Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=3)=[CH:17][CH:16]=2)=[CH:11][C:10]([C:31]([F:34])([F:33])[F:32])=[N:9]1.CO.C=O.[C:39]([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][N:14]([CH3:39])[C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=3)=[CH:19][CH:20]=2)=[CH:11][C:10]([C:31]([F:34])([F:32])[F:33])=[N:9]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(NCc3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(Cc1cc(C(F)(F)F)nn1-c1ccccc1Cl)c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1

Procedure:
Into an 8 mL vial was weighed 215 mg of N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3′-(methylsulfonyl)biphenyl-4-amine (0.42 mmol). Addition of 2 mL of methanol followed by 0.5 mL of acetic acid, and 150 μL of 37% aqueous formaldehyde solution afforded a solution that was treated with 40 mg of sodium cyanoborohydride (0.64 mmol). After 30 min. at room temperature the reaction was quenched by the addition of 6N HCl (aq.). After gas evolution had subsided, the reaction mixture was diluted with EtOAc and the aqueous was made basic by the addition of saturated aqueous NaHCO3. The basic aqueous was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford a colorless film. The crude product was purified by silica gel flash chromatography on a 12 g column using gradient elution from 0% to 100% EtOAc/hexane. Appropriate fractions were combined and concentrated in vacuo to afford N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-N-methyl-3′-(methylsulfonyl)biphenyl-4-amine as a colorless film. This material was impure by NMR analysis and was further purified by preparative reverse phase HPLC eluting with a gradient from 30% to 100% MeCN in H2O (each with 0.05% trifluoroacetic acid). The appropriate fractions were made basic by addition of saturated aqueous NaHCO3 solution and concentrated in vacuo to remove most of the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-N-methyl-3′-(methylsulfonyl)biphenyl-4-amine as a brittle foam that was broken up into a white powder, yield 126 mg (57% yield): 1H NMR (400 MHz, CDCl3): δ 8.11-8.08 (m, 1H, 7.84-7.79 (m, 2H, 7.62-7.56 (m, 2H, 7.52-7.40 (m, 5H), 6.72-6.67 (m, 2H), 6.52 (s, 1H), 4.43 (br s, 1H), 3.09 (s, 3H), 2.94 (S, 3H); MS (ESI) m/z 520.3 [M+H]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[S:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.ClCCl>C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:39][C:35]2[S:34][CH:38]=[CH:37][N:36]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)CCN(Cc1nccs1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Sodium triacetoxyborohydride (0:30 g, 1.42 mmol) is added to a stirred solution of 4-(3-methyl-butylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.19 g, 0.71 mmol), 2-thiazolecarboxaldehyde (0.12 ml, 1.42 mmol), and dichloromethane (3.5 ml). The reaction is stirred overnight at room temperature under nitrogen. The reaction is diluted with ethyl acetate, washed with aqueous saturated NaHCO3, dried over Na2SO4, filtered, and concentrated. Water is added to the residue, and the solution loaded onto a SCX-2 (10 g) column and washed with water (20 ml) and methanol (20 ml). The product is then eluted with 2M ammonia in methanol (30 ml). The filtrate is concentrated and the crude material purified on silica gel eluting with 0-50% ethyl acetate/hexanes to yield (0.20 g) of 4-{(3-methyl-butyl)-[(thiazol-2-yl)-methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=368 (M+1); 1H NMR (CDCl3): δ=7.67 (1H, d), 7.23 (1H, d), 4.17 (2H, brs), 3.93 (2H, s), 2.72-2.54 (5H, m), 1.78 (2H, brd), 1.7-1.57 (2H, m), 1.45-1.41 (10H, m), 1.40-1.32 (2H, m), 0.87 (6H, d).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])O[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2[N:46](C)[C:45](C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:46]([CH3:45])[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)n1C
Yield: 87.26 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-02) (1.8 g, 87.26%) was synthesized as a yellow solid from 3-benzyloxy-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-4H-pyran-2-carboxylic acid (12-02) (2.0 g, 4.6 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(C)=[O:21].ClC1C=CC=C(C(OO)=O)C=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N+:15]([O-:21])=[CH:14][CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc2ncccc2c1
Reactant: CC(C)=O
Agent: O=C(OO)c1cccc(Cl)c1
Product: CCCCCCCOc1ccc2c(ccc[n+]2[O-])c1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
6-Heptyloxyquinoline (1000.0 mg, 0.0041094 mol) was dissolved in acetone (20 mL, 0.3 mol), followed by m-chloroperbenzoic acid (1060 mg, 0.00493 mol) in small portions at 23° C. The reaction mixture was then stirred at 23° C. for 3 hours, and LC/MS indicated all the SM was converted to the desired product. A solution of sodium thiosulfate (1950 mg, 0.0123 mol) was added. The reaction mixture was then allowed to stir for 1 hour. Excess of solvents were removed under vacuum, and the residue was treated with DCM (100×3 mL). Combined organic layers were treated with sodium sulfate and filtrated. The crude mixture was then purified via chromatography (SiO2, 120 g, 0-8% MeOH/DCM) to give 653 mg (53%) pure product. 1H NMR (CHLOROFORM-d) δ: 8.65 (d, J=9.5 Hz, 1H), 8.38 (d, J=5.8 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.38 (dd, J=9.5, 2.5 Hz, 1H), 7.23 (dd, J=8.3, 6.0 Hz, 1H), 7.09 (d, J=2.5 Hz, 1H), 4.08 (t, J=6.5 Hz, 2H), 1.80-1.92 (m, 2H), 1.44-1.57 (m, 2H), 1.28-1.44 (m, 6H), 0.90 (t, J=6.8 Hz, 3H). MS (M+1): 260.20.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]SC.COS(OC)(=O)=O>FC(F)(F)C(O)=O.CO.[Zn]>[NH2:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CSCc1ccnc(Cl)c1N
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Solvent: COS(=O)(=O)OC
Solvent: CO
Product: Cc1ccnc(Cl)c1N
Reaction time: 68 h

Procedure:
3-amino-2-chloro-4-methylthiomethylpyridine prepared above in B (90.2 mg, 0.48 mmoles) was dissolved in trifluoroacetic acid (450 μl). To the resulting solution was added dimethylsulfate (57.1 mg, 0.452 mmoles) at ambient temperature and allowed to stand at ambient temperature for 68 hours, to produce an alkylation solution. A proton NMR spectrum of the alkylation solution revealed that complete alkylation had ocurred. The alkylation solution was then evaporated to dryness and the resultant residue was twice dissolved in methanol and evaporated to dryness, to produce an amber oil weighing 306.8 mg. The oil was dissolved in methanol (500 μl) and stirred in an atmosphere of nitrogen at ambient temperature while zinc dust (63 mg, 0.98 mmoles) was added portionwise over two hours. After complete addition of the zinc dust, the resultant mixture was allowed to continue stirring for 21 hours. An aliquot of the mixture was then removed for analysis by thin layer chromatography (silica gel; 3% methanol/dichloromethane as eluant) which revealed highly selective conversion to 3-amino-2-chloro-4-methylpyridine had occurred. The mixture was then filtered and the filtrate was concentrated to produce a dry residue. The residue was partitioned between ether and water (2 ml each). The layers were separated and the aqueous phase was extracted three additional times with 2 ml portions of ether. The ethereal extracts were combined and dried with anhydrous sodium sulfate, filtered and concentrated at reduced pressure to give 3-amino-2-chloro-4-methylpyridine as an oil weighing 66.6 mg. The oil solidified on standing. Product identity is confirmed by comparison of its proton NMR and TLC chromatographic properties (5% ethylacetate/dichloromethane, R =0.45; 3% methanol/dichloromethane, R =0.70) with those of an authentic sample.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:18][CH2:17][C:16]2[S:19][C:20]([NH2:22])=[N:21][C:15]=2[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>N1C=CC=CC=1.ClCCl.O>[C:5]([O:9][C:10]([N:12]1[CH2:18][CH2:17][C:16]2[S:19][C:20]([NH:22][C:1](=[O:3])[CH3:2])=[N:21][C:15]=2[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
95 mg acetyl chloride was added to 312 mg 2-amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylic acid tert-butyl ester in 5 mL pyridine at 15° C. The reaction was stirred 3 h at RT. The reaction was diluted with dichlormethane and 1 mL water was added. The solution was filtered over 40 mL Alox and 100 mL Extrelut and evaporated to give 127 mg of the desired product. (M+H)+: 312
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[NH3:6].[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: C1CNCCN1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: N
Product: c1csc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 28 %
Yield: 140.3 %

Procedure:
In 50 ml of acetonitrile was dissolved 5.0 g (0.0305 mole) of 2-bromothiazole, then, 13.1 g (0.153 mole) of piperazine, 8.4 g (0.061 mole) of potassium carbonate and a catalytic amount of potassium iodide were added to the solution, and the mixture was refluxed under heating for 5 hours. After the mixture was cooled to room temperature and then filtered, the filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (eluent; a chloroform:methanol:28% aqueous ammonia=40:9:1 mixed solution) to obtain 3.62 g of 1-(2-thiazolyl)piperazine as a colorless liquid.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[F:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[C:20]([CH3:29])[CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][C:20]=2[CH3:29])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(F)ccc1/C=C/[N+](=O)[O-]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)ccc1C1CN(Cc2ccccc2)CC1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (1.95 g, 8.21 mmol) in CH2Cl2 (30 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 4-fluoro-2-methyl-1-((E)-2-nitro-vinyl)-benzene (1.49 g, 8.22 mmol) and trifluoroacetic acid (0.60 ml, 0.82 mmol) in CH2Cl2 (30 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:6) afforded 0.77 g (30%) of the title compound as a light yellow oil. ES-MS m/e: 315.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[S:8][C:4]=2[CH:3]=1.Br.C1(S[C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[NH:28])C=CC=CC=1>C(O)C>[N:12]1([CH2:11][CH2:10][NH:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([NH:1][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])[CH:18]=[CH:17][C:5]=3[N:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: N=C(Sc1ccccc1)c1cccs1
Reactant: Nc1ccc2nc(NCCN3CCCC3)sc2c1
Agent: Br
Solvent: CCO
Product: N=C(Nc1ccc2nc(NCCN3CCCC3)sc2c1)c1cccs1

Procedure:
6-Amino-2-(2-pyrrolidin-1-yl-ethylamino)benzothiazole (Example 12, 28 mg, 0.11 mmol) and thiophene-2-carboximidothioic acid phenyl ester hydrobromide (32 mg, 0.11 mmol) in 3 mL of ethanol (denatured) was stirred at room temperature for 20 hours. The solvent was removed and the residue was partitioned between 5 mL of H2O and 10 mL of Et2O. The aqueous layer was concentrated to give the title compound. 1H-NMR (CD3OD): δ 8.08 (m, 2H); 7.72 (d, 1H, J=2.0 Hz); 7.64 (d, 1H, J=8.0 Hz); 7.30 (m, 2H); 3.86 (t, 2H, J=5.9 Hz); 3.50 (m, 6H); 2.10 (m, 4H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[CH:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH2:13]([NH2:15])C.[C-]#N.[Na+]>O>[CH2:1]([NH:3][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:13]#[N:15])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCN
Reactant: CC#N
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CCNC(C#N)c1ccccc1

Procedure:
A mixture consisting of 35 ml of acetonitrile; 10 ml of water; 16.8 g of benzaldehyde; 16 g of ethylamine hydrochloride and 10 g of sodium cyanide is stirred at room temperature for 2 days. It is then diluted with more water and extracted with benzene. The benzene extract is washed several times in the water and then dried over potassium carbonate. The solution is filtered and the filtrate is concentrated under reduced pressure to leave crude 2-ethylamino-2-phenylacetonitrile. This material is reduced with 11.5 g of lithium aluminum hydride in ether, following the procedure and workup already described. There is 10.7 g of β-ethylamino-2-phenylethylamine, dihydrochloride, m.p. 226°-229° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].F[C:9](F)(F)[C:10]([O:12]CC)=[O:11].C([O:19][C:20](=[O:23])[CH2:21]Br)C.[H-].[Na+]>>[CH2:3]([N:4]([CH2:9][C:10]([OH:12])=[O:11])[CH2:5][CH2:6][N:7]([CH2:21][C:20]([OH:19])=[O:23])[CH2:9][C:10]([OH:12])=[O:11])[CH2:2][N:1]([CH2:9][C:10]([OH:12])=[O:11])[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CBr
Reactant: NCCNCCN
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O

Procedure:
Various esters of DTPA were prepared from diethylenetriamine, 6. The primary amines could be selectively protected as the di-trifluoroacetamide by reaction with ethyl trifluoroacetate to produce 9 in good yield. Reaction of 9 with 3 equivalents of ethylbromoacetate and NaH produced the triester 10. Reaction of 9 with 1 equivalent of ethylbromoacetate produced the monoester 11.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:41][CH2:42][O:43]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:48][NH:49][CH3:50].C1C[O:54]CC1>>[CH:42]([OH:43])=[O:54].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:41][CH2:42][N:49]([CH3:50])[CH3:48])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCOS(C)(=O)=O)c4ccccc43)cn12
Reactant: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCN(C)C)c4ccccc43)cn12
Product: O=CO
Yield: 62 %

Procedure:
A yellow solution of Intermediate 127a (0.100 mmol) and dimethylamine (2M in THF, 1.0 mL, 2.0 mmol) in THF (1 mL) was stirred in a sealed vial at 60° C. for 16 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2 cartridge (5 g) and washed with MeOH (15 mL). The product was eluted with 2M NH3 in MeOH (15 mL); concentration in vacuo left a yellow film. MDAP (Method 7) gave the title compound as an off-white solid (42 mg, 62%). LCMS (Method 5): Rt 3.43 min, m/z 614.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.21 (9H, s), 1.46-1.56 (2H, m), 1.63-1.72 (2H, m), 1.76-1.85 (2H, m), 1.92-2.01 (2H, m), 2.03-2.11 (1H, m), 2.15-2.19 (1H, m), 2.21 (6H, s), 2.61 (2H, t, J=6.9 Hz), 2.91 (1H, ddd, J=12.2, 9.2, 4.0 Hz), 3.17 (1H, dt, J=12.2, 4.3 Hz), 3.28-3.36 (1H, m), 3.99 (2H, t, J=6.9 Hz), 4.87 (1H, td, J=8.5, 6.2 Hz), 5.53 (1H, t, J=4.1 Hz), 6.03 (1H, s), 6.97 (1H, d, J=8.7 Hz), 7.21 (1H, dd, J=9.8, 2.2 Hz), 7.29 (1H, td, J=7.3, 2.0 Hz), 7.34-7.41 (3H, m), 7.65 (1H, dd, J=9.8, 0.8 Hz), 7.71 (1H, d, J=2.1 Hz), 8.17 (1.4H, s), 8.48 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH:37]([NH:40][CH3:41])([CH3:39])[CH3:38]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:40]([CH:37]([CH3:39])[CH3:38])[CH3:41])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CNC(C)C
Reactant: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN(C)C(C)C)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 29) (219 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isopropyl-methylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (129 mg, 52%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.O/[N:53]=[C:54](\[NH2:62])/[CH2:55][C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1>ClCCl.O>[NH2:62]/[C:54](=[N:53]\[O:10][C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])=[O:11])/[CH2:55][C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1
Reactant: N/C(Cc1cccnc1)=N\O
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)Cc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 115.9 %

Procedure:
A solution of (2R)-2-(2-tert-butoxy-2-oxoethyl)-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.67 mmol) in dichloromethane (20 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (354 mg, 1.85 mmol), N-methylmorpholine (203 μl, 1.85 mmol) and 1-hydroxybenzotriazole hydrate (227 mg, 1.67 mmol). (1Z)-N′-hydroxy-2-(3-pyridinyl)ethanimidamide (WO 9600720) (374 mg, 1.67 mmol) followed by N-methylmorpholine (369 μl, 3.34 mmol) were added to the reaction mixture which was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (10 ml) and stirred for 20 minutes. The layers were separated via a 5 micron filter cartridge. The organic solvent was removed under reduced pressure to afford the title compound as a yellow oil (835 mg). This was used without further purification in the following step.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][C:26]=1[CH3:33]>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])=[CH:27][C:26]=1[CH3:33]
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Reactant: Cc1cc([Mg]Br)ccc1Cl
Product: Cc1cc(C(=O)c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)ccc1Cl

Procedure:
The product from Example 71E and 4-chloro-3-methylphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.47 (d, 3H), 1.75 (m, 1H), 1.80 (m, 2H), 2.10 (m, 2H), 2.38 (m, 1H), 2.44 (s, 3H), 3.50 (m, 2H), 3.55 (m, 1H), 3.80 (m, 2H), 6.85 (s, 1H), 7.5 (m, 3H), 7.7 (bs, 1H), 7.79 (dd, 1H), 8.01 (d, 1H); MS (ESI) m/z 382 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[CH:7]=1.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)[CH3:23].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:16]([C:13]([CH3:14])([O:12][C:8]2[CH:7]=[C:6]([CH2:5][C@H:4]([O:19][CH3:20])[C:3]([OH:2])=[O:21])[CH:11]=[CH:10][CH:9]=2)[CH3:15])=[O:18])=[CH:26][CH:25]=1)[CH3:23]
Reactant: CCc1ccc(CCN)cc1
Reactant: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)O)c1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCc1ccc(CCNC(=O)C(C)(C)Oc2cccc(C[C@H](OC)C(=O)O)c2)cc1

Procedure:
The title compound was prepared from (2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (EXAMPLE 56, step 2) and 2-(4-ethyl-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H31NO5 [M−H]−: 412.