Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Cl)cc21)c1ccccc1

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and benzoyl chloride in a similar manner as described above to give a pale yellow solid (81% yield). 1H-NMR (CDCl3): δ 9.02 (s, 1H), 7.79-7.73 (m, 2H), 7.54-7.48 (m, 1H), 7.46-7.39 (m, 3H), 7.21 (d, 1H), 7.10 (dd, 1H), 6.45 (d, 1H), 5.32 (m, 1H), 2.72 (m, 2H), 2.30 (m, 1H), 2.01-1.90 (m, 3H); MS m/z 323 (M−1).
Reaction SMILES: [CH:1]12[O:10][CH:2]1[CH2:3][C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:11]>>[NH2:11][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[OH:10]
Reactant: N
Reactant: c1ccc2c(c1)CC1OC21
Product: N[C@@H]1c2ccccc2C[C@H]1O

Procedure:
The trans amide can be made from the epoxide either (1) by treating the indene oxide with ammonia or a primary amine to produce a trans-1-amino-2-indanol and reacting the trans-1-amino-2-indanol with an acylating agent, or (2) by treating the epoxide with an amide anion to produce the trans hydroxy amide directly. In one embodiment the indene is oxidized with aqueous hypochlorite in the presence of a chiral salen catalyst to produce a partially resolved epoxide, which is converted to the partially resolved trans-1-amino-2-indanol by treating with ammonia or a primary amine followed by acylating with benzoyl chloride or acetic anhydride. The resulting benzamide or acetamide is recrystallized to yield substantially optically pure trans-1-benzamido-2-indanol or trans-1-acetamido-2-indanol. In two preferred embodiments, the cis-1-amino-2-indanols are (1S,2R)-1-amino-2-indanol and (1R,2S)-1-amino-2-indanol, produced by oxidation of indene in the presence of an R,R or S,S-salen catalyst respectively.
Reaction SMILES: [CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][NH:5][C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2].F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][N:5]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:22])([F:24])[F:23])[CH:14]=2)[C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CC[C@]1(O)CCN[C@H]1C(C)C
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(C(F)(F)F)c2)[C@H]1C(C)C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (203 mg), 4-fluoro-2-(trifluoromethyl)benzonitrile (189 mg) and lithium carbonate (163 mg), the title compound was obtained as colorless oil (yield: 180 mg, yield: 55%).
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][N:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[C:10]2=[O:30])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:31]1([C:2]2[C:7]([CH2:8][N:9]3[N:18]=[CH:17][C:16]4[C:11](=[CH:12][C:13]([C:19]5[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=5)=[CH:14][CH:15]=4)[C:10]3=[O:30])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:33][CH2:32]1
Reactant: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2cnn1Cc1cccnc1Br
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2cnn1Cc1cccnc1C1CC1
Temperature: 100 °C

Procedure:
A mixture of 2-((2-bromopyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (25 mg, 0.053 mmol), cyclopropyl boronic acid (14 mg, 0.16 mmol), dppf(Pd)Cl2 (6 mg, 0.0079 mmol), potassium carbonate (29 mg, 0.021 mmol) in degassed dioxane (1 mL) was heated at 100° C. for 3 hours. The layers were separated, the organic layer was concentrated and the residue was purified by reverse phase HPLC to provide 2-((2-cyclopropylpyridin-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white powder. C2-4H18F3N3O2. 438.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.Cl[C:27]([O:29][CH3:30])=[O:28].C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[C:7]([C:27]([O:29][CH3:30])=[O:28])=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: COC(=O)Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.50 g, 1.612 mmol, see Example 1) was dissolved in THF (15 mL) and cooled to −78° C. s-BuLi (2.54 mL, 3.56 mmol) was then added dropwise, and the solution was stirred at −78° C. for 30 minutes. Methyl chloroformate (0.38 mL, 4.98 mmol) was then added as a THF (2 mL) solution, and the reaction was stirred for an additional 30 minutes. The reaction was then quenched with saturated NH4Cl and allowed to warm to room temperature. The reaction was then extracted with DCM (3×50 mL), dried, and filtered to give a crude residue. The crude residue was purified by column chromatography with 5:1 hexane:DCM to give methyl 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.55 g, 91% yield).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I.O>CN(C)C=O>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: ClCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCn1c(-c2ccccc2)nc2ccccc21
Yield: 95.4 %

Procedure:
2.5 g (12.88 mmol) of 2-phenyl-benzimidazole was dissolved in 30 ml of N,N-dimethylformamide, and 5.3 g (38.6 mmol) of K2CO3 and 2.0 ml (16.7 mmol) of 1-chloro-4-iodobutane were added to the resulting solution, followed by mixing the mixture at a room temperature for 10 hours. The reactant was combined with 100 ml of water and extracted with ethylacetate (70 ml×5) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (n-hexane/ethylacetate=2/1) to obtain 3.5 g (yield 96%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[ClH:23]>ClCCl.O1CCOCC1>[ClH:23].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(F)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1ccc(OCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a cooled solution of tert-butyl 4-[(4-fluorophenoxy)methyl]piperidine-1-carboxylate (538 mg, 1.74 mmol; which may be prepared as described in Step 1) in dichloromethane (11.5 mL) was added dropwise HCl 4N in dioxane (8.5 mL). The solution was warmed to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure to give the title compound (416 mg, 97%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[CH:19][N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:3].Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:17][C:12]1[CH:11]=[C:10]([C:9]2[C:8](=[O:18])[N:7]3[CH:19]=[CH:20][S:21][C:6]3=[N:5][C:4]=2[CH:2]([NH:1][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:3])[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.037 g, 0.12 mmol), 6-bromo-9H-purine (0.048 g, 0.24 mmol), and N,N-diisopropylethylamine (0.042 mL, 0.24 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H14F2N7OS (M+H)+: m/z=426.1. Found: 426.0. 1H NMR (DMSO-d6, 400 MHz) δ 7.99 (1H, d, J=4.8 Hz), 7.63 (1H, s), 7.53 (1H, d, J=4.8 Hz), 7.24 (1H, m), 7.16 (2H, m), 6.88 (1H, br s), 5.41 (2H, br s), 5.05 (1H, m), 1.27 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −111 ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(#N)C>[NH:22]([C:2]1[N:7]=[N:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1)[NH2:23]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)nn2)CC1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(NN)nn2)CC1
Temperature: 80 °C
Yield: 58.7 %

Procedure:
A stirred mixture of tert-butyl 4-(6-chloropyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (870 mg, 2.94 mmol) and hydrazine hydrate (4.29 mL, 88.25 mmol) in acetonitrile (15 mL) was heated at 80° C. for 4 hours. The mixture was partially evaporated (removing MeCN) and diluted with water (10 mL). The reaction mixture was extracted with DCM (3×50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product as a gum, which crystallised on trituration with ether. The precipitate was collected by filtration, washed with ether and dried under vacuum to afford tert-butyl 4-(6-hydrazinylpyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (503 mg, 58.7%) as a cream crystalline solid.
Reaction SMILES: [NH2:1][CH:2]1[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:17][F:18])([CH2:15][F:16])[CH:3]1[OH:19].Br[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24](OC)=[O:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(#N)C>[F:18][CH2:17][C:4]1([CH2:15][F:16])[C@@H:3]([OH:19])[C@H:2]([N:1]2[CH2:21][C:22]3[C:23](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:24]2=[O:25])[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NC1c2cc([N+](=O)[O-])ccc2OC(CF)(CF)C1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2CN1[C@@H]1c2cc([N+](=O)[O-])ccc2OC(CF)(CF)[C@H]1O
Temperature: 80 °C
Reaction time: 6 h
Yield: 42.2 %

Procedure:
A mixture of 0.25 g of 4-amino-2,2-bisfluoromethyl-3,4-dihydro-6-nitro-2H-1-benzopyran-3-ol, 0.22 g of methyl 2-bromomethylbenzoate, 0.40 g of potassium carbonate, 0.09 g of potassium iodide and 5 ml of acetonitrile was stirred at 75-85° C. for 6 hours. Water was added thereto and the mixture was extracted with a mixed solvent of ethyl acetate and ether. After the organic layer was washed with 1N hydrochloric acid and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, AcOEt:hexane=1:1) and recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 0.15 g of trans-2,2-bisfluoromethyl-3,4-dihydro-4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-6-nitro-2H-1-benzopyran-3-ol represented by the following formula having a melting point of 285-288° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CC(N(C)C)=O.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>O>[F:19][C:20]([F:34])([F:35])[C:21]1[CH:22]=[C:23]([C:24]([NH:1][C:2]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:25])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(Cl)ccc1N
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
Under ice-cooling, 660 mg (3.56 mmol) of methyl 2-amino-5-chlorobenzoate was added to a DMAc (10 mL) solution comprising 1.00 g (3.62 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was stirred for a short time. Thereafter, the precipitates were collected by filtration, washed with water, and then air-dried, thereby giving methyl 2-({[3,5-bis(trifluoromethyl)phenyl]carbonyl}amino)-5-chlorobenzoate (yield: 99%).
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([OH:23])[CH:14]=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](Br)[CH:25]=[CH2:26].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([O:23][CH2:26][CH:25]=[CH2:24])[CH:14]=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: CCOc1ccc(O)c2c1C(=O)N(Cc1ccccc1)S2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(OCC)c2c1S(=O)(=O)N(Cc1ccccc1)C2=O
Temperature: 80 °C
Yield: 96 %

Procedure:
A mixture of 2-benzyl-4-ethoxy-7-hydroxysaccharin (1.0 g), allyl bromide (0.36 g), potassium carbonate (0.62 g) and methyl ethyl ketone (about 20 mL) was heated at 80° C. for one hour. More allyl bromide (0.36 g) was added and heating at 80° C. was continued for one and one-half hours. The mixture was cooled and poured into ice-water (500 mL). The solid was collected affording 2-benzyl-4-ethoxy-7-allyloxysaccharin, 1.08 g, 96% yield, mp 148°-149° C.
Reaction SMILES: N1C=CC=CC=1.[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8].[Cl:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([C:19](Cl)=[O:20])[C:14]=1[CH3:22]>ClCCl>[Cl:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([C:19]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:20])[C:14]=1[CH3:22]
Reactant: Cc1c(Cl)ncnc1C(=O)Cl
Reactant: CC(C)(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Cl)ncnc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. a solution of 5.8 mL pyridine and 15 mL tert.-butanol in 10 mL dichloromethane was added dropwise to 6.0 g 6-chloro-5-methyl-pyrimidine-4-carboxylic acid chloride in 10 mL dichloromethane. The reaction mixture was heated to RT and stirred for 30 min. The reaction mixture was diluted with dichloromethane and washed successively with a 2M sodium hydroxide solution, twice with a 10% aqueous citric acid solution and a sodium chloride solution. The organic phase was dried and evaporated down. The residue was taken up in dichloromethane and purified by flash chromatography. The product-containing fractions were evaporated down and dried.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[CH:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)=[CH2:21]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=COCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=COCCCCCOc1ccc(C(=O)O)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 128.6 %

Procedure:
Ethyl p-hydroxybenzoate (33.2 g), 5-bromopentylvinyl ether (58.0 g), potassium carbonate (41.5 g) and N,N-dimethylacetamide (200 mL) were put into a 500-mL three-neck flask, and stirred at 120° C. for 5 hours. After cooled, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (500 mL), and washed two times with water (100 mL). This was dried with anhydrous magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure, the residue was dissolved in methanol (100 mL), and a methanol solution (20 mL) of potassium hydroxide (16.8 g) was dropwise and gradually added thereto, and heated under reflux for 2 hours. After cooled, the formed crystal was collected through filtration and dissolved in water (1 L). Concentrated hydrochloric acid (25.7 mL) was added thereto, and the precipitated crystal was collected through filtration under reduced pressure, and washed with water. This was dried to give 4-(5-vinyloxypentyloxy)benzoic acid (TP-29C) (64.3 g, 90%). Production of 2,3,6,7,10,11-hexa(4-(5-vinyloxypentyloxy)benzoyloxy)triphenylene (TP-29):
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][NH:22][CH3:23])[C@@H:17]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38].CCN(C(C)C)C(C)C>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][N:22]([CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH3:23])[C@@H:17]2[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:8]=1
Reactant: CNC[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reactant: COC(=O)CCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CCCN(C)C[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 65 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((methylamino)methyl)cyclopentane from Example 18, Step B in 1 mL of acetonitrile was added 0.019 mL of methyl 4-chlorobutyrate and 0.037 mL of DIPEA. The reaction was heated at 50° C. for 48 hours, then an additional 0.038 mL of methyl 4-chlorobutyrate, 0.074 mL of DIPEA and 3 mg of tetrabutylammonium iodide were added and heating continued at 70° C. for 48 hours. The reaction was evaporated under a stream of nitrogen and the residue purified by prep TLC (10% methanol in ethyl acetate) to give 41 mg of title compound and 17 mg of recovered starting material. Mass spec (ESI): 564 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]1([OH:15])[CH2:14][CH2:13][CH2:12]1.[H-].[Na+]>C1COCC1>[CH:11]1([O:15][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCC2)nc1

Procedure:
A mixture of 2-chloro-5-nitropyridine (7.12 g, 45.0 mmol) and cyclobutanol (3.40 g, 47.2 mmol) in THF (30 mL) was vigorously stirred at 0° C. while NaH (1.18 g, 46.7 mmol) was added in three portions over ˜10-20 s under air (Caution: Extensive gas evolution). Reaction residue was rinsed down with additional THF (5 mL), followed by stirring under positive argon pressure in the ice bath for 1-2 more minutes. The ice bath was then removed and the brown homogeneous solution was stirred at “rt” for 1 h. The reaction was concentrated under reduced pressure at 80° C., taken up in 0.75 M EDTA (tetrasodium salt) (150 mL), and extracted with DCM (1×100 mL, 1×50 mL). The combined organic layers were dried (Na2SO4), concentrated, taken up in MeOH (2×100 mL) and concentrated under reduced pressure at 60° C. to provide the title compound as a thick dark amber oil that crystallized upon standing (7.01 g, 80%). 1H NMR (300 MHz, CDCl3) δ 9.04 (dd, J=2.84 and 0.40 Hz, 1H), 8.33 (dd, J=9.11 and 2.85 Hz, 1H), 6.77 (dd, J=9.11 and 0.50 Hz, 1H), 5.28 (m, 1H), 2.48 (m, 2H), 2.17 (m, 2H), 1.87 (m, 1H), 1.72 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=1.C=O.[BH3-][C:26]#N.[Na+]>C(O)(=O)C.CO>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)=[C:6]([N:17]([CH2:18][CH2:19][O:20][CH3:21])[CH3:26])[CH:5]=1
Reactant: [BH3-]C#N
Reactant: COCCNc1cc(C(=O)OC)ccc1N1CCN(C)CC1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCCN(C)c1cc(C(=O)OC)ccc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
To a solution of 170 mg of 3-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (0.55 mmol, 1 eq.) in 5 mL of acetic acid were added 3 mL of aqueous solution of formaldehyde and the resulting mixture stirred for 10 minutes at room temperature; a solution of NaCNBH3 (680 mg, 11 mmol, 20 eq.) in 3 mL of MeOH was then added at 0° C. and the solution stirred for 5 minutes. The solvent was removed and the crude washed with water and dichloromethane. The combined organic layers were evaporated and the crude was purified by flash column chromatography, using dichloromethane-methanol 95:5 as eluant, affording 150 mg of the desired product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH2:24]Br)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH:15]=1.[C-:26]#[N:27].[Na+].O>CN(C=O)C.O.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH2:24][C:26]#[N:27])=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH:15]=1
Reactant: [C-]#N
Reactant: N#Cc1cccc(-c2cc(-c3nc4ccccc4o3)ccc2CBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1-c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5′-(1,3-benzoxazol-2-yl)-2′-(bromomethyl)-1,1′-biphenyl-3-carbonitrile (183 mg, 0.47 mmol) and sodium cyanide (46 mg, 0.94 mmol) in DMF:H2O (5:1, 18 mL) and DMF (20 mL) was stirred at rt for 3 h. H2O was added to the reaction mixture and it was extracted with EtOAc (3×). The organics were combined, washed with brine (2×), dried over Na2SO4, and evaporated to dryness to give an orange oil. The crude was purified by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 30 min: 0 to 20% EtOAc) to afford the desired 5′-(1,3-benzoxazol-2-yl)-2′-(cyanomethyl)-1,1′-biphenyl-3-carbonitrile as a colorless solid (M.p. 175–176° C.). 1H NMR (CDCl3, 300 MHz) δ 8.34 (dd, 1H), 8.18 (s, 1H), 7.77 (m, 3H), 7.67 (m, 3H), 7.60 (m, 1H), 7.40 (m, 2H), 3.69 (s, 2H). MS (ESI) 336 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=O)[C:11]2([CH3:19])[CH3:18].O>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH2:12][C:11]2([CH3:19])[CH3:18]
Reactant: CC1(C)C(=O)Nc2ccc(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CNc2ccc(F)cc21
Temperature: 70 °C

Procedure:
Under an argon atmosphere a solution of 9.30 mL (9.30 mmol) of a 1M solution of lithium aluminium hydride in THF and 10 mL THF was slowly added dropwise to 1.40 g (7.81 mmol) 5-fluoro-3,3-dimethyl-1,3-dihydroindol-2-one in 50 mL THF. Then the reaction mixture was heated to 70° C. for 1 h. After cooling 2 mL water were added. The solution was dried on sodium sulphate and filtered off. The solvent was eliminated i. vac.