Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@H:14]([OH:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:39][C:40]1[CH:41]=[C:42](O)[CH:43]=[CH:44][CH:45]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:39][C:40]1[CH:45]=[C:44]([CH:43]=[CH:42][CH:41]=1)[O:17][C@@H:14]1[C@@H:12]2[C@@H:11]([CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=3)[CH2:13]2)[CH2:16][CH2:15]1
Reactant: O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: Oc1cccc(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cccc(O[C@H]2CC[C@@H]3CN(c4cccc(C(F)(F)F)n4)C[C@@H]32)c1
Reaction time: 7 h

Procedure:
To (3aR,4R,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-ol (90 mg, 0.331 mmol) from Example 30 and triphenylphosphine (173 mg, 0.661 mmol) was added tetrahydrofuran (1.150 mL) and 3-fluorophenol (0.059 mL, 0.661 mmol) followed by dropwise addition of diisopropyl azodicarboxylate (DIAD, 0.129 mL, 0.661 mmol). The reaction mixture was stirred for 7 hours and then quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic washes were purified by silica gel chromatography using 0-6% ethyl acetate/hexane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.56 (d, J=8.0, 1H), 7.31 (dd, J=15.3, 8.2, 1H), 7.02 (d, J=7.3, 1H), 6.92 (dt, J=11.2, 2.4, 1H), 6.89-6.77 (m, 2H), 6.56 (d, J=8.6, 1H), 4.65 (d, J=2.2, 1H), 3.69 (dd, J=11.0, 8.9, 1H), 3.52 (dd, J=10.7, 7.6, 1H), 3.41 (dd, J=11.3, 4.7, 1H), 3.25 (dd, J=10.7, 3.0, 1H), 2.93-2.78 (m, 2H), 2.10-1.94 (m, 2H), 1.82 (dt, J=13.8, 7.1, 1H), 1.50-1.37 (m, 1H); MS (ESI+) m/z 367 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6]3=[N:13][C@@H:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[N:5]3[C:4]=2[N:3]=1.[C:19]([O:22][CH2:23]Br)(=[O:21])[CH3:20]>>[CH3:1][C:2]1[N:10]([CH2:23][O:22][C:19](=[O:21])[CH3:20])[C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6]3=[N:13][C@@H:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[N:5]3[C:4]=2[N:3]=1
Reactant: CC(=O)OCBr
Reactant: Cc1nc2c([nH]1)C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12
Product: CC(=O)OCn1c(C)nc2c1C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12

Procedure:
Treat 5,6a(R),7,8,9,9a(S)-hexahydro-2,5-dimethylcyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one from Example 19a with bromomethyl acetate in accordance with Example 47 to give the title compound as a powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[OH:12].S1(=O)(=O)[N:17]2[CH2:18][CH2:19][CH2:20][C@H:16]2[CH2:15]O1.Cl>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[O:12][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1
Reactant: O=S1(=O)OC[C@@H]2CCCN21
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(Cl)c(OC[C@@H]2CCCN2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.2 %

Procedure:
Sodium hydride 55% in oil (1.4 g; 29.8 mmol) was added portionwise over 10 minutes to a stirred solution of 2,4,6-trichlorophenol (5.89 g; 29.8 mmol) in dry dimethylformamide (90 ml) at a temperature of 10° C. under nitrogen. The reaction mixture was stirred for 20 minutes at ambient temperature followed by the addition of (S)-tetrahydro-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (5.0 g; 30.6 mmol), which was prepared as described in example P14, in dimethylformamide (25 ml). The reaction mixture was stirred for 4 hours at ambient temperature then poured onto 1M HCl (400 ml) and extracted with ethyl acetate (2×200 ml). The combined ethyl acetate layers are washed with water (2×100 ml), saturated NaCl (100 ml) and then dried over Na2SO4. After removal of the solvent the residue (11.1 g oil) was dissolved in dioxane (150 ml) and treated with sulphuric acid (2.9 ml) and water (2.9 ml). The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was poured on sat. NaHCO3 (300 ml) and extracted with dichloromethane (3×200 ml). The organic layers are washed with saturated NaCl (100 ml) and then dried over Na2SO4. After evaporation of the solvent, the crude product (7.16 g in the form of a orange oil) was purified by flash chromatography over silica gel (eluent:dichloromethane/methanol 9:1) to afford 3.53 g (42.0% of theory) of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine as a oil.
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[O:4].[NH2:6][C:7]1[C:8]([F:35])=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:30])=[C:21]([N:24]4[CH2:28]C[C@H:26](N)[CH2:25]4)[N:22]=3)[C:17](=[O:31])[C:16]([C:32]([OH:34])=[O:33])=[CH:15]2)[CH:10]=[CH:11][C:12]=1[F:13].[CH:36]([O:39][CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]>C(O)=O>[CH:36]([O:39][CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37].[NH2:6][C:7]1[C:8]([F:35])=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:30])=[C:21]([N:24]4[CH2:25][CH2:26][C@H:1]([NH:2][CH:3]=[O:4])[CH2:28]4)[N:22]=3)[C:17](=[O:31])[C:16]([C:32]([OH:34])=[O:33])=[CH:15]2)[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: CN(C)C=O
Reactant: Nc1c(F)ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](N)C4)nc32)c1F
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: Nc1c(F)ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](NC=O)C4)nc32)c1F
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To 600 mg of N,N-dimethylformamide were added 210 mg of 1-(3-amino-2,4-difluorophenyl)-7-[(3S)-3-aminopyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 40 mg of formic acid. The solution was stirred at 120° C. for 1 hour. After 8 ml of diisopropyl ether was added and stirred, the solution was allowed to stand. The supernatant was decanted off. Then 2 ml of ethanol was added, and the solution was heated at reflux for 20 minutes and allowed to cool down. The precipitate was collected by filtration and washed with ethanol and then diisopropyl ether to give 180 mg of the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].O=[C:12]([CH3:19])[CH2:13][C:14](OCC)=[O:15]>CCO.CC(O)=O>[OH:15][C:14]1[N:1]([C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][N:10]=2)[N:2]=[C:12]([CH3:19])[CH:13]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccnc(NN)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(O)n(-c2cc(C#N)ccn2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of 2-hydrazinylisonicotinonitrile (536 mg, 4 mmol, PREPARATION 2) and ethyl 3-oxobutanoate (780 mg, 6 mmol) in EtOH (10 mL) and AcOH (2 mL) was stirred at 90° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (CH2Cl2) to afford the title compound (500 mg, 67%) as a yellow solid. [M+H] Calc'd for C10H8N4O, 201; Found, 201.
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)=[O:20])[CH2:13]1)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd]>[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)=[O:20])[CH2:13]1
Reactant: O=C(NC1CCCN(Cc2ccccc2)C1)c1ccc2[nH]ncc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NC1CCCNC1)c1ccc2[nH]ncc2c1
Reaction time: 4 h
Yield: 96.5 %

Procedure:
Ammonium formate (0.363 g) and 10% Pd—C (0.074 g) were added to a suspension of the N-(1-benzylpiperidin-3-yl)-1H-indazole-5-carboxamide (0.357 g, 1.06 mmol) obtained in Example 138 in ethanol (10 ml), and the resulting mixture was stirred for 4 hours with heating under reflux. The resulting solution was filtered by the use of Celite and then the solvent was distilled off from the filtrate to obtain a solid. The solid obtained was suspended in ethyl acetate, stirred to be washed, collected by filtration and dried under reduced pressure to obtain N-(3-piperidinyl)-1H-indazole-5-carboxamide (0.250 g, 96%).
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[CH:14]=[C:13](/[CH:15]=[C:16](\[O-])/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([N+:23]([O-])=O)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+]>C(O)(=O)C.C1(C)C=CC=CC=1.[Fe]>[CH2:26]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[C:13]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:23][C:12]2=[CH:11][N:10]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)/C([O-])=C/c1cc(N(Cc2ccccc2)Cc2ccccc2)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
To a solution of potassium (1Z)-1-[2-(dibenzylamino)-5-nitropyridin-4-yl]-3-ethoxy-3-oxoprop-1-en-2-olate (5.0 g, 10.6 mmol) in acetic acid (151.4 mL) was added iron powder (2.43 g, 43.5 mmol) under a nitrogen atmosphere. The mixture was warmed to 60° C. and stirred for 2 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to ca. 100 mL in volume. The concentrate was poured into rapidly stirring water (ca. 200 mL). The precipitate was observed. Ethyl acetate (150 mL) was added and the mixture was stirred until the solid was dissolved. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×). The combined extracts were washed with dilute NaHCO3 and saturated NaCl, and dried over Na2SO4. The solution was dark red. Consequently, activated charcoal (Darco G-60, 1.20 g) was added to the solution. After filtration through diatomaceous earth, the filtrate was concentrated to dryness to afford a dark brown solid. The solid was sonicated in toluene (ca. 75 mL) for 30 min. After standing at room temperature overnight, the solid was collected by filtration and rinsed with toluene to give ethyl 5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.80 g, 19%) as a yellow solid. Further manipulation of the mother liquors provided additional material (0.19 g, 5%): mp 169-174° C.; 1H NMR (300 MHz, CD3OD) δ1.38 (3H, t, J=7.0 Hz), 4.37 (2H, q, T=7.0 Hz), 4.75 (4H, s), 6.64 (1H, d, J=0.9 Hz), 6.85 (1H, d, J=0.9 Hz), 7.21-7.27 (10H, m), 8.48 (1H, s); ESI MS m/z 386 [C24H23N3O2+H]+; HPLC (Method A) >99% (AUC), tR=20.1 min.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCCC1.[C:16](Cl)(=[O:38])[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][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16](=[O:38])[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][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 88 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, 138 g of p-nitroaniline was dissolved in a mixed solvent consisting of 3000 ml of tetrahydrofuran and 140 ml of pyridine while passing nitrogen gas through the flask. Then, 395 g of docosanoylchloride placed in the dropping funnel was gradually dropped into the flask over a time span of 20 minutes, while stirring the reaction mixture. After the completion of the dropping, the reaction mixture was further stirred for 2 hours. A solid reaction product was produced. The solid reaction product was collected by filtering, the filtrate was concentrated under a reduced pressure to produce crystals. The crystals were collected and recrystallized from ethyl alcohol. As a result, 405 g of 4'-nitro-n-docosaneanilide was obtained at a yield of 88%.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@@H:21](O)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([O:9][C:8]2[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[O:6][CH3:7])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: COc1cc(C=O)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
In 50 ml of tetrahydrofuran were dissolved 3.04 g of vanillin, 3.74 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 5.24 g of triphenylphosphine. The thus prepared solution was mixed with 4.00 g of diethyl azodicarboxylate, and the mixture was stirred at room temperature for 18 hours. After concentrating the resulting reaction solution, the thus obtained residue was purified by subjecting it to silica gel column chromatography using an ethanol/chloroform mixture as an elution solvent. In this way, 5.0 g of the title compound was obtained in an oily form.
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])C.[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[Al](C)C.CCCCCC>ClCCl>[C:15]1([C@@H:21]([NH:23][C:4]([C:6]2[S:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[N:14]=2)=[O:5])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1nc2ccncc2s1
Reactant: C[C@H](N)c1ccccc1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: C[C@H](NC(=O)c1nc2ccncc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of thiazolo [5,4-c]pyridine-2-carboxylic acid ethyl ester (16 mg, 0.08 mmol) and 1(S)-phenyl ethyl amine (0.03 mL, 0.23 mmol)in dichloromethane(0.3 mL) was added a solution of trimethylaluminum in hexane(0.115 mL, 2.0 M., 0.23 mmol). The solution was then stirred for 5 hours at room temperature. After usual work-up, the product was purified by flash chromatography (CH2Cl2/EtOAc 1:1)and triturated in hexane to give 12 mg of the thiazolo derivative.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([O-:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Na+].[CH2:26](Cl)[CH2:27][CH2:28][CH3:29]>C1COCC1>[CH2:26]([O:24][CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCC([O-])CCCCCCCCCCC
Reactant: CCCCCl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(CCCCCCCCCCC)OCCCC
Temperature: -6.666666666666667 °C

Procedure:
40.3 g (0.118 mole) 12-tricosanol (Example 2) was heated with 3.0 g (0.13 mole, 10% molar excess) sodium metal to 130° C. for a period of 15 hrs during which most of the sodium dissolved with hydrogen evolution to form the corresponding alkoxide, sodium 12-tricosanolate, which is liquid at 130° C. The thus prepared sodium 12-tricosanolate was subsequently treated with 20 ml (0.19 mole, 60% molar excess) n-butyl chloride in the presence of 20 ml THF at 90° C. for 7 days. The resulting reaction mixture was quenched with aqueous sodium hydroxide and extracted with heptane. The heptane solution was cooled to 20° F. during which 8.9 g of solid precipitate (unconverted 12-tricosanol and 12-tricosanone) formed and was removed. The heptane was evaporated at 80° C., 10 torr to yield the 12-tricosanyl n-butyl ether (33.2 g) as a colorless oil having the following properties: VI=147, VIS100=2.768 cSt, VIS40=9.395, cloud point: −3° C., pour point: −4° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][OH:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>N1CCCC1>[CH2:15]([NH:19][C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:19]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:3][C:4]([CH3:14])=[N:5]2)=[CH:10][CH:9]=1)=[O:13])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1cc(Cl)c2ccc(CO)cc2n1
Reactant: CCCCN
Solvent: C1CCNC1
Product: CCCCNC(=O)c1ccc2c(N3CCCC3)cc(C)nc2c1
Yield: 43 %

Procedure:
(4-Chloro-2-methyl-quinolin-7-yl)-methanol (example 2, 200 mg, 0.80 mmol) was refluxed in butylamine (2 mL) for 6 h. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was separated, dried (MgSO4), and evaporated. The residue was chromatographed (SiO2, CH2Cl2/MeOH 19:1) to produce a yellow oil, which was heated in pyrrolidine (2 mL) at 70° C. for 16 h. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was separated, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) afforded the title compound (108 mg, 43%). White solid, ISP-MS: m/e=312.3 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C:16]1[N:20]([CH3:21])[C:19]2[CH:22]=[CH:23][C:24]([N:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)[CH3:27])=[CH:25][C:18]=2[N:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][S:44]([NH2:47])(=[O:46])=[O:45])=[CH:39][CH:38]=1>>[C:1]([O:5][C:6](=[O:35])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:16]1[N:20]([CH3:21])[C:19]2[CH:22]=[CH:23][C:24]([N:26]([CH3:27])[C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:36][C:37]4[CH:42]=[CH:41][C:40]([CH2:43][S:44](=[O:46])(=[O:45])[NH2:47])=[CH:39][CH:38]=4)[N:29]=3)=[CH:25][C:18]=2[N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Product: COc1ccc(N(C(=O)OC(C)(C)C)c2nc3cc(N(C)c4ccnc(Nc5ccc(CS(N)(=O)=O)cc5)n4)ccc3n2C)cc1

Procedure:
The title compound was prepared following the procedure of example 78 using {5-[(2-Chloro-pyrimidin-4-yl)-methyl-amino]-1-methyl-1H-benzoimidazol-2-yl}-(4-methoxy-phenyl)-carbamic acid tert-butyl ester (100 mg, 0.20 mmol) and (4-amino-phenyl)-methanesulfonamide (37 mg, 0.20 mmol) to give the desired product as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 9.20 (s, 1H), 7.81 (d, J=6.0 Hz, 1H), 7.65-7.73 (m, 3H), 7.54 (d, J=1.8 Hz, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.24 (dd, J=8.4 and 1.8 Hz, 1H), 7.16 (d, J=8.4 Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 6.75 (s, 2H), 5.69 (d, J=6.0 Hz, 1H), 4.14 (s, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.46 (s, 3H), 1.41 (s, 9H). MS (ESI) m/z=645 [M+H]+.
Reaction SMILES: [Mg].Br[C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].[CH2:11]([Si:14](OC)([O:17][CH3:18])[O:15][CH3:16])[CH2:12][CH3:13].Cl>CCOCC>[CH3:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:3]=1[Si:14]([CH2:11][CH2:12][CH3:13])([O:17][CH3:18])[O:15][CH3:16]
Reactant: CCC[Si](OC)(OC)OC
Reactant: Cc1cccc(C)c1Br
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCC[Si](OC)(OC)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
A 500 mL round bottomed flask was charged with magnesium powder (2.1 g, 86 mmol, Aldrich) and ether (250 mL, Aldrich). 2-Bromo-m-xylene (9.0 mL, 68 mmol, Aldrich) was added over a 25 minute period. The contents were refluxed overnight (18 hours). The brown solution was cooled to room temperature and propyl-trimethoxysilane (17.8 mL, 101 mmol) was added over 20 minutes. A white precipitate formed. The contents were stirred at room temperature overnight (18 hours). The reaction was poured into 0.2N aqueous HCl (500 mL), the layers were separated and the product extracted into ether (3×150 mL). The combined organic portions were dried (MgSO4), filtered, and the solvent removed via rotary evaporation (13.5 g crude). Distillation under reduced pressure (b.p. 57° C., 0.04 mm Hg) provided (2,6-dimethylphenyl)-propyl-dimethoxysilane (6.8 g, 28 mmol, 41% yield); C13H22SiO2 (Mw=238.40); 1H NMR (CDCl3) δ 7.2 (t, 1H), 7.0 (d, 2H), 3.6 (s, 6H), 2.5 (s, 6H), 1.4 (m, 2H), 1.0 (t, 3H), 0.9 (t, 2H); 13C NMR (CDCl3) δ 145.2, 131.0, 129.6, 128.0, 49.8, 23.4, 17.9, 16.7, 16.3; MS m/z (relative abundance) 238 (8), 195 (100), 165 (22), 133 (12), 119 (10), 105 (13), 91 (9), 59 (16).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:30])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.[NH2:34][CH2:35][C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1.C(N(CC)CC)C>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:30])=[C:23]([CH3:29])[CH:24]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: Cc1cc(Cl)ccc1OCC(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)COc2ccc(Cl)cc2C)C3)cc1

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 75 (0.3 mmol), methyl 4-(aminomethyl)benzoate hydrochloride (2.2 eq.) and triethylamine (2.4 eq.) in the manner of Example 68, m.p.165-167° C. MS [(+)ESI, m/z]: 558 [M+H]+ Anal. Calcd for C31H28CIN3O5: C, 66.72; H, 5.06; N, 7.53. Found: C, 66.46; H, 5.26; N, 7.24.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:25][O:24][C:20]1[C:19]2[CH:15]([NH:14][C:11]3[O:12][CH2:13][C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:27]=[CH:26][C:9]=4[N:10]=3)[CH2:16][O:17][C:18]=2[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CO2
Reactant: C1COCCN1
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CN4CCOCC4)cc3CO1)CO2
Yield: 35.4 %

Procedure:
Prepared from rac-2-chloro-N-[2-(4-methoxy-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 8) (50 mg, 0.129 mmol) and morpholine (225 ul, 2.578 mmol) according to the procedure described for Example 3 step B (here the reaction was sonicated for 2 min, which already lead to complete conversion). Obtained the title compound as a white solid (20 mg, 35%), MS (ISP) m/e=439.3 [(M+H)+].
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([CH2:23][C:24]#[N:25])[CH:20]=[CH:21][CH:22]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([CH2:23][C:24]#[N:25])[CH:20]=[CH:21][CH:22]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c1c(-c1cccc(CC#N)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#CCc1cccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of (3-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (120 mg) in acetonitrile (10 mL) were added sodium iodide (108 mg) and chloro(trimethyl)silane (0.366 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate to give the title compound (105 mg).