Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23]Cl)[N:9]=1.[CH2:34]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23][N:44]2[CH2:45][CH2:46][CH:41]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:42][CH2:43]2)[N:9]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=c1n(CCCCl)nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1Cc1ccccc1
Product: O=c1n(CCCN2CCC(Cc3ccccc3)CC2)nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1Cc1ccccc1

Procedure:
Prepared as for Example 6 using 3-(3,5-bis(tri-fluoromethyl)phenethyl)-4-benzyl-1-(3-chloropropyl)-5-oxo-1,2,4-triazole (Description 2) and 4-benzylpiperidine. MS m/e (CI+) 631 (100%, M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][CH3:17].C([Li])CCC.[P:23](Cl)([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:24]>>[CH3:17][O:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[P:23](=[O:24])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]
Reactant: CCOP(=O)(Cl)OCC
Reactant: COc1cccc(OC)c1-c1ccccc1Br
Agent: [Li]CCCC
Product: CCOP(=O)(OCC)c1ccccc1-c1c(OC)cccc1OC
Temperature: -78 °C
Yield: 65 %

Procedure:
To a 250-mL round-bottom flask equipped with a magnetic stir bar was added 2′-bromo-2,6-dimethoxybiphenyl (see Buchwald S L, Journal of the American Chemical Society 2005; 127:4685-4696) (7.02 g, 24.0 mmol, 1 equiv). Degassed, anhydrous tetrahydrofuran was added (80 mL) followed by N,N,N′,N′-tetramethylethylene-1,2-diamine (4.31 mL, 28.7 mmol, 1.2 equiv). The resulting solution was cooled to −78° C., and then n-butyllithium (11.5 mL, 28.7 mmol, 1.2 equiv, 2.5 Min hexanes) was added in a dropwise fashion. After the addition of 5 mL of n-butyllithium the reaction slurry could no longer be stirred. The reaction flask was warmed to 0° C. at which point the slurry became free-flowing. The remainder of the n-butyllithium (−6.5 mL) was added over the course of 10 minutes. The reaction was stirred for 90 minutes at 0° C., and then the aryllithium intermediate was quenched with diethyl chlorophosphate (4.15 mL, 28.7 mmol, 1.2 equiv). The reaction was re-cooled to −78° C. and stirred for 1 hour, then the cooling bath was removed and the flask was warmed to room temperature. At that point, the reaction solution was diluted with pH 7 phosphate buffer (100 mL). The reaction mixture was worked up by separating the phases and washing the aqueous layer with ethyl acetate (4×60 mL). The combined organic fractions were then washed once with brine (150 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by column chromatography (120-g column; gradient: 1.5 column volumes dichloromethane, ramp up to 88:12 dichloromethane:acetone over 10.5 column volumes, hold at 88:12 for 6 column volumes), the product was isolated as a white solid (5.49 g, 78 area % by HPLC, 65% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.07 (dd, J=14.1, 7.7 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 7.46-7.37 (m, 1H), 7.30 (t, J=8.3 Hz, 1H), 7.24-7.18 (m, 1H), 6.60 (d, J=8.4 Hz, 2H), 3.98-3.77 (m, 4H), 3.70 (s, 6H), 1.17 (t, J=7.1 Hz, 6H). 31P NMR (CDCl3, 202 MHz) δ ppm 15.2 (s).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:5]([S:2](=[O:4])(=[O:3])[N:27]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH3:26])[CH:6]=1
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: CNC1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OC)c(S(=O)(=O)N(C)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (2.0 g, 7.56 mmol) and diisopropylethylamine (1.94 ml, 11.34 mmol) in DCM (50 ml) is treated with N-methyl cyclohexylamine (0.70 ml, 9.07 mmol) at 0° C. The solution is stirred at room temperature for 3 hours and N-methyl cyclohexylamine (0.70 ml, 9.07 mmol) is added. The solution is partitioned between DCM (250 ml) and 0.5 N HCl (100 ml). The organic layer is washed with 0.5 N HCl (2×100 ml), sat. aq. NaHCO3 (2×100 ml) and water (100 ml), dried over MgSO4, and the solvent removed in vacuo to yield a yellow oil. Crystallisation (iPr2O/EtOAc) yields 3-(Cyclohexyl-methyl-sulfamoyl)-4-m ethoxy-benzoic acid methyl ester as yellow crystals; [M+H] 342.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[O:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.N([O-])=O.[Na+].[N-:17]=[N+:18]=[N-].[Na+]>Cl>[N:1]([C:2]1[C:3](=[O:12])[O:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N+:17]=[N-:18]
Reactant: Nc1cc2ccccc2oc1=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1cc2ccccc2oc1=O
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
3-Aminocoumarin (250 mg, 1.6 mmol) was dissolved in 30 mL of 3% HCl at room temperature. After cooling to 0-5° C., the solution was added drop-wise to a solution of NaNO2 (160 mg, 2.3 mmol) and stirred for two hours. Upon addition of NaN3 (150 mg, 2.3 mmol), the mixture was stirred at 0-5° C. for two hours followed by stirring at room temperature for three and a half hours. The precipitate was filtered, washed to neutral pH with water and dried under vacuum to afford a white solid; yield (226 mg, 78%); mp: 108-112° C.; 1H-NMR (300 MHz, CDCl3): δ 7.2-7.6 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[C:4]2[N:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([NH2:24])[CH2:19]1.CCN(C(C)C)C(C)C>CC(O)C.C([O-])(O)=O.[Na+]>[Cl:17][C:13]1[CH:12]=[C:11]([C:10]2[CH:9]=[N:8][N:5]3[CH:6]=[CH:7][C:2]([N:18]4[CH2:23][CH2:22][CH2:21][C@H:20]([NH2:24])[CH2:19]4)=[N:3][C:4]=23)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2cnn3ccc(Cl)nc23)c1
Reactant: N[C@H]1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@H]1CCCN(c2ccn3ncc(-c4cccc(Cl)c4)c3n2)C1
Yield: 28.2 %

Procedure:
A mixture of 5-chloro-3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.379 mmol), (S)-piperidin-3-amine (76 mg, 0.757 mmol), and DIEA (0.158 ml, 1.515 mmol) in 2-propanol (3 ml) was irradiated to 150° C. for 14 h in a Biotage microwave. After cooling, the mixture was diluted with saturated aqueous NaHCO3, and extracted three times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. After absorbing on celite, the compound was purified by chromatography (12 g silica, 0-15% methanol/DCM) to give (S)-1-(3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-3-amine (35 mg, 28% yield) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[N+:45]([O-:47])=[O:46])=[CH:30][CH:29]=2)[C@H:10]([O:48][CH2:49][C@H:50]([OH:57])[CH2:51][N:52]2[CH:56]=[N:55][CH:54]=[N:53]2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:27][O:26][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]([CH2:15][O:14][C@H:12]2[CH2:13][NH:8][CH2:9][C@@H:10]([O:48][CH2:49][C@H:50]([OH:57])[CH2:51][N:52]3[CH:56]=[N:55][CH:54]=[N:53]3)[C@@H:11]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[N+:45]([O-:47])=[O:46])=[CH:30][CH:29]=2)[CH:25]=1
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H](O)Cn3cncn3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12
Agent: Cl
Solvent: CO
Product: COc1cc(CO[C@H]2CNC[C@@H](OC[C@H](O)Cn3cncn3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (1) the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-[1,2,4]triazol-1-yl-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the (R)-1-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-3-[1,2,4]triazol-1-yl-propan-2-ol as colorless oil; MS: 684 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:29])[C:14]3[CH:19]=[C:18]([N:20]4[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]4)[CH:17]=[CH:16][C:15]=3[Cl:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CO.[CH3:32][Si](C=[N+]=[N-])(C)C>O1CCOCC1>[C:1]12([CH2:11][NH:12][C:13](=[O:29])[C:14]3[CH:19]=[C:18]([N:20]4[C:25](=[O:26])[N:24]([CH3:32])[C:23](=[O:27])[CH:22]=[N:21]4)[CH:17]=[CH:16][C:15]=3[Cl:28])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1COCCO1
Product: Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-adamantan-1-ylmethyl-2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide (66 mg, 0.159 mmol) in dioxane (1.5 ml) was added methanol (0.32 ml) followed by a 2.0 M solution of (trimethylsilyl)diazomethane (0.32 ml). After stirring for 18 hours at ambient temperature the mixture was concentrated under reduced pressure to give 67 mg of a light yellow amorphous solid. Mass Specrum (ES+) 429.6; (ES−) 427.6. Liquid chromatography retention time=2.8 min (using the LC/MS and method outlined for the examples in Table 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:32][CH2:33][CH3:34])=[CH:22][C:23]([Cl:31])=[C:24]([S:26]([NH:29][CH3:30])(=[O:28])=[O:27])[CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:35](Cl)([Cl:37])=[O:36].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:31][C:23]1[C:24]([S:26](=[O:28])(=[O:27])[NH:29][CH3:30])=[CH:25][C:20]([C:10]2[N:9]([C:35]([Cl:37])=[O:36])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]=2)=[C:21]([O:32][CH2:33][CH3:34])[CH:22]=1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In an analogous manner as described in example 29, 5-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-2-chloro-4-ethoxy-N-methyl-benzenesulfonamide was treated with phosgene and diisopropylethylamine in methylene chloride to give 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride. The crude carbamoyl chloride was then reacted with 1-hydroxybenzotriazole hydrate and diisopropylethylamine in methylene chloride to give the racemic 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carboxylic acid benzotriazol-1-yl ester after purification by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:30](Cl)=[O:31])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:33]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:30]([N:33]4[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34]4)=[O:31])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCNC1
Reactant: O=C(Cl)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Product: O=C(N1CCC(O)C1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.21 mmol) of the compound from Example 179A and 19 mg (0.21 mmol) of 3-pyrrolidinol were reacted according to the General Method 5. Yield: 43 mg (39% of theory)
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:5]=2[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][C:24]=2[O:35][CH3:36])[C:19]([Cl:37])=[CH:18][N:17]=1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:37][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:25][C:24]=2[O:35][CH3:36])=[N:21][C:16]([NH:13][C:10]2[CH:11]=[CH:12][C:5]3[CH2:4][CH2:3][C:2]([F:14])([F:1])[CH2:8][CH2:7][C:6]=3[CH:9]=2)=[N:17][CH:18]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(F)(F)CC2
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCC(F)(F)CC3)ncc1Cl
Reaction time: 0.17 h

Procedure:
Into a microwave vial was added 7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (55 mg, 0.00028 mol) and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (80 mg, 0.0002 mol) in isopropyl alcohol (4 mL, 0.05 mol). To this reaction mixture was added 4N HCl-dioxane (0.03 g, 0.0002 mol). The reaction was subjected to microwaves at 120° C. for 10 min. The reaction mixture was resubject to the microwave conditions (120° C. for 10 min) The reaction mixture was purified by prep HPLC using the Gilson system and a gradient of 30-50% acetonitrile-water. The peaks corresponding to product were combined extracted with methylene chloride and washed with bicarbonate and dried to give 5-Chloro-N*2*-(7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine a tan solid (34 mg, 30% yield). MP: 180-184° C.; 1HNMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.66 (broad s, 1H), 8.12 (s, 1H), 7.43 (s, 1H), 7.41 (d, 1H, J=8.84 Hz), 7.15 (d, 1H, J=8 Hz), 6.98 (d, 1H, 8 Hz), 6.71 (s, 1H), 6.54 (d, 1H, J=9 Hz), 3.78 (s, 7H), 3.18 (dd, 4H, J=5, 9 Hz), 2.65 (dd, 2H, J=5, 10 Hz), 1.97 (m, 4H); MS (m/e) 516 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.Cl.[CH3:39][O:40][C:41]([C:43]1[N:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:45]2[C:50]([C:51](=[O:55])[C:52]=1[CH2:53][NH2:54])=[CH:49][CH:48]=[C:47]([Cl:56])[CH:46]=2)=[O:42]>C(Cl)Cl>[CH3:39][O:40][C:41]([C:43]1[N:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:45]2[C:50]([C:51](=[O:55])[C:52]=1[CH2:53][NH:54][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=1)=[CH:49][CH:48]=[C:47]([Cl:56])[CH:46]=2)=[O:42]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(CNC(=O)c2ccc(S(C)(=O)=O)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-(methanesulfonyl)benzoic acid (50.2 mg, 0.251 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (140 mg, 0.301 mmol) N,N-diisopropylethylamine (162 mg, 1.25 mmol) and CH2Cl2 (10 mL) was stirred at room temperature for 5 min. After this time, 3-aminomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester hydrochloride (intermediate I) (95 mg, 0.251 mmol) was added. The reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated and purified by preparative reverse-phase HPLC, providing 7-chloro-3-[(4-methanesulfonyl-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydroquin-oline-2-carboxylic acid methyl ester. MS calcd. for C26H22ClN2O6S [(M+H)+] 525.1, obsd. 525.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Li].Cl[S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([O:31]C)=[O:30])=[N:27][CH:28]=1)(=[O:22])=[O:21].[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=1)(=[O:21])=[O:22]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cn1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)nc2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 961 mg, 3.84 mmol, 1.0 eq) was suspended in THF (10 ml) and stirred at −78° C. for 10 minutes. 1,1,1,3,3,3-Hexanemethyldisilazane lithium salt (LiHMDS, 1M in THF, 4.2 ml, 4.2 mmol, 1.1 eq) was added dropwise maintaining the temperature below −70° C. and the reaction mixture stirred for a further 30 minutes. A solution of methyl 5-(chlorosulfonyl)pyridine-2-carboxylate (Preparation 16, 1 g, 3.8 mmol, 1 eq) in THF (5 ml) was added dropwise maintaining the reaction temperature below −72° C. and the reaction mixture allowed to warm to room temperature for 2 hours. The reaction mixture was diluted with water (10 ml), extracted into ethyl acetate (5 ml), dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was dissolved in dioxane (5 ml), a solution of sodium hydroxide (311 mg, 7.77 mmol, 2 eq) in water (2 ml) was added and the reaction mixture stirred at room temperature for 30 minutes. The MeOH was evaporated and the remaining aqueous solution washed with ethyl acetate (10 ml). Brine (10 ml) was added to the aqueous phase and the solution extracted with ethyl acetate (10 ml). A precipitate formed in the organic phase which was collected by filtration to yield the title compound as a white solid (415 mg, 0.95 mmol, 25%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:35])[C@@H:15]([NH:31][C:32](=[O:34])[CH3:33])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC3C=CC=CC=3)[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:36][CH2:37][C:38]2([CH3:43])[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:35])[C@@H:15]([NH:31][C:32](=[O:34])[CH3:33])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:36][CH2:37][C:38]2([CH3:43])[CH2:39][CH2:40][CH2:41][CH2:42]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(=O)N[C@@H](Cc1cccc(OCc2ccccc2)c1)[C@H](O)[C@H]1CO[C@@H](OCC2(C)CCCC2)CN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)[C@H]1CO[C@@H](OCC2(C)CCCC2)CN1C(=O)OC(C)(C)C
Yield: 98.5 %

Procedure:
Hydrogenate (2R,5R)-5-[(1S,2S)-2-Acetylamino-3-(3-benzyloxyphenyl)-1-hydroxypropyl]-2-(1-methylcyclopentylmethoxy)-morpholine-4-carboxylic acid tert-butyl ester (244 mg) in methanol (15 mL) with 20% palladium hydroxide on carbon (26 mg) at 50 psi hydrogen for 18 hours. Filter and concentrate to give the desired compound (204 mg). MS(ES): m/z=507 [M+H]
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:39]=[CH:38][C:37]([S:40][CH3:41])=[CH:36][CH:35]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)=[O:8].C([O-])(O)=[O:49].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.[O-]S([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[C:3]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:35]=[CH:36][C:37]([S:40]([CH3:41])=[O:49])=[CH:38][CH:39]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:11][CH2:12][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:14][CH2:15]1)=[O:8]
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2ccc(SC)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2ccc(S(C)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred suspension of methyl sulfide 209 (75 mg, 0.11 mmol) and NaHCO3 (46 mg, 0.55 mmol) in DCM (3 mL) at 0° C. is treated with a solution of m-chloroperbenzoic acid (20 mg, 0.12 mmol) in DCM (1 mL) dropwise over 2 minutes. After stirring 2 h at RT, the reaction is diluted with aqueous Na2SO3 (10 mL) and extracted into DCM (3×10 mL). The combined DCM phases are then dried (Na2SO4) and reduced in vacuo. The residue is purified by column chromatography (gradient elution—10-90% EtOAc in heptane with 0.5% triethylamine) to give the title compound.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([OH:17])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:24][CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[CH2:26][CH2:27][OH:28]>>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([NH:24][CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH2:26][CH2:27][OH:28])=[O:17])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: NC(CCO)c1ccccc1Cl
Product: O=C(NC(CCO)c1ccccc1Cl)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general strategies and protocols outlined in Example 1, starting from 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3-amino-3-(2-chlorophenyl)-1-propanol (Intermediate 2), the title compound was obtained in 94% purity by HPLC.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([N:29]2[CH2:33][CH2:32][C@@H:31]([NH:34][C:35]([NH:37][C:38]4C=NC=CC=4)=[O:36])[CH2:30]2)=[N:12][C:13]=3[NH:17][C@H:18]([CH2:27][OH:28])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:4][C@@H:3]1[NH:44][C:45](=[O:48])[CH2:46][OH:47].[C:49]1([O:55]C(=O)NC2C=NC=CC=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([N:29]2[CH2:33][CH2:32][C@@H:31]([NH:34][C:35]([NH:37][CH2:38][C:53]4[CH:52]=[CH:51][CH:50]=[C:49]([OH:55])[CH:54]=4)=[O:36])[CH2:30]2)=[N:12][C:13]=3[NH:17][C@H:18]([CH2:27][OH:28])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:4][C@@H:3]1[NH:44][C:45](=[O:48])[CH2:46][OH:47]
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)NCc5cccc(O)c5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-((1S,2R,3S,4R)-2,3-Dihydroxy-4-{6-[(S)-1-hydroxymethyl-2-(4-hydroxy-phenyl)-ethylamino]-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-cyclopentyl)-2-hydroxy-acetamide (Example 195), by substituting (3-hydroxy-benzyl)-carbamic acid phenyl ester (Intermediate ZD) for pyridin-3-yl-carbamic acid phenyl ester (Intermediate ZB).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH3:11][N:12]1[CH2:16][CH2:15][C@H:14](O)[CH2:13]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:7]=1)[O:8][C@@H:14]1[CH2:15][CH2:16][N:12]([CH3:11])[CH2:13]1
Reactant: COc1ccc(Br)cc1O
Reactant: CN1CC[C@H](O)C1
Product: COc1ccc(Br)cc1O[C@@H]1CCN(C)C1
Yield: 58.4 %

Procedure:
The title compound was prepared by the method outlined for Preparative Example 63 using 5-bromo-2-methoxy-phenol (1.00 g, 4.926 mmol) and (S)-1-methyl-pyrrolidin-3-ol (601 mg, 5.94 mmol) to afford titled compound as a colorless solid (823 mg, 58%). LC/MS (Method B) 1.18 min, [M+1]+ 286/288.