Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Na].[CH3:5][O:6][C:7](=[O:16])[CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[SH2:17]>CO>[CH3:5][O:6][C:7](=[O:16])[CH2:8][CH:9]([SH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: S
Reactant: CCCCCCC=CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCCCCCC(S)CC(=O)OC
Temperature: 25 °C

Procedure:
A sodium methylate solution is freshly prepared from 0.3 g of sodium and 5 ml of methanol. 10 g of 2-nonenoic acid methyl ester are added to this solution and the mixture is cooled to -70°. After reaching this temperature, 20 ml of hydrogen sulphide are condensed in and the whole batch is transferred into a pre-cooled autoclave. The pressure-vessel is sealed and immediately heated at 50° in an oil-bath for 3 hours. The autoclave is subsequently cooled to room temperature, the excess hydrogen sulphide vented off and the reaction mixture washed with saturated common salt solution and dried. There are obtained 12.4 g of crude product which, after distillation, yields 5.7 g of pure 3-mercaptononanoic acid methyl ester of boiling point 70°/0.2 mm Hg, nD20 1.4602.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=[N:3]1.[CH3:10][C:11](C)([O-])C.[K+].BrCCBr.[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7]2([C:8]#[N:9])[CH2:11][CH2:10]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1CC#N
Reactant: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: Cn1nccc1C1(C#N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.3 %

Procedure:
To a solution of 2-(1-methyl-1H-pyrazol-5-yl)acetonitrile (65 mg, 0.54 mmol) in N,N-dimethylformamide (3 mL) were added potassium t-butoxide (1M in tetrahydrofuran, 1.2 mL, 1.2 mmol) and 1,2-dibromoethane (130 μL, 1.5 mmol). The reaction mixture was stirred for 16 h at room temperature then at 70° C. for 7 h. The mixture was cooled to room temperature, quenched with water (2 mL) and extracted with diethyl ether (3×10 mL). The combined organic layers were washed with brine (3 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dried under high vacuum. A solution of the residue and 1,2-dibromoethane (65 μL, 0.75 mmol) in N,N-dimethylformamide (0.5 mL) was added dropwise to a suspension of sodium hydride (washed, 23 mg, 1.0 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature. After 16 h, additional portions of 1,2-dibromoethane (25 μL, 0.29 mmol) and sodium hydride (8 mg, 0.35 mmol) were added to the reaction mixture at room temperature. After 2 h, the mixture was quenched with water (3 mL) and extracted with diethyl ether (2×10 mL). The combined organic layers were washed with brine (3 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to yield the volatile 1-(1-methyl-1H-pyrazol-5-yl)cyclopropanecarbonitrile (20.1 mg, 25%) as a brown oil. 1H NMR (500 MHz, CDCl3) δ 1.34-1.41 (m, 2H), 1.70-1.76 (m, 2H), 4.03 (s, 3H), 6.10 (d, 1H), 7.39 (d, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=O)[CH3:2].[CH:11]1([C:14]([NH:16][NH2:17])=[O:15])[CH2:13][CH2:12]1>C(O)C>[Cl:10][C:7]1[N:6]=[CH:5][C:4]([C:1](=[N:17][NH:16][C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:15])[CH3:2])=[CH:9][CH:8]=1
Reactant: NNC(=O)C1CC1
Reactant: CC(=O)c1ccc(Cl)nc1
Solvent: CCO
Product: CC(=NNC(=O)C1CC1)c1ccc(Cl)nc1

Procedure:
Following the general method of procedure 53 and making non-critical variations, except the product was purified by recrystallization from absolute ethanol rather than by chromatography, 5.25 gm (0.0337 mole) of 3-acetyl-6-chloropyridine and 3.40 gm (0.034 mole) of cyclopropanecarboxylic acid hydrazide yield 6.52 gm (81%) of the title compound having a melting point of 218.1° C.
Reaction SMILES: COC1C=CC=CC=1P(CCP(C1C=CC=CC=1)(C1C=CC=CC=1OC)=O)(C1C=CC=CC=1)=O.COC1C(P(C2C=CC=CC=2)CCP(C2C(OC)=CC=CC=2)C2C=CC=CC=2)=CC=CC=1.[CH3:67][O:68][C:69]1[CH:70]=[C:71]([C:77]([CH:98]([CH3:100])[CH3:99])([C:96]#[N:97])[CH2:78][CH2:79][CH2:80][C:81]2[N:82]([CH3:95])[CH2:83][C:84]3[C:89]([CH:90]=2)=[CH:88][C:87]([O:91][CH3:92])=[C:86]([O:93][CH3:94])[CH:85]=3)[CH:72]=[CH:73][C:74]=1[O:75][CH3:76]>C(O)(C)C>[CH3:67][O:68][C:69]1[CH:70]=[C:71]([C:77]([CH:98]([CH3:100])[CH3:99])([C:96]#[N:97])[CH2:78][CH2:79][CH2:80][CH:81]2[CH2:90][C:89]3[C:84](=[CH:85][C:86]([O:93][CH3:94])=[C:87]([O:91][CH3:92])[CH:88]=3)[CH2:83][N:82]2[CH3:95])[CH:72]=[CH:73][C:74]=1[O:75][CH3:76]
Reactant: COc1ccc(C(C#N)(CCCC2=Cc3cc(OC)c(OC)cc3CN2C)C(C)C)cc1OC
Agent: COc1ccccc1P(=O)(CCP(=O)(c1ccccc1)c1ccccc1OC)c1ccccc1
Agent: COc1ccccc1P(CCP(c1ccccc1)c1ccccc1OC)c1ccccc1
Solvent: CC(C)O
Product: COc1ccc(C(C#N)(CCCC2Cc3cc(OC)c(OC)cc3CN2C)C(C)C)cc1OC
Temperature: 50 °C

Procedure:
is added to a solution of RhCl(Pφ3)3 in isopropanol at 3 atm, and the mixture heated at 50° C. for 4 hours. The product is purified to produce 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (1). Alternatively, one may hydrogenate the double bond stereoselectively using a hydrogenation catalyst with an appropriate chiral ligand, for example, 1,2-bis[P-(2-methoxyphenyl)-P-phenylphosphinyl]ethane, usually abbreviated "DiPAMP." See Knowles, Acc. Chem. Res., 6, 106-112 (1983) and the references cited therein, incorporated herein by reference in full. Thus, for example, 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2-dihydroisoquinoline (39) is added to a solution of Rh(DiPAMP)2 in isopropanol under 3 atm of H2, and the mixture heated at 50° C. for 4 hours. The product is purified to produce optically active 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (1).
Reaction SMILES: [H-].[Na+].CS([O:7][CH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@H:18]2[C@H:22]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@H:21]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@@H:20]([CH2:39][O:40][CH3:41])[O:19]2)=[C:11]([NH:42][CH2:43][CH:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:10]=1)(=O)=O.[N:57]1([CH2:63][CH2:64]O)[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1.O>O1CCCC1>[Si:24]([O:23][C@@H:22]1[C@H:21]([O:31][Si:32]([C:35]([CH3:38])([CH3:36])[CH3:37])([CH3:33])[CH3:34])[C@@H:20]([CH2:39][O:40][CH3:41])[O:19][C@H:18]1[N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:9]([CH2:8][O:7][CH2:64][CH2:63][N:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1)=[N:10][C:11]=2[NH:42][CH2:43][CH:44]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:25])[CH3:26]
Reactant: OCCN1CCCCC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COCCN4CCCCC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium hydride (24 mg of an 80% dispersion in mineral oil, 0.81 mmol) was added to a stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (500 mg, 0.63 mmol) (preparation 16) and 2-(1-piperidinyl)-1-ethanol) (105 mg, 0.81 mmol) in tetrahydrofuran (5 ml). The reaction mixture was stirred for 24 hr at room temperature and then heated at reflux for a further 8 hr. The reaction mixture was then poured into cold water and extracted with ethyl acetate. The organic phase was separated, washed with brine and dried with anhydrous sodium sulfate. The solvent was then removed under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5) to give the title compound (101 mg) as an oil. MS: 833 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[N:14]1([CH2:20][CH2:21][CH2:22][N:23]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][S:24]2(=[O:31])=[O:30])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:27]2[CH2:26][CH2:25][S:24](=[O:30])(=[O:31])[N:23]([CH2:22][CH2:21][CH2:20][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[CH2:29][CH2:28]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: O=S1(=O)CCNCCN1CCCN1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(CCCN2CCCCC2)S(=O)(=O)CC1
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution of 3,4-dichlorophenyl isocyanate (59 mg, 0.31 mmol) in tetrahydrofuran (0.5 ml) was added dropwise at room temperature to a suspension of 2-(3-piperidin-1-yl-propyl)-[1,2,5]thiadiazepane 1,1-dioxide dihydrochloride (intermediate 13; 100 mg, 0.29 mmol) and triethylamine (116 mg, 1.15 mmol) in tetrahydrofuran (2 ml). The reaction mixture was stirred for 16 h, then partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloro-methane/methanol/25% aq. ammonia solution 95:5:0.25) produced the title compound (117 mg, 88%). White solid, MS (ISP)=463.0 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36](O)[CH3:37])=[C:32]([C:39]([F:42])([F:41])[F:40])[CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][C:32]=4[C:39]([F:42])([F:40])[F:41])[CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(O)c1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a nitrogen atmosphere, 2.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate are dissolved in 60 ml anhydrous dichloromethane. Consecutively, 1.56 g of 1-[4-fluoro-2-(trifluoromethyl)phenyl]ethanol, 3.3 g triphenylphosphine (polymer bound, ˜3 mmol/g) and 2.3 g of di-tert-butyl azodicarboxylate are added to the solution. The reaction mixture is stirred at room temperature for 15 h and then filtered. The filter cake is washed with 50 ml of a dichloromethane/methanol mixture (95:5). The filtrate is concentrated to dryness under reduced pressure. The crude is purified by flash chromatography [Silica gel, eluent: ethyl acetate/cyclohexane, elution gradient of 5/95 (v/v) to 70/30 (v/v) to yield the title product.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH2:21])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)C(N)(CO)CO>ClCCCl>[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH:21][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: O=S(=O)(NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was synthesized as part of library using the following procedure in a parallel synthesis fashion using 48 well red and blue minireactors. Typical procedure: To a solution of 22B (14 mg, 0.05 mmol) in DCE (0.5 mL) at RT was added NMM (0.109 mL, 0.1 mmol), followed by addition of benzene sulfonylchloride (17.6 mg, 0.1 mmol) in DCE (0.5 μL). The reaction mixture was shaken at RT for 24 h, and treated with 100 mg of PS-Trisamine (4 mmol/g loading) for 2 h to remove excess sulfonyl chloride. Contents were filtered into a synthesis tube rack (STR) and the solvent was dried in a speed vac. The resulting residue was chromatographed using Prep HPLC (conditions: Xterra MS-C18 (30×50 mm); Eluted with 10% to 100% B, 6 min gradient. (A=100% water−0.1% TFA and B=acetonitrile with 0.1% TFA); Flow rate at 30 mL/min. UV detection at 220 nm) to give compound 50 (13.8 mg, 69%). HPLC: 99% at 1.74 min (retention time) (Conditions: Xterra MS-C18 (2.1×50 mm); Eluted with 0% to 100% B, 2.75 min gradient. (A=100% water−0.1% TFA and B=acetonitrile with 0.1% TFA); Flow rate at 1 mL/min. UV detection at 220 nm). MS (ES): m/z 413 [M+H]+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.O[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:22]=1
Reactant: COC(=O)C(C)(C)CO
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COc1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
40% Diethyl azodicarboxylate-toluene solution (9.54 mL) was added to a tetrahydrofuran (40 mL) solution containing 4-bromophenol (2.0 g), methyl hydroxypivalate (2.77 g) and triphenylphosphine (5.49 g), and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10) to obtain methyl 3-(4-bromophenoxy)-2,2-dimethylpropanoate (3.2 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-2′,5′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G45) (160 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (115 mg, 0.5 mmol) according to the general procedure K. Obtained as an amorphous white substance (110 mg).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[CH3:31])=[CH:6][CH:5]=1.[Li+].[OH-].OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:31][C:16]1[CH:17]=[C:18]([C:21]([OH:30])([C:22]([F:25])([F:23])[F:24])[C:26]([F:27])([F:29])[F:28])[CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OCCCOc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2C)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1OCCCOc1ccc(C(=O)O)cc1
Yield: 66.3 %

Procedure:
94 mg (0.2 mmol) of 4-{3-[2-methyl-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-propoxy}-benzoic acid methyl ester (example 19) in 2 mL of THF were treated with 2 mL of 1M LiOH at room temperature overnight. 1M KHSO4 solution was added, the phases were separated, and the inorganic one was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated. The crude product was purified by column chromatography with CH2Cl2/MeOH 95:5 to give 60 mg (65%) 4-{3-[2-methyl-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-propoxy}-benzoic acid as a light yellow solid, MS: 451 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH2:14])=[CH:11]2)=[N:6]1.[O:16]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:30](=[O:31])[CH2:29][C:26]3[CH:27]=[CH:28][C:23]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)=[CH:11]2)=[N:6]1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: CN(C)CCn1cc2cc(N)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)CCn1cc2cc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)ccc2n1
Reaction time: 6 h

Procedure:
A mixture of 2-(2-Dimethylamino-ethyl)-2H-indazol-5-ylamine (49.0 mg, 0.243 mmol), (4-phenoxy-phenyl)-acetic acid (60.0 mg, 0.248 mmol), EDCI (57.0 mg, 0.298 mmol), N-hydroxybenzotriazole (40.0 mg, 0.296 mmol), N-methyl morpholine (64.0 mg, 0.633 mmol) and 2 mL of N,N-dimethylformamide was shaken for 6 hours. The solvents were removed under vacuo and the residue dissolved in 1.5 mL of a 1:1 mixture of dimethylsulfoxide/methanol was purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) ppm 2.49(s, 6H) 3.34 (t, 2H, J=6.44), 3.37 (s, 2H), 4.50 (t, 2H, J=6.44), 6.69–6.74 (m, 4H), 6.85 (m, 1H), 7.03 (m, 1H), 7.08–7.13 (m, 4H), 7.32 (m, 1H), 7.90 (s, 1H), 8.10 (s, 1H), 9.26 (s, 1H); MS (DCI/NH3) m/z 415 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:34](O)(=[O:37])[CH:35]=[CH2:36]>C(Cl)Cl.CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:34](=[O:37])[CH:35]=[CH2:36])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: C=CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
3-Nitroaniline (2.0 g, 14.48 mmol) was dissolved in CH2Cl2 (75 ml) and cooled to 0° C. To this solution were added EDC (8.3 g, 43.4 mmol), HOBT (5.9 g, 43.4 mmol), DIEA (12.6 ml, 72.4 mmol) and acrylic acid (3.97 ml, 57.9 mmol). The reaction mixture was kept at RT for 1.25 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography using 1:1 EtOAc/hexanes as the solvent to give N-(3-nitrophenyl)acrylamide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][NH:18][S:17](=[O:21])(=[O:20])[NH:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.C1C(=O)N([Br:30])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:30][C:9]1[CH:10]=[C:11]([CH:14]2[CH2:19][NH:18][S:17](=[O:21])(=[O:20])[NH:16][CH2:15]2)[CH:12]=[CH:13][C:8]=1[NH2:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CNS(=O)(=O)NC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C2CNS(=O)(=O)NC2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
[4-(1,1-Dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step, 100 mg, 0.305 mmol) was dissolved in TFA (1 mL). The resulting solution was stirred at RT for 30 min and concentrated in vacuo. The residue obtained (74.3 mg) was dried in vacuo for 1 h and dissolved in HOAc (2 mL). The resulting mixture was cooled to 0° C. and NBS (42.6 mg, 0.239 mmol) was added. The resulting mixture was stirred for 30 min, washed with aq NaHCO3 (2 mL) and concentrated. The residue was purified on silica (20-100% EtOAc-hexane) to obtain the title compound (49 mg, 52%): 1H-NMR (CD3OD; 400 MHz): δ 7.23 (d, 1H, J=2.0 Hz), 6.93 (dd, 1H, J=8.2, 2.0 Hz), 6.78 (d, 1H, J=8.2 Hz), 3.63 (m, 2H), 3.32 (m, 2H), 2.82 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][C:16]=1F>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:15][C:16]=1[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: O=Cc1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccn1-c1ccc(C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
A solution of pyrrole-2-carboxaldehyde (19.0 g, 0.2 mol) in N,N-dimethylformamide (50 ml) was added dropwise to a suspension of sodium hydride (80% dispersion in oil, 6.3 g, 0.21 mol) in N,N-dimethylformamide (100 ml), maintaining the temperature of the reaction between 5°-10° C. by means of ice-bath cooling. When the addition was complete, stirring was continued for 30 minutes, and then 3-chloro-4-fluorobenzotrifluoride (39.7 g, 0.20 mol) added. The mixture was stirred for 3 hours, then warmed to 50° C. for 18 hours. The mixture was cooled to room temperature and partitioned between diethyl ether and water. The ethereal extract was washed sequentially with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. Trituration with hexane gave 1-(2'-chloro-4'-trifluoromethylphenyl)pyrrole-2-carboxaldehyde as a pale yellow solid (30.6 g), m.p. 119°-120° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][C:19]1([CH2:25][C:26]([NH2:28])=[O:27])[CH2:22][S:21](=[O:24])(=[O:23])[CH2:20]1>>[NH2:28][C:26](=[O:27])[CH2:25][C:19]1([NH:18][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:20][S:21](=[O:23])(=[O:24])[CH2:22]1
Reactant: CC(CF)Oc1cc(C(=O)O)ncc1C1CC1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Product: CC(CF)Oc1cc(C(=O)NC2(CC(N)=O)CS(=O)(=O)C2)ncc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(1-fluoropropan-2-yloxy)picolinic acid (enantiomer A) (example 287e) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (37.5 mg, 56%); MS (ESI, m/z): 400.3 (M+H+).