Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:20]=[CH:19][C:10]([NH:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([N+:21]([O-])=O)[CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].C(O)(=O)C>C(OCC)(=O)C.[C].[Pd]>[NH2:21][C:9]1[CH:8]=[C:7]([S:4]([CH:1]([CH3:2])[CH3:3])(=[O:5])=[O:6])[CH:20]=[CH:19][C:10]=1[NH:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)S(=O)(=O)c1ccc(NCCN2CCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(NCCN2CCCC2)c(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture of crude 4-(isopropylsulfonyl)-2-nitro-N-(2-pyrrolidin-1-ylethyl)aniline (Step A), 10% palladium carbon (20 mg) and acetic acid (0.2 mL) in ethyl acetate (5 mL) was stirred for 2 h at room temperature under H2 atmosphere then the reaction mixture was filtered. The filtrate was evaporated under reduced pressure. The residue was purified by amine coated silica gel column chromatography (hexane:ethyl acetate=1:2) to give the title compound as an orange solid (122.9 mg, 52%, 2 steps).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[CH2:5][CH2:6][C:3]=12.C(N(CC)CC)C.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>C1C=CC=CC=1>[CH3:19][Si:18]([CH3:21])([CH3:20])[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[CH2:5][CH2:6][C:3]=12
Reactant: Oc1cccc2c1CC2
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C[Si](C)(C)Oc1cccc2c1CC2
Temperature: 5 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A larger batch of 4-trimethylsiloxybenzocyclobutene was synthesized from 6.56 gms of 4-hydroxybenzocyclobutene and 5.54 gms of triethylamine, taken up in 15 ml anhydrous benzene followed by the addition of a nearly three molar excess of chlorotrimethylsilane (20 ml in 15 ml dry benzene) to the reaction mixture maintained at 5° C. An instant white precipitation of triethylamine hydrochloride was observed. The solution was allowed to warm up on its own to 15° C. in about 5 hours and the reaction mixture was kept stirred overnight, It was warmed to 40° C. and maintained for about three hours. The reaction mixture was cooled and the isolation of the product was done exactly as described before. The weight of the light yellow oil (crude) was 7.93 g, 76% yield. Total amount of the colorless oil obtained from vacuum distillation was 7.07 grams. Anal. Calc.: C, 68.69%; H, 8.38%. Found: C, 69.15%; H, 8.44%.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]2[N:27]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2cccc(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester according to the method of Example 21. 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, 1H, J=3.5 Hz, 1.17 Hz), 7.41 (dd, 1H, J=5.1 Hz, 1.17 Hz), 7.19-7.16 (m, 3H), 7.08 (dd, 0.1H, J=5.1 Hz, 3.91 Hz), 6.81 (d, 2H, J=8.6 Hz), 6.75-6.62 (m, 3H), 4.17 (t, 2H, J=6.6 Hz), 3.26 (d, 1H, J=13.7 Hz), 3.14 (d, 1H, J=13.69 Hz), 2.98 (t, 2H, J=6.65 Hz), 2.36 (s, 3H), 1.45 (s, 3H). HRMS (ES+) m/z exact mass calcd for C26H25FNO5S 482.1437, found 482.1454.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].C(O)(C)(C)C.F[C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[C:39]([CH2:54][CH3:55])=[N:40][N:41]4[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=3)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1>O>[CH2:54]([C:39]1[C:38]2[C:42](=[CH:43][CH:44]=[CH:45][C:37]=2[NH:36][C:34]([C:31]2[N:28]3[CH:29]=[CH:30][C:25]([O:18][CH2:17][CH2:16][N:13]4[CH2:12][CH2:11][N:10]([CH:7]([CH3:9])[CH3:8])[CH2:15][CH2:14]4)=[CH:26][C:27]3=[N:33][CH:32]=2)=[O:35])[N:41]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=2)[N:40]=1)[CH3:55]
Reactant: CC(C)N1CCN(CCO)CC1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C(C)C)CC5)ccn34)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 50 mL round bottom flask was charged with solid potassium tert-butoxide (1.7 g, 14.8 mmol), 2-(4-isopropylpiperazin-1-yl)ethanol (2.88 g, 16.7 mmol), and tert-butanol (10 mL, 103 mmol). The mixture was stirred at ambient temperature for 1 hour before heating at 90° C. for 15 minutes to give a homogeneous mixture. 7-Fluoro-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (1.0 g, 2.3 mmol) was added in one portion. The mixture was heated at 90° C. with stirring for 16 hours. The mixture was cooled to ambient temperature before pouring into a 250 mL round bottom flask containing 150 mL of water. Vigorous stirring at ambient temperature for 2 hours resulted in a beige precipitate. The precipitate was collected by filtration and dried under high vacuum to give the product. MS (APCI), positive scan, m/z=581.1 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:9]([C:4]2[CH:3]=[C:2]([Br:1])[CH:12]=[CH:11][C:5]=2[C:6]([OH:8])=[O:7])=[O:10])=[CH:20][CH:19]=1
Reactant: Fc1ccccc1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1ccc(Br)cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 10 %

Procedure:
To a solution of 4-bromophthalic anhydride (50 g, 220 mmol) in fluorobenzene (300 mL) was added aluminum chloride (60 g, 450 mmol) by small portions under ice-cooling. The-obtained mixture was stirred at room temperature for 15 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether and the precipitated crystals were collected by filtration. The crystals were recrystallized from ethyl acetate to give a solid of a mixture (9:1)(7 g, 10%) of 2-(4-fluorobenzoyl)-4-bromobenzoic acid and 2-(4-fluorobenzoyl)-5-bromobenzoic acid. (2-(4-fluorobenzoyl)-4-bromobenzoic acid: 1H-NMR(CDCl3) δ: 7.06–7.17 (2H, m), 7.50 (1H, d, J=2.0 Hz), 7.69–7.79 (3H, m), 7.95 (1H, d, J=8.4 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:5]=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:26]1([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[N:5]=[C:4]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:3]=3)[CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N#Cc1c(Cl)nc(NCc2ccccn2)nc1NCc1ccccn1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCc2ccccn2)nc(NCc2ccccn2)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-[(pyridin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine in the presence of N-ethyl-diisopropylamine in dioxane at 90° C. during 18 hours to yield 4-(4-phenyl-piperazin-1-yl)-2,6-bis-[(pyridin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, yellowish solid; MS: [M+H]+=478.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>C1C=CC=CC=1>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:2]([CH3:3])[CH3:1])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: BrCc1ccc(Br)cc1
Solvent: c1ccccc1
Product: CN(C)Cc1ccc(Br)cc1

Procedure:
Reaction of dimethylamine with 4-bromobenzyl bromide in cold benzene gave 4-bromo-N,N-dimethylbenzylamine which was successively reacted with magnesium, formaldehyde, and cysteamine (in a similar procedure to Example 7) to give 2-[4-(dimethylaminomethyl)benzylthio]ethylamine as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:25]([CH2:27][C:28](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:29])#[N:26]>CN(C=O)C>[C:7]1([CH:4]2[CH2:3][CH2:2][N:1]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:6][CH2:5]2)[N:11]2[C:12]3[CH:18]=[CH:17][NH:16][C:13]=3[N:14]=[CH:15][C:10]2=[N:9][N:8]=1
Reactant: c1cc2c(ncc3nnc(C4CCNCC4)n32)[nH]1
Reactant: N#CCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC(c2nnc3cnc4[nH]ccc4n23)CC1
Reaction time: 3 h
Yield: 4.4 %

Procedure:
To a suspension of 1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.090 g, 0.37 mmol, Example #2) and pyridine (0.12 mL, 1.5 mmol) in DMF (5 mL) was added perfluorophenyl 2-cyanoacetate (0.14 g, 0.56 mmol, Preparation #6). After about 3 h at ambient temperature, the reaction mixture was quenched with MeOH (0.5 mL) and then purified by RP-HPLC (Table 2, Method b). The appropriate fractions were concentrated and lyophilized to afford 3-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile as a white solid (0.005 g, 4%): LC/MS (Table 2, Method a) Rt=1.24 min; MS m/z: 310 (M+H)+.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1.Cl[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=3)=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: 120 °C
Yield: 76 %

Procedure:
To N,N-dimethylformamide (50 ml) are added 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-hydroxyphenyl)-1-methyl-1H-1,2,4-triazole (3.04 g), 2-chloro-5-trifluoromethyl pyridine (1.70 g) and potassium carbonate (1.40 g), which is heated at 120° C. for 2 hours with stirring. After cooling to room temperature, the reaction solution is poured into water and extracted with ethyl acetate, and the layer is washed with water and dried over anhydrous magnesium sulfate. After the concentration under reduced pressure, the crude solid is purified by silica gel column chromatography using mixed solution of hexane-ethyl acetate as eluent to give 3.30 g of desired compound (melting point: 116.0°-117.0° C.).
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].C([Sn](=O)CCCC)CCC.[F:18][C:19]1[CH:20]=[C:21]([N:33]2[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:22]=[CH:23][C:24]=1[C:25]1[CH2:30][CH2:29][N:28]([C:31]#[N:32])[CH2:27][CH:26]=1.CO>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([N:33]2[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:22]=[CH:23][C:24]=1[C:25]1[CH2:30][CH2:29][N:28]([C:31]2[NH:32][N:3]=[N:2][N:1]=2)[CH2:27][CH:26]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C#N)CC3)c(F)c2)C(=O)O1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(c4nnn[nH]4)CC3)c(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Azidotrimethylsilane (154 mg) and dibutyltin oxide (97 mg) were added to a stirred suspension of Example 24 (240 mg) in dry toluene (10 ml), and the mixture stirred at 70° C. for 18 hours. On cooling, methanol (5 ml) was added and after stirring for 10 minutes the solvent was evaporated. The title compound was isolated by MPLC (20% MeOH/CH2Cl2, Merck 9385 silica) and crystallised on evaporating the fractions to a small volume. The title product was filtered off washed with a little cold methanol (150 mg, 56%).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[CH:15]=1)=[O:28]
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Product: CC(=O)CCCCn1cc(NC(=O)/C=C/c2ccc(F)cc2Cl)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[Li]CCCC.[CH3:16][C:17]1([CH3:28])[C:21]([CH3:23])([CH3:22])[O:20][B:19](OC(C)C)[O:18]1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[C:7]([B:19]3[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:28])([CH3:16])[O:18]3)[O:8][C:4]=2[CH:3]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Clc1ccc2ccoc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc3ccc(Cl)cc3o2)OC1(C)C
Reaction time: 1.5 h

Procedure:
To a solution of 6-chloro-1-benzofuran (2 g, 13.11 mmol) in tetrahydrofuran (30 mL) was added n-BuLi (10 mL, 2.5N) at −78° C. and stirred for 1.5 h. Then 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (4.4 g, 23.65 mmol) was added and stirred for 1.5 h. The reaction solution was quenched by water (100 mL), extracted with ethyl acetate (3×50 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum to give 2-(6-chloro-1-benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a reddish crude solid (3 g, crude).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][C:32]1[S:44][C:35]2=[N:36][C:37]([Cl:43])=[C:38]([C@H:40](O)[CH3:41])[CH:39]=[C:34]2[CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:31][C:32]1[S:44][C:35]2=[N:36][C:37]([Cl:43])=[C:38]([C@@H:40]([N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[CH3:41])[CH:39]=[C:34]2[CH:33]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H](O)c1cc2cc(Cl)sc2nc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](c1cc2cc(Cl)sc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a reaction flask was combined phthalimide (1.530 g, 10.40 mmol), triphenylphosphine (2.73 g, 10.40 mmol), (R)-1-(2,6-dichlorothieno[2,3-b]pyridin-5-yl)-ethanol (2.15 g, 8.66 mmol) and tetrahydrofuran (57.8 mL). The reaction was cooled to 0° C. and diisopropyl azodicarboxylate (2.043 mL, 10.40 mmol) was added dropwise. The reaction was removed from the ice bath and allowed to warm to rt and stir overnight. The reaction was diluted with ethyl acetate and washed with NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated. Purification using 5-10% ethyl acetate in hexanes afforded (S)-2-(1-(2,6-dichlorothieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione. 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.82 (m, 2H), 7.73*m, 2H), 7.18 (s, 1H), 5.90 (q, 7.3 Hz, 1H), 1.90 (d, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:13]1[O:17][C:16]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=1)=O.N1CCCCC1>CCO>[O:10]=[C:2]1[NH:1][C:9]2[C:4](/[C:3]/1=[CH:11]\[C:13]1[O:17][C:16]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C=O)o2)c1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c1
Yield: 91.4 %

Procedure:
A solution of oxindole (235 mg, 1.76 mmol), tert-butyl 3-(5-formylfuran-2-yl)phenylcarbamate (500 mg, 1.74 mmol) and piperidine (0.18 mL, 1.80 mmol) in EtOH (5.0 mL) was stirred at rt overnight. The resulting precipitate was collected by filtration to yield desired (E)-tert-butyl 3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)phenylcarbamate (640 mg). LCMS (ES): m/z 403 [M+1]+.
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:20])[C:8]([CH3:19])=[C:9]([C@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)[O:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Br[CH2:29][CH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>CN(C)C=O>[OH:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:20])[C:8]([CH3:19])=[C:9]([C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[CH2:29][CH2:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[O:10]2)=[CH:5][CH:4]=1
Reactant: BrCCOC1CCCCO1
Reactant: Cc1c([C@H]2CCCN2)oc2c(C)c(O)ccc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c([C@H]2CCCN2CCOC2CCCCO2)oc2c(C)c(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.6 %

Procedure:
To a solution of 7-hydroxy-3,8-dimethyl-2-[(2R)-pyrrolidin-2-yl]-4H-chromen-4-one hydrochloride (70 mg, 0.27 mmol) obtained in Example 2-3 and triethylamine (56 μL, 0.40 mmol) in dimethylformamide (1.5 mL), 2-(2-bromoethoxy)tetrahydro-2H-pyran (163 μL, 1.08 mmol) was added dropwise, and then the mixture was stirred at room temperature for 20 hours. Triethylamine (38 μL, 0.27 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (41 μL, 0.27 mmol) were further added dropwise thereto, and then the mixture was stirred at room temperature for 27 hours. The reaction solution was concentrated, and then the obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0→90/10) to obtain 77 mg of the title compound (yield: 74%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:15])=[C:4]([CH2:13][OH:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([I:15])=[C:4]([CH2:13][O:14][C:16](=[O:18])[CH3:17])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8]
Reactant: Nc1c(I)c(CO)c(I)c(C(=O)O)c1I
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)O)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
5-Amino-3-hydroxymethyl-2,4,6-triiodobenzoic acid (41.2 g, 0.076 mol) was dissolved in pyridine (100 ml), and acetic anhydride (80 ml) was added slowly with efficient stirring at room temperature. Stirring was continued overnight. The reaction mixture was then evaporated to a semisolid mass and treated with hydrochloric acid (2M, 250 ml). The white to grey precipitate formed was filtered off and washed with water (2×40 ml) and then dried. 44.2 g (100%) of product was isolated.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:7][CH:6]=1)=[O:4].[Br:18]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][Br:18])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-c2ccccc2C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2ccccc2CBr)cc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A 5 L three-necked 24/40 round-bottom flask equipped with a mechanical stirrer, a reflux condenser with a nitrogen inlet at the top, and a thermometer was charged with 53.42 g (0.204 mol) of 2'-methyl biphenyl-4-carboxylic acid methyl ester, 3.4 L carbon tetrachloride, 38.09 g (0.214 mol) of N-bromosuccinimide and 2.0 g of 2,2'-azobis(2-methylpropionitrile). The flask was degassed and flushed with nitrogen, the stirrer was started and the contents were refluxed for 5 hours. The reaction mixture was then cooled to room temperature, filtered and evaporated. The residual oil was purified by recrystallization from dichloromethane-hexane to afford 48.48 g (78%) of the product which had.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f27) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [S:1](F)(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16]>C(OCC)(=O)C>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][S:1](=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2]
Reactant: CN(C)CCN
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Solvent: CCOC(C)=O
Product: CN(C)CCNS(=O)(=O)c1ccc(N)cc1

Procedure:
5.26 g sulphanilic acid fluoride and 16.5 ml of N,N-dimethyl-ethylenediamine are stirred for 4 hours at 100° C., then dissolved in ethyl acetate and extracted three times with saline solution. The residue obtained by evaporation of the organic phase is crystallised from diethyl ether and dried at 60° C.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([CH2:16][CH2:17][CH3:18])[N:6]=[N:5]1)[CH2:2][CH3:3].[H][H]>C(O)(C)(C)C.[Rh]>[NH2:5][CH:4]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([NH2:6])[CH2:16][CH2:17][CH3:18])[CH2:1][CH2:2][CH3:3]
Reactant: CCCC1CC=CCCC=CCC(CCC)N=N1
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(C)(C)O
Product: CCCC(N)CCCCCCCCC(N)CCC
Yield: 47.5 %

Procedure:
942 g (3.79 moles) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomer mixture) are dissolved in a stirred autoclave in 3800 ml of tert-butanol. After addition of 90 g of a rhodium/alumina catalyst (5% by weight), hydrogen is introduced up to a pressure of 130-150 bar and hydrogenation is effected at 150°-180° C. until the uptake of hydrogen is complete. After cooling, excess hydrogen is blown off, the suspension is sucked from the autoclave and the catalyst is collected by suction over a small amount of hyflo (filter aid). The filtrate is concentrated by rotary evaporation and the product is purified by distillation, yielding as main fraction 462 g (48% of theory) of 4,13-diaminohexadecane as a colourless oil [b.p. 132°-135° C./0.01 torr; nD20. 1.4590; IR spectrum (liquid) includes bands at 3278 and 1613 cm-1 ].