Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)[CH3:3].Cl[C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH3:21])[CH:14]=1>>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:13]2[CH:14]=[C:15]([NH:19][CH2:20][CH3:21])[N:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: CCNc1cc(Cl)ncn1
Reactant: CN(C)Cc1cccc(N)c1
Product: CCNc1cc(Nc2cccc(CN(C)C)c2)ncn1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
The title compound is prepared as described in Example 143A but using 3-dimethylaminomethyl-phenylamine (334 mg, 2.20 mmol, 1 eq.), (6-chloro-pyrimidin-4-yl)-ethyl-amine (Example 143B) and stirring the reaction mixture for 3 h at 160° C. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 9:1) followed by trituration of the resulting solid in diethyl ether, affords 335 mg of the title compound as a beige solid: ESI-MS: 272.1 [MH]+; tR=1.18 min (purity: 100%, gradient J); TLC: Rf=0.16 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17].N1C=CC=CC=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17]
Reactant: COc1ccc(N)cn1
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2Cl)cn1
Yield: 34.1 %

Procedure:
A solution of (R)-N-(2,3-Dichloro-4-chlorosulphonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Method 1; 0.3 mmol) and pyridine (0.33 mmol) in DCM (5 ml) was added to a solution of 5-amino-2-methoxypyridine (0.3 mmol) in DCM (2 ml). The resultant mixture was stirred at ambient temperature overnight. The DCM was evaporated and resulting mixture was partitioned between EtOAc (5 ml) and 1 M HCl (4 ml), the EtOAc layer was separated and washed with saturated aqueous sodium hydrogen carbonate solution and brine then dried and evaporated to give the title compound as a gum (50 mg). M/z 486.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[CH3:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[OH:33].N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:31]1\[CH:32]=[C:23]([CH3:22])[C:24](=[O:33])[C:25]2[C:30]\1=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: Nc1c(N)n2n(c1=O)CCC2
Reactant: Cc1ccc2ccccc2c1O
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: CC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)c2ccccc2C1=O

Procedure:
0.58 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulphonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.58 mmol of 2-methyl-1-naphthol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:11][CH2:12][C:13]1[O:17][CH:16]=[CH:15][CH:14]=1)[CH:8]1[O:10][CH2:9]1>CCOCC>[C:1]([O:6][CH2:9][CH:8]([OH:10])[CH2:7][O:11][CH2:12][C:13]1[O:17][CH:16]=[CH:15][CH:14]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: c1coc(COCC2CO2)c1
Solvent: CCOCC
Product: C=C(C)C(=O)OCC(O)COCc1ccco1
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A mixture of methacrylic acid (10 g), furfuryl glycidyl ether (15 g) and triethylaminc (0.3 g) was heated to 100° C. for 2 hours then to 105° C. for an additional 2 hours. GC analysis showed 96% conversion. The mixture was taken up into ether, washed with water, followed by saturated sodium bicarbonate, dried with MgSO4 filtered and rotary evaporated to provide 23.7 g of a faintly yellow oil (94.8%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](O)=[O:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Cl:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31].C(N(CC)CC)C>ClCCl>[Cl:28][CH2:29][C:30]([NH:32][NH:33][C:19]([C:10]1[C:11]2[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)=[O:20])=[O:31]
Reactant: COc1cccc2c(C(=O)O)cn(CC3CCCCC3)c12
Reactant: NNC(=O)CCl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c(C(=O)NNC(=O)CCl)cn(CC3CCCCC3)c12
Reaction time: 3.5 h
Yield: 30.2 %

Procedure:
To a suspension of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (1.0 g, 3.48 mmol) in dichloromethane (20 ml) was added oxalyl chloride (0.6 ml, 6.96 mmol) and the reaction stirred for 3.5 h. The solvent was evaporated under reduced pressure and the resulting residue redissolved in dichloromethane (20 ml). To the solution was added chloroacetic acid hydrazide (1.3 g, 8.97 mmol) and triethylamine (2.9 ml, 20.9 mmol) and the reaction mixture stirred for 4 h and then left to stand overnight. The solvent was evaporated under reduced pressure and the resulting residue purified by flash column chromatography eluting with 50-100% (v/v) ethyl acetate in heptane to give 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid N′-(2-chloroacetyl)hydrazide (397 mg, 1.05 mmol).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.FC(F)(F)C(O)=O.[NH:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+]>CCO>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:19]3[CH2:24][CH2:23][CH:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)(=[O:35])=[O:34])[CH2:21][CH2:20]3)[O:3][C:4]=2[CH:10]=1
Reactant: Cc1ccc2nc(Cl)oc2c1
Reactant: O=S(=O)(Nc1ccccc1OC1CCNCC1)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1ccc2nc(N3CCC(Oc4ccccc4NS(=O)(=O)c4ccccn4)CC3)oc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Compound 21 is prepared using synthesis method 3: intermediate 2e (0.21 g, 1.25 mmol) and intermediate 6a are placed in 5 mL of EtOH in the presence of 0.3 g (3.58 mmol) of sodium bicarbonate, and the mixture is then stirred for 2 h at 80° C. After evaporation under reduced pressure the residue is taken up by water and extracted using AcOEt. After drying of the organic phases and reduction to dryness the residue obtained is triturated in a mixture of EtOH/Et2O and 0.32 g of solid is isolated by filtration (yield: 77%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.CON(C)[C:15]([C:17]1[O:21][CH:20]=[N:19][C:18]=1[CH3:22])=[O:16].[Cl-].[Na+]>C(OCC)C.C(O)C>[CH3:22][C:18]1[N:19]=[CH:20][O:21][C:17]=1[C:15]([C:2]1[CH:6]=[CH:5][O:4][CH:3]=1)=[O:16]
Reactant: CON(C)C(=O)c1ocnc1C
Reactant: Brc1ccoc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Cc1ncoc1C(=O)c1ccoc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
3-Bromofuran (2.5 g) in dry diethylether was stirred and cooled to -70° C. under an atmosphere of dry nitrogen and n-butyllithium (2.5M solution in hexane, 6.8 ml) was added dropwise. After 30 minutes, N-methoxy-N-methyl-4-methyl-5-oxazolecarboxamide (2.89 g) in dry diethylether was added dropwise. After a further 30 minutes the mixture was allowed to warm to room temperature. Ethanol (5 ml) was added followed by saturated aqueous sodium chloride. The mixture was extracted with dichloromethane and the material thus obtained was purified by flash chromatography to give the title compound. M.p. 82°-83.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]([C:11]2[N:12]([CH3:22])[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)O)[CH:6]=[CH:7][CH:8]=1)[CH3:2].CCN(CC)CC.CS([Cl:34])(=O)=O>C(Cl)Cl>[Cl:34][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[C:11]1[N:12]([CH3:22])[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1
Reactant: CCc1cccc(C(O)c2nc(-c3ccccc3)nn2C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cccc(C(Cl)c2nc(-c3ccccc3)nn2C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Intermediate 370.2 (350 mg, 1.2 mmol) was dissolved in CH2Cl2 (10 mL) and Et3N (0.50 mL, 3.6 mmol) and cooled to 0° C., MsCl (0.092 mL, 1.2 mmol) was added dropwise and the mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with H2O, brine, dried (Na2SO4) and concentrated to yield 370 mg of Intermediate 370.3 as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.15 (t, J=7.58 Hz, 3H) 2.56 (q, 2H) 3.71 (s, 3H) 6.30 (s, 1H) 7.09-7.16 (m, 1H) 7.21-7.29 (m, 2H) 7.28-7.43 (m, 3H) 7.99-8.05 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]1=[O:4].C(N(CC)CC)C.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[C:19]1([C:18]([NH:1][CH:2]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]2=[O:4])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC1CCCCNC1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1NCCCCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a stirred suspension of 125 g of α-amino-ε-caprolactam, 118 g of triethylamine and 600 ml of chloroform, 288 g of chlorotriphenylmethane was added under ice-cooling. The mixture was further stirred for an hour under the same conditions, followed by 2 hours' stirring at room temperature. Thus resulting precipitates were collected by filtration, washed thoroughly with acetone and dried to provide 330 g of α-triphenylmethylamino-ε-caprolactam, m.p. 240-241° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SC1C=CC=CC=1.BrCC1[C:40]2[C:35](=[CH:36][CH:37]=[C:38](C3C=CC=CC=3OC)[CH:39]=2)[NH:34]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21][NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSc1ccccc1)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenylsulfanylmethyl-1,2-dihydroquinoline 80 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 23 μL of thiophenol reacted to give 12 mg of the title compound as a foam.
Reaction SMILES: [H][H].[CH3:3][CH:4]([CH3:25])[CH2:5][O:6][C:7](=[O:24])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][S:18](=[O:22])(=[O:21])[CH2:19][CH:20]=2)=[C:11]([F:23])[CH:10]=1>>[CH3:3][CH:4]([CH3:25])[CH2:5][O:6][C:7](=[O:24])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]2)=[C:11]([F:23])[CH:10]=1
Reactant: CC(C)COC(=O)Nc1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Reactant: [H][H]
Product: CC(C)COC(=O)Nc1ccc(C2CCS(=O)(=O)CC2)c(F)c1

Procedure:
Following the general procedure of EXAMPLE 4 (and using knowledge known to those skilled in the art regarding reduction of unsaturated cyclic double bonds with hydrogen) and making non-critical variations but starting with 2-methylpropyl[4-(3,6-dihydro-1,1-ioxido-2H-thiopyran-4-yl)-3-fluorophenyl]carbamate (XV, EXAMPLE 12), the title compound is obtained, TLC Rf=0.73 (methanol/methylene chloride, 5/95); mp=181-182°;NMR (CDCl3) δ 7.36, 7.13, 7.01, 6.87, 3.95, 3.33-3.05, 2.42-2.33, 2.18, 2.01-1.94 and 0.96; CMR (CDCl3) δ 159.5, 153.5, 138.4, 127.3, 124.3, 114.2, 106.2, 71.5, 51.5, 34.4, 30.1, 27.9 and 18.9; MS (CI, NH3) m/z (relative intensity) 361 (100), 343 (30), 344 (10), 251(10), 243 (7) and 151(22).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=1[F:15])(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[CH:10][C:9]=1[F:15])(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)cc1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cccnc2)cc1F
Yield: 61 %

Procedure:
By carrying out the operation analogously to example 3, starting from 4-bromo-2-fluorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VI, and 3-pyridineboronic acid, the expected product is obtained in the form of a white solid with a yield of 61%.
Reaction SMILES: [Mg].[O:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.BrC1CC1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1C#N>C(O)(=O)C.O>[CH:5]1([C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])=[O:2])[CH2:3][CH2:4]1
Reactant: N#Cc1ccccc1F
Reactant: C1CCOC1
Agent: BrC1CC1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccccc1F)C1CC1
Yield: 29.4 %

Procedure:
To a stirred mixture of 10 parts of magnesium and 72 parts of tetrahydrofuran there were added portionwise 50 parts of bromocyclopropane, keeping the temperature below 10° C. At reflux temperature, there was added a solution of 50 parts of 2-fluorobenzenecarbonitrile in 72 parts of tetrahydrofuran. Stirring at reflux temperature was continued until completion of the reaction. The reaction mixture was cooled on ice (0°-5° C.) and decomposed with a mixture of ice, water and acetic acid. The product was extracted with trichloromethane (3×) and the combined extracts were washed with water (2×), dried, filtered and evaporated. The residue was distilled (1.33 Pa; 78°-105° C.) (2×), yielding 19.8 parts (29.4%) of cyclopropyl (2-fluorophenyl)methanone; bp. 100°-103° C. (at 1.3 Pa) (interm. 17).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C(OC1C=CC=C[N+]=1C)C1C=CC=CC=1.F[C:25](F)(F)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:34]([O:39][C@@H:40]1[C@@H:48]([CH2:49][CH2:50][OH:51])[C:47](=[O:52])[O:46][CH2:45][C@H:44]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C:43](=[O:61])[O:42][C@H:41]1[CH3:62])(=[O:38])[CH:35]([CH3:37])[CH3:36]>>[C:34]([O:39][C@@H:40]1[C@@H:48]([CH2:49][CH2:50][O:51][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:47](=[O:52])[O:46][CH2:45][C@H:44]([NH:53][C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])[C:43](=[O:61])[O:42][C@H:41]1[CH3:62])(=[O:38])[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCO
Reactant: FC(F)(F)c1ccccc1
Agent: C[n+]1ccccc1OCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOCc1ccccc1
Temperature: 83 °C
Yield: 36 %

Procedure:
A mixture of 2-benzyloxy-1-methylpyridinium triflate (255 mg, 0.73 mmol), α,α,α-trifluorotoluene (PhCF3, 0.75 mL), MgO (30 mg, 0.74 mmol), and (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-8-(2-hydroxyethyl)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (150 mg, 0.36 mmol) was heated at 83° C. for 1 day (d). The reaction mixture was cooled to room temperature (about 22° C.) and filtered through Celite®. The filtrate was concentrated under vacuum and purified by column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (66 mg, 36%): 1H NMR (300 MHz, CDCl3) δ 7.40-7.21 (m, 5H), 5.28 (m, 2H), 5.06 (t, J=10.0 Hz, 1H), 4.95-4.73 (m, 2H), 4.69 (s, 2H), 4.42 (s, 2H), 3.52-3.33 (m, 3H), 2.77 (td, J=11.5, 2.8 Hz, 1H), 2.60 (dq, J=14.0, 7.0 Hz, 1H), 1.42 (s, 9H), 1.26 (d, J=6.2 Hz, 3H), 1.19 (dd, J=7.0, 2.5 Hz, 6H); ESIMS m/z 530 ([M+Na]+).
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+].C(O)C>O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:21]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:20][C:2]=2[CH3:12])=[CH:6][CH:7]=1
Reactant: NC(=S)c1ccccc1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Yield: 68.2 %

Procedure:
A mixture of 2-bromo-4′-chloropropiophenone (45.0 g), thiobenzamide (24.7 g), sodium acetate (14.8 g) and ethanol (400 mL) was stirred with heating under reflux for 3 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 4-(4-chlorophenyl)-5-methyl-2-phenylthiazole (35.1 g, 68%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 90–91° C.
Reaction SMILES: [CH:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H][H]>C(O)C.[Pd]>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC=Cc1cc2ccccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCc1cc2ccccc2[nH]1

Procedure:
2-undec-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred until hydrogen consumption was completely stopped. The reaction mixture was filtered through celite. The solvent was evaporated to afford the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:4]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[NH:31][N:30]=2)[CH2:25][CH2:24]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][N:23]3[CH2:24][CH2:25][CH:26]([C:29]4[CH:33]=[C:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=5)[NH:31][N:30]=4)[CH2:27][CH2:28]3)=[CH:15][CH:16]=2)=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:4]=1
Reactant: COc1cc(-c2ccccc2)c(-c2ccc(C=O)cc2)nn1
Reactant: c1ccc(-c2cc(C3CCNCC3)n[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(c4cc(-c5ccccn5)[nH]n4)CC3)cc2)nn1
Reaction time: 0.25 h

Procedure:
4-(6-Methoxy-4-phenylpyridazin-3-yl)benzaldehyde (2-2; 80 mg, 0.27 mmol) was dissolved in dry dimethylformamide (2 mL) and 2-(3-piperidin-4-yl-1H-pyazol-5-yl)pyridine (1-4; 99 mg, 0.43 mmol) and acetic acid (0.14 mL, 2.3 mmol) were added. After stirring for 15 min., sodium triacetoxyborohydride (116 mg, 0.54 mmol) was added and the reaction mixture was stirred at ambient temperature for 12 hours. This reaction mixture was partially evaporated and the residue chromatographed on a silica gel column eluting with a 0-5% methanol/ethyl acetate sat'd with NH4OH. 3-methoxy-5-phenyl-6-(4-{[4-(5-pyridin-2-yl-1H-pyrazol-3-yl)piperidin-1-yl]methyl}phenyl)pyridazine (2-3) was obtained as a nearly pure viscous oil. NMR (CDCl3): δ8.60 (1H, d, J=5 Hz), 7.69-7.72 (2H, m), 7.23-7.35 (6H, m), 7.17 (2H, br d, J=7 Hz), 6.98 (1H, s), 6.61 (1H, s), 4.22 (3H, s), 3.52 (2H, s), 2.95 (2H, d, J=12 Hz), 2.72 (1H, m), 2.10 (2H, br t, J=1 Hz), 1.97 (2H, br d, J=12 Hz), 1.81 (2H, br q, J=11).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.C([Li])CCC.CN([CH:18]=[O:19])C.Cl>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:18]=[O:19])=[C:4]([F:9])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(F)cc(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 41.6 %

Procedure:
To a −78° C. solution of 1-chloro-3,5-difluoro-benzene (5.0 g, 34 mmol) in THF (70 mL) at was added n-butyl lithium (1.6 M in hexane, 19 mL). After 50 min, DMF (5.2 mL, 67 mmol) was added and the reaction was allowed to warm to rt over 18 h. After the addition of 0.5 M HCl (150 mL) and ether (150 mL), the aqueous layer was extracted with Et2O (3×). The combined organic extracts were dried and concentrated to provide a yellow solid. The crude material was dissolved in warm hexanes and a small amount of white solid formed upon cooling. This white solid was filtered off and discarded. The filtrate was concentrated to provide the title compound as a light yellow solid (2.5 g, 41%). 1H NMR (CDCl3): 10.3 (s, 1H), 7.06 (d, J=8.1 Hz, 2H).
Reaction SMILES: O.O.[Sn](Cl)Cl.CC1C=C(C([N:15]2[C:21]3[CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[CH:30]=[CH:31][CH:32]=[C:17]3[CH2:16]2)=O)C=CC=1C1C=CC=CC=1C(F)(F)F.CO>Cl>[CH3:29][O:28][C:26]([C:23]1[CH:24]=[CH:25][C:20]2[CH2:19][N:18]3[CH:30]=[CH:31][CH:32]=[C:17]3[CH2:16][NH:15][C:21]=2[CH:22]=1)=[O:27]
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)c1ccc(-c3ccccc3C(F)(F)F)c(C)c1)Cc1cccn1C2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2c(c1)NCc1cccn1C2
Temperature: 40 °C
Reaction time: 2 h
Yield: 426.9 %

Procedure:
To a stirred solution of tin(II) chloride dihydrate (23 g, 3.5 eq) in 2 N hydrochloric acid (106 mL) was added the [4-(2-formyl-1H-pyrrole-1-yl)methyl]-3-nitro]-benzoic acid methyl ester of Step A (8 g). Methanol (200 mL) was then added to this solution and the reaction mixture was stirred at 40° C. for 2 hours. The reaction was then cooled to room temperature, quenched by the addition of saturated aqueous sodium carbonate (20 mL) and filtered through Celite. The filter pad was washed with methanol and hot ethyl acetate. The filtrate and washings were combined, concentrated in vacuo to a volume of 300 mL and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a volume of 200 mL. Acetic acid (1 g) and 10% palladium on charcoal (1.5 g) were added and the mixture was hydrogenated overnight at atmospheric pressure. The reaction was then filtered through Celite and the solvent removed in vacuo to give a dark brown crystalline solid (16.4 g). This was dissolved in dichloromethane and filtered through a silica pad eluting with dichloromethane to provide the title compound as a yellow crystalline solid (11.7 g). Recrystallization from 1,2-dichloroethane yielded a yellow crystalline solid (5.7 g), m.p. 198–200° C.