Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1.C([Si]([O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH:55]2[CH2:57][O:56]2)=[CH:49][CH:48]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][NH:18][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([NH:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][NH:1][CH2:57][C@H:55]([OH:56])[CH2:54][O:53][C:50]4[CH:51]=[CH:52][C:47]([OH:46])=[CH:48][CH:49]=4)=[CH:28][CH:27]=3)[CH2:11][CH2:12]2)=[O:17])=[CH:25][CH:24]=1
Reactant: NCCOc1ccc(NC2CCN(C(=O)NCc3ccc(F)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 11.5 %

Procedure:
4-[4-(2-Aminoethoxy)anilino]-N-(4-fluorobenzyl)-1-piperidinecarboxamide (0.63 g, 1.4 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.53 g, 1.3 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.125 g, 0.15 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:28]5[C@H:27]([CH3:26])[CH2:31][O:30][C:29]5=[O:32])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cn2)CC1
Yield: 53.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (5-bromopyridin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (350 mg) described in Preparation Example 151 and (R)-4-methyloxazolidin-2-one (97 mg) described in Preparation Example 25, the title compound (197 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=1)[O:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=1)[O:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[OH:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCOc1cccc(C(O)CCNC(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(OCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the ester 130 (2.3 g, 6.0 mmol) in THF (80 mL) and MeOH (20 mL) was added NaOH solution (8 mL, 2N). The resulting mixture was stirred at room temperature for overnight following which the solvent was removed under reduced pressure and pH adjusted to 6 by the addition of cold dilute HCl. This was then extracted with DCM. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 4-(3-(3-(tert-butoxycarbonylamino)-1-hydroxypropyl)phenoxy) butanoic acid (131). The product was directly utilized for the next transformation. Yield (1.94 g, 91%): 1H NMR (400 MHz, CDCl3) δ 7.18-7.22 (m, 1H), 6.84-6.90 (m, 2H), 6.77 (dd, J=7.6, 1.6 Hz, 1H), 5.18 (bs, 1H), 4.48-4.53 (m, 1H), 3.96 (t, J=6.4 Hz, 2H), 2.93-2.99 (m, 2H), 2.38 (t, J=7.4 Hz, 2H), 1.90-1.96 (m, 2H), 1.64-1.71 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [C:1]([CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].O.C(C1(C)[O:32][C:31](=O)[CH:30]=[C:29]([CH3:34])O1)C>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:19]([N:23]1[C:29]([CH3:34])=[CH:30][C:31](=[O:32])[C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])=[C:1]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: O=C(CC(=O)c1ccccc1)Nc1ccccc1
Reactant: CCC1(C)OC(=O)C=C(C)O1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCn1c(C)cc(=O)c(C(=O)Nc2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
A mixture of 4.42 g (18.47 mmol) of α-benzoylacetanilide, 1.89 g (25.84 mmol) of n-butylamine, one drop of acetic acid and 25 ml of toluene was refluxed for 1.5 hours, while the resulted water and excess of butylamine were removed through a Dean-Stark's water separator, together with about 12 ml of toluene. While heating, to the mixture was dropwise added a solution of 7.2 g (46.18 mmol) of 2-ethyl-2,6-dimethyl-4H-1,3-dioxin-4-one in 16 ml of toluene within about 30 minutes and after the resulted mixture was refluxed for forty minutes, it was cooled to room temperature. The crystals precipitated was separated by filtration and dried under vacuo to afford 3.72 g of the title compound having mp. 189.5°-193° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[OH:19].CCN(CC)CC>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[O:19]
Reactant: OC(c1ccc(Cl)cc1)c1ccccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)c1ccccc1Br
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromobenzaldehyde (3.15 ml, 27.0 mmol) and THF (135 ml) at 0° C. was added (4-chlorophenyl)magnesium bromide solution (29.7 ml, 1M in THF, 29.7 mmol). The reaction was stirred at 0° C. for 30 min before addition of a saturated solution of ammonium chloride. The layers were separated and the aqueous extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage to afford (2-bromophenyl)(4-chlorophenyl)methanol. To a solution of DCM (100 ml) and oxalyl chloride (2.471 ml, 28.2 mmol) at −78° C. was added DMSO (3.34 ml, 47.0 mmol) and the reaction stirred at −78° C. for 15 min. After 15 min a solution of (2-bromophenyl)(4-chlorophenyl)methanol in DCM (25 ml) was added dropwise and stirred for 15 min at −78° C. before addition of Et3N (9.84 ml, 70.6 mmol). The cold bath was removed and the reaction was warmed to room temperature. To this solution was added water and the layers separated. The aqueous was extracted with DCM and the combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (2-bromophenyl)(4-chlorophenyl)methanone. m/z (ESI) 295, 297 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.N1C2C(=CC=CC=2)C=C1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([O:36]C)=O)=[CH:26]1>>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:34]([C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:25]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:26]=1)=[O:36]
Reactant: Nc1ccccn1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: c1ccc2[nH]ccc2c1
Product: O=C(Nc1ccccn1)c1cn(Cc2ccccc2)c2ccccc12

Procedure:
R5Br=Bromomethylbenzene; NH2A=2-aminopyridine; Indole starting material=methyl indole 3-carboxylate
Reaction SMILES: [I:1][C:2]1[C:3]2[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:4]=2[NH:5][N:6]=1.C(N=C=NCCCN(C)C)C.O[N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=N1.C(N(C(C)C)CC)(C)C.NCC1C=CC=CN=1>CN(C)C=O.C(OCC)(=O)C>[N:27]1[CH:28]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:29][NH:25][C:10]([C:8]1[S:9][C:3]2[C:2]([I:1])=[N:6][NH:5][C:4]=2[CH:7]=1)=[O:12]
Reactant: O=C(O)c1cc2[nH]nc(I)c2s1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccn1)c1cc2[nH]nc(I)c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
A mixture of 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylic acid [1.05 g, 3.57 mmol, Intermediate (29)], 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (821 mg, 4.28 mmol), 1-hydroxybenzotriazole (482 mg, 3.57 mmol) in dimethyl formamide (45 mL) is stirred at room temperature for 10 minutes. To it is added diisopropylethylamine (1.3 mL, 7.46 mmol) followed by a solution of 2-(aminomethyl)pyridine (425 mg, 3.93 mmol) in dimethyl formamide (2 mL). After stirring overnight, the reaction mixture is diluted with ethyl acetate (200 mL) and washed water, brine and dried over sodium sulfate. The residue is chromatographed on 35 g silica gel cartridge (ethyl acetate and 10% methanol in ethyl acetate) to give 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylic acid (pyridin-2-ylmethyl)-amide [1.08 g, 79%, Intermediate (30)] as a light yellow solid; LC/MS: 385 (M+H); 1H NMR [(CD3)2SO)]: δ 13.67 (1H, s), 9.35 (1H, t), 8.53 (1H), 8.01 (1H), 7.80 (1H), 7.36 (1H, d), 7.28 (1H), 4.58 (2H, d).
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18].O>ClC(Cl)C>[C:1]1([C@@H:7]([NH:9][C:17](=[O:19])[CH3:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(=O)N[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-(−)-1-phenylethylamine (121 g) and triethylamine (168 ml) in dichloroethane (1200 ml) was added dropwise acetyl chloride (78.2 ml) over 1 hr under ice-cooling and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (1000 ml) and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (143.4 g) as pale-yellow crystals, m.p.=99-101° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.N.[H][H]>C1COCC1.CO.[Ni]>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: [H][H]
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc2[nH]ncc2c1
Reaction time: 8 h

Procedure:
To a suspension of 1H-indazole-5-carbonitrile (0.235 g, 1.64 mmol) in THF (6 mL) was added 2 mL of 2 N ammonia in methanol and the flask was charged with 0.05 g Raney® 2800 nickel. A hydrogen balloon was attached to the flask and the system was purged 3 times with hydrogen. After stirring vigorously overnight the reaction mixture was diluted with methanol and filtered through a pad of celite. The solvent was evaporated in vacuo to provide 1-(1H-indazole-5-yl)methanamine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:12])([CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8].COC(C)(C)C.Cl[CH2:20][C:21]([O:23][CH3:24])=[O:22].C[O-].[Na+]>C(O)(=O)C>[CH3:24][O:23][C:21]([CH:20]1[C:7]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:12])[CH2:10][CH3:11])([CH3:8])[O:9]1)=[O:22]
Reactant: CCC(C)(CCCC(C)=O)OC
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: CCC(C)(CCCC1(C)OC1C(=O)OC)OC
Temperature: 0 °C
Yield: 67.5 %

Procedure:
860 g 6-Methoxy-6-methyl-2-octanone, 4 l tert.-butyl methyl ether and 648 g methyl chloroacetate were cooled to 0° C. under a blanket of nitrogen. Under further cooling, 350 g sodium methoxide was added in 6 portions over 20 minutes. The mixture was then stirred at room temperature till no more consumption of the ketone was observed (GC). After cooling to 0° C., 1 l 5% acetic acid (w/w) was added and the phases were separated. The aqueous phase was extracted with tert.-butyl methyl ether (500 ml). The combined organic phases were washed with water, concentrated KHCO3 solution, concentrated NaCl solution and dried over MgSO4. The yellow oil which remained after the removal of the solvent was distilled over a small Vigreux-column to give 823 g of 3-(4-methoxy-4-methyl-hexyl)-3-methyl-oxirane-2-carboxylic acid methyl ester (mixture of isomers, boiling point: 115°-128°/0.3 Torr=0.399 mbar).
Reaction SMILES: [CH3:1]N(C)C(=O)C.[CH:7]1([C:13]2[CH:44]=[CH:43][C:16]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:26]=[C:27]([N:30]([CH2:32][C:33]5[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=5)[CH3:31])[S:28][CH:29]=4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CCCCCC>[CH:7]1([C:13]2[CH:44]=[CH:43][C:16]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:26]=[C:27]([N:30]([CH2:32][C:33]5[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=5)[CH3:31])[S:28][CH:29]=4)=[CH:21][CH:20]=3)[CH3:1])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(NCc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(N(C)Cc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
Under an argon stream, N,N-dimethylacetamide (351 ml, 5.0 v/w) was added to methyl 4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate (70.3 g, 0.134 mol) obtained in Example 1(5) and potassium carbonate (73.9 g, 0.535 mol) was carefully added with stirring. After stirring the mixture at room temperature for 20 min., dimethyl sulfate (50.6 ml, 0.535 mol) was added. After stirring at 50° C. for 1 hr., potassium carbonate (18.4 g, 0.134 mol) and dimethyl sulfate (12.7 ml, 0.134 mol) were added and the mixture was stirred at 60° C. for 2 hr. After cooling to room temperature, n-hexane (422 ml, 6.0 v/w) was added, and the mixture was stirred for 1 hr. After ice-cooling, distilled water (562 ml, 8.0 v/w) was added. After stirring at room temperature for 1 hr., the resulting crystals were collected by filtration and washed with methanol (352 ml, 5.0 v/w) in a slurry form. Tetrahydrofuran (180 ml) was added to the obtained orange solid and insoluble materials were filtered off. The filtrate was concentrated to give the title compound (42.1 g, yield 58.3%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]1[O:7][CH2:6][C@@H:4](O)[C@H:2]1O.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=[O:21])[NH:11][C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.[BH3-]C#N.[Na+].O(CC=O)CC=O>O.CC#N.C(O)(=O)C.O>[CH3:20][O:19][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([N:8]3[CH2:2][CH2:1][O:7][CH2:6][CH2:4]3)=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[NH:11][C:12]2=[O:21])=[CH:17][CH:16]=1
Reactant: O[C@@H]1COC[C@@H]1O
Reactant: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2N)cc1
Agent: O=CCOCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2N2CCOCC2)cc1
Reaction time: 18 h
Yield: 8.3 %

Procedure:
NaIO4 (66 mg, 0.33 mmol) is added to a flask containing 1,4-anhydroerythritol (34 mg, 0.33 mmol) dissolved in a water/CH3CN mixture (1:1; 4 mL) and the mixture is maintained under stirring for 18 hours. 4-amino-7-methoxy-3-(4-methoxyphenyl)isoquinolin-1(2H)-one (compound 1) (100 mg, 0.33 mmol) and NaBH3CN (63 mg, 1 mmol) are then added to the solution of 2,2′-oxybis(acetaldehyde) prepared previously. Then, 3 drops of acetic acid are added and the medium is stirred for 3 hours at ambient temperature. The reaction is stopped by the addition of 10 mL of water. The medium is extracted with 3×10 mL of dichloromethane. The organic phases are washed with 3×10 mL of water, dried over MgSO4 and concentrated under vacuum. The residue is purified by silica gel column chromatography with dichloromethane-ethanol (100/0 to 98/2) as eluent in order to produce successively i) the compound 7-methoxy-3-(4-methoxyphenyl)-4-morpholinoisoquinolin-1(2H)-one 49 (10 mg, 8%) in the form of a white solid, mp>270° C.; 1H NMR (CDCl3): 8.18 (1H, br s), 7.99 (1H, d), 7.83 (1H, dd), 7.37 (3H, m), 7.03 (2H, d), 3.97 (3H, s), 3.91 (3H, s), 3.72 (4H, m), 2.90 (2H, m), 2.75 (2H, m); MS 367 (M+H); and ii) the compound 4-(2-(2-hydroxyethoxy)ethylamino)-7-methoxy-3-(4-methoxyphenyl)isoquinolin-1(2H)-one 50 (15 mg, 12%) in the form of a white solid, mp 139° C.; 1H NMR (CDCl3): 8.71 (1H, br s), 7.89 (1H, d), 7.82 (1H, s), 7.45 (2H, d), 7.34 (1H, dd), 7.01 (2H, d), 3.94 (3H, s), 3.87 (3H, s), 3.60 (2H, t), 3.49 (2H, t), 3.38 (2H, t), 3.03 (2H, t), 1.75 (1H, br s), MS 385 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O1CCCC1>[CH3:23][S:24]([O:1][CH2:2][CH:3]([NH:5][C:6]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])[CH3:4])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.6 %

Procedure:
In tetrahydrofuran (400 ml) were dissolved 46.5 g (222 mmol) of benzyl (2-hydroxy-1-methylethyl)carbamate and 26.96 g (266 mmol) of triethylamine, and a solution of 27.96 g (244 mmol) of methanesulfonyl chloride in tetrahydrofuran was slowly dropped thereinto at 0° C. After the resulting mixture was stirred at room temperature for 5 hours, the triethylamine hydrochloride precipitated was filtered under reduced pressure and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and water was added thereto, followed by three runs of extraction with ethyl acetate. The extract solution was washed with saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and the crude crystals thus obtained were washed twice with a solvent (hexane:ethyl acetate=4:1) to obtain 49.5 g (yield 78%) of 2-(benzyloxycarbonylamino)propyl methanesulfonate.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[S:23]([CH2:26][C@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])(=[O:25])=[O:24]>C(Cl)Cl>[C:9]1([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1][S:23]([CH2:26][C@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])(=[O:25])=[O:24])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@@H](C)CS(=O)(=O)Cl
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)CS(=O)(=O)NC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 1 g aminodiphenylmethane, 2 mL triethylamine in 20 mL CH2Cl2. The reaction was cooled to 0° C. and 1 g of methyl 3-chlorosulfonyl-2(R)-methylpropionate was slowly added. The reaction was stirred 1 hour then concentrated in vacuo. The residue was partioned between ethyl acetate and water. The organic phase was washed with brine, dried, and concentrated in vacuo. Trituration from Et2O/hexanes gave 1.15 g of methyl 3-[N-(diphenylmethyl)aminosulfonyl]-2(R)-methylpropionate as a white solid. HRMS (M+Li): calcd. 354.1351, obs 354.1569.
Reaction SMILES: [C:1]([O:4]CCCOC)(=[O:3])C.[OH:10][CH2:11][CH:12]1[CH2:16][O:15]C(=O)[O:13]1.[CH2:18]([NH2:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[OH:10][CH2:11][CH:12]([CH2:16][OH:15])[OH:13].[CH2:18]([NH:26][C:1](=[O:3])[O-:4])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C1OCC(CO)O1
Reactant: CCCCCCCCN
Reactant: COCCCOC(C)=O
Product: CCCCCCCCNC(=O)[O-]
Product: OCC(O)CO
Temperature: 70 °C

Procedure:
354 g of methoxypropyl acetate, 237 g (2 moles) of glycerol carbonate (Jeffsol GC from Huntsman; CAS RN: 931-40-8; molecular weight: 118.09) are introduced in succession, under nitrogen, into a three-necked flask equipped with a condenser and an addition funnel. The mixture is stirred at 230 revolutions per minute and heated to 70° C. Then 262.5 g (2.03 moles) of n-octylamine (CAS RN: 11-86-4; molecular weight: 129.25) are added to the reaction mixture in the course of 15 minutes. The reaction is strongly exothermic and the temperature of the reaction mixture reaches approximately 88° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:6])[CH:3](C)[OH:4].Br[CH:8]([CH3:18])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=[O:10].[I-].[Na+].[CH:21](Cl)(Cl)Cl>>[OH:4][CH2:3][C:2]([NH:1][CH:8]([CH3:18])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=[O:10])([CH3:6])[CH3:21]
Reactant: CC(N)C(C)O
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Reactant: ClC(Cl)Cl
Agent: [I-]
Agent: [Na+]
Product: CC(NC(C)(C)CO)C(=O)c1cccc(Cl)c1
Yield: 55 %

Procedure:
2-Amino-1-methyl-propan-1-ol (14 ml, 0.15 mol) was added to α-bromo-3′chloro propiophenone (18 g, 73 mmol) in suspension in chloroform (50 ml), with two crystals of sodium iodide. The reaction was heated under reflux overnight. After filtration the organic phase was extracted twice with a 2M HCl solution (2×100 ml). The aqueous phase wash washed with DCM then neutralised with sodium carbonate. The aqueous layer was extracted with DCM. The organic phase was dried over magnesium sulphate, filtered and evaporated. Recrystallisation from chloroform gives the desired compound in 55% yield as a white solid (10.2 g, 40 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[CH:2].I[C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>>[C:6]1([CH3:9])[CH:7]=[CH:8][C:3]([C:1]2[NH:13][C:12]3[C:14]([CH:2]=2)=[CH:15][CH:16]=[CH:17][CH:11]=3)=[CH:4][CH:5]=1
Reactant: Nc1ccccc1I
Reactant: C#Cc1ccc(C)cc1
Product: Cc1ccc(-c2cc3ccccc3[nH]2)cc1
Yield: 74 %

Procedure:
The general procedure was used to convert 1-Ethynyl-4-methyl-benzene and 2-iodoaniline to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 74% yield. 1H NMR (300 MHz, DMSO) δ 11.47 (s, 1H), 7.74 (d, J=7.72, 2H), 7.50 (d, J=7.72, 2H), 7.38 (d, J=7.91, 1H), 7.25 (d, J=7.72, 2H), 7.11-7.06 (t, J=7.91, 1H), 7.01-6.96 (t, J=7.35, 1H), 6.83 (s, 1H), 2.34 (s, 3H). 13C NMR (75 MHz, DMSO) δ 138.63, 137.85, 137.60, 130.31, 129.55, 125.77, 122.17, 120.72, 120.14, 112.04, 98.89, 21.65. Anal. Calcd. for C15H13N: C, 86.92; H, 6.32; N, 6.67. Found C, 86.69; H, 6.24; N, 6.76. m.p.: 213-215° C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:37])[C:14]2[O:20][C:19]3[C:21]([Cl:33])=[CH:22][C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:35])(=[O:34])[C:15]=2[CH:36]=1)=[O:10].CO>O>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:37])[C:14]2[O:20][C:19]3[C:21]([Cl:33])=[CH:22][C:23]([N:25]([C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:34])(=[O:35])[C:15]=2[CH:36]=1)=[O:10]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCC3)cc(Cl)c1O2
Reactant: O=C(Cl)C1CC1
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCN3CCCC3)C(=O)C3CC3)cc(Cl)c1O2
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (0.44 mL, 4.8 mmol) was added to a solution of Example 72k (0.3 g, 0.64 mmol) and the reaction mixture was stirred at 55° C. for 2 h. It was treated with methanol (1 mL), water and extracted with chloroform. The organic layer was washed with water, brine, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.280 g, (81.63%); 1H NMR (DMSO-d6): δ 0.71 (bs, 2H, CH2), 0.88 (bs, 2H, CH2), 1.87 (bs, 2H, CH2), 2.01 (bs, 2H, CH2), 2.70 (s, 3H, CH3), 3.00 (bs, 2H, CH2), 3.18 (bs, 2H, CH2), 3.57 (bs, 2H, CH2), 3.70 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 4.04 (bs, 2H, CH2), 5.38 (s, 2H, CH2), 7.78 (s, 1H, Ar), 7.98 (s, 1H, Ar), 8.19 (s, 1H, Ar), 8.22 (s, 1H, Ar); MS: m/e (CI+) 533 (M+1).