Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2].F>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:67])([CH3:68])[CH3:69])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (2.91 g) in acetonitrile (15 ml) was added a solution of 2% hydrogen fluoride in aqueous acetonitrile (2 ml), and the mixture stirred at room temperature. After 4 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (1.51 g). (1 H NMR was consistent with the desired structure).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25]C)=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O1CCCC1.[OH-].[Na+].Cl>O>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([OH:25])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate (1.0 g, 2.66 mmol) was added to tetrahydrofuran (20 mL). Aqueous sodium hydroxide (2.5 N, 2.7 mL) and water (2.5 mL) were added, and the suspension was heated to reflux and held for 16 hours. The solids all dissolved during this time. The reaction was cooled to room temperature, and hydrochloric acid solution (1 N, 11 mL) was added. The aqueous suspension was extracted with methylene chloride (2×20 mL). The combined organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to an oil. Trituration with 30 mL of dichloromethane yielded, upon filtration and drying, 0.90 g (94%) of 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid as a white solid: mp 126–128° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][CH:26]=1)[C:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([CH3:23])[C:13]([O:19][C:20](=[O:22])[CH3:21])=[CH:14][CH:15]=2)[O:10][CH:9]=1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][CH:26]=1)[CH:8]1[CH:17]([OH:18])[C:16]2[C:11](=[C:12]([CH3:23])[C:13]([O:19][C:20](=[O:22])[CH3:21])=[CH:14][CH:15]=2)[O:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1cccc(C2COc3c(ccc(OC(C)=O)c3C)C2O)c1

Procedure:
3′,7-Diacetoxy-8-methylisoflavan-4-ol was prepared from 3′,7-diacetoxy-8-methylisoflavone (0.25 g, 0.7 mmol) in methanol (50 ml) using palladium-on-charcoal (5%, 0.06 g) by the method described above.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:44])[N:10]([CH2:41][CH:42]=[CH2:43])[C:11]1[C:16](=[O:17])[N:15]2[C@H:18]([C:25]([N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[CH2:19][C@:20](N=[N+]=[N-])([CH3:21])[C:14]2=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]([O:49][C:50](=[O:86])[CH2:51][C@@]1(C)C2=NC=C(N(CC=C)C(OCC3C=CC=CC=3)=O)C(=O)N2[C@@H](C(=O)NC2C=CC=CC=2)C1)([CH3:48])([CH3:47])[CH3:46]>>[C:45]([O:49][C:50](=[O:86])[CH2:51][C@@:20]1([CH3:21])[C:14]2=[N:13][CH:12]=[C:11]([N:10]([CH2:41][CH:42]=[CH2:43])[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:44])[C:16](=[O:17])[N:15]2[C@@H:18]([C:25]([N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[CH2:19]1)([CH3:48])([CH3:47])[CH3:46]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)Nc1ccccc1)C[C@@]2(C)CC(=O)OC(C)(C)C
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)N(C(=O)OC(C)(C)C)c1ccccc1)C[C@@]2(C)N=[N+]=[N-]
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)N(C(=O)OC(C)(C)C)c1ccccc1)C[C@@]2(C)CC(=O)OC(C)(C)C
Yield: 82 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 18e, intermediate 38a (435.9 mg, 0.76 mmol), was protected to give 418.9 mg (82%) of intermediate 38b. MS (ESI) 673.4 (M+H+), 695.3 (M+Na+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:11]([CH3:19])([CH2:13][CH2:14][C:15](Cl)([CH3:17])[CH3:16])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:12][C:11]1([CH3:19])[C:7]2[C:6](=[CH:5][C:4]3[CH2:3][CH2:2][CH2:1][C:9]=3[CH:8]=2)[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13]1
Reactant: c1ccc2c(c1)CCC2
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)CCC3
Yield: 76 %

Procedure:
A flame dried 3 L three neck round bottom flask fit with a magnetic stirrer, condenser, heating mantle, and nitrogen inlet was charged with indane (49 mL, 0.40 mol, Aldrich), anhydrous methylene chloride (800 mL, Aldrich), and 2,5-dichloro-2,5-dimethylhexane. The mixture was heated to reflux and the aluminum chloride (5.65 g, 0.042 mol). was added portionwise while refluxing the reaction. The reaction mixture was quenched in 1 L 5% HCl/ice, the layers separated, and the combined organics washed with water until neutral to pH paper. The organics were then dried over anhydrous magnesium sulfate, stripped of solvent by rotary evaporation and distilled to yield 5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenz(f)indane (32.1 g, 105-110° C./0.4-0.45 mm Hg, 76-89% pure by GC). 1HNMR (CDCl3, 500 MHz) δ7.19 (s, 2H); 2.86 (t, J=7.5 Hz, 4H); 2.04 (p, J=7.5 Hz, 2H); 1.67 (s, 4H); 1.28 (s, 12H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1CCOC[CH2:18]1.C[O-].[Na+].CO>O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:17][CH3:18])=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 93 %

Procedure:
To a round bottom flask was added 2-benzyl-4,5-dichloropyridazin-3(2H)-one (7.14 gm, 27.99 mmol), dioxane (125 ml, anhydrous). To the resulting reaction mixture was slowly added 25%/NaOMe in MeOH solution (6.98 ml, 30.51 mmol). The reaction was stirred at rt for 70 min. After this time, the reaction mixture was diluted with water (200 ml). The resulting solution was poured into a separatory funnel and extracted with CH2Cl2 (2×100 ml). The combined organic layers were washed with saturated aqueous NaCl (10 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 120 gm silica gel) eluting with 0-5% MeOH/CH2Cl2 to give product 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one as colorless oil (6.5 gm, 93% yield). HPLC retention time (method A) 3.090 min; LCMS (M+H)=251.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([O:34][CH3:35])=[O:33]>>[CH3:35][O:34][C:32]([C:31]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([OH:14])([C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=2)=[CH:27][C:26]=1[F:25])=[O:33]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: COc1ccc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)cn1
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 150, step 2, 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(6-methoxy-pyridin-3-yl)-butan-2-ol (Example 175, step 3) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=498.2 [M+H+].
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8].[O:21]=[C:22]1[N:26]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:25](=[O:33])[CH:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)[S:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][N:26]1[C:25](=[O:33])[CH:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:42][CH2:43][CH:44]([NH:5][CH2:6][C@H:7]([OH:8])[C:9]4[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=4)[CH2:45][CH2:46]3)=[CH:37][CH:36]=2)[S:23][C:22]1=[O:21])[CH3:32]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)C1=O
Reaction time: 0.33 h
Yield: 73.5 %

Procedure:
Acetic acid (0.05 mL, 0.92 mmol) was added to a mixture of N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (which was obtained in Example 10) (113 mg, 0.46 mmol), ethyl 2-[2,4-dioxo-5-[4-(4-oxo-1-piperidineyl)benzyl]-1,3-thiazolidin-3-yl}acetate (which was obtained in Example 50) (180 mg, 0.46 mmol), and DMF (3 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (117 mg, 0.55 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 5/1) to produce an off-white solid (210 mg, 74% yield); mp 153-155° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18 (t, J=7.1 Hz, 3H), 1.30-1.60 (m, 2H), 1.80-1.83 (m, 2H), 2.50-2.65 (m, 4H), 2.80-2.85 (m, 4H), 3.40 (m, 2H), 3.60 (m, 1H), 4.13 (q, J=7.1 Hz, 2H), 4.47 (m, 1H), 5.04 (m, 1H), 6.80-6.90 (m, 3H), 6.97 (m, 1H), 7.1 (m, 2H), 7.19 (m, 1H); MS (ES) m/z: 621 (MH+); Anal. Calcd. for: C28H36N4O8S2×1CH3CO2H: C, 52.93; H, 5.92; N, 8.23. Found: C, 52.69; H, 5.63; N, 8.23.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.[CH2:22]([SH:25])[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=3[N:3]=[C:2]2[S:25][CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 125.9 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (100 mg, 0.27 mmol, intermediate 8) in DMF (5 mL) was added propane-1-thiol (24.7 mg, 0.32 mmol) followed by potassium carbonate (112.2 mg, 0.81 mmol). The reaction was stirred at 60° C. for 4 h. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude white solid product (124 mg, 99.9% yield). LCMS MH+ 365.
Reaction SMILES: [CH2:1]([Si:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[NH:7][C:6]1=[O:14])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:28]([O:32][C:33](Cl)=[O:34])[CH2:29][CH2:30][CH3:31]>ClCCl>[CH2:17]([Si:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:7]([C:33]([O:32][CH2:28][CH2:29][CH2:30][CH3:31])=[O:34])[C:6]1=[O:14])[CH3:18]
Reactant: CCCCOC(=O)Cl
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@H]1c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOC(=O)N1C(=O)[C@H](O[Si](CC)(CC)CC)[C@@H]1c1ccco1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
(3R,4R)-3-Triethylsilyloxy-4-(2-furyl)azetidin-2-one (0.58 g, 2.17 mmol) in 30 mL of dichloromethane was stirred with diisopropylethyl amine (0.4 mL, 2.30 mmol) and butylchloroformate (0.3 mL, 2.36 mmol) in addition to a catalytic amount of DMAP (N,N-dimethylaminopyridine). The solution was stirred for 1 h and diluted with dichloromethane and washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (eluted with 3:1 hexane/ethyl acetate) to give 523 mg of product (Y: 65%); IR(KBr) 1820, 1734, 1318, 1018, 734 cm-1 ; 1H NMR (CDCl3,300 MHz) δ7.38 (m, 1H), 6.35 (m, 2H), 5.09 (ABq, J=15.5, 5.6 Hz, 2H), 4.14 (m, 2H), 1.56 (m, 2H), 1.28 (s, 2H), 0.87 (t, J=8.7 Hz, 3H), 0.82 (t, J=7.9, 9H), 0.50 (m, 6H); 13C NMR (CDCl3,75.5 Hz) δ165.4, 149.1, 147.6, 142.9, 110.5, 109.9, 77.7, 66.6, 55.9, 30.5, 18.8, 13.6, 6.3, 4.3; DCIMS M+H calcd for C18H29NO5Si: 368, Found: 368.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH:21]1([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[CH2:28][CH2:27][N:26]=2)[CH2:24][CH2:23][CH2:22]1.F[C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[C:42]#[N:43]>O1CCCC1>[C:42]([C:41]1[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=1[C:21]1([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[CH2:28][CH2:27][N:26]=2)[CH2:22][CH2:23][CH2:24]1)#[N:43]
Reactant: COc1cc2c(cc1OC)C(C1CCC1)=NCC2
Reactant: N#Cc1ccccc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc2c(cc1OC)C(C1(c3ccccc3C#N)CCC1)=NCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (24.5 ml, 2M solution in hexane) was added to a solution of diisopropylamine (6.85 ml) in tetrahydrofuran (50 ml) at 0° C. The resulting solution of lithium diisopropylamide was stirred at 0° C. for 20 minutes. A solution of 1-cyclobutyl-3,4-dihydro-6,7-dimethoxyisoquinoline (10 g) in tetrahydrofuran (100 ml) was added. The mixture was stirred at 0° C. for 1 hour, then cooled to -70° C. and treated dropwise with 2-fluorobenzonitrile (4.42 ml). The mixture was stirred at -70° C. for 50 minutes, then allowed to warm slowly to ambient temperature. The mixture was poured onto hydrochloric acid and washed with ether. The aqueous phase was basified with ammonia solution and the product was extracted with ethyl acetate. The resulting solid (0.6 g) was collected by filtration. The filtrate was washed with brine, dried over magnesium sulphate and the solvent removed in vacuo to give further solid. The combined solids were recrystallised from acetonitrile yielding a solid which was dried in vacuo to give 1-[1-(2-cyanophenyl)cyclobutyl]-6,7-dimethoxy-3,4-dihydroisoquinoline (5 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[SH:27]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Reactant: Sc1cc(Cl)c(Cl)cc1Cl
Product: O=c1ccc2cc(OCCCCSc3cc(Cl)c(Cl)cc3Cl)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 198°-199° C.) and 2,4,5-trichlorothiophenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9]2[C:14]3[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)=[CH:16][NH:17][C:13]=3[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:28]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:14]3[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)=[CH:16][N:17]([CH2:39][CH2:38][CH2:37][CH2:36][NH:35][C:28](=[O:29])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:13]=3[CH:12]=[CH:11][N:10]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: COc1ccc(CNc2nccc3[nH]cc(-c4cccc(OC)c4)c23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nccc3c2c(-c2cccc(OC)c2)cn3CCCCNC(=O)OC(C)(C)C)cc1
Yield: 102.8 %

Procedure:
450 mg (1.1 mmol) of (4-methoxybenzyl)-[3-(3-methoxyphenyl)-1H-pyrrolo-[3,2-c]pyridin-4-yl]amine from Example B3, 428 mg (1.7 mmol) of 4-(BOC-amino)butyl bromide and 0.9 g (2.8 mmol) of caesium carbonate in 60 ml of DMF are warmed to 60° C. over the course of 12 h. Aqueous work-up at RT and chromatographic purification gives 600 mg (82%) of a colourless oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[CH3:16].C(Cl)(Cl)Cl>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCCCCCCCCBr
Temperature: 25 °C
Yield: 72 %

Procedure:
1000 g of 90% pure 11-bromoundecanoic acid (equivalent to 3.39 mol), 304.0 g (6.60 mol) of ethanol and 20.0 g of p-toluenesulfonic acid were introduced into 400 ml of chloroform in an experimental apparatus with water trap (for entrainers with higher specific gravity than water). The mixture was heated under reflux until water no longer separated out (about 6 hours). After the solution had cooled to room temperature it was washed successively with 1 l of water, 500 ml of saturated NaHCO3 solution and 1 l of water. The solvent was removed in vacuo. Vacuum distillation (b.p. 131-133° C./1 mbar) resulted in 716.3 g (2.44 mol, 72%) of ethyl 11-bromoundecanoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:28][CH2:29][CH2:30][C:31]#[N:32]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:28][CH2:29][CH2:30][C:31]#[N:32])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: N#CCCCBr
Reactant: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
To a solution of 5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid ethyl ester (1.50 g, 4.12 mmol) in dimethylformamide (15 mL) was added 60% sodium hydride (0.25 g, 6.18 mmol). The reaction mixture was stirred at ambient temperature under argon for 2.5 h. 4-Bromobutyronitrile (0.92 g, 6.14 mmol) was then added and the reaction mixture stirred for another 14 h at ambient temperature. The reaction was diluted with ethyl acetate and washed three times with water. The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 25% ethyl acetate/hexane) yielded an off-white solid (1.60 g, 95%). MS(ES) m/e 431.0 [M +H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12]Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].C(OCC)(=O)C>CCCCCC>[CH3:1][N:2]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:26]2[S:22][C:23](=[O:28])[NH:24][C:25]2=[O:27])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: O=C1CSC(=O)N1
Reactant: CN(CCc1ccccc1)S(=O)(=O)c1ccc(CBr)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1)S(=O)(=O)c1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
By the method of Example 1, N-methyl-N-(2-phenylethyl)-4-(bromomethyl)benzenesulfonamide (10.6 mmol, 3.9 g) and thiazolidine-2,4-dione (11.7 mmol 1.4 g,), using 1:2 ethyl acetate:hexane as eluant, were converted to 3.3 g purified title product as a gum.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15](N)=[O:16]>>[N+:11]([C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[NH:14][C:15](=[O:16])[NH:1]2)=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)c2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 160 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of 5 g (0.027 mol) of 2-amino-4-nitrobenzoic acid and 16.5 g (0.27 mol) 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. 4.8 g (80%) of 7-nitro-1,2,3,4-tetrahydro-quinazoline-2,4-dione were obtained as a white solid;
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:15]=[C:16]4[CH:21]=[CH:20][CH:19]=[N:18][N:17]4[CH:22]=3)[CH:11]=[CH:12][CH:13]=2)[N:4]=1.[CH3:23][O:24][CH2:25][CH2:26][NH2:27]>CCO>[N:15]1[C:14]([C:10]2[CH:9]=[C:8]([C:5]3[N:4]=[C:3]([CH2:2][NH:27][CH2:26][CH2:25][O:24][CH3:23])[O:7][N:6]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:22][N:17]2[C:16]=1[CH:21]=[CH:20][CH:19]=[N:18]2
Reactant: ClCc1nc(-c2cccc(-c3cn4ncccc4n3)c2)no1
Reactant: COCCN
Solvent: CCO
Product: COCCNCc1nc(-c2cccc(-c3cn4ncccc4n3)c2)no1

Procedure:
A mixture of 2-(3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine(1.5 mmol), sodium iodide(cat.) and 2-methoxyethanamine(3 mmol) in 25 mL EtOH was stirred under reflux for 2 h. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel to give the N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-methoxyethanamine.