Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([NH:5][C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)[CH2:3][CH3:4].[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50](O)=O)=O)=[CH:37][CH:36]=1)([O-:34])=[O:33].Br.C(N[C@H]1CCC2C(=CC=C(OC)C=2OC)C1)CC.COC1C=CC(SCC(NCCCCCC(O)=O)=O)=CC=1>>[ClH:1].[ClH:1].[CH2:2]([N:5]([C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]=2[O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:7]1)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][NH:44][CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=1)[CH2:3][CH3:4]
Reactant: CCCN[C@H]1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1
Reactant: O=C(O)CCCCCNC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: Br
Agent: CCCN[C@H]1CCc2c(ccc(OC)c2OC)C1
Agent: COc1ccc(SCC(=O)NCCCCCC(=O)O)cc1
Product: CCCN(CCCCCCNCCc1ccc([N+](=O)[O-])cc1)[C@H]1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1

Procedure:
By working in a way similar to that described in example 18 but by using Intermediate 27, prepared as described in example 14, and Intermediate 10, prepared as described in example 1, instead of (S)-N-propyl-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrobromide and of Intermediate 1 respectively, Intermediate 37 was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([O:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:26]=1.[CH3:34][N:35](C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([O:27][C:25]2[CH:24]=[N:23][CH:22]=[C:21]([CH:26]=2)[C:34]#[N:35])[CH:29]=1
Reactant: CN(C)C=O
Reactant: Brc1cncc(Oc2cccnc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Product: N#Cc1cncc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of polymer-bound triphenylphosphine (230 mg, 0.597 mmol, 0.150 eq) and palladium(II) acetate (63 mg, 0.28 mmol, 0.070 eq) in DMF (12 mL) stirred under argon at rt for 2 h. The supernatant DMF was removed, and fresh DMF (12 mL) was added. Compound 4 (1.0 g, 3.9 mmol, 1.0 eq) and zinc cyanide (470 mg, 4.00 mmol, 1.00 eq) were added, and the vial was subjected to microwave irradiation at 150° C. for 25 minutes. The resin was washed with ether, and the collected filtrate was washed (3×) with water and (1×) with brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 780 mg (100%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=1.4 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H), 8.51 (d, J=2.8 Hz, 1H), 8.47 (d, J=4.6 Hz, 1H), 8.13 (t, J=2.1 Hz, 1H), 7.63 (ddd, J=8.4, 2.7, 1.1 Hz, 1H), 7.49 (dd, J=8.5, 4.6 Hz, 1H); ES-MS [M+1]+:198.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Product: Brc1cccc(-c2ccccc2)n1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 2,6-dibromo-pyridine and phenylboronic acid. After purification the product still contained some 2,6-dibromo-pyridine starting material. The mixture was used directly in the next step.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:11][C:10]([CH3:13])([CH3:12])[O:9][C@@H:8]([CH2:14][C:15]([O:17][CH2:18]C)=[O:16])[CH2:7]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C@H:6]1[O:11][C:10]([CH3:12])([CH3:13])[O:9][C@@H:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7]1
Reactant: CCOC(=O)C[C@H]1C[C@@H](COC(C)=O)OC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Mixture of ethyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (80 grams), potassium carbonate (21 grams) in methanol (400 ml) was stirred for 2 hours at 0-10° C. The reaction mixture was quenched with water and then the reaction mixture extracted into methylene chloride and washed it with water. The methylene chloride from the reaction mixture was distilled off under reduced pressure to get the title compound.
Reaction SMILES: [CH:1]1([C:7]2[S:11][C:10]3[CH:12]=[C:13]([O:16]C)[CH:14]=[CH:15][C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:18]1([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:1]1([C:7]2[S:11][C:10]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:9]=3[C:8]=2[C:31]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:35][CH:34]=2)=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc2cc(C3CCCCC3)sc2c1
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(C2CCCCC2)sc2cc(O)ccc12

Procedure:
The product from Example 19, Step 2 and 4-(2-Piperidin-1-yl-ethoxy)-benzoyl chloride were coupled according to procedure C above and the methyl protecting group removed using etanethiol/aluminum trichloride to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34](O)=[O:35].CCN=C=NCCCN(C)C>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:35]
Reactant: O=C(O)Cc1ccccc1F
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccccc4F)c3)c2c1
Yield: 13.8 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2-fluorophenylacetic acid (0.11 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 30 mg (12% yield) of the title compound. 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.2 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.45 (t, 1H), 7.45–7.29 (m, 3H), 7.25–7.15 (m, 2H), 3.8 (s, 2H); ES-MS (m/z) 389 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:35]1[S:36][CH:37]=[C:38]([C:40]([O:42][CH3:43])=[O:41])[N:39]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:35]2[S:36][CH:37]=[C:38]([C:40]([O:42][CH3:43])=[O:41])[N:39]=2)[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1csc(Br)n1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1csc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a mixture of 136 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 64 mg of methyl 2-bromo-1,3-thiazole-4-carboxylate, and 38 mg of potassium carbonate was added 1.5 mL of DMSO at room temperature, and the mixed solution was stirred at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate, and the organic layer was then washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 113 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-1,3-thiazole-4-carboxylate as a colorless foamy substance. ESI+: 586
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:7][CH2:6]2.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].II.[Cl-].[NH4+]>[Zn].C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:8]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:7][CH2:6]2
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2=O)cc1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Product: CCOC(=O)CC1c2ccc(OC)cc2CCC1c1ccc(OC)cc1
Reaction time: 3 h

Procedure:
A stirred mixture of 3,4-dihydro-6-methoxy-2-p-methoxyphenylnaphthalen-1(2H)-one (10 g.), ethyl bromoacetate (17.8 g.), zinc (11.6 g.), benzene (200 ml.) and one crystal of iodine was heated under reflux under an atomsphere of argon for 10 minutes, allowed to continue to boil until the exothermic reaction subsided, heated again under reflux for a further 10 minutes and then cooled to laboratory temperature. Saturated aqueous ammonium chloride solution (100 ml.) was added, the mixture was filtered and the organic layer of the filtrate was separated, dried and evaporated to dryness. A 10% palladium-on-charcoal catalyst (2 g.) was added to a solution of the residue (13.1 g.) in ethyl acetate (300 ml.) and the mixture was stirred under an atmosphere of hydrogen for 3 hours, filtered, and rehydrogenated with fresh catalyst (2 g.) for 18 hours. The mixture was filtered, the filtrate was evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 25:1 v/v mixture of toluene and ethyl acetate. The ethyl [(1RS,2RS)-6-methoxy-2-p-methoxyphenyl-1,2,3,4-tetrahydronaphth-1-yl]acetate thus obtained was reduced with lithium aluminium hydride (4.4 g.) by a similar process to that described in Example 7, and the ethanol thus obtained (m.p. 98°-99° C.) was oxidised with pyridinium chlorochromate (8.6 g.) by a similar process to that described in the 6th paragraph of Example 2. There was thus obtained the desired acetaldehyde, m.p. 101°-103° C.
Reaction SMILES: Cl.[OH:2][CH:3]([CH3:11])[CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C.C(N(CC)CC)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]([N:8]1[CH2:9][CH2:10][CH:5]([CH2:4][CH:3]([OH:2])[CH3:11])[CH2:6][CH2:7]1)=[O:22]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(O)CC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)CC1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 233 mg of tert-butyl 4-(2-hydroxy propyl)piperidine-1-carboxylate in 4 mL of ethyl acetate was added 3 mL of 4M HCl/EtOAc, followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure to obtain 4-(2-hydroxypropyl)piperidine hydrochloride. To a solution of the 4-(2-hydroxypropyl)piperidine hydrochloride and 155 mg of indole-2-carboxylic acid in 5 mL of DMF were added 0.15 mL of triethylamine, 190 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 130 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.5M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then solidified using diisopropyl ether to obtain 49 mg of 1-[1-(1H-indol-2-ylcarbonyl)piperidin-4-yl]propan-2-ol as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][CH2:11][CH2:12][OH:13].[BH4-].[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:4]1([CH:1]([NH:10][CH2:11][CH2:12][OH:13])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCCO
Reactant: CC(=O)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(NCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.8 %

Procedure:
A mixture of acetophenone (2.00 g, 16.6 mmol, Eq: 1.00), 2-aminoethanol (3.05 g, 49.9 mmol, Eq: 3.00) and titanium(IV) isopropoxide (6.15 g, 6.41 ml, 21.6 mmol, Eq: 1.3) in absolute methanol (25 ml) was stirred under nitrogen at room temperature for 48 hrs. Sodium borohydride (630 mg, 16.6 mmol, Eq: 1.00) was then added at 0° C. and the resulting mixture was stirred for an additional 2 hr. The reaction was then quenched by adding water (1 ml). Stirring was continued at room temperature for 20 min., then the reaction mixture was acidified with 1N HCl. After filtration over a pad of Celite, washing with ethyl acetate, any drying over magnesium sulfate, the mixture was concentrated to obtain 2-(1-phenylethylamino)ethanol (oil, 2.71 g, 16.4 mmol, 98.5% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]([NH:13][CH3:14])[CH3:12])[O:10][C:6]=2[C:5]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[C:4]([F:28])[CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]([N:13]([CH3:29])[CH3:14])[CH3:12])[O:10][C:6]=2[C:5]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[N:17]([CH3:26])[C:16]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(C)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CC(c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1)N(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
0.5 g (1.2 mmol) of 3-[4-chloro-6-fluoro-2-(1-methylaminoethyl)benzofuran-7-yl]-1-methyl-6-trifluoromethyluracil and 0.40 g (2.9 mmol) of potassium carbonate were suspended in 50 ml of N,N-dimethylformamide, and 1.0 g (7.0 mmol) of methyl iodide was added thereto, followed by stirring at 60° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.35 g (yield: 68%) of the desired product as a purple glassy substance. Refractive index: 1.5341 (20° C.)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.BrC1C=CC(N)=CC=1.BrC1C=CC=CC=1C(OCC)=O>C(O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH3:12]
Reactant: CCc1cc(Cl)n2nccc2n1
Reactant: CCOC(=O)c1ccccc1-c1ccc(N)cc1
Agent: CCOC(=O)c1ccccc1Br
Agent: Nc1ccc(Br)cc1
Solvent: CCO
Product: CCOC(=O)c1ccccc1-c1ccc(Nc2cc(CC)nc3ccnn23)cc1

Procedure:
A solution of 800 mg (4.4 mmol) 7-chloro-5-ethylpyrazolo[1,5-a]pyrimidine (Example 1, Step B) and 1.0 g (4.1 mmol) ethyl 4'-amino-biphenyl-2-carboxylate (prepared from protected 4-bromoaniline and ethyl 2-bromobenzoate by the method of J. C. Adrian, Jr., C. S. Wilcox, J. Am. Chem. Soc. 1989, 111, 8055) in 40 ml dry ethanol was heated with reflux for 5 h. After cooling to room temperature pale yellow crystals of the title compound precipitated, which were filtered by suction and recrystallized from ethanol, m.p. 223°-225° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7](=O)[C:6]=2[CH:15]=1>[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:15]=1
Reactant: Cc1ccc2oc(C(=O)O)cc(=O)c2c1
Agent: [Pd]
Product: Cc1ccc2c(c1)CCC(C(=O)O)O2

Procedure:
6-Methyl-4-oxo-4H-1-benzopyran-2-carboxylic acid (Niviere, et al., 1965) was hydrogenated over a palladium-on-carbon catalyst to give 3,4-dihydro-6-methyl-2H-1-benzopyran-2-carboxylic acid. This acid was converted to the acid chloride with thionyl chloride and the acid chloride was converted to 9, obtained as white plates, mp: 67°-67.5° C., by treatment with 2-propenamine, all by the procedures described in Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@H:16]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C@H:16]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 4-tert-butylbenzenesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 576.2 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[CH3:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(OCC)(=O)C>[F:21][C:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:34]([C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]([F:23])=[CH:25][CH:26]=1)=[O:35])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4])([F:22])[CH3:20]
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC(F)(F)c1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(F)(F)c1cccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(1,1-difluoroethyl)phenyl]-1-(4-fluorophenyl)-1-propanol (0.40 g, 1.42 mmol) in acetonitrile (10 ml) were added 4-fluoronaphthalene-1-carboxylic acid (0.283 g, 1.49 mmol) and 1-hydroxybenzotriazole monohydrate (0.22 g, 1.49 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.49 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1, 2:1) and recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(1,1-difluoroethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide (0.52 g, 81%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.Br[CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])[CH3:20].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:18]=[C:19](/[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])\[CH3:20])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1ccc(Cl)cc1Cl
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1ccc(Cl)cc1Cl
Temperature: 85 °C

Procedure:
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.50 (d, 2H), 7.32 (m, 2H), 7.20 (s, 2H), 6.50 (s, 1H), 3.95 (m, 2H), 3.60-3.20 (m, 6H), 3.05 (s, 3H), 1.80 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[F:9][C:10]([F:38])([F:37])[C:11]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[CH2:34]([N:33]([CH2:32][C:11]([CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)([OH:31])[C:10]([F:9])([F:37])[F:38])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH2:35][CH3:36]
Reactant: O=C(O)c1ccsc1
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccsc1

Procedure:
Prepared similarly to Example 1 from 3-thiophenecarboxylic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Br[C:6]1[CH:7]=[C:8]([C:12]2([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH2:21])=[N:13]2)[CH:9]=[CH:10][CH:11]=1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[C:35]([Cl:37])[CH:36]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[Cl:30][C:31]1[CH:32]=[C:33]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([NH2:21])=[N:13]3)[CH:7]=2)[CH:34]=[C:35]([Cl:37])[CH:36]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cc1
Solvent: CC(=O)O
Product: COc1ccc(C2(c3cccc(-c4cc(Cl)cc(Cl)c4)c3)N=C(N)c3ccccc32)cc1
Yield: 28 %

Procedure:
The title compound was prepared as described for Example 78 (Scheme #14, N) starting from 1-(3-bromophenyl)-1-(4-methoxyphenyl)-1H-isoindole-3-amine acetate (Example 87) and (3,5-dichlorophenyl)boronic acid in 28% yield: 1H NMR (DMSO-d6) δ 7.78-7.74 (m, 2 H), 7.59-7.52 (m, 5 H), 7.47-7.41 (m, 2 H), 7.41-7.34 (m, 2 H), 7.23-7.18 (m, 2 H), 6.82-6.77 (m, 2 H), 3.69 (s, 3 H), 1.88 (s, 3 H); MS (ES) m/z 459, 461, 463 [M+1]+.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[NH2:1][CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(N)C1

Procedure:
A solution of 3-azido-N-t-butoxycarbonylpiperidine (850 mg) in ethyl acetate (50 ml) was hydrogenated in the presence of 10% Pd/C (550 mg) at atmospheric pressure for 2.5 h. The reaction mixture was then filtered through Celite and the filtrate concentrated in vacuo to give the title compound. 1H NMR (CDCl3) d 1.46 (s, 9 H), 1.66-2.05 (m, 4 H), 2.57 (br s, 1 H), 2.78 (m, 4 H), 3.80 (br d, 2 H).