Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][NH:1][C:2]3([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]3)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCC(N)(CO)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CO)(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 10 mL of a dichloromethane solution containing 0.39 g of tert-butyl 4-amino-4-(hydroxymethyl)piperidine-1-carboxylate, 0.25 g of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 86 μL of acetic acid were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with 0.48 g of sodium triacetoxyborohydride, and stirred at the same temperature for 2 hours. Thereto were added chloroform and an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [chloroform:gradient elution of methanol=100:0 to 80:20] to obtain 91 mg of a colorless oily substance, tert-butyl 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-4-(hydroxymethyl)piperidine-1-carboxylate.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23](/[C:20]1[CH:21]=[CH:22][C:17]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:19]=1)=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1(C)OB(c2ccc(/C=C/c3ccccc3)cc2)OC1(C)C
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(/C=C/c2ccccc2)cc1

Procedure:
Pd(dppf)Cl2 (0.141 g) was added to a mixture of (E)-1-bromo-4-styrylbenzene (1.00 g), potassium acetate (1.14 g) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.03 g) in DMF (dry) (10 mL). The mixture was stirred at 90° C. under nitrogen for 12 hr. The insoluble solid was removed by filtration through Celite pad (eluted with EtOAc). The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate. Activated-carbon powder and silica-gel were added and the mixture was shaken, sonicated and filtered through silica-gel/Celite pad (eluted with EtOAc). The filtrate was concentrated in vacuo to give the crude (E)-4,4,5,5-tetramethyl-2-(4-styrylphenyl)-1,3,2-dioxaborolane. Tetrakis(triphenylphosphine)palladium(0) (0.186 g) was added to a suspension of 3-bromopyridin-2-amine (0.557 g), the prepared (E)-4,4,5,5-tetramethyl-2-(4-styrylphenyl)-1,3,2-dioxaborolane and sodium carbonate (1.02 g) in DME (20 mL) and water (4 mL) and the mixture was stirred at 80° C. under nitrogen overnight. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (532 mg) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][N:5]2[C:6](=[O:9])[C:7]=1[Cl:8].CN1NCCCCCCC(C2CCCCCCCCC=2)=N1.Br[CH2:36][N:37]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[S:38]1(=[O:40])=[O:39].O>CN(C=O)C>[Cl:8][C:7]1[C:6](=[O:9])[N:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[O:1][CH2:36][N:37]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[S:38]1(=[O:39])=[O:40]
Reactant: O=C1c2ccccc2S(=O)(=O)N1CBr
Reactant: O=c1c(Cl)c(O)nc2ccccn12
Agent: CN1N=C(C2=CCCCCCCCC2)CCCCCCN1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1COc1nc2ccccn2c(=O)c1Cl
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a mixture of 2-hydroxy-3-chloropyrido[1,2-a]pyrimidine-4-one (0.324 g), and methyltriazabicyclodecene (0.24 mL) in DMF (15 mL) was added 2-bromomethylsaccharin (0.414 g). The mixture was stirred overnight, poured into water and the precipitate which formed was collected by filtration and recrystallized from DMF to afford 0.371 g (65%) of 2-[3-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-yl]oxymethyl-saccharin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([CH3:16])[C:5]2=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.CCOC(C)=O>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=3)[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([CH3:16])[C:5]2=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1cncc2[nH]c3c(N)cc(Cl)cc3c12
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cncc2[nH]c3c(NC(=O)c4cccnc4)cc(Cl)cc3c12
Reaction time: 12 h
Yield: 8.1 %

Procedure:
A solution of 6-chloro-4-methyl-9H-β-carbolin-8-ylamine (43 mg, 0.19 mmol) in pyridine (4 ml) was stirred at RT under an argon atmosphere. Nicotinoyl chloride hydrochloride (40 mg, 0.22 mmol) was added thereto and the reaction mixture was stirred for 12 hr. The solution was diluted with H2O (5 ml) and poured into a separatory funnel containing H2O (5 ml) and EtOAc (25 ml). The reaction mixture was shaken and the layers were separated. The aqueous layer was extracted with EtOAc (2×25 ml). The combined organic layers were washed with a saturated sodium bicarbonate solution (15 ml), followed by brine, then dried over MgSO4, filtered, and concentrated to yield N-(6-chloro-4-methyl-9H-β-carbolin-8-yl)-nicotinamide (5.2 mg) as an orange viscous oil. 1H-NMR (300 MHz, DMSO-d6): δ 11.67 (s, 1); 10.70 (s, 1); 9.27 (s, 1); 8.83 (s, 2); 8.45 (s, 1); 8.20-8.12 (m, 2); 7.83 (s, 1); 7.66 (s, 1); 2.80 (s, 3). NH4OAc standard conditions. DAD Rf=1.92 min. M+H=337.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:15]=[C:16]3[C:22]4[CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=[CH:26][C:21]=4[O:20][CH2:19][CH2:18][N:17]3[CH:30]=2)=[N:12][CH:11]=[N:10]1.[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:15]=[C:16]3[C:22]4[CH:23]=[C:24]([C:27]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[O:28])[CH:25]=[CH:26][C:21]=4[O:20][CH2:19][CH2:18][N:17]3[CH:30]=2)=[N:12][CH:11]=[N:10]1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccc(F)cc3F)cn1CCO2
Product: CC(C)(CO)NC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccc(F)cc3F)cn1CCO2

Procedure:
Following the procedure for 109, 2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 2-amino-2-methylpropan-1-ol gave 137. MS: (ESI+)=481.1. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=2.2 Hz, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.73-7.65 (m, 1H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.51-7.42 (m, 1H), 7.39 (s, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 4.96 (t, J=6.0 Hz, 1H), 4.49 (d, J=6.1 Hz, 4H), 3.52 (d, J=5.8 Hz, 2H), 1.35 (s, 6H)
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[N:26]1([C:31]2[CH:32]=[C:33]([CH2:37][NH2:38])[CH:34]=[CH:35][CH:36]=2)[CH:30]=[CH:29][N:28]=[CH:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:38][CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[CH:32]=3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NCc1cccc(-n2ccnc2)c1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCc3cccc(-n4ccnc4)c3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and (3-(1H-imidazol-1-yl)phenyl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[CH3:9][SH:10].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[N:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:3]=1[CH2:1][CH2:2][SH:10].[CH3:9][S:10][CH2:2][CH2:1][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: CS
Reactant: C=Cc1cnccn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CSCCc1cnccn1
Product: SCCc1cnccn1

Procedure:
g. 2-Pyrazinyl-ethyl mercaptan was prepared by reacting vinylpyrazine [obtained by the method described in J.Org.Chem. 27, 1363 (1962)] and hydrolizing the resulting thiolic acid ester according to the method described in J.Org.Chem. 22, 980 (1957). The product has a b.p. of 56.5°-60° C./0.003 mm. Hg. (1) h. 2-Pyrazinyl-ethyl methyl sulfide was prepared by reacting vinylpyrazine [c.f. J.Org.Chem. 27, 1363 (1962)] with methylmercaptan by the action of ultra violet light and in the presence of benzoyl peroxide by the method described in Acta Chem. Scand. 8, 295 (1954). The product was identified by mass spectrometry. It has a b.p. of 57°-69° C. at 0.05 mm. Hg.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[CH:25]=[C:26]([C:33](O)=[O:34])[N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=12>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=[N:24][CH:25]=2)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cnc2ccccn12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3ccccn23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Imidazo[1,2-a]pyridine-3-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=472.3.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25])=[C:17]([NH2:33])[CH:16]=1.[CH2:35](Cl)CCl>CN(C=O)C>[CH3:12][O:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]2[N:21]([CH2:22][CH2:23][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH3:25])[C:35]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=4[N:6]=3)=[N:33][C:17]=2[CH:16]=1)=[O:34]
Reactant: COC(=O)c1ccc(NCCN(C)C(=O)OC(C)(C)C)c(N)c1
Reactant: ClCCCl
Reactant: Nc1nc2ccc(Cl)cc2s1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2CCN(C)C(=O)OC(C)(C)C
Yield: 85.1 %

Procedure:
1-[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (1.9 g) was prepared by following General Procedure D starting from 6-chloro-benzothiazol-2-ylamine (920 mg), 3-amino-4-[2-(tert-butoxycarbonyl-methyl-amino)-ethylamino]-benzoic acid methyl ester (1.4 g), thioCDI (900 mg) and EDC (960 mg) in DMF (15 mL).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C)C=O.C(N(CC)CC)C>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C=Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A solution of 5 gm (29 mMol) 6-chloro-3-nitro-2-picoline in 40 mL dimethylformamide was treated with 5.83 mL (44 mMol) dimethylformamide dimethylacetal and the resulting mixture heated at 100° C. for 1.5 hours. At this point, 2 drops of triethylamine followed by 1.9 mL dimethylformamide dimethylacetal were added and heating continued for 2 more hours. The reaction mixture was concentrated under reduced pressure to provide the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=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.Cl.[CH2:69]([O:71][C:72](=[O:76])[CH2:73][CH2:74][NH2:75])[CH3:70].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:75][CH2:74][CH2:73][C:72]([O:71][CH2:69][CH3:70])=[O:76])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CCOC(=O)CCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (200 mg, 0.43 mmol) in 10 ml of anhydrous DMF were added HATU (179 mg, 0.47 mmol) and N,N-diisopropylethylamine (166 mg, 1.29 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of β-alanine ethyl ester hydrochloride (100 mg, 0.65 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added slowly until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give ethyl 3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoate as white solid. Yield: 200 mg, 82%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14](Cl)=O.C=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CCCC)CCCC)CCC.[CH3:38][C:39]1[CH:40]=[CH:41][C:42](C)=[CH:43][CH:44]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:14]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH:11]=[CH:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:6]=2)[CH:1]=1)=[CH:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: C=Cc1ccccc1
Reactant: Cc1ccc(C)cc1
Reactant: O=C(Cl)c1ccc2cc(C(=O)Cl)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Product: C(=Cc1ccc2cc(C=Cc3ccccc3)ccc2c1)c1ccccc1
Yield: 37 %

Procedure:
0.224 g (1 millimol) of palladium acetate, 12.65 g (50 millimols) of naphthalene-2,6-dicarboxylic acid dichloride, 13.04 g (125 millimols) of styrene and 18.53 g (100 millimols) of tri-n-butylamine in 50 ml of p-xylene are stirred for 2 hours at 120° C. The crude product is extracted in a Soxhlet and recrystallised from tetrahydrofuran. 6.1 g (37% of theory) of 2,6-distyrylnaphthalene are obtained as pale yellow crystals of melting point 294.7° C.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:22]=[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[N:25][CH:26]=1>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=2)[CH:11]=1)#[N:16]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1cncc(Br)c1
Product: CS(=O)(=O)c1cncc(C#Cc2cc(C#N)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 5-bromo-3-methylsulfonylpyridine (Combiblocks), the title compound was obtained as a yellow solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(N(C(C)C)C(C)C)C.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.O>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCN(C)CC3)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A mixture of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (50 mg, 0.1009 mmol, example 58), 1-methylpiperazine (25 μl, 0.252 mmol) and N-ethyl-N,N-diisopropyl amine (36 μl, 0.202 mmol) in DMA (1 ml) was heated in a sealed tube to 100° C. for 5 h. Then additional 1-methylpiperazine (25 μl, 0.252 mmol) was added and heating to 100° C. was continued overnight. The mixture was then cooled to room temperature and diluted with water. The pH was adjusted to 10 by addition of saturated Na2CO3 solution and the mixture was extracted 3 times with EtOAc. The combined organic layers were washed two times with Na2CO3 solution (pH 10) and with brine, dried over Na2SO4 and evaporated. The remaining brown gum was purified by silica gel chromatography (DCM/MeOH 98:2-19:1) to obtain the title compound (35 mg, 67%) as white foam. MS (EI): 515.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[NH:18][C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=S.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(#N)C>[CH3:17][C:4]1[CH:5]=[C:6]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[N:18]=[C:19]=[N:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(Oc2ncc(Cl)cc2Cl)cc(C)c1NC(=S)NC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Oc2ncc(Cl)cc2Cl)cc(C)c1N=C=NC(C)(C)C

Procedure:
A reaction vessel is charged with 16.6 g of N-[2,6-dimethyl-4-(3,5-dichloro-2-pyridyloxy)phenyl]-N'-tert-butylthiourea and 12.8 g of 2-chloro-1-methylpyridinium iodide in 150 ml of acetonitrile. With stirring, a solution of 8.4 g of triethylamine in 80 ml of acetonitrile is added dropwise at room temperature. The reaction mixture is subsequently stirred for 2 hours at 80° C. and then concentrated by rotary evaporation at 50° C. 150 ml of hexane are added to the residue and the resultant solution is filtered. The hexane phase is washed with three 30 ml portions of cold water, dried over sodium sulfate and filtered. The filtrate is concentrated by evaporation, affording the title compound of the formula ##STR5## as a clear pale yellow oil which crystallises on standing and has a melting point of 69°-71° C. (compound 1).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1.[Li]CCCC.C(O[K])(C)(C)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:38][CH3:39])=[C:27]([C:29]([CH3:37])([CH3:36])[CH2:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:28]=1>C1COCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:38][CH3:39])=[C:27]([C:29]([CH3:37])([CH3:36])[CH2:30][C:31]([CH2:1][C:2]2[NH:10][C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=2)([OH:35])[CH:32]([CH3:33])[CH3:34])[CH:28]=1
Reactant: Cc1cc2cnccc2[nH]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(C)C
Agent: CC(C)(C)O[K]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2cnccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.6 %

Procedure:
A solution of 2-methyl-1H-pyrrolo[3,2-c]pyridine (69 mg, 0.52 mmol) in 4 mL of THF was treated with 610 μL of n-BuLi (2.5 M in hexanes) at −78° C. After 5 minutes, tert-BuOK (1 M in THF, 1.0 mL) was added and the mixture was warmed to room temperature for 1.5 hours. The orange reaction mixture was cooled to −78° C. and 5-(5-fluoro-2-methoxyphenyl)-2,5-dimethylhexan-3-one (110 mg, 0.436 mmol) in 2 mL of THF was added dropwise. The mixture was stirred at −78° C. for 30 minutes, warmed to room temperature, quenched with 10 mL of saturated ammonium chloride solution, and diluted with 20 mL of ethyl acetate. The phases were separated and the aqueous layer was extracted with two 10 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Chromatography on SiO2 (MeOH in CH2Cl2, gradient, 0% to 10%) afforded 71.4 mg (43% yield) of the product as a white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH:22]([O:26][C:39](=[O:41])[CH3:40])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CCC[C@H](O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of Trans (racemic) 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol (8.84 g, 21.2 mmol) dissolved in DCM (5 ml) was added N,N-diisopropylethylamine (3.88 ml, 22.28 mmol), followed by 4-Dimethylamino pyridine (420.3 mg, 3.44 mmol) at room temperature. To this was added Acetyl chloride (6.04 ml, 84.90 mmol) dropwise with stirring at room temperature. The mixture was stirred for 4 hours at room temperature and concentrated under reduced pressure to give an oil, which was used, as is, for the next step. LCMS (Method M, ESI): RT=3.07 min, m+H=459.3.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[N:16][CH:15]=[CH:14]2>>[F:10][C:11]1[C:12]([N+:1]([O-:4])=[O:2])=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[N:16][CH:15]=[CH:14]2
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc2cnccc2c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(F)ccc2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under cooling 2.0 mL of concentrated nitric acid are added to 2.8 mL of sulphuric acid. Subsequently 350 mg of 6-fluoroisoquinoline (23) are added, the reaction is warmed up to room temperature and allowed to stir overnight. The reaction mixture is poured on ice, extracted with dichloromethane and adjusted to alkaline pH by addition of sodium hydroxide. The aqueous layer is extracted again with dichloromethane. The dichloromethane layer is dried over magnesium sulfate and evaporated to give 90 mg of 6-Fluoro-5-nitro-isoquinoline, which can be used without further purification. Rt=1.03 min (Method #1). Detected mass: 193.0 (M+H+).