Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][S:2]([O-:5])(=O)=O.OS(O[O-])(=O)=O.OS(O[O-])(=O)=O.[O-]S([O-])(=O)=O.[K+].[K+].[K+].[K+].[K+].[CH2:28]([NH:32][C:33](=[O:68])[CH:34]([CH3:67])[CH2:35][C@H:36]([OH:66])[C@@H:37]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:38][C@@H:39]([CH:55]([CH3:57])[CH3:56])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[C:43]([O:51][CH2:52]SC)[CH:42]=1)[CH2:29][CH2:30][CH3:31].[CH3:69]O>O>[CH2:28]([NH:32][C:33](=[O:68])[CH:34]([CH3:67])[CH2:35][C@H:36]([OH:66])[C@@H:37]([NH:58][C:59]([O:61][C:62]([CH3:63])([CH3:64])[CH3:65])=[O:60])[CH2:38][C@@H:39]([CH:55]([CH3:56])[CH3:57])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([CH3:49])([CH3:48])[CH3:50])=[C:43]([O:51][CH2:52][S:2]([CH3:69])(=[O:5])=[O:1])[CH:42]=1)[CH2:29][CH2:30][CH3:31]
Reactant: O=S(=O)([O-])O
Reactant: CO
Reactant: CCCCNC(=O)C(C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCSC)c1)C(C)C)NC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCNC(=O)C(C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCS(C)(=O)=O)c1)C(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
With stirring at 0° C., a solution of 115 mg of potassium monopersulfate triple salt in 0.5 ml of water is added dropwise to a solution of 74 mg of N-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-[3-(methylthio-methoxy)-4-tert-butyl-phenyl]-octanoic acid (N-butyl)amide in 0.5 ml of methanol and the mixture is then stirred at room temperature for a further 20 hours. The reaction mixture is partitioned between dichloromethane and water. The organic phases are concentrated by evaporation and the title compound is obtained from the residue by FC (11 g of silica gel, ethyl acetate/hexane=1:1): Rf (ethyl acetate/hexane=1:1)=0.26; FAB-MS (M+H)+ =627.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1.[CH3:43][O:44][CH2:45][CH2:46][C:47](Cl)=[O:48]>>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][O:23][CH2:22][CH2:21][CH2:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]2[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:8][CH:7]2[O:6][CH2:5][C:4]2[CH:40]=[CH:41][CH:42]=[C:2]([NH:1][C:47](=[O:48])[CH2:46][CH2:45][O:44][CH3:43])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(N)c2)cc1
Reactant: COCCC(=O)Cl
Product: COCCC(=O)Nc1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Example 116b, 0.610 g of tert-butyl 3-(3-aminobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.270 g of 3-methoxypropionyl chloride are reacted. The title compound is obtained as a beige oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.56.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([NH2:26])([CH2:16][C:17]#[C:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:12]([O:14]C)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N[C:32](=O)[O-:33])(C)(C)C.[CH:35]1[C:40](S(Cl)(=O)=O)=[CH:39][CH:38]=[C:37](I)[CH:36]=1>>[CH3:32][O:33][C:40]1[CH:39]=[CH:38][C:37]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]([NH2:26])([CH2:16][C:17]#[C:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:12]([OH:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)NC(=O)[O-]
Reactant: COC(=O)C(N)(CC#CCN1CCOCC1)S(=O)(=O)c1ccc(I)cc1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)C(N)(CC#CCN3CCOCC3)C(=O)O)cc2)cc1

Procedure:
Methyl 2-(4-iodophenylsulfonyl)-amino-6-morpholinohex-4-ynoate: The starting t-butyl-carbamate 31a (6.10 g, 18.7 mmol) is deprotected and coupled with pipsyl chloride (5.11 g, 16.84 mmol) as described for compound 31b to give the title compound as a pale yellow tar.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]12([CH2:34][CH2:35][C:36](O)=[O:37])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:36](=[O:37])[CH2:35][CH2:34][C:24]34[CH2:33][CH:28]5[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]5)[CH2:25]3)[CH2:31]4)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(O)CCC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)CCC34CC5CC(CC(C5)C3)C4)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3-(adamantan-1-yl)propionic acid (10 mg) under the agency of HATU (25 mg) and N,N-diisopropylethylamine (22 l) in dichloromethane (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [C:1](=[O:18])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([NH:22][C:23]1[C:24]([I:39])=[C:25]([N:34]([C:36](=[O:38])[CH3:37])[CH3:35])[C:26]([I:33])=[C:27]([C:30]([O-:32])=[O:31])[C:28]=1[I:29])(=[O:21])[CH3:20].[K+].[I-].[Na+]>CN(C=O)C>[C:19]([NH:22][C:23]1[C:24]([I:39])=[C:25]([N:34]([C:36](=[O:38])[CH3:37])[CH3:35])[C:26]([I:33])=[C:27]([C:30]([O:32][CH:3]([O:2][C:1]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:18])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:31])[C:28]=1[I:29])(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: O=C(Oc1ccccc1)OC(Cl)c1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(OC(=O)Oc2ccccc2)c2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1-Chloro-1-phenylmethyl phenyl carbonate (0.63 g, 2.4 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (1.44 g, 2.2 mmol) and sodium iodide (0.034 g, 0.23 mmol) in dry DMF (12 ml). After stirring at 60° C. for 2 hours and at room temperature for 18 hours the solvent was removed at reduced pressure. The residue was suspended in chloroform (20 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 0.90 g. Purity by HPLC: 96.6% 1H-NMR(DMSO-d6): delta=1.67 (NCH3COCH3); 2.05 (NHCOCH3); 2.96 (NCH3); 7.29-7.54 (phenyl); 7.71 (CH); 10.13 ppm (NH). FAB/MS: 854 (M+).
Reaction SMILES: [CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:23](I)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH-].[K+].C(O)CCC>CO>[CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1Cc2ccc(-c3ccc(O)cn3)cc2C1
Reactant: CCCCCCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCO
Product: CCCCCCCCCCOc1ccc(-c2ccc3c(c2)CC(CCCCCC)C3)nc1
Yield: 39.2 %

Procedure:
0.045 g (0.15 mM) of 2-hexyl-5-(5-hydroxypyridine-2-yl)indan, 0.05 ml (0.23 mM) of decyl iodide, 0.013 g (0.20 mM) of 85%-KOH and 1 ml of n-butanol were mixed and heat-refluxed for 130 minutes under stirring. After the reaction, methanol was added to the reaction mixture, followed by filtration under cooling with ice to obtain an insoluble matter. The insoluble matter was dried and purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1), followed by recrystallization from acetone to obtain 0.026 g of 2-hexyl-5-(5-decyloxypyridine-2-yl)indan (Yield: 39.2%). ##STR308##
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:14]1([N:19]2[C:23](N)=[C:22]([C:25]([NH2:27])=O)[C:21]([CH2:28][CH3:29])=[N:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1.[H-].[Na+].C[N:33](C=O)C>>[CH:14]1([N:19]2[C:23]3=[N:10][C:9]([C:8]4[CH:11]=[CH:12][CH:13]=[C:6]([N:1]5[CH:5]=[CH:4][N:3]=[CH:2]5)[CH:7]=4)=[N:27][C:25]([NH2:33])=[C:22]3[C:21]([CH2:28][CH3:29])=[N:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: N#Cc1cccc(-n2ccnc2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCc1nn(C2CCCC2)c2nc(-c3cccc(-n4ccnc4)c3)nc(N)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-(1-imidazolyl)benzonitrile (3.16 g), 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.77 g, 16.98 mmol) and DMF (75 ml) was added NaH (0.78 g, 60% dispersion in mineral oil). The reaction mixture was stirred at room temperature for about 2 days, then additional nitrile (0.1 equivalents) and NaH (0.2 equivalents) were added and the mixture was stirred at room temperature overnight. The solvent was stripped, and the residue was partitioned between chloroform (150 ml) and water (350 ml). The layers were separated, the aqueous layer was extracted with chlorform (2×100 ml), and the organic layers were combined, washed with brine, dried over MgSO4, filtered and stripped. The product was dissolved in hot tert-butyldimethyl ether, filtered and stripped. The residue was treated with CH3CN and the solid which formed was collected by filtration to afford 2.10 g of 1-cyclopentyl-3-ethyl-6-[3-(1-imidazolyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:18][CH:19](OC)OC)[C:14]([NH:16][CH3:17])=[O:15])=[CH:9][C:8]=1[C:24]([Cl:27])([Cl:26])[Cl:25].[ClH:33]>O>[CH3:17][N:16]1[CH:19]=[CH:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:28]=[CH:29][CH:30]=[C:3]([C:2]([Cl:31])([Cl:1])[Cl:33])[CH:4]=3)=[C:8]([C:24]([Cl:26])([Cl:27])[Cl:25])[CH:9]=2)[C:14]1=[O:15]
Reactant: Cl
Reactant: CNC(=O)N(CC(OC)OC)c1ccc(Oc2cccc(C(Cl)(Cl)Cl)c2)c(C(Cl)(Cl)Cl)c1
Solvent: O
Product: Cn1ccn(-c2ccc(Oc3cccc(C(Cl)(Cl)Cl)c3)c(C(Cl)(Cl)Cl)c2)c1=O

Procedure:
N-[4-[3-(Trichloromethyl)phenoxy]-3-(trichloromethyl) phenyl]-N-(2,2-dimethoxyethyl)-N'-methylurea (0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is refluxed for a period of about 30 minutes and then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portions of water and is then dried. The ethyl acetate is removed by mild warming under reduced pressure to yield the desired product 1-methyl-3[4-[3-(trichloromethyl)phenoxy]-3-(trichloromethyl)phenyl]-4-imidazolin-2-one.
Reaction SMILES: Cl.[NH:2]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:3]1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.O1CCOCC1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>O>[CH3:7][O:6][C:4]([CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][N:2]1[S:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=1)(=[O:35])=[O:34])=[O:5]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1CCCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C1CCCCN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl pipecolinate hydrochloride (10.0 g, 55.6 mmol), triethylamine (14.1 g, 19.4 mL, 139.2 mmol, 2.5 equiv), 1,4-dioxane (75 mL), and water (75 mL) are stirred at room temperature and then p-methoxyphenylsulfonyl chloride (13.8 g, 66.8 mmol, 1.2 equiv) is added. The resulting solution is stirred at room temperature overnight. The solution is then poured into water and extracted with CH2Cl2. The combined organic extracts are dried (Na2SO4) and concentrated to an oil under reduced pressure. Purification of the oil is accomplished by chromatography on silica gel using 7/3 hexane/EtOAc as the eluent. The product is obtained as a colorless oil which solidified upon standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH:31]([CH3:33])[CH3:32])([C:29]#[N:30])[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:27][CH3:28])=[C:21]([O:25][CH3:26])[CH:22]=3)[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:34][I:35]>CC(C)=O>[I-:35].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH:31]([CH3:33])[CH3:32])([C:29]#[N:30])[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:27][CH3:28])=[C:21]([O:25][CH3:26])[CH:22]=3)[CH:17]=[N+:16]2[CH3:34])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C#N)(CCCC2Cc3cc(OC)c(OC)cc3C=N2)C(C)C)cc1OC
Reactant: CI
Solvent: CC(C)=O
Product: COc1ccc(C(C#N)(CCCC2Cc3cc(OC)c(OC)cc3C=[N+]2C)C(C)C)cc1OC
Product: [I-]

Procedure:
The dihydroisoquinoline derivative of formula 40 is then N-alkylated using a compound of formula R3 -L to produce a 3,4-dihydroisoquinolinium derivative of formula 41 (step 2). For example, 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-3,4-dihydroisoquinoline (40) is dissolved in acetone with methyl iodide and heated at reflux to produce 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-3,4-dihydroisoquinolinium iodide (41).
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].[F:22]N(CC(C)(C)C)S(CCCC)(=O)=O>O1CCCC1.C1(C)C=CC=CC=1.CCOCC>[F:22][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: [H][H]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: CCCCS(=O)(=O)N(F)CC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(F)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
Diethyl phenylmalonate (708 mg, 650 μL, 3 mmole) was dissolved in anhydrous tetrahydrofuran (5 mL) under nitrogen. Sodium hydride (144 mg as a 60% oil dispersion, 3.6 mmole) was added and the mixture was stirred until hydrogen evolution ceased (about 15 minutes). The solution was then diluted with anhydrous toluene (10 mL) and added dropwise to a solution of N-fluoro-N-neopentyl-n-butylsulfonamide (675 mg, 3 mmole) in anhydrous toluene (5 mL) and the mixture was stirred at room temperature under nitrogen. After 30 minutes the reaction mixture was diluted with ether (100 mL), washed with aqueous 1N oxalic acid (30 mL), 10% aqueous potassium bicarbonate (30 mL), and saturated aqueous sodium chloride (30 mL) solutions, and then dried over anhydrous magnesium sulfate. Filtration, removal of solvent under reduced pressure, and purification by flash column chromatography (silica, 1:1 methylene chloride-hexane) yielded diethyl 2-fluoro-2-phenylmalonate as a colorless liquid (508 mg). 1H NMR was consistent with the desired structure.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:14])[NH2:13].[CH3:18]O>>[ClH:3].[ClH:3].[CH3:18][O:16][C:15](=[O:17])[C@H:7]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:13])[NH2:14])[NH:6][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: CN[C@@H](CCCNC(=N)N)C(=O)O
Product: CN[C@@H](CCCNC(=N)N)C(=O)OC
Product: Cl
Temperature: 40 °C

Procedure:
6.4 ml of thionyl chloride are added dropwise to a suspension of 15.06 g of N-methylarginine in 50 ml of absolute methanol at -10° C. The mixture is then allowed to come to room temperature, while stirring. Since starting material is still present after a reaction time of 17 hours, a further 9.6 ml of thionyl chloride are added in portions, the mixture is heated at 40° C. for 4 hours, the insoluble material is filtered off with suction and the filtrate is concentrated. The oily residue is dissolved in water, the insoluble material is filtered off and the product is freeze-dried.
Reaction SMILES: [NH2:1][C:2](=[S:26])[C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:13])[CH:12]=1)[N:9]=[CH:8][C:7]([C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:15])=[C:6]2[OH:25].[C:27]1(C)C=CC(S(O)(=O)=O)=C[CH:28]=1.C(OC(OCC)CBr)C>C(O)(=O)C.C(OCC)(=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([C:6]=2[OH:25])=[CH:4][C:3]([C:2]2[S:26][CH:27]=[CH:28][N:1]=2)=[CH:12][C:11]=3[F:13])=[O:15])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=S)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: CCOC(CBr)OCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(-c3nccs3)cc2c1O
Temperature: 100 °C
Yield: 544.9 %

Procedure:
To a suspension of the title compound of Example 52 (0.14 g) and p-toluenesulfonic acid (0.0084 g) in 2 mL acetic acid is added bromoacetaldehyde diethyl acetal (0.08 mL). The reaction is heated at 100° C. for approximately 45 minutes. The reaction is cooled to room temperature and diluted with 30 mL ethyl acetate. The solid is filtered and dried to give the desired product (0.11 g).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:16]([CH:18]([NH2:21])[CH2:19][CH3:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:21][CH:18]([CH2:19][CH3:20])[CH2:16][CH3:17])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCC(N)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 0.50 g of Boc-Pro-OH, 0.27 ml of 1-ethylpropylamine, 0.36 g of HOBt and 0.53 g of EDC hydrochloride were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 30 (Process 3) to give 324 mg of the title compound.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([Cl:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][Mg]Br.Cl>CCOCC>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:14])=[C:8]([Cl:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: Cl
Solvent: CCOCC
Product: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone (5 g, 22.72 mmol) dissolved in 12 ml of ether was added dropwise to 15 ml of a ether solution of methylmagnesium bromide (3M in ether) at 5° C. was added. After completion of addition the solution was stirred at 5° C. for 2 hours. 10 ml of 6N HCl solution is then added slowly to it and the solution is stirred for 10 minutes. The mixture is then extracted with diethyl ether. The ether layer is then washed with water and dried. The crude product obtained after concentrating the ether is subjected to flash chromatography (silica gel; ethyl acetate/hexanes:9:1) to give the product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]2.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CS(C)=O>[C:23]1([C:19]2[CH:18]=[C:17]([C:10]3[N:9]=[C:8]([NH:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[N:34]=[CH:33]5)[C:7]4[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:50]5[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]5)[CH:6]=4)[N:11]=3)[CH:22]=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN1CCNCC1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Solvent: CS(C)=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN1CCN(C)CC1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.30 g, 0.44 mmole) in DMSO (2 mL) was added 1-methylpiperazine (0.903 g, 1.00 mL, 9.02 mmole) and the reaction was stirred at 85° C. for 3 h. The mixture was poured onto ice-water (100 mL) and the crude product was filtered. The product was then dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (SiO2, 10% CH2Cl2/CH3OH-with 0.1% NH4OH) to give tert-butyl 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate which was taken on to the next step. HPLC retention time 6.00 mins.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([CH2:13][OH:14])=[CH:12][C:5]=2[O:4][CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:35]([O:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:36].CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[CH2:35]([O:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][C:42]([O:14][CH2:13][C:11]2[CH:10]=[CH:9][C:6]3[O:7][CH2:8][C:2]([CH3:15])([CH3:1])[CH2:3][O:4][C:5]=3[CH:12]=2)=[CH:41][CH:40]=1)[CH3:36]
Reactant: CC1(C)COc2ccc(CO)cc2OC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OCc2ccc3c(c2)OCC(C)(C)CO3)cc1
Reaction time: 1 h

Procedure:
To a mixture of (3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-methanol (31) (100 mg), polymer bound PPh3 (412 mg, ˜3 mmol/g on polystyrene) and ethyl-4-hydroxybenzoate in CH2Cl2 (4 ml) is added di-tert-butylazodicarboxylate (111 mg). The mixture is shaken 1 h, then the polymer is filtered off and the solvent is evaporated. Flash chromatography yields 74 mg of 4-(3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylmethoxy)-benzoic acid ethyl ester as a colourless oil, MS (ESI) 357.2 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[O:14]1[C:19]2([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:18][NH:17][CH2:16][CH:15]1[C:32]([O:34][CH3:35])=[O:33].C([O-])(O)=O.[Na+]>CCO>[F:9][C:8]([F:11])([F:10])[CH2:7][N:17]1[CH2:18][C:19]2([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[O:14][CH:15]([C:32]([O:34][CH3:35])=[O:33])[CH2:16]1
Reactant: COC(=O)C1CNCC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1CN(CC(F)(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 70 °C
Yield: 70 %

Procedure:
2,2,2-Trifluoroethyl trifluoromethanesulfonate (164 μL, 1.06 mmol) was added to a solution of 9-tert-butyl 2-methyl 1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate (222 mg, 0.71 mmol) and NaHCO3 (237 mg, 2.83 mmol) in anhydrous EtOH (6 mL) at room temperature. The reaction mixture was purged with argon, sealed with a cap and heated at 70° C. for 12 hours. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0 to 30% EtOAc in DCM as eluent to yield 9-tert-butyl 2-methyl 4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate (197 mg, 68%). ESI-MS m/z calc. 410.4. Found 411.5 (M+1)+; Retention time: 2.08 minutes (3 min run).