Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1)[C:2]#[CH:3].Br[C:13]1[C:14]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:22]1([N:21]2[C:14]3[N:15]=[C:16]([C:19]#[N:20])[N:17]=[CH:18][C:13]=3[CH:3]=[C:2]2[CH2:1][C:4]2[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: C#CCc1ccc(CO)cc1
Reactant: N#Cc1ncc(Br)c(NC2CCCCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ncc2cc(Cc3ccc(CO)cc3)n(C3CCCCC3)c2n1
Temperature: 85 °C
Yield: 107.2 %

Procedure:
To a solution of (4-prop-2-ynyl-phenyl)-methanol (10 mmol) and 5-bromo-4-cyclohexylamino-pyrimidine-2-carbonitrile (7 mmol) in DMF (20 ml) are added triethylamine (21 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.35 mmol) and copper (I) iodide (0.7 mmol). The reaction mixture is heated at 85° C. ca. for 2 h. The reaction mixture is quenched with saturated ammonium chloride and extracted with AcOEt. The organic layer is washed with brine and then dried over sodium sulfate and concentrated under vacuum to give 2.6 g of crude product, which is purified by silica gel column chromatography. Yield 58%.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=1)[CH2:6][CH2:7][Cl:8]>O>[Cl:2][CH2:3][CH2:4][N:5]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)[CH2:6][CH2:7][Cl:8]
Reactant: COC(=O)Cc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Solvent: O
Product: O=C(O)Cc1ccc(N(CCCl)CCCl)cc1
Yield: 84.5 %

Procedure:
Concentrated hydrochloric acid (10 ml) was added to 2.0 g (6.9 mmol) of methyl 4-[N,N-bis(2-chloroethyl)amino]phenylacetate, followed by stirring under heat for 1 hour over an oil bath controlled at 90° C. The reaction mixture was diluted with water and was then extracted three times with methylene chloride. As the raw material still remained, the reaction product was extracted with a 1N aqueous solution of sodium hydroxide. The water layer was acidified with hydrochloric acid and then extracted again with methylene chloride. The extract was dried and concentrated under reduced pressure. The residue so obtained was washed with n-hexane, whereby 1.61 g (5.83 mmol) of the title compound were obtained as white crystals (yield: 84.5%).
Reaction SMILES: [CH3:1][CH:2]([CH:9]1[C:13]2([CH3:30])[CH:14]([OH:29])[CH2:15][CH:16]3[C:21]4([CH3:27])[CH2:22][CH2:23][CH:24]([OH:26])[CH2:25][CH:20]4[CH2:19][CH:18]([OH:28])[CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:31][S:32](Cl)(=[O:34])=[O:33].CCOC(C)=O.Cl>N1C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[CH2:4][CH2:3][C@H:2]([C@@H:9]1[C@:13]2([CH3:30])[C@H:12]([C@H:17]3[C@H:16]([CH2:15][C@@H:14]2[OH:29])[C@:21]2([CH3:27])[C@H:20]([CH2:25][C@@H:24]([O:26][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:23][CH2:22]2)[CH2:19][C@H:18]3[OH:28])[CH2:11][CH2:10]1)[CH3:1]
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
To a solution of cholic acid methyl ester (25 g, 59.2 mmol) in pyridine (75 mL), stirring at 0° C., was added methanesulfonyl chloride (5.04 mL, 65.1 mmol) dropwise over 30 minutes. The reaction was allowed to warm to room temperature and stir for 6 hours. The reaction mixture was poured into a mixture of EtOAc (200 mL), 1 N HCl (200 mL), and ice. The layers were separated, and the organic layer was washed with 1N HCl (2×50 mL), dried (Na2SO4) and concentrated to provide a light yellow oil. The crude material was passed through a plug of silica eluting with 50% EtOAc/hexanes to provide 24.5 g (83%) of the title compound as a light yellow oil that foamed into a white, sticky foam when placed on the high vacuum pump.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.ClC1C=CC=CN=1.ClC1N=C(C2C=CC=CC=2)C(C(OCC)=O)=CC=1.N[C:57]1[N:62]=[C:61]([NH:63][CH2:64][CH2:65][NH:66][C:67]2[CH:72]=[CH:71]C(C3NC=CN=3)=C(C3C=CC(Cl)=CC=3Cl)[N:68]=2)[CH:60]=[CH:59][C:58]=1[N+:86]([O-:88])=[O:87]>C1(C)C=CC=CC=1.CC(N(C)C)=O.CCN(C(C)C)C(C)C.C1COCC1.C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:71][CH:72]=[C:67]([NH:66][CH2:65][CH2:64][NH:63][C:61]3[CH:60]=[CH:59][C:58]([N+:86]([O-:88])=[O:87])=[CH:57][N:62]=3)[N:68]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)c1ccc(C#N)cc1
Agent: CCOC(=O)c1ccc(Cl)nc1-c1ccccc1
Agent: Clc1ccccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(C#N)cc1

Procedure:
ethyl 2-(4-cyanophenyl)-6-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyridine-3-carboxylate (62258) was prepared from ethyl 3-(4-cyanophenyl)-3-oxopropanoate (ref. Wemple, J.; et. al. Synthesis 1993, 290-292.) as the starting material and THF/ethanol ratio of 1:5 as the solvent in the first step. The oxidation uses DDQ in toluene. The final product is achieved directly from the chloropyridine by reacting ethyl 6-chloro-2-phenylpyridine-3-carboxylate with 2-(2-aminoethylamine)-5-nitropyridine in DMA and Hünig's base at 120° C. for 18 hours. The procedures are analogous to the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16].C([O-])([O-])=O.[Cs+].[Cs+].C(=O)(O)[O-]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:4]([C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16])[C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:2]=1
Reactant: O=C1C(Cc2c(Cl)cccc2Br)CCN1C1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Product: O=C1C(Cc2c(Cl)cccc2Cc2ccccc2)CCN1C1CCCCC1
Yield: 121.1 %

Procedure:
Charge a flask with 3-(2-bromo-6-chloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (Example 56) (250 mg, 0.67 mmol), Pd(dppf)Cl2 (54 mg, 0.067 mmol) and Cs2CO3 (660 mg, 2.0 mmol) and purge with nitrogen. Add DMF (6 mL) and water (0.6 mL) and stir. Add Bn-9-BBN (0.5 M, 4.0 mL, 2.0 mmol) and heat to 60° C. for 1 hour. Pour into saturated aqueous bicarbonate and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate. Purify over silica gel (10% ethyl acetate in hexanes) to yield 155 mg (60%) of the title compound as a clear colorless oil. Mass spectrum (apci) m/z=382.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH2:9])[CH:3]=1.O(C)[C:11]([S-])=[S:12].[K+].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:11]([SH:12])=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: COC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Sc1nc2cc(Cl)ccc2o1
Reaction time: 3 h
Yield: 96.4 %

Procedure:
With the use of the apparatus described in Example 1, 143.6 g (1 mol) of 4-chloro-2-aminophenol and 181.3 g (1.02 mols) of potassium methyl xanthate (90%) in 500 ml of water were refluxed. The reaction was complete within 3 hours. The dark reaction solution was acidified with concentrated hydrochloric acid, the precipitate was suction-filtered and washed neutral with water. After drying in vacuo at 80° C., 179 g (96.7% of th.) of 5-chloro-2-mercaptobenzoxazole having a melting point of 269°-271° C. were obtained.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([Sn](C)(C)C)=[CH:6]1)(=[O:4])=[O:3].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CN(C)C=O.C(Cl)Cl.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>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:6]1)(=[O:4])=[O:3]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CS(=O)(=O)n1cc([Sn](C)(C)C)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(-c3cn(S(C)(=O)=O)c4ccccc34)c2cc1OC
Temperature: 90 °C

Procedure:
A solution of 1.33 g (4.01 mmol) of N-methylsulfonyl-3-trimethylstannylindole, 750 mg (3.34 mmol) of 4-chloro-6,7-dimethoxyquinazoline and 0.19 g (5 mol % 0.16 mmol) of Pd (PPh3)4 in 10 ml of dry dimethylformamide is flushed thoroughly with nitrogen and heated to 90° C. for 12 hours. The reaction mixture is diluted with methylene chloride washed with 10% ammonium hydroxide and stirred vigorously and then washed with water and the combined organics are washed with brine (75 mL), dried (MgSO4) and evaporated to dryness. Recrystallization from ethyl acetate yields 4-(1-methylsulphonylindol-3-yl)-6,7-dimethoxyquinazoline (m.p.>220° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[O:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]1>C1COCC1>[Br:8][C:6]1[CH:7]=[C:2]([C:11]2([OH:14])[CH2:12][CH2:13][O:9][CH2:10]2)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: O=C1CCOC1
Solvent: C1CCOC1
Product: OC1(c2cncc(Br)c2)CCOC1
Reaction time: 16 h
Yield: 10.2 %

Procedure:
To a cooled (−15° C.) solution of 3,5-dibromopyridine (1.2 g, 5.0 mmol) in THF (12 mL) is added a solution of isopropylmagnesium chloride-lithium chloride complex in THF (1.7 M; 2.9 mL, 4.9 mmol). The resultant mixture is stirred at −15° C. for 30 min and dihydro-furan-3-one (517 mg, 6.0 mmol) is added. After stirring for 16 h, the reaction is quenched with saturated aqueous NH4Cl solution and is extracted with EtOAc. The combined organic extracts are washed with water and brine, dried and concentrated under reduced pressure. Purification by flash column chromatography provides 125 mg of 3-(5-bromo-pyridin-3-yl)-tetrahydro-furan-3-ol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH3:16][CH:17]1[CH2:22][NH:21][CH2:20][CH:19]([CH3:23])[NH:18]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:21]2[CH2:20][CH:19]([CH3:23])[NH:18][CH:17]([CH3:16])[CH2:22]2)=[O:15])=[CH:4][N:3]=1
Reactant: CC1CNCC(C)N1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CC(C)NC(C)C3)c12

Procedure:
This compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 2,6-dimethylpiperazine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1([CH:15]([OH:29])[CH2:16][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([CH3:19])[CH3:18])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1([C:15](=[O:29])[CH2:16][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([CH3:19])[CH3:18])[CH2:13][CH2:14]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)C1(F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C1(F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
6 mL of a 2 M solution of oxalyl chloride in dichloromethane was diluted with 5 mL of dichloromethane and cooled on dry ice/acetone bath. To this solution was added dropwise a solution of 1.5 mL of DMSO in 5 mL of dichloromethane. After 10 minutes, a solution of the crude 1-(1-fluorocyclopropyl)-3-(5-fluoro-2-methoxyphenyl)-3-methylbutan-1-ol (0.8 g, 3 mmol) in 4 mL of dichloromethane was added and the mixture was stirred for 15 minutes. 4 mL of triethylamine was added, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature, quenched with water, and diluted with hexanes. The organic layer was separated, washed with water, dried, filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluent: hexanes to hexanes-ethyl acetate (10:1), gradient) to give 0.68 g of the title product as an oil which was used without additional purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22](=[O:24])[CH3:23]>>[CH2:21]([N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])[C:22]([CH3:23])=[O:24]
Reactant: CC(=O)CCl
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC(C)=O)c(=O)[nH]c1=O
Yield: 54 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and chloroacetone were reacted by the same way with the example 1 to obtain the titled compound (172 mg, yield: 54%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:9]([N:11]1[CH2:22][CH2:21][CH2:20][C@H:12]1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1>O>[NH2:1][C@H:2]([C:9]([N:11]1[CH2:22][CH2:21][CH2:20][C@H:12]1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: CCCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Solvent: O
Product: CCCCNC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]cn1

Procedure:
Using 1.63 g. (0.004 M) of BOC-His-Pro-NHCH2CH2CH2CH3, the title compound is synthesized in the same manner as described in Example 3 (c) for the synthesis of the methyl-compound. Yield 1.16 g.; optical rotation [α]D21 -65.0° (c=0.60, in water); thin-layer chromatography Rf1 =0.62.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1>>[CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:22]4[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: Cc1c(C)c(N2CCN(c3ccc(OC(F)(F)F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 50.9 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (311 mg, 1.0 mmol) synthesized in Reference example 61 and 1-bromo-4-(trifluoromethoxy)benzene (0.223 mL, 1.5 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 221 mg (yield 51%). Melting point was 216 to 219° C. (hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29](O)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([CH3:45])[C@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C@H:41]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29]([NH:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][C:38]=2[N:39]2[CH2:44][C@H:43]([CH3:45])[C@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C@H:41]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:40]2)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxylic acid (68 mg, 0.16 mmol), tert-butyl methyl [(3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (62 mg, 0.16 mmol) and HATU (190 mg, 0.500 mmol) in 2 mL of DMF, DIPEA (180 μL, 1.03 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a yellow solid (62.4 mg, 49%). LCMS calc. for C41H52N9O7 (M+H)+: m/z=782.4. Found: 782.4.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH3:25])=[O:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>CC(O)C.C(Cl)Cl.O>[CH3:25][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:26])=[O:24]
Reactant: CCOC(=O)C1(NC(=O)c2ccccc2S(C)=O)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)c1ccccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 39 h

Procedure:
A 50 mL flask containing the 2-(2-methylsulfinylbenzoyl-amino)-indan-2-carboxylic acid ethyl ester (0.50 g, 1.34 mmol) is charged with 1,4-dioxane (5 mL) and MeOH (5 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2.5 mL) is added followed by the LiOH (141 mg, 3.36 mmol). After 39 h, tlc analysis (silica, 5% i-PrOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜12 mL). The contents of the flask are poured into a separatory funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated by vacuum to constant weight of 0.39 g of white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:17]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(NCCc2ccc(O)cc2)nc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1ccc(CCNc2ncc(CC)cn2)cc1
Yield: 74.4 %

Procedure:
Alkylation of 4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}phenol (135 mg; 0.56 mmol) with ethyl 2-bromopropionate (0.18 ml; 1.39 mmol) as per general procedure C (conditions: 2 eq Cs2CO3, MeCN, 60C, 4 hr). provided ethyl 2-(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)propanoate (143 mg; 75% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 51 %

Procedure:
As described for example 147, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg, 0.3 mmol) was converted, using morpholine instead of cyclopropylmethylamine, to the title compound (58 mg, 51%) which was obtained as an off white solid. MS: m/e=381.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:40][CH3:41])=[C:34]([CH2:38][CH3:39])[CH:35]=2)[CH2:30]1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([N+:26]([O-])=O)[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C1(C)C=CC=CC=1.O=[Pt]=O>[NH2:26][C:14]1[CH:13]=[C:12]([C@@H:10]([OH:11])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:29]2[CH2:30][C:31]3[C:36](=[CH:35][C:34]([CH2:38][CH3:39])=[C:33]([CH2:40][CH3:41])[CH:32]=3)[CH2:37]2)[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCc1cc2c(cc1CC)CC(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c([N+](=O)[O-])c1)C2
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc2c(cc1CC)CC(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c(N)c1)C2
Reaction time: 6 h

Procedure:
(R)-2-[Benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethanol (3.00 g) is dissolved in THF (50 mL) and toluene (50 mL). A catalytic amount of PtO2 is added and the solution is stirred under an atmosphere of H2. The reaction is shown to be complete by TLC after 6 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hexane/ethyl acetate 1:1 Rf=0.75).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:17]=2)=[C:10]([CH3:32])[CH:9]=1)=[O:6]>CCO.CCOC(C)=O.[Ni]>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH3:32])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[OH:31])[CH:17]=2)=[C:12]([CH3:14])[CH:13]=1)=[O:6]
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(O)c3ccc(F)cc3)c2)c(C)c1
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of N-{4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid methyl ester (222 mg, 0.49 mmol) in a mixture of EtOH/EtOAc (4:1, 25 mL) was added nickel catalyst (2 mL, water and methanol washed). The mixture was hydrogenated under 50 psi at room temperature for 1 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by preparative TLC to give the title compound of Step A (159 mg) as a white solid. MS (APCI−) Calc.: 453.2, Found: 452.2 (M−1).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(N(CC)CC)C>[CH2:7]([O:6][C:1](=[O:5])[C@@H:2]([O:3][S:10]([CH3:9])(=[O:12])=[O:11])[CH3:4])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H](C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)OS(C)(=O)=O

Procedure:
An equal molar solution of (S)-ethyl lactate and triethylamine in dry methylene was treated with an equal molar amount of methane sulfonylchloride at 5°-10° C. After the addition was complete, the mixture was filtered to remove triethylamine hydrochloride. The filtrate was then washed with water, dried over MgSO4, and concentrated to give a high yield of ethyl-(S)-2[(methylsulfonyl)oxy]propionate.