Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[NH2:25]>>[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)CC(N)c1cccnc1
Product: CC(C)CC(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1cccnc1

Procedure:
In analogy to the procedure described in Example 293, 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69 b) and 3-methyl-1-(pyridin-3-yl)butan-1-amine (CAN 938459-12-2) were condensed to the title product. MS (EI): m/e=431.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>C(OCC)(=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([NH:18][C:16]2[CH:17]=[C:12]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=4)[CH:13]=[CH:14][C:15]=2[O:19][CH3:20])=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.137 g, 0.5 mmol) was mixed with 3,5-dichlorophenyl isothiocyanate (0.111 g, 0.54 mmol) in ethyl acetate (10 mL) and heated briefly to 50° C. and then allowed to stand overnight at room temperature. The reaction mixture was concentrated to dryness and triturated with hexanes/ethyl acetate, and the insoluble solid collected by filtration (0.214 g), mp 203-205° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.[Al](Br)(Br)Br>CCCCCC.C(Br)Br.[Al](Br)(Br)Br>[CH2:1]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: C=CCCCCCCCC
Agent: Br[Al](Br)Br
Solvent: CCCCCC
Solvent: BrCBr
Product: CCCCCCCCCCC12CC3CC(CC(C3)C1)C2

Procedure:
Decyl adamantane was prepared by reacting 140 g 1-decene, 54.4 gram adamantane in 100 cc n-hexane solvent and using 3 mmoles 1.0M AlBr3 in CH2Br2 or AlBr3 catalyst at 15°-50° C. reaction temperature. The product was isolated by quench the catalyst with dilute acid and aqueous work-up followed by distillation at 155° C. and 0.2 mm-Hg using a Kugelrohr to remove any C20 -material. The C30 + fraction was obtained in 80% yeild. It was hydrogenated at 200° C. and 500 psi H2 using 1 wt. % Ni/SiO2 catalyst.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]2[CH:9]=[CH:10][O:11][C:7]=2[C:6](Br)=[CH:5][CH:4]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][C@@H:23]1[CH2:28][CH3:29])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[F:1][C:2]([F:14])([F:13])[C:3]1[C:8]2[CH:9]=[CH:10][O:11][C:7]=2[C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[C@@H:23]([CH2:28][CH3:29])[CH2:24]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)c2occc12
Reactant: CC[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: CC[C@H]1CN(c2ccc(C(F)(F)F)c3ccoc23)CCN1C(=O)OC(C)(C)C
Yield: 83.5 %

Procedure:
Beginning with 1.45 gm (5.47 mMol) 4-trifluoromethyl-7-bromobenzofuran and 1.4 gm (6.53 mMol) 1-(tert-butoxycarbonyl)-2(S)-ethylpiperazine, 1.82 gm (84%) of the desired compound were prepared essentially as described in Example 1.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][N:11]2[C@H:17]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]1=[O:28]>CCOC(C)=O>[Cl:6][C:7]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][N:11]2[C@H:17]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:26][CH:27]=2)[C:18]1=[O:28]
Reactant: O=C1[C@@H](N2CCc3c2ccc(F)c3Cl)CCN1c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: O=C1[C@@H](N2CCc3c2ccc(F)c3Cl)CCN1c1ccc(S(=O)(=O)Cl)cc1
Temperature: 60 °C

Procedure:
Prepared using general procedure 62: To chlorosulfonic acid (2.0 mL) at 0° C. under N2 was added (S)-3-(4-chloro-5-fluoroindolin-1-yl)-1-phenylpyrrolidin-2-one (1.92 g, 5.8 mmol) in portions. The reaction mixture was heated to 60° C. for 20 min. and, after cooling to RT, carefully poured onto ice-water. EtOAc was added, the phases were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4 and concentrated to give 4-((S)-3-(4-chloro-5-fluoroindolin-1-yl)-2-oxopyrrolidin-1-yl)benzene-1-sulfonyl chloride which was used without further purification. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=429.3; tR=2.14 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:4][CH:3]=1.S(Cl)([Cl:23])(=O)=O.C(=O)([O-])O.[K+]>C(Cl)Cl>[Cl:23][C:15]1[N:14]2[C:10]([S:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=32)=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Clc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: Clc1ccc(-c2nc3sc4ccccc4n3c2Cl)cc1
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
To a solution of 2 g of 2-(p-chlorophenyl)imidazo[2,1-b]benzothiazole in 40 ml of methylene chloride was added a solution of 0.95 g of sulfuryl chloride in 5 ml of methylene chloride and after stirring for 10 minutes, 40 ml of an aqueous 10% potassium hydrogencarbonate solution was added to the mixture followed by stirring. The organic layer which formed was recovered, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to form crystals, which were recrystallized from ethanol to provide 1.4 g of 3-chloro-2-(p-chlorophenyl)imidazo[2,1-b]benzothiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][OH:19].C([O-])([O-])=O.[K+].[K+].O>CC(=O)CC>[OH:19][CH2:18][CH2:17][N:10]1[CH2:9][CH2:8][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)([OH:13])[CH2:12][CH2:11]1
Reactant: OCCBr
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1ccc(CC2(O)CCN(CCO)CC2)cc1
Yield: 69 %

Procedure:
A mixture containing 4-(4-methyl-benzyl)-piperidin-4-ol (5.1 g, 25 mmol), 2-bromoethanol (1.8 ml, 25 mmol) and K2CO3 (5.2 g, 37.5 mmol) in 2-butanone (120 ml) was refluxed for 22 hours. H2O (30 ml) was added and the aqueous phase was extracted with ethylacetate. Combined organic phases were dried over Na2SO4, and concentrated. The residue was chromatographed over silica gel (CH2Cl2 --MeOH, 9:1 +NH4OH (1%)) to provide 1-(2-hydroxy-ethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (4.3 g, 73%) as a yellow oil, MS: m/e=235.3 (M+).
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:27]C(=O)C)[C:20]([CH3:26])([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].C(C(CCCC(OC(=O)C)CCCCC)CCCCCCC(OCC)=O)(=O)C>>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:27])[C:20]([CH3:26])([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCC(C)(C)C(CCCC(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Agent: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Product: CCCCC(C)(C)C(O)CCCC(CCCCCCC(=O)O)C(C)=O

Procedure:
This compound is prepared as described in Example 1, Step D, except that ethyl 8-acetyl-12-acetoxy-13,13-dimethylheptadecanoate is substituted for ethyl 8-acetyl-12-acetoxyheptadecanoate. The product is purified by chromatography on silica gel with 2% methanol in chloroform as eluant and is obtained as a colorless viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.[Li]>CCOCC.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Li]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(Br)ccc1CO
Reaction time: 4 h
Yield: 80.4 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (1.0 g, 4.65 mmol) in Et2O (15 mL) was added lithium aluminumhydride (370 mg, 10.23 mmol) and the mixture was stirred for 4 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (4×100 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica, petrol ether/EtOAc) to give the title compound as a colorless gum (752 mg, 80%). 1H NMR (CDCl3, 400 MHz) δ 7.35-7.30 (2H, m), 7.24 (1H, m), 4.65 (2H, s), 2.32 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]=O)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: COC(=O)c1nc2n(c1C=O)C1CC(C1)c1ccc(Br)cc1-2
Reactant: C1CCNC1
Product: COC(=O)c1nc2n(c1CN1CCCC1)C1CC(C1)c1ccc(Br)cc1-2
Yield: 70 %

Procedure:
Methyl 10-bromo-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with pyrrolidine similarly to as described in Example 7 to afford 320 mg (70%) of methyl 10-bromo-3-(pyrrolidin-1-ylmethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate as a white solid. methyl 10-bromo-3-(pyrrolidin-1-ylmethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was subjected to General Procedure L to afford 130 mg (47%) of 10-bromo-3-(pyrrolidin-1-ylmethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. 10-bromo-3-(pyrrolidin-1-ylmethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 14 mg (19%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-3-(pyrrolidin-1-ylmethyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=[CH2:15])[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:15][O:25]1)=[O:16])[CH3:2]
Reactant: C=C(CCCC1CCCCC1)C(=O)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C1(CCCC2CCCCC2)CO1
Temperature: 0 °C

Procedure:
7.9 g of 5-cyclohexyl-2-methylenevaleric acid ethyl ester and 12.2 g of m-chloroperbenzoic acid in 100 ml of methylene chloride are boiled under reflux for 21 hours. The mixture is cooled to 0° C., the precipitate is filtered off and washed with 50 ml of methylene chloride and the combined filtrates are concentrated. The turbid, oily residue is dissolved in 60 ml of acetone and dilute sodium carbonate solution is added, while cooling with ice, until a pH value of 9 is reached. 100 ml of water are also added and the mixture is extracted with 3 times 100 ml of diethyl ether. The combined organic phases are dried over sodium sulphate and concentrated and the oily residue is distilled. This gives 4.9 g of the title compound, bp 100°-108° C. at 0.02 mm Hg (2.7 Pa).
Reaction SMILES: [OH:1][CH:2]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:3][CH2:4][CH:5]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:37])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[CH:24]([NH2:35])[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]=[N+:33]=[N-:34])=[CH:28][CH:27]=3)=[CH:12][CH:11]=2)[CH:6]1[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1.[C:52](C1CC(=O)N(O)C1=O)(=[O:66])[CH2:53][CH2:54][CH2:55][CH2:56][C@H:57]1[C@@H:65]2[C@@H:60]([NH:61][C:62]([NH:64]2)=[O:63])[CH2:59][S:58]1>CN(C)C=O>[N:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH:24]([NH:35][C:52](=[O:66])[CH2:53][CH2:54][CH2:55][CH2:56][CH:57]2[CH:65]3[NH:64][C:62](=[O:63])[NH:61][CH:60]3[CH2:59][S:58]2)[C:23](=[O:36])[NH:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17](=[O:37])[NH:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[C:8](=[O:9])[CH:5]([CH2:4][CH2:3][CH:2]([OH:1])[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:6]3[C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)=[CH:15][CH:14]=2)=[CH:27][CH:28]=1)=[N+:33]=[N-:34]
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)C2CC(=O)N(O)C2=O)N1
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCNC(=O)C(N)Cc3ccc(N=[N+]=[N-])cc3)cc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCNC(=O)C(Cc3ccc(N=[N+]=[N-])cc3)NC(=O)CCCCC3SCC4NC(=O)NC43)cc2)cc1
Yield: 54.6 %

Procedure:
40 mg (0.058 mmol) of compound 12 and 60 mg of D-biotinyl -N-hydroxysuccinimide 13 (Bachem) are solved in 0.5 ml DMF (dimethylformamide). It is evaporated after 1 h at room temperature. The residue is purified by flash chromatography (methylenchloride/methanol/conc. ammonia 30:5:1). 29 mg (55%) of compound 14 is obtained in form of an amorphic solid compound: C49H57N9O7S (912.12) MS (ESI+) 916.6 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.[FH:8].[F:9][C:10]1[C:15]([CH:16]2[O:18][CH2:17]2)=[C:14]([F:19])[C:13]([F:20])=[C:12]([F:21])[C:11]=1[F:22].C(OCC)C>O>[F:8][CH:16]([C:15]1[C:10]([F:9])=[C:11]([F:22])[C:12]([F:21])=[C:13]([F:20])[C:14]=1[F:19])[CH2:17][OH:18]
Reactant: Fc1c(F)c(F)c(C2CO2)c(F)c1F
Reactant: F
Solvent: O
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: OCC(F)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 30 h
Yield: 29 %

Procedure:
A Teflon vessel containing 2.7 g (22.5 mmol) of diisopropylamine was cooled in a dry-ice methanol bath, and to this was added dropwise 1.8 g (90 mmol) of anhydrous hydrogen fluoride to prepare 4.5 g (22.5 mmol) of (i-Pr)2NH. 4HF. To this was added dropwise 3.15 g (15 mmol) of (+)-pentafluorostyrene oxide at 0° C. and the resulted mixture was stirred for 30 hours under N2 at room temperature. To this was added 30 ml of diethyl ether and 30 ml of water and the aqueous layer was extracted with 20 ml of ether. The combined ether solution was washed with an aqueous solution of sodium carbonate and then water, and was dried over anhydrous sodium sulfate. After ether was distilled off, distillation under reduced pressure was carried out (Kugelrohr, 70-80° C./15 mmHg), thereby obtaining 1.0 g of (+)-2-fluoro-2-(pentafluorophenyl)ethanol. The yield was 29%, the GC purity was 98%, and [α]D25 was +12.0° (c=0.30, CHCl3). The other physical properties were mentioned above.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([OH:13])(=[O:12])[CH2:10][OH:11].N[C@H:15]([C:17](O)=[O:18])C>O1CCOCC1>[C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]1[O:11][C:17](=[O:18])[CH2:15][O:13][C:9]1=[O:12]
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(O)CO
Agent: O=C1CCCCCO1
Solvent: C1COCCO1
Product: O=C1COC(=O)CO1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A 1% w/w solution of epsilon-caprolactone/glycolide copolymer in 1,4-dioxane was prepared as follows. 1.5 grams of 36/64 poly(epsilon-caprolactone-glycolic acid) copolymer, obtained from American Polymer Incorporated (American Polymer Inc., Birmingham, Ala.), were added to 148.8 grams of 1,4-dioxane (Fisher Scientific, Raritan, N.J.) in a 250 milliliter Erlenmeyer screwed cap flask. The mixture was stirred for 4 hours in 60° C. water bath set on a temperature controlled heating plate. The polymer solution was filtered through an extra coarse thimble filter to remove any undissolved solids.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH:18]1([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]3[O:21][C:2]4[CH:3]=[C:4]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[N:5]=[CH:6][C:7]=4[N:8]=3)=[CH:11][CH:12]=2)[CH2:20][CH2:19]1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCC3CC3)cc2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCC4CC4)cc3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
A suspension of tert-butyl ((2S)-1-((4-chloro-5-((4-(cyclopropylmethoxy)benzoyl)amino)pyridin-2-yl)oxy)propan-2-yl)carbamate (500 mg), potassium carbonate (290 mg) and copper(I) iodide (20.0 mg) in DMF (10 mL) was stirred at 160° C. for 5 hr and 30 min under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (162 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=2)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: Cc1ccnc(Br)c1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: Cc1ccnc(N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)c1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-4-methyl-pyridine.
Reaction SMILES: N1CCOCC1.C([Li])CCC.Br[C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:17][C:14]=1[CH:15]=[O:16].[F:34]NS(C1C=CC=CC=1)(=O)=O.Cl>C1COCC1.C(OCC)C>[F:34][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:17][C:14]=1[CH:15]=[O:16]
Reactant: O=S(=O)(NF)c1ccccc1
Reactant: COc1cc(Br)c(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1COCCN1
Product: COc1cc(F)c(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.01 ml of morpholine in 50 ml of THF there was added 8.69 ml of n-butyllithium (2.66 M, hexane solution) at −78° C. under a nitrogen atmosphere, and the mixture was stirred at −40° C. for 30 minutes. A solution of 2-bromo-4-methoxy-5-triisopropylsilanyloxybenzaldehyde in 15 ml of THF was then added dropwise at −78° C., and the mixture was further stirred at −78° C. for 40 minutes. After further adding 11.1 ml of n-butyllithium (2.66 M, hexane solution) at −78° C., the mixture was stirred at −78° C. for 40 minutes, and then a solution of 10.6 g of N-fluorobenzenesulfonamide in 40 ml of THF was added dropwise at −78° C. and the reaction mixture was stirred overnight while raising the temperature to room temperature. Dilute hydrochloric acid was added to the reaction mixture, and extraction was performed with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (2.96 g) as a light yellow solid.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:9][C:10](OCC)=[O:11])C.CO.O>C1COCC1.C(OCC)(=O)C>[C:19]([O:18][C:16](=[O:17])[NH:15][C@H:7]([CH2:6][OH:5])[CH2:8][CH2:9][CH2:10][OH:11])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CO)CCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
Lithium borohydride (2.0 M in THF, 4.12 ml, 8.24 mmol) was cooled in an ice bath and a solution of (S)-2-tert-butoxycarbonylamino-pentanedioic acid diethyl ester (0.5 g, 1.65 mmol) in THF (5.5 ml) was added dropwise. The reaction was warmed to room temperature and stirred 16 h. Methanol was added very slowly to the reaction mixture. After a delayed, vigorous gas evolution had subsided, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate five times, and the combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to give 0.3 g (83%) of ((S)-4-hydroxy-1-hydroxymethyl-butyl)-carbamic acid tert-butyl ester. (M+Na)+=242.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[CH3:19][S:20]Cl.CSSC.ClCl>C(Cl)Cl>[Br:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:20][CH3:19])=[C:7]([OH:11])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc(O)c2)c(Br)c1
Reactant: CSCl
Agent: ClCl
Solvent: CSSC
Solvent: ClCCl
Product: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2Br)cc1O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3-(2-Bromo-4-nitrophenoxy)phenol (0.01 mole) and methylene chloride (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. The mixture is stirred until dissolved and cooled to about -20° C. A solution of methyl sulfenyl chloride freshly prepared by reacting dimethyl disulfide (0.015 mole) with chlorine (0.18 mole) in methylene chloride (100 ml) is then added dropwise to the reaction vessel over a period of about 40 minutes. After the addition is completed stirring is continued for 30 minutes with cooling and 30 minutes at room temperature. After this time the reaction mixture is washed with water (200 ml) with 5% aqueous sodium bicarbonate (200 ml) and again with water (200 ml). The washed solution is then dried by passing it through a phase separator. The dried solution is stripped of solvent under reduced pressure and the residue chromatographed using a clay column and hexane/ethyl acetate as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product 5-(2-bromo-4-nitrophenoxy)-2-(methylthio)phenol as the residue.