Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:13]I.[H-].[Na+]>O1CCCC1>[CH3:13][O:12][CH2:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CI
Reactant: OCC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1CCC2(CC1)OCCO2
Yield: 780 %

Procedure:
1,4-Dioxaspiro[4.5]decane-8-methanol (2 g, 1 mmol) (commercial available or prepared as in Bioorganic & Medicinal Chemistry, 13(23), 6309-6323; 2005) is methylated using MeI (1.81 mL, 29 mmol) and NaH (0.813 g, 20 mmol) in tetrahydrofuran to obtain after 2 hours of stirring at room temperature 1.4 g (7.8 mmol) of the desired compound. MS (m/e): 187.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH:17](/B(O)O)=[CH:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: OB(O)/C=C/c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(/C=C/c2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, (E)-styrylboronic acid, tetrakis(triphenylphosphine)palladium(O) and sodium carbonate in dioxane/water. EI-MIS m/e (%): 298 (M+, 84), 297 ([M—H]+, 100).
Reaction SMILES: CC1(C)[O:38][C@H:5]2[O:6][C@H:7]([CH2:15][N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]4([C:36]5[C:27](=[CH:28][C:29]6[O:34][CH2:33][CH2:32][O:31][C:30]=6[CH:35]=5)[O:26][CH2:25]4)[C:17]3=[O:37])[C@@H:8]3[O:12]C(C)(C)[O:10][C@@H:9]3[C@H:4]2[O:3]1>FC(F)(F)C(O)=O>[O:37]=[C:17]1[C:18]2([C:36]3[C:27](=[CH:28][C:29]4[O:34][CH2:33][CH2:32][O:31][C:30]=4[CH:35]=3)[O:26][CH2:25]2)[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]1[CH2:15][C@H:7]1[O:6][CH:5]([OH:38])[C@H:4]([OH:3])[C@@H:9]([OH:10])[C@H:8]1[OH:12]
Reactant: CC1(C)O[C@H]2[C@@H](O1)[C@@H](CN1C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc31)O[C@@H]1OC(C)(C)O[C@@H]12
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(C[C@H]2OC(O)[C@H](O)[C@@H](O)[C@H]2O)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.6 %

Procedure:
1′-{[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.45 g, 0.83 mmol) was suspended in 80% v/v aqueous trifluoroacetic acid (40 mL) and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue recrystallized from ethanol to afford 6-deoxy-6-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)-D-galactopyranose (0.025 g, 7%) as an off white solid: mp 122-126° C. (ethanol); 13C NMR (75 MHz, CDCl3) δ178.5, 155.2, 155.2, 155.1, 155.0, 144.5, 142.6, 142.2, 142.1, 138.0, 138.0, 132.3, 132.0, 129.0, 123.5, 123.4, 121.0, 120.9, 111.6, 111.4, 109.9, 109.7 99.2, 92.7, 79.9, 64.4, 63.8, 60.4, 58.0, 21.0, 14.2; MS (ES+) m/z 480.0 (M+23).
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:35]2[NH:40][C:39](=[O:41])[C:38]([C:42]3[CH:43]=[N:44][NH:45][CH:46]=3)=[CH:37][CH:36]=2)=[CH:17]\[C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[N:19]2CC2C=CC(OC)=CC=2OC)=[CH:12][CH:11]=1>FC(F)(F)C(O)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13](/[C:16](/[C:35]2[NH:40][C:39](=[O:41])[C:38]([C:42]3[CH:46]=[N:45][NH:44][CH:43]=3)=[CH:37][CH:36]=2)=[CH:17]\[C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[NH:19]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(Cl)cc2)c2ccc(-c3cn[nH]c3)c(=O)[nH]2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC[C@H](/C=C(\c2ccc(Cl)cc2)c2ccc(-c3cn[nH]c3)c(=O)[nH]2)N1
Temperature: 70 °C
Reaction time: 5 h
Yield: 71.4 %

Procedure:
Anisole (0.5 mL) was added to a solution of 6-{(E)-1-(4-chlorophenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-(1H-pyrazol-4-yl)pyridin-2(1H)-one (100 mg) in trifluoroacetic acid (1 mL), and the mixture was stirred at 70° C. for five hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) and recrystallized from ethyl acetate-hexane to give the title compound as a pale yellow powder (51.2 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=O)([O-:3])=[O:2].O.[NH2:23][NH2:24].C(OCC)(=O)C>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[C:9]3[N:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15](=[O:16])[NH:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cccnc1C(=O)c1cccc([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Yield: 108.1 %

Procedure:
To a solution of 2-(3-nitrobenzoyl)-3-methoxycarbonylpyridine (0.58 g, 2 mmoles) dissolved in ethanol (50 ml), was added hydrazine monohydrate (0.25 ml, 5.1 mmoles). The mixture was refluxed for 4 hours, cooled and ethyl acetate (50 ml) was added. The solid material was collected and dried, yielding 0.58 g of 8-(3-nitrophenyl)-pyrido[2,3-d]pyridazin-5-one, mp 302° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][C:5]([CH3:16])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:6])[CH3:2]>[Pd].C(OCC)(=O)C>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([CH3:6])[CH3:16])[CH3:18]
Reactant: CCN(CC)CC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)CC(C)(C)c1ccc(N)cc1
Reaction time: 16 h
Yield: 93.3 %

Procedure:
In a 100 mL round bottomed flask was charged N,N-diethyl-2-methyl-2-(4-nitrophenyl)propan-1-amine (1.45 g, 5.79 mmol), ethyl acetate (29 mL) and a nitrogen atmosphere was introduced to the flask. 10% Palladium on activated carbon was carefully introduced and the flask contents were purged (evacuate—backfill) twice with nitrogen and lastly with hydrogen dispensed from a balloon. The reaction was stirred for 16 h under the hydrogen atmosphere. The hydrogen was removed and the solution was filtered over Celite®, rinsed with methanol and the filtrate was concentrated in vacuo to give 4-(1-(diethylamino)-2-methylpropan-2-yl)aniline (1.19 g, 93.5%) as a light yellow oil. LC/MS (ESI+) 221 (M+H)+.
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH2:12][C:13]([OH:15])=O)=[C:7](N=C=O)[CH:6]=1)C=C.[CH2:25]([O:28][C:29](=[O:65])[C:30]([N:50]1[C@H:53]([SH:54])[C@@H:52]([C@H:55]([O:57][C:58]([O:60][CH2:61][CH:62]=[CH2:63])=[O:59])[CH3:56])[C:51]1=[O:64])=[P:31]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:26]=[CH2:27]>[Ag]>[CH2:25]([O:28][C:29](=[O:65])[C:30]([N:50]1[C@H:53]([S:54][C:13](=[O:15])[CH2:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])=[CH:10][CH:9]=2)[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C@@H:52]([C@H:55]([O:57][C:58]([O:60][CH2:61][CH:62]=[CH2:63])=[O:59])[CH3:56])[C:51]1=[O:64])=[P:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:26]=[CH2:27]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Reactant: C=CCOC(=O)N(CC(=O)O)c1ccc(OCC=C)cc1N=C=O
Agent: [Ag]
Product: C=CCOC(=O)Nc1ccc(N(CC(=O)S[C@@H]2[C@@H]([C@@H](C)OC(=O)OCC=C)C(=O)N2C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)OCC=C)cc1

Procedure:
Analogously to Example 1, 2.67 g of N-(4-allyloxy-carbonylaminophenyl)-N-(allyloxycarbonyl)-glycine are converted with 3.5 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester into the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]([CH:30]([F:41])[C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[C:28]([CH:42]4[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]4)[C:27]4[CH:26]([O:50]CC5C=CC(OC)=CC=5)[CH2:25][C:24]([CH3:61])([CH3:60])[CH2:23][C:22]=4[N:21]=3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1>>[F:49][C:45]1([F:48])[CH2:44][CH2:43][CH:42]([C:28]2[C:27]3[CH:26]([OH:50])[CH2:25][C:24]([CH3:60])([CH3:61])[CH2:23][C:22]=3[N:21]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:11]4[N:12]=[CH:13][C:8]([N:1]5[CH2:6][CH2:5][S:4][CH2:3][CH2:2]5)=[CH:9][N:10]=4)[CH2:19][CH2:18]3)[C:29]=2[CH:30]([F:41])[C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:40])[F:39])=[CH:35][CH:36]=2)[CH2:47][CH2:46]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: C1CSCCN1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(N5CCSCC5)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Reference Example 13 and Example 7 were performed except for using thiomorpholine instead of isonipecotic acid ethyl ester, and from 120 mg (0.144 mmol) of (−)-2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 11, 61 mg of the title compound was obtained as a white solid (yield: 58%).
Reaction SMILES: BrC1C=C(NC2C=CC(C#N)=CC=2)C=C(O[Si](C(C)C)(C(C)C)C(C)C)C=1.C([Si](C(C)C)(C(C)C)[N:32]1[C:40]2[C:35](=[C:36]([C:41]3[CH:42]=[C:43]([NH:58][C:59]4[CH:60]=[CH:61][C:62]([C:65]#[N:66])=[N:63][CH:64]=4)[CH:44]=[C:45]([O:47][Si](C(C)C)(C(C)C)C(C)C)[CH:46]=3)[CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33]1)(C)C>>[OH:47][C:45]1[CH:44]=[C:43]([NH:58][C:59]2[CH:60]=[CH:61][C:62]([C:65]#[N:66])=[N:63][CH:64]=2)[CH:42]=[C:41]([C:36]2[CH:37]=[CH:38][CH:39]=[C:40]3[C:35]=2[CH:34]=[CH:33][NH:32]3)[CH:46]=1
Reactant: CC(C)[Si](Oc1cc(Nc2ccc(C#N)nc2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1)(C(C)C)C(C)C
Agent: CC(C)[Si](Oc1cc(Br)cc(Nc2ccc(C#N)cc2)c1)(C(C)C)C(C)C
Product: N#Cc1ccc(Nc2cc(O)cc(-c3cccc4[nH]ccc34)c2)cn1

Procedure:
4-(3-Bromo-5-triisopropylsilanyloxy-phenylamino)-benzonitrile was converted to 5-[3-(1-triisopropylsilanyl-1H-indol-4-yl)-5-triisopropylsilanyloxy-phenylamino]-pyridine-2-carbonitrile, and the triisopropylsilyl groups were removed with tetra n-butylammonium fluoride to give 5-[3-hydroxy-5-(1H-indol-4-yl)-phenylamino]-pyridine-2-carbonitrile as described in Example 35. 1H NMR (400 MHz, CD3OD) δ 8.31 (dd, J=2.8, 0.4 Hz, 1H), 7.57 (dd, J=8.8, 0.8 Hz, 1H), 7.49 (dd, J=8.8, 2.8 Hz, 1H), 7.35 (m, 1H), 7.26 (d, J=3.2 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H), 7.05 (dd, J=7.2, 1.2 Hz, 1H), 6.97 (m, 1H), 6.89 (dd, J=2.4, 1.6 Hz, 1H), 6.66 (m, 1H), 6.61 (m, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:44]=[C:43]([F:45])[C:16]([CH2:17][S:18][C:19]2[N:20]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C:21]([C:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][CH3:35])[CH:28]=3)([CH3:26])[CH3:25])=[CH:22][N:23]=2)=[C:15]([F:46])[CH:14]=1)(C(C)(C)C)(C)C>CC#N.CC#N.O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]([C:21]2[N:20]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C:19]([S:18][CH2:17][C:16]3[C:15]([F:46])=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:44][C:43]=3[F:45])=[N:23][CH:22]=2)([CH3:26])[CH3:25])=[CH:28][C:29]=1[O:34][CH3:35]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCO[Si](C)(C)C(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Yield: 50.6 %

Procedure:
A solution of 2-(4-(3-(tert-butyldimethylsilyloxy)propoxy)-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)-propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (785 mg, 1.13 mmol) in CH3CN was treated with 5% HF in CH3CN/H2O (8:2) and purified by chromatography to afford the title compound (330 mg, 50%) as a white solid. MS (EI) m/z 577.4 (MH+).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][O:11][CH2:12]Cl.[CH2:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:15][CH3:16].O>C(Cl)Cl>[CH3:10][O:11][CH2:12][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=1
Reactant: CCCc1ccc(O)cc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCc1ccc(OCOC)cc1
Reaction time: 0.25 h

Procedure:
Ethyldiisopropylamine (10.3 mL) and chloromethyl methyl ether (4.5 mL) were added to a solution of 4-propylphenol (4.09 g) in methylene chloride (60 mL) under ice cooling to form a reaction solution. This reaction solution was stirred for 15 minutes under ice cooling, and then left overnight at normal temperature. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resultant product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target product (4.50 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([Sn](CCCC)(CCCC)CCCC)[CH2:4][CH3:5])[CH3:2].I[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:21]1[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][CH:20]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1ccc(I)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N(CC)CC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCN(CC)c1cccc(C)c1

Procedure:
Analogous reaction of N,N-diethylaminotributyltin with aromatic iodides were less efficient; however, satisfactory yields (>60% yields of isolated product) could be obtained in the presence of ammonium salts. Thus, the reaction of N,N-diethylaminotributyltin with p-iodotoluene in the presence of N-benzyltriethylammonium chloride in toluene at 100° C. afforded 3-(N,N-diethylamino)toluene in 63% isolated yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:14][CH2:13][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1cc(C)c2ccccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: COc1cc(CBr)c2ccccc2n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
0.95 g (5.48 mmol) of 2-methoxy-4-methyl quinoline was dissolved in 10 mL of 1,2-dichloroethane, and then 1.17 g (6.58 mmol) of N-bromosuccinimide and 44 mg (0.27 mmol) of 2,2′-azobisisobutyronitrile were added, and stirred for 2 hours while heated at 90° C. After stirring was completed, the solution was cooled to a normal temperature, and the solvent was removed under reduced pressure to obtain 4-(bromomethyl)-2-methoxyquinoline. The obtained 4-(bromomethyl)-2-methoxyquinoline was used in a next step without any particular isolation and purification.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:8]2[CH2:2][CH2:3][O:4][CH2:5][C:6]2=[O:7])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=C(COCCCl)Nc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1COCCN1c1ccc([N+](=O)[O-])cc1
Reaction time: 18 h

Procedure:
1.3 1 kg of “A1” is dissolved in 5 liters of acetonitrile at room temperature, 835 g of potassium carbonate are added, and the mixture is stirred at this temperature for 18 hours. The mixture is warmed to 50° and worked up analogously to Example 6, giving 4-(4-nitrophenyl)-3-oxomorpholine (“A2”), m.p. 150-152°.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][C:18]=3[O:33][CH3:34])=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1)(=O)=O>>[Cl:23][C:21]1[C:20]([C:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:41][CH2:42][CH:43]=2)=[CH:19][C:18]([O:33][CH3:34])=[C:17]([CH:22]=1)[C:15]([N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]2[CH2:6]1)=[O:16]
Reactant: O=S(=O)(Oc1cccc2ccccc12)C(F)(F)F
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Product: COc1cc(C2=CCCc3ccccc32)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Yield: 87.8 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[5-chloro-2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 1 Step E (0.170 g, 0.355 mmol) and naphthalen-1-yl trifluoromethanesulfonate (0.109 g, 0.391 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with 40% ethyl acetate in hexane followed by recrystallization from diethyl ether/pentane afforded the title compound (0.150 g) as white crystals, m.p.: 209–210° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][CH2:20][CH2:21][N:22]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:29][CH2:28]3)=O)[CH3:23])[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1.[OH-].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:54].Cl>C1COCC1.O>[ClH:54].[ClH:54].[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][N:27]3[CH2:28][CH2:29][CH:30]([O:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:31][CH2:32]3)[CH3:23])[O:15][CH2:16][CH2:17][O:18]2)=[CH:12][CH:13]=1
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CC(=O)N1CCC(Oc2ccccc2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCC1(c2ccc(F)cc2)OCCO1)CCN1CCC(Oc2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a suspension of 1.9 g (25.1 mmol) of lithium aluminum hydride (50% in oil; washed three times with hexane) in 75 ml dry THF, cooled by an ice bath, was added dropwise a solution of 1-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylaminoacetyl}-4-phenoxypiperidine (from above) in 75 ml of dry THF. The suspension was heated at reflux for 12 hours and allowed to cool to room temperature. To the mixture, in an ice bath were added slowly dropwise 1 ml of water, 1 ml of 15% NaOH and 3 ml of water. The mixture was filtered and washed with THF. The solvent was evaporated from the filtrate to provide an oil which was extracted with ether and washed with saturated sodium chloride. The solution was dried over potassium carbonate and filtered to provide an oil. The overall yield of the dihydrochloride was 7.47 g (82.0%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.Cl.[CH2:18]([CH2:25][NH:26][CH2:27][CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CCCCCC.C(OCC)C>[CH2:18]([CH2:25][NH:26][CH2:27][CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[OH:38])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=C1c2ccccc2CCC1CNCCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1(c2ccc(C(F)(F)F)cc2)c2ccccc2CCC1CNCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cooled (−78° C.), stirred mixture of n-butyllithium in hexane (1.6 M, 34.7 cm3) and diethyl ether (25 cm3) was added 4-bromobenzotrifluoride (7.8 g). After a further 15 min, 2-(N-benzylmethylamino)methyl-3,4-dihydro-2H-naphthalen-1-one hydrochloride (prepared using methods described in Process 1) was added portion-wise. The reaction mixture was then stirred for 1 h before being allowed to warm to room temperature and then water (50 cm3) was added. The organic layer was separated and washed with water (50 cm3). It was then extracted with hydrochloric acid (2 M, 50 cm3) and the acidic aqueous portion was basified with solid sodium carbonate and extracted with dichloromethane (100 cm3). The combined organic extracts were dried (Na2SO4) and the solvent was removed under reduced pressure to afford the title compound as a colourless oil.
Reaction SMILES: [CH2:1]([C:8]([CH2:15][S:16][CH3:17])(C(O)=O)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(CSC)(C(OCC)=O)C(OCC)=O)C1C=CC=CC=1.CO.Cl>O>[CH3:17][S:16][CH2:15][CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([OH:11])=[O:10]
Reactant: CSCC(Cc1ccccc1)(C(=O)O)C(=O)O
Agent: CCOC(=O)C(CSC)(Cc1ccccc1)C(=O)OCC
Agent: Cl
Solvent: CO
Solvent: O
Product: CSCC(Cc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 17.1 %

Procedure:
Preparation of 2-benzyl-2-(methylthiomethyl)malonic acid—Powdered potassium hydroxide (4.8 g, 86 mmol, 5.0 equiv) was added to a stirred solution of diethyl 2-benzyl-2-(methylthiomethyl)malonate (5.3 g, 17 mmol, 1.0 equiv) in 3:1 methanol:water (28 mL) at 23° C. The resulting pale yellow suspension was heated to 100° C. and stirred for 4 h. The cooled reaction mixture was acidified to pH≈9 with concentrated hydrochloric acid and washed with diethyl ether (4×50 mL). The aqueous layer was acidified to pH≈1 with concentrated hydrochloric acid and extracted with dichloromethane (4×60 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a white powder (3.1 g, 72%): 1H NMR (300 MHz, DMSO-d6) δ 7.13-7.34 (m, 5H), 3.15 (s, 2H), 2.73 (s, 2H), 2.08 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][C:6]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][C:4]=1B(O)O.Br[C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[CH:24]=[CH:25][C:26]([OH:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].Cl>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.C(OCC)(=O)C.O.COCCOC>[C:9]([C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:30]2[CH:31]=[CH:21][CH:22]=[C:23]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])[CH:29]=2)[CH:5]=[C:6]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: COc1c(B(O)O)cc(C(C)(C)C)cc1C(C)(C)C
Reactant: O=C(O)C=Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(-c2cccc(C=CC(=O)O)c2)cc(C(C)(C)C)cc1C(C)(C)C

Procedure:
2.2 g (8.3 mmol) of 2-methoxy-3,5-di-tert-butylphenylboronic acid, 942 mg (4.15 mmol) of 3-bromocinnamic acid and 70 ml of DME were introduced into a three-necked flask under a stream of nitrogen. 11.4 ml of aqueous potassium carbonate solution (2M) were added dropwise and the reaction medium was degassed. 144 mg (0.12 mmol) of tetrakistriphenylphosphinepalladium(0) were then added and the mixture was refluxed for 20 hours. Water and ethyl acetate were added to the reaction medium and this mixture was acidified to pH 1 with hydrochloric acid. The organic phase was separated out after settling had taken place, washed with water, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (75/25). After evaporation of the solvents, 990 mg (66%) of 3-(3′,5′-di-tert-butyl-2′-methoxy-3-biphenylyl)acrylic acid having a melting point of 182°-3° C. were collected.