Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH2:3]1.[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH2:21]([N:8]([CH:5]1[CH2:6][CH2:7][C:2]([OH:1])([CH3:20])[CH2:3][CH2:4]1)[C:9]1[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:22]
Reactant: CC=O
Reactant: COC(=O)c1cccc(NC2CCC(C)(O)CC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cccc(C(=O)OC)c1C)C1CCC(C)(O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 3-((4-hydroxy-4-methylcyclohexyl)amino)-2-methylbenzoate (1.4 g, 5.05 mmol) and acetaldehyde (0.7 ml, 13 mmol) in 20 ml of dichloroethane was added acetic acid (1.7 mL, 30 mmol) and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (3.2 g, 15 mmol) was added and the mixture was stirred at room temperature for overnight. The reaction mixture was neutralized with sat. NaHCO3 and extracted with DCM. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and the residue purified by silica gel column chromatography to afford the title compound (1.42 g, 94%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[C:40]([F:48])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:47])[F:46])=[C:40]([F:48])[CH:39]=2)[C:35]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
A solution of triphenylphosphine (312 mg, 1.19 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (212 mg, 1.19 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid (300 mg, 0.99 mmol). The resulting reaction mixture was stirred at 0° C. for 15 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (218 mg, 2.18 mmol). The resulting reaction mixture was stirred at 25° C. for 3 d. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide (243 mg, 64%) as a white solid: mp 194–195° C.; EI-HRMS m/e calcd for C18H18F4N2OS (M+) 386.1076, found 386.1076.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:22]([NH:23][C:24](=[O:57])/[C:25](=[N:51]\[O:52][CH2:53][CH:54]3[CH2:56][CH2:55]3)/[C:26]3[N:27]=[C:28]([NH:31]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:29][CH:30]=3)[C:21](=[O:58])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([O:17][C:18](=[O:20])[CH3:19])[CH3:16])=[O:13])(=[O:3])[NH2:2].O>C(O)=O>[NH2:31][C:28]1[S:29][CH:30]=[C:26](/[C:25](=[N:51]/[O:52][CH2:53][CH:54]2[CH2:56][CH2:55]2)/[C:24]([NH:23][C@@H:22]2[C:21](=[O:58])[N:10]3[C:11]([C:12]([O:14][CH:15]([O:17][C:18](=[O:20])[CH3:19])[CH3:16])=[O:13])=[C:6]([CH2:5][O:4][C:1](=[O:3])[NH2:2])[CH2:7][S:8][C@H:9]23)=[O:57])[N:27]=1
Reactant: CC(=O)OC(C)OC(=O)C1=C(COC(N)=O)CS[C@@H]2[C@H](NC(=O)/C(=N\OCC3CC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Solvent: O
Solvent: O=CO
Product: CC(=O)OC(C)OC(=O)C1=C(COC(N)=O)CS[C@@H]2[C@H](NC(=O)/C(=N\OCC3CC3)c3csc(N)n3)C(=O)N12
Reaction time: 1.5 h
Yield: 51 %

Procedure:
1-Acetoxy-1-ethyl (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-cyclopropylmethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]ceph-3-em-4-carboxylate (1.5 g) was dissolved in formic acid (15 ml) and water (7.5 ml) was added. After 1.5 hour at 21°, the mixture was filtered and the filter-cake was leached with formic acid-water (2:1). The combined filtrates were concentrated and the residue was mixed with isopropanol when a solution formed. This was evaporated to dryness and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous layer was extracted with more ethyl acetate and the combined organic layers were washed with brine and dried with magnesium sulphate. After evaporation, the residue was triturated with isopropanol (5 ml) to give the title compound (540 mg); [α]D21 +17.9° (c 1.2, CHCl3); λmax (ethanol) 238.5 nm (E1 cm1% 287), λinfl 256 nm (E1 cm1% 249) and λinfl 280 nm (E1 cm1% 179).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:14])[CH2:9][NH:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:22](Br)[CH:23]=[CH2:24]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([OH:14])[CH2:9][N:10]([CH2:11][CH2:12][OH:13])[CH2:24][CH:23]=[CH2:22])=[CH:6][CH:7]=1
Reactant: OCCNC[C@H](O)c1ccc(Cl)cc1
Reactant: C=CCBr
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: C=CCN(CCO)C[C@H](O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To (R)-1-(4-chlorophenyl)-2-[(2-hydroxyethyl)amino]-1-ethanol (755 mg, 3.5 mmol) produced in Example 12, dimethylacetamide (5 mL), triethylamine (532 mg, 1.5 equivalents) and allyl bromide (508 mg, 1.2 equivalents) were added. The mixture was stirred at 25° C. for 16 hours. Toluene (5 mL) and distilled water (5 mL) were added to the mixture, and the organic layer and aqueous layer were separated. The organic layer was washed twice with distilled water (5 mL), then concentrated and dried under vacuum, to obtain 817 mg of the title compound as colorless oil (yield: 79%, chemical purity: 92.2 area %). The retention time in the chemical purity analysis method was 2.0 min.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH:2]1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[Br:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH3:23])=[CH:17][C:16]=1[N:24]=[C:25]=[O:26]>>[Br:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH3:23])=[CH:17][C:16]=1[NH:24][C:25]([N:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH:2]1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:26]
Reactant: COc1cc(N=C=O)c(Br)cc1C
Reactant: O=C1C=CNC(c2cccnc2)C1
Product: COc1cc(NC(=O)N2C=CC(=O)CC2c2cccnc2)c(Br)cc1C

Procedure:
2,3-Dihydro-1H-[2,3′]bipyridinyl-4-one was reacted with 1-bromo-2-isocyanato-4-methoxy-5-methyl-benzene using the procedure of step 3 of Example 1 to afford 4-oxo-3,4-dihydro-2H-[2,3′]bipyridinyl-1-carboxylic acid (2-bromo-5-methoxy-4-methyl-phenyl)-amide, MS (M+H) 417.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:22][C:23]1[C:28]([Br:29])=[CH:27][C:26]([CH2:30][CH2:31]Cl)=[CH:25][C:24]=1[Br:33]>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:31][CH2:30][C:26]3[CH:27]=[C:28]([Br:29])[C:23]([NH2:22])=[C:24]([Br:33])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: Nc1c(Br)cc(CCCl)cc1Br
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
This compound was prepared analogous to Example 12 from N-[-3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 2-(4-amino-3,5-dibromophenyl)-ethyl chloride.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:48]=[C:49]3[CH:55]=[CH:54][NH:53][C:50]3=[N:51][CH:52]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH:53]1[C:50]2=[N:51][CH:52]=[C:47]([C:2]3[C:10]4[C:9]([NH:11][C@H:12]([C:14]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:18](=[O:26])[C:17]6=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]6[N:15]=5)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=3)[CH:48]=[C:49]2[CH:55]=[CH:54]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnc5[nH]ccc5c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 48 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (103 mg, 0.17 mmol) was treated with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (103 mg, 0.42 mmol), sodium carbonate (51 mg, 0.48 mmol), 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (43 mg, 0.05 mmol) in 1,2-dimethoxyethane (4 ml) and water (1 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 55 mg (48% yield, 96% purity) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([OH:3])=O.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1(C)C=C(C)C=C(C)C=1>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]2[C:11](=[O:13])[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]2=[O:3])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Solvent: Cc1cc(C)cc(C)c1
Product: O=C1Cc2ccccc2C(=O)N1c1ccc(Cl)cc1

Procedure:
2-(2-Carboxyphenyl)acetic acid (9 g) and 4-chloroaniline (6.3 g) in mesitylene (200 ml) were heated at reflux for 18 h, under Dean and Stark conditions. On cooling, the crude product crystallised out and was filtered off. Recrystallisation from ethanol/ethyl acetate gave 2-(4-chlorophenyl)isoquinoline-1,3(2H,4H )-dione, m.p. 178°-80° C. A mixture of this product (2.8 g) and phosphoryl chloride (10 ml) was heated at reflux for 21 h, and excess phosphoryl chloride was then eveporated at reduced pressure. The residue was stirred in ice-water for 4 h. and the precipitate filtered off and suspended in 2% aqueous sodium bicarbonate for 5 minutes. It was again filtered off, taken up in dichloromethane (150 ml) dried and evaporated. Column chromatography of the residue gave a brown solid, which was recrystallised from isooctane/ethyl acetate, to give 3-chloro-2-(4-chlorophenyl)isoquinolin-1(2H)-one m.p. 125°-7° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Br
Product: O=C(Cl)c1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C

Procedure:
A solution of 2-bromo-5-(trifluoromethyl)benzoic acid (10 g, 37.2 mmol) in thionyl chloride (44.2 g, 372 mmol) was heated at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then azeotroped with toluene to afford 2-bromo-5-(trifluoromethyl)benzoyl chloride, which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:49]=[CH:50][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:60]6[CH2:61][CH2:62][N:57]([C:52]7[CH:53]=[CH:54][CH:55]=[CH:56][N:51]=7)[CH2:58][CH2:59]6)=[O:36])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:42][CH:43]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(c5ccccn5)CC4)cc3F)cn2)cc1
Yield: 143.1 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 1-(2-pyridyl)piperazine (38.5 mg, 0.236 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-phenyl}-(4-pyridin-2-yl-piperazin-1-yl)-methanone as a yellow solid (139 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-285) as a yellow powder (54.8 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:25]([C:24]2[C:23]([Cl:22])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:32])=[O:26])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.5 %

Procedure:
To a solution of 4-amino-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (127.6 mmol, 37.57 g) and 2,6-dichlorobenzoyl chloride (140.6 mmol, 29.45 g) in dichloromethane (350 mL) was added diisopropylethylamine (192 mmol, 33.4 mL) at room temperature. The brown solution was stirred for 15 h at room temperature to afford a white suspension. At this time, TLC analysis of the mixture indicated the absence of starting material. The solids were collected by filtration and were washed with dichloromethane (150 mL) and air dried to obtain 52.75 g (88.4%) of a white solid: mp 192-194° C. 1H NMR (DMSO-d6) (400 MHz) δ 10.68 (s, 1H), 7.47-7.6 (m, 5H), 7.2-7.29 (m, 3H), 4.12-4.17 (m, 1H), 3.62 (s, 3H), 2.79-2.99 (m, 2H), 1.33 (s, 9H), 13C NMR, CDCl3 (100 Mhz) d 172.49, 161.82, 155.37, 136.99, 136.36, 131.28, 131.16, 129.48, 128.19, 119.31, 78.27, 55.3, 51.76, 35.9, 27.77. HR MS: Obs. mass, 466.1069. Calcd. mass, 466.1062).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11][C:12]([OH:14])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:11][C:12]([N:28]1[CH2:27][CH:26]2[CH:30]([C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][C:25]2=[O:31])[CH2:29]1)=[O:14]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: COc1cccc(OC)c1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.58 h
Yield: 59.2 %

Procedure:
N,N'-Carbonyldiimidazole (0.52 g) is added to a solution of 2-(2,6-dimethoxyphenyl)acetic acid (0.63 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 35 minutes at +5° C. The mixture is stirred for 35 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.05 g) and triethylamine (0.44 cc) in dichloromethane (25 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (16 cc) and isopropyl ether (15 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(2,6-dimethoxyphenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (0.89 g) melting at 224° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][CH3:11].S(Cl)([Cl:14])=O>ClCCl.CN(C)C=O>[Cl:14][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][CH3:11])[CH:4]=1
Reactant: COc1cc(CO)ccc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(CCl)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a solution of (4-fluoro-3-methoxyphenyl)methanol (Claudi, et al., J. Med. Chem. 1990, 33(9):2408) (0.90 g, 5.76 mmol) in anhydrous dichloromethane (10 mL) was added thionyl chloride (0.84 mL, 12 mmol) and anhydrous N,N-dimethylformamide (2 drops). The reaction mixture was stirred at ambient temperature for 16 h and concentrated in vacuo to afford 4-(chloromethyl)-1-fluoro-2-methoxybenzene (0.73 g, 72%) as a brown oil: 1H NMR (300 MHz, CDCl3) δ 7.05-6.86 (m, 3H), 4.53 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]1=[O:18].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)=[O:22].C(N(CC)CC)C>CO>[Cl:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:21]([CH2:20][N:15]1[CH2:14][CH2:13][CH:12]([N:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2][C:3]2=[O:18])[CH2:17][CH2:16]1)=[O:22]
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(N2Cc3ccccc3NC2=O)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
In this example, 2.67 g of 4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine mono-hydrochloride, 2.33 g of α-bromo-m-chloroacetophenone, 2.8 ml of triethylamine and 30 ml of methanol are mixed and stirred at room temperature overnight. Then, the white crystals deposited are separated by filtration, successively washed with methanol and water and dried to obtain 2.89 g of a crude product. The crude product is recrystallized from a mixed solvent of chloroform and ethanol to obtain 1.93 g of the desired product.
Reaction SMILES: [F:1][CH:2]([CH:6]1[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1)[CH:3]([F:5])[F:4].O.C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[F:1][CH:2]([CH:6]1[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1)[CH:3]([F:4])[F:5]
Reactant: FC(F)C(F)C1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: O=C1CCC(C(F)C(F)F)CC1

Procedure:
At 20 to 25° C., 6.2 g of 8-(1,2,2-trifluoroethyl)-1,4-dioxaspiro[4.5]decane were stirred in 40 ml of formic acid for 16 h. The reaction solution was subsequently poured into water, adjusted to pH 8 using potassium carbonate, extracted with methylene chloride and the organic phase was dried and concentrated to give the title product as a colourless oil which was reacted further without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14](S(C)=O)[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][C@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14]([NH:21][C@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24])[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)c1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Reactant: CC(C)C[C@@H](N)CO
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](CO)Nc1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Temperature: 100 °C
Reaction time: 18 h
Yield: 38.8 %

Procedure:
To the solution of 6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole (26 mg, 80 μmol) in 400 μL of NMP was added (R)-2-amino-4-methylpentan-1-ol (33 μL, 250 μmol) and DIPEA (17 μL, 100 μmol). The reaction solution was stirred at 100° C. for 18 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give (R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)-4-methylpentan-1-ol (12 mg, 31 μmol) as powder. ES/MS m/z 378.1 (MH+).
Reaction SMILES: C([C:3]1([C:19]([O-:21])=[O:20])[O:7][C:6]2=[C:8]([O:16]C)[CH:9]=[CH:10][C:11](C)([C:12]([O-:14])=[O:13])[C:5]2=[C:4]1[CH3:18])C.CN(C)P(=O)(N(C)C)N(C)C.O.[C:34]1(C)C=CC=C[CH:35]=1>>[CH2:34]([O:21][C:19]([C:3]1[O:7][C:6]2[C:8]([OH:16])=[CH:9][CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:5]=2[C:4]=1[CH3:18])=[O:20])[CH3:35]
Reactant: CCC1(C(=O)[O-])OC2=C(OC)C=CC(C)(C(=O)[O-])C2=C1C
Reactant: Cc1ccccc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1oc2c(O)ccc(C(=O)O)c2c1C
Temperature: 25 °C

Procedure:
The solution of 2-ethyl-4-methyl-7-methoxy-3-methylbenzo[b]furan-2,4-dicarboxylate (from step 5 of example 1) (13.0 g), sodium p-thiocresolate (20.26 g, 1.5 equiv.) and hexamethylphosphoric acid triamide (24.80 g, 1.5 equiv.) was heated in dry toluene at reflux temperature under nitrogen for 2-6 h. The reaction mixture was cooled to room temperature, water was added and aqueous layer was washed with dichloromethane. Aqueous layer was acidified at 10-15° C. with concentrated hydrochloric acid. The precipitated product was filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].C([Li])CCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].Cl>O1CCCC1>[CH2:29]([O:28][C:26](=[O:27])[C:7]1[C:6]([F:8])=[CH:5][CH:4]=[C:3]([NH2:9])[C:2]=1[F:1])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccc(F)c(C(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 2,4-difluoro-phenylamine (42, 5.11 mL, 50.7 mmol) in tetrahydrofuran (250 mL), cooled with dry ice/acetone bath under an atmosphere of nitrogen, was added n-butyllithium (1.60 M in hexane, 34.0 mL, 54.4 mmol) slowly. After 30 minutes, 1,2-Bis-(chloro-dimethyl-silanyl)-ethane (11.5 g, 53.4 mmol) dissolved in tetrahydrofuran (40.0 mL) was added to the reaction slowly. After 1 hour, n-butyllithium (1.60 M in hexane, 31.9 mL, 51.0 mmol) was added slowly to the reaction. The reaction was stirred at −78° C. for 30 minutes and then allowed to warm to room temperature over 40 minutes. The reaction was cooled to −78° C., followed by addition of n-butyllithium (1.60 M in hexane, 35.1 mL, 56.2 mmol) slowly. After 70 minutes, benzyl chloroformate (7.97 mL, 55.8 mmol) was added to the reaction. The reaction mixture was stirred at −78° C. overnight followed by addition of 2 N HCl (120 mL). The reaction was allowed to warm to room temperature for 2 hours. The organic layer was separated. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (43, 10.6 g, 79.7%). MS (ESI) [M+H+]+=264.1.