Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C@@H:5]([C:12]([OH:14])=[O:13])[C:4]([CH3:15])=[CH:3]1.[C:16](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C=O)C>[OH:1][C@@H:2]1[CH2:11][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10]2)[C@@H:5]([C:12]([O:14][CH3:16])=[O:13])[C:4]([CH3:15])=[CH:3]1
Reactant: CC1=C[C@H](O)CC2(CCCC2)[C@H]1C(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H]1C(C)=C[C@H](O)CC12CCCC2
Reaction time: 0.5 h
Yield: 36 %

Procedure:
At 5° C., a solution of the crude trans-9-hydroxy-7-methylspiro[4.5]dec-7-ene-6-carboxylic acid obtained (22.7 g) in DMF (150 ml) was treated with potassium carbonate (16.3 g, 118 mmol) and stirred for 30 min. The resulting mixture was then treated within 6 min. with methyl iodide (13.4 ml, 215 mmol), stirred for 2 h at 20° C., poured into cold 2N aqueous HCl (200 ml), and extracted twice with hexane (150 ml). The combined organic phases were washed with water (100 ml), with a saturated aqueous solution of NaCl (150 ml), dried (MgSO4), and concentrated, giving crude trans-methyl 9-hydroxy-7-methylspiro[4.5]dec-7-ene-6-carboxylate (12.85 g, 36%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[C:22]([C:27]([F:30])([F:29])[F:28])=[N:23][CH:24]=[CH:25][CH:26]=4)[N:19]=[C:18]([C:31]([OH:34])([CH3:33])[CH3:32])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Cl:35]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>CC#N.C(Cl)Cl>[Cl:35][C:17]1[C:18]([C:31]([OH:34])([CH3:32])[CH3:33])=[N:19][N:20]([C:21]2[C:22]([C:27]([F:30])([F:29])[F:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[C:16]=1[C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2cccnc2C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C1CCC(=O)N1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(O)c1nn(-c2cccnc2C(F)(F)F)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)c1Cl
Temperature: 75 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 2-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1-(2-(trifluoromethyl)-pyridin-3-yl)-1H-pyrazol-3-yl)propan-2-ol (10.6 g, 21 mmol) in MeCN (200 mL) was added N-chlorosuccinimide. The resulting solution was heated to 75° C. in a heating mantle. After stirring for 3 hours at 75° C. heating was discontinued and the solution was concentrated under reduced pressure to afford a yellow foam. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexane. Fractions that Were pure by TLC analysis were combined and concentrated under reduced pressure to afford a white sticky foam that was contaminated with succinimide as evidenced by NMR analysis. This material was taken up in CH2Cl2 and washed with saturated aqueous Na2CO3 (2×). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(4-chloro-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1-[2-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-3-yl)propan-2-ol (6.7 g, 60% yield) as an off-white foam. 1H NMR (400 MHz CDCl3): δ 8.85 (1H, m), 8.06 (1H, t), 7.86 (1H, m), 7.82-7.73 (2H, m), 7.67-7.62 (1H, m), 7.58 (1H, t), 7.28 (1H, d), 7.01 (1H, d), 3.08 (3H, s), 2.93 (1H, s), 1.73 (6H, s). MS(ES): 542 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:16]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:16]([N:19]1[CH2:24][CH2:23][CH:22]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: O=C1NCCn2c1cc1cc(O)ccc12
Reactant: CC(C)N1CCC(O)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 205.2 %

Procedure:
To the suspension of 1.0 g (4.9 mmol) 8-hydroxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one in 70 ml tetrahydrofuran, a solution of 0.92 g (0.64 mmol) 1-isopropyl-piperidin-4-ol (commercially available) in 25 mL tetrahydrofuran, and 2.4 mL (2.0 g, 9.9 mmol) tributylphosphine were added. Another 20 mL tetrahydrofuran was added, and then the suspension was cooled to 0° C. Within 60 min., 2.5 g (9.9 mmol) 1,1′-(azodicarbonyl)dipiperidine was added under stirring and the reaction was allowed to reach room temperature. After 16 hours the suspension was filtered and the filtrate was evaporated. The residue was flash-chromatographed two times on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) to give 0.43 g (26%) of the product as a light brown solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][N:7]=1.Cl[CH2:17][C:18]1[CH:37]=[CH:36][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][C:28]=2[CH3:29])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:29][C:28]1[O:27][C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:25][C:24]=1[CH2:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:8]2[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:7]2)=[CH:37][CH:36]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1c[nH]nc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1cccs1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-caboxylate (10.23 g), 4-(4-chloromethylphenoxy)methyl-5-methyl-2-phenyloxazole (14.66 g), potassium carbonate (13.09 g), and N,N-dimethylformamide (100 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate as colorless crystals (19.88 g, yield: 87%) from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 113˜114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[CH3:15][O:16][C:17](=[O:27])[C@@H:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][O:16][C:17](=[O:27])[C@@H:18]([NH:26][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:19][C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1
Reactant: COC(=O)[C@@H](N)Cc1ccncc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccncc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 185 mg, 0.94 mmol) in DMF (7 mL) was added 2-(S)-amino-3-pyridin-4-yl propionic acid methyl ester hydrochloride (Preparation 93, 204 mg, 0.94 mmol) followed by TBTU (333 mg, 1.04 mmol) and DIPEA (740 μL, 4.24 mmol), and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the residue partitioned between ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with water (2×30 mL), NaHCO3 solution (3×40 mL) then brine (3×50 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography (SiO2, EtOAc) gave the title compound as a pink powder. m/z (ES+)=359.11 [M+H]+; RT=2.42 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O.O>[CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13](=[O:15])[CH3:14])[CH:8]=2)[O:3]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CCc2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.0 g (30.82 mmol) of 2,2-dimethylchroman (Compound 56) in 50 ml of nitromethane was treated, under nitrogen, with 2.53 g (32.35 mmol) of acetyl chloride followed by 4.4 g (33 mmol) of aluminum chloride. The reaction mixture was stirred at room temperature for 3 hours and then cooled in an ice-bath and treated slowly with 50 ml of 6M HC1. The mixture was diluted with water and extracted with ether. The ether extracts were washed successively with saturated NaHCO3 solution, water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in-vacuo and the resultant residue was purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a white solid. PMR (CDCl3) : & 1.36 (6H, s), 1.84 (2H, t, J~6.8 Hz), 2.54 (3H, s), 2.82 (2H, t, J~6.8 Hz), 6.80 (1H, d, J~8.4 Hz), 7.69-7.76 (2H, m). MS exact mass, m/e 204.1140 (calcd. for C13H16O2, 204.1150).
Reaction SMILES: C(OC[N:10]1[C:19]2[C:14](=[CH:15][C:16]3[CH:24]([CH3:25])[CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20][C:17]=3[CH:18]=2)[CH2:13][CH2:12][C:11]1=[O:33])C1C=CC=CC=1.Br>>[CH3:25][CH:24]1[C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][C:17]=2[CH2:20][CH2:21][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:23]1)[NH:10][C:11](=[O:33])[CH2:12][CH2:13]3
Reactant: CC1CN(C(=O)OC(C)(C)C)CCc2cc3c(cc21)CCC(=O)N3COCc1ccccc1
Agent: Br
Product: CC1CN(C(=O)OC(C)(C)C)CCc2cc3c(cc21)CCC(=O)N3
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.4 %

Procedure:
670 mg of t-butyl 1-[(benzyloxy)methyl]-6-methyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate was stirred at room temperature for 3.5 hours in a 48% aqueous hydrobromic acid solution. The reaction mixture was extracted with hexane and a side-product, benzyl bromide, was removed. Then, the aqueous layer was alkalified by the addition of a 1 M aqueous sodium hydroxide solution, and 20 ml of tetrahydrofuran was added thereto. To the mixed liquid was added 500 mg of di-t-butyl dicarbonate, followed by stirring at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain 513 mg of t-butyl 6-methyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a colorless foamed substance.
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[N:12]2[Cl:16])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:23](I)[CH3:24]>CC(C)=O>[Cl:1][C:2]1[C:14]([O:15][CH2:23][CH3:24])=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[N:12]2[Cl:16])=[CH:4][CH:3]=1
Reactant: Oc1c(Cl)ccc2c3ccncc3n(Cl)c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1c(Cl)ccc2c3ccncc3n(Cl)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.3 %

Procedure:
A mixture of the product of example 38 (35 mg, 0.14 mmol), K2CO3 (100 mg), and ethyl iodide (0.014 ml, 0.17 mmol) in acetone (5 ml) was stirred in a closed reaction tube at RT for 3 days. After concentrating the reaction, the residue was partitioned in ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated to give crude product. The crude product was chromatographed (5% methanol in chloroform) on silica gel to give 8 mg of 7,9-dichloro-8-ethoxy-β-carboline.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH2:12][CH3:13])[CH:6]=[CH:5][C:4]=1[CH3:14].[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>O1CCCC1>[CH2:12]([O:11][CH2:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([CH3:14])=[C:3]([B:15]([OH:20])[OH:16])[CH:8]=1)[CH3:13]
Reactant: CCOCOc1ccc(C)c(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOCOc1ccc(C)c(B(O)O)c1
Yield: 86.4 %

Procedure:
1.4 g (59 mmol) of magnesium turnings are placed in tetrahydrofuran in a round-bottomed flask and under a stream of nitrogen. 13.2 g (54 mmol) of 2-bromo-4-ethoxymethoxy-1-methylbenzene diluted in a small amount of THF are added slowly. The medium is refluxed for 20 minutes. It is then added via a cannula to 15 ml (65 mmol) of triisopropyl borate. The mixture sets to a solid and is then poured into 1N hydrochloric acid solution and extracted with ether. The organic phase is dried over magnesium sulfate, filtered and then evaporated. 9.8 g (87%) of the expected product are obtained in the form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]3)=[CH:11][C:10]=2[F:21])[CH:5]=[CH:6][C:7]=1[Cl:8].C1(N=C=NC2CCCCC2)CCCCC1.[O:37]1[CH2:39][CH:38]1[CH2:40]O>C(Cl)Cl>[O:37]1[CH2:39][CH:38]1[CH2:40][O:19][C:18]([C:15]1([C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[C:10]([F:21])[CH:11]=2)[CH2:17][CH2:16]1)=[O:20]
Reactant: O=C(O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Reactant: OCC1CO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(OCC1CO1)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
1-(3′,4′-Dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid (2.00 g, 6.15 mmol), dicyclohexylcarbodiimide (DCC, 2.54 g, 12.30 mmol), 4-dimethyl-aminopyridine (DMAP, 0.075 g, 0.614 mmol), and oxiran-2-ylmethanol (0.490 ml, 7.38 mmol) were dissolved in dry DCM (40 mL). The reaction mixture was stirred at room temperature (r.t.) overnight, then it was filtered and the filtrate was evaporated to dryness to afford 4.4 g of crude. The crude was purified by gradient flash chromatography eluting with petroleum ether/EtOAc (from 97/3 to 90/10 v/v) to afford 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropane carboxylic acid oxiranylmethyl ester (1.0 g, 42.6% yield).
Reaction SMILES: N1C=CC=CC=1.Cl.[C:8]1(/[CH:14]=[CH:15]/[C:16]([NH:18][CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:34]([Cl:37])(=[O:36])[CH3:35]>O>[ClH:37].[C:8]1(/[CH:14]=[CH:15]/[C:16]([N:18]([C:34](=[O:36])[CH3:35])[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)=[O:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)Cl
Reactant: O=C(/C=C/c1ccccc1)NCCC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N(CCC1CCN(Cc2ccccc2)CC1)C(=O)/C=C/c1ccccc1

Procedure:
A pyridine solution (5 ml) of (E)-3-phenyl-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide. hydrochloride (0.25 g) and acetyl chloride (0.3 ml) was stirred at 60° C. for 2 hours. Water was added to the reaction mixture after being left standing for cooling; the mixture was dried over anhydrous sodium sulfate. The solvent was distilled off. The oily residue was subjected to silica gel column chromatography (developing solvent : ethyl acetate). The solvent of the solution containing the object compound was distilled off. To the residue was added an ethanol solution of 3N hydrogen chloride. The solvent was then distilled off to obtain hydroscopic amorphous powder (0.16 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:31])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][Si](C(C)(C)C)(C)C)[CH:18]=2)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[OH:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:15][C:14]([C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([C:10]([F:13])([F:11])[F:12])[CH:8]=1)=[O:31]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1cccc(O)c1)c1cc(C(F)(F)F)c(C(=O)O)s1

Procedure:
A mixture of 5-[3-(tert-Butyl-dimethyl-silanyloxy)-benzylcarbamoyl]-3-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (210 mg, 0.44 mmol), lithium hydroxide monohydrate (370, mg, 8.87 mmol), THF (4 mL) and water (4 mL) was stirred over weekend, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 120 mg (79%). MS m/e 346.0 (M+H+).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH2:24]([N:28]1[CH2:32][CH2:31][N:30]([C:33]2[S:34][C:35]([C:39](O)=[O:40])=[C:36]([CH3:38])[N:37]=2)[C:29]1=[O:42])[CH:25]([CH3:27])[CH3:26]>>[CH2:24]([N:28]1[CH2:32][CH2:31][N:30]([C:33]2[S:34][C:35]([C:39]([NH2:7])=[O:40])=[C:36]([CH3:38])[N:37]=2)[C:29]1=[O:42])[CH:25]([CH3:27])[CH3:26]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(N)=O
Yield: 54 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 54% yield: mp: 212-215° C. (methanol/hexanes); 1H NMR (300 MHz, CDCl3) δ 5.69 (s, 2H), 4.13-4.08 (m, 2H), 3.61-3.56 (m, 2H), 3.12 (d, J=7.5 Hz, 2H), 2.60 (s, 3H); 1.97-1.88 (m, 1H), 0.94 (d, J=6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 165.5, 157.9, 155.6, 153.8, 116.6, 51.5, 42.8, 41.9, 26.7, 19.9, 17.2; MS (ES+) m/z 282.9 M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCN(CCCNCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCN(CCCNCc1ccc(N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A mixture of the compound obtained in step d) (0.183 g, 0.382 mmol) in EtOH (20 cm3) and of FeO(OH) as catalyst (20 mg) was heated to 60° C. under N2 atmosphere. Then hydrazine hydrate (19.5 mg, 0.60 mmol) was added and the resulting mixture was stirred 18 h at RT. After filtration through celite the solvent was removed at the rotary evaporator to yield a yellow oil which was dried under reduced pressure. (0.112 g, 0.248 mmol, yield 65.0%).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)=O.CC(C)=O.[Cl:20][C:21]1[C:29]([F:30])=[C:28]([CH3:31])[C:27]([F:32])=[CH:26][C:22]=1[C:23](Cl)=[O:24].S(=O)(=O)(O)O>C(O)C.C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Cl:20][C:21]1[C:29]([F:30])=[C:28]([CH3:31])[C:27]([F:32])=[CH:26][C:22]=1[C:23]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:24]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1c(F)cc(C(=O)Cl)c(Cl)c1F
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(C)c(F)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
4.5 g of magnesium chips are suspended in 10 ml of anhydrous ethanol. 1 ml of carbon tetrachloride is added and, when the reaction has started, a mixture of 29.7 g of diethyl malonate, 20 ml of absolute ethanol and 80 ml of anhydrous toluene is added dropwise at 50°-60° C. The mixture is then heated at 50°-60° C. for a further hour and cooled to -5° C. to -10° C. with dry ice/acetone and a solution of 41.7 g of 2-chloro-3,5-difluoro-4-methylbenzoyl chloride in 20 ml of absolute toluene is slowly added dropwise at this temperature. The mixture is stirred at 0° to -5° C. for 1 hour and left to come to room temperature overnight, and a mixture of 80 ml of ice-water and 12 ml of concentrated sulphuric acid is allowed to run in, while cooling with ice. The phases are separated and subsequently extracted twice with toluene. The combined toluene solutions are washed with saturated NaCl solution and dried with Na2SO4 and the solvent is stripped off in vacuo. 65.1 g of diethyl 2-chloro-3,5-difluoro-4-methylbenzoyl-malonate are obtained as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=1)[NH2:6].[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:6]([C:5]1[CH:7]=[CH:8][C:9]([C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:16]=[S:17]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)ccc1-c1cnn(C)c1
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
Step K (3): Dichloromethane (25 mL) was added to a flask charged with 3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (1.5 g, 7.38 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (2.57 g, 11.1 mmol). The resulting mixture was stirred for 16 h at rt. The reaction mixture was concentrated in vacuo. The crude products were purified using silica gel chromatography (30% EtOAc/dichloromethane). The fractions containing product were combined and concentrated. The resulting solid was recrystallized from hexane to afford 4-(4-isothiocyanato-2-methoxyphenyl)-1-methyl-1H-pyrazole (1.46 g, 5.95 mmol, 81% yield) as a light yellow solid. LC-MS (M+H)+ 272.0. 1H NMR (500 MHz, chloroform-d) δ ppm 7.57 (d, J=1.83 Hz, 1 H) 7.07 (d, J=1.53 Hz, 1 H) 6.94-7.04 (m, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[CH:15][N:16]3C(OC(C)(C)C)=O)[CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])#[N:2].C1(C)C=CC=CC=1.C([Sn](CCCC)=O)CCC.C[Si]([N:58]=[N+:59]=[N-:60])(C)C>O.C(O)(=O)C>[NH:16]1[C:17]2[C:13](=[C:12]([C:10]3[CH:9]=[C:8]4[C:4]([CH:5]=[N:6][N:7]4[S:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)(=[O:29])=[O:30])=[C:3]([C:1]4[NH:2][N:60]=[N:59][N:58]=4)[CH:11]=3)[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(-c3cc(C#N)c4cnn(S(=O)(=O)c5ccccc5)c4c3)cccc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnn[nH]3)cc(-c3cccc4[nH]ccc34)cc21
Temperature: 90 °C
Yield: 33 %

Procedure:
To a round bottomed flask was charged 1,1-dimethylethyl 4-[4-cyano-1-(phenylsulfonyl)-1H-indazol-6-yl]-1H-indole-1-carboxylate (6.16 g, 12.36 mmol) followed by toluene (250 ml). The resulting solution was then treated with dibutyl(oxo)stannane (0.554 g, 2.224 mmol) and trimethylsilyl azide (3.3 ml, 25.09 mmol). The mixture was heated to 90° C. overnight, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in methanol/DCM and preabsorbed onto silica (20 g). This was placed on the top of a silica cartridge (750 g) and eluted with 0-40% methanol in DCM. The product containing fraction was evaporated to give a green foam which was placed into acetic acid (50 ml) and the mixture heated to 100° C. overnight. The mixture was heated for a further 24 h, then cooled to room temperature and water (250 ml) added. A precipitate formed, which was collected by filtration and air dried over the weekend to give the title compound as a pale grey solid (1.8 g).