Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.S(Cl)([Cl:8])=O.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][S:19]([O-:22])(=O)=[O:20].[Na+]>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][S:19]([Cl:8])(=[O:22])=[O:20]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])CCc1ccccc1Br
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CCc1ccccc1Br
Temperature: 100 °C
Reaction time: 66 h
Yield: 104 %

Procedure:
N,N-Dimethylformamide (4.2 mL) and thionyl chloride (5.1 mL, 69.7 mmol) were sequentially added to a suspension of sodium 2-(2-bromo-phenyl)ethanesulfonate (4.00 g, 13.9 mmol) in toluene. The mixture was stirred at 100° C. for 66 hours and then poured into ice water. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted with ether. The organic layers were combined and sequentially washed with water and saturated brine, and then dried over sodium sulfate and concentrated under reduced pressure to give 2-(2-bromophenyl)ethanesulfonyl chloride (4.10 g). This was used in the next step without further purification.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:20])[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][C:9]=1[NH:16][C:17](=[O:20])[O:18][CH3:19]
Reactant: COC(=O)Nc1cc(O)c(Cl)cc1F
Reactant: BrC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 84.6 %

Procedure:
Cyclopentyl bromide (4.07 g, 27.3 mmol) was added to an acetonitrile solution (50 ml) containing methyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (5.00 g, 22,8 mmol) and potassium carbonate (1.80 g, 13.0 mmol), and the mixture was heated under reflux for 4 hours. After reaction, the reaction liquid was cooled to room temperature, 1N hydrochloric acid (50 ml) was added thereto, and this was extracted with ethyl acetate (50 ml×2). The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed by distillation under reduced pressure to obtain methyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (5.56 g, 19.3 mmol). Yield: 84.8%.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:26]1[S:27][C:28]([CH2:31][CH2:32][C:33]([OH:35])=O)=[CH:29][N:30]=1)[NH:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:16])=[CH:10][CH:9]=1.CN(C=O)C.CCN=C=NCCCN(C)C.Cl.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56]>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:54][S:55]([NH:58][C:33](=[O:35])[CH2:32][CH2:31][C:28]1[S:27][C:26]([CH:4]([NH:5][C:6](=[O:25])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[O:16])=[CH:12][CH:13]=2)[CH2:3][CH:2]([CH3:36])[CH3:1])=[N:30][CH:29]=1)(=[O:57])=[O:56]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)O)s2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)NS(C)(=O)=O)s2)cc1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
A mixture of 3-[2-(3methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid (Example 13) (91 mg, 0.2 mmol), DMF (5 ml), EDCl (48 mg, 0.2 mmol) and DMAP (26 mg, 0.2 mmol) was stirred at room temperature. After 10 min. methane sulfonamide (51 mg, 0.5 mmol) was added. After stirring 16 h the solution was diluted with EtOAc and washed with 1N HCl (2×). The organic layer was dried over Na2SO4; filtered; and concentrated under reduced pressure. The resulting solid was purified by Flash 12 chromatography eluting with 10% AcOH in EtOAc to give 30 mg of the title compound as a white amorphous solid. MS [M−1]+ 584.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1([NH2:35])[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1>>[C:25]1([NH:35][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)[CH:18]=2)[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Product: CCCCCCCCCCCc1noc(-c2cccc(CNc3cccc4c3CCCC4)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 5,6,7,8-tetrahydronaphthalen-1-ylamine gave the title compound as an oil. M+(LC/MS(ESI)): 460.4. HPLC (Condition A), Rt: 6.32 min (HPLC purity: 68.9%).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]1[O:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:11]=2[O:10]1.CI.[NH4+].[Cl-]>C1COCC1>[CH2:9]1[O:17][C:16]2[CH:15]=[CH:14][C:13]([CH:18]([CH3:2])[C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:11]=2[O:10]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc2c(c1)OCO2
Temperature: -15 °C
Yield: 63 %

Procedure:
To a solution of LDA in THF (60 mL) was added methyl 3,4-methylenedioxyphenylacetate (2 g, 10.3 mmol) at -78° C. and the solution was warmed to -15° C. for 45 min. MeI (4.39 g, 30.9 mmol) was added and the reaction was warmed to room temperature for 16 h. The reaction mixture was then poured to a separatory funnel containing NH4Cl (80 mL) and the product was extracted with EtOAc (2×150 mL) and dried over Na2SO4. The crude product obtained by removal of the solvent was purified by flash chromatography to give the product as a colorless solid (1.36 g , 63%). 1H NMR (CDCl3) 6.75 (m, 3H), 5.95 (s 2H), 3.67 (s, 3H), 3.66 (m, 1H), 1.46 (d, J=7.4, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[N:5][CH:4]=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[N+:22]([O-])([OH:24])=[O:23].S(=O)(=O)(O)O>>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[N:5][CH:4]=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cnc(-c2ccccc2OCC)[nH]c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnc(-c2cc([N+](=O)[O-])ccc2OCC)[nH]c1=O
Temperature: 0 °C
Yield: 55 %

Procedure:
Ethyl 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)pyrimidine-5-carboxylate (1.0 g., 3.46 mmoles) was added over a twenty minute period to a cooled (ice-water), stirred mixture of 70% nitric acid (1.7 ml., d=1.42) and 96% sulfuric acid (0.29 ml., d=1.84). The mixture was stirred at room temperature for 19 hours. The solution was poured into ice-water (300 ml.). The mixture was triturated and then filtered. The collected solid was recrystallized from acetonitrile to give the title compound (0.64 g., 55%), m.p. 222°-224°.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:27])[C:10]([F:26])=[C:11]([N:15]4[CH2:22][C:21](=[N:23][O:24][CH3:25])[C:17]5([CH2:20][NH:19][CH2:18]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:28])[C:6]([C:29]([OH:31])=[O:30])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:32](O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:27])[C:10]([F:26])=[C:11]([N:15]4[CH2:22][C:21](=[N:23][O:24][CH3:25])[C:17]5([CH2:18][N:19]([CH3:32])[CH2:20]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:28])[C:6]([C:29]([OH:31])=[O:30])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CON=C1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12CNC2
Reactant: CCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CON=C1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12CN(C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
1-Cyclopropyl-5-amino-6,8-difluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was added to 10 ml of ethanol, and thereto 0.2 ml of acetic acid was dropped and 44 mg of p-formaldehyde was added. It was stirred at room temperature for 30 minutes and thereto 91 mg of sodium cyanoborohydride was added. It was stirred at room temperature for 2 hours. The resulting precipitate was filtered to give 280 mg of the titled compound(yield 90.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:34]([C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:38])[F:39])=[CH:33][CH:32]=4)(=[O:36])=[O:35])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cc3)cc2C1=O

Procedure:
The compound of example 91 was prepared analogous to compound of example 77 by reaction of compound of example 6 with 4-trifluoromethylbenzene sulfonyl chloride. The compound of example 91 was used directly without isolation for the preparation of compound of example 92.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]([CH3:19])=[O:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[O:8][CH2:16][C@H:17]1[CH2:19][O:18]1
Reactant: Oc1cc(Br)ccc1F
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(Br)cc1OC[C@H]1CO1
Yield: 82 %

Procedure:
A solution of the crude 5-bromo-2-fluorophenol (4.0 g) prepared using literature procedure [EP0238272] and (2R)-glycidyl 3-nitrobenzenesulfonate (5.37 g) in dry acetone (175 mL) was treated with potassium carbonate (8.58 g) and refluxed under nitrogen for 12 h. The reaction was cooled, filtered and filtrate was concentrated in vacuo and the residue was flash chromatographed (20% ethyl acetate/hexanes) to yield the desired product (4.25 g) in 82% yield. 1H NMR (400 MHz, CDCl3): 7.15-6.96 (m, 3H), 4.33 and 4.30 (dd, 1H), 4.02 and 4.00 (dd, 1H), 3.41-3.37 (m, 1H), 2.97 (m, 1H), 2.78 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12].[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:30])[C:27](O)=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([CH:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:30])[C:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[NH:6][C:5]3=[O:12])=[O:28])[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Solvent: CCOCC
Product: O=C(Nc1ccc2c(c1)C(=O)NC2=O)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-amino-isoindole-1,3-dione and (4-benzyl-piperidin-1-yl)-oxo-acetic-acid (Example 5b) according to the method described in Example 1c. Melting Point: 239-241° C. (diethylether)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C@H:11]1[CH2:15][CH2:14][C:13](=O)[CH2:12]1.[CH3:17][NH:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C@H:11]1[CH2:15][CH2:14][CH:13]([N:18]([CH3:19])[CH3:17])[CH2:12]1
Reactant: CNC
Reactant: O=C1CC[C@H](c2c[nH]c3ccc(F)cc23)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: CN(C)C1CC[C@H](c2c[nH]c3ccc(F)cc23)C1
Reaction time: 1 h
Yield: 121.2 %

Procedure:
A solution of (3S)-3-(5-fluoro-1H-indol-3-yl)-cyclopentanone (290 mg, 1.34 mMol), dimethylamine (2.0 M solution in THF, 6.7 mL, 13.4 mMol) in ethanol (10 mL) was stirred for 15 min. Sodium triacetoxyborohydride (1.1 g, 5.4 mMol) was added and the reaction stirred for 1 h. The reaction was extracted three times with ethyl acetate/aqueous sodium bicarbonate solution. The ethyl acetate extracts were dried over magnesium sulfate and concentrated in vacuo to give (3S)-3-(5-fluoro-1H-indol-3-yl)-cyclopentyl-dimethylamine (400 mg, 100%) as a cis/trans diastereomeric mixture. The diastereomeric mixture was separated by preparative chiral HPLC using a Chiralpak AD column (50×500 mm with 20 μm packing) and 10% ethanol/hexane (0.1% diethylamine added in hexane as modifier) as the eluent at a flow rate of 60 mL/min for 50 min. The UV detector was set at 280 nm, the injection loop volume was 10 mL, and the injection load was 35–165 mg in a ethanol/hexane (1:1) solution.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]=[C:9]2[OH:12])=[CH:4][N:3]=1.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]([CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[C:15]([C:14]([F:13])([F:23])[F:24])[CH:16]=3)[C:9]2=[O:12])=[CH:4][N:3]=1
Reactant: Oc1nncc2cnc(Br)cc12
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ncc2cnn1Cc1cccc(C(F)(F)F)c1

Procedure:
The alkylation of 7-bromo-1-hydroxy-3,6-diazaisoquinoline (1.00 g, 4.46 mmol) using 3-trifluoromethyl-benzyl bromide (1.60 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 7-(3-phenylprop-1-ynyl)-2-(3-trifluoromethylbenzyl)-2H-3,6-diazaisoquinolin-1-one
Reaction SMILES: C(N(CC1C=CC=CC=1)[C:9](=[O:35])[CH:10]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:14][C:13]=1[OH:34])[CH3:11])C1C=CC=CC=1.C(O)(=[O:45])C>Cl>[CH2:27]([N:19]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[C:16]([CH3:18])=[CH:17][C:12]([CH:10]([CH3:11])[C:9]([OH:35])=[O:45])=[C:13]([OH:34])[CH:14]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc(C(C)C(=O)N(Cc2ccccc2)Cc2ccccc2)c(O)cc1N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(=O)O
Agent: Cl
Product: Cc1cc(C(C)C(=O)O)c(O)cc1N(Cc1ccccc1)Cc1ccccc1

Procedure:
20 g of 2-(4-dibenzylamino-2-hydroxy-5-methylphenyl)-propionic acid dibenzylamide are heated under reflux for 3 hours in 40 ml of 2N hydrochloric acid and 40 ml of glacial acetic acid. The mixture is then concentrated to dryness by evaporation in vacuo and the residue is partitioned between ether and 1N sodium hydroxide solution. Acidification to a pH of 1 with hydrochloric acid and extraction yields 2-(4-dibenzylamino-2-hydroxy-5-methylphenyl)-propionic acid which, for purification, is chromatographed over silica gel in methylene chloride. The colourless crystals melt at 174°-175°. 15 g of the crystals are dissolved in 50 ml of ether and 6 g of dicyclohexylcarbodiimide are added thereto. After 30 minutes the urea formed is filtered off and the filtrate is concentrated to dryness by evaporation. In this manner 6-dibenzylamino-3,5-dimethylbenzofuran-2(3H)-one having a melting point of 122°-123° is obtained.
Reaction SMILES: S([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O)(C1C=CC(C)=CC=1)(=O)=O>C(OCC)(=O)C>[CH2:12]([OH:11])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCOC(C)=O
Product: OCCOCCOCCO
Temperature: 25 °C
Yield: 89 %

Procedure:
To a 25 mL schlenk flask with Kontes valve and stirbar under argon 1 (1.67 mmol, 0.423 g) was added and the flask evacuated and backfilled with argon 3×. Anhydrous DMF (12.2 mL) was added via syringe and the solution stirred at rt. Next, anhydrous CsCO3 (3.52 mmol, 1.15 g) was added followed by triethylene glycol ditosylate (0.808 mmol, 0.371 g) and the mixture stirred at rt. The vessel was closed, stirred and heated to 70° C. for ca. 12 h. The reaction was allowed to cool to rt then diluted with ethyl acetate (10 mL), filtered and the solid washed with ethyl acetate (3×100 mL) and filtered. The organic extracts were combined and washed with saturated NH4Cl(aq) (25 mL) then washed with brine (3×25 mL) dried over Na2SO4, filtered and the solvent removed by rotovaporation to afford the crude product. Purification by silica plug (ethyl acetate) afforded a white solid (0.464 g; 89% yield). IR (cm−1) 2947, 2884, 1683, 1601, 1476, 1397, 1110; 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 4H, ArH), 6.13 (s, 4H, ArCHO2), 4.18 (m, 4H, ArOCH2—), 4.02 (m, 16H, OCH2CH2O), 3.84 (m, 4H, ArOCH2CH2—), 3.78 (s, 4H, ArOCH2CH2OCH2CH2OCH2CH2OAr), 2.33 (s, 6H, ArCH3); {1H} 13C NMR (100 MHz, CDCl3) 154.5, 134.2, 130.8, 129.0, 99.1, 76.0, 70.9, 70.5, 65.5, 21.2.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=1)[C:11]#[N:12].[NH3:20]>C(O)C>[NH2:20][C:15]1[N:14]=[C:13]([CH:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:11]#[N:12])[CH:18]=[CH:17][N:16]=1
Reactant: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Reactant: N
Solvent: CCO
Product: N#CC(c1ccnc(N)n1)c1nc2ccccc2s1
Temperature: 150 °C
Yield: 51 %

Procedure:
A suspension of 1 (0.1 g, 0.35 mmol) in a 2M solution of ammonia in ethanol (10 ml) was heated up to 150° C. in a Parr vessel for 3 h. The solution was cooled down to r.t. and the yellow precipitate formed was filtered off then washed thoroughly with ethanol/water 1:1 and water. The precipitate was dried in vacuum at 40° C. affording 48 mg (51%) of the title compound as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:13])=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].C(O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2ccc(Cl)cc2[nH]1
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)ccc2c(O)c1[N+](=O)[O-]

Procedure:
A suspension of 7-chloro-4-hydroxycarbostyril (0.5g.) in glacial acetic acid (4 ml.) was nitrated with concentrated nitric acid (0.7ml.) at 100°C and worked up in the usual manner to give the title compound, m.p. (aqueous ethanol) 166°-167°C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CS(O[CH2:24][C@H:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:26])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:31]([O:30][C:28]([NH:27][C@H:25]([CH3:26])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OC[C@@H](C)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 21 h
Yield: 109 %

Procedure:
A suspension of ethyl 4′-hydroxybiphenyl-4-carboxylate (1.63 g), (R)-(+)-2-(tert-butoxycarbonylamino)propyl methanesulfonate (1.93 g), and cesium carbonate (2.70 g) in N,N-dimethylformamide (18 mL) was stirred at 50° C. for 21 hrs. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by aminopropyl silica gel flash column chromatography (eluent: n-hexane/ethyl acetate=1/1) to afford ethyl 4′-[(R)-2-(tert-butoxycarbonylamino)propyloxy]biphenyl-4-carboxylate (2.93 g).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[C:5]21[CH2:18][CH2:17][CH2:16][CH2:15]2.O.[NH2:20][CH2:21][C@H:22]([OH:24])[CH3:23]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]3[CH:3]=[CH:2][N:20]([CH2:21][C@H:22]([OH:24])[CH3:23])[C:12]=32)=[CH:7][CH:8]=1
Reactant: C[C@@H](O)CN
Reactant: Cc1ccc2c(c1)C(=O)C(CC=O)C21CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C21CCCC1
Reaction time: 0.75 h
Yield: 73.3 %

Procedure:
A solution of 2.42 g of (RS)-2'-(2-oxoethyl)-5'-methyl-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 3:2). 2.06 g (73%) of (R)-1-[7'-methyl-1',4'-dihydro-spiro[cyclopentane-1,4'-indeno[1,2-b]pyrrole]-1'-yl]-propan-2-ol were obtained as a red oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[CH3:34][NH:35][CH3:36]>>[CH3:34][N:35]([CH3:36])[C:29](=[O:30])[C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: CNC
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)N(C)C
Yield: 76 %

Procedure:
Using the same procedure as in Example 26, methyl (2S)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.54 mmol) was reacted with dimethylamine to give the title compound as a white solid (195 mg, 76%); NMR Spectrum 1.59 (d, 3H), 2.93 (s, 3H), 3.14 (s, 3H), 5.85 (q, 1H), 6.04 (s, 2H), 7.30 (d, 1H), 7.35 (d, 1H), 7.65 (d, 1H), 7.74 (m, 3H), 7.87 (dd, 1H), 8.20 (s, 1H), 8.51 (s, 1H), 8.55 (s, 1H), 11.15 (br s, 1H); Mass spectrum 474.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]([OH:30])([CH3:29])[CH3:28])[CH2:21][CH2:20]3)=[C:15]([O:31][CH3:32])[CH:14]=1)[CH2:6][CH2:5]2.CS([CH2:37][C@H:38]1[CH2:42][CH2:41][CH2:40][O:39]1)(=O)=O>>[OH:30][C:27]([CH3:28])([CH3:29])[CH2:26][N:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:16]2[CH:17]=[CH:18][C:13]([N:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:37][C@H:38]5[CH2:42][CH2:41][CH2:40][O:39]5)[CH:3]=4)[C:8]3=[O:12])=[CH:14][C:15]=2[O:31][CH3:32])[CH2:20][CH2:21]1
Reactant: CS(=O)(=O)C[C@H]1CCCO1
Reactant: COc1cc(N2CCc3cc(O)ccc3C2=O)ccc1N1CCCN(CC(C)(C)O)CC1
Product: COc1cc(N2CCc3cc(OC[C@H]4CCCO4)ccc3C2=O)ccc1N1CCCN(CC(C)(C)O)CC1

Procedure:
6-Hydroxy-2-{4-[4-(2-hydroxy-2-methyl-propyl)-[1,4]diazepan-1-yl]-3-methoxy-phenyl}-3,4-dihydro-2H-isoquinolin-1-one and (R)-2-methanesulfonylmethyl-tetrahydrofuran were reacted according to Method K1. In this way the product was obtained with molecular weight 523.68 (C30H41N3O5); MS (ESI): 524 (M+H+).