Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([C:21]([OH:23])=O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[CH3:25][O:26][C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([C:21]([N:31]3[CH2:30][CH2:29][C:28]4[C:33](=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:27]=4[O:26][CH3:25])[CH2:32]3)=[O:23])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: CC(=O)Nc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(NC(C)=O)cc3)nc3ccccc13)C2
Yield: 7 %

Procedure:
Reaction of 2-(4-acetamidophenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 63 (7% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 2.73 and 2.98 (2t, 2H), 3.49 and 4.02 (2t, 2H), 3.68-3.81 (4s, 6H), 4.41 and 4.93 (2s, 2H), 6.63 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.65-7.80 (m, 3H), 7.84-7.95 (2d, 1H), 8.03-8.13 (m, 2H), 8.41-8.49 (m, 2H), 10.23 (s, 1H); MS (ESI) m/z 483 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([OH:19])=O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].ClCCl.S(Cl)(Cl)=O.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>CCCCCCC.CN(C)C=O>[CH2:27]([N:29]([CH2:30][CH3:31])[C:17](=[O:19])[CH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)[CH3:28]
Reactant: CC(C)(C)c1cc(CC(=O)O)cc(C(C)(C)C)c1O
Reactant: CCNCC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCCCCCC
Product: CCN(CC)C(=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
7.92 g (0.03 Mol) of (3,5-di-tert-butyl-4-hydroxyphenyl)acetic acid are stirred overnight in 40 ml of heptane and 20 ml of dichloromethane with 4 ml of thionyl chloride and 4 drops of N,N-dimethylformamide. An additional 90 ml of heptane are added and then 90 ml of solvent and the excess amount of thionyl chloride are distilled off. The residual solution is cooled to room temperature and then 7.5 ml (0.072 mol) of diethylamine are added dropwise. The mixture is stirred one hour, then washed with water, 5% hydrochloric acid and water again. The solvent is evaporated in vacuo, and the residue is crystallized twice from acetonitrile to give 6.5 g of the intermediate product as colorless needles, melting at 111°-113° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.Cl[C:18]1[N:23]=[C:22]([CH2:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:21]=[C:20]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][C@@H:36]2[CH3:41])[N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.O.C(O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:34][C:31]1[CH:32]=[CH:33][C:28]([S:25]([CH2:24][C:22]2[CH:21]=[C:20]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C@@H:36]3[CH3:41])[N:19]=[C:18]([C:9]3[CH:10]=[CH:11][C:12]([NH2:13])=[CH:14][CH:15]=3)[N:23]=2)(=[O:27])=[O:26])=[CH:29][CH:30]=1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(F)cc2)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(N)cc2)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (136 mg, 0.19 mmol) was added to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.107 g, 5.05 mmol) and 2-chloro-4-[(4-fluorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1.50 g, 3.89 mmol) and sodium carbonate (5 mL, 10.00 mmol) in 18% DMF in DME:water:ethanol (7:3:2) (20 mL). The resulting solution was stirred at 90° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with water (2×20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 60% ethyl acetate in isohexane, to give the desired material as a cream solid (1.670 g).
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1.C(O)(=O)C.O.[Zn]>[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]([OH:31])=[O:4])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)c1ccccc1C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10452.2 %

Procedure:
--2,2,2-Trichloroethyl-2-[(z,z,z) octadeca-6,9,12-trienoyl]benzoate (15 1 g) was dissolved in a mixture of tetrahydrofuran (750 ml), acetic acid (675 ml) and water (75 ml). Zinc dust (150 g) was added. The mixture was stirred at room temperature under nitrogen for 1.5 hours and then allowed to stand for twenty hours. Excess zinc and zinc salts were filtered off through Celite washing the filter pad with tetrahydrofuran (100 ml) and the flitrate was evaporated at 25° C./10 mmHg to remove the tetrahydrofuran. The acetic acid and water was then removed at 25° C./0.5 mmHg. Higher temperatures tend to decompose the product. The resulting oil was dissolved in diethyl ether (1000 ml) and the resulting solution was washed with water (4×200 ml). After drying (Na2SO4), the ether was evaporated (25° C./10 mmHg) to give a pale yellow oil which was subjected to a dry column (Packing: Matrex silica (1 Kg), pore size 60A, particle size 35-70μm, Fraction size: 1000 ml). The requisite tractions were collected, the solvent evaporated as before, the last traces being removed at 25° C./0.1 mmHg to give 2-[(z,z,z) octadeca-6,9,12,-trienoyl]benzoic acid, (77.8 g, 68%) as a pale orange oil which solidified to a wax in the refrigerator.
Reaction SMILES: [O:1]1[CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[O:4][CH2:3][CH2:2]1.[C:10]([C:12]1[CH:13]=[C:14]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[C:27]([O:30][CH2:31][CH2:32][CH2:33]Cl)[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[F:18])#[CH:11].C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:10]([C:12]1[CH:13]=[C:14]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[C:27]([O:30][CH2:31][CH2:32][CH2:33][N:8]4[CH2:7][CH:6]5[O:1][CH2:2][CH2:3][O:4][CH:5]5[CH2:9]4)[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[F:18])#[CH:11]
Reactant: C#Cc1cc(Nc2ncnc3cc(OC)c(OCCCCl)cc23)ccc1F
Reactant: C1COC2CNCC2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C#Cc1cc(Nc2ncnc3cc(OC)c(OCCCN4CC5OCCOC5C4)cc23)ccc1F
Temperature: 70 °C
Yield: 43.7 %

Procedure:
A mixture of hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (0.40 g, 3.01 mmol, 1.0 eq), N-(3-ethynyl-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (0.87 g, 2.25 mmol, 0.75 eq), anhydrous K2CO3 (1.24 g, 9.0 mmol, 3.0 eq) and tetrabutylammonium iodide (55 mg, 0.15 mmol, 0.05 eq) in DMF (10 mL) was heated at 70° C. for 11 h. The reaction mixture was cooled to room temperature and quenched with water (10 mL). The resulted mixture was diluted with EtOAc (20 mL) and the organic phase was separated from the mixture. The water phase was extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/CH3OH) to give the crude product, which was recrystallized from CH2Cl2/PE to afford the title compound as a pale yellow solid (0.47 g, 44.00%), HPLC: 96.10%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 480.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.05 (2H, m), 2.68 (2H, m), 2.72 (2H, m), 2.95 (2H, dd, J=3.6, 10.0 Hz), 3.06 (1H, br s), 3.56 (2H, m), 3.76 (2H, m), 3.95 (3H, s), 4.08 (2H, m), 4.15 (2H, t, J=8.4 Hz), 7.20 (1H, t, J=8.8 Hz), 8.07-8.15 (2H, m), 8.43 (1H, s), 8.64 (1H, s) ppm.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH:24]=[O:25].C(=O)(O)[O-].[Na+]>CCCCCC.O.O1CCCC1.CCCCCCC>[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH:24]([OH:25])[C:18]1[C:17]([F:20])=[CH:16][N:15]=[C:14]([CH:10]2[O:11][CH2:12][CH2:13][O:9]2)[CH:19]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Fc1ccc(C2OCCO2)nc1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Solvent: CCCCCCC
Product: OC(c1cc(F)ccc1F)c1cc(C2OCCO2)ncc1F
Reaction time: 2 h
Yield: 196.8 %

Procedure:
Lithium diisopropylamide (a 1.8M heptane solution, 12 ml, 21.5 mmol) was added to a tetrahydrofuran (100 ml) solution of 2-(1,3-dioxolan-2-yl)-5-fluoropyridine (690 mg, 4.08 mmol) at −75° C. under an argon atmosphere. The resulting mixture was stirred for 2 hours. To the reaction mixture was added dropwise 2,5-difluorobenzaldehyde (2.1 ml, 19.5 mmol), followed by stirring for 2.5 hours. To the reaction mixture were added water and a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with diethyl ether. The extract was washed with brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=3:1) eluate was concentrated under reduced pressure to give the title compound (2.53 g, 8.03 mmol, 73%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[N:6][CH:7]=1.C[O-].[Na+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([NH:8][C:4]4[CH:5]=[N:6][CH:7]=[C:2]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:3]=4)[CH2:10][CH2:11]3)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: Clc1ccc2c(NC3CCC(Nc4cncc(Br)c4)CC3)ccnc2c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[O-]
Solvent: C1CCOC1
Product: Clc1ccc2c(NC3CCC(Nc4cncc(-c5ccccc5)c4)CC3)ccnc2c1

Procedure:
A mixture of example 370 (30 mg, 0.07 mmol), Pd(dppf)Cl2 (3 mg), sodium methoxide (7.5 mg, 0.14 mmol) and phenylboronic acid (9.7 mg, 0.07 mmol) in 1 ml THF was heated for 15 Hours at 65° C., concentrated. Residue was purified with high throughput reverse phase HPLC system to provide the desired compound. MS (ESI(+)Q1MS m/z 429 (M+H)+); 1 H NMR (300 MHz, DMSO-D6) δ ppm 1.75-2.01 (m, 8 H) 3.84 (m, 1 H) 4.04 (m, 1 H) 7.52-7.60 (m, 3 H) 7.74-7.84 (m, 4 H) 7.94 (d, J=2.03 Hz, 1 H) 8.13 (d, J=2.37 Hz, 1 H) 8.33 (s, 1 H) 8.58 (d, J=7.12 Hz, 1 H) 8.73 (d, J=9.15 Hz, 1 H) 8.94 (d, J=6.78 Hz, 1 H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25].C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.C(O)CCC>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccccc1I
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: COc1ccccc1NCc1ccccc1
Yield: 69.9 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μl, 1.20 mmol), 2-iodoanisole (130 μl 1.00 mmol), ethylene glycol (111 μl, 2.00 mmol) and 1-butanol (1.0 mL) at 100° C. Column chromatography using a solvent mixture (hexane/ethyl acetate=10/1, Rƒ=0.4) afforded N-(2-methoxyphenyl)benzylamine (149 mg, 70% isolated yield) as colorless liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH2:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)[CH3:2].[C:18]1([C:24](=NCC(OCC)=O)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.BrCC1C=CC(C#N)=C(F)C=1.C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC#N>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([N:16]=[C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:17])=[CH:8][C:9]=1[F:15])#[N:14]
Reactant: CCOC(=O)C(N)Cc1ccc(C#N)c(F)c1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#Cc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(C#N)c(F)c1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
2-Amino-3-(4-cyano-3-fluoro-phenyl)-propionic acid ethyl ester. In a 1.0 L flask, a mixture of ethyl 2-(diphenylmethyleneamino)acetate (267 g, 1.0 mol) and the catalyst Bu4NBr (32 g, 0.1 mol) in CH3CN (1000 mL) was treated sequentially with 4-(bromomethyl)-2-fluorobenzonitrile (232 g) and K2CO3 (276 g, 2 mol). The mixture was then stirred for 24 hrs at room temperature. The mixture was filtered and concentrated to give ethyl 3-(4-cyano-3-fluorophenyl)-2-(diphenylmethyleneamino)propanoate (400 g, 100% yield) as a yellow oil. The crude was treated with 2M HCl (600 mL) in THF (400 mL) overnight, and then extracted with EtOAc (3×200 mL). The water phase was basified with a saturated Na2CO3 to pH 10 and extracted with EtOAc (3×200 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield the title compound (153 g, yield 65% for the last three steps). The crude was not further purified and used straightly in next step.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.C(OC(C1N=CC2C(C=1O)=CC=C(OC1C=CC(OC)=CC=1)C=2)=O)CCC.P(Br)(Br)([Br:56])=O>C(#N)C>[Br:56][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([OH:5])=[O:7])[N:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2cc(Sc3ccccc3)ccc2c1O
Agent: CCCCOC(=O)c1ncc2cc(Oc3ccc(OC)cc3)ccc2c1O
Solvent: CC#N
Product: O=C(O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reaction time: 8 h

Procedure:
1,4-Dihydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (Example D-1 d) Compound A) (29.0 g) and phosphorous oxybromide (67.5 g) in 600 ml anhydrous acetonitrile was stirred at reflux for 4 hours. After cooling the reaction mixture was concentrated and saturated sodium bicarbonate solution and ethyl acetate were added to the residue and stirred overnight. Precipitate that formed between layers was collected and washed with water to give the title compound (10.2 g). MS-(+)-ion M+1=376.0, 378.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.C[CH2:14][N:15](CC)[CH2:16]C.CNC.C1COCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:15]([CH3:16])[CH3:14])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: CCN(CC)CC
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To 4-bromo-2-fluorobenzene-1-sulfonyl chloride (1.0 g, 3.7 mmol) and Et3N (1.5 mL, 11 mmol) in dichloromethane (10 mL) was added a solution of dimethylamine 2.0 M in THF (2.2 mL, 4.4 mmol). The reaction was stirred at ambient temperature for 30 minutes. The reaction was washed with 10 mL of 1N aqueous HCl and 10 mL of brine. Organics were dried over Na2SO4 and evaporated to dryness. Crude product was purified by chromatography on silica gel (eluting with 0-25% ethyl acetate in hexanes) to afford 4-bromo-2-fluoro-N,N-dimethylbenzenesulfonamide (780 mg, 75%).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.I[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.Br[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N:42]=1>C1COCC1.CC(N(C)C)=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:42][CH:43]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cn2)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
Zn dust (225 mg, 3.5 mmol) was stirred in THF (1 mL) under Ar and 1,2-dibromoethane (50 μL) was added at room temperature. The mixture was heated to 65° C. for 3 min and allowed to cool to room temperature before trimethylsilyl chloride (70 μL) was added and the mixture was stirred at room temperature for 30 min. A solution of 4-iodo-N-Boc-piperidine (840 mg, 2.7 mmol) in THF (1.5 mL) was slowly added and the reaction mixture was stirred at 40° C. for 2 h. Pd2(dba)3 (22 mg, 0.024 mmol) and P(2-furyl)3 (23 mg, 0.10 mmol) were mixed in THF (0.5 mL), the mixture stirred at room temperature for 10 min and then added to the organozink reagent solution, followed by 2-bromo-5-chloro-pyridine (624 mg, 3.24 mmol) in THF (1 mL) and DMA (4 mL). The reaction mixture was heated at 80° C. for 3 h, allowed to cool to room temperature and then filtered through Celite and diluted with EtOAc. The filtrate was washed with saturated aqueous NaHCO3 and brine, dried Na2SO4 and concentrated. Purification on SiO2 eluting with heptane/EtOAc 95:5 to 2:1 gave tert-butyl 4-(5-chloropyridin-2-yl)piperidine-1-carboxylate as an yellow oil (128 mg, 16%). The oil was dissolved in THF (1.5 mL) and conc HCl (1.5 mL) and stirred at RT for 30 min. Concentration several times with toluene and EtOH gave the title compound (89 mg, 89%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.[CH3:24][N:25]1[C:29]([C:30](O)=[O:31])=[CH:28][N:27]=[CH:26]1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:20][C:16]1([CH3:21])[NH:15][C:14](=[O:22])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([NH:1][C:30]([C:29]5[N:25]([CH3:24])[CH:26]=[N:27][CH:28]=5)=[O:31])[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1
Reactant: Cn1cncc1C(=O)O
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(N)cc43)sc2C(=O)N1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cncc1C(=O)Nc1ccc2c(c1)N(c1nc3c(s1)C(=O)NC(C)(C)C3)CCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.5 %

Procedure:
To a stirred solution of Example 42 (0.025 g, 0.08 mmol) in DCM (1 mL) were added 1-methylimidazol-5-ylcarboxylic acid (0.013 g, 0.10 mmol), DIPEA (0.02 mL, 0.10 mmol), EDC (0.030 g, 0.16 mmol) and HOBT (0.05 g, 0.04 mmol). The reaction mixture was stirred at r.t. for 18 h, then concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.01 g, 29%) as a yellow oil. δH (CDCl3) 9.25 (1H, s), 8.46-8.43 (1H, m), 7.33 (1H, dd, J 8.9 and 2.4 Hz), 7.07 (1H, d, J 0.9 Hz), 7.02 (1H, d, J 0.8 Hz), 6.94 (1H, d, J 8.9 Hz), 5.56 (1H, br. s), 4.36-4.29 (2H, m), 4.16-4.09 (2H, m), 4.11 (3H, s), 2.90 (2H, s), 1.40 (6H, s). LCMS (ES+) 439.4 (M+H)+, RT 2.69 minutes (Method 1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][C:28](C)([CH3:30])[CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(CC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2c(C(CC(C)C)C(=O)O)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 60 °C
Yield: 75.4 %

Procedure:
To a solution of methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-methyl-4-methylpentanoate (0.114 g; 0.27 mmol) in methanol (2.7 mL) and water (0.27 mL) was added a solution of sodium hydroxide 10 N (0.27 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.083 g (76%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15]C)=[CH:10][C:9]=2[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]([O-])([O-:26])[O:24][CH3:25].[Cl-].[Cl-].[Cl-].[Cl-].C=C.BrBr>[Zn].O.CO>[CH3:25][O:24][C:23]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:9]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:10]=1)[CH3:15])=[O:26]
Reactant: CCC(=O)c1ccc(Sc2ccccc2)c(CC(=O)OC)c1
Reactant: COC([O-])[O-]
Agent: BrBr
Agent: C=C
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1cc(C(C)C(=O)OC)ccc1Sc1ccccc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a mixture of 157.1 g (0.50 mol.) of methyl 2-phenylthio-5-propionylphenylacetate, 133.2 g (1.255 mol) of methyl orthoformate, 200 ml of methanol and 100 ml of ethylene tetrachloride was added 2.62 g (0.040 gram atom) of zinc powder, and the mixture was heated under stirring to a temperature of 40° to 45° C. To the solution was dropped 83.6 g (0.525 mol.) of bromine for 1 hour under stirring, and then the temperature was maintained at a temperature within 42° C. and 45° C. for 30 minutes. The reaction mixture was gradually heated to raise the external temperature to 120° C., under distilling off materials having a low boiling point (b.p. 32° to 65° C.). When almost all materials having a low boiling point were distilled off and the internal temperature almost lowered to approx. 80° C., to the reaction mixture was added 100 ml of ethylene tetrachloride. Then, the mixture was again heated to raise the internal temperature to a temperature of higher than 100° C., under distilling off remaining materials having a low boiling point. After the internal temperature was kept at a temperature of 100° to 110° C. for 1 hour, the reaction mixture was cooled to approx. 50° C. To the cooled reaction mixture was added 500 ml of water, and the mixture was stirred for a while. Insoluble materials were filtered off over a Celite and then was washed with three portions of 50 ml of 1,2-dichloroethane. The organic layer was separated from the filtrate and the washings. The aqueous layer was extracted with 150 ml of 1,2-dichloroethane. The extract was combined with the above-obtained organic layer and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was distilled under reduced pressure to obtain 141 g of the desired product as a yellow oil (yield 82%).