Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.CN(C)C=O.[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21](Cl)=[O:22]>C(N(CC)CC)C>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:21]([O:20][CH2:19][CH2:18][O:17][CH3:16])=[O:22])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: COCCOC(=O)Cl
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOC(=O)Nc1cc(Cl)nc(N)[n+]1[O-]

Procedure:
5 G. of 2,4-diamino-6-chloropyrimidine-3-oxide are suspended in 50 ml. of dimethylformamide and 5 ml. of triethylamine and cooled to 0° C. while stirring. 4.3 G. of chloroformic acid 2-methoxyethyl ester are added dropwise to the cold suspension in the course of 15 minutes. The mixture is cooled for 2 hours and then stirred at room temperature for 16 hours. The solvent is distilled off at 25° C. in a high vacuum and the residue is digested with methylene chloride. The precipitate obtained is filtered off and washed with methylene chloride, methanol and water. The filtrate is washed with water and dried over sodium sulfate. By concentrating the solvent, there is obtained pure 2-methoxyethyl 2-amino-6-chloro-4-pyrimidinecarbamate-3-oxide having a melting point of 176°-178° C. Additional material is obtained by subjecting the mother liquor to chromatographical separation on silica gel.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][CH2:34][CH2:35][OH:36].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:36][CH2:35][CH2:34][CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCCO)[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (250 mg, 0.561 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and 3-amino-1-propanol (90.04, 1.18 mmol), WSCI•HCl (165 mg, 0.861 mmol) and 4-dimethylaminopyridine (140 mg, 1.15 mmol) were added, followed by stirring at room temperature for 16 hours under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired product (216 mg, yield 77%) as a white solid.
Reaction SMILES: BrC1C=CC2C3N=C(N4C(C)=NN(C)C4=O)SC=3CCOC=2C=1.[I:24][C:25]1[CH:46]=[CH:45][C:28]2[C:29]3[N:30]=[C:31](N4C(C)=NN(C)C4=O)[S:32][C:33]=3[CH2:34][CH2:35][O:36][C:27]=2[CH:26]=1.[CH:47]([N:50]1[C:54](=[O:55])[NH:53][C:52]([CH3:56])=[N:51]1)([CH3:49])[CH3:48].BrC1C=CC2C3N=C(N4C(C)=NN(C(C)C)C4=O)SC=3CCOC=2C=1>>[I:24][C:25]1[CH:46]=[CH:45][C:28]2[C:29]3[N:30]=[C:31]([N:53]4[C:52]([CH3:56])=[N:51][N:50]([CH:47]([CH3:49])[CH3:48])[C:54]4=[O:55])[S:32][C:33]=3[CH2:34][CH2:35][O:36][C:27]=2[CH:26]=1
Reactant: Cc1nn(C(C)C)c(=O)[nH]1
Reactant: Cc1nn(C)c(=O)n1-c1nc2c(s1)CCOc1cc(I)ccc1-2
Agent: Cc1nn(C(C)C)c(=O)n1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Cc1nn(C)c(=O)n1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: Cc1nn(C(C)C)c(=O)n1-c1nc2c(s1)CCOc1cc(I)ccc1-2

Procedure:
Following a similar procedure for the mixture of 4-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one and 4-(8-iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one using 2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one, the mixture of 4-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one and 4-(8-Iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one (˜1:1) was isolated as an off-white solid (49 mg). LCMS: RT=5.17 min, [M+H]+=421/423 and 469
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10]2[C:4]([C:5]3[S:23][CH:22]=[CH:21][C:6]=3[N:7]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH2:8][CH2:9]2)=[N:3]1.[CH3:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>>[CH3:1][N:2]1[CH:11]=[C:10]2[C:4]([C:5]3[S:23][CH:22]=[CH:21][C:6]=3[N:7]([C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[CH3:24])=[CH:17][CH:18]=3)=[O:20])[CH2:8][CH2:9]2)=[N:3]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cn1cc2c(n1)-c1sccc1N(C(=O)c1ccc(N)cc1)CC2
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3cn(C)nc3-c3sccc32)cc1

Procedure:
As described for Example 5, 2,4,5,6-tetrahydro-2-methyl -6-(4-aminobenzoyl)pyrazolo[3,4-d]thieno[3,2-b]azepine is reacted with 2-methylbenzoyl chloride to give the product as crystals (from ethyl acetate), m.p. 257°-260° C.
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:27]([CH2:28][CH2:29][C@:7]12[CH3:8])[C@:20]1([CH2:21][O:22]C(=O)CC)[C:15](=[C:16]([CH3:30])[CH2:17][CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:4])[CH2:2][CH3:3].C(O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(COC(=O)CC)C(=CCC[C@@H]1C)CC3)(=O)CC>>[C:1]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:27]([CH2:28][CH2:29][C@:7]12[CH3:8])[C@:20]1([CH2:21][OH:22])[C:15](=[C:16]([CH3:30])[CH2:17][CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OC[C@]12CCCC(C)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)CC)CC[C@@H]12
Agent: CCC(=O)OC[C@@]12C(=CCC[C@@H]1C)CC[C@H]1[C@@H]3CC[C@H](OC(=O)CC)[C@@]3(C)CC[C@@H]12
Product: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=C(C)CCC[C@]4(CO)[C@H]3CC[C@]12C

Procedure:
Substituting 1α,17α-dimethyl-4-androsten-17β,19-diol dipropionate and 4-methyl-4-androstene-17β,19-diol dipropionate in the above procedure for the 1α-methyl-4-androstene-17β,19-diol dipropionate results in the formation of 1α,17α-dimethyl-4-androsten-17β,19-diol 17-propionate and 4-methyl-4-androstene-17β,19-diol 17-propionate, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:25](C)=[CH:24][C:4]=1[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6].Cl.FC(F)(F)C1N=CC(N[C@H]2CCC[C@@H]2N)=NC=1.[Br:47]C1C=CC=C(OC)C=1C(O)=O>>[Br:47][C:24]1[CH:25]=[CH:26][CH:27]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6]
Reactant: COc1cccc(Br)c1C(=O)O
Reactant: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Product: COc1cccc(Br)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 250 mg, 0.88 mmol) and 2-bromo-6-methoxybenzoic acid (CAS number 31786-45-5; 245 mg, 1.06 mmol) except this was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.[C:8]([C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=1)#[CH:9]>C1(C)C=CC=CC=1.O>[CH3:17][O:16][C:14]1[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=[C:10]([C:8]2[CH:9]=[N:7][NH:6][N:5]=2)[N:15]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc([N+](=O)[O-])c(OC)n1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1nc(-c2cn[nH]n2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 48 h
Yield: 231 %

Procedure:
Trimethylsilylazide (1.2 mL, 9.21 mmol) was added to a solution of 6-ethynyl-2-methoxy-3-nitropyridine (Preparation 200, 0.082 g, 0.460 mmol) in toluene (10.2 mL). The reaction mixture was stirred at 130° C. for 48 hours. The reaction was diluted with water and concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with cyclohexane/EtOAc 70/30 to 50/50 to afford the title compound as a beige solid (235 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH:56]1[CH2:61][CH2:60][CH:59]([C:62]2[C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=3[O:64][N:63]=2)[CH2:58][CH2:57]1>CN(C=O)C>[O:64]1[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=2[C:62]([CH:59]2[CH2:60][CH2:61][N:56]([C:21](=[O:22])[CH2:20][N:10]3[C:11]([C:13]4[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=4)=[N:12][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9]3)[CH2:57][CH2:58]2)=[N:63]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCC(c2noc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.4 %

Procedure:
32 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid was dissolved in 2 mL DMF. 32 mg TBTU and 26 μL DIPEA were added to this solution and the mixture was stirred for 5 minutes at RT. Then, 24 mg 3-piperidin-4-yl-benzo[d]isoxazolehydrochloride was added. The mixture was stirred for 2 h at RT. The reaction solution was purified by HPLC to yield 19.8 mg of the desired compound. Rt: 2.24 (method D), (M+H)+: 500
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28](O)=[O:29]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:28]([C:27]4[CH:31]=[CH:32][N:33]=[C:25]([N:24]([CH3:34])[CH3:23])[CH:26]=4)=[O:29])[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: CN(C)c1cc(C(=O)O)ccn1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Agent: Cl
Product: CN(C)c1cc(C(=O)N2CCC[C@H](COc3cccc4c3C(N)=NS(=O)(=O)N4)C2)ccn1

Procedure:
Prepared as in Example 2 from (S)-4-amino-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 2a) and 2-(dimethylamino)isonicotinic acid (8%). 1H NMR (400 MHz, DMSO-d6, 60° C.) δ1.45 (br m, 2H), 1.68 (br m, 1H), 1.90 (br m, 1H), 2.16 (br m, 2H), 3.00 (s, 6H), 3.30-4.09 (br m, 4H), 6.44 (d, J=5.6 Hz, 1H), 6.47 (s, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.69 (d, J=6.8 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.67 (br s, 2H), 10.67 (br s, 1H). MS 459 (MH+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH2:9][CH2:10][NH:11]C(=O)C(F)(F)F)[CH:5]=[CH:6][CH:7]=1.[C:19]([C:21]([OH:28])([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])#[CH:20]>>[NH2:11][CH2:10][CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:20]#[C:19][C:21]([OH:28])([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:3]=1)=[O:18]
Reactant: O=C(CCNC(=O)C(F)(F)F)c1cccc(Br)c1
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cccc(C(=O)CCN)c1)CCC
Reaction time: 3 h

Procedure:
N-(3-(3-Bromophenyl)-3-oxopropyl)-2,2,2-trifluoroacetamide (63) was coupled with alkynol 20 following the procedure described in Example 18 except that the reaction was run at 80° C. for 3 h to give 3-amino-1-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propan-1-one as a dark amber oil after purification by flash chromatography (20% EtOAc in hexanes). Yield (28.1 g, 99.6%). 1H NMR (400 MHz, DMSO-d6) δ 9.40 (br. t, 1H), 7.84-7.92 (m, 2H), 7.58-7.63 (m, 1H), 7.50 (t, J=7.6 Hz, 1H), 5.19 (s, 1H), 3.51 (q, J=5.7 Hz, 2H), 3.30 (t, J=6.7 Hz, 2H), 1.40-1.63 (m, 8H), 0.90 (t, J=7.2 Hz, 6H).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]([C:18]#[N:19])[CH:5]=1>ClCCl.C(O)(=O)C>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[C:6]([C:18]#[N:19])[C:5]=1[Br:1]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(N)c(Br)c1C#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 128.9 %

Procedure:
A solution of bromine (25.1 mmol) in dichloromethane (1.3 mL) was added dropwise, under an argon atmosphere, to a solution of amine II (27.9 mmol) in acetic acid (325 mL). After 2.5 h of stirring at room temperature, the solvent was removed in vacuo. The excess of acetic acid was co-evaporated with heptane to afford the expected compound III (10.1 g, quantitative yield) as a beige solid; mp 163° C.; IR (KBr) νmax/cm−1 3327, 2826, 2605, 2566, 2236, 1955, 1716, 1610, 1561, 1496, 1481, 1398, 1369, 1280, 1238, 1193, 1153, 1059, 963, 906, 838; 1H NMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H, NH), 7.11 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=8.7 Hz), 6.01 (s, 2H, NH2), 1.43 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 153.6, 144.1, 131.6, 126.9, 119.6, 116.1, 112.8, 107.8, 79.5, 28.1; HRMS calcd for C12H15N3O2Br (M+H+): 312.0348, found 312.0354.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([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.[NH2:39][C@@H:40]1[C:43](=[O:44])[NH:42][C@@H:41]1[CH2:45][N:46]1[N:50]=[C:49]([CH2:51][NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:48]([CH3:60])=[N:47]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:55]([O:54][C:53]([NH:52][CH2:51][C:49]1[C:48]([CH3:60])=[N:47][N:46]([CH2:45][C@@H:41]2[C@H:40]([NH:39][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([O:14][CH:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:16])[CH2:18][CH2:19]3)/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=3)[C:43](=[O:44])[NH:42]2)[N:50]=1)=[O:59])([CH3:58])([CH3:56])[CH3:57]
Reactant: Cc1nn(C[C@H]2NC(=O)[C@H]2N)nc1CNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)nc1CNC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (120 mg, 0.213 mmol), tert-butyl ((2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-5-methyl-2H-1,2,3-triazol-4-yl)methyl)carbamate (65.2 mg, 0.210 mmol) and HATU (86 mg, 0.22 mmol) in DMF (2.1 mL) at 0° C., was added DIPEA (0.073 mL, 0.420 mmol). After stirring for 16 h, the reaction mixture was diluted with EtOAc and washed with LiCl solution (5% aq). The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with LiCl solution (5% aq), saturated NaHCO3 (aq), brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude residue via silica gel chromatography (EtOAc-Heptane, 0-90%) afforded the title compound (144 mg, 82%). LCMS: Rt=1.12 min, m/z=830.5 (M+1) Method 2m_acidic.
Reaction SMILES: [BH4-].[Na+].[Te].C(O)(=O)C.C(N(CC1C=CC=CC=1)C(=O)C=[C:15]1[S:27][C:18]2=[N:19][C:20]3[C:25]([CH2:26][N:17]2[C:16]1=[O:28])=[CH:24][CH:23]=[CH:22][CH:21]=3)(C)(C)C>C(O)C>[O:28]=[C:16]1[N:17]2[C:18](=[N:19][C:20]3[C:25]([CH2:26]2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:27][CH2:15]1
Reactant: CC(C)(C)N(Cc1ccccc1)C(=O)C=c1sc2n(c1=O)Cc1ccccc1N=2
Agent: [BH4-]
Agent: [Na+]
Agent: [Te]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1CSC2=Nc3ccccc3CN12
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
A suspension of sodium borohydride (0.08 mol) and tellurium powder (0.034 mol) in 135 ml of anhydrous ethanol is heated under nitrogen atmosphere, preferably for about 15 min. After cooling to -20° C., 8.08 ml glacial acetic acid in 33.65 ml anhydrous ethanol solution (8.08:33.65 v/v) is added dropwise, and the mixture is stirred at -20° C. for 5 min. Stirring is followed by the addition of 0.013 mol of a substituted 2,3-dihydro-5H-thiazol[2,3-b]quinazoline derivative, synthesized by the procedures in the preceding sections (2) to (5), and dissolved in 13.5 ml anhydrous ethanol. The reaction mixture is allowed to warm up to ambient temperature and stirred for about 10 hours. The mixture is filtered through celite, and evaporated under reduced pressure. The residue is taken up in water and extracted with chloroform. The organic extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure, yielding the corresponding 2,3-dihydro-3-oxo-5H-thiazolo[2,3-b]quinazoline derivative with a saturated exocyclic bond at the 2 position of the 2,3-dihydro-5-thiazo[2,3-b]quinazoline moiety.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH:19]=1)=[O:17].O[Li].O>>[F:34][C:30]1[CH:29]=[C:28]([C:20]2[CH:19]=[C:18]([C:16]([NH:15][C:3]3[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:6]=[CH:7][C:2]=3[F:1])=[O:17])[C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3cccc(F)c3)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3cccc(F)c3)cc3ccccc23)c1

Procedure:
Compound 17b was synthesized from 16b (0.5 mmol) and LiOH.H2O (5 mmol) using the procedure according to the Method E described above.
Reaction SMILES: C[C@H]1P(C2C(P3[C@H](C)CC[C@H]3C)=CC=CC=2)[C@H](C)CC1.[O:21]=[C:22]1[CH2:26][CH2:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:23]1[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[H+].[B-](F)(F)(F)F>C(Cl)Cl>[CH3:36][CH2:35][CH2:34][CH2:33][CH2:32][CH:23]1[C:22](=[O:21])[CH2:26][CH2:25][CH:24]1[CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: CCCCCC1=C(CC(=O)OC)CCC1=O
Agent: C[C@@H]1CC[C@@H](C)P1c1ccccc1P1[C@H](C)CC[C@H]1C
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: CCCCCC1C(=O)CCC1CC(=O)OC
Reaction time: 1.5 h
Yield: 99 %

Procedure:
In a glovebox, into a 10 ml glass vial were placed 15.5 mg (0.0485 mmole) of [(COD)Ru(2-methylallyl)2], 14.9 mg (0.0485 mmole) of (R,R)-Me-DuPHOS and 250 μl of methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate (1.08 nmuole). To this suspension was added 0.630 ml of a 0.081 M solution of titrated HBF4.etherate (0.049 nunole) in CH2Cl2 with stirring. This concentrated solution was stirred for 1.5 hours, after which 21.5 g (95.9 mmole) of methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate and 11.5 ml of CH2Cl2 were added. The resulting yellow solution was placed in a 75 ml autoclave, purged with hydrogen and pressurized to 90 bar of hydrogen. After 8 hours, the solution was exposed to air and passed through a column of silica gel to separate the catalyst. This gave a 99% yield of the desired Hedione® product with the following ratios of isomers: cis/trans=98/2; (+)-cis/(−)-cis=82.4/17.6, 64.8% ee.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH:9]=O)[C:5]([CH2:11][OH:12])=[CH:4][N:3]=1.Cl.[NH2:14][C@@H:15]([C:20]([OH:22])=[O:21])[C:16]([SH:19])([CH3:18])[CH3:17].[OH-].[K+]>O>[CH3:17][C:16]1([CH3:18])[S:19][CH:9]([C:6]2[C:5]([CH2:11][OH:12])=[CH:4][N:3]=[C:2]([CH3:1])[C:7]=2[OH:8])[NH:14][C@H:15]1[C:20]([OH:22])=[O:21]
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ncc(CO)c(C2N[C@@H](C(=O)O)C(C)(C)S2)c1O
Reaction time: 16 h

Procedure:
2.03 g (10 mmoles) of pyridoxal hydrochloride are added to a solution containing 1.50 g (10 mmoles) of D-penicillamine and 0.56 g of potassium hydroxide in 10 ml of water. After stirring for 16 hours, the precipitate is filtered out to give the title acid in a yield of 2.26 g (75.7%) which can be purified by boiling with ethanol, m.p.: 201°-202° C., [α]D25 =+68.1°.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([NH:14][C:15](=[CH2:20])[C:16]([O:18][CH3:19])=[O:17])(=O)C>>[CH3:10][C:8]1[CH:9]=[C:2]2[C:3](=[CH:6][CH:7]=1)[CH:4]=[N:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20]2
Reactant: Cc1ccc(C=O)c(Br)c1
Reactant: C=C(NC(C)=O)C(=O)OC
Product: COC(=O)c1cc2cc(C)ccc2cn1
Yield: 50 %

Procedure:
methyl 6-methyl-isoquinoline-3-carboxylate was prepared using the procedure described in example 12A: 2-bromo-4-methylbenzaldehyde was reacted with methyl 2-acetamidoacrylate at 110° C. for 18 hours to yield methyl 6-methyl-isoquinoline-3-carboxylate (50%) as brown solid.
Reaction SMILES: [Cs].[ClH:2].[Cl:3][C:4]1[S:8][C:7]([C:9]([N:11]([CH2:22][C@@H:23]2[O:27][C:26](=[O:28])[N:25]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][C:36]4=[O:41])=[CH:31][CH:30]=3)[CH2:24]2)[CH:12]([C:19]([OH:21])=[O:20])[NH:13][CH2:14][CH2:15][CH2:16]C=O)=[O:10])=[CH:6][CH:5]=1>CN(C=O)C>[ClH:3].[Cl:2][C:4]1[S:8][C:7]([C:9]([N:11]([CH2:22][C@@H:23]2[O:27][C:26](=[O:28])[N:25]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][C:36]4=[O:41])=[CH:31][CH:30]=3)[CH2:24]2)[C@@:12]([C:19]([OH:21])=[O:20])([CH:5]([CH3:6])[CH3:4])[NH:13][CH2:14][CH2:15][CH2:16][CH2:7][CH:9]=[O:10])=[O:10])=[CH:6][CH:5]=1
Reactant: O=CCCCNC(C(=O)O)N(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [Cs]
Solvent: CN(C)C=O
Product: CC(C)[C@](NCCCCC=O)(C(=O)O)N(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 42 h

Procedure:
50 mg (90 μmol) of Example 2A are dissolved with 41 mg (117 μmol) of the caesium salt of Boc-valine (prepared from Boc-valine by General Procedure 1) in 10 ml of DMF. Stirring at 50° C. for 42 h is followed by concentrating and the residue is purified by preparative HPLC (method 1a). The appropriate fractions are concentrated and dried under high vacuum to obtain 26 mg (39% of theory) of the protected title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11].[BH4-].[Na+]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[OH:11]
Reactant: COc1ccc(C(=O)C=Cc2ccccc2O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(O)CCc2ccccc2O)cc1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
2-Hydroxy-4'-methoxychalcone (12.7 g) was stirred with ethanol (200 ml) and sodium borohydride (3.8 g) added in portions. The solution was stirred at room temperature, the solvent evaporated, and the residue washed with water and recrystallised from aqueous ethanol to give 3-(o-hydroxyphenyl)-1-(p-methoxyphenyl)propan-1-ol (8.60 g), m.p. 114°-116°. The total product was boiled under reflux with acetic acid (100 ml) for 2 hr., the solution evaporated, and the residue chromatographed on alumina, eluting with toluene, to yield 4'-methoxyflavan (8.0 g), m.p. 82°-83°.