Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([CH3:14])=[N:9][C:10]([Br:13])=[CH:11][CH:12]=2)[C:3]1=[O:15].C1COCC1.[CH3:21][C:22]([O-:24])=[O:23].[K+]>C1OCCOCCOCCOCCOCCOC1.C(OCC)(=O)C>[C:22]([O:24][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([CH3:14])=[N:9][C:10]([Br:13])=[CH:11][CH:12]=2)[C:3]1=[O:15])(=[O:23])[CH3:21]
Reactant: CC(=O)[O-]
Reactant: Cc1nc(Br)ccc1N1CCC(Br)C1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC1CCN(c2ccc(Br)nc2C)C1=O
Temperature: 70 °C
Yield: 51.3 %

Procedure:
A 500 mL round-bottom flask was charged with crude 3-bromo-1-(6-bromo-2-methylpyridin-3-yl)pyrrolidin-2-one from step A (18.5 g), THF (50 mL), 18-Crown-6 (576 mg, 2.18 mmol) and KOAc (12.84 g, 131 mmol). The mixture was heated at 70° C. under argon overnight. After cooling the reaction mixture to room temperature, ethyl acetate (50 mL) was added. The organic layer was separated and washed with water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated to a dark solid, which was purified by flash chromatography (silica gel, 20-100% ethyl acetate/hexane) to give 1-(6-bromo-2-methylpyridin-3-yl)-2-oxopyrrolidin-3-yl acetate (8.9 g, 65% yield for two steps) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.38 (q, J=8.3 Hz, 3H), 5.43 (t, J=8.2 Hz, 1H), 3.47-4.03 (m, 3H), 2.62-2.90 (m, 1H), 2.38-2.56 (m, 4H), 2.06-2.32 (m, 5H); MS (ESI) 314 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]#[N:13])[CH:6]=[C:5]2[S:14][CH3:15].[OH:16]OS([O-])=O.[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]#[N:13])[CH:6]=[C:5]2[S:14]([CH3:15])=[O:16]
Reactant: CSc1cn(CC#N)c2ccc(Cl)cc12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)c1cn(CC#N)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of (5-chloro-3-methylsulfanyl-indol-1-yl)-acetonitrile (1.0 g, 4.22 mmole) dissolved in methanol (65 ml) cooled to ca. 0° C., was added a cold solution (ca. 7° C.) of Oxone® (1.29 g, 2.11 mmole) dissolved in water (40 ml) in portions over a 10 minute time period. The cooling bath was removed and the solution was stirred at room temperature for 4 h. Tlc analysis at this point showed some unreacted starting material and thus 0.1 g more Oxone® was added and the mixture continued stirring overnight. The reaction mixture was evaporated to dryness and the residue was taken up in methanol and the insoluble material was filtered. The methanol soluble material was isolated by evaporation of the solvent and the residue was triturated with ether which was discarded and then with toluene. The solid which remained was further purified by column chromatography (silica gel) eluting with methanol:methylene chloride (3:97). The resulting (5-chloro-3-methanesulfinyl-indol-1-yl)-acetonitrile weighed 0.851 g (80% yield) after drying.
Reaction SMILES: [Si]([N:8]1[C@H:11]([CH2:12][C:13](=[O:28])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@@H:10]([C@H:29]([O:31][Si](C(C)(C)C)(C)C)[CH3:30])[C:9]1=[O:39])(C(C)(C)C)(C)C.Cl>CO.O.C(OCC)(=O)C>[OH:31][C@@H:29]([C@@H:10]1[C@@H:11]([CH2:12][C:13](=[O:28])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[NH:8][C:9]1=[O:39])[CH3:30]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(3S,4R)-1-(t-butyldimethylsilyl)3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one (7.9 mmol) is dissolved in 160 ml of 9:1 (v/v) methanol-water and cooled to 0° C. Concentrated hydrochloric acid (2.75 ml) is added and the resulting solution is stirred at 0° C. for 15 min., then allowed to warm to room temperature. The solution is stirred at room temperature for 2.5 hrs, then diluted with ethyl acetate (200 ml) and washed with water, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to yield (3S,4R)-3-[(R)1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]-azetidin-2-one.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Mg].C[O:18][B:19](OC)[O:20]C.B([O-])([O-])[O-]>C1COCC1.O>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([B:19]([OH:20])[OH:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Mg]
Agent: [O-]B([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
A dry reactor equipped with two addition funnels, nitrogen inlet, and a mechanical stirrer was set up over a dry ice bath. To one of the addition funnels was added a filtered, preformed Grignard reagent from the reaction of 4-(t-butyldimethylsilyloxy)-bromobenzene (28.7 g, 0.1 mol) with magnesium turnings (2.96 g, 0.12 mol) in THF (70 mL). To the other addition funnel was added trimethylborate (12.48 g, 0.12 mol) in THF (50 mL). The reactor was charged with about 10 mL of the borate solution and was cooled to -70° C. About 10 mL of the Grignard solution was then added. The remaining borate and Grignard solutions were then added in aliquots in such a way as to ensure a slight excess of borate. The reaction mixture was stirred at -70° C. for one hour then stirred at room temperature for 20 hours. The reactor was cooled to 0° C. and water (100 mL) was slowly added with vigorous stirring. The mixture was extracted with ether (400 mL). The ether layer was washed with water (2×200 mL), dried over anhydrous MgSO4, then concentrated on a roto-evaporator to afford a light-tan-colored solid (22.0 g, 87 percent). 1H and 13C NMR spectra were consistent with the following structure. ##STR11##
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH2:14]O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)[CH3:2].CCN(CC)CC.CS([Cl:27])(=O)=O.[Li+].[Cl-]>C(Cl)Cl.CN(C=O)C>[Cl:27][CH2:14][CH2:13][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CCO)c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CCCl)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A stirred solution of the above alcohol (XI; R=H) (4.0 g, 19 mmol) in CH2Cl2 (35 mL) containing NEt3 (2.91 mL, 21 mmol) was treated dropwise at 0 ° C. with methanesulfonylchloride (1.62 mL, 21 mmol). After being stirred at 0 ° C. for a further 30 min and at20 ° C. for 30 min, the reaction mixture was diluted with CH2Cl2 (35 mL) and washed successively with 1N HCl, 1N Na2CO3and saturated NaCl, and worked up to give the crude mesylate, which was immediately treated with LiCl (2 g) in dry DMF (20 mL) at 75° C. for 30 min. Removal of excess solvent under reduced pressure, and chromatography of the residue on SiO2 (EtOAc/petroleum ether, 1:4 ) gave N-(2-chloroethyl)-N-ethyl-3-nitroaniline (XII; R=H) (3.58 g, 82%)as yellow prisms, mp (petroleum ether) 56°-57 ° C. 1H NMR (CDCl3) 7.51 (dd, J=7.9, 1.9 Hz, 1 H, H-4), 7.48 (t, j=2.4 Hz, 1 H, H-2), 7.32 (m, 2 H, H-5), 6.95 (dd, J=8.4, 2.7 Hz, H-6), 3.70 (m, 2 H, NCH2CH2Cl), 3.64 (m, 2 H, CH2Cl), 3.50 (q, J=7.1 Hz, 2 H, NCH2CH3), 1.22 (t, J=7.1 Hz, 3 H, CH3). Anal.(C10H13ClN2O2) C,H,N,Cl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][CH:42]=[CH:41][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-])=O)[CH:33]=2)=[CH:13][CH:12]=1>O1CCCC1.[Ni]>[NH2:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:41]=[CH:42][CH:43]=[CH:44][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc([N+](=O)[O-])c2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(N)c2)cc1

Procedure:
The solution of 0.710 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(3-nitrobenzyloxy)piperidine-1-carboxylate in 10 ml of tetrahydrofuran is hydrogenated in the presence of 0.190 g of Raney nickel over 20 hours. The reaction mixture is filtered and the filtrate is concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.14 (1:2 EtOAc-heptane); Rt=4.93.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=2)(C(OCC=C)=O)[C:27]([O:29]CC=C)=[O:28])=[CH:20][CH:19]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH:26]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=2)[C:27]([OH:29])=[O:28])=[CH:22][CH:23]=1)=[O:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: C=CCOC(=O)C(CCc1ccc(C(=O)OC(C)(C)C)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC(CCc2ccc(C(=O)OC(C)(C)C)cc2)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 70.2 %

Procedure:
A solution of 0.79 ml (5.66 mmol) of triethylamine and 0.16 ml (4.29 mmol) of formic acid in 10 ml of dioxane is added to a solution of 920 mg (1.71 mmol) of diallyl {2-[4-(tert-butoxycarbonyl)phenyl]ethyl}[4-(methoxycarbonyl)benzyl]malonate, 31.5 mg (0.12 mmol) of triphenylphosphine and 7.7 mg (0.03 mmol) of palladium acetate in 10 ml of dioxane at room temperature. The reaction mixture is then stirred at 100° C. for 12 hours. After conversion is complete, the reaction solution is cooled and the solvent is removed in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→1:1). 497 mg (1.2 mmol, 61% yield) of a colourless solid are obtained.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:6]([C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:7][CH:8]=[C:9]([Cl:11])[CH:10]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:11][C:9]1[CH:10]=[C:5]2[NH:3][N:2]=[C:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]2=[N:7][CH:8]=1
Reactant: O=C(Cc1ccccc1F)c1ncc(Cl)cc1Cl
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: Fc1ccccc1Cc1n[nH]c2cc(Cl)cnc12
Temperature: 160 °C

Procedure:
A little DMAP and 238 mg (4.75 mmol) of hydrazine hydrate are added to a solution of 1.35 g (4.75 mmol) of 1-(3,5-dichloropyridin-2-yl)-2-(2-fluorophenyl)ethanone from example 2A in 12 ml of pyridine. The mixture is heated in a closed vessel in a microwave at 160° C. for 20 min and then concentrated in vacuo, and the residue is purified by chromatography on silica gel (eluent: dichloromethane/methanol 100:3). 507 mg (41% of theory) of the title compound and 388 mg of the uncyclized hydrazone are obtained. The latter is heated anew in 5 ml of DMF in the microwave at 200° C. for 1.5 h. The solution is concentrated and the residue is purified by preparative HPLC. A further 176 mg (12% of theory) of the title compound are obtained in this way.
Reaction SMILES: [C:1]([C:3]([CH3:11])([CH3:10])[CH:4]([OH:9])[CH2:5][C:6]([OH:8])=[O:7])#[N:2].[C:12]1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:3]([CH3:11])([CH3:10])[CH:4]([OH:9])[CH2:5][C:6]([O:8][CH3:12])=[O:7])#[N:2]
Reactant: Cc1ccccc1
Reactant: CC(C)(C#N)C(O)CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)CC(O)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
R-N-(p-Hydroxybenzyl)phenylethylamine salt (8.42 g, 22.7 mmol) of optically active 4-cyano-3-hydroxy-4-methylpentanoic acid was dissolved in water (20 mL) and toluene (20 mL) was added. 2N Aqueous potassium carbonate solution (22.7 mL, 45.4 mmol) was gradually added dropwise with vigorous stirring. After stirring vigorously at room temperature for 30 min, the mixture was partitioned and an organic layer was removed. Then, toluene (20 mL) and tetrabutylammonium bromide (1.01 g, 3.42 mmol) were added and dimethyl sulfate (3.15 g, 25.0 mmol) was dropwise added with vigorous stirring. The reaction mixture was stirred at room temperature for 2 hr, and a toluene layer was separated and concentrated under reduced pressure to give optically active methyl 4-cyano-3-hydroxy-4-methylpentanoate (3.62 g). The yield was 93.4% relative to optically active 4-cyano-3-hydroxy-4-methylpentanoic acid.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12](=[O:27])[N:13]2[CH:17]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:16][CH:15]=[N:14]2)[CH2:8][C:9](O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28]1([CH2:34][O:35][NH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN1CCOCC1.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:8][C:9](=[O:10])[NH:36][O:35][CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12]([N:13]2[C@H:17]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:16][CH:15]=[N:14]2)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccccc1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-oxo-4-{5-[(phenylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoic acid (336 mg, 0.90 mmol) in dichloromethane (DCM) (10 ml) was added O-(phenylmethyl)hydroxylamine (167 mg, 1.36 mmol), 4-methylmorpholine (0.26 ml, 2.35 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (123 mg, 0.90 mmol), and EDC (208 mg, 1.09 mmol) at 0° C. The reaction was left to warm to room temperature and stirred overnight. The reaction was washed with water (15 mL) and NaHCO3 solution (15 mL×3), and then concentrated to give the crude product as a mixture of diastereomers, which was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-phenyl-4,5-dihydro-1H-pyrazole-5-carboxamide (110 mg, 25% yield). MS: 477 ([M+H]).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]=[O:13].C(N(CC)CC)C>CC(C)=O>[C:1]1([C:7]2[CH:11]=[CH:10][N:9]([CH2:12][OH:13])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: OCn1ccc(-c2ccccc2)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
The mixture of 2.88 g of 3-phenyl-1H-pyrazole, 0.67 g of paraformaldehyde and 0.3 ml of triethylamine was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. After the mixture was filtered, hexane was added to the filterate to produce a crystal. The crystal was collected to obtain 2.64 g of 3-phenyl-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [BrH:1].C([NH:9][CH2:10][C:11](=[O:25])[CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])(OC(C)(C)C)=O>C(O)(=O)C>[BrH:1].[NH2:9][CH2:10][C:11](=[O:25])[CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: CC(C)(C)OC(=O)COC(=O)CCC(=O)CNC(=O)OC(C)(C)C
Agent: Br
Solvent: CC(=O)O
Product: NCC(=O)CCC(=O)OCC(=O)O
Yield: 92 %

Procedure:
A 30% solution of hydrogen bromide in acetic acid (12 mL) was added to the product of 1a (3.3 g; 9.5 mmol) cooled with an ice-water bath and stirred until the oil dissolved with evolution of gas. After stirring for 15 min, the mixture was triturated with hexane (4×20 mL) and diethyl ether (4×20 mL); the oil solidified to a tan powder. The residue was filtered and dried overnight in a drying pistol at ˜50° C. and 12 mm Hg. 4.44 g (92%) product was obtained (tan powder, mp 110-114° C. (dec.)).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[C:17]1([CH3:28])[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:19][CH:18]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:25](=[O:26])/[CH:24]=[CH:23]/[C:20]3[CH:21]=[CH:22][C:17]([CH3:28])=[CH:18][CH:19]=3)=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1ccc(/C=C/C(=O)O)cc1
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: Cc1ccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)cc1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-p-tolyl-acrylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=372.16.
Reaction SMILES: [Br:1][C:2]1([C:5]2[S:6][CH:7]=[C:8]([CH2:10][CH2:11]CC)[N:9]=2)[CH2:4][CH2:3]1.BrCC(=O)CCCC>>[Br:1][C:2]1([C:5]2[S:6][CH:7]=[C:8]([CH2:10][CH3:11])[N:9]=2)[CH2:3][CH2:4]1
Reactant: CCCCc1csc(C2(Br)CC2)n1
Agent: CCCCC(=O)CBr
Product: CCc1csc(C2(Br)CC2)n1

Procedure:
2-(1-Bromocyclopropyl)-4-butylthiazole 20 from 1-bromo-2-hexanone at 100° C. and a reaction time of 2 minutes.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[NH3:12].C([O-])([O-])=O.[K+].[K+].[Cl-].[Na+]>C1COCC1>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([NH2:12])=[O:10]
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nn(C)c(F)c1C(N)=O
Reaction time: 4 h

Procedure:
19.9 g of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride are added dropwise at 20-35° C. to a mixture of 35 g of 25 percent aqueous ammonia and 170 ml of THF. After stirring for 4 h, the organic solvent fraction is concentrated by evaporation under reduced pressure and 0.2 mol of potash and sodium chloride are added to saturation. After extracting four times with ethyl acetate and concentrating the combined organic phases by evaporation under reduced pressure, 16.6 g of a yellow solid are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20](=[O:26])(=[O:25])[NH:21][CH:22]3[CH2:24][CH2:23]3)[CH:15]=2)=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:27]([C:31]1[CH:36]=[CH:35][C:34]([Mg]Br)=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([S:20]([NH:21][CH:22]3[CH2:23][CH2:24]3)(=[O:25])=[O:26])[CH:17]=[CH:18][CH:19]=2)=[CH:10][C:3]=1[C:4](=[O:5])[C:34]1[CH:35]=[CH:36][C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:32][CH:33]=1
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cc(-c2cccc(S(=O)(=O)NC3CC3)c2)cnc1N
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)c2cc(-c3cccc(S(=O)(=O)NC4CC4)c3)cnc2N)cc1
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-(3-cyclopropylsulfamoyl-phenyl)-N-methoxy-N-methyl-nicotinamide (Intermediate GA) (0.08 g, 0.21 mmol) in THF (3 ml) is cooled to 0° C. 2M 4-tert Butyl phenyl magnesium bromide in THF (0.32 ml, 0.64 mmol) is added dropwise, and the resulting solution is stirred and allowed to warm to room temperature overnight. The reaction is quenched with 2M HCl (5 ml). The solvent is removed in vacuo and the residue purified by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water −0.1% TFA). The solid obtained is dissolved in DCM, washed with 2M NaOH. The solvent is removed in vacuo and the resulting solid is dried in vacuo at 40° C. overnight to yield the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (1H, d), 8.01 (1H, d), 7.97-7.89 (3H, m), 7.78 (1H, d), 7.72-7.67 (5H, m), 7.64 (2H, d), 2.18-2.13 (1H, m), 1.38 (9H, s), 0.47-0.38 (4H, m); MS m/z 450 [M+H]+
Reaction SMILES: [CH3:1][C:2]([CH2:4][Cl:5])=[CH2:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.S(=O)(=O)(O)O>ClCCl>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][C:9]=1[C:2]([CH3:3])([CH3:1])[CH2:4][Cl:5]
Reactant: COc1ccc(Br)cc1
Reactant: C=C(C)CCl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(Br)cc1C(C)(C)CCl
Yield: 49.4 %

Procedure:
β-Methallyl chloride (90.5 g, 1.0 mole) was added dropwise to a stirred mixture of p-bromoanisole (200 g, 1.07 mole) and sulphuric acid (34.2 g, 0.35 mole) at 35°-40° C. over about 2 hours. After 21/2 hours at ambient temperature, the mixture was dissolved in dichloromethane, washed with water, aqueous sodium bicarbonate and water again, dried over magnesium sulphate and run down. Distillation of the residue gave a small forerun b.p. about 54° C. at 0.2 mm Hg and a main fraction of 182 g (62%) b.p. 99°-120° C. at 0.15-0.2 mm Hg. Recrystallisation from petroleum ether (b.p. 80°-100° C.) gave 137 g pure title product m.p. 82°-4° C. Reduction in volume of the mother liquors afforded a further 14 g product.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([CH3:19])[CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8].[Li].[OH-]>CO>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][O:9][C:7]([NH:6][CH2:5][CH:4]([CH3:19])[C:3]([OH:20])=[O:2])=[O:8])=[CH:16][CH:15]=1
Reactant: COC(=O)C(C)CNC(=O)OCc1ccc(OC)cc1
Agent: [Li]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(COC(=O)NCC(C)C(=O)O)cc1
Yield: 97.3 %

Procedure:
A solution of N-4-methoxybenzyloxycarbonyl α-methyl β-alanine methyl ester (2.81 g, 10.0 mmol) in 30 mL of 25% aqueous methanol was treated with lithium is hydroxide (1.3 equivalents) at room temperature for a period of 2 h. The solution was concentrated in vacuo and the residue taken up in a mixture of water and ether and the phases separated and the organic phase discarded. The aqueous phase was acidified with aqueous potassium hydrogen sulfate to pH=1.5 and then extracted three times with ether. The combined ethereal phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2.60 g, 97% of N-4-Methoxybenzyloxycarbonyl α-methyl β-alanine (N-Moz-AMBA) which was purified by recrystallization from a mixture of ethyl acetate and hexane to give 2.44 g, 91% of pure product, mp 96-97° C., MH+=268. 1H NMR (D6-acetone/300 MHz) 1.16 (3H, d, J=7.2Hz), 2.70 (1H, m), 3.31 (2H, m), 3.31 (3H, S), 4.99 (2H, s), 6.92 (2H, 4, J=8.7 Hz), 7.13 (2H, d, J=8.7 Hz).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:14]([F:17])([F:16])[F:15])([OH:13])[C:4]([F:12])([F:11])[CH:5]([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.C1(C)C=CC=CC=1.[C:34](Cl)(=[O:38])[C:35]([CH3:37])=[CH2:36]>O>[C:34]([O:10][CH:5]([C:6]([F:9])([F:8])[F:7])[C:4]([F:11])([F:12])[C:3]([OH:13])([C:14]([F:15])([F:16])[F:17])[C:2]([F:18])([F:19])[F:1])(=[O:38])[C:35]([CH3:37])=[CH2:36]
Reactant: OC(C(F)(F)F)C(F)(F)C(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(=O)OC(C(F)(F)F)C(F)(F)C(O)(C(F)(F)F)C(F)(F)F
Yield: 71.3 %

Procedure:
To a mixture of 138 g of 1,1,1,3,3,5,5,5-octafluoro-2-(trifluoromethyl)pentane-2,4-diol (Synthesis Example [1-1]), 53.0 g of triethylamine, and 700 g of toluene, under ice cooling and with stirring, 45.4 g of methacrylic acid chloride was added dropwise. The mixture was stirred for 2 hours. Water was added to the reaction mixture to quench the reaction, followed by conventional work-up steps of washing, drying and concentration to give a crude product. It was purified by silica gel column chromatography, yielding 119 g (yield 71%) of the end compound, fluorinated ester.