Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[NH:8][C:7](=[S:23])[CH2:6][CH2:5]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCc2cc(Br)cc(Cl)c2N1
Solvent: Cc1ccccc1
Product: S=C1CCc2cc(Br)cc(Cl)c2N1
Temperature: 100 °C

Procedure:
To a stirred solution of 6-bromo-8-chloro-3,4-dihydroquinolin-2(1H)-one (80-1; 10 g, 0.038 mol) in toluene (130 mL) was added Lawesson's reagent (7.7 g, 0.019 mol). Reaction mass was refluxed at 100° C. for 3 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ: 11.25 (s, 1H), 7.61-7.60 (d, J=2.4 Hz, 1H), 7.48 (s, 1H), 2.96-2.93 (m, 2H), 2.85-2.81 (m, 2H). MS (M+2): 277.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-:29])=[O:28])=[C:6]([CH2:8][CH:9]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[H-].[Na+].I[CH2:33][CH3:34]>CN(C)C=O.CCOCC>[CH2:33]([C:18]([CH:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:27]([O-:29])=[O:28])([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])[CH3:34]
Reactant: CCI
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(C(=O)OC)(C(=O)OC)C(Cc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Yield: 108.2 %

Procedure:
[2-(5-Chloro-2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (15.29 g, 36.25 mmole) was dissolved in dry dimethylformamide (100 ml) under argon. Prewashed (ether, 3 times), 50% sodium hydride (1.04 g, 43.3 mmole) was added with stirring. (The mixture turned from yellow to a dark red color). Stirring was continued for 20 minutes before iodoethane (14.5 ml, 28.3 g, 181 mmole, 5 eq) was added dropwise, and the reaction mixture was allowed to stir for an additional 2 hours. The solution was diluted with ether and washed with water. The organic layer was dried (magnesium sulfate), concentrated, and vacuum-dried overnight to yield 17.65 g of crude product as a light yellow oil. This material was triturated with methanol leaving 12.73 g of white solid, melting point 95.5°-97.0° C. Additional product was present in the mother liquor.
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([C:66]3[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=3)=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:44][CH2:43][C@H:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:47][CH2:46]3)[C:50]=2[C:66]2[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=2)[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(Cl)cc2)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(Cl)cc2)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-chlorophenyl)naphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 81% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-chlorophenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=449.41 [M−16]+. 1H NMR (MeOD) δ: 7.94 (d, J=1.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.46-7.52 (m, 3H), 7.42 (d, J=9.3 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 4.07-4.17 (m, 1H), 3.66-3.75 (m, 2H), 2.00-2.08 (m, 2H), 1.77-1.84 (m, 2H), 1.52 (s, 3H), 0.92-1.25 (m, 5H), 0.84-0.89 (m, 9H)
Reaction SMILES: [CH:1]1([P:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[OH:33][S:34](O)(=[O:36])=[O:35].[OH-].[Na+:39]>CO>[CH:24]1([P:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([S:34]([O-:36])(=[O:35])=[O:33])[C:15]=2[O:22][CH3:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1.[Na+:39]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To an oven-dried 25 mL round bottom flask equipped with a Teflon-coated magnetic stir bar and rubber septum was added 2-dicyclohexylphosphino-2′6′dimethoxybiphenyl (5.13 g, 12.5 mmol) and CH2Cl2 (5 mL). The solution was cooled to 0° C. using an ice/water bath and then concentrated H2SO4 (32.5 mL, 625 mmol) was added dropwise. The solution slowly turned yellow in color. The solution was heated to 40° C. in a preheated oil bath and was allowed stir for 24 h. At this time it was cooled to 0° C. using an ice/water bath and crushed ice (˜50 g) was added. The solution turned cloudy and white in color. An aqueous solution of NaOH (6.0 M, ˜200 mL) was then added dropwise to the cooled solution until it became neutral (pH ˜7.0 as judged by pH paper). The aqueous solution was extracted with CH2Cl2 (3×300 mL) and concentrated under reduced pressure to give a light yellow solid. The crude material was then dissolved in a minimum amount of cold methanol (˜20 mL), filtered and concentrated (this cycle was repeated) to give sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (2) as a light yellow solid (6.35 g, 99%). Mp=165° C. (turned red, dec.) 1H NMR (400 MHz, CD3OD) δ: 7.88 (d, 1H, J=8.8 Hz), 7.60 (m, 1H), 7.36 (m, 2H), 7.22 (m, 1H), 6.76 (d, 1H, J=8.8 Hz) 3.70 (s, 3H), 3.39 (s, 3H), 1.14-2.01 (m, 22H). 13C NMR (125 MHz, CD3OD) δ: 161.3, 157.1, 143.3, 142.9, 137.9, 137.8, 133.7, 133.6, 133.3, 133.2, 131.9, 130.0, 129.3, 128.0, 127.9, 127.8, 105.9, 61.6, 56.1, 50.0, 37.0, 36.9, 34.8, 34.6, 31.7, 31.6, 31.5, 31.2, 31.0, 30.8, 30.7, 28.9, 28.8, 28.7, 28.4, 28.34, 28.31, 28.2, 27.8, 27.7. 31P NMR (162 MHz, CD3OD) δ: −8.02. IR (neat, cm−1): 3453, 2925, 2849, 1577, 1462, 1448, 1400, 1229, 1191, 1099, 1053, 736. Anal. Calcd for C26H34NaO5PS: C, 60.92; H, 6.69. Found: C, 60.40; H, 6.85. 1H NMR (d4-MeOH/D2O) is shown in FIG. 7. 31P NMR (d4-MeOH) is shown in FIG. 7.
Reaction SMILES: [Br-].[F:2][C:3]([F:26])([F:25])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[C:33]([C:35]1[CH:40]=[CH:39][C:38]([C@H:41]2[CH2:46][CH2:45][C@H:44]([CH:47]=O)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)#[N:34]>C1COCC1>[F:2][C:3]([F:26])([F:25])[CH2:4][CH:5]=[CH:47][C@H:44]1[CH2:45][CH2:46][C@H:41]([C:38]2[CH:39]=[CH:40][C:35]([C:33]#[N:34])=[CH:36][CH:37]=2)[CH2:42][CH2:43]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reactant: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H](C=CCC(F)(F)F)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3,3,3-trifluoropropyl)triphenylphosphonium bromide (9.0 g, 20.5 millimols) with THF (45 ml) was cooled down to -20° C., followed by adding t-BuOK (2.5 g, 22.5 millimols) to the mixture, stirring for 30 minutes, dropwise adding to the mixture, a THF (50 ml) solution of trans-4-(4-cyanophenyl)cyclohexanecarbaldehyde (4.8 g, 22.5 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the product in the same manner as in Example 1, to obtain raw 4-(trans-4-(4,4,4-trifluorobutenyl)cyclohexyl)benzonitrile (5.1 g).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)#N.[F:38]C1C=C(C=CC=1F)CN1C=CC=C(C(NCC2C=C(B(O)O)C=CC=2)=O)C1=O.[B].FC1C=C2C(I)=CNC2=NC=1>>[F:38][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Reactant: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: Fc1cnc2[nH]cc(I)c2c1
Agent: [B]
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(F)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid as activated boron species and 5-Fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine as substituted bicyclic heterocycle, to produce the title compound. 1H NMR (400 MHz, CDCl3) d ppm 12.504 (s, 1H) 10.457 (m, 1H) 8.609 (dd, J=7.3, 2.1 Hz, 1H) 8.541 (d, J=8.1 Hz, 1H) 8.259 (m, 1H) 7.788 (s, 1H) 7.605 (s, 1H) 7.576 (dd, J=6.5, 2.0 Hz, 1H) 7.522-7.366 (m, 3H) 7.221-7.094 (m, 2H) 7.044-6.993 (m, 1H) 6.517 (t, J=6.9 Hz, 1H) 5.178 (s, 2H) 4.739 (d, J=5.7 Hz, 2H); MS m/z=489.33 M+H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](COC)[C:11]3[C:16]([CH:23]=[O:24])=[C:17]([C:19]([O:21][CH3:22])=[O:20])[S:18][C:10]=3[C:9]=2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:4][CH:3]=1.CCOC(C)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]3[C:16]([CH:23]=[O:24])=[C:17]([C:19]([O:21][CH3:22])=[O:20])[S:18][C:10]=3[C:9]=2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:6][CH:7]=1
Reactant: COCn1c(-c2ccc(Cl)cc2)c(C2CCCCC2)c2sc(C(=O)OC)c(C=O)c21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)[nH]c2c1C=O
Yield: 70 %

Procedure:
A solution (0.11 M) of methyl 5-(4-chlorophenyl)-6-cyclohexyl-3-formyl-4-(methoxymethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in dioxane/aqueous HCl (6 N) (1:1) was heated at 130° C. under microwave irradiation for 10 min. After dilution with AcOEt, the resulting solution was basified with solid NaHCO8 and extracted with AcOEt. The combined organic phase was washed with brine, dried and concentrated under reduced pressure. The crude was triturated with Et2O/petroleum ether (1:9) to afford the title compound (70%) as a solid.
Reaction SMILES: [CH2:1](OP(O)(O)=O)[C@H:2]1O[C@H:5](OP(OP(O)(O)=O)(O)=O)[C@H:4](O)[C@@H:3]1O.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[NH2:54][C@H:55]([C:62]([OH:64])=[O:63])[CH2:56][C:57]1N=[CH:60][NH:59][CH:58]=1>>[NH2:54][C@H:55]([C:62]([OH:64])=[O:63])[CH2:56][C:57]1[C:5]2[C:60](=[CH:1][CH:2]=[CH:3][CH:4]=2)[NH:59][CH:58]=1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=P(O)(O)OC[C@H]1O[C@H](OP(=O)(O)OP(=O)(O)O)[C@H](O)[C@@H]1O
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
5-Phosphoribosyl-α-1-pyrophosphate (hereinafter, “PRPP”) and adenosine-5′-triphosphate (hereinafter, “ATP”) are the initial substrates in histidine biosynthesis. PRPP can sometimes induce the histidine biosynthesis to follow divergent pathways, resulting in the biosynthesis of pyrimidine nucleotides, purine nucleotides, pyridine nucleotides, and tryptophan (Escherichia coli and Salmonella, Second Edition, Editor in Chief: F. C. Neidhardt, ASM Press, Washington D.C., 1996).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]([C:14](=[O:21])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30]O)[CH:23]=1>>[C:1]([NH:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]([C:14](=[O:21])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][C:11]([O:13][CH2:30][CH2:29][CH2:28][C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSCC(CC(=O)O)C(=O)c1cccnc1
Reactant: OCCCc1cccnc1
Product: CC(=O)NCCSCC(CC(=O)OCCCc1cccnc1)C(=O)c1cccnc1
Yield: 65 %

Procedure:
The title compound was prepared from 3-{[2-(acetylamino)ethylthio]methyl}-4-oxo-4-(3-pyridyl)butanoic acid and 3-(3-pyridyl)propan-1-ol as described in the above Example 26 in 65% yield; ESMS (M+1+) 430.
Reaction SMILES: [CH2:1]([N:3]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:4]1[C:5]([CH3:37])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:8])[CH3:2].[CH3:44][N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:3]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:4]1[C:5]([CH3:37])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)[CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:8])[CH3:2]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCNCC3)nc2)cc(N(CC)C2CCOCC2)c1C
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C4CCN(C)CC4)CC3)nc2)cc(N(CC)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.4 %

Procedure:
To a stirred solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide (0.45 g, 0.76 mmol) and 1-methylpiperidin-4-one (0.173 g, 1.53 mmol) in dichloroethane (10 mL), acetic acid (0.276 g, 4.6 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.488 g, 2.3 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by column chromatography to afford the title compound (0.215 g, 41%).
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=2)=[O:9])[CH2:4][CH2:3][CH2:2]1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(#N)C>[CH:1]1([CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:14][CH:15]=2)=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=C(NCCC1CCC1)c1ccc(Cl)nn1
Solvent: CC#N
Product: O=C(NCCC1CCC1)c1ccc(N2CCNCC2)nn1
Yield: 78.8 %

Procedure:
To a solution of 6-chloropyridazine-3-carboxylic acid (2-cyclobutylethyl)-amide (1.2 g, 5.00 mmol) in acetonitrile (40 mL) was added piperazine (1.29 g, 15.00 mmol). The reaction mixture was heated to reflux overnight. The mixture was evaporated and the solid residue was taken in ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined ethyl acetates were dried over Na2SO4 and concentrated in vacuo to give the title compound as yellow solid (1.14 g, 78.4% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O>[CH:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:25]([CH:22]([CH3:24])[CH3:23])[C:26]=1[NH:27][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2)([CH3:34])[CH3:33]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Brc1cccc2ccc(-c3cccc4ccccc34)nc12
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1Nc1cccc2ccc(-c3cccc4ccccc34)nc12
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A mixture of 8-bromo-2-(1-naphthyl)quinoline (2.03 g, 6 mmol), 2,6-diisopropylaniline (1.3 ml, 7 mmol), Pd(dba)2 (72 mg, 0.12 mmol), L=(N-[2′-(dicyclohexylphosphino)[1,1′-biphenyl]-2-yl]-N,N-dimethylamine (94 mg, 0.24 mmol), NadtBu (0.72 g, 7.2 mol) and toluene (15 mL) is stirred for 8 h under an argon atmosphere at 105° C. in an oil bath. The mixture is then poured into water and extracted with benzene (3×50 mL). The combined organic phase is washed with water and brine, and is then concentrated. The residue is purified by column chromatography (silica gel 40, hexane/toluene 2:1). Yield: 1.7 g (66%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([NH2:42])=[O:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([NH2:42])=[O:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC(N)=O)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(CC(N)=O)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert. butyl 4'-[(2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C@H:49]([C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CC#N>[F:68][C:65]1[CH:64]=[CH:63][C:62]([C@@H:49]([NH:48][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([N:11]3[CH:15]=[CH:14][CH:13]=[N:12]3)=[N:5][CH:6]=2)=[O:10])[C:50]2[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=2)=[CH:67][CH:66]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: CCOP(C)(=O)c1ccc([C@H](N)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.7 %

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (5.15 g, 25 mmol) and Et3N (6.9 g, 68 mmol) in MeCN (100 ml) was added HATU (9.5 g, 25 mmol). The mixture was stirred for 5 min at room temperature and then compound 18-e (7 g, 23 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. Then it was concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (petroleum ether:ethyl acetate=2/1) to provide the product, 18-f, (8.1 g, 65.7%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[CH2:66][CH2:67]O>O1CCCC1>[N:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[CH2:66][CH2:67][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(O)cc4)CC3)C2)c2ccccc21
Reactant: OCCc1ccccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(OCCc5ccccn5)cc4)CC3)C2)c2ccccc21
Yield: 33 %

Procedure:
(1R)-1′-{[1-(4-Hydroxyphenyl)-cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (15 mg, 0.043 mmol), diisopropyl azodicarboxylate (20 ul, 0.10 mmol), and triphenylphosphine (24 ul, 0.10 mmol) were mixed in tetrahydrofuran (0.2 ml) at room temperature for 5 minutes. To the mixture, with stirring, was added 2-(2-pyridyl)ethanol (13 mg, 0.10 mmol). The resulting mixture then was stirred at room temperature overnight. Then the desired product was obtained from the mixture by prep-HPLC (6.4 mg, yield: 33%). LCMS: m/z 455.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[CH3:14][NH:15][CH3:16].C1COCC1.CCN(CC)CC>>[CH3:14][N:15]([CH3:16])[C:11]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:8]=1)=[O:13]
Reactant: CNC
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Yield: 84 %

Procedure:
was prepared by the reaction of 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (0.57 g, 2.67 mmol) with 2.0 M N,N-dimethylamine in THF (1.60 mL, 3.20 mmol) and Et3N (0.447 mL, 3.20 mmol) in a manner as described in Method A to give the desired amide as brown solid (0.54 g, 84%). 1H NMR (300 MHz, CDCl3) δ 8.63 (d, 1H, J=4.85 Hz), 7.74 (s, 1H), 7.35 (d, 1H, J=5.02 Hz), 3.28 (s, 3H), 3.22 (s, 3H); ESIMS (MH+): 240.95.
Reaction SMILES: N1C=CC(C2C(C3C=CC(OCC4C=NC5C(=CC=CC=5)N=4)=CC=3)=NN(CC(F)(F)F)C=2)=CC=1.[CH3:35][N:36]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[C:38]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)=[N:37]1.[CH3:54][O:55][C:56]1[CH:57]=[CH:58][CH:59]=[C:60]2[C:65]=1[N:64]=[C:63]([CH2:66]O)[CH:62]=[CH:61]2>>[CH3:54][O:55][C:56]1[CH:57]=[CH:58][CH:59]=[C:60]2[C:65]=1[N:64]=[C:63]([CH2:66][O:53][C:50]1[CH:51]=[CH:52][C:47]([C:38]3[C:39]([C:41]4[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=4)=[CH:40][N:36]([CH3:35])[N:37]=3)=[CH:48][CH:49]=1)[CH:62]=[CH:61]2
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Reactant: COc1cccc2ccc(CO)nc12
Agent: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cnc4ccccc4n3)cc2)n1
Product: COc1cccc2ccc(COc3ccc(-c4nn(C)cc4-c4ccncc4)cc3)nc12

Procedure:
Following the procedure for the preparation of 2-{4-[4-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxaline but substituting 4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol and (8-Methoxy-quinolin-2-yl)-methanol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=6.2 Hz, 2H), 8.15 (d, J=8.7 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.55 (s, 1H), 7.44 (m, 1H), 7.37 (m, 3H), 7.15 (d, J=5.8, Hz, 2H), 7.07 (d, J=7.5 Hz, 1H), 6.99 (d, J=8.7 Hz, 2H), 5.46 (s, 2H), 4.08 (s, 3H), 3.94 (s, 3H); MS: (M+H m/z=423.1).