Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])(CC)C.B(OC)(OC)OC.C(=O)([O-])[O-].[Na+].[Na+].Br[C:25]1[CH:26]=[C:27]([O:31][CH2:32][C@@H:33]2[CH2:37][CH2:36][CH2:35][N:34]2[CH3:38])[CH:28]=[N:29][CH:30]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:25]1[CH:26]=[C:27]([O:31][CH2:32][C@@H:33]2[CH2:37][CH2:36][CH2:35][N:34]2[CH3:38])[CH:28]=[N:29][CH:30]=1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: O
Product: CN1CCC[C@H]1COc1cncc(-c2ccco2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of furan (1.45 mL, 20.0 mmol) in THF (30.0 mL) was added sec-butyllithium (1.3M, 7.69 mL, 10.0 mmol) at -78° C. After half an hour at this temperature, trimethyl borate (2.27 mL, 20.0 mmol) was added. The reaction mixture was stirred at -78° C. for one hour and slowly warmed up to room temperature. Solvent was removed, and benzene (10.0 mL), sodium carbonate (2.0M, 5.0 mL), tetrakis(triphenylphosphine)palladium(0) (175 mg) and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (1.36 g, 5.0 mmol) were added. The reaction mixture was refluxed overnight, then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (1.27 g, 99%). MS (CI/NH3) m/z 259 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.70-2.22 (m, 4H), 2.28-2.40 (m, 1H), 2.51 (s, 3H), 2.66-2.75 (m, 1H), 3.10-3.18 (m, 1H), 3.97-4.11 (m, 2H), 6.51 (dd, J=4.8 Hz, J=3.6 Hz, 1H), 6.74 (d, J=4.9 Hz, 1H), 7.47 (dd, J=3.0 Hz, J=2.1 Hz, 1H), 7.53 (d, J=3.6 Hz, 1H), 8.22 (d, J=3.0 Hz, 1H), 8.54 (d, J=2.1 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.Br[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+:25].[Na+]>C(#N)C>[N:18]1[CH:19]=[CH:20][C:15]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:16][CH:17]=1.[Na+:25]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Brc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C([O-])c1ccc(-c2ccncc2)cc1
Temperature: 90 °C
Yield: 18 %

Procedure:
To a suspension of 4-carboxybenzeneboronic acid (0.660 g, 3.98 mmol) and 4-bromopyridine hydrochloride (0.770 g, 3.98 mmol) in dry acetonitrile (20 mL) was added 0.4 M aqueous sodium carbonate (20 mL) and the mixture was purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.240 g) was then added and the reaction mixture heated to 90° C. for 22 hours. The precipitated sodium salt was filtered, washed with acetonitrile and then dried in vacuo at 50° C. overnight to give the title compound (0.162 g, 18%) as a grey solid.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[CH3:19][C:20]([CH3:22])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[CH3:19][CH:20]([N:8]1[CH2:9][CH2:10][C:4]2=[CH:3][N:2]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[N:1]=[C:5]2[CH2:6][CH2:7]1)[CH3:22]
Reactant: CC(C)=O
Reactant: N#Cc1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCc2cn(-c3ccc(C#N)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(5,6,7,8-Tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzonitrile (may be prepared as described in Description 11) (assumed 0.148 mmol) was dissolved in dichloromethane (2 ml) and acetic acid (2 drops). Acetone (16 μl, 0.22 mmol) and sodium triacetoxyborohydride (47 mg, 0.22 mmol) were added and the mixture stirred at room temperature for 2 hours. Further aliquots of acetone (32 μl, 0.44 mmol) and sodium triacetoxyborohydride (47 mg, 0.22 mmol) were added and stirring continued for a further 70 hours. Methanol was added and the solution poured onto a 2 g SCX column which was eluted with methanol then 2M ammonia in methanol. The basic fractions were evaporated and the residue purified by flash chromatography eluting with 0-5% 2M ammonia in methanol/dichloromethane to afford the title compound (E34).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:28][C:27](=O)[CH:26]=[C:25]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N:36]3[CH:40]=[CH:39][N:38]=[N:37]3)[CH:31]=2)[O:24]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:28])[CH2:26][C:25](=[O:24])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnn3)c2)O1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methoxy-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J9) (306 mg. 1.0 mmol) and 2,2-dimethyl-6-(3-[1,2,3]triazol-1-yl-phenyl)-[1,3]dioxin-4-one (Example L9) (271 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow solid (394 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:16])[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[OH:16][C:6]1([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2nccs2)CC1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (1.0 g, 4.14 mmol) in 20 mL of THF/3 N HCl (1:1) was stirred for 1 h at 50° C. After cooling to room temperature, the mixture was treated with Na2CO3 to pH 8 and extracted with EtOAc three times. The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated to give 0.80 g (98%) of the title compound. MS (M+H)+=198.2.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-].Cl>C1COCC1>[F:33][C:30]([F:31])([F:32])[C:27]1[N:26]=[CH:25][C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:34])=[O:2])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 50 °C

Procedure:
A THF solution of (4-{4-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester was treated with 10% aqueous LiOH and heated to 50° C. overnight. Upon reaction completion, the mixture was acidified with concentrated HCl. The resulting precipitate was isolated by filtration to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ 1.08-1.19 (m, 1H) 1.14 (dd, J=12.63, 2.27 Hz, 1H) 1.44-1.56 (m, 1H) 1.50 (dd, J=12.51, 2.65 Hz, 1H) 1.75 (br. S., 1H) 1.84 (d, J=10.61 Hz, 4H) 2.14 (d, J=6.82 Hz, 2H) 2.54 (m, 1H) 7.33 (d, J=8:34 Hz, 2H) 7.65 (d, J=2.53 Hz, 1H) 7.68-7.74 (m, 1H) 7.70 (d, J=8.34 Hz, 1H) 7.89 (d, J=8.59 Hz, 1H) 7.95 (d, J=8.59 Hz, 2H) 8.46 (d, J=2.78 Hz, 1H) 8.54 (d, J=2.53 Hz, 1H) 9.20 (s, 1H); (M+H)+456.3. Alternatively, the methyl ester can be dissolved in a mixture of THF and water, and treated with aqueous sodium hydroxide (4 equiv). The mixture can then be stirred at 50 degrees for 12 hours, at which point the THF is removed under reduced pressure to yield an opaque, white slurry, which affords the title compound as the corresponding sodium salt upon filtration. 1H NMR (DMSO-d6, 500 MHz) δ 10.05 (s, 1H), 8.59 (d, 1H, J=2.8 Hz), 8.54 (s, 1H), 7.92 (d, 2H, J=8.2 Hz), 7.86 (d, 1H, J=8.8 Hz), 7.75 (dd, 1H, J=8.7.2.7 Hz), 7.69 (s, 2H), 7.27 (d, 2H, J=8.5 Hz), 2.45 (m, 1H), 1.84 (m, 4H), 1.67-1.80 (m, 3H), 1.41 (m, 2H), 1.02 (m, 2H); MS m/z 456 (M-Na+2H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:20])([F:19])[CH:4]([O:11][C:12]1[CH:18]=[CH:17][C:15](N)=[CH:14][CH:13]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N([O-])=O.[Na+].[I-:25].[K+]>O>[F:2][C:3]([F:20])([F:19])[CH:4]([O:11][C:12]1[CH:18]=[CH:17][C:15]([I:25])=[CH:14][CH:13]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [I-]
Reactant: CCCCCCC(Oc1ccc(N)cc1)C(F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CCCCCCC(Oc1ccc(I)cc1)C(F)(F)F

Procedure:
To 200 ml of water containing 25 g of 36% hydrochloric acid, were added 6.7 g of oa p-(1-trifluoromethyl-heptyloxy)-aniline, and cooled to a temperature below 5° C., followed by adding thereto dropwise 1.7 g of sodium nitrite dissolved in 10 ml of water. After the addition was over, stirring was continued for an hour, and then 20 g of potassium iodide dissolved in 20 ml of water were added thereto, followed by putting back the temperature gradually to room temperature and stirring was continued until no evolution of nitrogen was observed. After completion of the reaction, the product was extracted with hexane. The hexane phase was washed subsequently with water, an aqueous solution of sodium hydrogen sulfite and then water, followed by distilling off the hexane to obtain 77 g of oily oa p-(1-trifluoromethylheptyloxy)iodobenzene.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].[Na+].CS(O[CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>ClCCl.CO>[C:33]([O:32][C:30](=[O:31])[NH:29][C@H:26]1[CH2:25][CH2:24][C@H:23]([CH2:22][CH2:21][N:7]2[C:6]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=3[O:4][CH2:3][C:2]2=[O:1])[CH2:28][CH2:27]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1
Reactant: N#Cc1ccc2c(c1)NC(=O)CO2
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2C(=O)COc3ccc(C#N)cc32)CC1

Procedure:
3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60) (350 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{trans-4-[(tert butoxycarbonyl)amino]cyclohexyl}ethyl methanesulfonate (Intermediate 76) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) afforded the product as a solid (50%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]1[N:32]=[C:31]2[S:33][C:34]([NH2:36])=[N:35][C:30]2=[CH:29][CH:28]=1)[CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([NH:36][C:34]3[S:33][C:31]4[C:30]([N:35]=3)=[CH:29][CH:28]=[C:27]([O:26][CH2:24][CH3:25])[N:32]=4)=[O:16])=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CCOc1ccc2nc(N)sc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOc1ccc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2n1
Yield: 37.1 %

Procedure:
The compound of example A81 was obtained by similar method described in example A75 using (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.25 g, 0.73 mmol), 5-ethoxy-thiazolo[5,4-b]pyridin-2-ylamine (0.157 g, 0.80 mmol), HOBt (0.148 g, 1.10 mmol), and EDCI (0.210 g, 1.10 mmol), N-methyl morpholine (0.22, 2.20 mmol) in DMF (5 mL) to provide the title compound (0.140 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].C1[CH2:12][O:11]CC1.[Li].CCCCCCC.C1C[O:24]CC1.C(C1C=CC=CC=1)C>>[C:6]([C:2]1[S:1][C:5]([C:12]([OH:11])=[O:24])=[CH:4][CH:3]=1)#[N:7]
Reactant: C1CCOC1
Reactant: N#Cc1cccs1
Agent: [Li]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: N#Cc1ccc(C(=O)O)s1
Reaction time: 0.17 h
Yield: 22 %

Procedure:
In a 500 mL receiving flask are placed thiophene-2-carbonitrile (5.0 mL, 53.8 mmol) and THF (270 mL) and cooled in an acetone/solid CO2 bath. Lithium disopropylaoide (40.3 mL, 80.7 mmol, 2.0M solution in heptane/THF/ethylbenzene) is added in a slow stream via syringe. The solution is stirred for 10 min then quenched with an excess of dry ice. The reaction mixture is warned in a water bath and the THF removed in vacuo. The slurry is taken up in 1N NaOH and extracted with ether (3×). The aqueous layer is then acidified to pH<6 with conc. HCl, whereupon a brown precipitate forms. This precipitate is filtered off and to the resulting eluent is added 1N HCl which results in precipitation of the product. The product is collected by filtration then triturated with CH2Cl2Purification over silica gel (1:2.5:100 formic acid:MeOH:CH2Cl2) provides the product as a solid (1.79 g, 22%). 1H NMR (400 MHz, CDCl3) δ 14.10, 8.00, 7.80.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]3[S:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2I)=[CH:4][CH:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]3[S:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=c1c(I)c(/C=C/c2ccc(Cl)cc2)nc2sccn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1c(-c2ccccc2)c(/C=C/c2ccc(Cl)cc2)nc2sccn12
Temperature: 25 °C
Yield: 5932.6 %

Procedure:
To a stirred solution of Intermediate 1 (100 mg, 0.231 mmol) in toluene (20 ml) and ethanol (10 ml) was added phenylboronic acid (33 mg, 0.276 mmol) and Pd[(C6H5)3P]4 (26 mg, 0.023 mmol) in) followed by sodium carbonate (Na2CO3) (48 mg, 0.461 mmol) in water (10 ml). The reaction mixture was heated to reflux for 12 h under nitrogen. The reaction mixture was allowed to cool to room temperature. The residue obtained after evaporation was partitioned between ethyl acetate (500 ml) and water (100 ml). The organic layer was washed with brine (100 ml), dried (Na2SO4) and concentrated to afford a crude product which was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to give 5 g of the product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 6.85 (d, J=4.8 Hz, 1H), 7.53 (d, J=7.8 Hz, 3H), 7.77 (m, 4H), 7.88 (d, J=7.8 Hz, 1H), 8.02 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 265.31 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.FC1C=C([C:41]2[CH:46]=[CH:45][C:44]([C:47]([C@@H:49]3[CH2:53][CH2:52][CH2:51][C@H:50]3[C:54]([OH:56])=[O:55])=[O:48])=[CH:43][CH:42]=2)C=CC=1NC1SC2C=C(OC(F)(F)F)C=CC=2N=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([C:41]4[CH:42]=[CH:43][C:44]([C:47]([C@@H:49]5[CH2:53][CH2:52][CH2:51][C@H:50]5[C:54]([OH:56])=[O:55])=[O:48])=[CH:45][CH:46]=4)=[CH:3][CH:4]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Reactant: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC(F)(F)F)cc4s3)c(F)c2)cc1
Product: Cc1ccc2oc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCC[C@H]5C(=O)O)cc4)cc3)nc2c1
Yield: 17 %

Procedure:
This compound was prepared from N-(4-bromophenyl)-N-(5-methyl-1,3-benzoxazol-2-yl)amine (0.50 g, 1.65 mmol), methyl (1R,2R)-2-(4-bromobenzoyl) cyclopentanecarboxylate (0.57 g, 1.83 mmol, 94.5% ee) in a similar manner to the method described for (1R,2R)-2-({3′-fluoro-4′-[(6-trifluoromethoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid. Yield: 17%. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1 H), 8.05 (d, 2 H), 7.75–7.90 (m, 6 H), 7.35 (d, 1 H), 7.25 (s, 1 H), 6.95 (d, 1 H), 4.05 (q, 1 H), 3.20 (s, 1 H), 2.40 (s, 3 H), 2.15 (m, 1 H), 2.00 (m, 1 H), 1.55–1.80 (m, 4 H). LC-MS m/z 441.3 (MH+), ret. time 3.48 min.
Reaction SMILES: O[CH:2]1[C:6]2[S:7][CH2:8][CH2:9][S:10][C:5]=2[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[N:20]1([C:26]([CH:28]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:3]2[C:4](=[O:11])[C:5]3[S:10][CH2:9][CH2:8][S:7][C:6]=3[CH:2]2[CH2:28][C:26]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:27])=[CH:13][CH:14]=1
Reactant: COc1ccc(N2C(=O)C3=C(SCCS3)C2O)cc1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)C3=C(SCCS3)C2CC(=O)N2CCCCC2)cc1
Yield: 71.5 %

Procedure:
2,3,6,7-Tetrahydro-7-hydroxy-6-(4-methoxyphenyl)-5H-1,4-dithiino[2,3-C]pyrrol-5-one (1.48 g) and piperidinocarbonylmethylenetriphenylphosphorane (3.4 g) were dissolved in toluene (30 ml) under heating, and the solution was refluxed for 12 hours. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography (methylene chloride:ethyl acetate=10:1). The thus-obtained crude crystals were recrystallized from ethyl acetate-ether to give crystals (1.45 g) of 2,3,6,7-tetrahydro-6-(4-methoxyphenyl)-7-piperidinocarbonylmethyl-5H-1,4-dithiino[2,3-C]pyrrol-5-one, melting at 163°-164° C. and 183°-185° C. (double melting).
Reaction SMILES: C1([Li])C=CC=CC=1.C1C=CC=CC=1.CCOCC.[CH3:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[S:31]>O.C1C=CC=CC=1>[CH3:19][O:20][CH:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:30]([N:29]([CH3:33])[CH3:28])=[S:31]
Reactant: CN(C)C(=S)Cl
Reactant: COCc1ccccn1
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: COC(C(=S)N(C)C)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.10 mole of phenyl lithium in 100 ml. of benzene/ether at 0°C. is added dropwise 10.6 g. (0.084 mole) of 2-(methoxymethyl)pyridine dissolved in 75 ml. of benzene. To this mixture is added dropwise 10.0 g. (0.081 mole) of N,N-dimethylthiocarbamoyl chloride in 100 ml. of benzene. The resulting mixture is stirred at room temperature overnight, then poured into 100 ml. of water and acidified. The organic phase is extracted once with dilute aqueous acid. The combined aqueous phases are extracted twice with ether, then made basic to about pH 10 and extracted three times with chloroform. The combined chloroform extracts are dried over magnesium sulfate and the solvent is removed by evaporation. The residue is chromatographed, then distilled in vacuo to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [C:1]1(=[S:6])[S:5][CH2:4][CH2:3][S:2]1.F[B-](F)(F)F.[H+].[S:13]([CH2:18][CH:19]1[CH2:21][S:20]1)[CH2:14][CH:15]1[CH2:17][S:16]1>ClCCl>[S:13]([CH2:14][CH:15]1[CH2:17][S:16][C:1]2([S:5][CH2:4][CH2:3][S:2]2)[S:6]1)[CH2:18][CH:19]1[CH2:21][S:20][C:1]2([S:5][CH2:4][CH2:3][S:2]2)[S:6]1
Reactant: C(SCC1CS1)C1CS1
Reactant: S=C1SCCS1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: C1CSC2(S1)SCC(CSCC1CSC3(SCCS3)S1)S2
Temperature: -5 °C
Yield: 4.7 %

Procedure:
A mixture of ethylene trithiocarbonate (5.04 g, 0.037 moles) and tetrafluoroboric acid (1.0 ml) in anhydrous dichloromethane (50.0 ml) cooled to −5° C. and stirred under nitrogen, was treated dropwise with a solution of 2,2′-[thiobis(methylene)]bis-thiirane (3.34 g, 0.019 moles) in anhydrous dichloromethane (30.0 ml). The resulting mire was allowed to warm to room temperature and quenched with 5% sodium bicarbonate solution (50.0 ml). The separation of the organic layer followed by water washing, drying and evaporation afford a wet yellow solid. Purification of which by short-path chromatography (20% ethyl acetate/hexane over silica) afforded 2,2′-[thiobis(methylene)]bis-1,4,6,9-tetrathiaspiro[4.4]nonane (4.7% yield).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:15])[C:6]2=[O:14].[C:16]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+]>[CH3:15][CH:5]1[CH2:4][C:3]2[C:7](=[C:8]([CH3:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:2]=2[C:23]2[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)[C:6]1=[O:14]
Reactant: Cc1c(C)c(Br)c2c(c1C)C(=O)C(C)C2
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCCO
Product: Cc1c(C)c2c(c(-c3ccc(C(C)(C)C)cc3)c1C)CC(C)C2=O
Temperature: 80 °C
Yield: 104.8 %

Procedure:
17.5 g (65.5 mmol) of 4-bromo-2,5,6,7-tetramethyl-1-indanone (3c), 14 g (78.6 mmol) of 4-tert-butylphenylboronic acid, 17 g (160 mmol) of sodium carbonate, 200 ml of ethylene glycol and 35 ml of water were placed under a protective gas atmosphere in a reaction vessel and heated to 80° C. While stirring vigorously, a freshly prepared catalyst solution of 37 mg (0.16 mmol) of palladium acetate, 0.33 ml (0.6 mmol) of an aqueous TPPTS solution (0.6 molar) in 25 ml of water was added to the reaction components and the reaction mixture was refluxed for 3 hours until the reaction was complete. After cooling to room temperature, the ethylene glycol phase was extracted three times with a total of 900 ml of toluene. The combined toluene phases were washed twice with a total of 250 ml of sodium chloride solution and dried over 150 g of sodium sulfate. Removal of the solvent, drying of the residue and subsequent distillation in an oil pump vacuum gave 22 g of (3d).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][O:17][C:18]4[C:27]5[C:22](=[CH:23][C:24]([C:28]#[N:29])=[CH:25][CH:26]=5)[N:21]=[CH:20][CH:19]=4)=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:31]>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][O:17][C:18]4[C:27]5[C:22](=[CH:23][C:24]([C:28]([NH2:29])=[O:31])=[CH:25][CH:26]=5)[N:21]=[CH:20][CH:19]=4)=[N:14][N:15]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc2c(OCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1ccc2c(OCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1
Temperature: 90 °C

Procedure:
A mixture of 4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline-7-carbonitrile (0.300 g, 0.793 mmol) and SULFURIC ACID (3.00 ml, 56.3 mmol) was heated at 90° C. for 30 min. Quenched onto ice and sodium bicarbonate. Isolated solid by filtration and purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate. Removed volatiles. Product crashed out and was isolated by filtration. MS m/z=397.1 [M+1]+. Calc'd for C22H16N6O2: 396.4.