Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:26]=[CH:25][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH2:52][C:53]([CH3:56])([OH:55])[CH3:54].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[OH:55][C:53]([CH3:56])([CH3:54])[CH2:52][NH:51][C:22]([CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:14]2[CH:25]=[CH:26][C:11]([C@@H:3]3[O:4][C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:10]4[O:1][CH2:2]3)=[CH:12][CH:13]=2)[CH2:17][CH2:18]1)=[O:24]
Reactant: O=C(O)C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(O)CNC(=O)C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
To a solution of Intermediate K (50 mg, 0.14 mmol) in DMA (1 mL) is added HATU (59 mg, 0.16 mmol) followed by 1-amino-2-methyl-propan-2-ol (14 mg, 0.16 mmol) as a solution in DMA (1 mL) and DIEA (0.10 mL, 0.56 mmol) and the mixture stirred at rt overnight. Add water (0.1 mL) and purify by reversed phase HPLC eluting with 10-90% MeCN in water (+0.1% TFA). The concentrated pooled fractions are dissolved in 1:1 methanol/DCE and passed through a carbonate resin cartridge to provide the title compound 255 as a free base. (LC/MS method 16: ES+ m/z 426.5 [M+H]+, Rt=1.48 min)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][C:12]1[C:13](/[CH:18]=[CH:19]/[C:20]([OH:22])=O)=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:5]2.[CH3:23][C:24]1[S:25][C:26]([S:30]([NH2:33])(=[O:32])=[O:31])=[C:27]([CH3:29])[N:28]=1>>[CH3:23][C:24]1[S:25][C:26]([S:30]([NH:33][C:20](=[O:22])/[CH:19]=[CH:18]/[C:13]2[C:12]([CH2:11][C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:31])=[O:32])=[C:27]([CH3:29])[N:28]=1
Reactant: Cc1nc(C)c(S(N)(=O)=O)s1
Reactant: O=C(O)/C=C/c1ncccc1Cc1cc2cc(Cl)ccc2[nH]1
Product: Cc1nc(C)c(S(=O)(=O)NC(=O)/C=C/c2ncccc2Cc2cc3cc(Cl)ccc3[nH]2)s1

Procedure:
The acid of Step 4 (283 mg; 0.90 mmol) was coupled with 2,4-dimethyl-1,3-thiazole-5-sulfonamide (from Maybridge Chemical) according to step 5 of example 1 to yield 315 mg of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.O1CCCC1.C([Mg]Cl)(C)C.C([Cu])#N.P(OC)(OC)OC.Cl[CH2:30][C:31]1[C:39]2[C:34](=[N:35][CH:36]=[CH:37][CH:38]=2)[N:33]([Si:40]([CH:47]([CH3:49])[CH3:48])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])[CH:32]=1>O.C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([CH2:30][C:31]2[C:39]3[C:34](=[N:35][CH:36]=[CH:37][CH:38]=3)[N:33]([Si:40]([CH:41]([CH3:43])[CH3:42])([CH:47]([CH3:49])[CH3:48])[CH:44]([CH3:46])[CH3:45])[CH:32]=2)=[CH:3][CH:4]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCl)c2cccnc21
Reactant: Clc1ccc(I)cn1
Agent: N#C[Cu]
Agent: CC(C)[Mg]Cl
Agent: COP(OC)OC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Cl)nc2)c2cccnc21
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 58.9 %

Procedure:
Into a round bottom flask was added 5-iodo-2-chloro-pyridine (315.0 mg, 1.32 mmol) and tetrahydrofuran (12.0 mL, 0.15 mol) at −40° C. under an atmosphere of nitrogen. Into the reaction 2.0 M of isopropylmagnesium chloride in tetrahydrofuran (0.72 mL, 1.44 mmol) was added. The reaction mixture was stirred for 40 minutes at −40° C. TLC (hexane/ethyl acetate 2:1) indicated no starting material. Into the reaction mixture 0.6 M of CuCN.2LiCl in tetrahydrofuran (2.4 mL, 1.44 mmol) was added. The reaction mixture was allowed to come to room temperature for 5 minutes and trimethyl phosphite (0.29 mL, 2.4 mmol) was added. After 10 minutes, this solution was added into a round bottom flask containing compound 5 (315.0 mg) and toluene (8.0 mL). The reaction was stirred at 20° C. for 40 hours. The reaction mixture was poured into water and the compound extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage (dichloromethane/methanol 1:10) to give compound 6 (230 mg, yield=59.0%) as a white solid. Compound 6a (3-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine) (MS (ESI) [M+H+]+=288.1, 290.1) was prepared substituting 5-iodo-2-chloro-pyridine with 5-iodo-2-bromo-pyridine in Step 4, with reaction conditions and work up procedure the same as that for the synthesis of compound 6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](=[CH:12][N:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cnccc1-c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1oc2cc(Cl)ccc2c2ccncc12
Temperature: 60 °C
Yield: 72.4 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinic acid (0.3 g, 1.192 mmol) in anhydrous DMSO (1 mL) was added Cs2CO3 (0.388 g, 1.192 mmol) and the mixture was subjected to microwave heating for 2 h at 60° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with water (1×15 mL) and brine (1×15 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 8-chloro-5H-chromeno[3,4-c]pyridin-5-one (0.2 g, 0.863 mmol, 72% yield over 2 steps). 1H NMR (400 MHz, CDCl3) δ 9.57 (d, J=0.40 Hz, 1H), 8.98 (d, J=5.60 Hz, 1H), 8.01 (d, J=8.80 Hz, 1H), 7.88 (q, J=0.40 Hz, 1H), 7.44 (d, J=2.00 Hz, 1H), 7.39 (q, J=2.00 Hz, 1H); LCMS (ESI) m/e 232.6 [(M+H)+, calcd for C12H7ClNO2 232.0]; LCMS retention time (Method D): tR=0.81 min.
Reaction SMILES: C(OC(=O)NCC1C=CC(CNC(C2C(Cl)=NC=CC=2)=O)=CC=1)(C)(C)C.[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33](O)[CH:32]=1)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O1CCOCC1>[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28]
Reactant: CCOC(=O)c1cccc(O)c1
Agent: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)c2cccnc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccccc1
Temperature: 70 °C
Reaction time: 22 h
Yield: 0.1 %

Procedure:
(4-{[(2-Chloro-pyridine-3-carbonyl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester (12.0 g, 32.2 mmol) (see Preparation 7), 3-hydroxy-benzoic acid ethyl ester (6.42 g, 38.6 mmol) and caesium carbonate (15.7 g, 48.3 mmol) were stirred in dioxan (180 ml) at 70° C. under an atmosphere of nitrogen for 18 hours. Starting material remained, so a further aliquot of 3-hydroxy-benzoic acid ethyl ester (6.42 g, 38.6 mmol) and caesium carbonate (15.7 g, 48.3 mmol) were added along with dioxan (420 ml) and N,N-dimethylformamide (40 ml) and the reaction stirred at 70° C. for a further 22 hours. The solvent was then removed under reduced pressure, the residue partitioned between ethyl acetate (200 ml) and water (200 ml), and the organic layer separated. The organic layer was then washed with a saturated aqueous solution of sodium chloride (3-fold 100 ml), the solvent removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 50:50, by volume, ethyl acetate:hexane to give 3-{3-[4-tert-butoxycarbonylamino-methyl)-benzylcarbamoyl]-pyridin-2-yloxy}-benzoic acid ethyl ester (7.42 mg) as an off-white foam.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH3:8][S:9]([CH2:12][CH2:13][NH2:14])(=[O:11])=[O:10]>C(O)C>[CH3:8][S:9]([CH2:12][CH2:13][NH:14][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1)(=[O:11])=[O:10]
Reactant: O=C1NC(=S)CS1
Reactant: CS(=O)(=O)CCN
Solvent: CCO
Product: CS(=O)(=O)CCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (865 mg) in ethanol (10 mL) was added 2-(methylsulfonyl)ethanamine (1 g), and the mixture was stirred at room temperature for 3 hr. The precipitate was collected by filtration to give the title compound (1.39 g).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O.[CH2:22]([N:27](CCCCC)[C:28](=O)[C:29]1C=C(C=O)[CH:32]=[CH:31][C:30]=1OC)[CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:28]([N:27]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8](=[O:10])[C:7]1[CH:11]=[C:12]([CH:15]=[O:16])[CH:13]=[CH:14][C:6]=1[O:5][CH2:4][C:3]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=1[F:1])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=Cc1ccc(OCc2ccc(F)cc2F)c(C(=O)O)c1
Reactant: CCCCCN(CCCCC)C(=O)c1cc(C=O)ccc1OC
Product: CCCCCN(CCCCC)C(=O)c1cc(C=O)ccc1OCc1ccc(F)cc1F

Procedure:
N,N-Di-n-pentyl-2-(2,4-difluorobenzyloxy)-5-formylbenzamide was prepared from 2-(2,4-difluorobenzyloxy)-5-formylbenzoic acid (200 mg, 1 eq) using the same procedure as for N,N-di-n-pentyl-2-methoxy-5-formylbenzamide. The product was obtained as a pale brown oil (442 mg, 99%). 1H NMR (CDCl3) δ9.89 (s, 1H, O═C—H), 5.22 (d, 1H, CH2Ar), 5.10 (d, 1H, CH2Ar), 3.74 (m, 1H, NCH2), 3.14 (m, 1H, NCH2), 3.05 (m, 2H, NCH2).
Reaction SMILES: [CH2:1]([PH:8](=[O:14])[O:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]=[O:16]>>[CH2:1]([P:8]([CH2:15][OH:16])(=[O:14])[O:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCO[PH](=O)Cc1ccccc1
Reactant: C=O
Product: CCCCOP(=O)(CO)Cc1ccccc1

Procedure:
The title compound was prepared from benzylphosphinic acid, n-butyl ester and paraformaldehyde according to the method described in Procedure 31.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl.CN(C)C.[CH3:24][C:25]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:41])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:26][CH2:27][CH2:28][CH2:29][OH:30].CN(C)CCCN>C(Cl)Cl.C(OCC)(=O)C>[CH3:24][C:25]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:41])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:26][CH2:27][CH2:28][CH2:29][O:30][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=CCCCO)CCCC(C)CCCC(C)C
Agent: CN(C)C
Agent: CN(C)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.82 mL (5.9 mmol) of triethylamine, 0.90 g (4.7 mmol) of p-toluenesulfonyl chloride and 38 mg (0.39 mmol) of trimethylamine hydrochloride were added to a solution of 1.0 g (3.9 mmol) of 5,9,13-trimethyltetradec-4-en-1-ol in dry methylene chloride (3 mL) at 0° C., sequentially. After being stirred for 1 hour at room temperature, 0.12 mL (1.0 mmol) of N,N-dimethyl-1,3-propanediamine was added to the reaction mixture. After being stirred for 30 min, the mixture was diluted with ethyl acetate. The solution was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain (5,9,13-trimethyltetradec-4-enyl)tosylate as a crude product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Na+].Cl[CH2:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.[I-].[Na+].[OH-].[Na+].Cl>CN(C)C=O.C(OCC)(=O)C.O1CCCC1.CO>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1
Reactant: CC1CCc2ccccc2N1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CCc2ccccc2N1Cc1ccc(COc2ccc(CCC(=O)O)cc2)cc1
Temperature: 0 °C
Yield: 45.9 %

Procedure:
To a solution of 2-methyl-1,2,3,4-tetrahydroquinoline (0.19 mL, 1.32 mmol) in N,N-dimethylformamide (3.5 mL) was added sodium hydride (60% in oil, 53 mg, 1.32 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (0.35 g, 1.10 mmol) and sodium iodide (0.20 g, 1.32 mmol) were added to the obtained mixture and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an oil. Then, a mixture of the obtained oil, 1 N aqueous sodium hydroxide solution (2.2 mL), methanol (4.0 mL) and tetrahydrofuran (8.0 mL) was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 7 with 1 N hydrochloric acid, and diluted with ethyl acetate. The mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/2) to give the title compound (0.21 g, yield 47%) as beige crystals. MS (APCI−): 414 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([NH:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[C:25]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:26]
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(F)cc1)C(=O)O
Product: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 84 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-fluorophenoxy)aniline and (S)-2-(tert-butoxycarbonylamino)-3-(4-fluorobenzyloxy)propanoic acid, gave (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (200 mg, 84%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22](Br)[CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]([N:38]1[CH:46]=[C:45]2[C:40]([CH:41]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:43]=[CH:44]2)=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22]([C:42]4[CH:43]=[CH:44][C:45]5[C:40]([CH:41]=4)=[N:39][N:38]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:46]=5)[CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cc(Br)c4c(N)ncnn34)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)c2)CC1
Temperature: 80 °C
Yield: 40.1 %

Procedure:
The product from step 4 (150 mg, 0.32 mmol) and Intermediate C (138 mg, 0.41 mmol) were dissolved in 2 mL of 1:1-toluene:dioxane and degassed with a vacuum/N2 purge sequence (3×). 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) chloride-complex with methylene chloride (12 mg, 0.02 mmol) was added followed by 1 mL of 2M aqueous Na2CO3 solution and the mixture heated to 80° C. overnight. The heating bath was removed and the mixture diluted with water and EtOAc (5 mL each). The layers were separated and the aqueous phase was extracted with EtOAc and the combined organic phases were washed with water and brine, dried (Na2SO4), filtered and concentrated in, vacuo. The residue was purified by Isco® (Red-sep 12 eluting with 70%—100% EtOAc/hexanes) to give 77 mg (40%) of the title compound as a tan solid. 1H-NMR (DMSO-d6) 8.33 (s, 1H), 7.61 (s, 1H), 7.57 (bs, 2H), 7.40-7.24 (m, 7H), 7.22 (s, 1H), 7.08, (d, 1H), 7.06 (s, 1H), 6.77 (d, 1H), 6.58 (d, 1H), 6.25 (d, 1H), 5.55 (s, 2H), 3.47 (m, 4H), 3.18 (m, 4H), 1.42 (s, 9H); LC-MS [M+H]+=601.3, RT=3.12 min.
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+].ClC1C=CC(C2C(C3C=CC(Cl)=CC=3Cl)=CN3C(CC4C=NC(C(F)(F)F)=CC=4)=NN=C3C=2)=CC=1>O1CCOCC1.O.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>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:3]2[C:2]([C:32]3[CH:33]=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=3[Cl:30])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:24][CH:25]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Reactant: Cc1ccc(B(O)O)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)cn23)cn1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cn3c(Cc4ccc(C(F)(F)F)nc4C)nnc3cc2-c2ccc(Cl)cc2)c(Cl)c1
Yield: 61.6 %

Procedure:
The title compound (6.5 mg, 60%) as a white powder was prepared from 6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.020 mmol), 2-chloro-4-methylphenylboronic acid (6.7 mg, 0.039 mmol), K2CO3 (8.2 mg, 0.059 mmol) and Pd(PPh3)4 (2.8 mg, 0.002 mmol) in 1,4-dioxane (0.28 mL) and H2O (0.09 mL) by the procedures analogous to those described for 7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56E). LC/MS (method B): retention time=2.01 min, [M+H]+=527.3.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH2:12][CH2:13][C:14]([O:16]C)=[O:15].[OH-].[Li+].Cl.CCOC(C)=O>C1COCC1.CO>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CCN1CCc2ccccc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCN1CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Dissolve methyl 3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (0.3 g, 1.29 mmol) in THF (12 mL) and MeOH (4 mL). Add lithium hydroxide (0.2 g, 8.23 mmol, in 4 mL H2O). Stir at ambient temperature for 2 hours. Evaporate the solvents from reaction mixture under reduced pressure. Adjust the pH to 5 with 2N HCl. Add EtOAc (60 mL); wash with brine; dry over Na2SO4; filter; and concentrate the filtrate under reduced pressure to provide the title compound (colorless oil, 0.27 g, 95.8%). MS (m/z): 220 (M+1).
Reaction SMILES: CN(C)[CH:3]=[O:4].[CH2:6](Br)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]>O>[O:4]=[C:3]1[C:6]2[CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:7]=2[CH2:9][CH2:10][CH2:11]1
Reactant: CN(C)C=O
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Product: O=C1CCCc2oc(-c3ccccc3)cc21
Temperature: 80 °C
Reaction time: 47 h

Procedure:
A solution of 5.0 g. of 3-(1-pyrrolodinyl)-2-cyclohexan-1-one in 30 ml. of anhydrous dimethylformamide is treated dropwise over twenty minutes under nitrogen with a solution of 6.0 g. of phenacyl bromide in 10 ml. of anhydrous dimethylformamide. The mixture is stirred for 47 hours at 80°C., allowed to cool to ambient temperature, and then poured into water and stirred for 30 minutes. The resulting suspension is extracted with chloroform, the chloroform extracts are combined, washed with water and dried. The solvent is removed and the residue is dried under high vacuum and crystallized from ethanol to yield 4-oxo-2-phenyl-4,5,6,7-tetrahydrobenzo[b]furan, m.p. 132°-134°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[O:17])[CH:25]=1)[CH3:19]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Product: CCOC(=O)CCc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (131) (50 mg, 0.19 mmol) was coupled to aniline (124) (40 mg, 0.21 mmol) using Method D to give the product, which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O>Cl.O>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: O
Product: Nc1ccc2c(c1)C(=O)OC2
Yield: 83.8 %

Procedure:
To a solution of 6-nitroisobenzofuran-1(3H)-one (15.0 g, 0.0800 mol) in HCl/H2O (375 mL/125 mL) was added SnCl2-2H2O (75.0 g, 0.330 mol). The reaction mixture was heated at reflux for 4 h, quenched with water, and extracted with ethyl acetate (300 mL×3). The organic layer was dried over Na2SO4 was evaporated in vacuo to give 6-aminoisobenzofuran-1(3H)-one (10.0 g, 78%). 1H NMR (300 MHz, CDCl3) □ 7.23 (d, J=8.1, 1H), 7.13 (d, J=2.1, 1H), 6.98 (dd, J=8.1, 2.1, 1H), 5.21 (s, 2H), 3.99 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.CS(O)(=O)=O.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][O:16]3)[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1
Reactant: C1=COCCC1
Reactant: Clc1ncc2cn[nH]c2n1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: Clc1ncc2cnn(C3CCCCO3)c2n1
Temperature: 25 °C

Procedure:
To a suspension of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 6.47 mmol) (Ark, Cat. No. AK-30782) in THF (10 mL) at r.t. was added methanesulfonic acid (84 μL, 1.3 mmol), followed by dihydropyran (1.77 mL, 19.4 mmol). The mixture was stirred at r.t. over weekend. The reaction mixture was quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product which was directly used in the next step reaction without further purification. LCMS (M-84+H)+: m/z=155.1/157.0.
Reaction SMILES: C1(O)C=CC=CC=1.[C:8](C1C=CC=CC=1O)([CH2:11][CH3:12])([CH3:10])[CH3:9].C(C1C=CC(O)=CC=1)(CC)(C)C.[C:32]([C:37]1[CH:42]=[C:41]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:38]=1[OH:48])([CH2:35][CH3:36])([CH3:34])[CH3:33]>>[C:32]([C:37]1[CH:42]=[C:41]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])[CH:40]=[C:39]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])[C:38]=1[OH:48])([CH2:35][CH3:36])([CH3:34])[CH3:33]
Reactant: CCC(C)(C)c1ccccc1O
Reactant: CCC(C)(C)c1ccc(O)c(C(C)(C)CC)c1
Agent: CCC(C)(C)c1ccc(O)cc1
Solvent: Oc1ccccc1
Product: CCC(C)(C)c1cc(C(C)(C)CC)c(O)c(C(C)(C)CC)c1
Reaction time: 10 h
Yield: 10.8 %

Procedure:
The procedure of Example 1 was repeated except that 1.00 g (10.6 millimoles) of phenol, 11.4 g of the same C5 fraction as used in Example 1, and 1.00 g of Silica-Alumina "IS-28" (produced by Shokubai Kasei Kogyo Co., Ltd.) which had been burned at 500° C. for 10 hours were used. The acid strength of the silica alumina (as determined in the same manner as in Example 1) was as follows: H0 ≤- 8.2. The proportion of the unreacted phenol was 5.0%, and 0.05 g (2.9%) of o-tert-amylphenol, 0.22 g (12.6%) of p-tertamylphenol, 1.73 g (69.6%) of 2,4-di-tert-amylphenol, and 0.01 g (0.3%) of 2,4,6-tri-tert-amylphenol were formed.