Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=[C:5]([O:17][CH3:18])[N:4]=1.[NH2:19][CH2:20][CH2:21][OH:22].C(O)(=O)C>CCO>[CH3:1][O:2][C:3]1[C:8](/[C:9](/[NH:19][CH2:20][CH2:21][OH:22])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=[C:5]([O:17][CH3:18])[N:4]=1
Reactant: NCCO
Reactant: CCOC(=O)CC(=O)c1ccc(OC)nc1OC
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)/C=C(\NCCO)c1ccc(OC)nc1OC
Temperature: 90 °C
Yield: 98.2 %

Procedure:
To a solution of ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-oxopropanoate (500 mg, 1.97 mmol) in EtOH (4 mL) was added 2-aminoethanol (0.60 mL, 9.9 mmol) followed by acetic acid (0.63 mL, 9.9 mmol). The reaction mixture was heated to 90° C. for 16 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layer was concentrated in vacuo and the crude material was purified by chromatography on silica eluting with 20-80% EtOAc/heptane to provide the title compound (573 mg, 98%) as a clear gum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([O:29]CC)=O)=[C:20]2[N:19]=1.CCN(C(C)C)C(C)C>CCO>[F:12][C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:27](=[O:29])[C:26]1=[C:20]3[N:19]=[C:18]([CH:23]=[CH:22][N:21]3[N:24]=[CH:25]1)[N:14]1[C@@H:13]2[CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCCN)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1NCCCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Temperature: 200 °C
Yield: 51.3 %

Procedure:
(R)-ethyl 5-(2-(2-(3-aminoprop oxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (10 mg, 0.023 mmol) and DIEA (8.1 μL, 0.047 mmol) were combined in dry EtOH (0.1 mL) in a sealed vessel and heated at 200° C. overnight. The reaction was concentrated and purified by reverse-phase column chromatography (0-70% acetonitrile/H2O) to afford the title compound (4.5 mg, 50% yield). MS (apci) m/z=382.2 (M+H).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].C(Cl)(=O)C1C=CC=CC=1.[CH2:14]([C:16]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19]([CH2:26][CH3:27])[C:17]=1[NH2:18])[CH3:15].[OH-].[Na+]>CC(C)=O.O.C(O)C>[CH2:26]([C:19]1[CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=[C:16]([CH2:14][CH3:15])[C:17]=1[NH:18][C:2]([NH2:3])=[S:1])[CH3:27]
Reactant: CCc1cc([N+](=O)[O-])cc(CC)c1N
Reactant: N#C[S-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CCO
Product: CCc1cc([N+](=O)[O-])cc(CC)c1NC(N)=S
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To 2.34 g (24.1 mmol) of potassium thiocyanate in 30 ml of acetone was added 2.32 ml (20.0 mmol) of benzoyl chloride. The mixture was then refluxed for 15 min, cooled to r.t., and 3.16 g (16.3 mmol) of 2,6-diethyl-4-nitroaniline obtained from step C was added. The mixture was then refluxed for 15 min, cooled to r.t., and poured into 200 ml of ice-water. The precipitate was collected and washed with water, then dissolved in a solution comprising 0.70 g (18 mmol) of sodium hydroxide in 5 ml of water and 50 ml of ethanol. The solution was refluxed for 1 hr, cooled to r.t., poured into icewater, then the precipitate was collected, washed with water several times, and dried. The solids were then triturated with ethyl acetate to yield 2.44 g (59.2%) of product. NMR (CDCl3, d6 -DMSO):δ 1.30 (t, 6H), 2.74 (q, 4H), 6.9 (b, 2H), 7.98 (s, 2H), 9 (b, 1H).
Reaction SMILES: [C:1]1([C:7]2([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][C:8]32[O:12][CH2:11][CH2:10][O:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1([CH3:43])[O:28][C@H:27]([CH2:29][O:30][C:31]2[C:40]([CH3:41])=[CH:39][C:34](/[C:35](=[N:37]/O)/[NH2:36])=[CH:33][C:32]=2[CH3:42])[CH2:26][O:25]1.C(N=C=NC(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(#N)C>[CH3:23][C:24]1([CH3:43])[O:28][C@H:27]([CH2:29][O:30][C:31]2[C:32]([CH3:42])=[CH:33][C:34]([C:35]3[N:37]=[C:20]([CH2:19][CH2:18][CH2:17][C:7]4([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:16][CH2:15][CH2:14][CH2:13][C:8]54[O:12][CH2:11][CH2:10][O:9]5)[O:21][N:36]=3)=[CH:39][C:40]=2[CH3:41])[CH2:26][O:25]1
Reactant: Cc1cc(/C(N)=N/O)cc(C)c1OC[C@@H]1COC(C)(C)O1
Reactant: O=C(O)CCCC1(c2ccccc2)CCCCC12OCCO2
Agent: CC(C)N=C=NC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: Cc1cc(-c2noc(CCCC3(c4ccccc4)CCCCC34OCCO4)n2)cc(C)c1OC[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a solution of 4-(6-phenyl-1,4-dioxaspiro[4.5]decan-6-yl)butanoic acid (62.0 mg, 0.204 mmol) and (R,Z)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N′-hydroxy-3,5-dimethylbenzimidamide (50 mg, 0.17 mmol) in acetonitrile (2 mL) was added N,N′-diisopropylcarbodiimide (0.032 mL, 0.204 mmol), and the mixture was stirred for 1 hr at room temp. Then 1M TBAF (0.221 mL, 0.221 mmol) was added, and the mixture was stirred at room temp for 18 hrs. It was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc once more. Combined extracts were washed with Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (24 g silica gel) eluting with 3:7 followed by 1:1 EtOAc-hexane to give 3-(4-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3,5-dimethylphenyl)-5-(3-(6-phenyl-1,4-dioxaspiro[4.5]decan-6-yl)propyl)-1,2,4-oxadiazole as an oil (57 mg). LC/MS: m/e 563.21 (M+H)+.
Reaction SMILES: CS(OCCOC12[CH2:19][C:13]3([CH3:20])[CH2:14][C:15]([CH3:18])([CH2:17][C:11]([CH2:21][N:22]4[C:26]([CH3:27])=[C:25]([I:28])[CH:24]=[N:23]4)([CH2:12]3)[CH2:10]1)[CH2:16]2)(=O)=O.[CH3:29][OH:30]>CN>[CH3:18][C:15]12[CH2:16][C:29]3([O:30][CH2:11][CH2:21][NH:22][CH3:26])[CH2:19][C:13]([CH3:20])([CH2:12][C:11]([CH2:21][N:22]4[C:26]([CH3:27])=[C:25]([I:28])[CH:24]=[N:23]4)([CH2:10]3)[CH2:17]1)[CH2:14]2
Reactant: CO
Reactant: Cc1c(I)cnn1CC12CC3(C)CC(C)(C1)CC(OCCOS(C)(=O)=O)(C3)C2
Agent: CN
Product: CNCCOC12CC3(C)CC(C)(CC(Cn4ncc(I)c4C)(C3)C1)C2

Procedure:
A solution of 2-({3-[(4-iodo-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec-1-yl}oxy)ethyl methanesulfonate (2.5 g) in 2 M methylamine in methanol (15 mL) was heated to 100° C. for 20 minutes in a Biotage Initiator microwave reactor. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic layer was dried with sodium sulfate, filtered and concentrated to give the title compound which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1.[Br:16]Br>C(Cl)Cl>[Br:16][C:6]1[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][NH:9][C:5]=1[CH2:4][CH2:3][O:2][CH3:1]
Reactant: BrBr
Reactant: COCCc1cc(-c2ccccc2)n[nH]1
Solvent: ClCCl
Product: COCCc1[nH]nc(-c2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of 5-(2-methoxyethyl)-3-phenyl-1H-pyrazole (2.0 g, 9.89 mmol) in DCM (100 mL) was added bromine (4.74 g, 29.7 mmol) dropwise at 0° C. The reaction was stirred at 0° C. for 1 h and then at room temperature for 2 h before quenching with Na2SO3 (10% aqueous). The organic phase was removed and the aqueous layer was extracted with DCM (2×50 mL). The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give the title compound (2.5 g). LCMS m/z=281.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.87 (t, J=6.82 Hz, 2H), 3.27 (s, 3H), 3.62 (t, J=6.82 Hz, 2H), 5.75 (s, 1H), 7.35-7.51 (m, 3H), 7.75-7.82 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17](O)=[O:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([NH:8][NH:9][C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:12]2[CH3:11])=[O:18])=[N:6][CH:7]=1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: Cc1cc(F)cnc1NN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(F)cnc1NNC(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
A solution of Intermediate 105b (76 mg, 0.537 mmol), (S)-1-methyl-pyrrolidine-2-carboxylic acid (55 mg, 0.72 mmol) and HOBT (8 mg, 0.72 mmol) in anhydrous DCM (5 mL) was treated with EDC (138 mg, 0.717 mmol) and stirred at RT under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with DCM and washed with brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM, to afford the title compound (76 mg, 56%). 1H NMR (400 MHz, CDCl3): 1.74-2.05 (3H, m), 2.15-2.33 (4H, m), 2.34-2.46 (1H, m), 2.52 (3H, s), 3.02-3.12 (1H, m), 3.15-3.25 (1H, m), 6.70 (1H, s), 7.08-7.18 (1H, m), 7.90 (1H, d, J=2.8 Hz), 9.52 (1H, br s).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:12]=[CH:13]/[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:12]=[CH:13]/[C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: ClCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Reactant: c1c[nH]cn1
Product: C(=C/c1ccccc1OCCCn1ccnc1)\c1nc2ccccc2o1

Procedure:
The title compound was prepared by the procedure of Example 1 starting with (A) of Example 1 (8.0 g, 25 mmol) and using imidazole in place of dibutylamine to produce 2.1 g (24% yield) of the free base of the title compound which was converted to the HCl salt, mp 158°-159° C. IR(KBr): 3400, 1600 cm-1. MS: 346(MH+). 1H NMR (CD3OD): δ 9.09 (s, 1H), 7.82-6.81 (m, 12H), 4.51 (t, J=5.4 Hz, 2H), 4.08 (t, J=5.1 Hz, 2H), 2.41 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[NH2:19][C:20]1[S:21][CH:22]=[C:23]([C:25](=[N:29][O:30][CH3:31])[C:26]([OH:28])=O)[N:24]=1.[CH3:32][C:33]([O:35][CH2:36][C:37]1[CH2:46][S:45][C@@H:40]2[C@H:41]([NH2:44])[C:42](=[O:43])[N:39]2[C:38]=1[C:47]([OH:49])=[O:48])=[O:34]>CC(N(C)C)=O.C(Cl)Cl>[C:33]([O:35][CH2:36][C:37]1[CH2:46][S:45][C@@H:40]2[CH:41]([NH:44][C:26](=[O:28])[C:25]([C:23]3[N:24]=[C:20]([NH2:19])[S:21][CH:22]=3)=[N:29][O:30][CH3:31])[C:42](=[O:43])[N:39]2[C:38]=1[C:47]([OH:49])=[O:48])(=[O:34])[CH3:32]
Reactant: CON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1

Procedure:
The process of claim 1 comprising reacting at low temperature, in dimethylacetamide, in the presence of triethylamine, tosyl chloride and the syn isomer of 2-(2-amino-4-thiazolyl)-2-methoxyimino-acetic acid and reacting the resulting product with 7-amino-cephalosporanic acid in methylene chloride in the presence of triethylamine to obtain the syn isomer of 3-acetoxymethyl-7[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH:9]=2)[CH:4]=1.[C:22]1([C:28]2[C:32]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][NH:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([CH2:2][N:30]1[CH:31]=[C:32]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:28]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:29]1)[CH:12]=[CH:11]2
Reactant: Fc1ccccc1COc1ccc2cc(CCl)ccc2c1
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4ccccc4F)ccc3c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
2-Chloromethyl-6-(2-fluorobenzyloxy)naphthalene (540 mg) and ethyl 3-(3-phenyl-1H-pyrazol-4-yl]propionate (390 mg) were dissolved in N,N-dimethylformamide (10 ml). Sodium hydride (60%, oily, 70 mg) was added to the solution at 0° C., which was stirred at room temperature for two hours. The reaction mixture was poured into saturated aqueous sodium chloride solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[6-(2-fluorobenzyloxy)-2-naphthylmethyl]-3-phenyl-1H-pyrazole-4-yl]propionate (0.58 g, yield: 72%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[NH:34]1[C:38](B(O)O)=[CH:37][CH:36]=[N:35]1.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>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:36]2[NH:35][N:34]=[CH:38][CH:37]=2)[CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Reactant: OB(O)c1ccn[nH]1
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: [Na+]
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1ccn[nH]1)c(OCc1ccccc1)c2=O
Yield: 62.5 %

Procedure:
Intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.150 g, 0.27 mmol) was reacted with 1H-pyrazol-5-ylboronic acid (0.060 g, 0.54 mmol), sodium carbonate (0.085 g, 0.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.070 g) to give 0.085 g (62% yield) of the title material as a white solid after chromatography on silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.63 (6H, s, 2×CH3), 4.03 (4H, m, 2×CH2), 4.65 (2H, d, J=6.5 Hz, NCH2), 5.25 (2H, s, OCH2), 6.54 (1H, d, J=2.5 Hz, CH), 7.03 (1H, m, aromatic), 7.25 (1H, dd, J=2.5 Hz and J=9.8 Hz, aromatic), 7.35 (3H, m, aromatics), 7.53 (2H, m, aromatics), 7.56 (1H, d, J=2.5 Hz, CH), 7.60 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.96 (1H, broad t, NH). HRMS (ESI+) calculated for C27H27FN5O4 [M+H+]: 504.2047. found: 504.2068.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27](O)=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][OH:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CSc4ccccc4C(=O)O)ccc3o2)n1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(-c2cc3cc(CSc4ccccc4CO)ccc3o2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.6 %

Procedure:
To a mixture of 4-tert-butyl-2-[5-(2-carboxyphenylthiomethyl)benzofuran-2-yl]thiazole (0.65 g) in tetrahydrofuran (10 ml), lithium aluminum hydride (0.12 g) was added under cooling with ice bath. After being stirred at ambient temperature for 5 hours, the resulting mixture was poured into a mixture of ice and diluted aqueous hydrochloric acid and extracted with toluene. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and toluene (1:9). The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-[5-(2-hydroxymethylphenylthiomethyl)benzofuran-2-yl]thiazole (0.45 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])(=[O:4])=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:21][C@H:19]([CH3:20])[CH2:18][C:14]1[C:13]2[C:17](=[C:9]([O:8][CH2:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:29])[CH:10]=[CH:11][CH:12]=2)[NH:16][CH:15]=1
Reactant: C[C@H](Cc1c[nH]c2c(OCC(=O)NS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)Cc1c[nH]c2c(OCC(=O)NS(C)(=O)=O)cccc12

Procedure:
A solution of tert-butyl (R)-{2-[7-(2-methanesulfonylamino-2-oxoethoxy)-1H-indol-3-yl]-1-methylethyl}carbamate (0.14 g, 0.33 mmol) and trifluoroacetic acid (1 mL) in methylene chloride (4 mL) is stirred at room temperature for 8 hours. The mixture is concentrated to give the desired (R)—N-{2-[3-(2-aminopropyl)-1H-indol-7-yloxy]acetyl}methane-sulfonamide.trifluoroacetate (0.13 g, yield: 90%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[S:4][C:5]1[CH:6]=[CH:7][C:8]([N+:16]([O-])=O)=[CH:9][C:10]=1[CH2:11]2>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[S:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:16])=[CH:9][C:10]=1[CH2:11]2
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1cccc(Br)c1S2
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)Cc1cccc(Br)c1S2
Yield: 102.6 %

Procedure:
Zn dust (34.87 g, 533 mmol) was added to a stirred solution of 5-bromo-2-nitro-9H-thioxanthene (28.64 g, 88.9 mmol) in glacial acetic acid (300 ml) at 0° C. (ice bath). After one hour the ice bath was removed and the solution was left to react overnight at room temperature. The mixture was filtered through a pad of Celite and washed with copious amount of dichloromethane and the filtrate was evaporated in vacuo. Water was added (800 ml) to the residue and the pH was adjusted to pH 8 by addition of concentrated ammonia (100 ml). The solid formed was filtered and dried in a vacuum desiccator to give the title compound (26.64 g) and was used without any further purification. m/z (LC-MS, ESP), RT=4.53 min, (M++1)=294-292, (1:1, bromine isotope ratio present)
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.S(Cl)([Cl:15])=O>>[S:1]1[C:5]2[C:6]([C:10]([Cl:15])=[O:12])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2nnsc12
Product: O=C(Cl)c1cccc2nnsc12
Temperature: 90 °C

Procedure:
12.54 g (0.070 mol) of benzo-1,2,3-thiadiazole-7-carboxylic acid are mixed with 80 ml of thionyl chloride. The mixture is heated and maintained at a bath temperature of 90° C. for 8 hours. The excess thionyl chloride is then removed by distillation in a rotary evaporator at a bath temperature of 40° C. The resulting oil solidifies; m.p. 107° C.
Reaction SMILES: Br[C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].C(P(C(C)(C)C)C1C=CC=CC=1)(C)(C)C.C1(C(N)C2CCCCC2)CCCCC1.C1(C=CC(O)=CC=1)O.[CH:50]([Cl:52])=[CH2:51].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(N(C)C)=O>[Cl:52][CH:50]=[CH:51][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: Cc1c(Br)c(C(F)(F)F)nn1C
Reactant: C=CCl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1)C(C)(C)C
Solvent: CC(=O)N(C)C
Product: Cc1c(C=CCl)c(C(F)(F)F)nn1C
Temperature: 130 °C
Reaction time: 30 h
Yield: 69 %

Procedure:
2.00 g (8.23 mmol) of 4-bromo-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole, 18.5 mg (0.08 mmol) of palladium acetate and 60.3 mg (0.165 mmol) of tetra-n-butylammonium bromide are weighed into the glass insert of an autoclave together with 73.2 mg (0.329 mmol) of di(tert-butyl)phenylphosphine, 1.77 g (9.05 mmol) of dicyclohexylmethylamine, 9.1 mg (0.082 mmol) of hydroquinone and dimethylacetamide (22.8 ml), and placed under a protective gas atmosphere. Subsequently, 2.57 g (41.2 mmol) of vinyl chloride are metered in at 20° C. and the reaction mixture is stirred at 130° C. for 30 h. After the end of the reaction, the mixture is cooled, poured onto cold, dilute hydrochloric acid and extracted with CH2C12. The combined organic phases which have been dried over magnesium sulphate are concentrated. The product is obtained as a solid in a 69% yield.
Reaction SMILES: C[O-].[Na+].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].CS(O[C@@H:20]([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])(=O)=O.[Cl-].[NH4+]>CO.C(Cl)Cl>[CH3:25][C@@H:20]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCC[C@H](C)OS(C)(=O)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CCCC[C@@H](C)C(C(=O)OCC)C(=O)OCC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
At room temperature, 28.9 g of sodium methoxide (95% pure, 0.51 mol) were dissolved in 150 ml of dry methanol under protective nitrogen gas in a three-neck flask with internal thermometer, dropping funnel and stirrer. Subsequently, 85.3 g of diethyl malonate (0.533 mol) were added dropwise at from 30 to 35° C., in the course of which a suspension initially formed and dissolved toward the end of the addition. The clear mixture was stirred at 50° C. for 60 min and 80 g of (S)-1-methylpentyl methanesulfonate (0.444 mol) were added undiluted. The mixture was heated to 66° C. and stirred for 6 h. After cooling to 25° C., the suspension was admixed with 400 ml of methylene chloride and 300 ml of 5% by weight ammonium chloride solution. After phase separation, the organic phase was washed with 100 ml of water and then dried over sodium sulfate. After distillative removal of solvent, diethyl [(R)-1-methylpentyl]malonate was obtained in a yield of 94 g. The product comprises dimethyl ester and ethyl methyl ester, formed by transesterification, and unconverted malonic ester. The corrected yield is 84% of theory.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[CH:18]=[CH:17][O:16][CH:15]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9](I)=[CH:8][CH:7]=2)#[N:2].[CH3:19][Si:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][SH:23].CC(C)([O-])C.[K+]>CCO.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>[C:1]([C:3]1[CH:4]=[C:5]([C:14]2[CH:18]=[CH:17][O:16][CH:15]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([S:23][CH2:22][CH2:21][Si:20]([CH3:25])([CH3:24])[CH3:19])=[CH:8][CH:7]=2)#[N:2]
Reactant: C[Si](C)(C)CCS
Reactant: N#Cc1cc(-c2ccoc2)c2ccc(I)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: C[Si](C)(C)CCSc1ccc2c(-c3ccoc3)cc(C#N)cc2c1
Yield: 70.6 %

Procedure:
A mixture of 3-cyano-1-(furan-3-yl)-6-iodonaphthalene (2.5 g, 7.25 mmol), 2-(trimethylsilyl)ethanethiol (974 mg, 7.25 mmol), potassium tert-butoxide (1.624 g, 14.5 mmol) and (Ph3P)4Pd (200 mg, 0.17 mmol) in EtOH (250 mL) was refluxed for 6.5 h. After evaporation of the EtOH, the residue was partitioned between Et2O and H2O. The crude product from the organic phase was chromatographed on silica gel, eluting with a 1:9 mixture of EtOAc and hexane to afford the title product (1.8 g) as an amber oil.