Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[C:14]2[NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1.[CH3:22]C#N>[Pd](Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6]/[C:7](/[CH3:22])=[CH:8]/[C:9]1[C:14]2[NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CC#N
Reactant: COC(=O)CCCC#Cc1cccc2c1NCCNC2=O
Agent: Cl[Pd]Cl
Product: COC(=O)CCC/C(C)=C/c1cccc2c1NCCNC2=O
Temperature: 75 °C
Yield: 88 %

Procedure:
Palladium chloride (0.418 mmol, 0.074 g) was added to a solution of 6-(5-Oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-yl)-hex-5-ynoic acid methyl ester (8.36 mmol, 2.39 g) in 50 mL CH3CN. The reaction mixture was heated at 70-80° C. for 2.5 h. The solvent was removed and the residue was purified by flash silica gel chromatography eluting with a gradient of 0-5% MeOH in EtOAc to give 2.11 g (88%) of a yellow solid: mp=175-176° C.; 1H NMR (DMSO-d6) δ 1.86-1.98 (m, 2H), 2.43 (t, 2H, J=6.0 Hz), 2.75 (t, 2H, J=6.0 Hz), 3.52-3.54 (m, 2H), 3.57 (s, 3H), 4.21 (br s, 2H), 6.34 (s, 1H), 7.07 (t, 1H, J=6.0 Hz), 7.65 (d, 1H, J=6.0 Hz), 7.75 (d, 1H, J=6.0 Hz), 8.23 (t, 1H, J=6.0 Hz); HRMS calcd. for C16H18N2O3 (M+) 286.1317, found (M+) 286.1310; Anal. C16H18N2O3.0.25H2O) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[CH3:19][NH:20][CH3:21]>O1CCOCC1.C(O)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([N:20]([CH3:21])[CH3:19])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: CNC
Solvent: C1COCCO1
Solvent: CCO
Product: CN(C)c1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
0.07 g (0.000179 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 1.5 ml of dioxane and treated with 3.0 ml of 5.6M dimethylamine in ethanol. The mixture was stirred at room temperature for 2 hrs., the solvents were removed and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1 and 1:3. There was obtained 0.04 g (63%) of [4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-yl]-dimethylamine as yellowish crystals; m.p.: 170-172° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:12]=[CH:11]/[CH2:10][CH:9]([OH:13])[CH3:8])[CH:3]=1
Reactant: C=CCC(C)O
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(O)C/C=C/c1cccnc1
Temperature: 140 °C
Yield: 96.8 %

Procedure:
A mixture of 3-bromopyridine (7.50 g, 47.46 mmol), 4-penten-2-ol (4.90 g, 56.96 mmol), palladium(II) acetate (106 mg, 0.47 mmol), tri-o-tolylphosphine (575 mg, 1.89 mmol), triethylamine (28.4 mL, 204.11 mmol) and acetonitrile (25 mL) were heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with chloroform (3×200 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give a pale-yellow oil (7.50 g, 81.0 %).
Reaction SMILES: Br[CH:2]([CH2:7][O:8][CH3:9])[C:3]([O:5]C)=[O:4].[F:10][C:11]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].[Li+].[OH-].Cl>CN(C=O)C.C1COCC1.CO.O>[F:10][C:11]1([F:16])[CH2:15][CH2:14][N:13]([CH:2]([CH2:7][O:8][CH3:9])[C:3]([OH:5])=[O:4])[CH2:12]1
Reactant: COCC(Br)C(=O)OC
Reactant: FC1(F)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: COCC(C(=O)O)N1CCC(F)(F)C1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 2-bromo-3-methoxypropanoate (132.0 mg, 0.66 mmol), 3,3-difluoropyrrolidine (70.6 mg, 0.66 mmol) and K2CO3 (91.2 mg, 0.66 mmol) in DMF (2 mL) was heated at 90° C. for 3 hours. The mixture was subjected to standard aqueous workup to afford a residue which was dissolved in THF/MeOH/H2O (3:2:1, 5 mL). LiOH (6N, 3.3 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The solution was acidified to pH5 by addition of 6N HCl. All solvents were removed under vacuum to give a crude 2-(3,3-difluoropyrrolidin-1-yl)-3-methoxypropanoic acid (58) which was used without purification. MS m/z 210.1 (M+1)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:18]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=2[S:20][CH:21]=1>>[Cl:26][C:25]1[C:18]2[C:17]([CH2:16][N:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:14]=[C:6]3[C:4]([OH:3])=[O:5])=[CH:21][S:20][C:19]=2[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccc2scc(CBr)c12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: O=C(O)c1cc2ccccc2n1Cc1csc2cccc(Cl)c12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-4-chloro-benzo[b]thiophene (Li. 17) and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 340.0 ([M−H]−).
Reaction SMILES: [O:1]=[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH2:3]Br.[Cl:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1>O1CCOCC1>[O:1]=[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH2:3][N:26]1[CH2:25][CH2:24][N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH2:28][CH2:27]1
Reactant: O=C1CCc2cc(C(=O)CBr)ccc2N1
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: C1COCCO1
Product: O=C1CCc2cc(C(=O)CN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
3.0 6-(1-oxo-2-bromoethyl)-3,4-dihydrocarbostyril and 5.5 g of 4-(3-chlorophenyl)piperazine were dispersed in 50 ml of dioxane and the dispersion was stirred at 50° C. for 5 hours. Then the reaction mixture was cooled and the insoluble matters formed in the reaction mixture were removed and the dioxane mother liquor was concentrated under a reduced pressure to dryness. 80 Milliliter of ether was added to the dried matter to effect the crystallization. Crude crystals thus obtained were recrystallized from dioxane-water to obtain 3.1 g of 6-{1-oxo-2-[4-(3-chlorophenyl)-1-piperazinyl]ethyl}-3,4-dihydrocarbostyril in light yellow needle-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH:14]([CH3:16])[CH3:15])([CH2:20][CH2:21][CH2:22][Cl:23])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCCCBr
Reactant: COc1ccc(C(C#N)C(C)C)cc1OC
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(C#N)(CCCCl)C(C)C)cc1OC

Procedure:
Alternatively, one may prepare compounds of the invention via the procedures of Scheme III. In the first step, a derivative of formula 6a (see Scheme II) is alkylated with a 1,3-dihalopropane using a strong base in a suitable aprotic solvent to produce a derivative of formula 21 (step 1). For example, 2-(3,4-dimethoxyphenyl)-2-isopropylacetonitrile is treated with sodium amide in toluene and 1-bromo-3-chloropropane to produce 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-chloropropyl)acetonitrile (21).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][C:7]=1[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:76][C:77]1[CH:91]=[CH:90][C:89]([F:92])=[CH:88][C:78]=1[CH2:79][C:80]1[O:84][N:83]=[C:82]([C:85](O)=[O:86])[CH:81]=1>CO.CN(C=O)C>[C:15]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])=[C:6]2[CH2:5][CH2:4][NH:1][C:85]([C:82]1[CH:81]=[C:80]([CH2:79][C:78]2[CH:88]=[C:89]([F:92])[CH:90]=[CH:91][C:77]=2[F:76])[O:84][N:83]=1)=[O:86])#[N:16]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCN=[N+]=[N-]
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 70 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A mixture of 3-(2-azidoethyl)-2-(triethylsilyl)-1H-indole-5-carbonitrile (0.400 g; 1.23 mmol) and triphenylphosphine (0.523 g; 2.00 mmol) in methanol (10 mL) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in a mixture of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid intermediate 74 (0.318 g, 1.33 mmol), HATU (0.506 g; 1.33 mmol) and N,N diisopropylethylamine (0.614 mL; 3.33 mmol) in DMF (10 mL), was stirred at room temperature for 72 hours. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate; the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane) to yield 0.338 g (48%) of N-(2-(5-cyano-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a solid.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N:6]1([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:11][CH:10]=[CH:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)(=O)C.Cl.O>[N:6]1([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:7][CH:8]=[CH:9][CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(CCN2CC=CCC2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(CCN2CC=CCC2)cc1

Procedure:
2.5 g (11.1 mmol) of tin dichloride dihydrate are added at ambient temperature to a solution of 1.5 g (6.46 mmol) of 4-[2-(3,6-dihydro-2H-pyridin-1-yl)-ethyl]-nitrobenzene, prepared analogously to Example 254, in 7 ml of glacial acetic acid and 2.5 ml of concentrated hydrochloric acid. The mixture is heated for 4 hours to 100° C., then another 2.5 g (11.1 mmol) of tin dichloride dihydrate are added and the mixture is heated for 12 hours to 100° C. After cooling the solvent is eliminated in vacuo and the residue taken up in water. The mixture is made alkaline with 4N sodium hydroxide solution and extracted with dichloromethane. After removal of the solvent in vacuo the product is obtained as an oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:43])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:43][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[S:11]([N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:22])[F:23])[CH2:10][CH2:9]1)(=[O:12])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1S(=O)(=O)N1CCN(C(=O)C(F)(F)F)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(N1CCN(S(=O)(=O)c2cc(F)ccc2CBr)CC1)C(F)(F)F
Yield: 48.9 %

Procedure:
To a solution of Intermediate 2 (9.5 g, 27 mmol) in CCl4 (70 mL) was added AIBN (0.5 g, 3 mmol) and the mixture was brought to reflux. NBS (5.3 g, 30 mmol) was added and the mixture was refluxed for 4 h, cooled and filtered to remove solids. Concentration and purification by flash chromatography (0% to 25% EtOAc/hexane) gave the title compound as colorless oil (5.715 g, 49% yield). 1H NMR (300 MHz, CDCl3) δ: 7.65-7.60 (2H, m), 7.33-7.27 (1H, m), 4.83 (2H, s), 3.82-3.79 (2H, m), 3.74-3.71 (2H, m), 3.34-3.30 (4H, m). LCMS (M+H) calcd for C13H14BrF4N2O3S: 433.97; found: 435.11.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([Br:13])[C:10]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[N:9][C:8]=1[CH3:19])C.Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:13][C:11]1[C:10]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[N:9][C:8]([CH3:19])=[C:7]([CH:12]=1)[C:6]([OH:20])=[O:5]
Reactant: CCOC(=O)c1cc(Br)c(OCC2CC2)nc1C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(OCC2CC2)c(Br)cc1C(=O)O

Procedure:
Sodium hydroxide solution (1 N, 3.6 mL) was added to a solution of 5-bromo-6-cyclopropylmethoxy-2-methyl-nicotinic acid ethyl ester (0.58 g, 1.8 mmol) in THF (5.3 mL). The mixture was heated for 5 h to 70° C., cooled and neutralized with hydrochloric acid (1 N, 1.8 mL). After addition of citric acid the product precipitated and was purified by chromatography on silica gel with a dichloromethane:methanol gradient to yield the title compound as colorless solid, MS (ISP) 284.1 (M−H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]4[CH3:26])=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[CH:5][N:4]=1.Cl.[C:32]([O:36][C:37](=[O:41])[CH2:38][NH:39][CH3:40])([CH3:35])([CH3:34])[CH3:33].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O>[CH3:40][N:39]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]4[CH3:26])=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[CH:5][N:4]=1)[CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:41]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: CC1CCCCN1c1ccc(-c2nc(-c3ccnc(CCl)c3)no2)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccnc(CN(C)CC(=O)OC(C)(C)C)c3)no2)cc1C(F)(F)F

Procedure:
A solution of 3-(2-(chloromethyl)pyridin-4-yl)-5-(4-(2-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (0.065 g; 0.15 mmol), sarcosine t-butyl ester hydrochloride (0.031 g; 0.17 mmol) and K2CO3 (0.046 g; 0.34 mmol) in dioxan (2 mL) was heated at 70° C. for 96 hours. DCM and water were added to the reaction mixture. The mixture was poured through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with DCM/MeOH (100% DCM to 10% MeOH/DCM) to afford the title product. 1H NMR (CDCl3, 400 MHz) δ 8.75 (1H, dd, J=5.1, 0.9 Hz), 8.51 (1 H, d, J=2.1 Hz), 8.34 (1 H, dd, J=8.4, 2.1 Hz), 8.21 (1 H, s), 7.91 (1 H, dd, J=5.1, 1.7 Hz), 7.55 (1 H, d, J=8.4 Hz), 3.98 (2 H, s), 3.34 (2 H, s), 3.12-3.01 (2 H, m), 2.59 (1 H, td, J=11.0, 3.0 Hz), 2.48 (3 H, s), 1.87-1.40 (6 H, m), 1.51 (9 H, s), 0.86 (3 H, d, J=6.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C1C(=O)N([Br:23])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1.CC(=O)OCC>[Br:23][CH2:15][C:12]1[CH:13]=[CH:14][C:3]2[C:2]([Cl:1])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[S:5][C:4]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc2cc(C)ccc2c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2cc(CBr)ccc2c1Cl
Yield: 68.6 %

Procedure:
2.5 g (10.4 mmol) of 3-chloro-2-methoxycarbonyl-6-methylbenzo[b]thiophene (prepared according to J. Org. Chem. 41, 3399 (1976)) are boiled under reflux in 150 ml of chlorobenzene with 1.87 g of NBS and 420 mg of dibenzoyl peroxide for 5 h. After distilling off the chlorobenzene in a rotary evaporator, the residue obtained is taken up in EA, and the EA solution is washed with satd. NaHCO3 solution, 10% strength Na2SO3 solution and satd. NaCl solution, dried over Na2SO4 and concentrated. Chromatography on SiO2 using EA/Hep 1:20 yields 2.28 g of the title compound.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl.[OH-].[Na+]>[Sn](F)F.C1OCCOCCOCCOCCOCCOC1>[CH2:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH:12]1[O:14][CH2:13]1
Reactant: ClCC1CO1
Reactant: CC(C)CCCCCO
Agent: C1COCCOCCOCCOCCOCCO1
Agent: F[Sn]F
Agent: [Na+]
Product: CC(C)CCCCCOCC1CO1
Temperature: 125 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
A reactor equipped with stirrer, reflux condenser, dropping funnel and thermometer is charged with 130.23 g (1.0 mol) of isooctanol (mixture of isomers), 3.14 g (0.02 mol) of powdered tin difluoride and 5.28 g (0.02 mol) of 18-crown-6 (crown ether) and the charge is heated to 125° C. The, with efficient stirring, 86.26 ml (1.1 mol) of epichlorohydrin are added over 30 minutes. The reaction is allowed to continue for 20 hours, during which time the temperature rises to about 130° C. The reaction mixture is cooled to 55° C. and then, at this temperature, 88 g (1.1 mol) of a 50% aqueous solution of sodium hydroxide are added dropwise with efficient stirring over 30 minutes. After stirring for 6 hours at 55°-60° C. and cooling to room temperature, the suspension is filtered and the filtrate is washed with ethyl acetate. The phases are separated, and the aqueous phase is extracted with 2×100 ml of ethyl acetate. The combined organic phases are washed with as small an amount of 10% KH2PO4 solution as possible and then with water until neutral, dried over magnesium sulfate and filtered. The filtrate is freed from solvent on a rotary evaporator under vacuum (bath temperature 50° C.). Yield: 180.7 g (97% of theory) of colourless isooctanol glycidyl ether (mixture of isomers) for which the following analytical values are obtained: epoxy value: 4.71 eq/kg (88% of theory); total chlorine content: 2.7%; hydrolysable chlorine content: 122 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[C:7]2[NH:11][C:10](=[O:12])[N:9]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[C:8]2=[O:21])=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]2[N:11]([CH3:24])[C:10](=[O:12])[N:9]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[C:8]2=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1ccc(C=C2NC(=O)N(c3cc(F)ccc3F)C2=O)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc(C=C2C(=O)N(c3cc(F)ccc3F)C(=O)N2C)cc1
Yield: 186.3 %

Procedure:
The 5-(4-methylbenzylidene)-3-(2,5-difluorophenyl)-imidazolidine-2,4-dione (2.25 g, 7.16 mmol), cesium carbonate (1.22 g, 3.76 mmol) and methyl iodide (1.5 g, 3.76 mmol) were stirred together in DMF (20 mL) overnight. The solution was then diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine (saturated), dried (over MgSO4), filtered and concentrated to give 2.3 grams of 5-(4-methylbenzylidene)-3(2,5-difluorophenyl)-1-methylimidazolidine-2,4-dione, m.p. 136°-140° C. (compound 104 under Table B).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:16]=[CH:15][C:9]3=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]3[C:7](=[O:17])[C:6]=2[CH:18]=1.[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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:14][C:12]1[CH:13]=[C:8]2[C:7](=[O:17])[C:6]3[CH:18]=[C:2]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=[CH:4][C:5]=3[CH:16]=[CH:15][C:9]2=[N:10][CH:11]=1
Reactant: CS(N)(=O)=O
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CS(=O)(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 95 °C
Reaction time: 12 h

Procedure:
7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (5.00 g. 15.7 mmol), methyl sulfonamide (1.49 g, 15.7 mmol), Pd2(dba)3 (0.714 g, 0.78 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene (XANTPHOS) (1.36 g, 2.35 mmol) and cesium carbonate (15.3 g, 47.0 mmol) were added to a dry flask through which argon was purged. The flask was charged with 100 mL of dry dioxane and argon was bubbled through the solution for 10 minutes. The reaction mixture was heated to 95° C. and stirred under argon. After 12 hours, the reaction mixture was concentrated and dissolved in 2000 mL ethyl acetate and 1000 mL water. The organic layer was separated and washed with 500 mL of brine, dried with magnesium sulfate, filtered, and concentrated. The resultant solids were dissolved in 150 mL of a 3:1 mixture of hot dichloromethane/methanol and allowed to cool to ambient temperature with stirring. After 3 h, 150 mL of hexanes were added and the resulting slurry was allowed to stir. After 12 hours, an additional 50 mL hexanes were added. After 4 hours, the solids were filtered and dried to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19].O>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9]2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1nc2cc(Br)ccc2[nH]c1=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nc2cc(Br)c([N+](=O)[O-])cc2[nH]c1=O
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 7-bromo-3,4-dihydro-3-oxoquinoxaline-2-carboxylate (2.60 g, 8.75 mmol) in acetic acid (35 ml) was added dropwise fuming nitric acid (1.40 ml, 31.5 mmol) at 60° C., and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water (300 ml). The precipitate was collected by filtration, washed with water, and then air-dried to obtain 2.79 g of the title compound as yellow powder. Yield 93%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11](OC)=[N:10][S:9]2(=[O:19])=[O:18])[CH:5]=[CH:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C@@H:28]([NH2:30])[CH3:29]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:30][C@H:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])[CH3:29])=[N:10][S:9]2(=[O:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1ccccc1F
Reactant: COC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1
Solvent: ClCCl
Product: C[C@H](NC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1)c1ccccc1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 62.8 %

Procedure:
A solution of 209 mg of 5-(3-bromophenyl)-2-methoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 92 mg of (S)-1-(2-fluorophenyl)ethylamine in 5 ml of methylene chloride was stirred at room temperature for 1 hour and the conversion was checked by LCMS. Since no conversion had taken place yet, the solvent was concentrated by rotary evaporation and the residue was stirred at room temperature for 19 hours. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (170 mg) with a molecular weight of 469.4 g/mol (C20H22BrFN2O3S); MS (ESI): m/e=469 (M+H+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][NH:12][C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[C:11]1=[O:21]
Reactant: COC(=O)CCCCCCCBr
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccc(F)cc2)c1=O

Procedure:
The product is product as described in example 1 from 2.16 g of NaH (80% suspension in mineral oil), 18.3 g of 1-(4-Fluorophenyl)-5-phenyl-4-imidazolin-2-one, 150 cc. of DMF, 17.1 g of 8-bromocaprylic acid methyl ester and 2.16 g of NaJ.