Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)[N:29]=1>ClCCl.N1C=CC=CC=1>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[C:36]([NH:40][C:14]([C:1]3[C:13]4[CH2:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:15])[CH:37]=[CH:38][CH:39]=2)[N:29]=1
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Reactant: Nc1cccc(-c2cccnn2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2cccnn2)c1)c1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 13.8 %

Procedure:
To a suspension of 1-fluorenecarboxylic acid (184 mg) and oxalyl chloride (0.2 ml) in dichloromethane (4 ml) was added N,N-dimethylformamide (0.01 ml), and the mixture was stirred for 2 hours. The resultant solution was evaporated to give a crude acid chloride. To a suspension of 3-pyridazin-3-yl-phenylamine (150 mg) and pyridine (0.21 ml) in dichloromethane (2 ml) was dropwise added a solution of the acid chloride obtained above in dichloromethane. (5 ml) followed by stirring for an hour. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-(3-(pyridazin-3-yl)phenyl)-9H-fluorene-1-carboxamide (44 mg, 13.8%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O>[Zn].O>[Cl:3][N:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Cl:3])[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Product: Clc1ccccc1N(Cl)Nc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a stirred solution of 50% NaOH (1 mL, 12.5 mM) was added 2-chloronitrobenzene (3.14 g, 20 mM) and the resulting solution was heated to 60° C. Zinc dust (3 g, 46 mM) was added at such a rate as to keep the temperature of the reaction below 80° C. After the addition was complete, 20% NaOH (6 mL, 30 mM) was added followed by water (10 mL). An additional quantity of zinc dust (4 g, 71 mM) was then added in one portion. The resulting mixture was stirred between 75°-80° C. for 30 minutes. The mixture was cooled to room temperature and the solids were filtered and extracted with ether. The combined filtrates were dried over Na2SO4 and concentrated. Purification via flash column chromatography gave a solid which was then triturated with ether. This afforded the titled product as a yellow solid (1.2 g, 60%). NMR (CDCl3): 7.31 (m, 2H), 7.11 (m, 2H), 6.94 (m, 2H), 6.76 (m, 2H), 6.21 (br s, 2H). MS(CI): 253(M+1).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C1COCC1>[C:1]1([CH2:7]/[CH:8]=[CH:9]\[N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CC#Cc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: C1CCOC1
Solvent: c1ccc2ncccc2c1
Product: O=C1c2ccccc2C(=O)N1/C=C\Cc1ccccc1

Procedure:
The title compound was prepared from the title product (15 g, 57.4 mmol) of Example 153 by hydrogenation using Lindlar catalyst (2.25 g) and quinoline (0.79 g, 6.09 mmol) in THF (150 ml). The reaction mixture was hydrogenated at 5 psi and 0° to obtain a quantitative yield of the cis product.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[CH2:32]([O:35][C:36](Cl)=[O:37])[CH2:33][CH3:34]>>[CH2:32]([O:35][C:36]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:37])[CH2:33][CH3:34]
Reactant: CCCOC(=O)Cl
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCCOC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 17 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and propylchloroformate (Aldrich), to afford 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid propyl ester. HRMS, observed: 414.2140; Calcd for (M+H)+: 414.2136.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1.[C:18]([N:21]1[CH2:25][CH2:24][NH:23][C:22]1=[O:26])(=[O:20])[CH3:19].CNCCNC.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>[Cu]I>[C:18]([N:21]1[CH2:25][CH2:24][N:23]([C:10]2[C:4]3[C:5](=[CH:6][N:7]=[C:2]([Br:1])[CH:3]=3)[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=2)[C:22]1=[O:26])(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCNC1=O
Reactant: Brc1cc2c(I)nn(C3CCCCO3)c2cn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2nn(C3CCCCO3)c3cnc(Br)cc23)C1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution containing 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (1.00 g, 2.45 mmol), 1-acetylimidazolidin-2-one (0.3768 g, 2.941 mmol), N,N′-Dimethylethylenediamine (0.528 mL, 4.90 mmol), Copper(I) iodide (0.467 g, 2.45 mmol) and Potassium carbonate (0.4064 g, 2.941 mmol) in 1,4-Dioxane (40.0 mL, 512 mmol) was stirred at 75° C. for 2 h. The reaction was filtered thru celite and concentrated. The crude product purified by Isco column (1% MeOH/EtOAc/Hep eluted at 55% EtOAc) to give 1-acetyl-3-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)imidazolidin-2-one (620 mg, 62% yield). ESI MS m/z=408.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].BrC[C:37]1[CH:42]=[CH:41]C=C[C:38]=1[Cl:43].[NH4+].[Cl-].Cl>C1COCC1>[ClH:43].[Cl:43][C:38]1[CH:37]=[CH:42][CH:41]=[CH:25][C:24]=1[CH2:23][S:22][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Reactant: Clc1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1csc(Nc2ncc(SCc3ccccc3Cl)cc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.4 %

Procedure:
A 1 dram vial was charged with methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol). THF (1 mL) and KOtBu (0.59 mL, 0.59 mmol) were added and the reaction mixture was stirred at room temperature for 5 minutes. 1-(Bromomethyl)-2-chlorobenzene (0.024 mL, 0.19 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. Saturated aqueous NH4Cl (1 mL) was added and the reaction mixture was stirred for 10 minutes. The phases were separated and the aqueous phases were washed with EtOAc. The combined organic layers were concentrated and purified on silica gel to afford 5-(2-chlorobenzylthio)-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (48.2 mg, 58.3% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 7.80 (d, 1H), 7.60-7.55 (m, 3H), 7.46-7.34 (m, 4H), 7.27 (td, 1H), 7.18 (td, 1H), 7.10 (dd, 1H), 6.81 (q, 1H), 5.31 (s, 2H), 4.22 (s, 2H), 2.30 (d, 3H); Mass spectrum (apci) m/z=238.0 (100), 454.0 (90), 362.9 (80).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][CH:12]=1.O1CCCC1.[H][H]>[C].[Pd].C(O)C>[NH2:24][C:23]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:2][CH3:1]
Reactant: CNc1cc(Oc2cccc(NC(=O)OC(C)(C)C)c2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CNc1cc(Oc2cccc(NC(=O)OC(C)(C)C)c2)ccc1N
Yield: 100.9 %

Procedure:
Using tert-butyl {3-[3-(methylamino)-4-nitrophenoxy]phenyl}carbamate (10.9 g, 30.4 mmol), 10% palladium-carbon (1.8 g), tetrahydrofuran (150 mL), ethanol (100 mL) and hydrogen (3 atm) as starting materials, and in the same manner as in Example C1(iii), the title compound (10.1 g) was obtained as a black tar-like substance.
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])[CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][CH2:7][CH2:6]2.Br[CH2:24][CH2:25][OH:26].CCN(C(C)C)C(C)C>O1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:8]([CH2:24][CH2:25][OH:26])[CH2:7][CH2:6]2
Reactant: OCCBr
Reactant: COc1cc2c(cc1OC)C(CCc1ccccc1)NCC2
Solvent: C1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)C(CCc1ccccc1)N(CCO)CC2
Temperature: 90 °C

Procedure:
A solution of 6,7-dimethoxy-1-phenethyl-1,2,3,4-tetrahydro-isoquinoline (example A21, 59.5 mg, 0.2 mmol) and 2-bromoethanol (28.3 μL, 0.4 mmol) in tetrahydropyran (3 mL) is treated with DIPEA (68 μL, 0.4 mmol), and the reaction mixture is heated at 90° C. in a sealed flask for 5 days. The reaction is mixture evaporated to dryness, and the residue is purified by preparative HPLC, to provide the title compound.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCC(=O)N2CCOCC2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(OCC(=O)N2CCOCC2)cc1
Reaction time: 1 h

Procedure:
A solution of bromine (8.0g.) in chloroform (30ml.) was added dropwise to a stirred solution of 4-(4-acetylphenoxyacetyl)morpholine (13.15g.) in chloroform (120ml.) at 35° C. After 1 hour, the reaction mixture was filtered and the filtrate was washed with water (2 × 30ml.), dried and evaporated. The residue was recrystallised from methanol/ether to give 4-[4-(bromoacetyl)phenoxyacetyl]morpholine, m.p. 105°-107° C.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:13]([CH3:20])[N:12]=2)=[CH:7][CH:6]=1>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:15]1[C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)=[N:12][N:13]([CH3:20])[C:14]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nn1C
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1c(I)c(-c2ccc(OC)cc2)nn1C
Reaction time: 4 h

Procedure:
Silver sulfate (640 mg, 2.053 mmol) and iodine (0.106 mL, 2.053 mmol) were added successively to a solution of methyl 3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate (405.8 mg, 1.648 mmol) in EtOH (20.0 mL) at 25° C. and the reaction was stirred vigorously for 4 h. The reaction mixture was filtered through a plug of Celite®. The filtrate was diluted with EtOAc (20 mL) and washed with satd Na2SO3 (10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 20% EtOAc in hexanes over 2394 mL) to afford methyl 4-iodo-3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate, as a colorless solid. Rf=0.33 (20% EtOAc/hexanes). LCMS calc.=373.01. found=372.89 (M+H)+. 1H NMR (600 MHz, CDCl3): δ 7.68 (d, J=8.6 Hz, 2H); 6.97 (d, J=8.6 Hz, 2H); 4.22 (s, 3H); 3.96 (s, 3H); 3.85 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.[C:7]12([C:17](Cl)=[O:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.[C:20]1([NH:26][C:27](=[S:30])[NH:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:7]12([C:17]([NH:29][NH:28][C:27]([NH:26][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[S:30])=[O:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NNC(=S)Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NNC(=S)Nc1ccccc1)C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h

Procedure:
Pyridine (0.808 mL, 10 mmol) was added dropwise at room temperature to a stirred solution of 1-adamantanecarbonyl choride (A) (1 g, 5 mmol) and 4-phenyl-3-thiosemicarbazide (B) (0.845 g, 5.05 mmol) in CH2Cl2 (10 mL). After stirring for 4 h, the solvent was removed in vacuo, and the residue washed with water and dried to give 1-(1-adamantylcarbonyl)-4-phenyl thiosemicarbazide (C).
Reaction SMILES: [NH2:1][C@:2]([C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:39]([OH:41])=[O:40])[CH2:21][C:22]1[N:26]=[CH:25][N:24](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)[CH:23]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH2:4][CH3:5])[CH3:3].[CH:42]1([CH2:48][C@H:49]([NH-:59])[CH:50]([OH:58])[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1.C1(S)C=CC=CC=1>>[NH2:1][C@:2]([C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:39]([OH:41])=[O:40])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH2:4][CH3:5])[CH3:3].[CH:42]1([CH2:48][C@H:49]([NH-:59])[CH:50]([OH:58])[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: CC[C@](C)(N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)C(=O)O
Agent: Sc1ccccc1
Agent: [NH-][C@@H](CC1CCCCC1)C(O)Cc1ccccn1
Product: CC[C@](C)(N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
380 mg of Iva-Phe-His(DNP)-1(S)-cyclohexylmethyl-2(R,S)-hydroxy-3-(2-pyridyl)propylamide are reacted with thiophenol to give the title compound in analogy to reference example 1(a).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([CH:21]([OH:36])[CH:22]([NH2:35])[CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH3:33])[CH:27]=[C:26]([F:34])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C@@H:16]1[CH3:43])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH:35][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH3:33])[CH:27]=[C:26]([F:34])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:41])([CH3:40])[CH3:42])[C@@H:16]1[CH3:43])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCCOc1cc(F)cc(CC(N)C(O)[C@H]2CO[C@@H](OCC(C)(C)C)[C@H](C)N2C(=O)OC(C)(C)C)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)C)[C@H](C)N2C(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
Add acetic anhydride (0.07 g, 0.70 mmol) to (2R,3S,5R)-5-[2-Amino-3-(3-fluoro-5-propoxy-phenyl)-1-hydroxy-propyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (0.34 g, 0.66 mmol) and triethylamine (0.10 g, 0.99 mmol) in tetrahydrofuran (6 mL) at room temperature and stir 1 hour. Dilute with ethyl acetate and wash with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. Dry over magnesium sulfate, filter and concentrate. Purify on 12 g silica gel eluting with 100:0 to 20:80 hexanes:ethyl acetate to give 0.175 g of the desired compound as an oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:8]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[Cl:35])=[C:9]([Cl:26])[C:10]2[N:11]([C:13]([CH2:16][NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][N:15]=2)[CH:12]=1)=[O:6].CO.O.Cl>O>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:8]2[C:7]([C:5]([OH:6])=[O:4])=[CH:12][N:11]3[C:13]([CH2:16][NH:17][CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[CH:14][N:15]=[C:10]3[C:9]=2[Cl:26])=[C:29]([Cl:35])[CH:30]=1
Reactant: COC(=O)c1cn2c(CNCC(=O)OC(C)(C)C)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CNCc1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cn12
Yield: 84.8 %

Procedure:
Sodium hydroxide (1.0 M aqueous solution, 0.16 mL, 0.16 mmol) was added to a solution of 7-(4-bromo-2-chlorophenylamino)-3-[(tert-butoxycarbonylmethylamino)-methyl]-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (60) (15 mg, 0.026 mmol) in 4:1 MeOH/water (5 mL). When the reaction was complete, the solution was diluted with water, acidified to pH 3 by addition of 1.0 M aqueous HCl, and extracted with ethyl acetate. The organic extracts were dried over NaSO4, filtered, concentrated in vacuo to provide the desired product as a white crystalline solid (12 mg, 84%). MS (APCI−) m/z 541, 543, 545 (M-; Cl, Br pattern) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si](C)(C)N[Si](C)(C)C.[Na].[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:28](=O)[O:27][CH2:26]2>C(COC)OC.CN(C=O)C>[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:28](=[C:5]1[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]1=[O:11])[O:27][CH2:26]2
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 31.3 %

Procedure:
To a solution of 5-chlorooxindole (0.629 g, 3.78 mmol) in 10.0 mL monoglyme was added 7.51 mL sodium hexamethyldisilazane (1.0 M in THF) over 3 min. After stirring at room temperature for 8 min, a solution of 5-aminophthalide (0.561 g, 3.78 mmol) in 3.0 mL of DMF was added over 1 min. The mixture was stirred for 40 min and then quenched into 4% aqueous HCl solution. The aqueous solution was neutralized to pH 7 with 1 M NaOH and then made basic with saturated NaHCO3. The solid was filtered and washed with H2O and then partitioned between EtOAc and saturated NaHCO3 (heated to dissolve the solid). The organic phase was washed with H2O, brine and then dried with Na2SO4. The solvent was removed in vacuo and the residue triturated with MeOH to give the title compound (353 mg, 31%) as a yellow solid.
Reaction SMILES: [CH:1]1([S:4]([O-:6])=[O:5])[CH2:3][CH2:2]1.[Br-].[Mg+2].Cl[C:10]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].[OH-].[Na+].CS(C)=O>[Cu]I.O>[CH:1]1([S:4]([C:10]2[N:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S([O-])C1CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Agent: [Cu]I
Agent: [Br-]
Agent: [Mg+2]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)nc1S(=O)(=O)C1CC1
Temperature: 120 °C

Procedure:
To a 100 ml round bottom flask was loaded magnesium bromide cyclopropanesulfinate (928 mg, 4.43 mmol), 2-chloro-6-(trifluoromethyl)nicotinic acid (250 mg, 1.11 mmol), CuI (844 mg, 4.43 mmol), NaOH (44.3 mg, 1.11 mmol), 20 ml dimethyl sulfoxide and 4 ml water. The resulting reaction mixture was flushed with nitrogen gas and heated at 120° C. for 18 hr. After cooling down to room temperature, the reaction mixture was diluted with 60 ml ethyl acetate and 60 ml water. It was filtered through a pad of celite, which was then rinsed with 20 ml ethyl acetate. The layers were separated from filtrates, and the organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on reverse phase column eluted with water/acetonitrile gradient solvent to give desired product was white solid (152 mg, 0.52 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-])=O)=[C:5]([CH:12]=[CH:13][CH:14]=1)[NH:6][CH2:7][CH2:8][CH2:9][O:10][CH3:11].CO>[Zn].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][CH:12]=[C:5]([NH:6][CH2:7][CH2:8][CH2:9][O:10][CH3:11])[C:4]=1[NH2:15]
Reactant: COCCCNc1cccc(OC)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: COCCCNc1cccc(OC)c1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 100 mL round bottomed flask was added 3-methoxy-N-(3-methoxypropyl)-2-nitroaniline (36A) (560 mg, 2.33 mmol) and methanol (46 mL). Zinc metal (2.11 g, 32.4 mmol) and acetic acid (2.0 mL) was added and the mixture was stirred at room temperature for 5 hr. The mixture was filtered through a fritted Buchner funnel and the solvent was removed under vacuum. Ethyl acetate (100 mL) was added and the precipitate was filtered through a Buchner funnel with a pad of Celite. The filtrate was concentrated under vacuum to leave 3-methoxy-N1-(3-methoxypropyl)benzene-1,2-diamine (37B) as a yellow oil which was used without further purification. ESI-MS:mlz 211.4 (M-F1-1)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH3:15])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[CH3:15][N:14]([CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CN(CC1CCCN1C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CN(CC1CCCN1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 118.3 %

Procedure:
To a solution of 2-[(methanesulfonyl-methyl-amino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.63 g) in dichloromethane (10 mL) at room temperature was added hydrogen chloride (3.0 mL of a 2 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 72 h and then reduced in vacuo to give N-methyl-N-pyrrolidin-2-ylmethyl-methanesulfonamide as a crystalline solid (0.49 g).
Reaction SMILES: C([O:3]CC)C.[Cl:6][C:7]1[CH:26]=[CH:25][C:10]([CH2:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][CH2:16][CH:17]3[C:22]([OH:24])=[O:23])=[CH:9][CH:8]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][CH2:16][CH:17]3[C:22]([OH:24])=[O:23])=[O:3])=[CH:25][CH:26]=1
Reactant: CCOCC
Reactant: O=C(O)C1CCCc2c(Cc3ccc(Cl)cc3)cccc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1cccc2c1CCCC2C(=O)O
Reaction time: 8 h

Procedure:
To 200 ml. of ethyl ether is added 15 g. of 5-(p-chlorobenzyl)-1,2,3,4-tetrahydro-1-naphthoic acid, and a solution of 5 g. of sodium dichromate in 24 ml. of 6N sulfuric acid is added dropwise. After stirring overnight, 100 ml. of water is added and the ethereal layer is further washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the oily residue is purified by column chromatography on silica gel equilibrated with oxalic acid with chloroform as the eluent and, then recrystallized from benzene. The described procedure gives 5-(p-chlorobenzoyl)-1,2,3,4-tetrahydro-1-naphthoic acid, melting point: 152.5°-153.5° C.