxy)methyl)tetrahydrofuran-3-yl)methanol (4.49 g, 8.4 mmol), ammonium formate (3.2 g, 50 mmol) and 10% palladium on carbon (500 mg) in dry MeOH (40 mL) was stirred at RT under nitrogen overnight. The catalyst was removed by filtration through Celite®—washing with methanol. The filtrate was evaporated and the residue was partitioned between DCM (100 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was further extracted with DCM (100 mL×4). The combined extracts were dried (Na2SO4), filtered and evaporated to give the title compound (4.18 g). 1H NMR (400 MHz, MeOH-d4) δ ppm: 2.73-2.84 (m, 1 H) 3.17 (dd, J=10.03, 5.14 Hz, 1 H) 3.27 (dd, J=9.96, 3.61 Hz, 1 H) 3.65-3.79 (m, 2 H) 3.88 (dd, J=8.93, 3.06 Hz, 1 H) 4.16-4.24 (m, 1 H) 4.27 (d, J=9.05 Hz, 1 H) 6.88-7.00 (m, 2 H) 7.18-7.31 (m, 9 H) 7.38-7.45 (m, 6 H) 7.58-7.67 (m, 1 H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]1([NH:15][OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:17][C:18]1[O:19][CH:20]=[C:21]([CH3:26])[C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[CH:9]1([N:15]([C:23]([C:22]2[C:21]([CH3:26])=[CH:20][O:19][C:18]=2[CH3:17])=[O:24])[OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1coc(C)c1C(=O)Cl
Reactant: ONC1CCCCC1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1coc(C)c1C(=O)N(O)C1CCCCC1
Reaction time: 1 h

Procedure:
30 Parts of triethylamine is added to a suspension of 25 parts of N-cyclohexylhydroxylamine hydrochloride in 480 parts of benzene. After the mixture has been stirred for 1 hour, 20 parts of 2,4-dimethylfuran-3-carboxylic chloride is dripped in at room temperature. After the mixture has been stirred for a further 2 hours it is suction filtered, the residue is washed with benzene and the combined benzene phases are washed with water, dried with anhydrous sodium sulfate and evaporated. There is obtained 34 parts of N-cyclohexyl-2,4-dimethylfuran-3-hydroxamic acid in the form of an oil. This oil is dissolved in 370 parts of dichloromethane; at room temperature and while stirring, 18 parts of sodium hydroxide in 70 parts of water, and 28 parts of dimethyl sulfate are added to the solution. After the mixture has been stirred for 1 hour the organic phase is separated, washed with water, dried with sodium sulfate, evaporated and chromatographed using silica gel with a mixture of equal portions of ethyl acetate and cyclohexane. When the eluate is evaporated there is obtained 32 parts of O-methyl-N-cyclohexyl-2,4-dimethylfuran-3-hydroxamic acid having a boiling point at 0.01 mm Hg of 122° to 124° C and the refractive index nD25 : 1.5010. ##SPC13##
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl-].[Li+].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[N:43][CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[N:40]=2)[CH2:35][CH2:34]1>O1CCOCC1.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.[Cu]I>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:41]3[CH:42]=[N:43][CH:44]=[C:39]([N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)[N:40]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCN(C)CC2)n1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cncc(N4CCN(C)CC4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 22 h

Procedure:
(S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50.0 mg, 0.101 mmol), tetrakis(triphenylphosphine)palladium(0) (17.4 mg, 0.015 mmol), lithium chloride (12.8 mg, 0.302 mmol), and copper(I) iodide (5.8 mg, 0.030 mmol) were taken in a microwave vial and the vial vacuum pumped and flushed with argon three times. To this mixture was added 2-(4-methylpiperazin-1-yl)-6-(tributylstannyl)pyrazine (56.4 mg, 0.121 mmol) in dioxane (1.0 mL), and the resulting mixture was stirred at 90° C. for 22 h. Purification by flash column chromatography on silica gel using 79:20:1 DCM/MeOH/NH3 (0 to 100%) in DCM provided the product. LCMS-ESI+ calc'd for C31H37ClN5O3S (M+H+):594.2; Found: 593.6 (M+H+).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15](O)=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:18])[C:7]=2[C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:27][C:28](=[O:46])/[CH:29]=[CH:30]/[C:31]1[CH:45]=[CH:44][C:34]2[N:35]([CH3:43])[C:36]([C:38]3([NH2:42])[CH2:41][CH2:40][CH2:39]3)=[N:37][C:33]=2[CH:32]=1)C>>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]([NH:42][C:38]4([C:36]5[N:35]([CH3:43])[C:34]6[CH:44]=[CH:45][C:31](/[CH:30]=[CH:29]/[C:28]([OH:27])=[O:46])=[CH:32][C:33]=6[N:37]=5)[CH2:39][CH2:40][CH2:41]4)=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:18])[C:7]=2[C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)nc(C1(N)CCC1)n2C
Reactant: Cn1c(-c2cnccn2)c(C2CCCC2)c2ccc(C(=O)O)cc21
Product: Cn1c(C2(NC(=O)c3ccc4c(C5CCCC5)c(-c5cnccn5)n(C)c4c3)CCC2)nc2cc(/C=C/C(=O)O)ccc21

Procedure:
3-cyclopentyl-1-methyl-2-pyrazin-2-yl-1H-indole-6-carboxylic acid 5-1 (prepared using procedures described in WO 03/010141) and (E)-3-[2-(1-aminocyclobutyl)-1-methyl-1H-benzimidazol-5-yl]acrylic acid ethyl ester 4-2 were coupled, followed by saponification of the ethyl ester, using analogous procedures to those described in Example 4 to give (E)-3-(2-{1-[(3-Cyclopentyl-1-methyl-2-pyrazin-2-yl-1H-indole-6-carbonyl)amino]cyclobutyl}-1-methyl-1H-benzimidazol-5-yl)acrylic acid 5-2 (compound 4003, Table 4).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:3]1>[Cl-].[NH4+].C(O)C.[Fe]>[CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:13])[F:15])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:3]1
Reactant: CC1(C)CC(c2ccccc2[N+](=O)[O-])Nc2ccc(C(F)(F)F)cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C

Procedure:
To a suspension of 4,4-dimethyl-2-(2-nitrophenyl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (2.56 g, 7.3 mmol) in saturated aqueous ammonium chloride (20 mL) and ethanol (30 mL) was added iron powder (1.2 g, 21.0 mmol) at room temperature After addition, the resulting mixture was stirred at reflux under Nitrogen for 3 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The solvent of ethanol in filtrate was removed under reduced pressure and the water phase was extracted with ethyl acetate. The combined organic phase was dried, concentrated to give 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline. The product was used in the next step without further purification. LC/MS m/e obsd. (ESI+) [(M+H)+] 321.1.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[Si:12]([O:19][CH2:20][C:21]([CH3:24])([NH2:23])[CH3:22])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Si:12]([O:19][CH2:20][C:21]([N:23]1[C:2]2[N:3]=[CH:4][N:5]=[C:6]([Cl:11])[C:7]=2[CH:8]=[CH:9]1)([CH3:24])[CH3:22])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(N)CO[Si](C)(C)C(C)(C)C
Reactant: O=CCc1c(Cl)ncnc1Cl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1ccc2c(Cl)ncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 1 using (4,6-dichloropyrimidin-5-yl)acetaldehyde and 1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropan-2-amine to afford the title compound as a yellow oil in 38% yield, 377 mg.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH3:27])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Li+]>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:28])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[C:8]2[O:26][CH3:27]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(Cc2ccc(Cl)cc2)c(C)nc2c(Cl)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzyl)-4-methoxy-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.059 g), methanol (2.0 mL), saturated aqueous lithium hydroxide solution (0.25 mL) and water (0.4 mL) was stirred at room temperature for 15 hours, The methanol was removed under reduced pressure and the pH of the residue adjusted to 1 by the addition of 1.0 M aqueous hydrochloric acid. Purification by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (20% to 80% of organic modifier) gave title compound as a yellow solid, 0.060 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:11]OC(=O)OC.CCN(CC)CC>C(OCC)(=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)OC
Reactant: Brc1cnc2cc[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1ccc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
A solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine (54 kg from multiple batches based on wt % assay, 274 mol) in ethyl acetate from the previous step was distilled under vacuum at 45±5° C. to a volume of about 110 L (2 L/kg) and then cooled to 25±5° C. Dimethylcarbonate (33.0 kg, 367 mol) and Et3N (22.0 kg, 217 mol) were added and the mixture was distilled under vacuum at 50±5° C. to a volume of about 85 L. N,N-dimethylformamide (82.5 kg, 1.6 L/kg) was added and the mixture was distilled under vacuum at 50±5° C. until no distillate was observed. The mixture was cooled to 25±5° C., and dimethylcarbonate (165 kg, 1833 mol), Et3N (60.5 kg, 598 mol), and tetrabutylammonium bromide (11.0 kg) were added. The reaction mixture was heated to 88±5° C. After 12 hours at 105-110° C. (jacket temperature), which corresponded to 83-85° C. reaction mixture temperature, HPLC analysis indicated 59.6% of the starting material remained. The jacket temperature was increased to 115-120° C. (corresponding to 84-87° C. reaction mixture temperature). After 18 hours at 115-120° C. (jacket temperature) HPLC analysis indicated 0.2% of the starting material remained. The mixture was cooled to 25° C. and then concentrated under vacuum at 55±5° C. to remove most of the dimethylcarbonate and Et3N. Next, the mixture was cooled to 25° C. and MTBE (340 kg) was added, followed by water (440 kg). The mixture was stirred for 30 minutes. Stirring was stopped and the mixture was left for 30 minutes for phase separation to occur. The aqueous phase was extracted with MTBE (2×209 kg). The MTBE phases were combined and washed with brine solution (286 kg). Activated charcoal (2.7 kg) was added to the organic phase, which was stirred for 1 hour and then filtered through a pad of Celite. The filter cake was washed with MTBE (55 kg). The organic layers were combined (750 kg, 6.45% by HPLC-assay) and distilled to dryness to obtain the title compound as yellow oil (48.4 kg). The product was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15](C)=[N:16]C(C)=CC=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li]CCCC.[CH3:40][N:41]1C(C=O)=CN=[N:42]1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:41]([CH3:40])[N:42]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1
Reactant: Cn1nncc1C=O
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a 50 mL flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.45 g, 3.37 mmol, Intermediate 47: step d) was added THF (25 mL) at room temp which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. which remained homogeneous and then n-BuLi (2.5 M in hexanes, 1.3 mL, 3.25 mmol) was added dropwise. The color of the solution became a dark reddish-brown color. After 2 minutes, 1-methyl-1H-1,2,3-triazole-5-carbaldehyde (580 mg, 5.22 mmol, in 3 mL THF, Intermediate 50: step a) was introduced and the color of the mixture went from dark brown to greenish to a yellow color within about 2 minutes. The mixture was allowed to warm to −20° C. over 45 minutes at which time the contents were quenched with aqueous NH4Cl. The mixture was diluted further with water and extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a yellowish oil. The crude material was chromatographed on silica gel (5% CH3CN-DCM increasing to 30% CH3CN+2% MeOH) to give the title compound as an off white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:28])[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(NCCCCl)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCCNC(=O)c2ccc(F)cc2)CC1
Reaction time: 5 h

Procedure:
A mixture of 1.92 g (0.01 mol) of 1-(2-methoxyphenyl)-piperazine and 2.15 g (0.01 mol) of N-(3-chloropropyl)-4-fluorobenzamide was added to a mixture of toluene (20 ml) and triethylamine (2 ml) under agitation. The resulting mixture was gradually heated to the refluxing temperature at which the mixture was held for 5 hours. After completion of the reaction, the mixture was cooled and the precipitating salt was filtered off. The filtrate was extracted with 20 ml of benzene, and the extract was washed first with saturated aqueous sodium bicarbonate, then washed with water twice. By drying with anhydrous magnesium sulfate and subsequent concentration, 1-(2-methoxyphenyl)-4-[3-(4-fluorobenzoyl)aminopropyl]piperazine was produced as an oily substance. The oil was dissolved in methanol (30 ml) and the solution was saturated with hydrogen chloride gas. Upon concentration of the saturated solution, a crystal of the piperazine in hydrochloride form was obtained (2.9 g). m.p. 231.7° C. (recrystallized from ethanol).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH:16]=[CH2:17])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].O1CCCC1>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH:16]=[CH2:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: C=CCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCON=C(C(=O)O)c1csc(N)n1
Yield: 59.6 %

Procedure:
A solution of ethyl 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 3.6 g.), 2 N aqueous solution of sodium hydroxide (14.1 ml.), tetrahydrofuran (14.1 ml.) and methanol (15 ml.) was stirred at 40° C. for 1.5 hours. The resultant solution was concentrated in vacuo, and the residue was dissolved in water. After the solution was adjusted to pH 2.8 with 10% hydrochloric acid under ice cooling, the precipitates were collected by filtration, washed with water and acetone in turn and dried to give 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetic acid (syn isomer, 1.91 g.), mp. 187° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(F)c(Cl)c1

Procedure:
The title compound was synthesized from methyl 4-(3-chloro-4-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.034 g, 0.11 mmol) and lithium hydroxide (0.023 g, 0.55 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound. 17 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.97-2.16 (m, 1H) 2.44-2.67 (m, 3H) 2.67-2.85 (m, 2H) 3.19-3.29 (m, 1H) 6.31 (s, 1H) 7.10-7.15 (m, 2H) 7.28 (d, J=7.52 Hz, 1H) 19F NMR δ ppm −122.88 (q, J=7.1 Hz); LCMS-MS (ESI−) 292.0 (M−H); HPLC (UV=98.1%), (ELSD=100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:30])[C@@H:27]([NH2:29])[CH3:28]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:26][C@@H:27]([NH2:29])[CH3:28])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: C[C@H](N)CN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC[C@H](C)N)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2S)-propane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.86 (d, J=7.58 Hz, 1 H), 7.71 (d, J=7.33 Hz, 1 H), 7.67-7.60 (m, 1 H), 7.49 (t, J=7.33 Hz, 1 H), 7.42 (d, J=8.59 Hz, 1 H), 7.28-7.19 (m, 2 H), 6.07-5.83 (m, 1 H), 5.02 (brs, 2 H), 3.62 (s, 1 H), 3.56-3.46 (m, 2 H), 3.37 (s, 2 H), 3.28-3.11 (m, 4 H), 2.36 (s, 3 H), 0.92-0.80 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=1.[CH3:18][N:19]([CH3:33])[C:20]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.C(O)(=O)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[CH2:13][CH2:14][N:15]([CH:23]2[CH2:22][CH2:21][C:20]([N:19]([CH3:33])[CH3:18])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:24]2)[CH2:16][CH:17]=1
Reactant: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc2[nH]cc(C3=CCN(C4CCC(c5ccccc5)(N(C)C)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-methoxy-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (212 mg, 1.0 mmole) and 4-dimethylamino-4-phenylcyclo-hexanone (217 mg, 1.0 mmole) were dissolved in dry 1,2-dichloroethane (20 ml). Glacial acetic acid (1.0 mmole) and sodium triacetoxy boron hydride (300 mg, 1.4 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (4×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds. The diastereoisomer mixture was obtained as a colourless solid in a yield of 343 mg (80%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11][CH2:12][CH3:13])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11]([CH2:12][CH3:13])=[O:19])[CH:3]=1
Reactant: CCSc1cc(Cl)cc(C)c1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCS(=O)c1cc(Cl)cc(C)c1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a stirred solution of 4-chloro-2-ethylsulfanyl-6-methyl-benzonitrile (synthesized according to the method described in section a) of example 2) (1.00 g, 4.73 mmol) in dichloromethane (20 ml) is added meta-chloroperoxybenzoic acid (0.58 g, 2.36 mmol, 70% suspension) portion wise at 0° C. The resulting mixture is stirred at 0° C. for 15 min. The white suspension is dissolved in ethyl acetate (25 ml) and the solvent is distilled off. The residue is again diluted with ethyl acetate (15 ml) and washed with 10% sodium sulphite solution (3×15 ml), saturated sodium hydrogen sulfate solution (3×15 ml), brine (15 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 8% ethyl acetate/hexane) to yield 4-chloro-2-(ethylsulfinyl)-6-methyl-benzonitrile (0.4 g, 1.76 mmol, 37%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[C:5]1[N:10]=[CH:9][C:8]([N:11]=CN(C)C)=[CH:7][N:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].CCOCC>O1CCOCC1>[CH2:17]([O:16][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[N:6]=[CH:7][C:8]([NH2:11])=[CH:9][N:10]=1)[CH3:18]
Reactant: CCOC(OCC)c1ncc(N=CN(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(OCC)c1ncc(N)cn1
Yield: 94.1 %

Procedure:
2-Diethoxymethyl-5-(dimethylaminomethyleneamino)pyrimidine (6.3 g, 25 mmol) and a 5% aqueous solution of potassium carbonate (69 ml) in dioxane (40 ml) were heated at reflux for 6 hours. The reaction mixture was concentrated to a yellow solid which was triturated with ether to 2-diethoxymethyl-5-aminopyrimidine as a cream solid (4.64 g, 92% yield):
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Br)=[O:33])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]4)=[CH:4][CH:3]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: COc1ccc(C(=O)Br)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(OC)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 310 was prepared analogous to compound of example 304 by reaction of compound of example 223 with 4-methoxy benzoyl bromide. The compound of example 310 was used directly without isolation, for the preparation of compound of example 311.