Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:35]=[CH:34][C:16]([O:17][CH:18]([CH3:33])[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=O)=[CH:15][CH:14]=1)[CH:6]=[N:5]2.C1COCC1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:35]=[CH:34][C:16]([O:17][CH:18]([CH3:33])[C:19](=[S:42])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=S)Nc1ccc(OC(F)(F)F)cc1
Reaction time: 2 h

Procedure:
A mixture of 2.0 g (4.1 mmol) of 2-(4-((6-fluoro-2-quinoxalinyl)oxy)phenoxy)-N-(4-(trifluoromethoxy)phenyl)propanamide and 40 ml of dry THF in a 100 ml flask was placed in a water-filled ultrasonic bath. Phosphorous pentasulfide (0.22 g) was added and the mixture sonicated while maintaining the reaction temperature below 40° C. by occasional addition of ice to the water bath. Additional P2S5 (1.76 g) was added in portions at 20 minute intervals over the next hour. Sonication was continued for an additional 2 hours and the mixture then filtered and the solid washed well with methylene chloride. The combined filtrates were treated with charcoal, filtered and evaporated to dryness. The residue was purified first by chromatography over silica gel, eluting with CH2Cl2, and then by preparative scale HPLC, eluting with 85:15 hexane: acetone. This left 1.1 g (53 percent of theoretical) of the above-named product as a yellow glassy solid. (Compound 34)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:5]=2[N:6]=1.Br>>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc2nc(N)sc2c1
Agent: Br
Product: Nc1nc2ccc(O)cc2s1
Temperature: 25 °C

Procedure:
2-Amino-6-methoxybenzothiazole was reacted with hot aqueous HBr at a temperature of >70° C. for about 3 hours and then the clear solution was cooled to ambient temperature overnight. The precipitated solids were collected, dissolved in hot water and the pH was adjusted to between 4.5-5.5. The resultant solids were collected, dried and re-crystallized from isopropanol. Second crop material was collected. The solids were vacuum dried to give 2-amino-6-hydroxybenzothiazole.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[NH:11][S@](C(C)(C)C)=O.[ClH:18].C(#N)C>CO.O1CCOCC1>[ClH:18].[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[NH2:11]
Reactant: CC(C)(C)[S@](=O)N[C@H]1CCc2c(Br)cccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CC#N
Product: N[C@H]1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a stirred suspension of crude (S)-N-((S)-4-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide IND INT-11 (46 g, 145 mol) in MeOH (100 mL) was added 4N HCl in dioxane (109 mL) and the yellow suspension was stirred at room temperature for 3 h. The crude reaction was diluted with MeOH (100 mL) and filtered. The filtrate was concentrated and the solid obtained was dispersed into acetonitrile (600 mL) and refluxed for 90 min. The suspension was cooled to 0° C. and the solid filtered to produce 25 g of (69%) (S)-4-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride IND INT-13 which was used in the next step without purification. LCMS-ESI (m/z) calculated for C9H10BrN: 211.09; found 197.0 [M-NH2]+, tR=1.76 min. 1H NMR (400 MHz, DMSO) δ 8.76 (s, 2H), 7.71 (d, J=7.5 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.26 (t, J=7.7 Hz, 1H), 4.80 (s, 1H), 3.06 (ddd, J=16.9, 8.9, 5.2 Hz, 1H), 2.93-2.76 (m, 1H), 2.57-2.39 (m, 1H), 2.11-1.92 (m, 1H); 13C NMR (101 MHz, DMSO) δ 144.12, 141.60, 131.71, 129.02, 124.54, 119.29, 55.30, 31.52, 29.10.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22](OS(C(F)(F)F)(=O)=O)[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4].[C-:37]#[N:38]>[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.CN(C)C=O>[F:36][C:2]([F:35])([F:1])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:37]#[N:38])[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4]
Reactant: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3c(OS(=O)(=O)C(F)(F)F)cccc31)C2)C(F)(F)F
Reactant: [C-]#N
Agent: [Pd]
Agent: [Zn+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F

Procedure:
A solution of trifluoromethanesulfonic acid 9-[8-(2,2, 2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthen-4-yl ester in a deoxygenated solvent such as dimethyl formamide (0.5 to 2 M solution) may be treated with a catalytic amount of a palladium catalyst such as tetrakis(triphenylphosphine) palladium ( 0.01 to 0.1 equiv) and a cyanide source such as zinc cyanide (1.5 to 3 equiv). The mixture may be heated to 100° C. to 150° C. under an argon atmosphere for 1 to 5 hr. After cooling, the mixture may be partitioned between a saturated sodium bicarbonate solution and an organic solvent such as ethyl acetate. The organic phase may be separated, dried over an appropriate drying agent such as sodium sulfate, filtered, and evaporated. The residue may be purified over silica gel using a mixture of organic solvents or via reverse phase chromatography to yield Compound 2b.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[O:15]>>[OH:15][CH:14]([CH:2]([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4])[C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: CCOC(=O)C=O
Product: CCOC(=O)C(O)C(C)C(=O)c1ccc(OC)cc1
Temperature: 135 °C

Procedure:
A mixture of 82 g of 4-methoxypropiophenone and 76.6 g of ethyl glyoxylate is heated at 135° C. for 15 hours.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([N+:19]([O-])=O)=[CH:13][C:14]=2[N+:16]([O-])=O)[C:9]([NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[N:8]1)[CH3:2].CO.O.Cl>[Fe].C(Cl)(Cl)Cl>[CH2:31]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH2:19])=[CH:13][C:14]=2[NH2:16])[C:9]([NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[N:8]1)[CH3:32]
Reactant: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2c([N+](=O)[O-])cc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2c(N)cc(N)cc12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 23.7 %

Procedure:
A mixture consisting of 12.0 g of the 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-5,7-dinitroindazole, 18 g of iron powder, 60 ml of methyl alcohol, 30 ml of water and 3 ml of hydrochloric acid was stirred for 1.5 hours at 70° C. After cooling, the mixture was filtered, and the pH of the filtrate was adjusted to 11 with an aqueous potassium carbonate solution. The filtrate was extracted three times with 50 ml of ethyl acetate, and the ethyl acetate layer was washed with water. The layer was dried over anhydrous sodium sulfate, and ethyl acetate was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 2.46 g of 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-5,7-diaminoindazole having the following analytical values in a yield of 23%.
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.CCOCC>CO>[CH3:1][O:12][C:11]([C@@H:8]1[CH2:7][C@@H:6]([OH:5])[CH2:10][NH:9]1)=[O:13]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C

Procedure:
Acetyl chloride (7.6 ml; 107 mmol) was added slowly to MeOH (70 ml). The reaction was exothermic. (2S,4R)-4-Hydroxy-2-pyrrolidinecarboxylic acid (10 g; 76.2 mmol) was added and the mixture was refluxed for 4 hours. At this time, another portion of 3 ml of acetyl chloride in 30 ml of MeOH was added. The mixture was refluxed an additional 3 hours. The reaction was cooled to room temperature and ~750 ml of Et2O was added. The resulting colorless crystals were filtered and dried to afford 11.89 g of the title A compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A quantity of 6.0 g of 3-chloro-2,4-difluorobenzoic acid is suspended in 20 ml of dichloromethane. A quantity of 2.99 ml of oxalyl chloride and 2 drops of DMF are then added. The suspension is stirred at room temperature overnight and the desired product is collected after evaporation of the solvent.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:18]Cl>C(O)(=O)C>[Cl:18][C:14]1[CH:15]=[CH:16][C:8]2[C:7](=[O:17])[NH:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[C:9]=2[CH:13]=1
Reactant: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Reactant: ClCl
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c(=O)c2cc(Cl)ccc12
Temperature: 25 °C

Procedure:
A mixture of 11.15 g of 5H-dibenz[b,e]azepin-6,11-dione and 600 ml of glacial acetic acid is heated on a steam bath until the solid dissolves. To the solution (70° C.) is added chlorine gas. chlorine is bubbled through the solution until a precipitate begins to form. The mixture is allowed to cool to room temperature and is filtered to give 7.3 g of product, m.p. 290° C. to 295° C.
Reaction SMILES: C(N)(=[O:8])C1C=CC=CC=1.C(#N)C1C=CC=NC=1.[C:18]([NH2:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.C=C(CCC#N)C#N>C(#N)C1C=CC=CC=1.O.N1C=CC=CC=1>[CH2:20]=[C:19]([CH2:24][CH2:23][C:22]([NH2:21])=[O:8])[C:18]([NH2:26])=[O:25]
Reactant: NC(=O)c1ccccc1
Reactant: NC(=O)c1cccnc1
Agent: C=C(C#N)CCC#N
Agent: N#Cc1cccnc1
Solvent: O
Solvent: N#Cc1ccccc1
Solvent: c1ccncc1
Product: C=C(CCC(N)=O)C(N)=O
Temperature: 120 °C

Procedure:
Into 10 ml stainless steel tubes were charged 0.1 mmole RhCl3 . 3H2O, 0.4 mmole TLTTP, 4 ml pyridine, 1-2 g of nitrile and a stoichiometric equivalent amount of water. The tubes were pressurized to 150 psig with nitrogen and heated at 120° C. for 17 hours and then the products were determined. In this manner, benzonitrile was converted to benzamide and nicotinonitrile was converted to nicotinamide. These reactions were repeated on a scale up of about 10-times using methyleneglutaronitrile as the nitrile, 115° C. for 27 hours and a nitrogen pressure of 210 psig to produce 2-methyleneglutaramide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][O:8]/[N:9]=[C:10](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[S:17][CH:18]=1)\[C:11]([OH:13])=O)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:61]1([CH2:66][C@H:67]2[NH:70][C:69](=[O:71])[C@H:68]2[NH2:72])[CH:65]=[N:64][CH:63]=[N:62]1>C(Cl)Cl.CCOC(C)=O>[N:61]1([CH2:66][C@@H:67]2[C@H:68]([NH:72][C:11](=[O:13])/[C:10](=[N:9]\[O:8][CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:27])/[C:14]3[N:15]=[C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[S:17][CH:18]=3)[C:69](=[O:71])[NH:70]2)[CH:65]=[N:64][CH:63]=[N:62]1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N[C@@H]1Cn1cncn1)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
To a solution of (Z)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (108 mg, 0.269 mmol) in DCM (2.7 mL) at 0° C. was added DIPEA (141 μL, 0.808 mmol) followed by HATU (113 mg, 0.296 mmol). To the resulting solution, after 20 min, was added a solution of (3S,4R)-4-((1H-1,2,4-triazol-1-yl)methyl)-3-aminoazetidin-2-one (50 mg, 0.299 mmol) in DCM. After 1 h of stirring it was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM) to afford the title compound (106 mg, 72%). LCMS: R=0.78 min, m/z=551.2 (M+1) Method 2m_acidic.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[CH2:28][CH3:29])=[O:17])=[CH:4][C:3]=1[O:30]C.B(Cl)(Cl)Cl>C(Cl)Cl.CCOC(C)=O.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[CH2:28][CH3:29])=[O:17])=[CH:4][C:3]=1[OH:30]
Reactant: CCc1n[nH]c2ccc(NC(=O)C3=C(C)NC(=O)CC3c3ccc(Cl)c(OC)c3)cc12
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1n[nH]c2ccc(NC(=O)C3=C(C)NC(=O)CC3c3ccc(Cl)c(O)c3)cc12
Temperature: 30 °C
Reaction time: 72 h
Yield: 2.1 %

Procedure:
The product from Example 96 (0.050 g, 0.11 mmol, 1.0 equiv) was cooled to −78° C. in 1.5 mL CH2Cl2 and BCl3 (1.0 M in CH2C2, 1.70 mL, 1.71 mmol, 15.0 equiv) was added dropwise. The reaction was warmed to 30° C. and stirred for 72 hours. The reaction mixture was diluted with EtOAc and water and basified to pH 14 with 6N NaOH. The phases were separated, and the aqueous phase was acidified to pH 4 with 6N HCl and the product was extracted into EtOAc. The organic layer was washed with sat'd NaCl and concentrated en vacuo. The residue purified by reverse-phase HPLC (10-95% CH3CN/H2O, 0.1% TFA over 6 minutes, retention time 3.48 min) to provide 1 mg (0.7%) of the title compound as a white solid. MS (ES+) m/e 425 [M+H]+
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[Cl:31])[C:22]3[CH2:21][CH2:20][N:19]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:18](=[O:38])[C:17]=3[C:16]=2[CH3:39])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:23]1[C:22]2[CH2:21][CH2:20][N:19]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:18](=[O:38])[C:17]=2[C:16]([CH3:39])=[C:15]1[C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: Cc1c2c(n(-c3ccc(F)cc3Cl)c1-c1ccc(O[Si](C)(C)C(C)(C)C)cc1)CCN(N1CCCCC1)C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c2c(n(-c3ccc(F)cc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
2-[4-(tert-Butyldimethylsilanyloxy)phenyl]-1-(2-chloro-4-fluorophenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one (0.929 g, 1.63 mmol) was suspended in THF (10 ml) and TBAF (1M in THF, 1.64 ml) was added. The reaction mixture was stirred at rt for 1 h whereafter the solvent was evaporated and ethyl acetate/water added. The phases were separated and the organic phase dried and evaporated. The crude product was recrystallised from ethyl acetate/toluene to yield the product as an orange solid (0.223 g, 23% over 3 steps).
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.[CH:35](=O)[CH3:36].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:35][CH3:36])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccccc1

Procedure:
4-Amino-N-((1-(6-benzylaminohexyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (1.3 g) as starting compound, acetaldehyde (0.16 ml) and sodium cyanoborohydride (0.37 g) were reacted and treated in the same manner as in Example 136 to give 0.25 g of 4-amino-5-chloro-N-((1-(6-(N-ethyl-N-benzylamino)hexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:47][CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:57][N:54]1[CH2:55][CH2:56][N:51]([CH2:50][CH2:49][CH2:48][NH:47][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]3[C:12]([CH3:24])=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)=[O:7])[CH:14]=3)=[CH:20][CH:19]=2)=[O:22])[CH2:52][CH2:53]1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Reactant: CN1CCN(CCCN)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCCN2CCN(C)CC2)cc1
Yield: 16.7 %

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), TBTU (60 mg, 0.186 mmol), 1-(3-aminopropyl)-4-methylpiperazine (25 mg, 0.156 mmol) and DIPEA (81 μl, 0.467 mmol) in DMF (1 ml) were stirred at room temperature for 2 h. The DMF was evaporated under vacuum and the residue dissolved in chloroform and filtered through an aminopropyl SPE (3 g). The filtrate was purified by flash chromatography on silica, eluting with DCM/ethanol/ammonia (110:8:1), which after evaporation of the solvents under vacuum gave N-(4′-{[3-(4-methylpiperazin-1-yl)propylamino]carbonyl)-6-methyl-1,1′-biphenyl-3-yl)-3-furamide (12 mg, 17%). NMR; δH [2H6]-DMSO 9.91,(1H, s), 8.55,(1H, t), 8.35,(1H, s), 7.90,(2H, d), 7.78,(1H, t), 7.66,(1H, dd), 7.59,(1H, d), 7.43,(2H, d), 7.27,(1H, d), 6.98,(1H, m), 3.29,(2H, m), 2.48-2.20,(10H, m), 2.19,(3H, s), 2.13,(3H, s), 1.68,(2H, m). LCMS: retention time 2.37 min, MH+461.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.Cl.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28]1[N:29]=[C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[S:31][CH:32]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28]1[N:29]=[C:30]([N:33]2[CH2:34][CH2:35][N:36]([C:7]([C:6]3[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=3[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:37][CH2:38]2)[S:31][CH:32]=1
Reactant: Clc1ccc(-c2csc(N3CCNCC3)n2)c(Cl)c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(-c3ccc(Cl)cc3Cl)cs2)CC1
Yield: 17 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[4-(2,4-dichloro-phenyl)-thiazol-2-yl]-piperazine dihydrochloride. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) (yield 17%). MS (m/e): 558.1 ({37Cl}M+H+, 19%), 555.9 ({37Cl35Cl}M+H+, 58%), 554.1 ({35Cl}M+H+, 100%).
Reaction SMILES: [CH2:1](NC(=O)C(C)O)CCCCCCC.[OH-].[K+].C(O)(=O)C(C)O.C1OC1.[CH2:26]([C:34](C)([OH:38])[C:35]([NH2:37])=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:27]([CH2:26][CH:34]([OH:38])[C:35]([NH2:37])=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:1]
Reactant: CCCCCCCCNC(=O)C(C)O
Reactant: CCCCCCCCC(C)(O)C(N)=O
Agent: CC(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CO1
Product: CCCCCCCCCC(O)C(N)=O
Temperature: 25 °C

Procedure:
100 g of N-octyllactamide were admixed with 1 g of 45% KOH in a pressurized reactor and dried for one hour at 115° C. and reduced pressure. Then, at 130° C., 3 mol equivalents of ethylene oxide were metered in over 40 minutes and the product was kept for a further 45 minutes at this temperature for a post reaction time. After cooling to room temperature, the mixture was neutralized with lactic acid. The product was obtained in the form of a clear, brownish liquid. Using 1H-NMR analysis, an addition of 3.1 mol of ethylene oxide per mol of octyllactamide was determined.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.CO[C:24](OC)([CH3:26])[CH3:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C@H:3]2[CH2:2][O:1][C:24]([CH3:26])([CH3:25])[N:14]2[C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc([N+](=O)[O-])cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl N-[(1S)-2-hydroxy-1-(4-nitrobenzyl)ethyl]carbamate (22.3 g), 2,2-dimethoxypropane (46.3 ml), p-toluenesulfonic acid monohydrate (1.43 g) and dichloromethane (200 ml) was stirred at room temperature for 15 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with isopropyl ether to give tert-butyl (S)-4-(4-nitrobenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (16.9 g) as a pale yellow powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[CH3:29]C([O-])(C)C.[K+].CI>CN(C=O)C.C1COCC1>[CH3:29][O:1][CH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1
Reactant: Cc1c(CO)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CI
Product: COCc1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Temperature: 0 °C

Procedure:
To a solution of compound 3B (9.0 mg, 0.025 mmol) in DMF:THF (1:1, 1 mL) at 0° C. was added KOtBu (1.5 M in THF, 0.025 mL, 0.038 mmol). After stirring for 45° min at 0° C., methyl iodide (2 μL, 0.025 mmol) was added and the reaction mixture was stirred for an additional 1h, warmed to 25° C., and stirred for 3h. No reaction was observed during this time. The reaction mixture was cooled once more to 0° C., additional KOtBu (1.5 M in THF, 0.25 mL, 0.38 mmol) was added and the reaction mixture was stirred for 30 min, after which time additional methyl iodide (20 μL, 0.25 mmol) was added. After stirring for an additional 2h at 0° C., the reaction was quenched by the addition of saturated aqueous NH4Cl (10 mL) and dichloromethane (10 mL). The layers were separated, the aqueous phase was extracted with dichloromethane (2×10 mL) and the combined organic extracts were dried over MgSO4, filtered concentrated, and purified by preparative HPLC (YMC S5 ODS 20×100 mm, eluting with 30-100% aqueous methanol over 15 min containing 0.1% TFA, 20 mL/min) to afford the desired product as a yellow semi-solid. HPLC: 100% at 4.27 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 200 nm). MS (ES): m/z 385.21 [M+H]+.