Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]([I:12])=[C:7]([I:11])[C:8]([OH:10])=[O:9].N1C=CC=CC=1.[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[I:11][C:7](=[C:6]([I:12])[I:5])[C:8]([O:10][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:9]
Reactant: c1ccccc1
Reactant: O=C(O)C(I)=C(I)I
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)C(I)=C(I)I
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 0.3 ml of thionyl chloride in 2 ml of benzene was added dropwise to a mixture of 0.3 g of triiodoacrylic acid, 0.3 ml of pyridine and 3 ml of benzene. The mixture was then stirred at room temperature for 45 minutes, after which the solvent was distilled off under reduced pressure. 5 ml of benzene and 0.3 ml of pyridine were added to the resulting residue, and then 0.3 g of phenol was added, with ice-cooling, after which the mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into an ice-cooled dilute solution of hydrochloric acid and then extracted with diethyl ether. The extract was washed, in turn, with a saturated aqueous solution of sodium bicarbonate, water and then a saturated aqueous solution of sodium chloride. The resulting solution was dried over anhydrous sodium sulphate and then the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography through silica gel eluted with a 100:12 by volume mixture of hexane and ethyl acetate, to give 0.18 g of the title compound, melting at 83°-84.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5][N:4]=1.[Br:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16](I)=[CH:15][C:14]=1[CH3:21]>>[Br:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)=[CH:15][C:14]=1[CH3:21]
Reactant: COc1cc(B(O)O)ccn1
Reactant: Cc1cc(I)cc(C)c1Br
Product: COc1cc(-c2cc(C)c(Br)c(C)c2)ccn1

Procedure:
The title compound is prepared from 2-methoxy-pyridine-4-boronic acid and 2-bromo-5-iodo-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.24 min; Mass spectrum (ESI+): m/z=293/295 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:14]([NH:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21](C(=O)C(C)(C)C)[N:20]=[CH:19]4)[CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12C(NC3C=C4C(=CC=3)N(C(=O)C(C)(C)C)N=C4)C(CC1)CN2.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH:14]([NH:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)[CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)n1ncc2cc(NC3C4CCC3N(Cc3ccccc3)C4)ccc21
Agent: CC(C)(C)C(=O)n1ncc2cc(NC3C4CCC3NC4)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(CN2CC3CCC2C3Nc2ccc3[nH]ncc3c2)cc1
Reaction time: 18 h
Yield: 50 %

Procedure:
A solution of 1-(5-((1SR,4SR,7RS)-2-benzyl-2-azabicyclo[2.2.1]heptan-7-ylamino)-1H-indazol-1-yl)-2,2-dimethylpropan-1-one (the intermediate benzyl compound of Example 11, 175 mg, 0.44 mmol) in methanol (2.5 mL) was treated with potassium carbonate (72 mg, 0.52 mmol), and the mixture was stirred for 18 h. The mixture was partitioned between ethyl acetate and water, and the organic phase was dried over sodium sulfate and evaporated to a residue. Chromatography of the residue on silica gel afforded the title compound (70 mg, 50%). 1H NMR (CDCl3) δ 9.80 (br s, 1H), 7.88 (s, 1H), 7.39-7.21 (m, 6H), 6.92-6.85 (m, 2H), 3.80 (m, 1H), 3.63 (s, 1H), 3.16-3.12 (m, 2H), 2.40-2.37 (m, 1H), 2.04-1.96 (m, 2H), 1.85-1.76 (m, 2H), 1.60-1.40 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)=[C:12]([CH:16]=2)[C:13]([OH:15])=[O:14])[CH:5]=[N:6][CH:7]=1.[CH2:23](Cl)[CH2:24]Cl.C1C=CC2N(O)N=NC=2C=1.ClC1C=C(CN)C=CC=1OC.CN1CCOCC1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)=[C:12]([CH:16]=2)[C:13]([O:15][CH2:23][CH3:24])=[O:14])[CH:5]=[N:6][CH:7]=1
Reactant: ClCCCl
Reactant: Cc1cncc(-c2ccc(-c3cnccn3)c(C(=O)O)c2)c1
Agent: COc1ccc(CN)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cc(-c2cncc(C)c2)ccc1-c1cnccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of the carboxylic acid (3-4, 0.062 g, 0.186 mmol, 1 equiv), EDC (0.053 g, 0.279 mmol, 1.5 equiv), and HOBt (0.045 g, 0.297 mmol, 1.6 equiv) in DMF (1 mL), 1-(3-chloro-4-methoxyphenyl)methanamine (0.045 g, 0.260 mmol, 1.4 equiv) was added followed by N-methylmorpholine (0.102 mL, 0.929 mmol, 5 equiv) and the reaction was stirred overnight at room temperature The reaction mixture was filtered and put on a reverse phase preparative HPLC system running acetonitrile/water with a TFA buffer (5 to 75% CH3CN in water). The cleanest fractions were pooled, concentrated and freebased to afford the product (3-5) as a white solid. Data for H-1: HRMS [M+H] C25H21ClN4O2 calc'd 445.1426. found 445.1439.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=1.C1COCC1.CN1CCCC1=O.[CH2:31]([Mg]Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CCOCC>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: CCCCCC[Mg]Br
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCc1ccc(C(=O)OC)cc1
Reaction time: 0.08 h
Yield: 92.1 %

Procedure:
A flame-dried two-necked flask is charged under argon with 4-(trifluoromethylsulfonyloxy)benzoic acid methyl ester (760 mg, 2.66 mmol), Fe(acac)3 (47 mg, 0.13 mmol), THF (30 mL) and N-methylpyrrolidone (NMP, 1.7 mL). A solution of n-hexylmagnesium bromide (2M in Et2O, 1.7 mL, 3.4 mmol) is added via syringe to the resulting red solution, causing an immediate color change to dark brown and finally to violet. The resulting mixture is stirred for 5 min, the reaction is diluted with Et2O and is carefully quenched upon addition of aq. HCl (1M, ca. 10 mL). Work-up followed by flash chromatography of the crude product as described above provides 4-hexylbenzoic acid methyl ester as a colorless syrup (540 mg, 93%). The spectroscopic and analytical data are identical to those compiled above.
Reaction SMILES: [NH2:1][CH:2]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Cl:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[ClH:26]>C(O)C>[ClH:16].[ClH:26].[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][CH:2]([NH:1][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: ClCCCN1CCCCC1
Reactant: CC(C)CCC(N)C(O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C)CCC(NCCCN1CCCCC1)C(O)c1ccccc1
Yield: 33 %

Procedure:
A mixture of (1RS,2SR)-2-amino-5-methyl-1-phenylhexan-1-ol (415 mg, 2 mmol) and 1-(3-chloropropyl)piperidine (324 mg, 2 mmol) was melted at 70° C. in a nitrogen atmosphere. The mixture was heated at 110° to 120° C. for 3 hours. After being cooled, the reaction mixture was dissolved with heating in ethanol, followed by addition of concentrated hydrochloric acid (0.2 ml). After the mixture was cooled, precipitated crystals were collected by filtration and washed with ethanol. The crystals were recrystallized from ethanol to obtain 0.27 g of the title compound as white crystals (yield: 33%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[N:15]=[N:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:18][C:7]=2[N:6]=1>C(COC)OC>[C:19]1([C:17]2[N:16]=[N:15][C:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]([N:2]([CH3:3])[CH3:1])=[N:6][C:7]=3[CH:18]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1nc2cc(-c3ccccc3)nnc2c2ccccc12
Reactant: CNC
Solvent: COCCOC
Product: CN(C)c1nc2cc(-c3ccccc3)nnc2c2ccccc12
Yield: 53.3 %

Procedure:
Dimethylamine (6 g), 6-chloro-3-phenyl-pyridazino-[4,3-c]isoquinoline (5.83 g, 0.02 mol) and dimetoxyethane (120 ml) are heated at 120° C. for about 8 hours in a bomb. Then the reaction mixture is concentrated to dryness under reduced pressure, the residue is disaggregated with water (200 ml) and the solid recovered by filtration is dried, yielding 5.8 g of a crude product which is crystallized from acetone to give 3.2 g of the product of the title. M.p. 134°-136° C. A further crop of about 1,7 g is obtained by purifying the residue of the concentration of the mothers liquors by means of a silica gel column chromatography which uses chloroform as the eluent. Overall yield 4,9 g (81,5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[C:8]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:10]=1[NH:11]C(=O)C)=[O:4].O.S(=O)(=O)(O)O>CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[C:8]([C:15]([F:16])([F:17])[F:18])=[CH:9][C:10]=1[NH2:11])=[O:4]
Reactant: COC(=O)c1cc(-c2cccc(C#N)c2)c(C(F)(F)F)cc1NC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(-c2cccc(C#N)c2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A solution of 4-acetylamino-3′-cyano-6-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (1.2 g, 3.3 mmol) in MeOH (10 mL)/water (2 mL) was cooled to 0° C., and concentrated sulfuric acid (0.7 mL) was added dropwise. Upon completion of the addition, the mixture was heated to reflux for 2 h under nitrogen, and then allowed to cool to r.t. The mixture was poured on ice water and extracted three times with 25 mL each of EtOAc. The combined organic phases were washed twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo providing 4-amino-3′-cyano-6-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (700 mg, 2.19 mmol, 66%) as a yellow foam, ESI-MS: m/z 321 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[C:23](=O)[CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:27]([NH2:29])[CH3:28].C([BH3-])#N.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH:23]([NH:29][CH2:27][CH3:28])[CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCN
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C(C)=O)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNC(C)c1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Temperature: 60 °C

Procedure:
(2′-Acetyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.222 g, 0.61 mmol), ethylamine (2M in THF; 0.46 mL, 0.91 mmol), sodium cyanoborohydride (0.058 g, 0.91 mmol), and acetic acid (0.05 mL, 0.91 mmol) were combined in MeOH (2.2 mL) and heated to 60° C. overnight. Analytical LCMS showed starting material remained, so the reaction was stirred at 60° C. over the weekend. Once minimal starting material was seen by analytical LCMS, the mixture was cooled to room temperature and neutralized with saturated aqueous NaHCO3. The solution was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[CH3:36][C@@H:37]1[NH:42][CH2:41][CH2:40][N:39]([C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=2)[CH2:38]1>C(#N)CC.CS(C)=O>[CH3:36][C@@H:37]1[N:42]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][S:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:41][CH2:40][N:39]([C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=2)[CH2:38]1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Reactant: C[C@H]1CN(c2ccc(C#N)cc2)CCN1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCC#N
Product: C[C@H]1CN(c2ccc(C#N)cc2)CCN1Cc1cnc2c(c1)NC(=O)[C@@H]1CSCCN21
Temperature: 90 °C
Yield: 21.6 %

Procedure:
To a suspension of (R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (100 mg, 0.617 mmol) in propiononitrile (1.2 mL) was added (cyanomethyl)trimethylphosphonium iodide (180 mg, 0.74 mmol) and DIEA (0.323 ml, 1.80 mmol) and finally (S)-4-(3-methylpiperazin-1-yl)benzonitrile hydrochloride (0.147 g, 0.617 mmol). The vial was heated to 90° C. for 16 hours. The crude r×n was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic) to give the product as a tan solid (58 mg, 22% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (s, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.56 (d, J=9.1 Hz, 2H), 6.92-7.11 (m, 3H), 4.87 (dt, J=13.6, 2.7 Hz, 1H), 4.25 (dd, J=10.9, 3.0 Hz, 1H), 3.84 (d, J=13.4 Hz, 1H), 3.66 (d, J=10.6 Hz, 1H), 3.58 (d, J=12.6 Hz, 1H), 2.87-3.12 (m, 3H), 2.64-2.83 (m, 5H), 2.39-2.48 (m, 2H), 2.06-2.19 (m, 1H), 1.14 (d, J=6.1 Hz, 3H). [M+H] calc'd for C23H26N6OS, 434; found, 434.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[O:14][N:13]=1)=O)C>C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:10][OH:9])[CH:16]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)on1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(-c2cccc(Cl)c2)on1
Yield: 79.2 %

Procedure:
Lithium aluminum hydride (320 mg, 8.4 mmol) was slowly added to a solution of 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (2.0 g, 8.4) in THF (100 ml) at r.t After 1 h, the reaction mixture was quenched with water and then extracted with EA. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The resulting residue was then purified by column chromatography using 15-40% EA in hex. to afford the title compound (1.32 g, 75%,). 1H NMR: 7.78 (s, 1H), 7.68 (m, 1H), 7.43 (m, 2H), 6.63 (s, 1H), 4.84 (d, 2H), 2.23 (t, 1H).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([C:14]#[C:15][Si](C)(C)C)=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:20]1[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:26])[CH2:21]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[C:14]([C:12]1[S:13][C:9]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:20]3[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=4)=[O:26])[CH2:21]3)[CH2:4][CH2:3]2)=[CH:10][N:11]=1)#[CH:15]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: C[Si](C)(C)C#Cc1ncc(C2(O)CCC(=O)CC2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#Cc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(2-trimethylsilanylethynyl-thiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1 followed by TBAF work-up.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].[CH2:20]([O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)[CH3:21]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH2:20][CH3:21])[CH:28]=1)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cl
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1cccc(-c2c(C(=O)OC)c(C(C)C)nc3ccc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 20 step C from 4,6-dichloro-2-isopropyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 31 step A, 200 mg, 0.67 mmol) and 3-ethoxyphenylboronic acid (72 mg, 0.54 mmol). Sticky liquid (105 mg, 41%). LC-MS: 384 (M+H)+.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[Na].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]([CH2:18][CH2:19][CH3:20])=[C:13](Cl)[C:12]=2[CH:22]=1>C(O)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]([CH2:18][CH2:19][CH3:20])=[C:13]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:12]=2[CH:22]=1
Reactant: CCCc1c(Cl)c2cc(Br)ccc2oc1=O
Reactant: CCCCS
Agent: [Na]
Solvent: CCO
Product: CCCCSc1c(CCC)c(=O)oc2ccc(Br)cc12
Reaction time: 0.5 h

Procedure:
1-Butanethiol (0.39 ml) was added dropwise to a solution of sodium (0.08 g) in ethanol (3 ml). The solution was stirred for 1/2 hour and then added slowly to a refluxing solution of 6-bromo-4-chloro-3-propyl-2H-1-benzopyran-2-one (1 g) in ethanol (4 ml). The mixture was heated under reflux for 41/2 hours, filtered hot through kieselguhr and the filtrate allowed to cool. The precipitate was purified by silica gel column chromatography to give 6-bromo-4-butylthio-3-propyl-2H-1-benzopyran-2-one, m.p. 62-4° (compound 15)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([OH:28])[CH:15]=2)=[CH:9][C:8]=1[CH3:29])[CH3:2].[N:31]1([CH2:37][CH2:38]O)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH2:38][CH2:37][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:29])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccccc3)c2)cc1C
Reactant: OCCN1CCOCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCCN3CCOCC3)c2)cc1C
Reaction time: 16 h

Procedure:
[4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.48 mmol), 2-morpholin-4-yl-ethanol (0.22 g; 0.67 mmol) and tributylphosphine (0.24 mL; 0.96 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.24 g; 0.96 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After stirring for 16 h the reaction mixture was evaporated to dryness and purified by flash chromatography (ethyl acetate:heptane (1:3→1:9). Yield: 150 mg. HPLC-MS: m/z: 532.6 (M+H); Rt: 2.07 min.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[N:11]([C:14]3[C:15]([O:21][CH3:22])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=[C:35]([N:48]([CH3:50])[CH3:49])[N:34]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[CH:19]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:38]4[C:33]([O:32][CH3:31])=[N:34][C:35]([N:48]([CH3:49])[CH3:50])=[N:36][CH:37]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[C:15]([O:21][CH3:22])=[N:16][CH:17]=1
Reactant: COc1nc(N(C)C)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ncc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(C#N)cc1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1nc(N(C)C)ncc1-c1cc2c(n1C(C)C)C(c1ccc(C#N)cc1)N(c1cc(Cl)cnc1OC)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 4-[2-bromo-5-(5-chloro-2-methoxy-pyridin-3-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate BG) and 4-methoxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Intermediate W) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. ESI-MS: tR=1.20 min, [M+H]+ 558/560 (LC-MS 1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:9]([O:8][N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=[O:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [O-][n+]1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccccn1OCc1ccccc1
Temperature: 25 °C
Yield: 84 %

Procedure:
2-hydroxypyridine-1-oxide (0.50 g, 4.5 mmol) was reacted with benzyl bromide (0.64 mL, 5.4 mmol) in DMF (10 mL) in the presence of K2CO3 (1.8 g, 13.5 mmol) at 80° C. for 16 h. After cooling to room temperature, the solvent was removed by rotary evaporation. The crude product was redissolved in DCM and washed twice with water. The organic layer was then dried over MgSO4, filtered, and concentrated resulting in 7 as a white solid in 84% yield (0.78 g, 3.8 mmol) without the need for further purification. 1H NMR (400 MHz, CDCl3) δ=7.41-7.36 (m, 5H), 7.25 (td, J1=6.8 Hz, J2=2.0 Hz, 1H), 7.10 (dd, J1=7.2 Hz, J2=2.0 Hz, 1H), 6.68 (dd, J1=9.2 Hz, J2=1.6 Hz, 1H), 5.91 (td, J1=6.8 Hz, J2=1.6 Hz, 1H), 5.28 (s, 2H). 13C NMR (100 MHz, CDCl3) δ=159.2, 138.9, 136.9, 133.9, 130.3, 129.6, 128.9, 122.9, 104.7, 78.6. ESI-MS(+): m/z 202.19 [M+H]+, 224.29 [M+Na]+.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][C@H:6]([C@H:11]([OH:13])[CH3:12])[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C1COCC1.CO>[CH2:5]([C@H:6]([C@H:11]([OH:13])[CH3:12])[C:7]([OH:9])=[O:8])[C:4]#[CH:3]
Reactant: COC(=O)[C@H](CC#C[Si](C)(C)C)[C@@H](C)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#CC[C@@H](C(=O)O)[C@@H](C)O
Temperature: 23 °C
Reaction time: 20 h
Yield: 85.9 %

Procedure:
To a solution of methyl (2R,3R)-2-(3-trimethylsilyl-2-propyne-1-yl)-3-hydroxybutanoate (5.6 g, 24.56 mmol) in THF-methanol (3:1, 160 mL) is added 2 M aqueous sodium hydroxide solution (40 mL, 36.8 mmol). The solution is stirred at 23° C. for 20 h, then concentrated and extracted with hexanes (100 mL). The aqueous layer is acidified to pH=3 with 1 M HCl and is extracted with two 100 mL portions of ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(2-propyne-1-yl)-3-hydroxybutanoic acid as an oil (3.0 g, 86% yield).