Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(#N)C.CN(C)C=O>[NH:4]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:20](=[O:21])[O:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)[CH:9]=[CH:10][CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Nc1cccc(-c2nnn[nH]2)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
A solution of [3-(1H-tetrazol-5-yl)phenyl]amine (0.97 g, 0.006 mol) in acetonitrile (25 mL), dimethylformamide (3 mL) and pyridine (0.97 mL, 0.95 g, 0.012 mol) under argon at 0° was treated with p-nitrophenyl chloroformate (1.21 g, 0.006 mol) and was stirred at room temperature overnight The reaction mixture was concentrated in vacuo and an effort was made to partition the remaining oil between ethyl acetate and 1M HCl, resulting in separation of a pink solid insoluble in either phase. The solid was sintered off and the organic layer was dried over magnesium sulfate, concentrated in vacuo to give additional product The two crops were combined, triturated with wet ether and dried in vacuo to yield 1.52 g of 3-(1H-tetrazol-5-yl)phenylcarbamic acid, 4-nitrophenyl ester, m.p. 186°-188° C. TLC, silica gel, EtOAc/MeOH/HOAc (20:1:.2), Rf =0.65; M.S. (M+H)+ at 327, M.W. 326. This material was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O.O>[CH3:9][S:8][C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(S)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: CSc1cccc(O)c1
Reaction time: 0.75 h

Procedure:
3-Hydroxythiophenol (5.0 g, 39.7 mmol) and potassium carbonate (6.03 g, 43.6 mmol) were stirred in acetone (80 mL) at 0° C. Iodomethane (2.5 mL, 40 mmol) was added dropwise, and the reaction stirred for 45 min. The solution was diluted with H2O (150 mL) and extracted with EtOAc (2×100 mL). Organics were washed with brine (100 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (25% EtOAc/hexanes) 5.08 g (91%) of 3-methylsulfanyl-phenol as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.15 (t, 1H, J=8.1 Hz), 6.82 (d, 1H, J=8.1 Hz), 6.74 (t, 1H, J=1.8 Hz), 6.60 (dd, 1H, J=8.1, 1.8 Hz), 4.86 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15](=[O:17])[NH:14][C:13]=2[CH:18]=1.C(N(CC)CC)C>O1CCCC1>[O:17]=[C:15]1[NH:14][C:13]2[CH:18]=[C:9]([CH2:8][CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[CH:11][C:12]=2[O:16]1
Reactant: O=c1[nH]c2cc(CCO)ccc2o1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1ccc2oc(=O)[nH]c2c1
Reaction time: 3 h
Yield: 27.9 %

Procedure:
Methanesulfonyl chloride (0.23 ml, 2.93 mmol) was added dropwise, at room temperature, to a solution of alcohol (b) (0.5 g, 2.79 mmol) and triethylamine (0.41 ml, 3 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred for 3 hours. More methane sulfonyl chloride (0.1 ml) and triethylamine (0.1 ml) were added and stirring was continued over night. The same amount of reagent was added yet again and stirring continued for 2 hours. The solvent was then concentrated, the residue was suspended in water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated. The solid residue was chromatographed on silica gel eluting with heptane-ethyl acetate (1-1) to give the product (0.2 g, 28%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]([C:41]1C=[CH:45][CH:44]=[CH:43][C:42]=1O)([CH3:40])([CH3:39])[CH3:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:37]([CH3:40])([CH3:39])[CH3:38])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccccc1O
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Oc4ccccc4C(C)(C)C)cc3C)c2cc1OC
Yield: 99.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-(tert-butyl)phenol (35 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 96%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br-:1].[OH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCCCCCCCCCCBr
Solvent: CC#N
Product: OCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A solution 10-bromodecanol (23.7 g) and triphenylphosphine (78.6 g) in dry acetonitrile (100 ml) was refluxed for 48 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]3[O:30][CH2:29]3)=[CH:22][CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH2:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH:28]([OH:30])[CH2:29][NH:35][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:25]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(c2ccc(OCC3CO3)cc2)C2CCCc3ccccc32)cc1
Reactant: CCCCN
Solvent: CCO
Product: CCCCNCC(O)COc1ccc(C(c2ccc(OC)cc2)C2CCCc3ccccc32)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(4-(2,3-epoxypropyloxy)phenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (400 mg, 0.01 mol), n-butyl amine (1.0 ml, 0.01 mol) and ethanol (10 ml) was refluxed for 8 hrs. Ethanol was distilled off and the residue was passed through basic alumina using benzene:ethyl acetate as the eluent. The solvent was distilled off yielding the required product. Yield 230 mg (48.93%).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C1COCC1>[CH3:13][O:14][C:15](=[O:24])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)Cc1ccc(C)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
n-BuLi (1.60M in hexanes, 40.7 mL, 65.1 mmol) was added to a 0° C. solution of diisopropylamine (9.4 mL, 67.0) in 280 mL THF. The mixture was allowed to stir at 0° C. for 30 minutes, then cooled to −78° C. A solution of p-tolyl-acetic acid methyl ester (10.48 g, 63.8 mmol; prepared from p-tolyl-acetic acid) in 10 mL of THF was added to the −78° C. LDA solution by syringe, which was then stirred for 45 minutes. Neat tert-butyl bromoacetate (28 mL) was added by syringe, and the reaction was stirred 15 minutes at −78° C. The bath was removed, and the reaction was allowed to warm to room temperature. After stirring an additional 5 hours, the reaction mixture was quenched with saturated NH4Cl solution, and the organics were removed in vacuo. The oily mixture was extracted with ethyl acetate, and the organics were combined. The organic was dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was purified by on silica gel (25:1 hexanes:EtOAc) to afford the 2-p-tolyl-succinic acid 4-tert-butyl ester 1-methyl ester as a pale yellow oil (15.3 g, 86%). 1H NMR (CDCl3, 400 MHz) δ 7.16 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 3.99 (dd, J=10.4, 5.6 Hz, 1H), 3.66 (s, 3H), 3.09 (dd, J=16.8, 10.4 Hz, 1H), 2.57 (dd, J=16.8, 5.6 Hz, 1H), 2.32 (s, 3H), 1.41 (m, 1H). HPLC Rt=3.71 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([NH2:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[S:31][C:30]([C:32](Cl)=[O:33])=[CH:29][CH:28]=1.CCN(CC)CC.C(Cl)Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:10]([NH:25][C:32]([C:30]2[S:31][C:27]([Cl:26])=[CH:28][CH:29]=2)=[O:33])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](N)C1
Reactant: O=C(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(Cl)s2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
Cis-3-amino-4-benzyloxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (450 mg, 1.288 mmol), from Part F of Example 112, was added to a cooled mixture (0° C.) of 5-chloro-thiophen-carboxylic chloride (233 mg, 1.288 mmol), Et3N (0.54 mL, 3.864 mmol), and CH2Cl2 (10 mL). The mixture stirred overnight at rt. EtOAc (70 mL) was added. The mixture was washed with brine, and the organic phase dried over MgSO4 and concentrated. The crude product was purified by silica gel flash column chromatography (30% MeOH/EtOAc) to yield cis-4-benzyloxycarbonylamino-3-[(5-chloro-thiophene-2-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (236 mg). LC-MS: (M-100): 394.
Reaction SMILES: C(OC([N:8]1[CH2:23][CH2:22][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:24]>C(OCC)(=O)C>[ClH:24].[C:16]1([C:13]2[N:14]=[CH:15][C:10]3[CH2:9][NH:8][CH2:23][CH2:22][C:11]=3[N:12]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(-c3ccccc3)ncc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(-c2ncc3c(n2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester (prepared according to the method of Example 101, Step C, 304 mg, 0.98 mmol) in ethyl acetate (2 mL) was added hydrogen chloride (2.5 M in ethyl acetate, 3.9 mL, 9.76 mmol). This mixture was stirred at room temperature for 16 h and concentrated to give 256 mg (>100%) of the title compound of Example 101, Step D as a pale yellow solid. 1H NMR (CD3OD, 400 MHz) δ 8.75 (s, 1H), 8.42-8.38 (c, 2H), 7.51-7.45 (c, 3H), 4.48 (s, 2H), 3.68 (t, 2H) 3.35-3.25 (buried, 2H); MS (APCI) 212 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]=[C:4]([N:10]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][C@H:12]([C:20]([NH:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:21])[CH2:11]2)[CH:3]=1.[CH:29]1C=C(Cl)C=C(C(OO)=O)C=1.[O-:40][S:41]([O-:43])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([S:41]([CH3:29])(=[O:43])=[O:40])[N:5]=[C:4]([N:10]2[C@H:15]([C:16]([F:18])([F:19])[F:17])[CH2:14][CH2:13][C@H:12]([C:20]([NH:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:21])[CH2:11]2)[CH:3]=1
Reactant: CSc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Reactant: O=S([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To cis-1-[6-chloro-2-(methylthio)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (590 mg, 1.350 mmol) in CH2Cl2 (12 mL) was added mCPBA (757 mg, 3.38 mmol), and the reaction mixture was stirred for 1 hour at room temperature. A saturated solution of Na2SO3 was added, and the resulting mixture was stirred for 30 minutes. The mixture was poured onto saturated aqueous NaHCO3 and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound (640 mg) as a white solid. LC-MS (ES) m/z=469, 471 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:15]([CH:17]=O)=[CH:16][C:9]=23)[C:5]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[N:4]1)[CH3:2].[CH2:37]([NH:39][CH2:40][CH2:41][OH:42])[CH3:38]>>[CH2:37]([N:39]([CH2:17][C:15]1[N:14]([S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])[C:10]2=[N:11][CH:12]=[CH:13][C:8]([C:6]3[C:5]([C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=4)=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=3)=[C:9]2[CH:16]=1)[CH2:40][CH2:41][OH:42])[CH3:38]
Reactant: CCn1cc(-c2ccnc3c2cc(C=O)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CCNCCO
Product: CCN(CCO)Cc1cc2c(-c3cn(CC)nc3-c3ccc([N+](=O)[O-])cc3)ccnc2n1S(=O)(=O)c1ccccc1

Procedure:
Following the procedure described in Intermediate 101 using 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde and 2-(ethylamino)ethanol provided the title compound as a yellow solid. ESMS [M+H]+: 651.4.
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[NH:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.S(Cl)([Cl:21])=O>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:21])=[N:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(-n2cccn2)nc(-n2cccn2)c1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1nc(-n2cccn2)nc(-n2cccn2)c1Br
Yield: 61.2 %

Procedure:
To a solution of 1 g (3.26 mmol) of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4(3H)-one (intermediate 8) in 10 ml of DMF and 40 ml of DCM was added dropwise a solution of 0.71 ml (9.8 mmol) of thionyl chloride in 10 ml DCM. The reaction mixture was refluxed for two hours, at which time no starting material was observed by TLC. The solution was extracted two times with 10 ml of saturated solution of NaHCO3 and Brine. The organic layer was separated, dried with MgSO4 and concentrated to give 0.65 g (61.5%) of the 4-chloro-pyrimidine derivative.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][C:23]1[N:24]([C@@H:29]2[CH2:38][C:37]3[C:32](=[C:33]([F:40])[CH:34]=[C:35]([F:39])[CH:36]=3)[O:31][CH2:30]2)[C:25](=[S:28])[NH:26][CH:27]=1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.SCC(O)=O.[OH-].[K+].O>CN(C)C=O.CO.O>[CH2:1]([NH:8][CH2:21][CH2:22][C:23]1[N:24]([C@@H:29]2[CH2:38][C:37]3[C:32](=[C:33]([F:40])[CH:34]=[C:35]([F:39])[CH:36]=3)[O:31][CH2:30]2)[C:25](=[S:28])[NH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1)Cc1ccccc1
Agent: O=C(O)CS
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of (R)—N-benzyl-N-(2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)ethyl)-2-nitrobenzenesulfonamide (compound K′, 8 g, 13.64 mmol) and 2-mercaptoacetic acid (2.84 ml, 40.9 mmol) in dimethylformamide (DMF) (80 ml) was added 10N potassium hydroxide (10.23 ml, 102 mmol) in one portion with water cooling and the mixture was stirred at 20-25° C. under HPLC control for 3 hours. Methanol-water 1:1 (160 ml) was slowly added with stirring, the mixture was stirred for 2 hours at 20-25° C. Precipitate was collected, washed with MeOH-water 1:1 (80 ml), dried to give (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (4.96 g, 12.35 mmol, 91% yield).
Reaction SMILES: [F:1][C:2]([F:10])(S(F)(=O)=O)C(O)=O.[F:11][C:12]([F:37])([F:36])[C@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:35])[C:21]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([NH2:30])=[N:23][C:22]=2[O:31][CH2:32][CH2:33][OH:34])[CH2:15][CH2:14]1>CC#N.[Cu]I>[F:37][C:12]([F:36])([F:11])[C@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:20](=[O:35])[C:21]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([NH2:30])=[N:23][C:22]=2[O:31][CH2:32][CH2:33][O:34][CH:2]([F:10])[F:1])[CH2:17][CH2:18]1
Reactant: Nc1nc(OCCO)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CC#N
Product: Nc1nc(OCCOC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
2,2-Difluoro-2-fluorosulfonylacetic acid (205 μl, 1.98 mmol) in MeCN (20 ml) is added via a syringe pump to a mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-(2-hydroxy-ethoxy)-6-amino-5-nitro-nicotinamide (390 mg, 0.994 mmol) and CuI (94 mg, 0.49 mmol) in MeCN (40 ml) over 2.5 h at 55° C. It is stirred for additional 20 min, then the mixture is concentrated and purified via extensive chromatography.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=1)=O.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C=O)C.COC(OC)OC>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][CH2:1][C:3]2[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=Cc1ccc(C(=O)NCCC(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: O=C(O)CCNC(=O)c1ccc(CNc2ccc(Br)cc2)cc1
Reaction time: 1 h

Procedure:
The above resin bound 3-(4-formylbenzoylamino)propionic acid (50 mg) was treated with a solution of 4-bromoaniline (500 [mol) in a mixture of DMF (500 μL) and trimethylorthoformate (500 μL). Glacial acetic acid (100 μL) was added and the mixture was shaked for 1 hour at 25° C. Sodium cyanoborohydride (750 μmol) suspended in a mixture of DMF and trimethyl-orthoformate (1:1, 1 mL) was added and the mixture was vortexed at 25° C. for 16 hours followed by filtration and washing with a mixture of DMF and water (4:1, 2×1 mL) followed by 3×1 mL DMF and 2×1 mL dichloromethane to afford the desired product.
Reaction SMILES: II.BrCCBr.Cl[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19](/[CH:22]=[N:23]/[S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])=[CH:18][CH:17]=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([CH:22]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[NH:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])=[CH:18][CH:17]=1
Reactant: COc1ccc(/C=N/[S@](=O)C(C)(C)C)cn1
Reactant: ClC1CCOCC1
Agent: II
Solvent: BrCCBr
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(N[S@](=O)C(C)(C)C)C2CCOCC2)cn1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Mg (10.6 g, 438 mmol) was dispersed in THF (160 mL) and 1 crystal of I2 and 1,2-dibromoethane (0.25 mL) were added. 4-Chlorotetrahydro-2H-pyran, dissolved in THF (50 mL), was added dropwise and the mixture was heated at 70° C. for 1.5 h. The solution was cooled to 0° C. and the product from step A was added dropwise as a solution in toluene (100 mL). The reaction was aged at rt for 2 h and the mixture was filtered eluting with MTBE. The reaction was quenched with sat. NH4Cl (aq) and extracted twice with EtOAc. The organic layers were combined and washed with brine, dried with Na2SO4, filtered and concentrated. The resulting oil was purified by flash chromatography on silica gel gradient eluted with 100% EtOAc to 8% MeOH in EtOAc affording the desired slow eluting diastereomer, (B-1). HPLC/MS: 327.1 (M+1); Rt=231 min. The fast eluting isomer on silica gel (B-2) was also isolated. HPLC/MS: 327.1 (M+1); Rt=2.15 min
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>ClCCl>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[O:23])=[CH:25][CH:26]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccncc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h

Procedure:
to a solution of 4-(aminomethyl)pyridine (12.9 ml, 127 mmol) and pyridine (51.4 ml, 636 mmol) in 150 mL dichloromethane cooled by an ice bath was added 4-nitrobenzoyl chloride (24.8 g, 133 mmol) all at once, generating a dark red reaction solution. LC-MS at 5 minutes indicated reaction complete and the desired product predominated. The reaction was stirred at room temperature overnight then the solid collected by filtration. LC-MS indicated that the filtrate was desired product. The solid was washed with 5% aqueous sodium hydroxide solution until aqueous layer was alkaline then the solid collected by filtration. The solid was dried overnight in a vacuum dessicator over P2O5 (28.4 g, 87%). ESI+ m/z=258.1 [MH]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=3)[CH:7]=[CH:6][C:5]2=1.[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]=1[CH3:42])=[O:32].C([O-])([O-])=O.[Na+].[Na+]>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>[C:15]([C:13]1[CH:14]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH:31]=[O:32])=[C:34]([CH3:42])[CH:35]=2)[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[C:8]([C:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:20][CH:19]=3)[CH:7]=[CH:6][C:5]2=1)(=[O:17])[NH2:16]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(Br)cc23)CC1
Reactant: Cc1cc(B(O)O)ccc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(-c2cc(C(N)=O)c3[nH]c4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)ccc4c3c2)ccc1C=O
Reaction time: 4 h

Procedure:
To the reaction mixture above (483A) was added 4-formyl-3-methylphenylboronic acid (103 mg, 0.627 mmol), Pd(Ph3P)4 (11.14 mg, 9.64 μmol) and Na2CO3 (0.482 mL, 0.964 mmol). The mixture was stirred at 105 C for 4 hrs. The mixture was filtered and then purified using preparative HPLC to give titled product. MS (ESI) m/z 508.31 (M−H)−.