Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([C:8]3[N:9]=[C:10]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)=[CH:28][CH:27]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)oc3C)c2)cc1

Procedure:
The title compound was prepared from 4-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole, and 4-methoxy-benzeneboronic acid in substantially the same manner, as described in Example 1 step c, and was obtained as a white solid, mp 93-94° C.; MS m/e 409 (M+);
Reaction SMILES: S(=O)(=O)(O)O.[F-:6].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:24][C:25]1[CH:26]=[C:27]([N+]([O-])=O)[C:28]([C:31]#[N:32])=[N:29][CH:30]=1.Cl>CN(C=O)C>[Br:24][C:25]1[CH:26]=[C:27]([F:6])[C:28]([C:31]#[N:32])=[N:29][CH:30]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: N#Cc1ncc(Br)cc1F
Temperature: -40 °C

Procedure:
Sulfuric acid (0.02 eq) was added to a solution of tetrabutylammonium fluoride (3 eq) in DMF (5 vol) and the mixture cooled to −40° C. A solution of the compound of Step 2 (1 eq) in DMF (2 vol) was added maintaining the temperature <−35° C. After about 20 minutes 2N HCl (3 vol) was added followed by 1N HCl (15 vol). The precipitated product was collected by filtration to give the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.O.[OH-].[Li+]>CO>[CH:15]1([N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cnn(C2CCCCC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(C2CCCCC2)c1C(F)(F)F
Temperature: 80 °C
Yield: 86.3 %

Procedure:
Cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.265 g, 0.91 mmol) was dissolved in methanol (1.4 mL). Water (1.4 mL) and lithium hydroxide (0.029 g, 1.21 mmol) were added and the mixture was heated at 80° C. for 1.5 hours. After cooling to room temperature, the methanol was removed in vacuo. Tetrahydrofuran was added to the residue and then removed in vacuo to ensure complete removal of the methanol. 6N HCl was added to the aqueous residue to pH 2-3, resulting in precipitation of a solid. The solid was collected by filtration, washed with water and dried under high vacuum at 100° C. to give 1-cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.206 g, 86%). Mass spectrum: m/z: 263.3 (M+H).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[OH:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[O:22][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Reactant: Fc1ccc(CBr)cc1
Product: Fc1ccc(COc2cc3ccc(Br)cc3cc2C23CC4CC(CC(C4)C2)C3)cc1
Yield: 85.9 %

Procedure:
Following the basic procedure of Example 11, by reacting 1.1 g (3 mmol) of 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene with 420 μl (3,3 mmol) of 4-fluorobenzyl bromide, 1.2 g (86%) of the expected compound was obtained in the form of a colorless oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].[S:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[S:26][CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Reactant: c1cscn1
Product: O=C(c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1)c1nccs1

Procedure:
This compound is prepared by method C using compound 12j and thiazole
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>O1CCCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:20])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc(I)cc1
Solvent: C1CCOC1
Product: NC(=S)c1ccc(I)cc1
Yield: 134.5 %

Procedure:
A mixture of 2.1 g of 4-iodobenzamide, 30 ml of tetrahydrofuran, and 2 g of Lawesson's reagent was heated to reflux for 1 hour. It was partitioned between toluene and 10% aqueous sodium carbonate solution. The organic phase was dried and evaporated. The crude product was passed over a plug of silica gel using acetone/hexane 1:1 for elution. Crystallization from methylene chloride/hexane gave 1.75 g of yellow crystals with m.p. 163-165° C.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CC(N(C)C)=O.Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[N:27][CH:28]=1>C1COCC1.[Zn]>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][C:23]2[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[N:27][CH:28]=2)[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
Rieke Zinc (slightly excess by estimation) was stirred in 10 mL of THF under argon. tert-Butyl 4-(bromomethyl)piperidine-1-carboxylate (1.0 g, 3.6 mmol) in 5 mL of THF was added. The resulting mixture was stirred at rt for 3 h. The solution was then allowed to settle and the supernatant was transferred via a syringe to a stirred 5 mL of DMA solution. Methyl 5-bromopicolinate (0.78 g, 3.6 mmol) and Cl2Ni(Ph2PCH2CH2PPh2) were added sequentially, and the resulting mixture was stirred at rt for 60 h. LC-MS indicated a partial conversion. The reaction mixture was quenched with 15 mL of sat. NH4Cl, and extracted with 50 mL of EtOAc. The organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give an oil which was purified by silica gel flash chromatography, eluting with 10-80% EtOAc in hexanes, to give methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)picolinate as a white solid (200 mg, 17%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[N+:8]([C:11]1[C:12]([Cl:20])=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:14][NH2:15])([O-:10])=[O:9]>C1COCC1>[N+:8]([C:11]1[C:12]([Cl:20])=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:14][NH:15][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])([O-:10])=[O:9]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 8 h

Procedure:
2,2-Dimethyl-propionic acid chloride (0.124 mL, 1.01 mmol) is added to a mixture of 3-nitro-2,4-dichloro-benzylamine (0.28 g, 1.01 mmol) and TEA (0.35 mL, 2.52 mmol) in THF (10 mL) and it is stirred overnight. The reaction mixture is concentrated, diluted with EtOAc, washed successively with 5% aq NaHCO3 solution and brine, dried with Na2SO4 filtered and concentrated.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](O)=[N:7][C:8]=1[CH3:9])#[N:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]([C:1]#[N:2])=[C:8]([CH3:9])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1O
Product: CCOC(=O)c1cc(C#N)c(C)nc1Cl

Procedure:
200 g of 5-cyano-2-hydroxy-6-methyl-3-pyridine-carboxylic acid, ethyl ester (1 mol) are refluxed with stirring in 750 ml of phosphorous oxychloride for 5 hours. The excess of phosphorous oxychloride is removed in vacuo and the residue poured in 1 kg of ice. 2-chloro-5-cyano-6-methyl-3-pyridine-carboxylic acid, ethyl ester crystallizes and is filtered off. Yield 170 g (76%); m.p. 43°-45° C. (petrol ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:33])([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][NH:29][C:28]2=[O:32])=[CH:23][CH:22]=1)[CH:17]([F:19])[F:18]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:29]1[C:28](=[O:32])[N:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:16]([F:15])([F:33])[CH:17]([F:18])[F:19])=[CH:26][CH:25]=2)[CH:31]=[N:30]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ncn1-c1ccc(OC(F)(F)C(F)F)cc1
Product: C[C@@H](n1ncn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 53.8 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.0 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.11 g of 4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (0.99 g) was obtained as a colorless oil.
Reaction SMILES: C([O-])(=O)C.[Na+].[C:6]([C:9]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:10]=1[O:11][CH2:12]C(O)=O)(=O)[CH3:7].O>C(OC(=O)C)(=O)C>[F:20][C:18]1[CH:17]=[CH:16][C:10]2[O:11][CH:12]=[C:6]([CH3:7])[C:9]=2[CH:19]=1
Reactant: CC(=O)c1cc(F)ccc1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1coc2ccc(F)cc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 0.4 %

Procedure:
Anhydrous sodium acetate (139.3 mmol, 11.4 g) was added to a solution of the title compound of Example 14, Step A (3.24 mmol, 1.6 g) in acetic anhydride (70 mL) and heated for 3 hours at 110° C. After cooling, the reaction mixture was poured into water (100 mL) and stirred for 1 hour. The aqueous solution was extracted with ether (2×100 mL), washed with 3% aqueous KOH (2×20 mL) and water (2×20 mL). The washed ether layer was collected, dried, filtered and the filtrate was evaporated to a brown residue, which was purified by silica gel chromatography (eluent:hexanes) to obtain the desired product, 5-fluoro-3-methyl benzofuran (59%, 1.77 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:11][N:12]([CH3:21])[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[C:37]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:11][N:12]([CH3:21])[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:7]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CC(CCN1CCC(N)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of N-[4-(4-aminopiperidino)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide (1.5 g) in dichloromethane (35 mL) was added triethylamine (0.60 mL) and acetic anhydride (0.41 mL), and the resulting solution was allowed to stir for 30 minutes. The mixture was diluted with dichloromethane and was washed (0.3N sodium hydroxide, water), dried, and evaporated. The material was dissolved in toluene and the resulting solution was evaporated to give the title compound (1.63 g) as a white solid; MS: m/z=476(M+1). Analysis for C25H31Cl2N3O2 ·0.2 C6H5CH3 : Calculated: C, 64.07; H, 6.63; N, 8.49; Found: C, 64.04; H, 6.59; N, 8.32.
Reaction SMILES: [CH2:1]([OH:10])[C:2]([CH2:4][O:5]P(O)(O)=O)=[O:3].[N:11]([CH:14]([CH2:17][OH:18])[CH:15]=[O:16])=[N+:12]=[N-:13].[OH-].[Na+].CO>C(O)C(N)(CO)CO>[N:11]([C@H:14]([CH2:17][OH:18])[C@H:15]([OH:16])[C@@H:1]([OH:10])[C:2](=[O:3])[CH2:4][OH:5])=[N+:12]=[N-:13]
Reactant: O=C(CO)COP(=O)(O)O
Reactant: [N-]=[N+]=NC(C=O)CO
Agent: NC(CO)(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=N[C@H](CO)[C@H](O)[C@@H](O)C(=O)CO
Reaction time: 48 h
Yield: 30 %

Procedure:
DHAP (0.5 mmole) was added to an aqueous solution of 2-azido-3-hydroxypropanal (1 mmole in 40 ml) and the pH value adjusted to 7.0 with 10N NaOH. To this solution was added rhamnulose-1-phosphate aldolase from E. coli (4 g), which had been treated with egg white lysozyme (40 mg) in Tris buffer (pH 7.5, 25 ml) for one hour at 35° C., to form a mixture and the mixture stirred slowly for two days. The stirred mixture was adjusted to a pH value of 4.7, and acid phosphatase (400 units) added. The resulting mixture was incubated at 37° C. for 48 hours, neutralized to a pH value of 7.0 and lyophilized. The residue was treated with MeOH and filtered to remove the insoluble material. The MeOH was removed under reduced pressure and the crude product purified with silica gel column chromatography (CHCl3 :MeOH=6:1) to give 5-azido-5-deoxy-D-xylo-hexulose in 30 percent yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[O:11].[BH4-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: O=Cc1cc2ccccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
To a stirring solution of 1.02 g (6.96 mmol) of benzofuran-2-carbaldehyde (Aldrich) in 20 mL of MeOH at 0° C. was added 1.02 g (26.9 mmol) of NaBH4. The ice bath was removed, and the mixture was allowed to cool to r.t. (Reaction was exothermic). After 45 min., the mixture was concentrated, and H2O was added and 1N HCl to pH=7. The aqueous layer was extracted with EtOAc (2×), and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography provided 1 g of benzofuran-2-ylmethanol as a colorless oil in quantitative yield.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:23])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)C>[CH3:22][O:21][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:35]3[CH2:34][CH2:33][N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[O:25][CH3:24])[CH2:37][CH2:36]3)[C:9](=[O:23])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: COc1cc(OC)c2c(C)c(CCOS(C)(=O)=O)c(=O)oc2c1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2c1
Yield: 71 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 35) and 1-(2-methoxyphenyl)piperazine; yield 71%; m.p. 140°-142° C. (from ethanol).
Reaction SMILES: C([N:8]([CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([C:40](=[O:42])[NH2:41])[CH:34]=1)[CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]([CH3:28])[N:20]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[C:40]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][C:36]=1[OH:39])[O:32][CH2:31][CH2:30][NH:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]([CH3:28])[N:20]=2)=[CH:17][CH:18]=1)(=[O:42])[NH2:41]
Reactant: [H][H]
Reactant: Cn1nc(-c2ccc(OCC(O)CN(CCOc3ccc(O)c(C(N)=O)c3)Cc3ccccc3)cc2)nc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Cn1nc(-c2ccc(OCC(O)CNCCOc3ccc(O)c(C(N)=O)c3)cc2)nc1C(F)(F)F

Procedure:
After the addition of 2 g of palladium-on-carbon catalyst (5%), a solution of 22 g of crude 1-[N-benzyl-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]]-3-[4-(1-methyl-5-trifluoromethyl-1H-1,2,4-triazol-3-yl)-phenoxy]-2-propanol in 320 ml of methanol is hydrogenated under normal conditions until the calculated quantity of hydrogen has been absorbed (3 hours). The product, which has partly crystallised out, is made into a solution by the addition of 1000 ml of dioxan and heating, the catalyst is filtered off and the filtrate is concentrated by evaporation. The crystalline residue that remains is recrystallised from approximately 400 ml of dioxan and yields 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)-phenoxy]-2-propanol having a melting point of 206°-208°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)(=[O:25])=[O:24])=[C:16]([O:33][CH3:34])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:36]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)(=[O:25])=[O:24])=[C:16]([O:33][CH3:34])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(Cl)c2)cc2c1CCN2S(=O)(=O)c1cccc(Cl)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: COC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3-chloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 521.1 (M+H+.), was prepared in analogy to example 21, steps 1 to 6. Step 5 was performed using 3-chloro-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3-chloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8].Cl.[CH3:31][N:32]([CH3:37])[CH2:33][C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:31][N:32]([CH3:37])[CH2:33][C:34]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])=[O:35]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCN)ccc21
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)NCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Yield: 83.2 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(2-dimethylamino-acetylamino)-ethyl]-amide (64 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-amino-ethyl)-amide dihydrochloride (75 mg), N,N-dimethylglycine hydrochloride (24 mg), HBTU (79 mg), and DIEA (46 uL). LC/MS: m/z 486.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.64-8.44 (m, 1H), 8.22 (bs, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.83-7.59 (m, 2H), 7.55-7.45 (m, 1H), 7.41 (d, 1H), 3.79-3.56 (m, 5H), 3.44-3.34 (m, 2H), 3.20-3.09 (m, 2H), 2.71 (s, 6H).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][NH2:24])[CH:19]=[CH:20][CH:21]=1.[BH4-].[Na+]>>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][NH:24][CH2:23][CH2:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:25])[F:26])[CH:17]=3)=[CH:10][C:4]=2[O:3]1
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Agent: [BH4-]
Agent: [Na+]
Product: FC1(F)Oc2ccc(CNCCc3cccc(C(F)(F)F)c3)cc2O1

Procedure:
(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine was synthesized in analogy to the above procedure using 100 mg of 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde (0.54 mmol), 102 mg of 2-(3-trifluoromethylphenyl)-ethylamine (0.54 mmol) and 31 mg of sodium borohydride (0.81 mmol). The isolated colorless semisolid (110 mg, 57%) was used in the following step without further purification. MS (ISP) 360.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH2:38]([S:41](Cl)(=[O:43])=[O:42])[CH2:39][CH3:40]>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:41]([CH2:38][CH2:39][CH3:40])(=[O:43])=[O:42])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: CCCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To a solution of the product of Example 353E (16.7 mg, 0.037 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and 1-propane sulfonyl chloride was added (0.005 mL, 0.041 mmol). The mixture was warmed to 23° C. and stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile/0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (9.9 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ 0.15 (d, J=4.04 Hz, 2 H) 0.42 (d, J=7.35 Hz, 2 H) 0.99 (m, 4 H) 1.69 (m, 2 H) 2.84 (d, J=7.35 Hz, 2 H) 3.06 (m, 2 H) 4.27 (d, J=6.25 Hz, 2 H) 6.35 (bs, 1 H) 7.37 (s, 1 H) 7.42 (t, J=7.54 Hz, 2 H) 7.75 (t, J=6.07 Hz, 1 H) 7.87 (t, J=7.17 Hz, 1 H) 8.07 (d, J=8.46 Hz, 1 H) 8.15 (dd, 1 H) 14.52 (bs, 1 H).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[N:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[CH:39][C:38]=1[F:46].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>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:43]([C:41]3[CH:40]=[CH:39][C:38]([F:46])=[C:37]([C:31]4[C:30]([F:29])=[CH:35][CH:34]=[CH:33][C:32]=4[F:36])[N:42]=3)=[O:44])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cccc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (6.0 mg, 0.015 mmol), 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (4.7 mg, 0.018 mmol), HATU (15.0 mg, 0.038 mmol), DMF (0.036 mL) and DIPEA (6.0 mg, 0.046 mmol) were mixed together and stirred at room temperature for 1 h. The mixture was filtered, concentrated under reduced pressure, and purified by preparative LC-MS (XBridge™ preparative C18, 30×10 mm 5 μm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the sub-title compound as a colorless gum (4.0 mg, 42%). LCMS calc. for C32H35F3N5O5 (M+H)+: m/z=626.3. Found: 626.1.