Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:18])[C:3](=[C:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=O)O.[CH:19]1[C:24]([NH:25][NH2:26])=[CH:23][CH:22]=[C:21]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:20]=1.Cl>C(O)C>[F:1][CH:2]([F:18])[C:3]1[C:5]2[CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([O:15][CH3:16])[CH:9]=[CH:8][C:7]=3[C:6]=2[N:25]([C:24]2[CH:19]=[CH:20][C:21]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:22][CH:23]=2)[N:26]=1
Reactant: COc1ccc2c(c1)CCC(=C(O)C(F)F)C2=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)CCc1c(C(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Yield: 81.4 %

Procedure:
A 500 mL one neck round bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 3,4-dihydro-6-methoxy-2-[2,2-difluoro-1-hydroxyethylidene]-1(2H)-naphthalenone from Step 1 (2.54 g, 10 mmol), 4-sulfonamidophenylhydrazine hydrochloride (2.91 g, 13 mmol) and 250 mL of absolute ethanol. The solution was warmed to reflux for 15 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and with brine, dried over anhydrous MgSO4, filtered and reconcentrated in vacuo. The residue was recrystallized from a mixture of ethanol and water to give 4-[3-(difluoromethyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide (3.3 g, 82%): mp 256°-257° C.
Reaction SMILES: C[Si](I)(C)C.C[O:7][CH2:8][C@H:9]([CH3:38])[O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:37]=[CH:36][NH:35][N:34]=3)=[CH:29][CH:28]=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15]>C(#N)C.C(OCC)(=O)C>[OH:7][CH2:8][C@H:9]([CH3:38])[O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:37]=[CH:36][NH:35][N:34]=3)=[CH:29][CH:28]=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(-c3cc[nH]n3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(-c3cc[nH]n3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
Trimethylsilyl iodide (0.080 mL, 0.559 mmol) was added to a solution of 3-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(1H-pyrazol-3-yl)phenoxy]benzamide (50 mg, 0.112 mmol) in acetonitrile (2 mL) and the reaction mixture allowed to stir at RT for 18 hours. The reaction was diluted with ethyl acetate (15 mL) and quenched by the addition of saturated aqueous sodium bicarbonate solution (20 mL). The organic phase was washed with saturated aqueous thiosulphate solution (20 mL) and dried (MgSO4). The volatiles were removed under reduced pressure and the resulting oil purified by chromatography on silica, eluting with 0-100% ethyl acetate in iso-hexane, to give the title compound as a colourless solid (40 mg).
Reaction SMILES: Br[C:2]1[CH:22]=[N:21][C:5]2[NH:6][C:7](=[O:20])[CH2:8][N:9]([CH2:10][C:11]3[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=3[Cl:19])[C:4]=2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:19][C:12]1[C:13]([F:18])=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH2:10][N:9]1[CH2:8][C:7](=[O:20])[NH:6][C:5]2[N:21]=[CH:22][C:2]([C:33]3[CH:32]=[N:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)=[CH:3][C:4]1=2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: O=C1CN(Cc2c(F)ccc(F)c2Cl)c2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCO
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3c(F)ccc(F)c3Cl)CC(=O)N4)cn2)CC1
Temperature: 130 °C
Yield: 28.9 %

Procedure:
A mixture of 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-one (42 mg, 0.11 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (40 mg, 0.13 mmol), palladium (II) acetate (4 mg) and triphenylphosphine (14 mg) in n-propanol (1.0 mL) was degassed with argon while adding a 1.26 M aqueous solution of Na2CO3 (0.12 mL) followed by water (0.38 mL). This mixture was heated in a microwave for 10 minutes at 130° C., cooled to room temperature and extracted into CH2Cl2. The organic phase was passed through a plug of Na2SO4, absorbed onto florisil and evaporated to dryness. This material was purified by silica gel chromatography by eluting with increasing amounts of 5% NH4OH/methanol in dichloromethane. The isolated material was recrystallized from methanol to give the title compound (15.4 mg, 29%). m.p. 235-236° C. (dec); LCMS: m/z=485/487 (M+H+); 1H-NMR (CDCl3-d6, 400 MHz) δ 8.22 (d, J=2.4 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.49-7.46 (m, 1H), 7.16 (s, 1H), 7.15-7.06 (m, 1H), 7.05-6.93 (m, 1H), 6.69 (d, J=8.8, 1H), 5.43, (s, 2H), 4.81 (s, 1H), 4.24 (s, 2H), 3.61-3.59 (m, 4H), 2.55-2.52 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[N:18]=[C:19]([NH:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:20]2[N:21]([C:23]([CH3:26])=[N:24][N:25]=2)[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34]CN(C(C)C)C(C)C.C=O>C1COCC1>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[N:18]=[C:19]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[C:20]2[N:21]([C:23]([CH3:26])=[N:24][N:25]=2)[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2c(NC3CCNCC3)nc(-c3nc4ccccc4n3Cc3ccccc3)cn12
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Solvent: C1CCOC1
Product: Cc1nnc2c(NC3CCN(C)CC3)nc(-c3nc4ccccc4n3Cc3ccccc3)cn12
Reaction time: 2 h

Procedure:
N-[6-(1-benzyl-1H-1,3-benzodiazol-2-yl)-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]piperidin-4-amine (93 mg; 0.21 mmol) is dissolved in 300 μl THF, treated with DIPEA (62 μl; 0.29 mmol) and formaldehyde (62 μl; 0.83 mmol). To this reaction mixture STAB (62 mg; 0.29 mmol) is added and the reaction mixture is stirred for 2 hours. The crude reaction mixture is purified by reversed phase chromatograph (Method: prep. HPLC1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=O)[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=O)([O-:3])=[O:2].[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>CO>[N+:1]([C:4]1[CH:13]=[C:8]([C:9]([NH:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])=[O:11])[CH:7]=[C:6]([CH:5]=1)[C:14]([NH:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])=[O:16])([O-:3])=[O:2]
Reactant: COC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Reactant: NCC(O)CO
Solvent: CO
Product: O=C(NCC(O)CO)c1cc(C(=O)NCC(O)CO)cc([N+](=O)[O-])c1
Yield: 84 %

Procedure:
Dimethyl 5-nitro-isophthalate and 2.4 molar equivalents of 1-amino-2,3-propanediol were refluxed in methanol for twenty hours and the resulting 5-nitro-N,N′-bis(2,3-dihydroxypropyl)isophthalamide was isolated in 84% yield. The latter compound was suspended in aqueous hydrochloric acid and hydrogenated in the presence of a palladium oxide/charcoal catalyst. The resulting 5-amino-N,N′-bis(2,3-dihydroxypropyl)-isophthalamide was not isolated but the acid solution containing it was iodinated with sodium iodine dichloride to obtain 5-amino-2,4,6-triiodo- N,N′-bis(2,3-dihydroxypropyl)isophthalamide in 71% yield from the nitro compound (over-all yield of 59.5% from dimethyl 5-nitroisophthalate). Subsequent reactions are described for the preparation of 5-[N-(2,3-dihydroxy-propyl)acetamido]-2,4,6 triiodo-N,N′-bis(2,3-dihydroxypropyl)isophthalamide, useful as an X-ray contrast agent.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:43][CH2:42][N:41]([CH:44]6[CH2:47][O:46][CH2:45]6)[CH2:40][C@H:39]5[CH3:48])=[CH:34][N:33]=4)[C:28](=[O:49])[N:27]([CH3:50])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:43][CH2:42][N:41]([CH:44]6[CH2:47][O:46][CH2:45]6)[CH2:40][C@H:39]5[CH3:48])=[CH:34][N:33]=4)[C:28](=[O:49])[N:27]([CH3:50])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 8.2 %

Procedure:
A solution of 106b (90.0 mg, 0.13 mmol) in MeOH (10 mL) was added NaBH4 (15.0 mg, 0.39 mmol). The mixture was stirred at 20° C. for 2 h. It was then evaporated and the residue was purified by reverse-phase prep-HPLC to afford 106 (7.3 mg, 8%) as a white solid. LCMS: (M+H)+ 681.4. 1H NMR (500 MHz, DMSO) δ 8.63 (d, J=2.5, 1H), 8.57 (d, J=5.0, 1H), 8.54 (d, J=2.0, 1H), 8.47 (s, 1H), 7.91 (s, 1H), 7.86 (d, J=3.0, 1H), 7.78 (d, J=12.5, 1H), 7.53 (d, J=5.0, 1H), 7.47 (d, J=2.0, 1H), 7.36-7.39 (m, 1H), 7.25 (d, J=9.5, 1H), 4.90 (s, 1H), 4.54-4.58 (m, 2H), 4.47 (t, J=6.0, 1H), 4.39-4.43 (m, 3H), 3.69 (s, 1H), 3.61 (s, 3H), 3.37-3.42 (m, 1H), 3.09-3.11 (m, 1H), 2.95 (t, J=9.0, 1H), 2.54-2.56 (m, 1H), 2.30-2.37 (m, 2H), 2.19 (t, J=8.0, 1H), 1.39 (s, 9H), 0.94-0.93 (d, J=6.5, 3H)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(#N)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:9][C:8]1[CH:16]=[CH:17][C:5]([C:3](=[O:4])[CH2:2][N:27]2[CH2:28][CH2:29][N:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH2:25][CH2:26]2)=[CH:6][CH:7]=1)[CH3:15]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CCOC(=O)COc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 1 h

Procedure:
Ethyl 4-bromoacetylphenoxyacetate (6.0 g) was added to a stirred, cooled (4° C.) solution of 1-(4-pyridyl)piperazine (6.5 g) in acetonitrile (225 ml). Stirring was continued for 1 hour at 4° C., then overnight at ambient temperature when the precipitated solid was removed by filtration. The filtrate was evaporated in vacuo and the solid residue triturated with water, filtered, then washed with water and dried. Recrystallization from a small volume of ethanol gave the title compound, 1.71 g, as a cream coloured solid: m.p. 113°-114° C.; NMR (d6DMSO) δ8.15(2H,d), 7.98(2H,d), 7.02(2H,d), 6.80(2H,d), 4.89(2H,d), 4.17(2H,q), 3.84(2H,s), 3.32(4H,t), 2.62(4H,t) 1.22(3H,t); m/e 384 (M+H)+ ; calculated for C21H25N3O4 : C, 65.8; H, 6.6; N, 11.0. found: C, 65.5; H, 6.6; N, 10.8%.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]CC.O>C1C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Yield: 74.1 %

Procedure:
8.6 ml (76.08 mmol) of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 15 grams of powdered potassium hydroxide and 27.5 grams (76.08 mmol) of 1-bromoeicosane were stirred in 150 ml benzene and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 70 ml. The reaction mixture was then cooled to room temperature and 150 ml of water was added. The reaction mixture was then extracted thrice with 150 ml diethyl ether, the combined organic phase was washed with 100 ml water, and the solvent was then removed under reduced pressure. The obtained residue was dissolved in 105 ml of a 90:10:5 (v/v) methanol:water:concentrated hydrochloric acid mixture, and the resulting solution was refluxed until the solution became clear. The solution was then cooled to room temperature and 100 ml water was added. The product was extracted with 150 ml chloroform, washed consecutively with 150 ml water, 150 ml saturated aqueous solution of sodium carbonate, and again with 150 ml water. The solvent was then removed under reduced pressure and the product was crystallized from 200 ml hexane, yielding 21.0 grams of pure 1-eicosanyl-sn-glycerol, which was dried in a desiccator under reduced pressure with phosphorus oxide. The yield was 81.5%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:6]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: N[C@H](CO)Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)N[C@H](CO)Cc1ccccc1
Yield: 86.4 %

Procedure:
5 g (27.6 mmol) of 2-methyl-5-nitrobenzoic acid were reacted with 4.2 g (27.6 mmol) of (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 7.5 g (87%) of the product were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]1([C:29]2[O:30][C:31]([C:37]([F:40])([F:39])[F:38])=[C:32]([C:34](O)=[O:35])[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:34]([C:32]2[N:33]=[C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:30][C:31]=2[C:37]([F:39])([F:40])[F:38])=[O:35])=[CH:14][N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CN(CCOCC(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN(CCOCC(=O)OC(C)(C)C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 30.2 %

Procedure:
{2-[Methyl-(5-nitro-pyridin-2-yl)-amino]-ethoxy}-acetic acid tert-butyl ester (218 mg, 0.7 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (189 mg, 0.735 mmol), Et3N (394 uL, 2.8 mmol) and BOP (325 mg. 0.735 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield [2-(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-ethoxy]-acetic acid tert-butyl ester as a solid (110 mg). ES-MS calcd for C25H27F3N4O5 (m/e) 520.51, obsd 521.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.Br[C:16]1[S:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:17]=1>>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:16]3[S:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:17]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(Br)s1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)s1

Procedure:
Using the same general procedure described in the preceeding Example 11, but using instead 4,4-dimethyl-6-ethynylthiochroman and ethyl 5-bromothiophene-2-carboxylate, the title compound was synthesized.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:9][Br:17])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Cc1ncc(Br)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncc(Br)cc1Br
Temperature: 25 °C
Yield: 54.8 %

Procedure:
To a solution of 52A (1.25 g, 4.98 mmol) in CCl4 (7 ML) was added NBS (0.89 g, 4.98 mmol) followed by catalytic AIBN and the mixture was heated to reflux for 4 hours. The reaction was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 10% CH2Cl2/Hexane then 50% CH2Cl2/Hexane) to give 52B (0.90 g, 55%). HPLC Rt=2.85 min.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.[N:10]1([C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN(C=O)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>[CH3:1][CH:2]([CH2:8][CH3:9])/[CH:3]=[CH:4]/[C:5]([N:13]1[CH2:14][CH2:15][N:10]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([F:29])([F:27])[F:28])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:12]1)=[O:7]
Reactant: FC(F)(F)c1ccc2c(N3CCNCC3)ccnc2c1
Reactant: CCC(C)/C=C/C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)/C=C/C(=O)N1CCN(c2ccnc3cc(C(F)(F)F)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4-Methylhex-2-enoic acid (26 mg, 0.2 mmol) was dissolved in DMF (0.5 ml) together with diisopropylethylamine (35 μl), HATU was added (76 mg, 0.2 mmol) and the mixture was stirred at room temperature for 15 minutes. 4-piperazin-1-yl-7-(trifluoromethyl)quinoline (56 mg, 0.2 mmol) was dissolved in DMF (0.5 ml) together with diisopropylethylamine (35 μl), the two solutions were combined and stirred at room temperature overnight. The mixture was evaporated to dryness under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 62.6 mg (0.16 mmol, 80%). MS (APCI) m/z=391.9 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22].[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]2[CH2:18][CH2:19][CH2:20][S:21]2(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=S(=O)(Cl)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)CCCN1Cc1ccc(Br)cc1
Yield: 93.7 %

Procedure:
A solution of 4-bromobenzylamine (1.85 g, 10 mmol) and triethylamine (2 g, 20 mmol) in dimethylformamide (30 ml) was treated with 3-chloropropanesulfonyl chloride (1.78 g, 10 mmol) by dropwise addition over 10 minutes with stirring under argon. This mix was stirred for 30 minutes before being treated with a 60% suspension of sodium hydride in mineral oil (1.2 g, 30 mmol of NaH) portionwise and the whole mix stirred at room temperature for 3 days. The reaction mixture was partitioned between water (50 ml) and dichloromethane (30 ml). The organic layer was dried over sodium sulphate and reduced to minimum volume by rotary evaporation. The residue was added to a 20 g pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (2.72 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Na+].[CH2:28]([N:30]([CH2:35][CH3:36])[CH2:31][C:32]([O-])=[O:33])[CH3:29].O.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44]([OH:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1>C1(C)C=CC=CC=1>[C:38]1([CH3:48])[CH:39]=[CH:40][C:41]([S:44]([OH:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1.[CH2:28]([N:30]([CH2:31][C:32]([O:26][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[S:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)=[O:33])[CH2:35][CH3:36])[CH3:29]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)s2)cc1OC
Reactant: CCN(CC)CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)CC(=O)OC1CCN(c2ccc(/C=C(\C#N)c3ccc(OC)c(OC)c3)s2)CC1
Yield: 27.9 %

Procedure:
Compound 6 (480 mg) was dissolved in toluene (100 mL), and N,N-diethylglycin sodium salt (296 mg) and p-toluenesulfonic acid monohydrate (490 mg) were added to the solution, followed by stirring under reflux for 5 hours. The solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (CHCl3-MeOH), to thereby yield the target product (yield: 237 mg, 37.7%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:10][CH:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])(C)(C)C.Cl>ClCCl.O1CCOCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:9]1[CH2:10][CH:8]1[C:6]([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)C1CC1c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)C1CC1c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-pyridin-2-yl-cyclopropanecarboxylic acid tert-butyl ester (1.6 g, 7.3 mmol) in dichloromethane (30 mL) was added a solution of anhydrous HCl in dioxane (4.0M, 15 mL). The solution was allowed to stir at ambient temperature overnight then evaporated to yield the product as a yellow oil.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8])=O.[CH3:18][NH:19][CH2:20][CH2:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[CH:25]=[N:24][CH:23]=1>>[CH3:18][N:19]([CH2:20][CH2:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[CH:25]=[N:24][CH:23]=1)[CH2:1][CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8]
Reactant: CNCCc1cncc2cc(OC)c(OC)cc12
Reactant: CC1=C(C)C2C(=O)NC(=O)C2(CCC=O)C=C1
Product: COc1cc2cncc(CCN(C)CCCC34C=CC(C)=C(C)C3C(=O)NC4=O)c2cc1OC

Procedure:
Prepared from 2-(2-formyl-ethyl)-5,6-dimethyl-phthalimide and 4-(2-methylamino-ethyl)-6,7-dimethoxy-isoquinoline analogously to Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14]>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:12][C:13](=[O:14])[NH:1]2
Reactant: NC(N)=O
Reactant: Nc1cccc(Cl)c1C(=O)O
Product: O=c1[nH]c(=O)c2c(Cl)cccc2[nH]1
Temperature: 160 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A mixture of 2.0 g (11 mmol) of 2-amino-6-chlorobenzoic acid and 1.4 g (23 mmol) of urea was heated to 160° C. for 2 hrs. and at 180° C. for a further 2 hrs. The resulting brown mass was triturated with 200 ml of methanol, filtered off and dried in a vacuum. 1.2 g (53%) of 5-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione were obtained as white crystals;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[N:6][CH:7]=2)=[CH:27][CH:26]=1
Reactant: Brc1ccc(C#CCCc2ccc(CN3CCCC3)cc2)nc1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccc(C#CCCc3ccc(CN4CCCC4)cc3)nc2)cc1
Temperature: 100 °C

Procedure:
A mixture of 100 mg (0.27 mmol) 5-bromo-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine, 85 mg (0.54 mmol) 4-chloro-phenylboric acid, 15.7 mg (0.014 mmol) tetrakis-triphenylphosphane-palladium, 0.28 mL of a 2 M aqueous Na2CO3 solution in 10 mL 1,4-dioxane is heated for 8 h at 100° C. under an argon atmosphere. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified over neutral Alox (ICN Alumina N+5% H2O; cyc/EtOAc 7:3). The product fractions are evaporated down, the residue is triturated with PE and suction filtered.