Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1([O:23][C:24](=O)[NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)C=CC=CC=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:24]([N:14]2[CH2:13][CH2:12][N:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:16][CH2:15]2)=[O:23])[CH:27]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Product: O=C(Nc1cccnc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from 1-benzo[1,3]dioxol-5-ylmethyl-piperazine and pyridin-3-yl-carbamic acid phenyl ester in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 8.44-8.43 (m, 1H), 8.19-8.17 (m, 1H), 7.98-7.95 (m, 1H), 7.18-7.16 (m, 1H), 6.83-6.80 (m, 2H), 6.70 (s, 1H), 5.89 (s, 2H), 3.55-3.52 (m, 4H), 3.47 (s, 2H), 2.51-2.48 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:17][C:18]([CH3:26])([CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:19]#[N:20]>>[C:19]([C:18]([NH:17][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([CH3:26])[CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])#[N:20]
Reactant: CC(N)(C#N)CS(C)(=O)=O
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Br)cn1
Product: CC(C#N)(CS(C)(=O)=O)NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 78d) and 2-Amino-3-methanesulfonyl-2-methyl-propionitrile (Example 80a) as starting material and isolated (570 mg, 77%) as a yellow oil; MS (ESI, m/z): 444.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24]C(OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[Cl:35][CH2:36][C:37]1C=C[CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1.Cl>>[ClH:35].[CH3:44][O:43][C:39]1[CH:40]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:23][S:22][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=1
Reactant: COc1cccc(CCl)c1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: COc1cccc(CSc2cnc(Nc3nc(C)cs3)c(OCc3ccccc3)c2)c1
Yield: 74.7 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 1-(chloromethyl)-3-methoxybenzene (0.024 mL, 0.17 mmol) were reacted according to the method of Example 43 to afford 5-(3-methoxybenzylthio)-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (61.7 mg, 75.4% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 7.84 (d, 1H), 7.57 (m, 3H), 7.44-7.33 (m, 3H), 7.17 (t, 3H), 6.80 (m, 4H), 5.29 (s, 2H), 4.17 (s, 2H), 3.68 (s, 3H), 2.30 (s, 3H); Mass spectrum (apci) m/z=450.0 (100), 359.0 (80), 238.0 (75).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][C@H:12]2[CH3:28])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>O1CCOCC1.NC[C@@H]1CCCC[C@H]1CN>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:15][CH2:16][N:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:37]4[CH:41]=[CH:40][N:39]=[CH:38]4)[CH:3]=3)(=[O:10])=[O:9])[C@H:12]([CH3:28])[CH2:13]2)=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:19]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(Br)c1
Reactant: c1c[nH]cn1
Agent: NC[C@@H]1CCCC[C@H]1CN
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(-n2ccnc2)c1
Temperature: 120 °C
Yield: 75 %

Procedure:
A suspension of (R)-1-(3-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazine (168 mg, 0.35 mmol), 1,2-trans-diaminomethylcyclohexane (2.9 mg, 0.015 mmol), K3PO4 (8.5 mmg, 0.06 mmol) and Imidazole (41 mg, 0.6 mmol) in dioxane (0.6 mL) was degassed and heated to 120° C. in a sealed tube till disappearance of starting material as monitored by LCMS. The crude reaction mixture was filtered through a pad of Celite and washed with EtOAc. The crude product was purified on SiO2 column eluted with hexanes/EtOAc to give the desired product as a white solid (123 mg, 75%). HRMS: calcd for C21H20F4N4O2S+H+, 469.13158. found (ESI-FTMS, [M+H]1+), 469.13336.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1.Cl[CH:10]([CH3:18])[CH2:11][CH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1.[OH-].[Na+].C1COCC1>CN(C=O)C.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:10]([CH3:18])[CH2:11][CH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1
Reactant: CC(Cl)CCc1nnn[nH]1
Reactant: Oc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCc1nnn[nH]1)Oc1cccc(O)c1

Procedure:
A mixture of 1.43 g (0.013 mol) 1,3-dihyroxybenzene, 2.1 g (0.013 mol) 5-(3-chlorobutyl)tetrazole and 15 ml (2N, NaOH) in 15 ml DMF and 50 ml THF are stirred overnight at 60° C. bath temperature. The reaction mixture is poured into water and extracted with ether. The ether extract is washed with water, dried and concentrated to dryness under reduced pressure. The residue is passed through a silica gel column using hexane/ethylacetate (3:1) as eluent. Evaporation of eluent gives the tetrazole product which is used directly in the next step.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][C:14]([C@@:16]12[CH2:24][N:23](CC3C=CC=CC=3)[CH2:22][C@@H:21]1[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15]>ClCCl>[CH3:12][O:13][C:14]([C@@:16]12[CH2:24][N:23]([C:2]([O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:3])[CH2:22][C@@H:21]1[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@]12CCCC[C@H]1CN(Cc1ccccc1)C2
Solvent: ClCCl
Product: COC(=O)[C@]12CCCC[C@H]1CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.8 %

Procedure:
Benzyl chloroformate (33.4 mL, 234 mmol) was added to a solution of [(1R*,6R*)-8-benzyl-8-azabicyclo[4.3.0]nonan-1-yl]carboxylic acid methyl ester (21.3 g, 77.9 mmol) in dichloromethane (259 mL) in a nitrogen atmosphere, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Then, the residue (58.0 g) was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→80:20→75:25) to give 17.5 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][N:4]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:12])[F:13])=[N:4]2)=[CH:16][CH:17]=1)[CH2:23][CH3:24]
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CCCOc1ccc(Br)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCCOc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
A mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (152 mg, 0.8 mmol), 1-bromo-4-(propyloxy)benzene (177 mg, 0.8 mmol), N,N-dimethylglycine (16 mg, 0.16 mmol), copper (I) iodide (16 mg, 0.08 mmol), potassium carbonate (235 mg, 1.7 mmol) in dimethylsulfoxide (3 ml) was heated in a microwave reactor at 180° C. for a total of 50 minutes. Fresh N,N-dimethylglycine (16 mg, 0.16 mmol) and copper (I) iodide (16 mg, 0.08 mmol) was added and heating continued at 180° C. for a further 30 minutes. The reaction mixture was then filtered through a 5 g sep-pack column with 40 ml 1:1 ethyl acetate in petroleum ether. The solvent was removed by rotary evaporation and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was retained and washed with brine (2×10 ml), then dried over sodium sulphate. The solvent was removed by rotary evaporation and the sample purified by MDAP. The relevant fractions were combined and the solvent removed by rotary evaporation to give the title compound (23 mg, 9%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[C:6]([CH:25]=1)=[N:7][C:8]1[N:9]([N:21](C=O)[CH3:22])[CH:10]=[C:11]([C:16]([O:18]CC)=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.Cl>C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[C:6]([CH:25]=1)=[N:7][C:8]1[N:9]([NH:21][CH3:22])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2
Reactant: CCOC(=O)c1cn(N(C)C=O)c2nc3cc(Cl)c(F)cc3cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reaction time: 4 h
Yield: 97.7 %

Procedure:
A suspension of 16.4 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 164 cm3 of acetic acid and 164 cm3 of an aqueous 17.5% hydrochloric acid solution is heated at a temperature close to 100° C., with stirring, for 4 hours. After cooling to a temperature close to 10° C., 165 cm3 of 30% slate lime is added at between 10° and 20° C. The product is drained and washed with 3 times 150 cm3 of water, 3 times 150 cm3 of ethanol and 3 times 150 cm3 of diethyl ether. 13.64 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 354°-356° C., which is used for the subsequent steps without further purification.
Reaction SMILES: S1C(C2C3C=C(OCC)C(OCC)=CC=3CC(=O)NN=2)=CC2C=CC=C[C:2]1=2.[S:28]1[C:32]([C:33]2[C:39]3[CH:40]=[C:41]([O:47][CH2:48][CH3:49])[C:42]([O:44][CH2:45][CH3:46])=[CH:43][C:38]=3[CH:37]([CH2:50][CH2:51][CH3:52])[C:36](=[O:53])[NH:35][N:34]=2)=[CH:31][C:30]2[CH:54]=[CH:55][CH:56]=[CH:57][C:29]1=2>>[S:28]1[C:32]([C:33]2[C:39]3[CH:40]=[C:41]([O:47][CH2:48][CH3:49])[C:42]([O:44][CH2:45][CH3:46])=[CH:43][C:38]=3[CH:37]([CH2:50][CH2:51][CH3:52])[C:36](=[O:53])[N:35]([CH3:2])[N:34]=2)=[CH:31][C:30]2[CH:54]=[CH:55][CH:56]=[CH:57][C:29]1=2
Reactant: CCOc1cc2c(cc1OCC)C(c1cc3ccccc3s1)=NNC(=O)C2
Reactant: CCCC1C(=O)NN=C(c2cc3ccccc3s2)c2cc(OCC)c(OCC)cc21
Product: CCCC1C(=O)N(C)N=C(c2cc3ccccc3s2)c2cc(OCC)c(OCC)cc21
Yield: 34 %

Procedure:
By replacing 1-(2-benzo[b]thienyl)-7,8-diethoxy-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIab in example IIIba by 1-(2-benzo[b]thienyl)-7,8-diethoxy-5-n-propyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIac and proceeding in the same manner, the abovenamed product is obtained. Yield: 34%. M: 61–63° C. 1H-NMR (200 MHz, CDCl3): d 1.01 (t, J=7.34, 3H, (CH2)2CH3), 1.39–4.55 (m, 8H, CH2CH2CH3+2×OCH2CH3), 1.75–2.42 (m, 2H, CH2CH2CH3), 3.04–3.11 (m, 1H, 5-H), 3.45 (s, 3H, 3-CH3), 3.99–4.23 (m, 4H, 2×OCH2CH3), 6.83 (s, 1H Ar), 7.12 (s, 1H Ar), 7.35–7.44 (m, 3H Ar), 7.72–7.89 (m, 2H Ar).
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:47])[C@@H:9]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][CH:11]([O:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[C:12](=[O:27])[NH:13][CH2:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=1[O:25][CH3:26])([CH3:6])([CH3:5])[CH3:4]>CC(O)C>[C:3]([O:7][C:8](=[O:47])[C@@H:9]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][C@H:11]([O:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[C:12](=[O:27])[NH:13][CH2:14][C:15]1[C:16]([O:25][CH3:26])=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=1[O:21][CH3:22])([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1cc(OC)c(CNC(=O)C(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OS(=O)(=O)c2ccc(C)cc2)c(OC)c1
Solvent: CC(C)O
Solvent: CO
Product: COc1cc(OC)c(CNC(=O)[C@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OS(=O)(=O)c2ccc(C)cc2)c(OC)c1

Procedure:
Following the procedure in the preparation of 11, compound 11″ was prepared from alcohol 10″ (1.69 g, 3.40 mmol) as a pale white foamy solid (2.12 g, 96% yield): [α]26D=+14.1 (c=1.01, MeOH); HPLC of 11″ for purity: 97.7%, [major peak: Rt=23.7 min; minor peak: 16.2 min; column: Chiralcel ODH (250×4.6 mm), UV detector, 210 nm, 5% 2-propanol in hexanes; flow rate: 1.0 mL/min]. 1H NMR (200 MHz, CDCl3) δ 7.75 (d, 2H, J=8.4 Hz), 7.25 (d, 2H, J=8.4 Hz), 6.91 (br s, 1H), 6.14 (s, 2H), 5.12 (br s, 1H), 4.94 (t, 1H, J=6.0 Hz), 4.52 (dd, 1H, J1=14.0 Hz, J2=6.0 Hz), 4.30 (dd, 1H,//=14.4 Hz, J2=5.2 Hz), 4.18 (br s, 1H), 3.84 (s, 3H), 3.82 (s, 6H), 2.42 (s, 3H), 2.32-2.22 (m, 2H), 1.45 (s, 9H), 1.43 (s, 9H). 13C NMR (50 MHz, CDCl3) δ 170.7, 167.1, 161.2, 159.5, 155.5, 145.5, 133.1, 130.1, 128.2, 106.3, 90.9, 82.4, 79.9, 56.0, 55.6, 50.8, 35.0, 32.7, 28.5, 28.1, 21.8. HRMS calcd for C31H45N2O11S (M+H)+: 653.2744. found: 653.2729.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:8]=[C:7]([CH2:9][CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Nc1ccc(CC2CCCC2)cc1Br
Product: Nc1ccc(CC2CCCC2)cc1-c1cccc(Cl)c1

Procedure:
2-bromo-4-cyclopentylmethylaniline and 3-chlorobenzene boronic acid can be combined to form 2-(3-chlorophenyl)-4-cyclopentylmethylaniline,
Reaction SMILES: [N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=1.[OH-].[Na+].C(O)(=O)C>O>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][N:27]=1
Reactant: O=C1CCC(c2ccccc2O)=NN1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccccc2O)n[nH]1
Yield: 82.9 %

Procedure:
Sodium 3-nitrobenzenesulphonate (2.96 g) and 6-(2-hydroxyphenyl)-4,5-dihydro-3(2H)pyridazinone (2.5 g) were added to a stirred solution of sodium hydroxide (1.31 g) in water (25 ml) and the mixture was heated under reflux for 2.5 hours. Acetic acid was added to the warm stirred solution until there was no further precipitation and the mixture was pH 9. The mixture was filtered to give 6-(2-hydroxyphenyl)-3(2H)-pyridazinone (2.05 g) m.p. 287°-292°. A sample recrystallised from 2-methoxyethanol had m.p. 295°-299°.
Reaction SMILES: O[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O.CN(C)C1C=CC=CC=1>ClC1C=CC=CC=1>[Cl:14][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[CH:4][N:3]=1
Reactant: CC(=O)c1cnc(O)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Clc1ccccc1
Product: CC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 94.7 %

Procedure:
3.4 g (20 mmol) of 2-hydroxy-3-chloro-5-acetylpyridine are stirred with 3.7 g (24 mmol) of phosphorus oxychloride and 2.4 g (20 mmol) of N,N-dimethylaniline in 75 ml of chlorobenzene at 100° C. for 1.5 hours. The mixture is stirred into 200 ml of ice-water and extracted with ethyl acetate. Drying and evaporation gives 3.6 g (95%) of 2,3-dichloro-5-acetylpyridine, melting point: 80° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11](OC)[O:12]C)=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncccc1C(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ncccc1C=O

Procedure:
To a solution of 3-(dimethoxymethyl)-2-pyridinecarboxylic acid methyl ester (1.02 g) in dioxane (20 mL) was added water (20 mL), followed by p-toluenesulfonic acid (0.30 g). This solution was heated at 55°-60° C. for 24 hours. The reaction mixture was cooled, diluted with water (50 mL), treated with aqueous saturated sodium bicarbonate until the pH was 7.5-8.0, and extracted with methylene chloride (3×). The combined organic extracts were washed with dilute brine (3×), dried (K2CO3) and evaporated to afford a light yellow solid which yielded 540 mg (62.5%) of an almost pure product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:12])OC(C)=C.[Br:13][C:14]1[C:15]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[C:16]2[N:22]=[C:21]([C:23]3[CH:31]=[CH:30][C:26]([N:27]([CH3:29])[CH3:28])=[CH:25][CH:24]=3)[NH:20][C:17]2=[N:18][CH:19]=1.CN1CCCC1>C1COCC1>[Br:13][C:14]1[C:15]([N:32]2[CH2:33][CH2:34][N:35]([C:7]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:12])[CH2:36][CH2:37]2)=[C:16]2[N:22]=[C:21]([C:23]3[CH:31]=[CH:30][C:26]([N:27]([CH3:29])[CH3:28])=[CH:25][CH:24]=3)[NH:20][C:17]2=[N:18][CH:19]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCNCC4)c(Br)cnc3[nH]2)cc1
Reactant: C=C(C)OC(=O)Nc1nccs1
Agent: CN1CCCC1
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A solution of prop-1-en-2-yl thiazol-2-ylcarbamate (prepared according to the procedure described in J. Org. Chem. 2005, 70, 6960-6963) (40 mg, 0.054 mmol) and 4-(6-bromo-7-(piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-N,N-dimethylaniline (1.0 eq, 0.054 mmol, 22 mg) in THF (0.5 mL) was heated to 55° C. Then N-methylpyrrolidine (0.1 eq, 0.005 mmol, 5 μL) was added and the mixture stirred at 55° C. for 2 h. Concentration in vacuo gave crude material as a solid. A small sample was purified by semi-preparative hplc to give the pure product as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 2.99 (s, 6H, N(CH3)2), 3.58-3.62 (m, 4H, piperazine N(CH2)2), 3.74-3.78 (m, 4H, piperazine N(CH2)2), 6.81 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 7.22 (d, J=3.6 Hz, 1H, thiazole H-4 or H-5), 7.35 (br s, 1H, NH), 7.48 (d, J=3.6 Hz, 1H, thiazole H-4 or H-5), 8.02 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 8.19 (s, 1H, imidazo[4,5-b]pyridine H-5).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][S:22]C(=O)C)[C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH:6]([CH2:21][SH:22])[C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(CSC(C)=O)CSC(C)=O)C1
Agent: N
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(CS)CS)C1

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 4 to yield (S)-1-(3-mercapto-2-mercaptomethyl-1-oxopropyl)-4,4-dimethoxy-L-proline.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:39]([CH3:40])=[N:38][C:37]2=[CH:41][C:34]3=[N:35][N:36]2[C:13]=1[N:14]1[CH2:46][CH2:45][C:17]([CH3:47])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([CH3:44])[O:24][C:25]2[CH:26]=[C:27]([CH3:43])[CH:28]=[CH:29][C:30]=2[CH:31]([CH3:42])[O:32][CH2:33]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:39]([CH3:40])=[N:38][C:37]2=[CH:41][C:34]3=[N:35][N:36]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:47])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([CH3:44])[O:24][C:25]2[CH:26]=[C:27]([CH3:43])[CH:28]=[CH:29][C:30]=2[C@H:31]([CH3:42])[O:32][CH2:33]3)[CH2:45][CH2:46]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)ccc1C(C)OC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(c1)O[C@@H](C)CCCCOC1(C)CCN(CC1)c1c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(nn13)CO[C@H]2C
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-[(20S)-4,12,16,20,26-pentamethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl]acetate (10 mg, 0.015 mmol) and sodium hydroxide (0.077 mL, 0.077 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then cooled to rt and purified by preparative HPLC to isolate the first eluting isomer (2S)-2-(tert-butoxy)-2-[(12S,20S)-4,12,16,20,26pentamethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl]acetic acid (4.0 mg, 41.8%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.24 (d, J=7.7 Hz, 1H), 6.82 (s, 1H), 6.74 (d, J=7.7 Hz, 1H), 6.31 (s, 1H), 5.56-5.43 (m, 2H), 4.63-4.39 (m, 4H), 3.66-3.51 (m, 4H), 2.85 (d, J=11.0 Hz, 1H), 2.48 (s, 3H), 2.28 (s, 3H), 1.94-1.86 (m, 2H), 1.75-1.48 (m, 8H), 1.28 (d, J=6.2 Hz, 3H), 1.19 (d, J=8.4 Hz, 6H), 1.14 (s, 9H). LCMS (M+1)=623.3.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12](Br)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[F:35])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:27]([F:35])[CH:28]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Cn1c(NCc2ccccc2)ncc(Br)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cn1c(NCc2ccccc2)ncc(-c2ccc(OCc3ccccc3)c(F)c2)c1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 2-(benzylamino)-5-bromo-3-methylpyrimidin-4(3H)-one (0.130 g, 0.442 mmol), 4-(benzyloxy)-3-fluorophenylboronic acid (0.130 g, 0.530 mmol), Pd(PPh3)4 (0.026 g, 0.022 mmol) and lithium chloride (0.075 g, 1.77 mmol) in dioxane (2 mL) and 2M aqueous Na2CO3 (2 mL) was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with 10:1 CH2Cl2/EtOAc. The product was obtained (146 mg; 80%) as an off-white foam solid. 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.55 (dd, 1H), 7.48-7.43 (m, 2H), 7.43-7.29 (m, 8H), 7.26-7.15 (m, 2H), 5.18 (s, 2H), 4.62 (d, 2H), 3.42 (s, 3H). LRMS (APCI pos) m/e 416 (M+1).