Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2([C:11]#N)[CH2:10][CH2:9][CH2:8]2)=[C:4](I)[CH:3]=1.C([Li])(C)(C)C.C1C[O:24]CC1>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([CH2:6][C:7]3([CH2:10][CH2:9][CH2:8]3)[C:11]2=[O:24])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#CC1(Cc2ccc(Br)cc2I)CCC1
Agent: [Li]C(C)(C)C
Product: O=C1c2cc(Br)ccc2CC12CCC2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A dried flask charged with 1-(4-bromo-2-iodobenzyl)cyclobutanecarbonitrile (Intermediate 37, 2.60 g, 6.91 mmol), was dissolved in dry THF (100 mL) under an argon atmosphere. The resulting mixture was cooled to −78° C. and then was tert-butyllithium (1.7 M in pentane, 8.13 mL, 13.83 mmol), added dropwise. The reaction was stirred for 1.5 h at −78° C. and then the reaction was quenched with MeOH (0.5 mL), followed by aq. hydrochloric acid (2 M, 10 mL). The resulting solution was concentrated to remove the organic solvent and then partitioned between DCM and water. The organic phase was dried over MgSO4 and concentrated to give a crude product which was purified by flash chromatography (eluent: heptane/EtOAc20:1-15:1-10:1) to afford the title compound (1.1 g, 63% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.97-2.13 (m, 3H), 2.13-2.24 (m, 1H), 2.45-2.60 (m, 2H), 3.24 (s, 2H), 7.31 (d, 1H), 7.67 (dd, 1H), 7.88 (d, 1H); GC MS (EI) m/z 250 M
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-])=O)[CH:7]=1>[Pd].CCO>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH:7]=1)[NH2:13]
Reactant: Cc1ccc(OCCN(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(OCCN(C)C)cc1N
Reaction time: 12 h
Yield: 107.2 %

Procedure:
Palladium on carbon (10% by weight, 300 mg) and N,N-dimethyl-2-[(4-methyl-3-nitrophenyl)oxy]ethanamine (2.6 g, 12 mmol), dissolved in EtOH (40 mL), were transferred to a Fischer-Porter vessel. The vessel was evacuated twice and back-filled with N2. The N2 pressure was released and the vessel kept under a 60 psi of H2 pressure for 12 h. The H2 pressure was released, the reaction filtered through celite, and concentrated to provide the title compound (2.5 g, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.09 (s, 3H), 2.32 (s, 6H), 2.69 (t, J=5.9 Hz, 2H), 3.58 (br s, 2H), 4.01 (t, J=5.9 Hz, 2H), 6.27-6.31 (m, 2H), 6.90-6.95 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:34]([O-])=O)[C:6]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[S:27][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:13])=[N:7][C:8]=1[O:9][CH2:10][CH3:11])#[N:2].[Cl-].[NH4+]>O1CCCC1.[Zn]>[NH2:34][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[S:27][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:13])=[N:7][C:8]([O:9][CH2:10][CH3:11])=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)c([N+](=O)[O-])cc1C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)c(N)cc1C#N
Yield: 44.3 %

Procedure:
To a stirred solution of the compound prepared in Example 448 (48 mg) in tetrahydrofuran (1 mL) at ambient temperature was added zinc dust (120 mg), and to the resulting stirred mixture added saturated ammonium chloride (0.5 mL). The resulting mixture was stirred at ambient temperature for 17 hours. The reaction mixture was diluted with tetrahydrofuran (5 mL) and filtered through a glass microfibre filter. The flask and filter were rinsed with additional tetrahydrofuran. The combined filtrate and rinses were concentrated to remove most of the tetrahydrofuran, and the residue was partitioned between ethyl acetate and water, with addition of 10% sodium carbonate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 99/1 chloroform/methanol to provide the title compound (20 mg) with the following physical data. 1H NMR (CDCl3): δ 8.60 (d, J=4.4 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.79 (m, 2H), 7.68 (s, 1H), 7.32 (m, 2H), 5.77 (broad s, 2H), 4.35 (q, J=7.2 Hz, 2H), 3.80 (broad s, 2H), 3.33 (t, J=6.8 Hz, 2H), 2.99 (d, J=10.8 Hz, 2H), 2.11 (t, J=10.8 Hz, 2H), 1.76 (d, J=12.0 Hz, 2H), 1.60 (broad s, 1H), 1.41 (m, 5H);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+].C(OCC)(=O)C>C(O)C.O.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[N:21][OH:22])=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(C=O)cc2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2ccc(C=NO)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a stirred suspension of 3-(4-Formyl-phenyl)-azetidine-1-carboxylic acid tert-butyl ester (Preparation 38, 6.5 g, 24.904 mmol, 1 equivalents) in ethanol:water (1:1, 120 mL) was added hydroxylamine hydrochloride (2.5 g, 37.356 mmol, 1.5 equivalents) followed by sodium acetate (3.67 g, 44.82 mol, 1.8 eq). Resulting reaction mixture was stirred at room temperature for 0.5 hours. Progress of the reaction was monitored by TLC using 20% ethyl acetate in hexane and visualized in UV light (254 nm). Reference of new spot and starting material was 0.32 and 0.67 respectively. After consumption of starting material, solvents was evaporated under reduced pressure and extracted with DCM (3×25 mL). Evaporation of volatiles provided light yellow solid (6.5 g, 94.51%). LC-MS and 1H NMR was consistent. 1H NMR (400 MHz, DMSO-d6) δ 1.39 (s, 9H), 3.81 (broad s, 3H), 4.42 (broad s, 2H), 7.36 (d, J=8 Hz, 2H), 7.57 (d, J=8 Hz, 2H), 8.12 (s, 1H), 11.19 (s, 1H). LC-MS (m/z):=277.30 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:29]Br>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]2[C:10]3[CH2:9][NH:8][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([F:34])=[C:26]([F:25])[CH:27]=3)[N:12]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Reactant: Fc1ccc(CBr)cc1F
Product: Fc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCCNC3)cc1F
Yield: 6.6 %

Procedure:
The title compound (0.005 g) was prepared from 3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylic acid tert-butyl ester (Example 59, Step C; 0.07 g) using 3,4-difluorobenzyl bromide (0.06 g) in place of benzyl chloride in Example 59, Step D. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12; found, m/z 374.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.34 (m, 4H), 7.16-7.10 (m, 1H), 6.98-6.97 (m, 1H), 6.89-6.88 (m, 1H), 5.27 (s, 2H), 3.81 (s, 2H), 3.09-3.06 (m, 2H), 2.80-2.76 (m, 2H), 1.75-1.70 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[C:4]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:19]([O-])([O-])[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[Br:1][C:2]1[C:3]([F:18])=[C:4]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[C:5]([C:7](=[CH:19][O:20][CH2:21][CH3:22])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(Br)c1F
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1F
Temperature: 130 °C
Reaction time: 4.5 h
Yield: 99.5 %

Procedure:
A mixture of ethyl 3-bromo-2,4,5-trifluorobenzoylacetate (1.5 g), ethyl orthoformate (1.0 g) and acetic anhydride (1.2 g) was stirred at 130° C. for 4.5 hours and then concentrated to give the title compound (1.75 g) as yellow oil.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([CH:15]([CH3:17])[CH3:16])[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.OCC1SC(B(O)O)=CC=1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]([CH2:6][C:5]2[CH:18]=[CH:19][C:2]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]([CH3:17])[CH3:16])=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)N(Cc1ccc(Br)cc1)c1ccc(F)cc1
Agent: OCc1ccc(B(O)O)s1
Product: CC(C)N(Cc1ccc(-c2ccc(C=O)cc2)cc1)c1ccc(F)cc1
Yield: 65 %

Procedure:
When the product of Step B and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl) thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar process afforded the title compound in 65% yield, as creamy gum. 1H-NMR (CDCl3) 10.03 (s, 1H); 7.92 (d, 2H, J=7.97 Hz); 7.56 (d, 2H, J=7.95 Hz); 7.38 (d, 2H, J=8.29 Hz); 6.86 (t, 2H, J=8.46 Hz); 6.67-6.62 (m, 2H); 4.38 (s, 2H); 4.17-4.12 (m, 1H); 1.2 (d, 6H, J=6.96 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=O)[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NCCN1CCCC1

Procedure:
5-Chloro-1,3-dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide to give the title compound.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].I[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>O1CCCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([C:16]1[CH:15]=[C:14]([C:8]#[C:7][C:6]([O:10][CH2:11][CH3:12])=[O:9])[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: N#Cc1cccc(I)c1
Reactant: C#CC(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1cccc(C#N)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 51.1 %

Procedure:
A solution of n-butyllithium (2.50 Min hexanes, 16.8 mL, 41.9 mmol 1.20 equiv) was added dropwise to a solution of ethyl propiolate (4.11 g, 41.9 mmol, 1.20 equiv) in tetrahydrofuran (350 mL) at −78° C. After stirring for 15 minutes at −78° C., a solution of zinc chloride (1.0 M in diethyl ether, 84 mL, 84 mmol, 2.4 equiv) was added and the cooling bath was removed. After stirring for 2 hours, 3-iodobenzonitrile 8.00 g (34.9 mmol, 1 equiv) and Pd(Ph3P)4 (2.0 g, 1.7 mmol, 0.05 equiv) were added and the reaction mixture was heated to 50° C. After stirring for 90 minutes, the reaction mixture was cooled to 22° C. and filtered. The filtrate was concentrated to ˜½ volume, then was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography on silica gel (hexanes, grading to 50% ethyl acetate-hexanes) to afford ethyl 3-(3-cyanophenyl)prop-2-ynoate (3.55 g, 51%) as a light-orange solid. Calcd (M+1)+: 200.1. Found: 200.1.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH2:23]([N:30]([CH3:38])[CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:35]3[CH2:34][CH2:33][CH:32]([CH2:31][N:30]([CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH3:38])[CH2:37][CH2:36]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(Cc1ccccc1)CC1CCNCC1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CN(Cc1ccccc1)CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and benzyl-methyl-piperidin-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (56%, colourless crystals). HPLC-MS m/z=500.2 (M+1), Rt: 3.18 min.
Reaction SMILES: [CH2:1]1[O:17][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[CH2:24]([NH:25][CH2:1][CH:2]([OH:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][CH2:1][CH:2]([OH:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCCCCCCN
Reactant: CCCCCCCCCCCCCCC1CO1
Product: CCCCCCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCCCCCC

Procedure:
Condensation of 1-hexadecene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxyhexadecylamine] (I: R = CH3 (CH2)13, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: [CH3:1][C:2]1([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[N:6]=2)[CH2:4][CH2:3]1.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:21]2=[C:22]([CH:25]=1)[O:23][CH2:24][C:18]1[CH:17]=[C:16]([CH2:15][N:9]3[C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[N:6]=[C:5]3[C:2]3([CH3:1])[CH2:4][CH2:3]3)[CH:35]=[CH:34][C:19]=1/[C:20]/2=[C:30](/[CH3:33])\[C:31]#[N:32]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: CC1(c2nc3ccccc3[nH]2)CC1
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4(C)CC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 39.8 %

Procedure:
Using 2-(1-methylcyclopropyl)-1H-benzo[d]imidazole (58 mg, 0.335 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (60 mg, 40%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](OCC)=[O:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>C1COCC1>[OH:21][CH2:20][C:16]1[CH:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(CO)c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
tert-Butyl-4-(3-(ethoxycarbonyl)phenyl)piperazine-1-carboxylate (0.20 g, 0.60 mmol) was dissolved in THF (1 mL) and lithium borohydride (0.10 g, 7.5 eq) was added in three portions. The reaction mixture stirred at rt for 48 h then quenched with saturated ammonium chloride under ice-cooling. The aqueous phase was extracted with DCM and the combined organic phases dried over sodium sulfate and evaporated to afford tert-butyl 4-(3-(hydroxymethyl)phenyl)piperazine-1-carboxylate (0.16 mg, 0.54 mmol, 90%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)(C)(C)C>ClCCl>[NH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1ccc(Oc2ccc(CCNC(=O)OC(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(Oc2ccc(CCN)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
Add trifluoroacetic acid (10 mL) dropwise to a solution of {2-[4-(4-acetylamino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3.7 g, 10 mmol) in dichloromethane (50 mL) at 0° C. Warm to room temperature and stir overnight. Concentrate on a rotary evaporator, dissolve residue in methanol then apply to a strong cation exchange column (Varian, 0.79 meq/g), and wash with methanol. Elute the product with 2M ammonia in methanol then concentrate on a rotary evaporator to yield N-{4-[4-(2-amino-ethyl)-phenoxy]-phenyl}-acetamide (2.3 g): 1H NMR (DMSO-D6, 300.00 MHz): 9.97 (s, 1H), 7.58 (d, 2H, J=8.8 Hz), 7.19 (d, 2H, J=7.9 Hz), 6.92 (dd, 4H, J=21.3, 8.1 Hz), 3.60-3.05 (m, 3H), 2.73-2.55 (m, 3H), 2.04 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:30]3[CH:37]=[CH:36][C:33]([CH3:34])=[CH:32][CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-methylbenzaldehyde. MS (ESI) m/z 483.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:23]2[CH:24]=[C:19]([Cl:18])[N:20]=[CH:21][N:22]=2)[CH:3]=1
Reactant: CC1(C)OB(c2cc(Cl)ccc2N)OC1(C)C
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(Cl)cc1-c1cc(Cl)ncn1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (3 g, 11.83 mmol, 1.00 equiv) in dioxane (120 mL), water (20 mL), 4,6-dichloropyrimidine (4.4 g, 29.53 mmol, 2.50 equiv), triphenylarsine (360 mg, 1.18 mmol, 0.10 equiv), K3PO4 (3.8 g, 17.90 mmol, 1.50 equiv), Pd(PPh3)2Cl2 (390 mg, 0.56 mmol, 0.05 equiv). The resulting solution was stirred for 3 h at 75° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50˜1:10). This resulted in 1.5 g (53%) of 4-chloro-2-(6-chloropyrimidin-4-yl)benzenamine as a yellow solid.
Reaction SMILES: Br[CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26].[I-].[K+]>S(=O)(=O)(O)O>[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][C@H:2]([C:3]([OH:5])=[O:4])[CH:20]([CH3:22])[CH3:21]
Reactant: Cc1ccccc1N
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Product: Cc1ccccc1N[C@H](C(=O)O)C(C)C
Temperature: 0 °C

Procedure:
To m-phenoxybenzyl α-bromoisovalerate (2 g, 0.0055 mole), 24°, is added 2-methylaniline (2.95 g, 0.0275 mole) followed by a catalytic amount of potassium iodide (20 mg). The reaction mixture is heated, 110°-115°, for about 36 hours, and then poured into ice-water (30 ml) and 2 N sulfuric acid (10 ml) and extracted with ether (3×30 ml). The combined ether extracts are washed with water (2×30 ml) until neutral and with brine (10 ml) followed by drying over calcium sulfate. The reaction product is concentrated under vacuum and isolated by preparative TLC to yield 3-phenoxybenzyl ester of N-(2-methylphenyl)valine. MS m/e 389.2 (M+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([CH2:13][CH2:14][C:15]([NH2:17])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl>C1COCC1.CO>[N:7]1([CH2:13][CH2:14][CH2:15][NH2:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC(=O)CCN1CCCCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: NCCCN1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled suspension of LiAlH4 (10.31 g, 0.27 mole) in THF (100 ml), a solution of 1-piperidine-propanamide, 4-(diphenylmethylene) 29.01 g, 0.091 mole) in THF (100 ml) was added dropwise. After stirring for 0.5 hours, the ice-bath was removed, the reaction mixture refluxed for six hours, quenched (EtOAc and 10% NaOH) and the resulting granular precipitate removed by filtration. The filtrate was concentrated to ca 20 ml, dissolved in CHCl3, washed with H2O, and the solvent removed to give a yellow-green oil. This was dissolved in MeOH, treated with HCl gas and the solvent evaporated. The residue crystallized from CH2Cl2 -Et2O to give 1-piperidinepropaneamine, 4-(diphenylmethylene)dihydrochloride hemihydrate as white solid in quantitative yield; mp 249°-252° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([OH:15])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc2ccc(O)cc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccc(OCc3ccccc3)cc2c1
Reaction time: 2 h
Yield: 36 %

Procedure:
Treat a solution of 7-hydroxynaphthalene-2-carboxylic acid methyl ester (2.84 g, 14.0 mmol) and benzyl bromide (1.84 mL, 15.5 mmol in DMF (14 mL) with cesium carbonate (9.10 g, 27.9 mmol). Stir the mixture for 2 h and concentrate. Dissolve the crude residue in EtOAc (150 mL) and 1 N HCl (50 mL). Wash the organic layer with brine (3×100 mL), dry over Na2SO4, and filter. Concentrate the filtrate and purify using medium pressure silica gel chromatography (10:90 EtOAc:hex) to give the title compound as a white solid (1.47 g, 36%). MS (ES) m/e 293 (M+1).
Reaction SMILES: C([N:3](CC)CC)C.[OH:8][CH:9]1[CH2:13][N:12]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[CH:11]([C:25]([OH:27])=O)[CH2:10]1.ClC(OCC)=O>C(#N)C>[OH:8][CH:9]1[CH2:13][N:12]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[CH:11]([C:25]([NH2:3])=[O:27])[CH2:10]1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2
Agent: CCOC(=O)Cl
Solvent: CC#N
Product: NC(=O)C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2
Reaction time: 0.33 h

Procedure:
1.1 equivalents of triethylamine are added to 4.5 g (0.016 mol) of the 4-hydroxy-1-[3,4-methylenedioxybenzoyl]pyrrolidine-2-carboxylic acid obtained in Example 5 suspended in 130 ml of acetonitrile at 0° C. The reaction mixture is stirred for 20 minutes and then 1.1 equivalents of ethyl chloroformate are added while maintaining the temperature between 0° and 5° C. After stirring for 20 minutes, ammonia is bubbled through the reaction mixture. The precipitate formed is separated. The filtrate is removed under vacuum, the precipitate obtained is recrystallized in acetonitrile.