Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].C(N(CC)CC)C.[Cl:26][C:27]1[C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[S:30][C:31]=1[C:32](Cl)=[O:33]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:32]([C:31]2[S:30][C:29]3[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=3[C:27]=2[Cl:26])=[O:33])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2N)c1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)Nc2ccccc2NC(=O)c2sc3ccccc3c2Cl)c1
Reaction time: 20 h
Yield: 72.8 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-1,2-benzenediamine (500 mg, 2.1 mmol) and triethylamine (0.44 mL, 3.2 mmol) in methylene chloride (100 mL) was added 3-chlorobenzo[b]thiophene-2-carbonyl chloride (490 mg, 2.1 mmol). After stirring for 20 h, the mixture was concentrated in vacuo and chromatographed (silica gel, 25% ethyl acetate/75% hexane) to give 660 mg (73%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[CH:5]=O.[C:21]([C:25]1[CH:26]=[C:27]([NH2:32])[C:28]([NH2:31])=[CH:29][CH:30]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]2[NH:31][C:5]([C:4]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)=[C:2]([CH3:1])[CH:3]=3)=[N:32][C:27]=2[CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: Cc1cc(C=O)ccc1OCCCN1CCN(C)CC1
Product: Cc1cc(-c2nc3cc(C(C)(C)C)ccc3[nH]2)ccc1OCCCN1CCN(C)CC1
Yield: 80.5 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (516 mg, 1.87 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (307 mg, 1.87 mmol, 1.0 equiv), and Na2S2O5 (461 mg, 2.43 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 633 mg (81%) of the title compound. MS (electrospray): mass calculated for C26H36N4O, 420.29; m/z found, 421.5 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.90-7.85 (m, 2H), 7.65-7.40 (m, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 4.14-4.11 (m, 2H), 2.90-2.28 (m, 16H), 2.06-2.03 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:14]1[O:16][CH:15]1[CH2:17]O.C([OH:22])(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:17][CH2:15][CH:14]([OH:22])[OH:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: OCC1CO1
Reactant: CC(C)O
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNCCC(O)O)cc1OC

Procedure:
To a solution of β-(3,4-dimethoxyphenyl)ethylamine (151.0 g, 0.83 m) in isopropanol (160 ml) heated at 50° is added a solution of glycidol (24.8 g, 0.33 m) in isopropanol (25 ml) over 30 minutes. After heating at 50° for 30 minutes and at 70° for 15 hours, the solvent is concentrated under reduced pressure. The residue is distilled at 224°-227° C. at 0.7 mm to yield I (47.9 g, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:24]1[CH:25]=[CH:26][C:27]2[N:33]3[C:34]([CH3:37])=[N:35][N:36]=[C:32]3[C@H:31]([CH2:38][C:39]([NH:41][CH2:42][CH3:43])=[O:40])[N:30]=[C:29]([C:44]3[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=3)[C:28]=2[CH:51]=1)(=O)=O.O>COCCOC.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>[Cl:50][C:47]1[CH:46]=[CH:45][C:44]([C:29]2[C:28]3[CH:51]=[C:24]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH:25]=[CH:26][C:27]=3[N:33]3[C:34]([CH3:37])=[N:35][N:36]=[C:32]3[C@H:31]([CH2:38][C:39]([NH:41][CH2:42][CH3:43])=[O:40])[N:30]=2)=[CH:49][CH:48]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(OC)cc3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
4-Methoxybenzeneboronic acid (50.5 mg), sodium carbonate (64.5 mg) and bis(triphenylphosphine)palladium(II) chloride (19.4 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl trifluoromethanesulfonate (for a preparation see Intermediate 3) (150 mg) in DME (3 ml) and water (1 ml) was added and the reaction mixture was heated at 120° C. for 20 min (microwave). The reaction mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with water (10 ml) and brine (10 ml). The organic phase was dried and the solvent was evaporated. The residue was chromatographed (0-5% methanol:DCM) to give 2-{(4S)-6-(4-chlorophenyl)-1-methyl-8-[4-(methyloxy)phenyl]-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl}-N-ethylacetamide as a light brown solid (84 mg). LCMS (formate): MH+ 500/502, RT 1.08 min
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([NH:9][CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3].[CH3:15][S:16]([NH:19][CH2:20][CH2:21]Cl)(=[O:18])=[O:17].C(=O)([O-])O.[Na+].O>CO>[NH:1]([C:5]1[CH:13]=[CH:12][C:8]([N:9]([CH2:21][CH2:20][NH:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3]
Reactant: CCNc1ccc(NC(C)=O)c(C)c1
Reactant: CS(=O)(=O)NCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(CCNS(C)(=O)=O)c1ccc(NC(C)=O)c(C)c1

Procedure:
A mixture of 57.6g of 4-acetamino-3-methyl-N-ethylaniline, 52g of βmethanesulfonamidoethyl chloride, 27.7g of sodium hydrogen carbonate, 70g of water and 70ml of methanol were refluxed for 5 hours, and thereafter the methanol was distilled out under reduced pressure. Water was added to the reaction system and an oily product separated out. This oily product was poured into ethyl acetate and cooled to obtain white 4-acetamino-3-methyl-N-(β-methanesulfonamidoethyl)-N-ethylaniline.
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]1[O:27][C:26](=[O:28])[C:25]([CH3:29])=[C:24]([OH:30])[C:23]=1[CH3:31].OS([O-])(=O)=O.[K+]>C1COCC1>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]1[O:27][C:26](=[O:28])[C:25]([CH3:29])=[C:24]([O:30][S:9]([CH3:8])(=[O:11])=[O:10])[C:23]=1[CH3:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Et3N (130 μl) and methanesulfonyl chloride (24 μl) were added to a suspension of 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg) in THF (5 ml), and the mixture was stirred at room temperature for one hour. The reaction solution was poured into aqueous KHSO4 and extracted with AcOEt, and the organic layer was rinsed with saturated saline and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=2/1) to obtain 6-(benzofuran-2-yl)-3,5-dimethyl-4-methanesulfonyloxy-2H-pyran-2-one.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:11][C@H:10]2[NH2:12])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[F:18][CH:19]([F:29])[C:20]1[C:24]([C:25](Cl)=[O:26])=[CH:23][N:22]([CH3:28])[N:21]=1.CCOC(C)=O.CCCCCC>ClCCl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@H:10]2[NH:12][C:25]([C:24]2[C:20]([CH:19]([F:29])[F:18])=[N:21][N:22]([CH3:28])[CH:23]=2)=[O:26])=[CH:7][CH:8]=1
Reactant: N[C@@H]1C[C@@H]1c1ccc(F)cc1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: Cn1cc(C(=O)N[C@@H]2C[C@@H]2c2ccc(F)cc2)c(C(F)F)n1
Yield: 85.3 %

Procedure:
cis-2-(4-Fluoro-phenyl)-cyclopropylamine hydrochloride (0.153 g, 0.815 mmol) was dissolved in dichloromethane (4.5 ml) and stirred with NaHCO3 (1 M, 4.5 ml). 3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carbonyl chloride (0.190 g, 0.978 mmol) was added dropwise. After three hours rapid stirring tlc (50% EtOAc/hexane) showed the reaction to be finished. The mixture was separated between dichloromethane and water, washed with NaCl (sat), dried (MgSO4), and evaporated to yield 245 mg of nearly pure product, which was washed with cyclohexane to yield 215 mg (85%) of the product as a white solid m.p. 141-143° C.
Reaction SMILES: C([N:3]1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1.[ClH:24].[C:25]([C:28]1[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][C:34]([OH:36])=O)=[CH:30][CH:29]=1)(=[NH:27])N.Cl.[NH2:40][CH2:41][CH2:42][N:43]([CH2:61][C:62]([O:64][CH3:65])=[O:63])[C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45].OC1C2N=NNC=2C=CC=1>CN(C)C=O>[ClH:24].[NH2:3][N:27]=[CH:25][C:28]1[CH:29]=[CH:30][C:31]([CH:32]=[CH:33][C:34]([NH:40][CH2:41][CH2:42][N:43]([CH2:61][C:62]([O:64][CH3:65])=[O:63])[C:44]([O:46][CH2:47][CH:48]2[C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=3[C:55]3[C:60]2=[CH:59][CH:58]=[CH:57][CH:56]=3)=[O:45])=[O:36])=[CH:37][CH:38]=1
Reactant: CCN1CCOCC1
Reactant: N=C(N)c1ccc(C=CC(=O)O)cc1
Reactant: COC(=O)CN(CCN)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: COC(=O)CN(CCNC(=O)C=Cc1ccc(C=NN)cc1)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.7 g (6 mmol) of N-ethylmorpholine and 0.8 g (4 mmol) of DCC are added, at 0° C., to 0.7 g (3 mmol) of 4-amidinocinnamic acid hydrochloride, 1.2 g (3 mmol) of methyl N-(2-aminoethyl)-N-(9-fluorenylmethoxycarbonyl)aminoacetate hydrochloride and 0.4 g (3 mmol) of hydroxybenzotriazole in 20 ml of dimethylformamide. The mixture is stirred at 0° C. for one hour and then at room temperature for 20 h, filtered from the precipitated urea and concentrated. The residue is taken up in ethyl acetate and washed with sodium hydrogen carbonate solution, and the organic phase is dried and concentrated. The product is chromatographed, for purification, on Sephadex LH20 using an homogeneous mixture of butanol/glacial acetic acid/water.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([OH:13])[CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[OH:14][CH2:15][CH2:16]C#N>>[C:15]([O:13][CH:11]([CH3:12])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[C:9]#[N:10])(=[O:14])[CH3:16]
Reactant: Cc1ccc(C(C#N)C(C)O)cc1
Reactant: N#CCCO
Product: CC(=O)OC(C)C(C#N)c1ccc(C)cc1

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(4-methylphenyl)-3-hydroxybutanenitrile in place of 2-2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile in the above described procedure. The preparation of 2-(4-methylphenyl)-3-hydroxybutanenitrile is described in Example 17. The recovered ester product was a colorless oil (85% yield).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:18][C:19]#[N:20]>CN(C=O)C>[O:6]=[C:2]1[NH:3][CH2:4][CH2:5][N:1]1[CH2:18][C:19]#[N:20]
Reactant: N#CCBr
Reactant: O=C1NCCN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#CCN1CCNC1=O
Temperature: 45 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
A solution of imidazolidin-2-one (0.75 g, 8.71 mmol) in DMF (17 mL) was treated drop-wise with LiHMDS (1M THF, 10.45 mL, 10.45 mmol), stirred for 2 h, treated with bromoacetonitrile (0.607 mL, 8.71 mmol) and heated at 45° C. overnight. The mixture was cooled to RT, treated with satd. NH4Cl, extracted with EtOAc (4×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 2-(2-oxoimidazolidin-1-yl)acetonitrile (65 mg, 6%). 1H NMR (400 MHz, DMSO-d6): δ 6.38 (s, 1 H), 4.66 (s, 2 H), 3.98-3.93 (m, 2H), 3.91-3.86 (m, 2H); MS (ESI) m/z: 126.1 (M+H+).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])/[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:65][C@@H:66]1[C:84](=[O:85])[N:68]2[C:69]([C:81]([OH:83])=[O:82])=[C:70]([CH2:73][S:74][C:75]3[N:79]([NH2:80])[N:78]=[N:77][N:76]=3)[CH2:71][S:72][C@H:67]12.C(N(CC)CC)C.NC1C(CSC2N(NC(C)C)N=NN=2)=C(C(O)=O)N2C(=O)C[C@H]2S1>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])/[C:27]([NH:65][C@@H:66]2[C:84](=[O:85])[N:68]3[C:69]([C:81]([OH:83])=[O:82])=[C:70]([CH2:73][S:74][C:75]4[N:79]([NH2:80])[N:78]=[N:77][N:76]=4)[CH2:71][S:72][C@H:67]23)=[O:29])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1N
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.9 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(tert-butoxycarbonylmethoxyimino)acetic acid (3.80 g, 7 mmol), 1-hydroxybenzotriazole (1.09 g, 8.05 mmol) and N,N'-dicyclohexylcarbodiimide (1.59 g, 7.7 mmol) in dimethylacetamide (40 ml) was stirred at room temperature for 2 hours. To the solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.76 g, 8.4 mmol) and triethylamine (1.70 g, 16.8 mmol) in dimethylacetamide (20 ml) and water (2.8 ml) and the mixture was stirred at room temperature for 17 hours. Then the mixture was treated in a manner similar to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-(tert-butoxycarbonylmethoxyimino)acetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (4.96 g, 83%).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([CH:34]=1)[C:31](Cl)=[O:32].O>C(Cl)Cl>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:31](=[O:32])[C:30]2[CH:34]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=2[O:35][CH3:36])[N:8]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CC(C)(C)c1cc(N)n(C[C@H]2CCCO2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)Nc1cc(C(C)(C)C)nn1C[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To the mixture of Example 45B (1.25 g, 5.6 mmol) in CH2Cl2 (50 mL) cooled with an ice-bath was added triethylamine (2.3 mL, 16.8 mmol), and 5-chloro-2-methoxybenzoyl chloride (the product from Step A of Example 11C) (1.15 g, 5.6 mmol) dropwise. The mixture was stirred at ambient temperature for 2 hours, then treated with water (50 mL) and CH2Cl2 (50 mL). The organic layer was washed with brine and concentrated. Purification by flash chromatography (silica gel, Et3N/MeOH/EtOAc, (1:10:90) in hexane in 10-40% gradient) afforded 1.75 g (80%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 (s, 9H), 1.46-1.59 (m, 1H), 1.61-1.82 (m, 2H), 1.84-1.97 (m, 1 H), 3.54-3.76 (m, 2H), 3.97 (s, 3H), 4.01-4.23 (m, 3H), 6.31 (s, 1H), 7.28 (d, J=8.72 Hz, 1H), 7.62 (dd, J=8.73, 2.78 Hz, 1H), 7.81 (d, J=2.78 Hz, 1H), 10.25 (s, 1H)); MS (ESI) m/z 392 [M+H]+, 390 [M−H].
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([OH:19])([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15].[CH3:20][C:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH2:22][CH:23]=O>CO.CC(O)=O.CCOC(C)=O>[C:29]([O:28][C:27](=[O:33])[NH:26][C:21]([CH3:25])([CH3:20])[CH2:22][CH2:23][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([OH:19])([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Reactant: CCCC(O)(CCC)c1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCC(O)(CCC)c1ccccc1NCCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.40 g (22.27 mmol) of sodium cyanoborohydride is added to a solution of 3.10 g (14.05 mmol) of 4-(2-aminophenyl)heptan-4-ol and 3.60 g (17.88 mmol) of tert-butyl (1,1-dimethyl-3-oxopropyl)carbamate in MeOH (40 mL) and AcOH (6 mL). The mixture is stirred for 16 hours at RT, diluted with EtOAc, and washed with 0.5 M aqueous KHSO4 and saturated aqueous NaCl, dried with sodium sulfate, and evaporated down in vacuo. The crude product is used in the next reaction step without any further purification. Yield: 6.00 g (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:12])([CH2:10][OH:11])[CH2:8][OH:9])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C1COCC1>[OH:9][CH2:8][C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1)([CH3:12])[CH2:10][OH:11]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(CO)(CO)c1cc(N)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(CO)(CO)c1cc(NC(=O)Oc2ccccc2)no1

Procedure:
To a stirred mixture of 2-(3-aminoisoxazol-5-yl)-2-methylpropane-1,3-diol (1 equivalent) and potassium carbonate (2-5 equivalents) in anhydrous THF at rt is added dropwise phenyl chloroformate (1-2 equivalents) and stirring is continued at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is concentrated under reduced pressure and the residue is partitioned between water and dichloromethane. The organic layer is separated and the aqueous layer is further extracted with dichloromethane. The combined organic extracts are washed with water or brine, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford phenyl 5-(1,3-dihydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([CH3:25])[CH2:13]1.C(N(CC)CC)C>CO.[Pt]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:14]([CH3:25])[CH2:13]2)=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2F)CCN1C(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H]1CN(Cc2ccc(N)cc2F)CCN1C(=O)OC(C)(C)C
Reaction time: 2.75 h

Procedure:
1,1-Dimethylethyl (2S)-4-[(2-fluoro-4-nitrophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D65) (2.05 g, 5.801 mmol) was taken up in methanol (50 mL) and wet (50% w/w water) 5% platinum on carbon (2 g) and triethylamine (8 mL, 58.01 mmol) were added. The mixture was hydrogenated at atmospheric pressure and room temperature for 2.5-3 h. The mixture was filtered and the filtrate concentrated to give the crude product which was purified by column chromatography. Elution with EtOAc/pentane yielded the title compound as an almost colourless gum (1.15 g). δH (CDCl3, 400 MHz) 7.11 (1H, t), 6.42 (1H, dd), 6.35 (1H, dd), 4.17 (1H, br.s), 3.79 (1H, d), 3.72 (2H, s), 3.43 (2H, m), 3.07 (1H, td), 2.74 (1H, m), 2.58 (1H, d), 2.14 (1H, dd), 1.99 (1H, m), 1.45 (9H, s), 1.20 (3H, d).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[N:4]=1.[NH:18]1[CH2:23][CH2:22]N[CH2:20][C@@H:19]1[CH2:24][CH2:25][OH:26].C(N(C(C)C)CC)(C)C.CS(C)=O>C1(C)C=CC=CC=1>[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([N:17]3[CH2:22][CH2:23][NH:18][C@@H:19]([CH2:24][CH2:25][OH:26])[CH2:20]3)[C:5]=2[N:4]=1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Reactant: OCC[C@H]1CNCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCO)C1
Yield: 13.9 %

Procedure:
Combine 2-methyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine hydrochloride (0.458 g, 1.72 mmol), (S)-2-piperazin-2-yl-ethanol (0.518, 3.98 mmol), diisopropylethylamine (0.346 mL, 1.99 mmol), dimethyl sulfoxide (1.5 mL) and toluene (4.5 mL) and heat to 110° C. for 48 hours. Evaporate the mixture and apply the material to 20 g of SCX, elute with methanol followed by 5% 2N ammonia-methanol in dichloromethane and finally 100% 2N ammonia-methanol. Purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 10% 2N ammonia-methanol in dichloromethane, to obtain (S)-2-[4-(2-methyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-yl)-piperazin-2-yl]-ethanol (0.082 g, 0.239 mmol, 14%): mass spectrum (APCI): m/z=344.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]([N:9]([CH3:27])[CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([N:20]([CH3:26])[CH2:21][CH2:22][C:23]([OH:25])=O)=[O:19])[CH2:14][CH2:13]2)=[O:8])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:36][NH2:37]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7](=[O:8])[N:9]([CH3:27])[CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18](=[O:19])[N:20]([CH3:26])[CH2:21][CH2:22][C:23](=[O:25])[NH:37][CH3:36])[CH2:14][CH2:13]2)=[CH:28][CH:29]=1
Reactant: CN(CC[C@H]1CC[C@H](C(=O)N(C)CCC(=O)O)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)CCN(C)C(=O)[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(Cl)cc2)CC1
Reaction time: 1.5 h

Procedure:
A solution of 0.088 g (0.20 mmol) of trans-3-[(4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexanecarbonyl)-methyl-amino]-propionic acid in 2 mL of CH2Cl2 was treated at RT with 1 drop of DMF, followed by 0.019 mL (0.22 mmol, 1.1 eq) of oxalyl chloride and stirring was continued for 90 min. The solvent was evaporated, the residue was redissolved in 2.5 mL of CH2Cl2 and added to a solution of 0.25 mL (2.00 mmol, 10 eq) of methylamine (33% solution in EtOH) in 2 mL of CH2Cl2 at 0° C. The reaction mixture was stirred at 0° C. for 3/4 h, then partitioned between Et2O (×3)/aqueous 10% KHSO4. The organic phases were washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 20 g silica gel (CH2Cl2:MeOH 98:2 to 95:5) gave 0.042 g (48%) of pure trans-methyl-(2-{4-[methyl-(2-methylcarbamoyl-ethyl)-carbamoyl]-cyclohexyl}-ethyl)-carbamic acid 4-chloro-phenyl ester, MS: 438 (MH+, 1Cl).