Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[C:13]([S:16]([Cl:19])(=[O:18])=[O:17])[S:14][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:12]=[C:13]([S:16]([Cl:19])(=[O:18])=[O:17])[S:14][CH:15]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)c2csc(S(=O)(=O)Cl)c2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1cc(S(=O)(=O)c2ccc(CBr)cc2)cs1

Procedure:
A solution of 18.0 g (0.053M) of 4-(4-methylphenylsulfonyl)-thiophene-2-sulfonyl chloride, 46.0 g (0.258 m) N-bromosuccinimide and 100 mg benzoyl peroxide in 175 ml CHCl3 was heated at reflux and irradiated with a sun lamp for 45 minutes. The cooled mixture was then extracted with 3×100 ml portions of water, 5% sodium thiosulfate, brine and dried. The solvent was stripped to give the title compound as an oil.
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[C:6]([O:8]CC)=O)C.Cl.[C:22]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)(=[NH:24])[NH2:23]>[Na].CO>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:5]1[C:4]([OH:20])=[N:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:24][C:6]=1[OH:8]
Reactant: CCOC(=O)C(Oc1ccccc1OC)C(=O)OCC
Reactant: N=C(N)c1ccncc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COc1ccccc1Oc1c(O)nc(-c2ccncc2)nc1O

Procedure:
Diethyl-(2-methoxy-phenoxy)malonate is dissolved in a solution of sodium in methanol. Thereafter 4-amidino-pyridine hydrochloride is added to obtain 5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidin-4,6-diol (or a tautomeric derivative). This compound is heated with phosphorus oxychloride to yield 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine which is boiled with peracetic acid to obtain 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-1-oxide. By reaction of this compound with 5-isopropyl-pyridine-2-sulfonamide potassium there is obtained 5-isopropyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl amide which is added as a solution in dimethoxyethane to a solution of sodium in ethylene glycol. 5-Isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl amide is obtained which is heated with trimethylsilylcyanide and triethylamine in acetonitrile to obtain 5-isopropyl-pyridine-2-sulphonic acid 2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl-amide. This is then heated with ammonium chloride and sodium azide in dimethyl formamide to yield 5-isopropyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide (see WO 96/19459).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([S:18]([NH:21][C:22]3[C:27]([O:28][CH3:29])=[N:26][C:25]([CH3:30])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].O.Cl>C(O)C>[OH:5][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([S:18]([NH:21][C:22]3[C:27]([O:28][CH3:29])=[N:26][C:25]([CH3:30])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(C(C)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.8 %

Procedure:
Sodium tetrahydridoborate (0.051 g) was added portionwise over 5 minutes to a solution of 2-(4-acetylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.135 g) in ethanol (5 ml). The mixture was stirred for 45 minutes at ambient temperature and was then poured into water (20 ml) and acidified to pH 3 with 2M hydrochloric acid. The mixture was extracted with ethyl acetate (3×20 ml). The extracts were combined, washed with water and saturated sodium chloride solution and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 10-70% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 2-[4-(1-hydroxyethyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.096 g) as a foam; 1H NMR (CDCl3 +CD3COOD): 1.55 (d, 3 H), 2.3 (s, 3 H), 3.85 (s, 3 H), 4.95 (q, 1 H), 7.25 (s, 1 H), 7.3 (d, 2 H), 7.35 (d, 2 H), 7.55 (dd, 1 H), 8.7 (d, 1 H), 8.85 (d, 1 H); mass spectrum (+ve ESP): 401 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[CH:13]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:14]([C:17]([O:19][CH2:20][CH2:21]Br)=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].[I-].[Na+].CC(C)=O.S1C=CC=C1CC(NC1S[C@@H]2CC(=O)N2C(C([O-])=O)C=1C(OCC[I:67])=O)=O>C(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[CH:13]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:14]([C:17]([O:19][CH2:20][CH2:21][I:67])=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1=C(C(=O)OCCI)C(C(=O)[O-])N2C(=O)C[C@H]2S1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)OCCBr)=CS[C@H]12
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)OCCI)=CS[C@H]12
Reaction time: 16 h

Procedure:
Benzhydryl 7-(2-thienylacetamido)-3-(2-bromoethoxycarbonyl)-2-cephem-4-carboxylate (7.61 g., 12 mmol.) was combined with sodium iodide (6.75 g., 45 meq.) in 100 ml. acetone. The reaction mixture was degassed and then heated to 35° with stirring for 16 hours. The reaction mixture was filtered and evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water (3X) and brine and dried (Na2SO4). Evaporation in vacuo to dryness provided 7.78 g. (95.5%) of benzhydryl 7-(2-thienylacetamido-3-(2-iodoethoxycarbonyl)-2-cephem-4-carboxylate: ir (CHCl3) 1785 cm-1 (β-lactam C = O); nmr (CDCl2) δ 2.96 (t, 2, J = 7.0 Hz, --OCH2 --), 3.80 (s, 2, side chain CH2), 4.24 (t, 2, J = 7.0 Hz, --OCH2 --), 4.95 (d, 1, J = 4.0 Hz, C6 --H), 5.24 (q, 1, J = 4.0 Hz, C7 --H, rest of the signal covered by C4 --H), 5.50 (s, 1, C4 --H), and 7.80 (s, 1, C2 --H).
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]\[CH2:4][O:5][C:6]1[C:14]2[S:13][C:12]([CH3:15])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:16]1[C:26]2[CH2:25][CH2:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[CH:21]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl[CH2:38]/C=C\CCl>>[CH:27]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[CH:21]([N:31]3[CH2:32][CH2:33][N:34]([CH2:38]/[CH:2]=[CH:3]\[CH2:4][O:5][C:6]4[C:14]5[S:13][C:12]([CH3:15])=[N:11][C:10]=5[CH:9]=[CH:8][CH:7]=4)[CH2:35][CH2:36]3)[C:22]=2[CH:30]=[CH:29][CH:28]=1.[Cl:1]/[CH:2]=[CH:3]\[CH2:4][O:5][C:6]1[C:14]2[S:13][C:12]([CH3:15])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: ClC/C=C\CCl
Reactant: c1ccc2c(c1)CCc1ccccc1C2N1CCNCC1
Agent: Cc1nc2cccc(OC/C=C\Cl)c2s1
Product: Cc1nc2cccc(OC/C=C\CN3CCN(C4c5ccccc5CCc5ccccc54)CC3)c2s1

Procedure:
The title compound was prepared according to Method GA from cis-7-(3-chloroallyloxy)-2-methyl-benzothiazole and 1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazine. mp 114° C.; LSIMS m/z 496. The cis-7-(3-chloro-allyloxy)-2-methyl-benzothiazole was prepared by Method IV, with cis-1,4-dichloro-2-butene as the alkylating agent.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13].[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](Cl)=[O:36])=[CH:30][CH:29]=1)[CH3:26]>[Zn].CCOC(C)=O>[CH2:17]([N:14]([CH2:15][CH3:16])[C:12]([C:11]1[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:9]([NH:8][C:35](=[O:36])[CH2:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][CH2:25][CH3:26])=[CH:29][CH:30]=2)[CH:10]=1)=[O:13])[CH3:18]
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Reactant: CCN(CC)C(=O)c1ccc([N+](=O)[O-])c(N)c1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOc1ccc(CC(=O)Nc2cc(C(=O)N(CC)CC)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirring toluene solution (100 mL) of 3-amino-N,N-diethyl-4-nitro-benzamide (1.00 g, 4.21 mmol) were added 4-ethoxyphenylacetyl chloride (1.25 g, 1.5 eq) and zinc dust (415 mg, 1.5 eq). The solution was stirred at rt overnight. Another 0.5 eq of acid chloride and zinc dust were then added and the solution stirred at rt for another 24 h. The solution was then filtered through celite and rinsed with EtOAc. The organic phase was washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 1:1/hex:EtOAc on silica gel to furnish the desired product (1.52 g, 90% yield). 1H NMR (400 MHz, CDCl3) d 8.81 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 7.26 (m, 3H), 7.15 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 2H), 4.06 (q, J=7.2 Hz, 2H), 3.75 (s, 2H), 3.54 (q, J=6.8 Hz, 2H), 3.24 (q, J=6.8 Hz, 2H), 1.59 (br s, 1H), 1.42 (t, J=6.8 Hz, 3H), 1.25 (t, J=6.8 Hz, 3H), 1.16 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][S:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OCCc1ccsc1
Reactant: Oc1ccc(Cl)nc1I
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OCCc2ccsc2)c(I)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution 6-chloro-2-iodopyridin-3-ol (6.75 g, 26.4 mmol), 2-(3-thienyl) ethanol (3.79 mL, 34.4 mmol), and triphenylphosphine (9.01 g, 34.4 mmol) in tetrahydrofuran (140 mL) was added diisopropyl azodicarboxylate (6.76 mL, 34.4 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by column on silica gel (eluted at EtOAc/Hexanes=1:20) to give 5.5 g of 6-chloro-2-iodo-3-(2-(thiophen-3-yl)ethoxy)pyridine. Yield: 58%. 1H NMR (DMSO, 400 MHz): δ7.50-7.43 (m, 3H), 7.34 (d, J=1.6 Hz, 1H), 7.17 (d, J=4.8 Hz, 1H), 4.29 (t, J=6.4 Hz, 2H), 3.10 (t, J=6.4 Hz, 2H). LC-MS (ESI): m/z=366 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13]3[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][NH:4][CH2:3]1.[BH3-][C:20]#N.[Na+].C=O.Cl>CO.O>[CH3:20][N:4]1[CH2:3][C:2](=[O:1])[C:14]2[C:13]3[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5]1
Reactant: [BH3-]C#N
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(C)C3
Reaction time: 2 h

Procedure:
Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (0.04 g, 0.016 mmol) and NaCNBH3 (2.4 mg, 0.04 mmol) were added to a round bottomed flask, which were then dissolved in MeOH (2 mL), and treated with 0.5 mL of a 27% solution of formaldehyde in water. This mixture was stirred for 2 h, after which, 2N HCl (2 mL) was added, followed by stirring for 15 min. The mixture was taken to pH=11 by addition of concentrated, aqueous NaOH and extracted with methylene chloride (3×10 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21](I)[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2].O1C=C[CH:26]=[C:25]1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)C=C)CCC>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([CH:25]=[CH2:26])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(I)c(N)nc1=O
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1cn([C@@H]2O[C@H](C)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)nc1N
Temperature: 40 °C
Reaction time: 19 h
Yield: 915.3 %

Procedure:
To a solution of 2',3'-di-O-acetyl-5'-deoxy-5-iodocytidine, (1.6 g, 3.66 mmol) in 10 ml DMF were added Pd2 (dba)3 (67 mg, 0.073 mmol) and tri-2-furylphosphine (85 mg, 0.366 mmol) and tri-n-butyl(vinyl)stannane (2.1 ml, 7.318 mmol) under Ar atmosphere at room temperature. After stirring for 19 h, tri-n-butyl(vinyl)stannane (2.1 ml, 7.318 mmol ) was added to the reaction mixture, which was then warmed up to 40° C. with stirring for 24 hours. The solvent was removed in vacuo, and the residue purified by silica gel column chromatography (eluent: ethyl acetate~CH2Cl2 : MeOH=95: 5) to give 2',3'-di-O-acetyl-5'-deoxy-5-vinylcytidine (1.13 g, 92%) as a colorless solid:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (2.10 g, 0.009 mol), 4-chlorophenyl isothiocyanate (1.81 g, 0.01 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.71 g (75%), m.p. 151°-154 ° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.OS(O)(=O)=O.[CH3:14]O>>[NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:14])=[O:7])[N:3]=[CH:2]1
Reactant: CO
Reactant: O=C(O)c1c[nH]cn1
Agent: O=S(=O)(O)O
Product: COC(=O)c1c[nH]cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1H-Imidazole-4-carboxylic acid (5 g, 44.6 mmol) was dissolved in MeOH (100 ml). Into the solution, H2SO4 (10 ml) was added at 0° C. The resulting mixture was stirred at 80° C. for overnight. The solvent was concentrated under reduced pressure. The pH was adjusted to 9 with aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was concentrated to give the product. Yield 5.2 g. 1H-NMR (400 MHz; DMSO-d6): δ 3.74 (s, 3H), 7.79 (bs, 2H), 12.75 (bs, 1H). LC-MS: [M+1]=127.23.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH:17]=[CH:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)c1cccc(C=CCC2SCC(=O)N2CCC2(O)CCCCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1cccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)c1

Procedure:
3-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propenyl}benzoic acid (7.8 g., 0.02 mole) (the compound of Example 11) in ethanol (125 ml.) is hydrogenated over 2.5 g. of a 5% Pd on charcoal catalyst at 1 atmosphere pressure and 27° C. When the theoretical amount (0.02 mole) of hydrogen has been absorbed, the catalyst is filtered off, the solvent evaporated, and the residue chromatographed on silica gel with 4% methanol in chloroform as the eluant. The title compound is obtained as a colorless, viscous oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:21]1([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH:30]([C:34]([NH2:36])=[O:35])[CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:29][CH:30]2[C:34]([NH2:36])=[O:35])=[CH:8][CH:9]=1
Reactant: Fc1ccc(C(=CCCCBr)c2ccc(F)cc2)cc1
Reactant: NC(=O)C1CN(Cc2ccccc2)CCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C1CN(Cc2ccccc2)CCN1CCCC=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 61.9 %

Procedure:
A mixture of 74.2 parts of 1,1'-(5-bromo-1-penten-1-ylidene)bis[4-fluorobenzene], 43.8 parts of 4-(phenylmethyl)-2-piperazinecarboxamide, 38.9 parts of N,N-diethylethanamine and 1350 parts of N,N-dimethylformamide was stirred for 20 hours at 70° C. The reaction mixture was evaporated in vacuo and the residue was stirred in dichloromethane. The precipitate was filtered off. The filtrate was washed three times with 200 parts of water and once with 200 parts of a diluted ammonium hydroxide solution, dried, filtered and evaporated. The residue was purified by column chromatography over silical gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 58.9 parts (61.9%) of 1-[5,5-bis(4-fluorophenyl)-4-pentenyl]-4-(phenylmethyl)-2-piperazinecarboxamide as a residue (int. 33).
Reaction SMILES: [F:1][C:2]([F:30])([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=3)=[N:17]2)=[CH:12][CH:11]=1)[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].C1(P([N:45]=[N+:46]=[N-:47])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[F:1][C:2]([F:30])([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([N:45]=[N+:46]=[N-:47])=[O:27])=[CH:23][CH:22]=3)=[N:17]2)=[CH:12][CH:11]=1)[C:3]([F:9])([F:8])[C:4]([F:6])([F:5])[F:7]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(-c2ncn(-c3ccc(C(F)(F)C(F)(F)C(F)(F)F)cc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ncn(-c3ccc(C(F)(F)C(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 28.5 %

Procedure:
4-(1-(4-(Perfluoropropyl)phenyl)-1H-1,2,4-triazol-3-yl)benzoic acid (400 mg, 0.92 mmol) was dissolved in 7 mL of isopropanol and treated with diphenylphosphoryl azide (0.300 g, 1.09 mmol) and triethylamine (0.200 g, 2.0 mmol). The solution was allowed to stir for 6 h, then it was cooled to 0° C. and the resulting solid was filtered, washed with a minimum amount of iPrOH, and dried under high vacuum to give the azide as an off-white solid (0.120 g, 30%). This solid was not further characterized, but used directly in the subsequent Curtius rearrangement to prepare molecule A113, using conditions described in Example 39.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:26][C:27](O)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:26][C:27]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)CC1CCCCC1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1CCCCC1)C2
Reaction time: 0.5 h

Procedure:
Triethylamine 0.84 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.95 g, and stirred at o@C for 30 min. Cyclohexyl acetic acid 0.72 g and WSC 1.35 g were added therein, then the reaction mixture was gradually changed to room temperature and stirred for 25 hours. The reaction mixture was washed with saturated sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-cyclohexylacetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 0.38 g and refluxed for 1 hour. The reaction mixture was cooled, then added 6N hydrochloric acid and 1N sodium hydroxide thereto, and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform acetone methanol=10:1:0.1) to obtain the product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C(O)(=O)C>CC(O)C>[C:13]([C@@:10]1([CH2:15][CH3:16])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[CH:27][CH:28]=3)[N:7]=2)[C:9]1=[O:17])#[N:14]
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Reactant: CNC(=O)c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C(=O)NC)cc3)n2)C1=O
Yield: 41.8 %

Procedure:
A solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (51 mg), 4-amino-N-methylbenzamide (32 mg) and acetic acid (12 μL) in 2-propanol (1 mL) was stirred in a microwave reactor at 150° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (31 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O.O>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)COc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 89 %

Procedure:
To a stirred solution of 2-bromo-4-chlorophenol (3.38 g, 16.3 mmol) in anhydrous 1-methyl-2-pyrrolidinone (25 ml) under an atmosphere of nitrogen, was added cesium carbonate (8.0 g, 24.4 mmol). The mixture was cooled to 0° C. before addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.78 g, 16.3 mmol) drop-wise over 2 minutes. The reaction was allowed to warm to room temperature and stirred for 14 hours. To encourage complete reaction the reaction mixture was warmed to 120° C. for 3 hours. The reaction mixture was cooled to room temperature then water (50 ml) was added. The layers were separated and the aqueous was extracted with heptane (3×50 ml). All organic extracts were combined then dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo to afford crude title compound as a yellow oil (4.20 g, 89%). Material was taken on without further purification.