Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1[C:27]2[CH2:28][CH2:29][CH:30]([NH2:32])[CH2:31][C:26]=2[NH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:32][CH:30]4[CH2:29][CH2:28][C:27]5[N:23]=[CH:24][NH:25][C:26]=5[CH2:31]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCc2nc[nH]c2C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCc2nc[nH]c2C1
Yield: 57 %

Procedure:
To a solution of 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (1 g, 3 mmol) and 4,5,6,7-Tetrahydro-3H-benzoimidazol-5-ylamine (450 mg, 3.3 mmol) in ethanol (50 ml) was added DIPEA (1 ml, 9.9 mmol). The mixture was heated to reflux for 1 h. Volatile components were removed, and the residue was extracted with ethyl acetate, washed with water and brine, the organic layer was purified by column chromatography (eluting with 10˜20% methanol in dichloromethane) to give 0.75 g (57%) of (1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-amine. LCMS (Method J, ESI): RT=0.95, m+H=438.9; 1H NMR (400 MHz, CDCl3+2 drops of CD3OD) δ: 9.20-9.15 (m, 1H), 9.05 (s, 1H), 8.17-8.14 (m, 2H), 8.05-8.00 (s, 1H), 7.65-7.48 (m, 2H), 7.55-7.45 (m, 2H), 6.80-6.75 (m, 1H), 4.60-4.50 (m, 1H), 3.30-3.20 (m, 1H), 2.95-2.80 (m, 3H), 2.30-2.00 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:29][C:30]1[C:31]([NH2:45])=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[NH2:45][C:31]1[N:32]=[CH:33][C:34]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:35][C:30]=1[CH3:29]
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Product: Cc1cc(-c2nc(N3CCOCC3)c3nc(CN4CCC(C(C)(C)O)CC4)ccc3n2)cnc1N

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol (0.185 g) was reacted with 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to produce 90.9 mg of 132 following reverse phase HPLC purification. MS (Q1) 478.3 (M)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[N+:15]([C:18]1[CH:23]=[C:22]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1Cl)([O-:17])=[O:16]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][C:19]2[CH:20]=[CH:21][C:22]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH:11]=[C:10]([O:12][C:19]2[CH:20]=[CH:21][C:22]([S:24]([C:27]([F:29])([F:30])[F:28])(=[O:26])=[O:25])=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])c1

Procedure:
Using procedure as in example 10, a reaction of methyl 3,5-dihydroxybenzoate (50 mg, 0.297 mmol), NaH (26 mg, 2.2 equiv.) and 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (172 mg, 0.595 mmol) afforded 3,5-bis-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-benzoic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([OH:45])[CH:40]=3)[O:35]2)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:45][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:40]=3)[O:35]2)=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccc(Cl)cc1)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2ccc(Cl)cc2)O3)nc1

Procedure:
2-(4-Chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 330 mg of 2-(4-chlorophenyl)chroman-4,6-diol. The product was purified by column chromatography using heptane-ethyl acetate (2:1) as an eluant. 1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.54-7.47 (m, 4H), 7.25 (d, 1H, J 2.8 Hz), 7.22 (d, 1H, 9.1 Hz), 7.02 (dd, 1H, J 8.8, 2.8 Hz), 6.89 (d, 1H, J 8.8 Hz), 5.65 (d, 1H, J 6.4 Hz), 5.33 (d, 1H, J 10.6 Hz), 4.98 (m, 1H), 2.34 (m, 1H), 1.94 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:41][N:42]([C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:43](=[O:58])[C@H:44]([NH:56][CH3:57])[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][CH2:15][C:16](=[O:18])[N:56]([CH3:57])[C@@H:44]([C:43](=[O:58])[N:42]([CH3:41])[C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a solution of (2S)-2-(((carboxy)methoxy)methyl)-pyrrolidin-1-carboxylic acid tert-butylester (1.2 g, 4.5 mmol) in dichloromethane (20 ml) were added 1-hydroxy-7-azabenzotriazole (612 mg, 4.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (950 mg, 4.95 mmol) and the mixture was stirred for 30 min. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (605 mg, 1.5 mmol) in dichloromethane (10 mL) was added followed by diisopropylethylamine (0.33 ml, 2.0 mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was washed with water (10 ml), aqueous sodium bicarbonate (10 ml), water (2×10 ml), brine (10 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (40 g) with ethyl acetate/heptane 4:1 to give 760 mg of (2S)-2-([N-methyl-N-{(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)pyrrolidine-1-carboxylic acid tert-butylester. The obtained product was taken up in 50% trifluoroacetic acid in methylene chloride (5 ml) and stirred for 10 min. Then saturated sodium bicarbonate was added until pH 8 and the phases were separated. The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The product was redissolved in water (30 ml) and acetic acid (2 ml) was added and the mixture was liophilized to give 720 mg of the acetate salt of the title compound as an amorphous powder.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([CH3:42])[C:39]([O:43]CC4C=CC=CC=4)=[C:38]([CH3:51])[CH:37]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:52]=[CH:53][CH:54]=[CH:55][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:37]=[C:38]([CH3:51])[C:39]([OH:43])=[C:40]([CH3:42])[CH:41]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:28][CH2:29][S:30](=[O:33])(=[O:34])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:52]=[CH:53][CH:54]=[CH:55][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCS(=O)(=O)CC3)CC2)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCS(=O)(=O)CC3)CC2)cc(C)c1O

Procedure:
A solution of 45 mg (0.06 mmol) (R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 10 mL MeOH was combined with 10 mg 10% Pd/C and hydrogenated at RT and 3 bar hydrogen pressure until the reaction came to an end. The catalyst was removed by suction filtering and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:34]([O:36][CH3:37])=[O:35])=[CH:17][C:18]=3[N:19]3[C:25]=2[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[NH:22][CH:21]([C:30]([O:32][CH3:33])=[O:31])[CH2:20]3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>CCOC(C)=O>[Cl:1][CH2:2][C:3]([N:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[C:25]2=[C:12]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[C:13]3[CH:14]=[CH:15][C:16]([C:34]([O:36][CH3:37])=[O:35])=[CH:17][C:18]=3[N:19]2[CH2:20][CH:21]1[C:30]([O:32][CH3:33])=[O:31])=[O:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Nc1ccccc1-3
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)N(C(=O)CCl)c1ccccc1-3
Temperature: 40 °C

Procedure:
Chloroacetyl chloride (5 eq) was added to a sealed tube containing dimethyl 13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-6,10-dicarboxylate (1 eq.). The mixture was heated at 40° C. overnight. The mixture was allowed to cool to RT before being diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound (quant.). MS (ES+) m/z 509 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][N:26]([CH2:34][CH2:35][CH2:36][O:37][CH3:38])C(=O)OC(C)(C)C)=[CH:19][CH:18]=2)=[N:6][C:7]=1[C:8](=[O:16])[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.Cl.[OH-].[Na+].CC1CCCO1>O>[NH2:1][C:2]1[C:7]([C:8]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:16])=[N:6][C:5]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][NH:26][CH2:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:21][CH:22]=2)=[CH:4][N:3]=1
Reactant: COCCCN(CCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC1CCCO1
Product: COCCCNCCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Temperature: 70 °C

Procedure:
Tert-butyl (3-{4-[5-amino-6-(pyridin-3-ylcarbamoyl)pyrazin-2-yl]phenyl}propyl)(3-methoxypropyl)carbamate (1 kg) and water (8 L) were added to the reactor, stirred and heated up to 70° C. 36% Hydrochloric acid (606 ml) was added slowly controlling rate of gas evolution. The contents were stirred for 45 minutes at 70° C. The pH was adjusted to 3-4 by addition of sodium hydroxide (325 ml). The contents were cooled to 50° C. and 2-methyltetrahydrofuran (5 L) was added. The pH was then adjusted to pH 11-12 by the addition of 48% sodium hydroxide liquor (170 ml). The contents were then cooled to 40° C. The batch allowed to settle and the two layers separated. The aqueous layer was washed with 2-methyltetrahydrofuran (2.5 L). The combined organic layers were washed with a solution of 10% w/v aqueous sodium chloride solution. The organic layer was distilled to remove 3.75 L of distillate. The remaining liquors were heated to 50° C. and methyl-t-butyl ether (4 L) added. The liquors were cooled to 10° C. over 4 hours then isolated by filtration. The solid was washed with methyl-t-butyl ether (2 L×2) and dried in a vacuum oven at 50° C. 3-amino-6-(4-{3-[(3-methoxypropyl)amino]propyl}phenyl)-N-pyridin-3-ylpyrazine-2-carboxamide (721 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[NH:24]1[CH:28]=[N:27][C:26]([SH:29])=[N:25]1.B(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:24]2[CH:28]=[N:27][C:26]([S:29][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)=[N:25]2)([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: Sc1nc[nH]n1
Agent: FB(F)F
Solvent: ClCCl
Product: Clc1ccc(C(Sc2ncn(C(c3ccc(Cl)cc3)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)n2)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Yield: 37.1 %

Procedure:
The procedure of Example 5(b) was followed, using 1.26 g (3.47 mmol) of tris(4-chlorophenyl)methanol, 0.52 g (5.1 mmol) of 1,2,4-triazole-3-thiol, 4.0 mL of CH2Cl2 and 1.25 mL (10 mmol) of BF3 etherate. Isolation followed by flash chromatography (75 g SiO2, 40% EtOAc-hexanes) gave 0.51 g of the title compound, followed by 0.71 g of an unstable product that turned into the title compound upon standing in solution. A 0.44 g sample of the first-eluted material was recrystallized from MeOH giving 0.18 g of (15), m.p. 219°-221° C. (dec).
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[CH2:1]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccccc1CCc1ccccc1
Product: COC(=O)c1ccc(NCc2ccccc2CCc2ccccc2)cc1

Procedure:
Methyl 4-[N-(2-(phenethyl)benzyl)amino]benzoate was prepared from 2-(phenethyl)benzaldehyde and methyl 4-aminobenzoate using a similar method to that of Example 4 paragraph (G).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(I)ccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: OCc1cc(I)ccc1Cl
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A solution of 2-chloro-5-iodobenzoic acid (28 g, 99 mmoles) and toluene (198 mL) was cooled to 0° C. A 1M diisobutyl aluminium hydride (DIBAL) solution in toluene 208 mL, 208 mmol) solution was added drop wise over 20 minutes. The solution was allowed to slowly warm to rt. After 16 h the solution was cooled to 0° C., MeOH and 1M HCl was slowly added (exothermic reaction). The solution became clumpy and was filtered and the clumps washed with EtOAc. The organic phase was then isolated and the aqueous layer washed with EtOAc. The combined organic extracts were then washed with brine, dried (Na2SO4), and concentrated. The product was purified by Biotage chromatography (0%-100% EtOAc/Hexanes) to afford 9.01 g of product as a solid (34%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.85 (d, J=2.02 Hz, 1 H) 7.55 (dd, J=8.34, 2.27 Hz, 1 H) 7.09 (d, J=8.34 Hz, 1 H) 4.74 (s, 2 H) 2.25 (s, 1 H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: OCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: BrCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.8 %

Procedure:
To a solution of 5.8 g (42 mmol) of 3-bromopropanol prepared in step B and 3.5 g (42 mmol) of dihydropyran in 15 mL of methylene chloride is added 20 mg (0.116 mmol) of p-toluenesulfonic acid, and the reaction mixture is stirred at room temperature for 7 hours, then washed with 10% NaOH solution and brine, dried, and evaporated to dryness to give 8.7 g of title product in 96% yield.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.Cl.C([O-])([O-])=[O:18].[K+].[K+]>>[OH:18][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(CBr)c2ccccc12
Agent: Cl
Agent: [K+]
Product: O=C(O)c1ccc(CO)c2ccccc12

Procedure:
4-Bromomethylnaphthoic acid (16 g, 160 mmol) in an aqueous solution of K2CO3 (10%, 100 mL) was stirred at 70° C. for 30 minutes. The reaction mixture was cooled and made acidic with conc. HCl. The resulting precipitate was filtered and dried to give the desired product as a yellow solid in quantitative yield.
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(C5CCCN5[C:46](=[O:56])[CH:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])=NC=4)=CC=3)=CC=2)=CN=1)=O)CCC(F)(F)F.[CH3:58][O:59][C:60](=[O:105])[NH:61][CH:62]([C:71]([N:73]1[CH2:77][CH2:76][CH2:75][CH:74]1[C:78]1[NH:79][C:80]([C:83]2[CH:88]=[CH:87][C:86]([C:89]3[CH:94]=[CH:93][C:92]([C:95]4[NH:96][C:97]([CH:100]5[CH2:104][CH2:103][CH2:102][NH:101]5)=[N:98][CH:99]=4)=[CH:91][CH:90]=3)=[CH:85][CH:84]=2)=[CH:81][N:82]=1)=[O:72])[CH2:63][CH2:64][O:65][CH2:66][C:67]([F:70])([F:69])[F:68]>>[CH3:55][O:54][C:52](=[O:53])[NH:51][CH:47]([C:46]([N:101]1[CH2:102][CH2:103][CH2:104][CH:100]1[C:97]1[NH:96][C:95]([C:92]2[CH:93]=[CH:94][C:89]([C:86]3[CH:87]=[CH:88][C:83]([C:80]4[NH:79][C:78]([CH:74]5[CH2:75][CH2:76][CH2:77][N:73]5[C:71](=[O:72])[CH:62]([NH:61][C:60]([O:59][CH3:58])=[O:105])[CH2:63][CH2:64][O:65][CH2:66][C:67]([F:70])([F:68])[F:69])=[N:82][CH:81]=4)=[CH:84][CH:85]=3)=[CH:90][CH:91]=2)=[CH:99][N:98]=1)=[O:56])[CH:48]([CH3:50])[CH3:49]
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1
Reactant: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
Product: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1
Yield: 45 %

Procedure:
This compound was made in 45% yield by the same procedure as (4,4,4-Trifluoro-1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl)-carbamic acid methyl ester, using [1-(2-{5-[4′-(2-Pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-3-(2,2,2-trifluoroethoxy)-propyl]-carbamic acid methyl ester as the starting material. LCMS-ESI+: calculated for C41H49F3N8O7: 822.87; observed [M+1]+ : 823.45. 1H-NMR: 400 MHz, (CD3OD) δ: 7.82-7.72 (m, 4H), 7.69-7.65 (m, 4H), 7.38-7.32 (m, 2H), 5.22-5.16 (m, 2H), 4.65-4.61 (m, 1H), 4.26-4.21 (m, 1H), 4.04-3.84 (m, 6H), 3.72-3.48 (m, 8H), 2.39-1.98 (m, 10H), 1.88-1.78 (m, 1H), 1.01-0.89 (m, 6H) ppm.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][C:21]1[O:22][C:23]([CH2:26][C:27]2[S:28][C:29]3[CH:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:33]=[CH:32][C:30]=3[N:31]=2)=[N:24][N:25]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:20][C:21]1[O:22][C:23]([CH2:26][C:27]2[S:28][C:29]3[CH:35]=[C:34]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:33]=[CH:32][C:30]=3[N:31]=2)=[N:24][N:25]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 131.2 %

Procedure:
To a solution of Compound 45a (460 mg, 0.81 mmol) in DCM (5 mL) was added TFA (5 mL) and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was co-evaporated with toluene (3×) and DCM, then dried under high vacuum to give (S)-benzyl 2-amino-3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)propanoate (500 mg, 100% yield) as a yellow solid. LCMS=1.90 min using analytical method (B), 471.0 (M+H). In a separate flask, to a solution of sulfurisocyanatidic chloride (170 mg, 1.2 mmol) in DCM (2 mL) was added 2-methylpropan-2-ol (90 mg, 1.2 mmol) in DCM (2 mL) and the reaction mixture stirred for 20 min. The resulting solution was then added to a mixture of (S)-benzyl 2-amino-3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)propanoate (500 mg, 0.81 mmol) and TEA (0.56 mL, 4.0 mmol) in DCM (5 mL) and the reaction mixture stirred for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc, washed with 1 N HCl solution and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (6 mL) and treated with TFA (3 mL) then stirred for 1 h. The mixture was concentrated under reduced pressure, co-evaporated under reduced pressure with toluene and DCM, and the residue purified by silica gel chromatography eluting with 0-10% MeOH/DCM to give Compound 45b (380 mg, 86% yield) as a yellow solid. LCMS=2.00 min using analytical method (B), 550.2 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.15-8.08 (m, 1H), 8.06-8.00 (m, 1H), 7.76-7.70 (m, 1H), 7.66-7.58 (m, 2H), 7.50-7.44 (m, 2H), 7.42-7.27 (m, 7H), 5.65-5.58 (m, 1H), 5.23-5.19 (m, 1H), 5.16-5.09 (m, 2H), 4.73-4.61 (m, 3H), 3.53-3.30 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH2:20][C:21]4[CH:26]=[CH:25][C:24](F)=[CH:23][C:22]=4F)[CH:19]=3)[C:6](=[O:29])[N:5]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:4]=2[N:3]=1.[Cl:35]C1C=CC=CC=1CBr.N1CCOCC1>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:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:35])[CH:19]=3)[C:6](=[O:29])[N:5]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:4]=2[N:3]=1
Reactant: CCCCCn1c(=O)n(CCCc2cnn(Cc3ccc(F)cc3F)c2)c(=O)c2[nH]c(Cl)nc21
Reactant: Clc1ccccc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCc2cnn(Cc3ccccc3Cl)c2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 5.5 h

Procedure:
Prepared by the method for 8-chloro-1-(3-{1-[(2,4-difluorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione, Example 6 but from 2-chlorobenzyl bromide (164 mg, 0.8 mmol). However, in order to complete the deprotection step further tetrakis(triphenylphosphine)palladium(0) (40 mg) and morpholine (0.15 ml) were added and stirring continued for a further 5.5 h. Purification by aminopropyl SPE as above afforded the title compound as a solid (42 mg).