Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([N:27]4[CH2:32][CH2:31][S:30][CH2:29][CH2:28]4)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CSCCN1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Product: c1ccc(COc2ccc(Nc3ncnc4cnc(N5CCSCC5)cc34)cc2)cc1

Procedure:
Prepared according to Procedure C from 4-(4-benzyloxyanilino)-6-chloropyrido[3,4-d]pyrimidine and thiomorpholine; δH (CDCl3) 9.00 (1H,s), 8.59 (1H,s), 7.59 (2H, d), 7.28-7.50 (5H,m), 7.03 (2H,d), 6.56 (1H,s), 5.09 (2H,s), 3.92-4.18 (4H,m), 2.62-2.92 (4H,m); m/z (M+1)+430.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:31][NH:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[NH2:30][C:28]([C:16]1[CH:17]=[C:18]([C:21]2[CH:25]=[C:24]([CH2:26][N:32]([CH3:31])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[S:23][CH:22]=2)[CH:19]=[C:20]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH:9]1[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]1)=[O:29]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: CCOC(=O)CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (45 mg, 100 μmol) in dimethyl sulfoxide (1.0 mL) was added ethyl N-methylglycinate (320 μmol) and 2 to 3 drops of glacial acetic acid. The resulting mixture is agitated overnight. After 18 h, sodium triacetoxyborohydride (200 mg, 1000 μmol) is added. This mixture is agitated for 1.5 h followed by purification by Gilson Preparatory HPLC to give 16.5 mg of the title compound (30.0%).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:44])[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[S:17]([NH:20][C:21](=[O:36])[C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)(=[O:19])=[O:18])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH3:4].[CH3:45]C(N)CCC.C(N)CCC>>[CH3:45][CH:1]([NH:5][C:6](=[O:44])[O:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][N:16]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[S:17]([NH:20][C:21](=[O:36])[C:22]2[CH:23]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:25]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:27]=2)(=[O:18])=[O:19])[CH2:13][CH2:14]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(C)N
Reactant: CCCCNC(=O)OCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: CCCCN
Product: CCCC(C)NC(=O)OCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
Following the procedure to make (13), 1-methylbutyl amine was substituted for butyl amine to give the title compound after purification. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.12 (s, 1H), 7.37 (d, 2H), 7.24 (t, 2H), 7.17 (t, 1H), 6.79 (d, 1H), 4.35 (s, 2H), 3.60 (d, 2H), 3.41 (m, 1H), 3.30 (water), 2.89 (d, 2H), 2.48 (DMSO), 1.62 (m, 2H), 1.55 (m, 2H), 1.34-1.19 (m, 6H), 0.96 (d, 3H), 0.80 (t, 3H), 0.62 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ncccn2)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.6 %

Procedure:
110 mg 4-hydroxy-4-pyrimidin-2-yl-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 2.5 mL pyridine and 0.18 ml phosphoroxychloride was added. The reaction was stirred one day at RT. The reaction was decomposed with water and extracted with DCM. The organic layer was dried and the solvent was removed to give 84 mg of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.CC(C)([O-])C.[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[C:35]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=4)[CH2:5][CH2:6]3)[N:34]=[CH:33][N:32]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)ncn2)CC1
Reactant: Brc1ccc2c(c1)CCN2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(Br)ccc43)ncn2)CC1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
5-Bromoindoline (60 mg, 0.3 mmol) and potassium tert-butoxide (0.1 g, 3 eq) were stirred for 5 minutes in dioxane (1 mL). 3a (0.1 g, 1.05 eq) was added and the mixture was stirred at 80° C. for 72 h. The solvent was removed under vacuum and the residue was dissolved in THF and purified by preparative HPLC to give 3b.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O>C(Cl)Cl.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.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(I)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1ccc(C#Cc2ccccc2)cc1
Reaction time: 2 h
Yield: 108.6 %

Procedure:
4-Iodophenyl acetate (50.00 g, 0.191 mol), phenylacetylene (23.40 g, 0.229 mol), and triethylamine (54 mL) are added to a 250-mL round bottom flask fitted with a condenser/nitrogen inlet, a thermometer, and a stopper. PdCl2(PPh3)2 (0.200 g, 0.286 mmol) and PPh3 (1.50 g, 5.73 mmol) are then added and the mixture heated to reflux. When the reaction mixture reaches 40° C., CuI (0.054 g, 0.286 mmol) is added. After 2 hours, the reaction is allowed to cool. The mixture is diluted with methylene chloride and poured into water (500 mL). The aqueous layer is extracted with methylene chloride (100 mL). The combined organic layers are washed with three 300-mL portions of water, dried (MgSO4), and filtered. The solvent is removed in vacuo to give 49 g of a yellow solid. The material is recrystallized from hexanes to give light yellow crystals, mp 104.5° C. to 105.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])([O-])=O>CO.[OH-].[OH-].[Pd+2]>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][C:5]1[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=1[NH2:1])[CH3:19]
Reactant: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)CCc1ccc(N)cc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.6 %

Procedure:
A suspension of Pd(OH)2/C (10%, 3.0 g) and (E)-ethyl 3-(2,4-dinitrophenyl)acrylate (12.0 g, 45.1 mmol) in MeOH (80 mL) was stirred at 25° C. under an atmosphere of H2 (45 psi) for 15 h. The mixture was filtered and the filtrate was concentrated in vacuo to give 3-(2,4-diamino-phenyl)-propionic acid ethyl ester (8.6 g, 98%), which was used directly in the next step without further purification. A solution of ethyl 3-(2,4-diaminophenyl)propanoate (8.6 g, 41.3 mmol) in EtOH (50 mL) was stirred at 85-100° C. for 48 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. EtOAc (10 mL) was added to the residue and the precipitate was collected by filtration to give 7-amino-3,4-dihydro-1H-quinolin-2-one (5.8 g, 87%). 1H NMR (DMSO-d6, 400 MHz): δ 9.83 (brs, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.12 (m, 2H), 4.95 (brs, 2H), 2.65 (t, J=7.2 Hz, 2H), 2.36 (t, J=7.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2ccccc2s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2ccccc2s1
Yield: 71.6 %

Procedure:
A mixture of 2-methylbenzothiazole (2.0 g, 13.40 mmol), N-bromosuccinimide (2.39 g, 13.40 mmol), and AIBN (0.5 g, 3.04 mmol) in CCl4 (40 mL) was refluxed for 12 h, then the mixture was cooled and filtered. The filtrate was concentrated and purified by silica gel chromatography (5% EtOAc/hexane) to give the title compound (2.19 g, 72%) as a yellow oil: 1H NMR (250 MHz, DMSO-d6): δ 5.12 (s, 2H), 7.5 (m, 2H), 8.01 (dd, J=7.9, 1.8 Hz, 1H), 8.15 (dd, J=7.9, 1.8 Hz 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:23][CH3:24].[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([N:13]([CH2:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:23][CH3:24]
Reactant: CCc1cc(Oc2cccc(NCC(O)C(F)(F)F)c2)ccc1Cl
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1cc(Oc2cccc(N(CC3CCCCC3)CC(O)C(F)(F)F)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
The 3-[[3-(4-chloro-3-ethylphenoxy)phenyl]amino]-1,1,1-trifluoro-2-propanol product from EX-18C was dissolved in 12 mL of tetrahydrofuran. To this stirred solution was added cyclohexanecarboxaldehyde (0.032 g, 0.285 mmol), followed by sodium tri-acetoxyborohydride (0.079 g, 0.370 mmol and concentrated acetic acid (0.020 g, 0.325 mmol). The resulting mixture was stirred at room temperature for 18 h. Additional cyclohexanecarboxaldehyde (0.032 g, 0.285 mmol) was added and the mixture was allowed to stir at room temperature for another 18 h. The reaction was quenched with saturated sodium bicarbonate and extracted with methylene chloride. The organic layers were combined, dried over MgSO4 and concentrated to an orange/brown oil. The crude product was purified by flash column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to give 0.080 g (61%) of the desired 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][3-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow-orange oil (>95% pure by HPLC). HRMS calcd.: 456.1917 [M+H]+, found: 456.1942. 1H NMR (CDCl3) δ 0.82-1.01 (m, 2H), 1.22-1.27 (m, 3H), 1.73-1.76 (m, 5H), 2.74 (dd, 2H), 3.15 (dd, 2H), 3.23 (dd, 1H), 3.52 (m, 1H), 3.80 (dd, 1H), 4.28 (m, 1H), 6.34 (d, 2H), 6.42 (d, 1H), 6.83 (dd, 1H), 6.98 (d, 1H), 7.19 (t, 1H), 7.29 (d, 1H). 19F NMR (CDCl3) δ−79.06 (d, 3F).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH3:15])[C@H:10]([CH2:16][N:17]([C:21](=[O:36])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])[CH:23]=2)[CH:18]([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]1([CH2:43][C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH3:15])[C:44](=[O:45])[CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:10]([CH2:16][N:17]([C:21](=[O:36])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])[CH:23]=2)[CH:18]([CH3:19])[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC)C(C)C)cc1OCCCOC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)C(=O)Cc2ccccc2)C(C)C)cc1OCCCOC

Procedure:
From (3R,4R)-3-({[4-ethyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-4-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.7 g, 1.38 mmol), phenylacetyl chloride (0.22 mL, 1.66 mmol) and triethylamine (0.21 mL, 2.1 mmol) in CH2Cl2 (40 mL) and purification by flash chromatography on silica gel (c-hexane/AcOEt 1:1 to 0:1) to give the title compound as colorless oil. TLC, Rf (AcOEt)=0.30. MS (LC-MS): 624.0 [M+H]+; tR (Waters Symmetry C18 column, 20-100% CH3CN/H2O/5 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.41 min.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[N+:8]([CH2:11][CH2:12][CH3:13])([O-:10])=[O:9].Cl>C(#N)C.O>[CH3:4][CH:3]([CH:11]([N+:8]([O-:10])=[O:9])[CH2:12][CH3:13])[CH2:2][C:1]([O:6][CH3:7])=[O:5]
Reactant: C/C=C/C(=O)OC
Reactant: CCC[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CCC(C(C)CC(=O)OC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 84.7 %

Procedure:
A solution of 4 g (40 mmol) of methyl crotonate and 4.72 g (53 mmol) of 1-nitropropane in 20 mL of acetonitrile was treated with 6 mL (40 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU). After stirring for 22 h at room temperature the reaction mixture was diluted with water and acidified with 2N HCl. The solution was extracted with Et2O and the Et2O layer was washed with brine, dried and concentrated. The residue was chromagraphed on a flash column using 10% Et2O-Hexane to isolate 6.41 g (85%) of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[CH:47]1([C:53]2[C:54]3[CH:55]=[CH:56][C:57]([C:77]([O:79][CH3:80])=[O:78])=[CH:58][C:59]=3[N:60]3[C:67]=2[C:66]2[CH:68]=[CH:69][CH:70]=[CH:71][C:65]=2[O:64][CH2:63][CH:62]([CH2:72][CH2:73][C:74](O)=[O:75])[CH2:61]3)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>CN(C=O)C>[C:34]([O:33][C:31]([N:25]1[CH2:30][CH2:29][N:28]([C:74](=[O:75])[CH2:73][CH2:72][CH:62]2[CH2:61][N:60]3[C:59]4[CH:58]=[C:57]([C:77]([O:79][CH3:80])=[O:78])[CH:56]=[CH:55][C:54]=4[C:53]([CH:47]4[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]4)=[C:67]3[C:66]3[CH:68]=[CH:69][CH:70]=[CH:71][C:65]=3[O:64][CH2:63]2)[CH2:27][CH2:26]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)O)COc1ccccc1-3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COc1ccccc1-3
Temperature: 50 °C

Procedure:
HATU (1.1 eq) was added to a stirred mixture of tert-butyl piperazine-1-carboxylate (1.1 eq), DIPEA (2.5 eq) and 3-[14-cyclohexyl-11-(methoxycarbonyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-7-yl]propanoic acid (0.03 M) in DMF under N2 at RT. The reaction was warmed at 50° C. for 10 min. The reaction was allowed to cool to RT before being partitioned between EtOAc and 1N HCl (aq). The organics were washed with 1N HCl (aq), sat. aq. NaHCO3, water and brine before being dried (Na2SO4), filtered and concentrated in vacuo. The material was taken on without further purification (88%). (ES+) m/z 630 (M+H)+; 652 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10](O)(=[O:14])[CH:11]([CH3:13])[CH3:12].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: CC(C)C(=O)NNc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 45.8 %

Procedure:
A solution of 5-fluoro-2-hydrazinyl-pyridine (0.59 g, 4.65 mmol), isobutyric acid (528 mg, 6 mmol), and HOBt hydrate (153 mg, 1 mmol) in DCM (10 mL) was treated with EDC (1.15 g, 6 mmol). The reaction mixture was stirred at RT for 40 min, poured onto sat. aq. sodium bicarbonate (40 mL), extracted with four portions of DCM, dried (Na2SO4), evaporated and purified by FCC using 10-30% EtOAc/DCM to give the title compound (0.42 g, 46%). LCMS (method 2): Rt 2.46 min, m/z 198 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([CH3:15])[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([CH3:15])[N:11]=2)=[CH:6][CH:5]=1
Reactant: Cc1noc(COc2ccc([N+](=O)[O-])cc2)n1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Product: Cc1noc(COc2ccc(N)cc2)n1

Procedure:
In like manner to the preparation of 5-[(4-aminophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole, 5-(4-nitrophenoxymethyl)-3-methyl-1,2,4-oxadiazole was reacted with aqueous solution of sodium hydrosulfite and K2CO3 to prepare 5-[(4-aminophenox)ymethyl]-3-methyl-1,2,4-oxadiazole. 1H NMR (CDCl3): δ 6.82 (d, 2H, J=8.8 Hz), 6.63 (d, 2H, J=8.8 Hz), 5.15 (s, 2H), 3.38 (br s, 2H), 2.41 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[C:5]([C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[C:9]#[N:10])=O.[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].CO.C(=O)(O)[O-].[Na+]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:7]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=2[C:9]#[N:10])=[N:26][S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: N#Cc1c(F)cccc1C(=O)c1ccc(F)c(Br)c1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1cccc(F)c1C#N
Temperature: 25 °C
Yield: 54.7 %

Procedure:
2-(3-Bromo-4-fluoro-benzoyl)-6-fluoro-benzonitrile (7.9 g, 24.5 mmol) dissolved in dry THF (40 mL) was added to a solution of titanium (IV) ethoxide (12.7 ml, 61.3 mmol) in dry THF (30 mL) at room temperature. 2-Methyl-2-propanesulfinamide (3.57 g, 29.4 mmol) was added and the resulting mixture was heated at reflux temperature for 22 h. The reaction mixture was cooled to room temperature and methanol (120 mL) was added, followed by addition of saturated sodium bicarbonate (12 mL). The resulting suspension was filtered through a pad of sodium sulfate and the solids were washed thoroughly with ethyl acetate. The filtrate was concentrated in vacuo and purified by flash column chromatography using a gradient of 30-50% ethyl acetate in hexanes to afford 5.7 g (55% yield) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH2:25][CH2:26][CH2:27]Cl>CS(C)=O.O>[CH:7]1([NH:13][CH2:27][CH2:26][CH2:25][O:24][C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCCCC1
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc2cc(OCCCNC3CCCCC3)ccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and cyclohexylamine (0.29 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-cyclohexyl-[3-(naphthalen-2-yloxy)-propyl]amine, solid. m.p. 98° C. (yield 0.61 gm, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[NH:7][C:8]([CH:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Br[CH2:27][CH2:28]Cl>CC#N>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[N:7]3[CH2:28][CH2:27][N:13]4[CH2:14][CH2:15][CH2:16][CH:12]4[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: O=c1[nH]c(C2CCCN2)nc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=c1c2ccc(Br)cc2nc2n1CCN1CCCC21
Yield: 29.3 %

Procedure:
A solution of 7-bromo-2-(pyrrolidin-2-yl)quinazolin-4(3H)-one (158 mg, 0.49 mmol), K2CO3 (0.5 g, 3.6 mmol), a catalytic amount of NaI, and 1-bromo-2-chloroethane (70 mg, 0.49 mmol) in CH3CN was stirred at 80° C. overnight. After dilution with H2O (30 mL), the mixture was extracted with ethyl acetate (3×100 mL). Then the combined organic layers were dried over Na2SO4 and concentrated to give crude product. After purified by column chromatography, 46 mg of the desired product was obtained. MS (ESI): 320, 322 (MH+)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Br[C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1
Reactant: Nc1ccc(Br)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Fe]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A mixture of 4-trifluoromethoxylbenzeneboronic acid (300 mg, 1.45 mmol), p-bromoaniline (100 mg, 0.58 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (24 mg,0.029 mmol), 1,1′-bis(diphenylphosphino)ferrocene (16 mg, 0.029 mmol) and potassium carbonate (0.58 ml of a 2M aqueous solution, 1.16 mmol) in 5 ml 1,4-dioxane was heated at reflux under nitrogen for 20 hr. The reaction mixture was cooled to room temperature, diluted with 40 ml water and extracted with 2×40 ml ethyl acetate. The combined ethyl acetate extracts were washed with 40 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 15 g), eluting with 10:1 hexane/ethyl acetate to yield the title compound as a tan solid (70 mg, 48% yield). MS: 254.1 (M+1)