Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:35][CH2:36]1)[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23]
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(Cl)c1
Temperature: 100 °C
Yield: 85.5 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (150 mg, 0.643 mmol), 3-chloro-N-cyclopropyl-4-(piperazin-1-yl)benzamide (216 mg, 0.772 mmol), (cyanomethyl)trimethylphosphonium iodide (250 mg, 1.029 mmol) and N,N-diisopropylethylamine (562 μl, 3.22 mmol) were suspended in Propiononitrile (Volume: 1931 μl) and heated in a closed vial at 100° C. for 4 h. The reaction mixture became a dark brown solution with a precipitate. It was cooled to room temperature and the precipitate was filtered off, washed with MeCN (2 mL) and suspended in MeCN (15 mL) with heating and sonication. It was then cooled to ambient temperature, the precipitate was filtered off, washed with MeCN (2 mL) and dried in vacuum to afford (S)-3-chloro-N-cyclopropyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (272.4 mg, 0.550 mmol, 86% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 8.39 (d, J=4.3 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.3, 2.0 Hz, 1H), 7.66 (s, 1H), 7.16 (d, J=8.6 Hz, 1H), 6.97 (d, J=1.8 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.84 (dd, J=11.4, 2.8 Hz, 1H), 3.38 (s, 2H), 3.02 (br. s., 4H), 2.77-2.88 (m, J=0.8 Hz, 1H), 2.60 (td, J=12.6, 2.5 Hz, 1H), 2.49-2.55 (m, J=3.5, 1.8, 1.8 Hz, 4H), 2.04 (br. d, J=12.6 Hz, 1H), 1.86-1.87 (m, OH), 1.84 (br. s., 1H), 1.64 (br. d, J=12.6 Hz, 1H), 1.32-1.57 (m, 3H), 0.61-0.72 (m, 2H), 0.51-0.61 (m, 2H); [M+H] calc'd for C26H31ClN6O2, 495; found, 495.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([F:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:31]1[CH2:36][CH2:35][CH:34]([CH2:37][OH:38])[CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C=O)C>[F:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:29]=[CH:30][C:2]([N:31]4[CH2:36][CH2:35][CH:34]([CH2:37][OH:38])[CH2:33][CH2:32]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(Cl)nc1
Reactant: OCC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(N2CCC(CO)CC2)nc1
Temperature: 140 °C
Yield: 38.4 %

Procedure:
A mixture of 6-chloro-N-[7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-yl-methyl]-nicotinamide (55 mg, 0.129 mmol), piperidin-4-yl methanol (22.3 mg, 0.194 mmol), triethylamine (0.036 mL, 258 mmol), and DMF (2 mL) was heated in a sealed tube at 140° C. for 5 hr. The crude material was purified by reverse phase chromatography (10% acetonitrile-water ramped to 60% acetonitrile-water). The product 4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid [7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-amide (25 mg, 38%) was isolated as a light yellow solid. MS calcd. for C28H26F2N4O3 [(M+H)+] 505.2, obsd. 505.1.
Reaction SMILES: N1C=CC(C2C=CC(=[O:13])NN=2)=CC=1.[N:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:21][CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1.BrBr>C(O)(=O)C>[OH2:13].[N:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(c2ccncc2)=NN1
Agent: BrBr
Agent: O=c1ccc(-c2ccncc2)n[nH]1
Solvent: CC(=O)O
Product: O
Reaction time: 6 h

Procedure:
B-11. 6-(4-Pyridinyl)-3(2H)-pyridazinone--A 2 liter 3-necked round bottom flask was equipped with a mechanical stirrer, a reflux condenser and a dropping funnel. Into the flask was placed 750 ml. of acetic acid and 16.3 g. of 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone. The mixture was heated on a steam bath for about 20 minutes and then a solution containing 50 ml. of bromine and 150 ml. of acetic acid was initially added dropwise. The first 50 ml. of solution was added over a period of about 20 minutes whereupon solid began precipitating. The rest of the bromine solution was then added all at once followed by the addition of 60 ml. more of bromine. Most of the solid redissolved and the resulting mixture was heated with stirring on a steam bath for 6 hours and then allowed to stand at room temperature over the weekend (about 65 hours). A small amount of crystalline solid was filtered off and the filtrate was heated in vacuo to remove the solvent. The remaining residue was treated with 500 ml. of boiling water whereupon most of the residue dissolved. Sodium bisulfite was added to the hot mixture until bubbling of sulphur dioxide ceased. The mixture was made weakly basic to litmus paper by adding sodium bicarbonate. The solid that separated was collected, recrystallized from isopropyl alcohol and dried in a vacuum oven over P2O5 at 45° C. for seventeen hours to produce 6.0 g of 6-(4-pyridinyl)-3(2H)-pyridazinone hydrate (6:1), m.p. 222°-224° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=1.[O:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:19][C:15]1([CH2:16][CH2:17][CH2:18][O:13][CH2:14]1)[CH:9]([CH3:10])[C:8]2=[O:11]
Reactant: O=C1CCCOC1
Reactant: CCC(=O)c1cc(Br)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC1C(=O)c2cc(Br)ccc2OC12CCCOC2
Reaction time: 8 h
Yield: 7.7 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxyphenyl)propan-1-one (5.7 g, 25 mol), dihydro-2H-pyran-3(4H)-one (5 g, 50 mmol) and pyrrolidine (3.4 g, 48 mmol) in methanol (80 mL) was stirred overnight. The reaction mixture was removed in vacuo, and H2O was added. The resulting solution was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-3-methyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (1.2 g, 16%). 1HNMR (CDCl3): 1.16-1.27 (m, 3H), 1.51-1.57 (m, 1H), 1.66-1.73 (m, 1H), 1.91-2.08 (m, 2H), 2.59-2.69 (m, 1H), 3.46-3.56 (m, 2H), 3.88-3.98 (m, 2H), 6.97 (m, 1H), 7.58 (m, 1H), 7.95 (s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([OH:11])[CH:9]=[CH2:10].C(N(CCCC)CCCC)CCC.CCCCCCCCCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([CH2:10][CH2:9][CH:8]=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Product: O=CCCc1ccccc1
Yield: 62 %

Procedure:
0.1 g Palladium acetate, 10.2 g iodobenzene, 4.4 g allyl alcohol, 9.3 g tributylamine were heated together with 20 ml diphenyl ether as solvent and 2 g tridecane as internal standard. After 45 minutes at 135° the iodobenzene was 91% reacted to produce 62% 3-phenylpropanal and 13% hydratropic aldehyde based on conversion.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](SC1C=CC=CC=1)=[CH:6][C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:32]=2)=[CH:18][CH:17]=1)[CH3:2].[Na].[ClH:61]>CO>[ClH:61].[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:29][N:30]=[N:31][N:32]=2)=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCc1cc2c(c(Sc3ccccc3)cc(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCc1cc2c(c(CC)n1)CCC(=O)N2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 0 °C

Procedure:
5,7-Diethyl-1-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2,3,4-tetrahydro-1,6-naphthyridin-2-one (A) (5.0 g) was added to a solution of sodium (2.05 g) in methanol (100 ml) and the solution was heated at reflux for 16 hours under an atmosphere of argon. The mixture was cooled to 0° C. and acidified with concentrated hydrochloric acid (20 ml). The precipitated solid was collected by filtration and recrystallised successively from isopropanol (60 ml), water (30 ml) and ethanol (10 ml) to give 5,7-diethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2,3,4-tetrahydro-1,6-naphthyridin-2-one hydrochloride (2.36 g), m.p. 260°-263° C. (decomposition); microanalysis, found: C, 65.6; H, 5.9; N, 17.8%; C26H26N6O.HCl requires: C, 65.7; H, 5.7; N, 17.7.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:1])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a mixture of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (6.0 g, 39 mmol), 4-fluorophenylboronic acid (16.3 g, 116 mmol), cupric acetate (14 g, 78 mmol) and pyridine (12 g, 0.156 mol) in DCM (300 mL) is added 4 Å molecular sieves (5 g). The reaction mixture is stirred at RT overnight open to air. After the solids are filtered and washed with water, the filtrate is extracted with DCM (100 mL). The organic layer is dried over MgSO4 and concentrated. The residue is purified by silica gel column chromatography eluting with PE:DCM (2:1 to 0:1) to give the product (9.6 g, 100% yield). MS (m/z): 248.0 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[CH:20][CH:21]=1>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@H:10]([O:12][C:17]1[C:16]([Br:15])=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncccc1Br
Reactant: C[C@@H](O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](COCc1ccccc1)Oc1ncccc1Br
Reaction time: 0.5 h

Procedure:
To a stirred solution of (R)-1-(benzyloxy)propan-2-ol (2.0 g, 12 mmol) in dry DMF (5 mL) was added NaH (1.5 g, 36 mmol) at 0 Celsius. The reaction mixture was then stirred for 30 min before adding 3-bromo-2-chloropyridine (2.3 g, 12 mmol) and stirring continued for another 4 h. The reaction was quenched by slow addition of water (10 mL) and the resultant mixture extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated to dryness, and the crude product purified by FCC to provide the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[NH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.F[P-](F)(F)(F)(F)F.[N:30]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:34]2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:34][NH:30][C:9](=[O:11])[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[NH:14][CH:13]=1
Reactant: O=C(O)CC(c1ccccc1)c1c[nH]c2cccnc12
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CNC(=O)CC(c1ccccc1)c1c[nH]c2cccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a RT solution of 3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propionic acid (150 mg, 0.56 mmol) in DMF (2 mL) was added MeNH2 (2 M in THF, 0.85 mL, 1.7 mmol) followed by benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (300 mg, 0.67 mmol) and TEA (0.12 mL, 0.85 mmol). The mixture was stirred at RT for 3 h, then a saturated solution of NaHCO3 was added, and the mixture was extracted 3 times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH), affording N-Methyl-3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propionamide.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>CC(C)=O>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][CH2:19][CH2:20][N+:21]([CH3:23])([CH3:22])[O-:38])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:6]=1
Reactant: CN(C)CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: C[N+](C)([O-])CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reaction time: 18 h
Yield: 48 %

Procedure:
To a solution of 2-(4-([1,1′-biphenyl]-4-ylmethoxy)phenyl)-N-(2-(dimethylamino)ethyl)acetamide (0.2 g) in acetone (30 ml) was added m-chloroperbenzoic acid (0.2 g) and stirring was continued at room temperature for 18 hr. The reaction mixture was concentrated. The residue was recrystallized twice from ethyl acetate to obtain the titled compound (0.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:12])[CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][C:30](Cl)=[O:31])[CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH2:19]([C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][C:30]([C:16]2[CH:15]=[CH:14][C:13]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:12])[CH2:10][CH3:11])=[CH:7][C:2]=3[F:1])=[CH:18][CH:17]=2)=[O:31])[CH2:27][CH2:28]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCC(C)Cc1ccc(-c2ccccc2)c(F)c1
Reactant: CCCC[C@H]1CC[C@H](CC(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@H](CC(=O)c2ccc(-c3ccc(CC(C)CC)cc3F)cc2)CC1
Temperature: 23 °C

Procedure:
A mixture of (+)-2-Fluoro-4(2-methylbutyl)biphenyl (10 gram) and trans-4-n-butylcyclohexylacetyl chloride (9.4 gram) in dichloromethane (20 ml) was added over 20 minutes to a cooled (5°-10° C.), stirred suspension of anhydrous aluminium chloride 6.1 gram) in dichloromethane (20 ml). After the addition the reaction mixture was allowed to warm to 23° C. and left stirring for 17 hours. The resulting solution was added to water (200 ml), extracted successively with petroleum spirit (bp. 60°-80°:180 ml +100 ml). The organic extract was then washed with water (200 ml), dried over anhydrous sodium sulphate (5 gram) and evaporated. The yellow crystalline residue (17.9 gram) was recrystallised from ethanol (35 ml) at 25° C. to give the product (14.8 gram; 85% yield). The product had mp=71.4°-72.1° C.; VirtualCH-I, (68.5°-68.8° C.). It was found to be 99.5 % pure by glc.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.[H-].[Na+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH2:14]Cl.O>CN(C)C=O>[Cl:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH2:14][C:13]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:12]=2[O:11][CH3:10])[CH:3]=1
Reactant: COc1ccc(OC)c(CCl)c1
Reactant: Oc1cc(Cl)sn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC)c(COc2cc(Cl)sn2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-chloro-3-hydroxyisothiazole (4.0 g, 0.03 mole) in 15 ml of dimethyl formamide was added dropwise to a stirred suspension of 60% NaH in oil (1.4 g, 0.035 mole) in 25 ml of dimethyl formamide at 0° C. under N2. After 15 minutes, a solution of 2,5-dimethoxybenzyl chloride (5.6 g, 0.03 mole) in 10 ml of dimethyl formamide was added dropwise and the mixture was stirred at room temperature for 24 hours. The dark reaction mixture was poured into water and extracted with diethyl ether. The diethyl ether extract was washed with water, dried (MgSO4), and concentrated. The residual white solid was purified by column chromatography on silica gel, using diethyl ether/hexane (1/1) as eluant. 5-Chloro-3-(2,5-dimethoxybenzyloxy)isothiazole was obtained as a white solid; 4.7 g; mp 52°-55° C.
Reaction SMILES: [I:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12]([NH2:14])=O)[C:3]=1[O:15][CH3:16].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[C:12]([C:4]1[C:3]([O:15][CH3:16])=[C:2]([I:1])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=1)#[N:14]
Reactant: COc1c(C(N)=O)cc2c(c1I)CCCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1c(C#N)cc2c(c1I)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a stirred, cooled (0° C.) suspension of 4-iodo-3-methoxy-5,6,7,8-tetrahydro-2-naphthalenecarboxamide (2.06 g, 6.22 mmol), triethylamine (2.77 mL, 19.91 mmol), and THF (40 mL) was added trifluoroacetic anhydride (1.23 mL, 8.71 mmol) dropwise via syringe. After addition, the ice bath was removed and the reaction stirred overnight at ambient temperature. The mixture was cooled to 0° C. and excess trifluoroacetic anhydride destroyed with H2O (2 mL). Ethyl acetate (50 mL) was added and the organic layer was washed with H2O (3×25 mL) and brine (25 mL), dried (NaSO4), filtered, concentrated in vacuo and purified by chromatography (100% DCM) to afford a light brown solid (1.96 g, 100%). 1H NMR (CDCl3) δ 7.29 (s, 1H), 4.0 (s, 3H), 2.74 (m, 4H), 1.76 (m, 4H), MS m/z 314 (M+H).
Reaction SMILES: ClC1SC(C[N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH2:15])[CH2:9]2)=CC=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20]Br>>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20][N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH2:15])[CH2:9]1
Reactant: NCC1CN(Cc2ccc(Cl)s2)CCO1
Reactant: Fc1ccc(CBr)cc1F
Product: NCC1CN(Cc2ccc(F)c(F)c2)CCO1

Procedure:
Intermediate 20 was prepared in an analogous manner to Intermediate 1 (Alternative Procedure) from Intermediate 19 and 3,4-difluorobenzyl bromide, followed by deprotection to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][O:15][C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])[CH2:9]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][O:15][C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])[CH2:9]1)=[S:39]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN(CC)C(=O)OCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)OCC1CN(C(=S)c2cc(OC)c(OC)c(OC)c2)CCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
1.7 g (3.66 mmol) of 4-(3′,4′,5′-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine, prepared according to the protocol described in step 8.1 of Example 8, are dissolved in 34 ml of THF and cooled in an ice bath. 1.7 g (1 equivalent) of Lawesson's reagent are added portionwise thereto. The solution is stirred at 0° C. for 30 minutes and then at room temperature overnight. The solvent is then removed under vacuum and the residue is rapidly purified on a column of silica gel (eluents: CH2Cl2 and then 1% MeOH in CH2Cl2) to give 1.1 g of 4-(3′,4′,5′-trimethoxythiobenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine in the form of a viscous yellow product. Yield: 62.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[Cl:11][C:12]1[C:13]([F:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([F:22])=[C:14]([S:18]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:10])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Reactant: CSc1ccc(Cl)cc1N
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1cccc(Cl)c1F
Yield: 61.6 %

Procedure:
Following General Procedure B, the title compound (386 mg, 62%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (297 mg, 1.71 mmol) and 3-chloro-2-fluoro-benzenesulfonyl chloride (392 mg, 1.71 mmol).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([N:16]1[CH2:24][C@H:23]([O:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH:36]=[CH2:37])[CH:34]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:27]=2)[CH2:22][C@H:17]1[C:18]([O:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:11][CH2:12][CH3:13])=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[CH2:54]([S:59](Cl)(=[O:61])=[O:60])[CH2:55][CH2:56][CH:57]=[CH2:58]>CCOC(C)=O.CN(C=O)C>[CH2:54]([S:59]([NH:8][C@H:9]([C:14]([N:16]1[CH2:24][C@H:23]([O:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH:36]=[CH2:37])[CH:34]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:27]=2)[CH2:22][C@H:17]1[C:18]([O:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:11][CH2:12][CH3:13])(=[O:61])=[O:60])[CH2:55][CH2:56][CH:57]=[CH2:58]
Reactant: C=CCCCS(=O)(=O)Cl
Reactant: C=Cc1ccc2nc(-c3ccccc3)cc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)[C@H](CCCC)NC(=O)OC(C)(C)C)C3)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCS(=O)(=O)N[C@@H](CCCC)C(=O)N1C[C@H](Oc2cc(-c3ccccc3)nc3ccc(C=C)cc23)C[C@H]1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
Compound 32 (115 mg, 0.196 mmol) was dissolved in EtOAc (5 mL) cooled to 0° C. and treated with anhydrous HCl gas for 10 min. The reaction mixture was then concentrated to give a solid. The solid was dissolved in DMF (2 mL) and DIPEA (0.1 mL, 0.57 mmol) was added. The reaction was cooled to 10° C. and 4-pentenesulfonyl chloride (35 mg, 0.20 mmol) (Culshaw, P. N.; Walton, J. C., J. Chem. Soc., Perkin Trans. 2 (1991), 8, p 1201) was then added. The mixture was stirred at RT for 30 min, quenched with aqueous NaHCO3 and extracted with EtOAc. The EtOAc extract was dried over NaSO4, filtered, concentrated to an oil and chromatographed on silica to give 33 (94 mg, 78% yield) as a foam. LRMS (M+1)+=620.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[N:3]=1.C([Li])CCC.CN([CH:20]=[O:21])C>C1COCC1>[CH:9]([O:8][C:4]1[N:3]=[C:2]([CH:20]=[O:21])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CN(C)C=O
Reactant: CC(C)Oc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(C=O)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
6-isopropoxypyridine-2-carbaldehyde was prepared in a manner similar to that described in D. L. Comins, M. O. Killpack, J. Org. Chem. 1990 55 69-73 for the methoxy analog. 2-bromo-6-isopropoxypyridine (1 g, 4.6 mmole) was dissolved in 10 ml dry THF under argon, cooled to −78° C. and treated with added 2.5 M n-Butyl lithium (1.9 mL, 4.8 mmole) keeping the temperature of the reaction below −65° C. After the reaction had stirred 45 min DMF (0.717 mL, 9.25 mmole) was added, again keeping temp below −60° C., the reaction was stirred for 15 min, then quenched with saturated bicarbonate solution. The layers were separated, the aqueous extracted with CHCl3, the organic layers dried over Na2SO4, filtered and evap carefully, and the residue chromatographed in 0-50% Ether/hexanes to give the product as an oil. LCMS (m+1)=165.2
Reaction SMILES: C(O[C:5]1([C:11]#[CH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)C.[CH3:13][NH2:14].CO>>[C:11]([C:5]1([NH:14][CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)#[CH:12]
Reactant: CN
Reactant: C#CC1(OC(C)=O)CCCCC1
Solvent: CO
Product: C#CC1(NC)CCCCC1

Procedure:
This was synthesized in the same manner as in Production Example 18 except that 1-acetoxy-1-ethynylcyclohexane (Production Example 17) and a 40% methylamine/methanol solution were used.