Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[S:16][C:15]([CH3:17])=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[S:16][C:15]([CH3:17])=[N:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: Cc1nnc(S)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2nnc(C)s2)s1
Temperature: 120 °C
Yield: 61.6 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (1.76 g), 5-mercapto-2-methyl-1,3,4-thiadiazole (1.3 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (40 ml) was heated at 120° C. for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure and water was added to this residue. The mixture was extracted with a mixture of tetrahydrofuran and ethyl titrate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-5-(2-methyl-l,3,4-thiadiazol-5-ylthio)thiazole (1.65 g, yield: 60.7%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1COCCN1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 51 %

Procedure:
As described for example 147, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg, 0.3 mmol) was converted, using morpholine instead of cyclopropylmethylamine, to the title compound (58 mg, 51%) which was obtained as an off white solid. MS: m/e=381.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[F:8][C:9]1[C:14](O)=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19].C1(N=C=NC2CCCCC2)CCCCC1>CCOC(C)=O>[F:8][C:9]1[C:14]([O:5][C:4](=[O:6])[CH2:3][N:2]([CH3:7])[CH3:1])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19]
Reactant: CN(C)CC(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CN(C)CC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 0.40 M solution of N,N-dimethylglycine (82.0 mg, 0.800 mmol) in EtOAc (2.00 mL, filtered through activated alumina) were added pentafluorophenol (162 mg, 0.880 mmol) and 1,3-dicyclohexylcarbodiimide (182 mg, 0.88 mmol). The reaction mixture was stirred for 12 h at rt at which time it was filtered (washing with EtOAc) and concentrated. Ester 18 was used immediately without further purification.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C:38]1[CH2:39][CH2:40][NH:41][CH2:42][CH:43]=1>O1CCOCC1>[CH3:25][N:23]([CH3:24])[C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:41]2[CH2:42][CH:43]=[C:38]([C:32]3[C:31]4[C:35](=[CH:36][CH:37]=[C:29]([O:28][CH3:27])[CH:30]=4)[NH:34][CH:33]=3)[CH2:39][CH2:40]2)=[O:26])[CH2:12][CH2:13]1
Reactant: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: COc1ccc2[nH]cc(C3=CCN(C(=O)NCC4CCC(c5ccccc5)(N(C)C)CC4)CC3)c2c1
Reaction time: 20 h
Yield: 32.1 %

Procedure:
(4-dimethylamino-4-phenylcyclohexyl-methyl)-carbamic acid phenyl ester (528.7 mg, 1.5 mmole) was added to a solution of 5-methoxy-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (317.9 mg, 1.5 mmole) in dioxane (10 ml). The reaction mixture was then boiled for 20 hours under reflux. The reaction mixture was a suspension at RT. The solid was filtered off, washed with cold dioxane (3×1 ml) and dried. The solid was part of the polar diastereomer of 4-(5-methoxy-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl-methyl)-amide (99 mg, m.p. 120°-125° C., 14%). The reaction solution (filtrate and wash phases) was concentrated by evaporation. The residue contained phenol as well as the non-polar product and the remainder of the polar product. The diastereoisomers were separated and purified by flash chromatography on silica gel (75 g). Methanol (900 ml) was used as eluent. The non-polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (234 mg, m.p. 98°-104° C., 32%) and a further part of the polar diastereoisomer (120 mg, m.p. 108°-111° C., 16%) were thereby obtained in pure form.
Reaction SMILES: N1CCOCC1.[C:7]([Si:11]([CH3:27])([CH3:26])[O:12][CH2:13][CH2:14][CH2:15][C:16]1[C:17]([C:24]#[N:25])=[C:18]([S-:23])[NH:19][C:20](=[O:22])[CH:21]=1)([CH3:10])([CH3:9])[CH3:8].Br[CH2:29][C:30]([NH2:32])=[O:31]>C1COCC1>[C:7]([Si:11]([CH3:27])([CH3:26])[O:12][CH2:13][CH2:14][CH2:15][C:16]1[C:17]([C:24]#[N:25])=[C:18]([S:23][CH2:29][C:30]([NH2:32])=[O:31])[NH:19][C:20](=[O:22])[CH:21]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: NC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)OCCCc1cc(=O)[nH]c([S-])c1C#N
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCc1cc(=O)[nH]c(SCC(N)=O)c1C#N
Reaction time: 2 h
Yield: 360.4 %

Procedure:
To a solution of 0.940 g (2.28 mmol) of the above morpholine salt in THF (15 mL), cooled to 0° C., was added 0.315 g (0.280 mmol) of 2-bromoacetamide as a solid in one portion. The mixture was stirred and allowed to slowly warn to room temperature over a 2 h period during which time salts precipitated from solution. The mixture was filtered through diatomaceous earth to remove solids and the filter pad was washed with EtOAc. The mixture was concentrated under reduced pressure to provide 0.385 g (44%) of 2-{4-[3-(t-butyl-dimethyl-silanyloxy)-propyl]-3-cyano-6-oxo-1,6-dihydro-pyridin-2-ylsulfanyl}-acetamide as an orange foam.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C@@H:12]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]([NH:15][C@@H:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:14].[O:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46](O)=[O:47])[CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:29][CH:28]([CH3:30])[CH2:27][C@H:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:46](=[O:47])[CH2:45][N:42]1[CH2:43][CH2:44][O:39][CH2:40][CH2:41]1)[CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Referring to FIG. 45. DIPEA (592 μL, 3.6 mmol, 2.6 eq) was added to a mixture of (S)-benzyl 2-((S)-2-amino-4-phenylbutanamido)-4-methylpentanoate hydrochloride (600 mg, 1.4 mmol), 2-morpholinoacetic acid (312 mg, 2.1 mmol, 1.5 eq) and HATU (816 mg, 2.1 mmol. 1.5 eq) in CH2Cl2 (25 mL) and the mixture was stirred overnight at RT. The reaction mixture was washed with water and the aqueous layer was extracted once with CH2Cl2. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-100% EtOAc in heptanes, followed by 10% MeOH in EtOAc) to yield product (700 mg, 98%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]([F:11])([F:10])[C:3](=O)/[CH:4]=[CH:5]/OCC.C[N:13](C)[CH:14]=[CH:15][C:16]#[N:17].C([O-])(=O)C.[NH4+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:15]([C:16]#[N:17])=[CH:14][N:13]=1
Reactant: CCO/C=C/C(=O)C(F)(F)Cl
Reactant: CN(C)C=CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(F)(F)Cl)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
(3E)-1-Chloro-4-ethoxy-1,1-difluorobut-3-en-2-one (7.36 g, 40 mmol) was dissolved in dry toluene (40 mL) and treated with 3-dimethylaminoacrylonitrile (4.61 g, 48 mmol) at room temperature. The solution was heated at about 100° C. for 3.5 hr. The solvent was then removed under reduced pressure and the remaining mixture was re-dissolved in dimethyl formamide (DMF; 20 mL), treated with ammonium acetate (4.62 g, 60 mmol) and stirred at room temperature overnight. Water was added to the reaction mixture and the resulting mixture was extracted with ether-CH2CH2 (1:2, v/v) twice. The combined organic layer was washed with brine, dried, filtered and concentrated. The residue was purified on silica gel to give 3.1 g of 6-[chloro(difluoro)methyl]nicotinonitrile (A) as light colored oil in 41% yield. GC-MS: mass calcd for C7H3ClF2N2 [M]+ 188. Found 188.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:20])OCC)=[CH:11][C:10]=2[N+:21]([O-:23])=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:26][O:27][CH:28]([O:32][CH3:33])[CH2:29][NH:30][CH3:31]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:30]([CH2:29][CH:28]([O:32][CH3:33])[O:27][CH3:26])[CH3:31])=[O:20])=[CH:11][C:10]=2[N+:21]([O-:23])=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1
Reactant: CNCC(OC)OC
Solvent: Cc1ccccc1
Product: COC(CN(C)C(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1)OC

Procedure:
Ethyl [4-(4-nitrophenoxy)-3-nitrophenyl]carbamate (0.1 mole) and toluene (100 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. N-(2,2-dimethoxyethyl)methanamine (0.15 mole) is added to the vessel and the mixture is refluxed for 16 hours. Solvent is then removed by mild warming under reduced pressure to yield the desired product N-[4-(4-nitrophenoxy)-3-nitrophenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea.
Reaction SMILES: [O:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](Cl)([Cl:11])=[O:10].C(Cl)Cl>CN(C)C=O>[Cl:11][C:9]([O:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(Cl)Cl
Reactant: OOc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)OOc1ccccc1

Procedure:
The intermediate phenoxy chloroformates are prepared by reaction of the appropriate phenoxyalcohol with excess phosgene in an inert solvent such as methylene chloride in the presence of a catalytic quantity of dimethyl formamide. The reaction is carried out at 20°-80° C. The solvent and excess phosgene is then removed under vacuo to give the desired intermediate phenoxy chloroformate.
Reaction SMILES: [CH2:1]([N:8]([CH:28]1[CH2:31][N:30]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:29]1)[CH2:9][CH:10]([OH:27])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:47][C:48]([O:50][CH3:51])=[O:49].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)N(C)CCC1.O>[CH3:51][O:50][C:48](=[O:49])[CH2:47][N:41]([C:38]1[CH:37]=[CH:36][C:35]([S:32]([N:30]2[CH2:29][CH:28]([N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH:10]([OH:27])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:18]=3)[CH2:31]2)(=[O:34])=[O:33])=[CH:40][CH:39]=1)[CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: COC(=O)CBr
Reactant: CCCCNc1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)CC(O)COc3ccc(OCc4ccccc4)cc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: CCCCN(CC(=O)OC)c1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)CC(O)COc3ccc(OCc4ccccc4)cc3)C2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 47.5 %

Procedure:
To a solution of 1-{benzyl-[1-(4-butylamino-benzenesulfonyl)-azetidin-3-yl]amino}-3-(4-benzyloxy-phenoxy)-propan-2-ol (0.10 g, 0.15 mmol) in N,N′-dimethylpropyleneurea (1 ml) was added methyl bromoacetate (46 mg, 0.3 mmol) and potassium carbonate (28 mg, 0.2 mmol), and the mixture was stirred at 50° C. for 2 days. It was then cooled to room temperature and diluted with water (20 ml). The aqueous phase was removed, and the residue dissolved in ethyl acetate (20 ml). The organic solution was washed with brine, and dried over anhydrous sodium sulfate. It was then filtered and evaporated, and the residue was chromatographed on silica gel (ethyl acetate-hexanes/1:1) to give 50 mg of a colorless gum; MS (ES) m/z 702.2 (MH+); HRMS (FAB) Calcd. for C39H48N3O7S (MH+): 702.3213, Found: 702.3231.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:15][C:4]1[CH:3]=[C:2]([O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: Cc1cc(F)ccc1C(=O)OC(C)(C)C
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Oc2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 130 °C
Reaction time: 12 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 4-fluoro-2-methylbenzoate (1 g, 4.8 mmol) in methylsulfinylmethane (45 mL) were added phenol (0.43 g, 4.6 mmol) and potassium carbonate (1.24 g, 9 mmol). Then the mixture was stirred at 130° C. for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was separated, washed with water (20 mL). The organic phase was separated and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give tert-butyl 2-methyl-4-phenoxybenzoate (1.1 g, 86%) as a yellow solid. LRMS (M+H+) m/z: calcd 284.14. found 284.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[C:31]([O:35][C:36](=[O:44])[N:37]([CH3:43])[CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36](=[O:44])[N:37]([CH:38]1[CH2:42][CH2:41][N:40]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]=3[C:27]([F:29])([F:30])[F:28])[N:8]=[CH:9]4)[C:18](=[O:24])[N:19]=2)[CH2:39]1)[CH3:43])([CH3:34])([CH3:32])[CH3:33]
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Product: CN(C(=O)OC(C)(C)C)C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-methyl-carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester following General Procedure B.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][C:6](=[O:8])[CH:5]([CH3:9])[C:4](=[O:10])[O:3]1.[CH2:12](Br)[CH:13]=C.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)C>[CH3:11][C:2]1([CH3:1])[O:3][C:4](=[O:10])[CH:5]([CH2:9][CH:12]=[CH2:13])[C:6](=[O:8])[O:7]1
Reactant: C=CCBr
Reactant: CC1C(=O)OC(C)(C)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=CCC1C(=O)OC(C)(C)OC1=O
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a 500 mL 3-necked round bottomed flask equipped with a stir bar, thermowell and a condenser connected to a nitrogen line was added 10.0 g (0.0632 mole) of 2,2,5-trimethyl-1,3-dioxane-4,6-dione, 7.7 g (0.0632 mol) of allyl bromide, 21 g (0.152 mol) of potassium carbonate and 200 mL of acetone. The mixture was refluxed with stirring overnight at which time it was allowed to cool, diluted with 200 mL of ethyl ether and filtered through a bed of Celite/activated charcoal. The filtrate was washed with water and brine and dried overnight over anhydrous sodium sulfate. The suspension was filtered and the filtrate evaporated on a rotary evaporator to yield 11 g of 2,2-dimethyl-5-allyl-1,3-dioxane-4,6-dione compound as shown in Formula (IV)) as a clear, colorless oil.
Reaction SMILES: [C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2cccc(O)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2cccc(O)c2)cc1
Yield: 90.8 %

Procedure:
To a cold (5° C.) solution of 1,1-dimethylethyl (2E)-3-{4-[cycloheptylidene(3-hydroxyphenyl)methyl]phenyl}-2-propenoate (194) (0.200 g, 0.49 mmol) in CH2Cl2 (8 mL) was added TFA (2 mL). The resultant mixture was stirred for 3 h at RT. The reaction mixture was concentrated under reduced pressure and the crude product. purified by silica gel chromatography using n-hexanes:EtOAc (4:1 to 3:2) as an eluent to afford 0.155 g (90%) of compound 195 as an off-white foam. 1H NMR (300 MHz, CD3OD): δ 7.65 (d, J=15.9 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.21 (d, J=7.8 Hz, 2H), 7.10 (app t, J=7.5 Hz, 1H), 6.32 (br d, J=8.7 Hz, 3H), 6.45 (d, J=15.9 Hz, 1H). 2.33 (br s, 4H), 1.61 (br s, 8H). LCMS (ESI): m/z 347 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22](Cl)=[C:23]([Br:25])[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[H-].[Na+].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.C(O)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22]([O:37][C:34]4[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=4)=[C:23]([Br:25])[CH:24]=3)(=[O:17])=[O:18])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Oc2ccc(Cl)cc2)c(Br)c1
Temperature: 100 °C
Yield: 52.6 %

Procedure:
The mixture of [4-(5-Bromo-6-chloro-pyridine-3-sulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (50 mg, 0.10 mmol), sodium hydride (60% dispersed in mineral oil, 20 mg, 0.50 mmol) and 4-chlorophenol (0.4 mL, 3.79 mmol) in N,N-dimethylformamide (1.5 mL) was heated in a microwave oven at 100° C. for 15 minutes, then acidified with acetic acid to pH 5, filtered through a glass funnel and purified by preparative HPLC to afford {4-[5-bromo-6-(4-chloro-phenoxy)-pyridine-3-sulfonylamino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (30 mg, 52.6%) as a white powder. MS calcd for C22H22BrClN4O5S 548, obsd (ESI+) [(M+H)+]: 569.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([O:13]C)[CH:10]=[CH:9][C:8]=2[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]([CH3:22])[O:4][N:3]=1.B(Br)(Br)Br>ClCCl>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=2[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: CCOC(=O)CCc1ccc(OC)cc1-c1c(C)noc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(O)cc1-c1c(C)noc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with 10 mL of dichloromethane. To the stirred solvent was added ethyl 3-[2-(3,5-dimethyl-1,2-oxazol-4-yl)-4-methoxy phenyl]propanoate (0.120 g, 0.4 mmol). The reaction mixture was cooled to 0° C. and boron tribromide (0.099 g, 0.4 mmol) was added drop wise. After stirred for 30 minutes, the reaction mixture was quenched with ethanol (1 mL) at 0° C. by slow addition. The reaction mixture was concentrated to distill off the solvent; ethyl acetate (10 mL) was added. The organic layer was washed with saturated NaHCO3 solution (10 mL), followed by brine solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as colorless oil (0.1 g, yield: 90.90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[CH3:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2([OH:62])[CH2:61][CH2:60][NH:59][CH2:58]2)=[CH:53][CH:52]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([C:14]([N:59]3[CH2:60][CH2:61][C:57]([C:54]4[CH:55]=[N:56][C:51]([CH3:50])=[CH:52][CH:53]=4)([OH:62])[CH2:58]3)=[O:16])=[CH:12][O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1
Reactant: Cc1ccc(C2(O)CCNC2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(C)nc3)C2)cc1
Yield: 26.4 %

Procedure:
A solution of 3-(4-methoxyphenyl)isoxazole-4-carboxylic acid (7 mg, 0.03 mmol), N-ethyl-N-isopropylpropan-2-amine (16 μL, 0.09 mmol, 3 equ.) and TBTU (12 mg, 0.036 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(6-methylpyridin-3-yl)pyrrolidin-3-ol dihydrochloride (8 mg, 0.03 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z: calcd for C21H21N3O4: 379.1532, found 379.1529.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[C:5]([CH3:13])[N:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[C:5]([CH3:13])[N:4]=1
Reactant: COC(=O)c1cc(C)nc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nc(C)cc(C(=O)O)n1
Yield: 46.1 %

Procedure:
15.5 g of methyl 2-methoxy-6-methylpyrimidine-4-carboxylate are added to a stirred solution of 3.6 g of sodium hydroxide in 100 ml of methanol and 10 ml of water. Stirring is continued at room temperature until the starting material disappears (TLC checking; 3 h). The methanol is distilled off under reduced pressure, the residue is taken up in water and the mixture is extracted once with ethyl acetate. The aqueous phase is acidified to pH 2 with conc. hydrochloric acid and then stirred for 1 h, and the product is filtered off with suction. 6.6 g of 2-methoxy-6-methylpyrimidine-4-carboxylic acid of melting point 161°-163° C. are obtained in this way. Concentration and extraction of the mother liquor using dichloromethane additionally gives 3.1 g of product of melting point 159°-161° C.