Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[C:5]([C:24](O)=[O:25])[CH:4]=[N:3]1.[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[C:24]([N:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1)=[O:25])=[O:23]
Reactant: C1CSCCN1
Reactant: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)cnn1C
Product: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)N2CCSCC2)cnn1C

Procedure:
The product was obtained starting from 1-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethylcarbamoyl)-1H-pyrazole-4-carboxylic acid (40 mg, 113 μmol) and thiomorpholine (14.4 mg, 14.3 μL, 135 μmol) according to the method described in example 37, step 3 as colorless oil (41.7 mg, 94.9 μmol, 84.0%).
Reaction SMILES: [F:1][C:2]1([C:18](O)=[O:19])[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[F:21][C:22]([F:31])([F:32])[O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:18]([C:2]2([F:1])[CH2:3][CH2:4][N:5]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)(=[O:9])=[O:10])[CH2:6][CH2:7]2)=[O:19])=[CH:29][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(F)(C(=O)O)CC2)cc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: Cc1ccc(S(=O)(=O)N2CCC(F)(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Yield: 32.7 %

Procedure:
This material was made in analogy to example 1 from 4-fluoro-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (0.2 g) and 4-trifluoromethoxy-aniline (0.118 g) to give the desired 4-fluoro-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.1 g) as a white solid. MS (ESI): 461.2 MH+).
Reaction SMILES: ClC1C=C(Cl)C=CC=1COC1C=CC([N+]([O-])=O)=CC=1N1C=CN=C1.[Sn](Cl)Cl.Cl.N1(C2C=C(C=CC=2OC)N)C=CN=C1.[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([O:55]C)=[C:48]([N:50]2[CH:54]=[CH:53][N:52]=[CH:51]2)[CH:49]=1>CCOCC>[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([OH:55])=[C:48]([N:50]2[CH:54]=[CH:53][N:52]=[CH:51]2)[CH:49]=1
Reactant: COc1ccc(Cl)cc1-n1ccnc1
Agent: COc1ccc(N)cc1-n1ccnc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCOCC
Product: Oc1ccc(Cl)cc1-n1ccnc1

Procedure:
1.1 g. of the 1-(2-methoxy-5-nitrophenyl)-imidazole obtained in Example 65 is reduced by heating for 5 minutes with 3.75 g. of tin(II) chloride in 20 ml. of concentrated hydrochloric acid. The thus-formed 3-(1-imidazolyl)-4-methoxyaniline (830 mg.) is converted according to Sandmeyer in the usual way into the 1-(5-chloro-2-methoxyphenyl)-imidazole (610 mg.; m.p. 52°-57°). After ether cleavage according to the literature citation in Example 56, 4-chloro-2-(1-imidazolyl)-phenol is obtained (425 mg.), which is etherified analogously to Example 58 with the use of 4 25 mg. of 2,4-dichlorobenzyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH2:28][NH:27][N:26]([S:31]([CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)(=[O:33])=[O:32])[C:25]=3[CH2:24]2)[CH2:11][O:10]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH2:28][NH:27][N:26]([S:31]([CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)(=[O:32])=[O:33])[C:25]=3[CH2:24]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2CC3=C(C2)N(S(=O)(=O)C2CCCC2)NC3)CO[C@@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](N2CC3=C(C2)N(S(=O)(=O)C2CCCC2)NC3)CO[C@@H]1c1cc(F)ccc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate obtained in Step A above (49 mg, 0.089 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (2 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated and purified by preparative thin layer chromatography eluting with 5% methanol containing 10% NH4OH in dichloromethane to give the title compound.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1>C(O)C>[CH2:2]([O:1][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)[CH3:3]
Reactant: CC[O-]
Reactant: N#Cc1ccc(Cl)nc1
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Add sodium ethoxide (1.6 mL of 21% w/v in ethanol, 4.8 mmol) to a solution of 6-chloronicotinonitrile (612 mg, 4.41 mmol) in anhydrous ethanol (15 mL) and heat the reaction at reflux for 3 h. Cool to room temperature and stir overnight under nitrogen atmosphere. Concentrate in vacuo and dissolve the residue into dichloromethane. Wash with saturated aqueous NaHCO3, dry over MgSO4 and concentrate in vacuo to give the desired intermediate as an off-white solid (545 mg, 83%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH2:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:16][C:8]12[CH2:14][CH:12]3[CH2:11][CH:10]([CH2:15][C:6]([C:4]([O:3][CH3:2])=[O:5])([CH2:13]3)[CH2:7]1)[CH2:9]2)=[O:22]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C12CC3CC(CC(NC(=O)c4cccc(Cl)c4)(C3)C1)C2
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 3-amino-adamantane-1-carboxylic acid methyl ester HCl salt (Hermogenes N. J. et al.; U.S. Pat. No. 7,947,680 B2) (160 mg, 0.65 mmol) and 3-chlorobenzoic acid (130 mg, 0.78 mmol) in DMF (5 mL) was added DIEA (340 mg, 2.6 mmol) and HATU (300 mg, 0.78 mmol) under N2. After stirring at room temperature for an hour, the reaction was quenched with brine, the aqueous layer was extracted with ethyl acetate (3×20 mL), and the combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1) to afford 220 mg (97%) of the title compound, methyl 3[(3-chlorobenzoyl)amino]adamantane-1-carboxylate, as a white solid. ESI-MS m/z: 348 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[CH2:14][CH2:13][S:12]2.[Br:17]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:17][C:16]1[N:15]2[C:11]([S:12][CH2:13][CH2:14]2)=[N:10][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc(-c2cn3c(n2)SCC3)c(Cl)c1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc3n(c2Br)CCS3)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The 6-(2,4-dichlorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole (0.6 g) prepared above and N-bromosuccinimide (0.45 g) were dissolved in dimethylformamide (5 ml). The mixture was heated to reflux and stirred for 18 h at room temperature. The mixture was diluted with water (60 ml) and allowed to crystallize. The liquid was decanted and the residue was dissolved in methylene chloride and dried with magnesium sulfate. The organic residue was chromatographed on silica gel with hexanes/ethyl acetate (3:1) as eluent to give the desired product as a solid (m.p. 200-202° C.); NMR (CDCl3, 200 MHz) δ: 7.4-7.2 (3H), 4.2 (m, 2H), 3.9 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:15]([O:17][CH3:18])=[O:16])[C:7](=[CH:12][C:13]=1[OH:14])[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2].N1C[CH2:22][CH2:21][CH2:20]1>CC(C)=O>[CH3:20][C:21]1([CH3:22])[CH2:2][C:1](=[O:3])[C:4]2[CH:5]=[C:6]([C:15]([O:17][CH3:18])=[O:16])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][C:13]=2[O:14]1
Reactant: COC(=O)c1cc(O)c(C(C)=O)cc1C(=O)OC
Reactant: C1CCNC1
Solvent: CC(C)=O
Product: COC(=O)c1cc2c(cc1C(=O)OC)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In 100 ml of acetone was dissolved 4.2 g of dimethyl 4-acetyl-5-hydroxyphthalate synthesized in accordance with the process of Bulletin of the Chemical Society of Japan, Vol. 57, p. 3221 (1984). To the solution were added 1.0 ml of pyrrolidine and a small amount of Molecular Sieve (3A), followed by stirring at room temperature for 3 days. Any insoluble material was removed by filtration, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.6 g (86.3%) of a yellow oily substance.
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:7][CH:6]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>CO>[OH:1][CH:2]([CH2:22][NH:26][CH:23]([CH3:25])[CH3:24])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:7][CH:6]=1
Reactant: O=C1CCC(c2ccc(OCC3CO3)c3ccccc23)=NN1
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)c2ccccc12
Yield: 75 %

Procedure:
A mixture of 6-[4-(2,3-epoxypropoxy)-1-naphthyl]-4,5-dihydro-3(2H)-pyridazinone (10 g, 0.034 mole), methanol (100 ml) and isopropylamine (17.4 ml, 0.2 mole) was heated under reflux for one hour. Evaporation under reduced pressure gave an oil which was purified on a silica column with chloroform-methanol to give 6-[4-(2-hydroxy-3-isopropylaminopropoxy)-1-naphthyl]-4,5-dihydro-3(2H)-pyridazinone (9g, 75%, m.p. 131°-135° C.). The hydrochloride, crystallised from 2-propanol had m.p. 195°-197° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)=O.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=C1COc2ccc(CO)cc2N1
Reaction time: 14 h
Yield: 69.3 %

Procedure:
A solution of methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-carboxylate (30 g, 0.145 mol) in dry CH2Cl2 (500 mL) was cooled to −78° C. and added DIBAL-H (51 g, 0.36 mol) over a period of 45 min and then stirred at the same temperature for 14 h. The reaction mixture was quenched with 1.5N HCl and filtered off the solid product. The solid compound was dried under vacuum to give 6-(hydroxymethyl)-2H-1,4-benzoxazin-3(4H)-one (18 g, 69%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][N+:13]([O-])=C(C)[CH:11]=1>C(Cl)(Cl)Cl>[C:5]([O:4][CH2:1][C:2]1[CH:11]=[C:10]([O:9][CH3:8])[C:15]([CH3:16])=[CH:14][N:13]=1)(=[O:7])[CH3:6]
Reactant: COc1cc(C)[n+]([O-])cc1C
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc(COC(C)=O)ncc1C

Procedure:
55 ml of acetic anhydride were added dropwise at room temperature to a solution of 19.9 g of 4-methoxy-2,5-dimethylpyridine 1-oxide in 75 ml of chloroform. After boiling under reflux for 2 hours the solution was evaporated, the residue was dissolved in 100 ml of toluene and again evaporated. The residue was taken up in 100 ml of ethyl acetate and the solution was extracted three times with 50 ml of saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The product was chromatographed on 100 g of silica gel with ether and there was obtained (4-methoxy-5-methyl-2-pyridyl)methyl acetate in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:39]=[CH:38][C:25]([CH2:26][N:27]([CH2:34][CH:35]([F:37])[F:36])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:40][CH3:41])=[C:4]([CH3:42])[N:3]=1.[NH2:43][C@@H:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][OH:47]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:43][C@@H:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][OH:47])[C:5]([CH2:21][C:22]2[CH:39]=[CH:38][C:25]([CH2:26][N:27]([CH2:34][CH:35]([F:36])[F:37])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:40][CH3:41])=[C:4]([CH3:42])[N:3]=1
Reactant: CCOC(=O)CN(Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1)CC(F)F
Reactant: CCC[C@H](N)CCO
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC(=O)OCC)CC(F)F)cc1OC
Yield: 75.8 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of step (ii) (520 mg) and (S)-3-aminohexan-1-ol (300 mg). The sub-title compound (340 mg) was obtained as a colourless gum; 1H NMR (CDCl3); 6.90-6.88 (2H, m), 6.78 (1H, d), 5.73 (1H, tt), 4.60 (1H, d), 4.55 (2H, br s), 4.15 (2H, q), 4.11-4.03 (1H, m), 3.88 (3H, s), 3.85 (2H, s), 3.66 (2H, s), 3.47-3.37 (3H, m), 3.25 (1H, ddd), 3.04 (2H, dt), 2.33 (3H, s), 1.83-1.73 (1H, m), 1.51-1.32 (3H, m), 1.25 (3H, t), 1.06-0.99 (2H, m), 0.73 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[Li]CCCC.[C:18](=[O:20])=[O:19]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C=O
Reactant: FC(F)(F)c1cc(I)cc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1
Temperature: -75 °C

Procedure:
To a stirred solution of 1.1 g of 2-chloro-4-iodo-6-trifluoromethyl-pyridine (3.58 mmol) in 15 ml THF under argon at −75° C., were added 2.2 ml of n-BuLi (1.6 M in hexane) within 15 min (temperature kept between −72° C. and −75° C.). After 5 additional min stirring at −75° C., the reaction mixture was poured on an excess of freshly crushed dry ice and stirred until RT was reached. The reaction mixture was then concentrated in vacuo, the remaining residue treated with 2M aqueous HCl and the resulting mixture was extrated with diethylether. The combined organic phases were washed with water, and then extracted with saturated NaHCO3 solution. The aqueous phase was then acidified with concentrated HCl, extracted twice with diethylether and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The remaining residue was recrystalized from 12 ml hot n-hexane, leading to 0.459 g (56%) of 2-chloro-6-trifluoromethyl-isonicotinic acid as an off-white solid. MS: 224.0 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:27][NH2:28]>O1CCOCC1>[NH:27]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:28]
Reactant: COc1cc(C(=O)N2CCc3nnc(Cl)cc3C2)cc(OC)c1OC
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCc3nnc(NN)cc3C2)cc(OC)c1OC

Procedure:
12.8 g of 3-chloro-5,6,7,8-tetrahydro-6-(3,4,5-trimethoxybenzoyl)pyrido[4,3-c]pyridazine and 40 cc of hydrazine hydrate in 40 cc of dioxane are stirred at a bath temperature of 100° for 41/2 hours. The title compound has a M.P. of 194°-197° (decomp., from absolute ethanol/methanol 2:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[C:23](Cl)([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24].Cl>O.O1CCOCC1.O1CCOCC1>[C:23]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:24]
Reactant: Nc1cccc(-c2ccc(C(=O)O)cc2)c1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2ccc(C(=O)O)cc2)c1)OCC1c2ccccc2-c2ccccc21
Temperature: 3 °C
Reaction time: 3 h

Procedure:
Dissolve 3′-aminobiphenyl-4-carboxylic acid (Preparation B, Step 3) (1.07 g, 5 mmol) and Na2CO3 (1.33 g, 12.5 mmol ) in H2O-dioxane (2:1, 45 mL), and cool the solution to ˜3° C. Add Fmoc-Cl (1.3 g) in dioxane (10 ml); stir at ice bath temperature for 3 hours, allow to warm to room temperature and stir for another 4 hours. Pour into ice water and acidify with aqueous HCl. Extract with EtOAc. Dry extracts over MgSO4, and strip solvent in vacuo. Recrystallize residue from CH3CN to give the title compound. HPLC Retention Time, 22.6 minutes (condition (b)).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:4][C:3]=1[Br:29].[NH2:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][C:37](O)=[O:38])[N:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[NH2:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][C:37]([NH:1][C:2]2[CH:28]=[CH:27][C:5]([CH2:6][C@H:7]3[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:8]3[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:4][C:3]=2[Br:29])=[O:38])[N:35]=1
Reactant: Nc1nc(CC(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(N)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(NC(=O)Cc3csc(N)n3)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.3 %

Procedure:
To a solution of 81 mg (0.18 mmol) of tert-butyl (2R,5R)-2-(4-amino-3-bromobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (i-80b) and (2-amino-1,3-thiazol-4-yl)acetic acid (45 mg, 0.18 mmol) in 2.0 mL anhydrous DMF was added HOBt (31 mg, 0.23 mmol) followed by EDC (45 mg) and DIEA (0.16 mL, 0.88 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×2 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by Gilson reverse phase HPLC eluting with a gradient of 10-90% acetonitrile in water with 0.05% TFA buffer to afforded the product (75 mg, 81%). m/z (ES) 601 (M)+ and 603 (M+2)+, also 623 (MNa)+ and 625 (MNa+2)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>>[O:22]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(Oc2ccccc2)cc1
Temperature: 150 °C
Reaction time: 48 h

Procedure:
A suspension of potassium carbonate (1 eq.), 4-flurobenzaldehyde, and phenol (1.2 eq.) was heated to 150° C. and stirred for two days. The reaction was allowed to cool to room temperature and poured into saturated aq. sodium bicarbonate and ice. The solution was extracted with ether. The combined organic layers were washed with water and dried with Na2SO4. Concentration under vacuum gave pure product as an orange oil.
Reaction SMILES: C(OC(C1C(N)=C(NC2C=CC=CC=2OC)N=C(N[C@H]2CCN(C(OC(C)(C)C)=O)C2)[N:7]=1)=O)C.C(OC([N:42]1[CH2:46][CH2:45][C@H:44]([NH:47][C:48]2[N:56]=[C:55]3[C:51]([NH:52][C:53](=[O:65])[N:54]3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[O:63][CH3:64])=[C:50]([C:66]([O:68]CC)=O)[N:49]=2)[CH2:43]1)=O)(C)(C)C>ClCCl>[CH3:64][O:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[N:54]1[C:53](=[O:65])[NH:52][C:51]2[C:55]1=[N:56][C:48]([NH:47][C@H:44]1[CH2:45][CH2:46][NH:42][CH2:43]1)=[N:49][C:50]=2[C:66]([NH2:7])=[O:68]
Reactant: CCOC(=O)c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc(Nc2ccccc2OC)c1N
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CCNC3)nc21
Yield: 132.1 %

Procedure:
(S)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (S)-Ethyl 5-amino-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.357 g, 0.756 mmol) and carbonyldiimidiazole (1.22 g, 7.56 mmol) in dichloromethane (20 mL) were reacted according to general procedure F and purified using biotage chromatography (0-100% ethyl acetate in hexanes) to afford a mixture of the title product (0.369 g, 98%). MS (ESI) m/z 499.5 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH:8]([CH2:10]C(O)=O)[CH2:9][C:5]=2[CH:4]=1.C[N:17](C=O)C.S(Cl)(Cl)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH:8]([CH2:10][NH2:17])[CH2:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC(CC(=O)O)O2
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(CN)O2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To 81 g of 5-methoxy-2,3-dihydro-3-benzofuranacetic acid in 250 ml of dichloromethane were added 0.5 ml of DMF and 48 ml of thionyl chloride. The mixture was stirred for 10 minutes and then heated at reflux for 1 hour. Dichloromethane and thionyl chloride were evaporated, and remaining traces of thionyl chloride were removed by evaporation with n-heptane. The resulting acid chloride was dissolved in 240 ml of acetone and added dropwise to a stirred solution of 25.5 g of NaN3 in 120 ml of water at 10°-15° C. Cold toluene (1500 ml) was added, and the organic phase was separated, washed with brine, dried (MgSO4) and finally placed in a 5 l beaker and heated slowly to 80° C. When the N2 evolution had ceased 600 ml of conc. hydrochloric acid and 900 ml of water were added. The resulting mixture was stirred overnight at room temperature. The water phase was separated and made alkaline (pH 10-11) by addition of ammonium hydroxide and finally extracted with dichloromethane. The organic phase was evaporated and the remaining oil was dissolved in 1000 ml of dil. hydrochloric acid. This solution was left for 16 hours and then added to 600 ml of ammonium hydroxide at 0° C. Dichloromethane was added, the organic phase was separated, dried (Na2SO4) and evaporated yielding 61 g of product as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:10](OCC)=[O:11].O1CCCC1.CC(C)([O-])C.[K+]>O>[OH:11]/[CH:10]=[C:4]1/[C:5](=[O:8])[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3]/1
Reactant: CCOC=O
Reactant: CC1(C)CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(=O)/C(=C/O)C1
Temperature: 2.5 °C
Reaction time: 12 h

Procedure:
4,4-Dimethylcyclohexanone (20 g), ethyl formate (15.8 g, 1.35 eq) and tetrahydrofuran (100 ml) were charged in a 250 ml flask and the mixture was cooled to 0-5° C. Potassium t-butoxide (1M in tetrahydrofuran 191 mL, 1.2 equiv) was slowly added while maintaining the temperature below 0° C. The reaction mixture was mixed at −5 to +5° C. and monitored for completion by GC analysis. After mixing overnight, no starting material was observed. Water (140 mL) was slowly added, and the resulting mixture was extracted with heptane (150 mL). The pH of the aqueous layer was adjusted with 6 M HCl to pH=1-2 (˜40 g HCl) and the extracted with toluene (80 mL). The organic layer was washed with 20% aqueous NaCl (2×140 mL). The product solution in toluene was used directly in the next step within 12 hours (storage at 0° C.).