Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CNCCNC.[I-:18].[Na+].O>O1CCOCC1>[I:18][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: [I-]
Reactant: Brc1cnc2ccccc2c1
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Ic1cnc2ccccc2c1
Reaction time: 18 h
Yield: 87.2 %

Procedure:
3-Bromoquinoline (64.00 g, 308 mmol), N,N′-dimethylethylenediamine (13.5 ml, 127 mmol), cuprous iodide (12.00 g, 63.0 mmol) and sodium iodide (112 g, 747 mmol) in dioxane (300 ml) was placed into a preheated oil bath at 100° C. After stirring for 18 h, the heterogeneous mixture was diluted water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with methylene chloride as the eluant to afford 68.47 g (87% yield) of 3-iodoquinoline as a yellow solid. Method [8] retention time 6.47 min by HPLC (M+=256).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[O:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[O:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
N-tert-Butyl-2-(3-methylisoxazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 74.2 mol) was dissolved in dichloromethane (1.3 mL) and treated with trifluoroacetic acid (169 mg, 114 μL, 1.48 mmol). The mixture was stirred at room temperature for 16 h, then concentrated and re-dissolved in dichloromethane (1.3 mL), methanol (0.65 mL) and ammonium hydroxide (0.2 mL) and stirred at room temperature for 1 h. The mixture was concentrated and diluted with water, triturated and filtered. The solid obtained was washed with ether and dried to give N-tert-butyl-2-(3-methylisoxazol-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (16 mg, 45.8 mol, 62%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.53 (s, 1H), 11.06 (s, 1H), 8.14 (d, J=3.0, 1 H), 8.09 (s, 1H), 7.57 (s, 1H), 6.18 (s, 1H), 2.17 (s, 3H), 1.48 (s, 9H); MS (EI/CI) m/z: 315.1 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(NC(C)C)(C)C.C[Si](C[Li])(C)C.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([B:26]([OH:27])[OH:25])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccccn1
Agent: [Li]C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ncccc1B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A mixture of 2-methoxypyridine (23.2 g) and diisopropylamine (1.35 mL) in THF (223 mL) was added to (trimethylsilylmethyl)lithium (218 mL, 13.8 weight percent in hexanes) at −20° C. The lithiation was 84% complete after 7 hours. Tri-isopropylborate (40.8 g) was added at 20° C. over 40 minutes. The mixture was stirred overnight at ambient temperature. 5 percent NaOH (aq, 225 mL) was added. The aqueous layer was removed and brought to pH 5 by adding 10% HCl (aq). The resulting white precipitate was isolated by filtration. After drying, 22.23 g of 2-methoxypyridine-3-boronic acid was obtained (68% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[CH2:28]([N:30]([CH3:40])[CH2:31][C:32]1[N:33]=[C:34]([N+:37]([O-])=O)[NH:35][CH:36]=1)[CH3:29].CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[CH2:28]([N:30]([CH2:31][C:32]1[N:33]=[C:34]([NH:37][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[F:27])=[CH:14][CH:15]=2)=[O:3])[NH:35][CH:36]=1)[CH3:40])[CH3:29]
Reactant: CCN(C)Cc1c[nH]c([N+](=O)[O-])n1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: [Ni]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCN(C)Cc1c[nH]c(NC(=O)c2ccc(-c3c(F)c(OC)cc(OC)c3F)c3nccnc23)n1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1) and stirring the reaction mixture for 3 h at 70° C. Ethyl-methyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 157.1) instead of 2-nitroimidazole was used in Step 14.3, and Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. Title compound: ESI-MS: 483.9 [M+H]+; TLC: Rf=0.10 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:12]1([CH2:15]O)[CH2:14][CH2:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:15][CH:12]3[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCC1CC1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1c(I)cn2CC1CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (419 mg, 1.50 mmol), cyclopropylmethanol (165 μL, 147 mg, 2.04 mmol), and PS-PPh3 (2.12 mmol/g; 1.41 g, 2.99 mmol) in dry THF (10 mL), cooled by ice/water, was added DIAD (440 μL, 452 mg, 2.23 mmol; 1.5 equiv.), then the cooling bath was removed and the mixture was vortexed overnight. The resin was filtered off and washed thoroughly with THF, and the filtrate and washings were combined and concentrated. Chromatography of the crude material thus obtained on silica gel (Jones Flashmaster, 2 columns, 10 g/70 mL cartridge each, eluting with CH2Cl2) gave the title compound as an off-white solid. 1H NMR (CDCl3, 400 MHz): δ=0.41-0.47 (m, 2H), 0.63-0.69 (m, 2H), 1.20-1.31 (m, 1H), 4.12 (d, J=7.2 Hz, 2H), 7.52 (s, 1H), 8.61 (s, 1H). MS (ES+): m/z 333.9/335.9 (100/38) [MH+]. HPLC: tR=3.7 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[C:13](OC(=O)C)(=O)C.Cl>>[C:5]([NH:6][C:7]1[C:1](=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:2]([OH:4])=[O:3])(=[O:12])[CH3:13]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)Nc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 94 %

Procedure:
The isatoic anhydride and acetic anhydride were combined in a three necked, round bottomed flask equipped with a mechanical stirrer, dropping funnel, thermometer, reflux condenser and drying tube. The acetic anhydride was added to the mixture through the dropping funnel over a period of 30 minutes. The reaction was heated to 90°-100° C for 1.5 hours and then cooled to room temperature. The cooled reaction mixture was poured into a kilogram of ice containing 150 ml of concentrated hydrochloric acid. The white solid which precipitated was isolated, washed with 200 ml of water and dried to give 51.5 parts (94% yield) of N-acetylanthranilic acid having m.p. 183°-185° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.CCOCC.[Cl-].[CH3:18][C:19]1[C:25](=O)NC(=O)N([C@@H]2O[C@@H]3COP(O)(O[C@H]3C2)=O)[CH:20]=1.ClCl>>[C:19]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)([CH3:25])([CH3:20])[CH3:18]
Reactant: Cc1cn([C@H]2C[C@@H]3OP(=O)(O)OC[C@H]3O2)c(=O)[nH]c1=O
Reactant: Oc1ccccc1
Agent: ClCl
Agent: FB(F)F
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(O)cc1

Procedure:
To a solution of phenol, 1 molar in hexanes, at 40°-45° C. stirred in a three neck flask fitted with condenser, pressure-equalized dropping funnels, magnetic stirrer and dry-nitrogen inlet/outlet, was added freshly distilled undiluted boron trifluoride etherate (0.07 mole). Subsequently olefin or tert.-chloride (0.2 molar in hexanes) was added dropwise. The olefins used were the model compound TMP, or the olefin telechelic PIB; the tert.-chlorides used were CTMP, or the tert.-chloride telechelic PIB. The olefin end group concentration of the olefin telechelic PIB was determined by 1H NMR and it was assumed that the precursor, i.e., the tert.-chlorine telechelic PIB, contained the same concentration of end groups. After the addition was complete (8-10 hours) the temperature was raised to 50°-55° C. and stirring was continued for ~30 hours. It was observed that in the presence of more than 10% of the catalyst based on the total quantity of phenol, and at a relatively high temperature of ~60° C., cracking of TMP occurred and p-tert.-butyl phenol was obtained. The reactor was cooled to room temperature and the brown oily layer (if any) was removed. Approximately 200 ml water were slowly added and the content of the flask was transferred to a separatory funnel. The aqueous layer was removed and the organic layer washed 8-10 times with hot water (40°-50° C.) followed by washing with 50% aqueous solution of methanol. The methanol was removed by washing with cold water. Great care must be taken to remove even traces of free phenol. The presence of phenol in the washing water was monitored by its UV absorption. Washing was continued until the aqueous and the organic layer were free of phenol (GPC technique, UV detector). The organic layer was dried over anhydrous Na2SO4, the solvent then removed by rotary evaporation and the product was dried at 60° C. under vacuum.
Reaction SMILES: [Cl-].[CH2:2]([O:6][C:7](=[O:10])[CH2:8][NH3+:9])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH2:22]([O:21][C:19](=[O:20])[C:18]([NH:9][CH2:8][C:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])=[O:10])=[O:24])[CH3:23]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCCOC(=O)C[NH3+]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCOC(=O)CNC(=O)C(=O)OCC
Temperature: 50 °C

Procedure:
A mixture of 2-butoxy-2-oxoethanaminium chloride (573.5 g, 3.42 mol), triethylamine (415 g, 4.1 mol), and diethyl oxalate (1.0 kg, 6.8 mol) in ethanol (7 L) was heated at 50° C. for 3 hours. The product mixture was cooled and concentrated under vacuum. The residue was dissolved in methylene chloride and washed with two 4 L portions of water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residual oil was subjected to column chromatography on silica gel eluting with heptane/ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH:38]1([CH2:44][N:45]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH:38]1([CH2:44][N:45]2[CH2:49][CH2:48][CH:47]([NH:50][C:30]([NH:20][C:19]3[CH:21]=[CH:22][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)=[CH:17][C:18]=3[N+:23]([O-:25])=[O:24])=[O:36])[CH2:46]2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1CCN(CC2CCCCC2)C1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NC4CCN(CC5CCCCC5)C4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
Chloroform (13 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) to prepare a solution. Triphosgene (96 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 1-(Cyclohexylmethyl)-3-pyrrolidinamine (64 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (34 mg, yield 21%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)cc1

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.5 g) is synthesized according to the general procedure using 4-methoxybenzyl chloride (0.92 g; 5.86 mmol) and K2CO3 (2.3 g; 16.6 mmol) at RT for 20 h. After filtration and evaporation of the solvent the crude material is de-acetylated under reflux conditions in 2-propanol (15 ml) and hydrochloric acid (6 N; 45 ml). Pure 5-amino-1-(4-methoxy-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.71 g) precipitates by pouring the reaction mixture into ice-water.
Reaction SMILES: [Cl:1][C:2]1[C:21]2[C@:16]([CH3:24])([C@H:17]3[CH2:23][C@H:18]3[C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:4]([C@H:5]3[C@:12]([CH3:26])([CH2:13][C@H:14]2[OH:25])[C@@:8]([O:27][C:28](=[O:30])[CH3:29])([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6]3)[CH:3]=1.ClC1C2[C@](C)([C@H]3C[C@H]3C(=O)C=2)[C@@H]2[C@H]([C@H]3[C@](C)(CC2)[C@@](OC(=O)C)(C(=O)C)CC3)C=1.[C:60]1(=[O:66])[O:65][C:63](=[O:64])[CH2:62][CH2:61]1>>[C:60]([O:25][C@@H:14]1[CH2:13][C@@:12]2([CH3:26])[C@@H:5]([CH2:6][CH2:7][C@:8]2([O:27][C:28](=[O:30])[CH3:29])[C:9](=[O:11])[CH3:10])[C@H:4]2[C@H:15]1[C@:16]1([CH3:24])[C:21]([C:2]([Cl:1])=[CH:3]2)=[CH:20][C:19](=[O:22])[C@@H:18]2[CH2:23][C@H:17]12)(=[O:66])[CH2:61][CH2:62][C:63]([OH:65])=[O:64]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3[C@H](O)C[C@@]21C
Agent: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3[C@H](OC(=O)CCC(=O)O)C[C@@]21C

Procedure:
0.433 g. of 6-chloro-11α-hydroxy-17-acetoxy-1α,2α-methylene-4,6-pregnadiene-3,20-dione -- prepared from 6-chloro-17-acetoxy-1α,2α-methylene-4,6-pregnadiene-3,20-dione by microbiological hydroxylation as described in the following paragraph -- is reacted analogously to A9 with succinic acid anhydride and worked up. After purification by way of the sodium salt, 230 mg. of (6-chloro-17-acetoxy-3,20-dioxo-1α,2α-methylene-4,6-pregnadien-11α-yl) hydrogen succinate is obtained as a foam. UV: ε280 = 15,500.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:30]=1[CH:31]=[CH:32][C:33](O)=[O:34]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:33](=[O:34])[CH:32]=[CH:31][C:30]1[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:29]=1[O:28][CH3:27])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1cccc(C=CC(=O)O)c1OC
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: COc1cccc(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1OC
Yield: 70 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 2,3-dimethoxycinnamic acid under the conditions described in example 86 to yield 70% of the desired product.
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:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[O:24][CH3:25])[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH:30]1[CH2:35][OH:36].C(N(C(C)C)CC)(C)C>C(#N)C>[OH:36][CH2:35][CH:30]1[N:29]([CH3:28])[CH2:34][CH2:33][N:32]([CH2:2][C:3]([NH:5][C:6]2[CH:27]=[CH:26][C:9]3[N:10]=[C:11]([NH:14][CH:15]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][C:22]=5[O:24][CH3:25])[CH2:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:31]1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CC2
Reactant: CN1CCNCC1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CN4CCN(C)C(CO)C4)cc3CO1)CC2
Yield: 67 %

Procedure:
Prepared from rac-2-chloro-N-[2-(7-methoxy-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 55, step A) (150 mg, 0.39 mmol), commercially available rac-(1-methyl-piperazin-2-yl)-methanol (CAS no. 141108-61-4) (76 mg, 0.58 mmol) and diisopropylethyl amine (198 ul, 1.17 mmol) in acetonitrile (5 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (125 mg, 67%), MS (ISP) m/e=480.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:24]([O:23][C:21]([CH2:20][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=2[N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:7]1=[O:9])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Cl)cc21

Procedure:
A mixture of 4.00 g (14.9 mmol) of tert-butyl 5-chloro-2-oxo-2,3-dihydro-benzimidazole-1-carboxylate (Via), 3.19 g (16.4 mmol) of tert-butyl bromoacetate and 7.28 g (22.3 mmol) of cesium carbonate in acetonitrile (80 ml) was heated under reflux for 3 h. The solvent was removed in vacuo, the residue was mixed with water, and the aqueous mixture was extracted four times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0-5% ethyl acetate in dichloromethane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH3:20][Si:21](Cl)([CH3:25])[CH:22]([CH3:24])[CH3:23].CN([CH:30]=[O:31])C>C1COCC1.O>[CH:22]([Si:21]([CH3:25])([CH3:20])[C:2]1[CH:7]=[CH:6][C:5]([CH:30]=[O:31])=[CH:4][CH:3]=1)([CH3:24])[CH3:23]
Reactant: CC(C)[Si](C)(C)Cl
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)[Si](C)(C)c1ccc(C=O)cc1
Temperature: -78 °C
Yield: 87.2 %

Procedure:
1,4-Dibromo-benzene (1.18 g, 5 mmol) was dissolved in THF (15 ml) and cooled to −78° C. Under argon a 1.6 M solution of n-butyl lithium in hexane (3.13 ml, 5 mmol) was added slowly under stirring keeping the temperature below −70° C. After complete addition the reaction was stirred at −78° C. for 30 min and dimethyl-isopropyl-silylchloride (683 mg, 5 mmol) was added carefully keeping the temperature again below −70° C. The reaction was stirred at −78° C. for 30 min and a 1.6 M solution of n-butyl lithium in hexane (3.13 ml, 5 mmol) was added at this temperature keeping the temperature below −70° C. After stirring for 30 min at −78° C. DMF (1.1 g, 15 mmol) was added in one portion and the reaction was allowed to warm to rt. Water was added and the solvent was evaporated. The reaction was extracted twice with diethylether. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated, to yield 4-(isopropyl-dimethyl-silanyl)-benzaldehyde (900 mg, 87%) as a colorless oil. The product was pure enough to be used directly in the next step. MS (ISP): 207.1 (M+H)+. 1HNMR (CDCl3, 300 MHz): δ 10.0 (s, 1H), 7.84 (d, J=8.1 Hz, 2H), 7.67 (d, J=8.1 Hz, 2H), 0.93-0.99 (m, 7H), 0.28 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:13]1([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[NH2:24])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C.C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]3[N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: NC1CCCCC1N1CCCC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCO
Solvent: CC#N
Product: Clc1ccc2c(NC3CCCCC3N3CCCC3)ccnc2c1

Procedure:
3.87 g from 3.6 g of 4,7-dichloroquinoline and 3.06 g of (2-pyrrolidin-1-yl-cyclohexyl)-amine (reaction duration 24 hours at 120° C.); colourless crystals from acetonitrile/ethanol, m.p.: 228°-231° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[F:10][C:11]([F:22])([F:23])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
A solution of 19 (2.5 g, 18 mmol) in DME (90 mL) was added 4-trifluoromethoxy phenyl boronic acid (1.1 mol eq, 4.46 g) and NaHCO3 (3 mol eq, 4.66 g) suspended in water (50 mL). The mixture was degassed under vacuum, then Tetrakispalladium was added (catalytic amount) and the reaction stirred at 100° C. under inert atmosphere for 12 h. The solvent was removed under reduced pressure and water was added to the residue (100 mL). The aqueous phase was extracted with EtOAc (3×50 mL) and the combined organic layer was washed with brine (100 mL) and dried over Na2SO4. The solvent was evaporated under vacuum to obtain 20B as a pale yellow crystals (96% Yield, 4.6 g, 17.4 mmol). 1HNMR (DMSO, 200 MHz) δ 7.5 (dd, 2H, J=2), 7.84 (dd, 1H, J=1.8), 8.31 (d, 2H, J=9.8), 8.54 (d, 1H, J=2), 8.93 (dd, 1H, J=1.9).
Reaction SMILES: [Na].[OH-:2].[K+].[CH3:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]([C:12](Cl)(Cl)Cl)O.[OH2:16]>CO>[CH3:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:12]([OH:16])=[O:2]
Reactant: [OH-]
Reactant: O
Reactant: Cn1cccc1C(O)C(Cl)(Cl)Cl
Agent: [K+]
Agent: [Na]
Solvent: CO
Product: Cn1cccc1CC(=O)O
Reaction time: 1.5 h
Yield: 76 %

Procedure:
A 50 ml round-bottomed flask, fitted with magnetic stirrer, oil bath preheated to 56° C. and addition funnel, is charged with a solution of 2.28 g (13.1 mmol, 3.47 eq) sodium hydroxulfite in 6 ml H2O+2 ml of the above KOH solution. To this reaction mixture is added a solution of 0.86 g (3.77 mmol) 1-methyl-α-trichloromethylpyrrole-2-methanol in 3 ml methanol, and then the remaining KOH solution is added dropwise over 5 min. After 1.5 hours, the flask is cooled and the reaction is washed with 15 ml Et2O. The aqueous phase is acidified with concentrated HCl to give pH 1-2, saturated with solid NaCl, and extracted three times with 30 ml of Et2O. The latter organic extracts are combined and dried over Na2SO4. The solvent is removed under reduced pressure to afford 0.40 g (76%) of crude 1-methylpyrrole-2-acetic acid.