Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:8][C:9]=1[N:10]([C@@H:20]([CH3:24])[CH2:21][CH2:22][NH2:23])[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N+](C1C=CC([O:40][C:41](=O)[O:42][CH:43]2[CH:50]3[CH:46]([O:47][CH2:48][CH2:49]3)[O:45][CH2:44]2)=CC=1)([O-])=O.C(N(C(C)C)CC)(C)C>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:25]#[C:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]([C@@H:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:41]([O:42][CH:43]1[CH:50]2[CH:46]([O:47][CH2:48][CH2:49]2)[O:45][CH2:44]1)=[O:40])[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC2OCCC12
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@@H](C)CCN
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@@H](C)CCNC(=O)OC1COC2OCCC12
Reaction time: 1 h

Procedure:
A mixture of crude 3-[[3-Amino-1-(S)-methyl-propyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester in ACN (3.0 mL) was treated with carbonic acid hexahydro-furo[2,3-b]furan-3-yl ester 4-nitro-phenyl ester (0.11 g, 0.375 mmol) followed by diisopropylethyl amine (0.1 mL, 0.625 mmol) and DMAP (cat). The reaction was stirred for 1 h and quenched with CH3OH (1 mL). Solvent was removed under reduced pressure and the crude material was partitioned between EtOAc, and ½ sat NaHCO3(aq). The organics were dried over Na2SO4, solids filtered and solvent removed under reduced pressure. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[3-(hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-1-(S)-methyl-propyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was isolated by reverse phase HPLC and carried forward wet to the next reaction.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1C2C=CC=C(O[P+](N3CCCC3)(N3CCCC3)N3CCCC3)C=2N=N1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[CH2:93]([O:100][C:101]1[CH:102]=[C:103]([CH:106]=[CH:107][CH:108]=1)[CH2:104][NH2:105])[C:94]1[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1.Cl>CN(C)C=O.O>[CH2:93]([O:100][C:101]1[CH:102]=[C:103]([CH:106]=[CH:107][CH:108]=1)[CH2:104][NH:105][C:8](=[O:10])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)[C:94]1[CH:95]=[CH:96][CH:97]=[CH:98][CH:99]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: NCc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cc(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)c2nn[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(-c2ccccc2)cc1)NCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
To a solution of 4-biphenyl acetic acid (2.29 g, 10.45 mmol) in dimethylformamide, DMF, (30 ml) was added diisopropylethylamine, DIEA, (5.47 ml, 31.35 mmol) and stirred at room temperature for 15 min, then benzotriazolyloxy-tris[pyrrolidino]-phosphonium hexafluorophosphate, PyBOP™, (5.43 g, 10.45 mmol) was added and the stirring was continued for further 30 min, then 3-benzyloxybenzylaminehydrochloride (2.6 g, 10.45 mmol) was added and the stirring continued for 24 hrs. The reaction mixture was then poured on to ice cooled water acidified with (10 ml) 1 N HCl and extracted with ethyl acetate (100 ml) and the organic layer washed with saturated solution of NaHCO3, water and brine, dried over Na2SO4 and the solvent removed under vacuum to give a yellowish-white powder of the desired compound (2.65 g) 62% yield.
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:8][CH:7]([CH2:9][OH:10])[CH2:6][CH:5]1[C:11]([OH:13])=[O:12])[CH3:3].[CH3:14][CH2:15]O>>[CH2:2]([CH:4]1[CH2:8][CH:7]([CH2:9][OH:10])[CH2:6][CH:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:3]
Reactant: CCO
Reactant: CCC1CC(CO)CC1C(=O)O
Agent: Cl
Product: CCOC(=O)C1CC(CO)CC1CC
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
HCl gas was bubbled through a solution of 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylic acid (7.29 g, 42.3 mmol) in EtOH (60 mL) at about 25° C. for about 10 min. The reaction mixture was stirred at about 25° C. for about 72 h. The solvent was removed under reduced pressure. The crude residue was partitioned between water (30 mL) and DCM (3×30 mL). The combined organic extracts were concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc/heptane to give ethyl 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (4.89 g, 58%) as a yellow oil: 1H NMR (CDCl3) δ 4.23-4.02 (m, 2H), 3.74-3.47 (m, 2H), 2.96-2.83 (m, 1H), 2.31-2.17 (m, 1H), 2.15-1.98 (m, 2H), 1.97-1.84 (m, 1H), 1.79-1.66 (m, 1H), 1.65-1.50 (m, 1H), 1.49-1.37 (m, 1H), 1.30-1.21 (m, 5H), 1.04-0.82 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:9])[CH3:8].[CH3:10][C:11]1[C:12]([CH:17]=O)=[N:13][CH:14]=[CH:15][CH:16]=1.[BH4-].[Na+]>CO>[CH3:10][C:11]1[C:12]([CH2:17][NH:9][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:8])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(N)c1ccccn1
Reactant: Cc1cccnc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccnc1CNC(C)c1ccccn1
Yield: 60 %

Procedure:
Using General Procedure B, reaction of 1-Pyridin-2-yl-ethylamine and 3-methylpyridine-2-carbaldehyde in MeOH with NaBH4 gave (3-Methyl-pyridin-2-ylmethyl)-(1-pyridin-2-ylethyl)-amine as a pale yellow oil (0.21 g, 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20][N:21](C(OC(C)(C)C)=O)[CH3:22])[O:17][N:16]=4)=[C:10]3[C@@H:9]3[CH2:30][CH2:31][N:8]3[C:7](=[O:32])[C:6]=2[CH:33]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20][NH:21][CH3:22])[O:17][N:16]=4)=[C:10]3[C@@H:9]3[CH2:30][CH2:31][N:8]3[C:7](=[O:32])[C:6]=2[CH:33]=1
Reactant: CN(Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Yield: 85 %

Procedure:
7.74 g (17 mmol) of crude (S)-7-fluoro-12,12a-dihydro-1-[5-(N-BOC-N-methylaminomethyl)-1,2,4-oxadiazol-3-yl]-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred for 2 hours in 25 ml of trifluoroacetic acid. The solution was concentrated, the residue was taken up in water and the solution was washed twice with methylene chloride. The aqueous phase was made alkaline with 25% ammonia and extracted seven times with methylene chloride. There were obtained 5.12 g (85%) of (S)-7-fluoro-12,12a-dihydro-1-(5-methylaminomethyl-1,2,4-oxadiazol-3-yl)-9H,11H-azeto[2,1-c]imidazo-[1,5-a][1,4]benzodiazepin-9-one of m.p. 187°-190°, which was converted into the hydrochloride of m.p. 155°-160°.
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1[C:17]([O:18]CC2C=CC=CC=2)=[C:16]([CH2:26][OH:27])[C:15]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[O:29])=[CH:14][N:13]=1)=[O:11])C1C=CC=CC=1>[Pd].CO>[F:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][NH:30][C:28]([C:15]2[C:16]([CH2:26][OH:27])=[C:17]([OH:18])[C:12]([C:10]([NH:9][OH:8])=[O:11])=[N:13][CH:14]=2)=[O:29])=[CH:37][CH:36]=1
Reactant: O=C(NCc1ccc(F)cc1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Agent: [Pd]
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1cnc(C(=O)NO)c(O)c1CO
Yield: 90 %

Procedure:
The product of example 1, N2,3-bis(benzyloxy)-N5-(4-fluorobenzyl)-4-(hydroxymethyl)pyridine-2,5-dicarboxamide, (0.170 g, 0.330 mmol, 1 eq) and 10% Pd/C catalyst (5 mg) were stirred in 4.0 mL of methanol under an atmosphere of hydrogen for 1 hour. The catalyst was filtered and the reaction mixture was concentrated under vacuum yielding 0.100 g of N5-(4-fluorobenzyl)-N2,3-dihydroxy-4-(hydroxymethyl)pyridine-2,5-dicarboxamide (90% yield) as a white solid; 1H-NMR (400 MHz, MeOD): δ=8.17 (s, 1H), 7.44 (m, 2H), 7.09 (t, 2H), 4.78 (s, 2H), 4.58 (s, 2H); MS-ESI m/z 336 [MH]+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f28) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([CH:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]3[CH:20]=[C:21]([O:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[CH:23][C:10]=3[NH:9][C:8]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[CH2:32](I)[CH3:33]>>[C:1]1([CH:7]2[N:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11]3[CH:20]=[C:21]([O:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[CH:23][C:10]=3[N:9]([CH2:32][CH3:33])[C:8]2=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCI
Reactant: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(c1ccccc1)C(=O)N2
Solvent: CI
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(c1ccccc1)C(=O)N2CC
Yield: 65 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 3,5-diphenyl-8-ethoxy-7-methoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIba), and methyl iodide by ethyl iodide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 65%. M: 178–180° C. 1H-NMR (CDCl3, 300 MHz): d 1.06–1.11 (m, 3H, NCH2CH3), 1.55–1.59 (m, 3H, OCH2CH3), 3.77 (s, 3H, OCH3), 4.19–4.26 (m, 2H, OCH2), 4.01 (AB system, ? d=0.70, JAB=13.7, 2H, NCH2), 6.77 (s, 1H Ar), 6.92 (s, 1H Ar), 7.35–7.74 (m, 10H Ar).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[CH3:19][C:20]1[C:21]([CH2:26][OH:27])=[N:22][CH:23]=[CH:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([O:27][CH2:26][C:21]2[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:7]=1
Reactant: Cc1cccnc1CO
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(-c2nc(N)nc(OCc3ncccc3C)c2C#N)o1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 3-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccsc1
Yield: 91.7 %

Procedure:
3-Thiophene carboxylic acid (10.04 g, 78.3 mmol) was dissolved in dichloromethane (250 ml) and 4-dimethylaminopyridine (9.57 g, 78.3 mmol), N,O-dimethylhydroxylamine hydrochloride (7.64 g, 78.3 mmol), N-methylmorpholine (8.6 ml, 78.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15.01 g, 78.3 mmol) added and the resultant solution stirred for 24 h at room temperature. The reaction was diluted with dichloromethane (100 ml) and washed with aqueous 2M hydrochloric acid (3×30 ml), aqueous saturated sodium bicarbonate solution (2×30 ml) and water (3×30 ml). The organic phase was dried (magnesium sulphate), filtered and evaporated to give the title compound as a colourless oil (12.3 g, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]1[CH:9]=[C:8]3[C:21]([CH3:29])([CH3:28])[C:22]4[C:27]([C:7]3=[CH:6][C:5]2=1)=[CH:26][CH:25]=[CH:24][CH:23]=4.[Li]CCCC.[B:35](OC)([O:38]C)[O:36]C>C1COCC1>[B:35]([C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]1[CH:9]=[C:8]3[C:21]([CH3:29])([CH3:28])[C:22]4[C:27]([C:7]3=[CH:6][C:5]2=1)=[CH:26][CH:25]=[CH:24][CH:23]=4)([OH:38])[OH:36]
Reactant: COB(OC)OC
Reactant: CC1(C)c2ccccc2-c2cc3c4cc(Br)ccc4n(-c4ccccc4)c3cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-c2cc3c4cc(B(O)O)ccc4n(-c4ccccc4)c3cc21
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
22.3 g (51 mmol) of 7-bromo-12,12-dimethyl-10-phenyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene 12 are dissolved in 600 ml of dry THF and cooled to −78° C. At this temperature, 26.2 ml (65.7 mmol/2.5 M in hexane) of n-BuLi are added over the course of about 5 min., and the mixture is subsequently stirred at −78° C. for a further 2.5 h. At this temperature, 7.3 ml (65.7 mmol) of trimethyl borate are added as rapidly as possible, and the reaction is allowed to come slowly to RT (about 18 h). The reaction solution is washed with water, and the precipitated solid and the organic phase are dried azeotropically with toluene. The crude product is washed by stir-ring with toluene/methylene chloride at about 40° C. and filtered off with suction, giving 16 g (82%) of the product as white solid.
Reaction SMILES: N(C(OC(C)(C)C)=O)CC(NCC(NCC(O)=O)=O)=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:54]([O:73][CH2:74][C@H:75]([CH2:96]OP(OCCN)(O)=O)[O:76][C:77](=[O:95])[CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84]/[CH:85]=[CH:86]\[CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH3:94])(=[O:72])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]/[CH:62]=[CH:63]\[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71].Cl.C(OCC)C>CN(C=O)C.C(Cl)(Cl)Cl>[C:54]([O:73][CH2:74][CH:75]([O:76][C:77](=[O:95])[CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84]/[CH:85]=[CH:86]\[CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH3:94])[CH3:96])(=[O:72])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]/[CH:62]=[CH:63]\[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCN)OC(=O)CCCCCCC/C=C\CCCCCCCC
Agent: CC(C)(C)OC(=O)NCC(=O)NCC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(C)OC(=O)CCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 0.21 h
Yield: 112.9 %

Procedure:
Boc-Gly-Gly-Gly-OH (382 mg, 1.34 mmol) and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (532 mg, 1.4 mmol) were dissolved in DMF (5 mL). N,N-Diisopropylethylamine (488 uL, 2.8 mmol) was added and the mixture was allowed to stir at room temperature for 10-15 minutes. Afterwards, a solution of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (833 mg, 1.12 mmol) in chloroform (5 mL) was added and the reaction vessel was flushed with argon. After 16 hours at room temperature, the reaction mixture was concentrated and partitioned between dichloromethane (50 mL) and H2O (50 mL), extracted with dichloromethane (3×50 mL), dried with sodium sulfate, filtered and concentrated. Material was purified via silica gel chromatography using a dichloromethane/methanol gradient to yield colorless oil residue. To this, 2 M HCl/Diethyl Ether (5 mL) was added and the reaction mixture was allowed to stir in a H2O bath for approximately 2 hours. The reaction mixture was concentrated and the residue was taken up in dichloromethane (75 mL), washed with saturated sodium bicarbonate solution (75 mL), extracted product with dichloromethane (3×75 mL), dried with sodium sulfate, filtered and concentrated to yield (Z)-(2R)-3-(2-(2-(2-(2-aminoacetamido)acetamido)acetamido)ethoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl dioleate as a semi-solid (765 mg, 90%). Verified by NMR.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)[CH:8]=[CH:9][CH:10]=1)#[N:4].Cl[CH2:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]2[C:26]=1[CH2:27][CH2:28][CH3:29]>CN(C=O)C>[CH2:27]([C:26]1[N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]2=[N:19][C:18]=1[CH2:17][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]#[N:4])[CH2:28][CH3:29]
Reactant: CCCc1c(CCl)nc2ccccn12
Reactant: N#Cc1cccc(-c2ncc[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2cccc(C#N)c2)nc2ccccn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (13.5 mg of 60% wt., 0.34 mmol) is added to a solution of 3-cyano-(1H-imidazol-2-yl)benzene (57.2 mg, 0.34 mmol) in anhydrous DMF (3.5 mL). After 15 minutes, 2-chloromethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine (70.5 mg, 0.34 mmol) is added and the reaction mixture is stirred at ambient temperature for 18 hours. Concentration at reduced pressure followed by purification by chromatography on silica gel (5% MeOH/CHCl3) provides 3-{1-[(3-propylimidazo[1,2-a]pyridin-2-yl)methyl]-1H-imidazol-2-yl}benzonitrile as a light yellow solid. TLC (5% MeOH/CHCl3) Rf=0.50. 1H NMR (CDCl3): 8.13, s (1H); 8.07, d (1H); 7.90, d (1H); 7.71, d (1H); 7.60, d (1H); 7.58, d (1H); 7.20, dd (1H); 7.14, bs (2H); 6.85, t (1H); 5.32, s (2H); 2.70, t (2H); 1.50, p (2H), 0.90, t (3H). LRMS m/z (M+1) 342.30.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:20][C:21]([N:23]2[CH:27]=[CH:26]N=C2)=[O:22])[S:5][C:6]=1[C:7]1[N:8]=[C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[S:10][CH:11]=1.[CH3:28][O:29]CCN>CN(C=O)C>[CH3:28][O:29][CH2:26][CH2:27][NH:23][C:21]([NH:20][C:4]1[S:5][C:6]([C:7]2[N:8]=[C:9]([C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])[S:10][CH:11]=2)=[C:2]([CH3:1])[N:3]=1)=[O:22]
Reactant: COCCN
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1csc(C(=O)N2CCOCC2)n1
Solvent: CN(C)C=O
Product: COCCNC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCOCC3)n2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To N-[4′-methyl-2-(morpholin-4-ylcarbonyl)-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide, prepared in Step III, described above (50 mg; 0.17 mmol; 1 eq.), is added DMF (2 ml) and 2-methoxyethylamine (Fluka)(16 μl; 0.19 mmol; 1.10 eq.). The mixture is stirred 10 min at rt. Solvents are evaporated and the crude product is crystallized in MeOH, affording Compound (36) as a white-off solid (42.1 mg; 60%). 1H NMR (DMSO-d6, 300 MHz) δ 2.41 (s, 3H), 3.30 (m, 5H), 3.39 (m, 2H), 3.68 (m, 6H), 4.33 (m, 2H), 6.67 (m, 1H), 7.91 (s, 1H), 10.41 (br s, 1H). M− (ESI): 410.09; M+ (ESI): 412.12. HPLC (method A), Rt: 2.41 min (purity: 99.7%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.[BH4-].[Na+].Cl>O1CCCC1>[CH3:14][O:13][C:6]1[C:7]([CH2:9][C:10]([OH:12])=[O:11])=[CH:8][C:3]([CH3:1])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1
Reactant: COc1cc(-c2ccccc2)c(C=O)cc1CC(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2ccccc2)c(C)cc1CC(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4 g of 2-Formyl-5-methoxy-4-biphenylacetic acid are dissolved in 300 ml of dry tetrahydrofuran and 2.5 g of sodium borohydride added. The reaction mixture is warmed to 80° for 40 minutes and, after cooling, dropped onto 150 g of ice, acidified with 2 N hydrochloric acid and extracted three times with ethyl acetate. The organic phases are washed with saturated brine, dried over Na2SO4 and concentrated. The residue is hydrogenated in 200 ml of ethyl acetate in the presence of 250 mg of Pd (10% on active charcoal) at a hydrogen pressure of 2 atmospheres. After three hours, the reaction mixture is filtered through talc and the filtrate evaporated. The product is recrystallized from ethyl acetate. M. pt. 127°-128°.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:20][C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:24])=O>CN(C=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:20]=[C:19]([Cl:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(-c2nc(Cl)c3ccccc3n2)c1
Temperature: 25 °C

Procedure:
To 3-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl acetate was added thionyl chloride (100 mL) and DMF (2 mL) and the reaction was heated to reflux for 4 h. The flask was allowed to cool to RT and then concentrated in vacuo. The crude product was azeotroped with toluene (2×50 mL), taken up in CH2Cl2 (300 mL) and washed with saturated NaHCO3 (3×50 mL), water (1×50 mL) and brine (1×50 mL), dried with MgSO4 and concentrated in vacuo to give 3-(4-chloroquinazolin-2-yl)phenyl acetate. (9.77 g, mmol, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[N:35]=[C:36]([C@@H:39]5[CH2:43][C:42]6([O:48][CH2:47][CH2:46][CH2:45][O:44]6)[CH2:41][N:40]5C(OCC5C=CC=CC=5)=O)[NH:37][CH:38]=4)=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[N:21]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]>C(O)C.[Pd]>[CH2:41]1[C:42]2([O:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:43][C@@H:39]([C:36]2[NH:37][CH:38]=[C:34]([C:31]3[CH:30]=[CH:29][C:28]([C:25]4[CH:26]=[CH:27][C:22]([C:20]5[N:21]=[C:17]([C@@H:13]6[CH2:14][CH2:15][CH2:16][N:12]6[C:10]([C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])=[O:11])[NH:18][CH:19]=5)=[CH:23][CH:24]=4)=[CH:33][CH:32]=3)[N:35]=2)[NH:40]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5C(=O)OCc5ccccc5)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C

Procedure:
Phenylmethyl (3S)-3-(4-{4′-[2-((2S)-1-{N-[(methyloxy)carbonyl]-L-valyl}-2-pyrrolidinyl)-1H-imidazol-4-yl]-4-biphenylyl}-1H-imidazol-2-yl)-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate (Intermediate 22) (1.44 g, 1.83 mmol) was hydrogenated in ethanol (100 mL) with balloon under the catalysis of Pd/C for 20 hrs to give methyl [(1S)-1-({(2S)-2-[4-(4′-{2-[(3S)-6,10-dioxa-2-azaspiro[4.5]dec-3-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate (Intermediate 19). ES LC-MS m/z=654.4 (M+H)+.