Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.[Cl:40][C:41]1[CH:42]=[C:43]([C@H:48]([CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][CH:57]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[S@:66]([CH3:68])=[O:67])[CH2:56][CH2:55]2)[CH2:49][NH:50][CH3:51])[CH:44]=[CH:45][C:46]=1[Cl:47]>C(Cl)Cl.C(O)(=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([C@H:48]([CH2:52][CH2:53][N:54]2[CH2:55][CH2:56][CH:57]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[S@:66]([CH3:68])=[O:67])[CH2:58][CH2:59]2)[CH2:49][N:50]([CH3:51])[C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:15])[CH:44]=[CH:45][C:46]=1[Cl:47]
Reactant: CNC[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(C(=O)O)c2ccccc2c1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Reaction time: 0.17 h
Yield: 79 %

Procedure:
A stirred solution containing 3-cyano-1-naphthoic acid (0.1 g, 0.5 mmol), N,N-diisopropylethylamine (0.16 g, 1.26 mmol), and dry DCM (2.5 mL) was treated with a solution of tetramethylfluoroformamidinium hexafluorophosphate (TFFH) (0.16 g, 0.60 mmol) in dry DCM (1.0 mL). After 10 min, a solution containing N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine (0.22 g, 0.5 mmol) and dry DCM (0.6 mL) was added, and the solution stirred for 60 h, then diluted with DCM and 1M aqueous acetic acid. After mixing, the layers were allowed to separate, the organic layer was removed, and the aqueous layer was extracted with additional DCM (2×). The organic extracts were combined, washed (saturated NaHCO3), dried (Na2SO4), filtered, and the DCM evaporated in vacuo. The residue was purified by chromatography (0-10% CH3OH in DCM) to give the title compound (0.25 g) as a white, foamy residue. MS: m/z 632 (M+H). The product was converted to the citrate salt and isolated by filtration from Et2O to afford the N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methyl-3-cyano-1-naphthamide citrate hydrate (1:1:0.75) (290 mg) as a white solid. MS: m/z 632 (M+H). Analysis for C35H35Cl2N3O2S C6H8O7.0.75 H2O: calculated: C, 58.74; H, 5.35; N, 5.01. found: C, 58.74; H, 5.24; N, 5.02. The title compound could also be converted, in similar maimer, to the citrate hydrate (1.0:1.0:1.0).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:13]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C(=O)OC)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 35.5 g of methyl 4-hydroxybenzoate and 50.2 g of methyl 2-chloro-5-nitrobenzoate dissolved in 500 ml of N,N-dimethylformamide (DMF), was added 48.4 g of anhydrous potassium carbonate, and the mixture was stirred for 3 hours at 80° C. Water was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained crude product was recrystallized from methanol to yield 67.7 g of methyl 2-(4-methoxycarbonylphenoxy)-5-nitrobenzoate (melting point: 103-105° C.) (Reaction Scheme (24) described below).
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:13](=[O:16])[N:12]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:11]4[NH:10][C:9]=3[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:1]1([N:7]2[CH2:15][C:14]3[C:13](=[O:16])[N:12]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:11]4[N:10]([CH3:27])[C:9]=3[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2[nH]c3cc(-c4ccccc4)nn3c(=O)c2CN1C1CCCCC1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n3nc(-c4ccccc4)cc13)CN(C1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a suspension of 6-cyclohexyl-4,7-dihydro-2-phenyl-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8(6H)dione (2.00 g, 5.75 mmole) and potassium carbonate (795 mg, 5.75 mmole) in dry dimethylformamide (DMF, 30 mL) was added methyl idodide (0.72 mL, 12 mmole). The flask was stoppered tightly and stirred at room temperature for 24 hours. The mixture was diluted with water (150 mL), stirred for 10 minutes and suction filtered. The collected solid was washed once with water and once with 95% ethanol. Drying under vacuum left 1.91 g of white powdery solid. Crystallization from 95% ethanol (500 mL) afforded the titled product as fine white needles (1.73 g, 83%, m.p. 276°-279°). 1H NMR (CDCl3, δ) 8.05 (m, 2H, 2-phenyl H), 7.45 (m, 3H, 3,4-phenyl H), 6.45 (s, 1H, pyrazole-H), 4.33 (s, 2H, lactam CH2), 4.16 (s, 3H, CH3), 4.15 (m, 1H, cyclohexyl CH), 1.1-2.0 (m, 10H, cyclohexyl CH2); IR (mull, cm-1) 1693, 1627, 1590, 1574; UV (ethanol) λmax (ε) 206 (27,300), 226(23,920), 268(33,740), 285sh(15,570), 295(10,940), 338(6,090); MS m/e (rel. intens.) 363 (M+1, 25) 362 (M+, 100), 319(35), 280(66); Analysis calc'd for C21H22N4O2 =C, 65,59; H, 6.12 N, 15.46; Found=C, 69.64; H, 6.21; N, 15.43. TLC (silica, ethylacetate) Rf 0.80.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.S(=O)(=O)(O)O.[Cl:11][C:12]1[N:20]=[CH:19][C:18]([S:21](=[O:32])(=[O:31])[NH:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)=[CH:17][C:13]=1[C:14]([NH2:16])=O>>[Cl:11][C:12]1[N:20]=[CH:19][C:18]([S:21]([NH:22][C:23]2[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=2)(=[O:32])=[O:31])=[CH:17][C:13]=1[C:14]#[N:16]
Reactant: NC(=O)c1cc(S(=O)(=O)Nc2cc(F)cc(F)c2)cnc1Cl
Agent: O=S(=O)(O)O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(S(=O)(=O)Nc2cc(F)cc(F)c2)cnc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
3.4 ml (36.2 mmol) of phosphoryl chloride and a drop of concentrated sulfuric acid are added to 0.315 g (0.906 mmol) of 2-chloro-5-(N-(3,5-difluorophenyl) sulfamoyl)nicotinamide. The reaction mixture is stirred for 2 hours at 90° C. and then added drop by drop to ice. The brown solid is filtered, rinsed with water and then dried under vacuum. 0.217 g of 6-chloro-5-cyano-N-(3,5-difluorophenyl)pyridine-3-sulfonamide is obtained in the form of a light brown solid (yield=72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@@H:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1c(Nc2ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc2c1CC[C@H](N1CCOCC1)CC2

Procedure:
The title compound was prepared from 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 179. Product was isolated as tan solid (36 mg, 33%). LCMS (m/e) 539 (M+H), 1H NMR (CDCl3, 400 MHz) δ 8.02 (d, 1H, J=8.3 Hz), 7.81 (s, 1H), 6.88 (d, 1H, J=8.3 Hz), 6.31 (m, 1H), 6.25 (m, 1H), 5.85 (s, 1H), 5.55 (s, 1H), 4.19 (t, 1H, J=7.3 Hz), 3.01 (s, 4H), 3.72 (s, 3H), 3.49 (m, 2H), 3.07-3.15 (m, 4H), 2.91 (m, 2H), 2.76 (m, 1H), 2.38-2.47 (m, 3H), 2.18 (d, 1H, J=9.6 Hz), 1.61 (d, 1H, J=9.3 Hz), 1.48 (m, 2H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)([Cl:12])=O.CP(=O)(C)CCl>ClC1C=CC=CC=1>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(Cl)Cl
Agent: CP(C)(=O)CCl
Solvent: Clc1ccccc1
Product: O=C(Cl)c1ccccc1

Procedure:
In the device described for example 1, 122 g of benzoic acid are reacted with phosgene after having added 0.1 g of dimethyl-chloromethyl-phosphine oxide. At the beginning the operation is carried out at a temperature just above the melting point of the benzoic acid (122°C), but while the reaction is continuing the temperature is brought down to approx. 100°C. So as to avoid sublimation, it is useful to add to the reation mixture approx. 20 g of chlorobenzene. The phosgene absorption is terminated after abt. 2 hours. After a postreaction of another hour a more then 99% crude yield of a slightly colored benzoyl chloride is obtained which, for further purification, may be submitted to further distillation under reduced pressure. The net yield is abt. 136 g corresponding to 97% theoretical yield.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]12[CH2:12][N:9]([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=O.Br.O=C(C12CN(CC1)CC2)C=O.C(=O)(O)O.[NH2:29][NH:30][C:31]([NH2:33])=[NH:32].Cl.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:33][C:31]1[N:30]=[N:29][CH:3]=[C:4]([C:6]23[CH2:12][N:9]([CH2:10][CH2:11]2)[CH2:8][CH2:7]3)[N:32]=1
Reactant: O=C(CBr)C12CCN(CC1)C2
Reactant: N=C(N)NN
Agent: Br
Agent: Cl
Agent: O=C(O)O
Solvent: O
Product: Nc1nncc(C23CCN(CC2)C3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
4-(α-bromoacetyl) -1 -azabicyclo[2.2.1 ]heptane hydrobromide (EP-0366304, Description 19) (0.5 g, 1.67 mmol) was converted into 2-oxo-2- (1-azabicyclo [2.2.1]hept-4-yl)ethanal hydrobromide as described in Example 3. The crude aldehyde was immediately treated with a suspension of aminoguanidine bicarbonate (0.25 g, 1.84 mmol) in water (10 ml) and the solution was acidified to pH6 with 5M hydrochloric acid. After stirring overnight at room temperature the reaction mixture was saturated with potassium carbonate then extracted into chloroform (4×20 ml). The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. The residue was crystallised from isopropanolpentane to afford the title compound (E4) as a brown solid (0.14 g, 43%) . This was converted into the oxalate salt m.p. 178° C. (dec) (from methanol-ether).
Reaction SMILES: C(N)C1C=CC=CC=1.C(O[C:17]([N:19](C)[C@H:20]([C:24]([NH:26][C@H:27]([C:31]([NH:33][C@H:34]([P:36](=[O:39])([OH:38])[OH:37])[CH3:35])=[O:32])[CH2:28][CH2:29][CH3:30])=[O:25])[CH2:21][CH2:22][CH3:23])=O)C1C=CC=CC=1>>[CH3:17][NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:31]([NH:33][C@H:34]([P:36](=[O:37])([OH:39])[OH:38])[CH3:35])=[O:32])[CH2:28][CH2:29][CH3:30])=[O:25])[CH2:21][CH2:22][CH3:23]
Reactant: CCC[C@H](NC(=O)[C@H](CCC)N(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CCC[C@H](NC)C(=O)N[C@@H](CCC)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 7(A)(ii) from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-N-methyl-L-norvalyl-L-norvalyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(N-methyl-L-norvalyl-L-norvalylamino)-ethylphosphonic acid of melting point 294°-295° C. (decomposition); [α]D20 =-52.6°; [α]36520 =-190° (c=0.5%, freshly prepared in 0.1-N sodium hydroxide).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:42])[CH:14]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[N:15]2[C:19]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=3[N:17]=[C:16]2[C:26]2[C:27]([O:34][CH3:35])=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(#N)C.O>[CH:36]1([CH:14]([N:15]2[C:19]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=3[N:17]=[C:16]2[C:26]2[C:27]([O:34][CH3:35])=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:13]([NH:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CCOC(=O)C1CCC(NC(=O)C(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)N[C@H]2CC[C@H](C(=O)O)CC2)C2CCCCC2)c(OC)n1
Temperature: 100 °C

Procedure:
To a solution of 4-{2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetylamino}-cyclohexanecarboxylic acid ethyl ester (350 mg, 0.60 mmol, 1.0 equiv) in a mixture of acetonitrile/water (2:1, 5 mL) was added a solution of aqueous 6 M NaOH (0.3 mL, 1.80 mmol, 3.0 equiv) and the reaction mixture heated by microwave irradiation to 100° C. for 30 min. The solvent was removed under reduced pressure and the crude reaction mixture adjusted to pH=3 by addition of a solution of 1 M HCl and the aqueous layer extracted with a mixture of dichloromethane/isopropanol (4:1). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified over a short silica column eluting with a gradient of dichloromethane/methanol yielding 0.31 g (93%) of the title compound. MS (ES+): 558 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH3:9])[N:5]=[C:4]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[N:3]=1.[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CC#N.C(O)(C(F)(F)F)=O>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][N:8]([CH3:9])[C:6]2[N:7]=[C:2]([N:36]3[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]3)[N:3]=[C:4]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: CN(CCCc1ccc(Cl)cc1)c1nc(Cl)nc(NCCc2ccc(O)cc2)n1
Reactant: OCCN1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CN(CCCc1ccc(Cl)cc1)c1nc(NCCc2ccc(O)cc2)nc(N2CCN(CCO)CC2)n1
Yield: 91 %

Procedure:
The title compound was prepared in 91% yield via the procedure outlined for Example 14 using 4-[2-({4-chloro-6-[[3-(4-chlorophenyl)propyl](methyl)amino]-1,3,5-triazin-2-yl}amino)ethyl]phenol and 1-(2-hydoxyethyl)piperazine to give a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.23 (d, 2H, J=8.0), 7.10 (d, 2H, J=8.0), 7.09 (d, 2H, J=8.0), 6.67 (d, 2H, J=8.0), 4.88(s, br, 1H), 3.80-3.55 (m, 9H), 3.05 (s, br, 3H), 2.77 (t, 2H, J=6.6), 2.57-2.48 (m, 8H), 1.86 (s,br, 2H); low-resolution MS (ES+) m/e 526 (MH+); RP-HPLC (Capcell Pak C-18 25 cm×4.6 mm; 0-95% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=11.20 min, 99% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([O:12][C@H:13]3[C@H:17]4[O:18][CH2:19][C@@H:20]([OH:21])[C@H:16]4[O:15][CH2:14]3)[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:5]2=[N:6][C:7]=1I.[B:30]1([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([O:12][C@H:13]3[C@H:17]4[O:18][CH2:19][C@@H:20]([OH:21])[C@H:16]4[O:15][CH2:14]3)[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:5]2=[N:6][C:7]=1[C:42]1[CH:43]=[CH:44][C:39]([B:30]2[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]2)=[CH:40][CH:41]=1
Reactant: CC1(C)OB(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(I)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Temperature: 70 °C

Procedure:
A mixture of (3R,3aR,6R,6aR)-6-(6-chloro-5-iodo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol (2.00 g), 1,4-benzenediboronic acid dipinacol ester (2.38 g), Na2CO3 (2 M aqueous solution, 5.42 mL), and 1,4-dioxane (15 mL) is purged for 5 minutes with argon. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)-CH2Cl2-complex (PdCl2(dppf)×CH2Cl2) (206 mg) is added and the mixture is stirred over night at 70° C. The reaction mixture is partitioned between water and ethyl acetate. The organic phase is washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 99:1→97:3) to give the title compound. LC (method 1): tR=1.27 min; Mass spectrum (ESI+): m/z=630 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[CH:17]1([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrC1CCCC1
Reactant: OCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCC1CCN(C2CCCC2)CC1

Procedure:
To a solution of 3-(piperidin-4-yl)-1-propanol (4.7 g, 33 mmol) in acetonitril (100 mL) was added potassium carbonate (25 g, 180 mmol) and cyclopentylbromide (24.5 g, 164 mmol) and the reaction mixture was stirred at reflux temperature overnight. The mixture was allowed to cool, then filtered and the solvent evaporated. The residue was dissolved in ethyl acetate (150 mL) and the organic mixture was dried (MgSO4). The mixture was filtered and the solvent was evaporated. The residue was treated with diethyl ether (100 mL) and the organic phase was decanted and evaporated. This afforded 5.8 g of 3-(1-cyclopentylpiperidin-4-yl)-1-propanol contaminated with probably cyclopentylbromide. 1H NMR (400 MHz, CDCl3) δ 1.2-2.0 (m, 17H), 2.05-2.15 (m, 1H), 2.45 (pent., 1H), 2.95-3.05 (m, 2H), 3.55-3.65 (m, 2H), 4.28-4.36 (m, 2H).
Reaction SMILES: [N:1]1([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26]C)=[O:25])[CH:14]=3)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[N:1]1([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc2nc(N3CCCCCC3)c(-c3ccccc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2nc(N3CCCCCC3)c(-c3ccccc3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(azepan-1-yl)-3-phenylquinoxaline-6-carboxylate (136 mg, 0.37 mmol, 1.00 equiv, 98%) in methanol (10 mL), sodium hydroxide (75.3 mg, 1.88 mmol, 5.00 equiv). The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 63.1 mg (47%) of 2-(azepan-1-yl)-3-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([OH:19])=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([Cl:22])=[O:19])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(O)[C@@]12C[C@@H](c3ccccc31)c1ccc(Cl)cc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)[C@@]12C[C@@H](c3ccccc31)c1ccc(Cl)cc12
Yield: 100.3 %

Procedure:
To a stirred suspension of (9S, 10S)-2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (1.0 g, 3.62 mmol), prepared as described in Example 109a, in toluene (10 mL) was added thionyl chloride (0.29 mL, 3.98 mmol). After refluxing for 1.5 h, the mixture was concentrated to give the title compound as a light yellow solid (1.05 g, quant.); MS(CI): 289 (M+H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([F:20])[C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[CH:7][N:6]=1.[CH2:22]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:16]([C:15]1[CH:18]=[CH:19][C:12]([O:11][C:8]2[CH:7]=[N:6][C:5]([C:4]([F:21])([F:20])[F:3])=[N:10][CH:9]=2)=[CH:13][CH:14]=1)=[CH2:22]
Reactant: O=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a suspension of NaH (373 mg, 9.32 mmol) and methyltriphenylphosphonium bromide (799 mg, 2.237 mmol) in THF (5 mL), which was stirred at 0° C. for 1 h was added 4-{[2-(trifluoromethyl)-5-pyrimidinyl]oxy}benzaldehyde (500 mg, 1.864 mmol). The mixture was stirred at room temperature for 2 h, and then quenched with NH4Cl sat. solution. The organic layer was separated and the aqueous phase was extracted with DCM. The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification via flash chromatography then afforded the title compound (300 mg, 1.127 mmol, 60.4% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11]C)=[O:10])=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:5]=[C:4]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:9]([OH:11])=[O:10])=[C:6]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:5]=[C:4]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[N:3]=1
Reactant: COC(=O)C(Cc1ccccc1)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc(N3CCCCC3)nc(C)c2C(Cc2ccccc2)C(=O)O)cc1
Yield: 84.2 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)-3-phenylpropanoate (0.087 g; 0.203 mmol), sodium hydroxide 10N (0.203 mL; 2.02 mmol) in methanol (2 mL) to afford 0.071 g (80%) of the title compound as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]([F:21])([F:20])[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:14][CH2:13]2.Br[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:25]([CH3:38])[CH:24]=1>C1(C)C=CC=CC=1>[CH3:29][C:27]1[CH:28]=[C:23]([N:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([F:8])([F:20])[F:21])[CH:11]=3)[CH2:16]2)[CH:24]=[C:25]([CH3:38])[C:26]=1[NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(C(F)(F)F)ccc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0 mmol) were added to dry toluene (150 mL purged with argon) and stirred for 30 minutes under argon. Potassium tert-butoxide (4.75 mg, 42.3 mmol), 6-Trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (4.82 g, 20.3 mmol) and N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g, 16.8 mmol) were then added, and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature and recrystallized from toluene to afford the title compound as a solid. (5.55 g, 79%).