Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.Br[C:5]1[CH:6]=[CH:7][C:8]2[N:14]([C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[O:16])[CH2:13][CH2:12][C:11]([C:22]([O:24][CH3:25])=[O:23])=[CH:10][C:9]=2[CH:26]=1.B([O-])([O-])O[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:39]([O:38][CH2:37][CH2:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([C:5]2[CH:6]=[CH:7][C:8]3[N:14]([C:15]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:16])[CH2:13][CH2:12][C:11]([C:22]([O:24][CH3:25])=[O:23])=[CH:10][C:9]=3[CH:26]=2)=[CH:34][CH:33]=1)[CH2:40][CH2:41][CH3:42]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)c2cccs2)CC1
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)c2cccs2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
In toluene (10 ml), ethanol (1.0 ml) and water (1.0 ml) were suspended methyl 7-bromo-1-(2-thienylcarbonyl)-2,3-dihydro-1-benzazepine-4-carboxylate (210 mg), 4-butoxyethoxyphenyl borate (166 mg) and potassium carbonate (192 mg), and the mixture was stirred for 30 minutes under argon atmosphere. Then, to the suspension was added tetrakistriphenylphosphinepalladium (43 mg), and the mixture was heated at 100° C. for 5 hours under argon atmosphere. After allowing to cool, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(2-thienylcarbonyl)-2,3-dihydro-1-benzazepine-4-carboxylate (201 mg) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=3)[N:11]([CH3:23])[C:10]2=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)[N:11]([CH3:23])[C:10]2=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cccc(C2C(=O)N(c3ccc(Cl)c(Cl)c3)C(=O)N2C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)N(c2ccc(Cl)c(Cl)c2)C(=O)C1c1cccc(O)c1
Reaction time: 2 h

Procedure:
10.5 mL of boron trifluoride/dimethyl sulphide complex are added dropwise, at ambient temperature, to 3.7 g of a solution of 3-(3,4-dichlorophenyl)-5-(3-methoxyphenyl)-1-methylimidazolidine-2,4-dione in 60 mL of dichloromethane in a flask equipped with a magnetic stirrer and a nitrogen intake. After 2 hours at ambient temperature, the mixture is poured over a saturated aqueous sodium bicarbonate solution and subjected to extraction with ethyl acetate. The mixture is dried over magnesium sulphate and concentrated. The residue is crystallised in isopropyl ether (white solid; m=3 g; Yd=84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[CH2:20]([NH:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH3:23].BrC1C=CC(F)=C(C2N=C(NC3C=CN=CC=3)C3C(=NC=CN=3)N=2)C=1>>[CH2:20]([N:24]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[C:16]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:19])[N:17]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCNc1ccncc1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Agent: Fc1ccc(Br)cc1-c1nc(Nc2ccncc2)c2nccnc2n1
Product: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-butylaminopyridine 113 following the procedure described for 4-(4-pyridylamino)-2-(5-bromo-2-fluorophenyl)pteridine 1 (LCMS analysis).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([C:27]3[CH:28]=[C:29]([C:33]4[N:34]=[C:35]([C:46](=[O:48])[CH3:47])[S:36][C:37]=4[C:38]4[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[CH:40][CH:39]=4)[CH:30]=[CH:31][CH:32]=3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2)([S:13]([CH3:16])(=[O:15])=[O:14])[CH3:12].C(Cl)Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:46]([C:35]2[S:36][C:37]([C:38]3[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[CH:40][CH:39]=3)=[C:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:25]4[CH:26]=[C:17]([C:11]([CH3:10])([S:13]([CH3:16])(=[O:15])=[O:14])[CH3:12])[CH:18]=[C:19]5[C:24]=4[N:23]=[CH:22][CH:21]=[CH:20]5)[CH:28]=3)[N:34]=2)([OH:48])[CH3:47])=[CH:4][CH:3]=1
Reactant: CSc1ccc(-c2sc(C(C)=O)nc2-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CO
Solvent: ClCCl
Product: CSc1ccc(-c2sc(C(C)(O)c3ccc(Cl)cc3)nc2-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1

Procedure:
Prepared according to the general procedure Cer-1 using 4-chlorophenylmagnesium bromide and methylketone from step 3. Flash chromatography (CH2Cl2:MeOH, 96:4) afforded the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.[C:18]([O:22][C:23](=[O:26])[CH2:24][NH2:25])([CH3:21])([CH3:20])[CH3:19].Cl.COC(=O)CN>>[C:18]([O:22][C:23](=[O:26])[CH2:24][NH:25][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:1])=[CH:16][CH:15]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: COC(=O)CN
Agent: Cl
Product: COc1ccc(CNCC(=O)OC(C)(C)C)cc1

Procedure:
According to Example 1, Step 1, by substituting 4-methoxybenzaldehyde for 4-benzyloxybenzaldehyde and glycine tert-butyl ester hydrochloride for glycine methyl ester hydrochloride, the title compound was obtained as a yellow oil (80% yield).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17](Cl)[CH:18]=[CH:19][CH:20]=5)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.[H-].[Na+].O>CN(C)C=O.CCOCC>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([O:32][C:28]6[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=6)[CH:18]=[CH:19][CH:20]=5)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=34)[N:5]=2)[CH2:2][CH2:3]1
Reactant: Oc1cccc(Cl)c1
Reactant: Cn1c(=O)c2c(Cl)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(Oc3cccc(Cl)c3)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Temperature: 110 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A mixture of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-5-oxo-6-chloro-4,5-dihydro-imidazo(1,5-a)quinazoline (0.4 g, 1.2 mmol), 3-chlorophenol (0.4 g, 3 mmol), and sodium hydride (55% dispension in oil, 0.14 g, 3 mmol) in 20 ml of dry dimethylformamide was stirred for 8 h at 110° C., cooled to room temperature and poured into 30 ml of water and 5 ml of ether. The mixture was then stirred for 30 min. at 0° C. and the precipitate was filtered off, rinsed with water and dried giving 0.28 g (57%) of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-5-oxo-6-(3-chlorophenoxy)-4,5-dihydroimidazo(1,5-a) quinazoline, M.p. 201°-203° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].C([Li])CCC.[CH2:16]=[O:17]>C1COCC1>[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:16][OH:17])([CH3:10])[CH3:9]
Reactant: C=O
Reactant: CC(C)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1ccccc1CO
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of 1-bromo-2-isopropylbenzene (2.50 g, 12.56 mmol) in anhydrous THF (40 mL), 2,2′-dipyridyl (ca 2 mg) was added under nitrogen atmosphere (Zhi et al., 2003, which is incorporated herein by reference). The mixture was cooled down minus 78° C., and a solution of n-butyllithium (5.52 mL, 2.5 M in hexanes, 13.82 mmol) was added dropwise via syringe within the period of ten minutes. Upon addition, the mixture was stirred for 30 minutes, then warmed up to minus 30° C., and a flow of formaldehyde (generated from 1.77 g of paraformaldehyde by heating at 160° C.) was passed through the solution until the deep red color disappeared completely. The mixture was quenched with saturated ammonium chloride (5 mL), then poured into brine (15 mL). Organic layer was separated; aqueous layer was extracted twice with dichloromethane (20 mL each); combined extracts were dried over anhydrous Na2SO4, evaporated, and purified by silica gel chromatography to yield 2-isopropylbenzyl alcohol (1.11 g, 59%) as an oil. 1H NMR (400 MHz, CDCl3): δ 7.30 (m, 3H, Ph-H), 7.18 (m, 3H, Ph-H), 4.75 (s, 2H, CH2OH), 3.27 (sep, J=6.6 Hz, 1H, CH(CH3)2), 1.53 (s, 1H, CH2OH), 1.26 (d, J=6.6 Hz, 1H, CH(CH3)2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([CH:14]=[O:15])=[CH:5][CH:4]=1.CC(=CC)C.[O-:21]Cl=O.[Na+]>CC(O)(C)C.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:21])=[O:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)c2c(C)cccc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)O)c2c(C)cccc12

Procedure:
To a solution of 4-methoxy-8-methyl-1-naphthaldehyde (above Step-4 intermediate) (4.4 g, 22 mmol) in tBuOH (50 mL) and 2-methyl-2-butene (23.3 mL, 220 mmol) at 0° C. was added, a solution of NaClO2 (6.0 g, 66 mmol) and NaH2PO4 (9.1 g, 66 mmol) in water (40 mL) drop wise and the reaction mixture was stirred at RT overnight. After completion (TLC), the solvent was evaporated and the residue was basified with 10% NaOH solution and washed with CH2Cl2 (2×50 mL). The aqueous layer was then acidified with 1 N HCl and extracted with EtOAc (4×100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried and filtered. After removal of solvent, the desired compound was obtained (4.5 g, 95%) as an off white solid.
Reaction SMILES: Cl.Br[C:3]1[N:4]=[C:5]([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=12.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][C:41]=1[O:55][CH3:56])=[O:38])[N:31]2[CH3:36]>>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:3]3[N:4]=[C:5]([C@H:13]4[CH2:18][CH2:17][C@H:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)[CH2:15][CH2:14]4)[N:6]4[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=34)=[CH:42][C:41]=1[O:55][CH3:56])=[O:38])[N:31]2[CH3:36]
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCNCC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Agent: Cl
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCNCC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C

Procedure:
Reaction of 1-bromo-8-methyl-3-((trans)-4-(piperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine hydrochloride (40 mg) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (42 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol) gave 4-methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(piperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (8 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH3:44])=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH3:44])=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccccc3F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS-No. 335255-65-7] (227 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow solid (381 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[C:10]4[CH:24]=[CH:23][S:22][C:11]=4[C:12](=[O:21])[NH:13][C:14]=3[C:15]([CH3:20])=[CH:16][C:17]=2[O:18][CH3:19])[CH:5]=[CH:4][C:3]=1[C@@H:25]([CH3:36])[CH2:26][N:27](C)[C:28](=O)OC(C)(C)C.[ClH:37]>CCOCC>[ClH:37].[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[C:10]4[CH:24]=[CH:23][S:22][C:11]=4[C:12](=[O:21])[NH:13][C:14]=3[C:15]([CH3:20])=[CH:16][C:17]=2[O:18][CH3:19])[CH:5]=[CH:4][C:3]=1[C@@H:25]([CH3:36])[CH2:26][NH:27][CH3:28]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CN(C)C(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: CCOCC
Product: CNC[C@H](C)c1ccc(-c2c(OC)cc(C)c3[nH]c(=O)c4sccc4c23)cc1F
Yield: 85 %

Procedure:
Following General Procedure D1, (R)-tert-butyl 2-(2-fluoro-4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propyl(methyl)carbamate (50 mg, 0.10 mmol) was reacted with HCl in ether (5 mL) to afford the desired product (35 mg, 85%) as an yellow solid; 1H NMR (500 MHz, CD3OD) δ 7.63 (d, J=5.4 Hz, 1H), 7.53 (dt, J=28.7, 7.8 Hz, 1H), 7.29 (s, 1H), 7.17-7.04 (m, 2H), 6.10 (dd, J=31.6, 5.4 Hz, 1H), 3.75 (s, 3H), 3.68-3.24 (m, 3H), 2.78 (d, J=13.3 Hz, 3H), 2.64 (s, 3H), 1.52 (dd, J=7.0, 3.2 Hz, 3H); ESI MS m/z 411 [C23H23FN2O2S+H]+; HPLC 98.2% (AUC), tR=11.79 min.
Reaction SMILES: C1(C([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH:28]([OH:49])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:51]1[N:56]=[CH:55][CH:54]=[CH:53][N:52]=1>>[CH:43]1([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][CH:28]([O:49][C:51]2[N:56]=[CH:55][CH:54]=[CH:53][N:52]=2)[CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][OH:20])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: OC(COCCCCCCCCCCCCC1CCCCC1)COCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1ncccn1
Product: OCCOCCOCC(COCCCCCCCCCCCCC1CCCCC1)Oc1ncccn1
Yield: 83.9 %

Procedure:
The procedure of Reference Example 2 was applied for a reaction of 2-[2-[3-(12-cyclohexyldodecyloxy)-2-hydroxypropoxy]ethoxy]ethyl triphenylmethyl ether (7.69 g) with 2-chloropyrimidine (3.36 g) to yield the desired compound (4.88 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][C@H:10]2[C:21]([O:23]C)=[O:22])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[OH-].Cl>CO>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C@H:10]([C:21]([OH:23])=[O:22])[CH2:11]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Boc anhydride (3.0 g, 13.7 mmol) was added to a solution of (3S,4R)-methyl 4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate (3.10 g, 11.3 mmol) in THF (100 mL) and TEA (4 mL). The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (8:1) to give (3S,4R)-1-tert-butyl 3-methyl 4-(3,4-dichlorophenyl)pyrrolidine-1,3-dicarboxylate (LCMS (APCI+) [M-Boc+H]+ 274.1; Rt: 4.17 min). The (3S,4R) -1-tert-butyl 3-methyl 4-(3,4-dichlorophenyl)pyrrolidine-1,3-dicarboxylate was redissolved in MeOH (50 mL), and LiOH (3M, 10 mL) was added. The mixture was stirred at room temperature for 6 hours. 2N HCl (15 mL) was added to the mixture. The solvent was removed, and the residue was subject to column chromatography, eluted by DCM/MeOH (40:1-10:1) to give (3S,4R)-1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid (1.95 g). (LCMS (APCI+) [M-Boc+H]+ 260.1; Rt: 3.67 min.)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C([O-])(=O)C.[Cs+].[CH3:28][NH2:29].CO.O>CN(C)C=O.[Cu](I)I>[CH3:28][NH:29][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(Br)cc12
Reactant: CN
Agent: I[Cu]I
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
30 mg (0.08 mmol) of the 7-bromo-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one prepared in Step A, 18.6 mg (0.098 mmol) of copper iodide (I), and 39.1 mg (0.204 mmol) of cesium acetate were suspended in 0.5 ml of dry dimethylformamide. Thereafter, 200 μl of a 40% methylamine-methanol solution was added to the suspension, and the obtained mixture was then stirred at 100° C. overnight. Thereafter, water was added to the reaction solution, and the mixture was then extracted with methylene chloride. The extract was washed with a saturated saline solution, and was then dried over anhydrous magnesium sulfate. The extract was concentrated. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=100:1), so as to obtain 15.4 mg (61%) of 7-methylamino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCOc1ccc(C=O)cc1OC
Temperature: 100 °C

Procedure:
To a stirred solution of vanillin (3)(2 g, 13.16 mmol) and methyl 4-bromobutyrate (2.38 g, 13.16 mmol) in DMF (20 cm3) was added freshly ground anhydrous potassium carbonate (2.03 g, 14.47 mmol). The resulting pale pink suspension was heated at 100° C. for 90 mins, after which time the suspension has become milky pink in appearance. The mixture was then poured into water (50 cm3) and extracted with Et2O (3×30 cm3). The combined organic extracts were washed with water (2×30 cm3), then 1M HCl (2×30 cm3) before being dried (MgSO4) and concentrated in vacuo. The pale pink solid 4 was used without further purification (2.7 g, 82%). m.p. 69° C. [lit. (D. L. McMinn and M. M. Greenberg, Tetrahedron, 1996, 52, 3827) m.p. 68-69° C.]. Found C, 62.0; H, 6.3; C13H16O5 requires C, 62.0; H, 6.4%; Rf 0.44 (SiO2, hexane:EtOAc, 2:1 v/v); νmax (KBr disc)/cm−1 3100-2700 (m), 1740 (s), 1680 (s); δH (300 MHz, CDCl3) 2.19 (2H, q, J=6.6 Hz, CH2), 2.56 (2H, t, J=6.6 Hz, CH2), 3.68 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.15 (2H, t, J=6.6 Hz, CH2), 6.97 (1H, d, J=8.0 Hz, H-6′), 7.40 (1H, dd, J=8.0 Hz, J=1.8 Hz, H-5′), 7.44 (1H, d, J=1.8 Hz, H-3′), 9.84 (1H, s, CHO) ppm; δC (100 MHz, CDCl3) 24.1 (CH), 30.2 (CH2), 51.5 (OCH3), 55.8 (OCH3), 67.3 (CH), 109.2 (CH), 111.5 (CH), 126.6 (CH), 130.0, 149.7, 153.7, 173.3 (COOCH3), 190.8 (CHO) ppm; m/z (FAB) 253 [(MH+), 50%].
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH3:10])[N:5]=1.Cl.[NH2:14][OH:15].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:10][C:6]1[N:5]=[C:4]([CH:3]=[N:14][OH:15])[CH:9]=[CH:8][N:7]=1
Reactant: COC(OC)c1ccnc(C)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nccc(C=NO)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 4-dimethoxymethyl-2-methyl-pyrimidine (10 g) from I.1.1 in methanol (100 mL) was added 8.2 g of hydroxylamine hydrochloride and 10% HCl and the reaction mixture was heated under reflux for 2 h. After cooling to room temperature, the pH was adjusted to 8 using solid sodium carbonate. The mixture was stirred for 30 minutes. The solid was sucked off, dried at 50° C. under reduced pressure to yield 6.0 g (73%) of the title compound as white solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][CH2:18][C@H:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][S:35]([C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)(=[O:37])=[O:36])[CH2:11][CH2:12]3)[O:22][C:21]=2[CH:23]=1
Reactant: NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 59.3 %

Procedure:
Triethylamine (0.62 ml) was added to a solution of (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (0.44 g) and 4-fluorobenzenesulphonyl chloride (0.65 g) in dichloromethane (22 ml) under nitrogen and stirred for 3 hours. The reaction was left to stand for 14 hours then diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with a 19:1 mixture of dichloromethane and methanol gave a yellow oil which on trituration with diethyl ether yielded (S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluorobenzene-sulphonamide as a yellow solid (0.4 g); m.p. 127-129° C., [α]D22 -41.3° (c=0.72, MeOH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH:16]=[C:15]([C:17](OC)=[O:18])[C:14]([CH3:21])=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([N:12]2[CH:16]=[C:15]([CH:17]=[O:18])[C:14]([CH3:21])=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: COC(=O)c1cn(-c2ncc(C(F)(F)F)cc2Cl)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1nn(-c2ncc(C(F)(F)F)cc2Cl)cc1C=O
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
To a solution (150 mL) of methyl 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-3-methyl-1H-pyrazole-4-carboxylate (7.0 g) synthesized above in tetrahydrofuran was added dropwise diisobutylaluminum hydride (1.5M toluene solution, 58.4 mL) at 0° C. After stirring for 30 min, the reaction mixture was poured into 2N hydrochloric acid of 0° C., and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was evaporated. The residue was treated in the same manner as in Example 1(5) to give the title object compound (1.7 g, 27%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[NH2:6][OH:7].[CH2:8](O)C>>[OH:7][NH:6][C@H:2]([C:3]([OH:5])=[O:4])[CH3:8].[NH2:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: CCO
Reactant: NO
Agent: NCC(=O)O
Product: C[C@H](NO)C(=O)O

Procedure:
3 g of N-(R, 2-bromo propanoyl)-glycine obtained by condensation of 2-bromo propionic acid (prepared according to E. Fischer et al., Annalen, 357, 1 (1907) with the glycine are dissolved in 100 ml of anhydrous ethanol and stirred for 48 hours with anhydrous hydroxylamine according to Example 5.