Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14](=[O:35])[CH:15]=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CCC2(CC1)OCCO2
Yield: 81.1 %

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decan-8-one (5.00 g, 32.0 mmol) in 65 mL of anhydrous toluene was treated with methyl(triphenylphosphoranylidene)acetate (13.9 g, 41.6 mmol). The mixture was stirred at reflux for 18 h under nitrogen. Solvent was removed and the crude was purified by silica gel column chromatography using a 20% EtOAc:hexanes mixture as eluent to afford (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (5.51 g, 81%) as a colorless oil.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[CH:19][C:18]=2[C:22]([OH:24])=O)=[CH:13][CH:12]=1.[CH3:25][CH:26]1[NH:30][CH2:29][C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([OH:31])[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:21][N:20]=[CH:19][C:18]=2[C:22]([N:30]2[CH:26]([CH3:25])[CH2:27][C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([OH:31])[CH2:29]2)=[O:24])=[CH:15][CH:16]=1
Reactant: CC1CC(O)(c2ccccc2)CN1
Reactant: O=C(O)c1cn[nH]c1-c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CC(O)(c2ccccc2)CN1C(=O)c1cn[nH]c1-c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 26.2 %

Procedure:
N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.04 mmol) was added to a solution of 5-(4-chlorophenyl)-1H-pyrazole-4-carboxylic acid (11 mg, 0.048 mmol, 1.2 equ.), 5-methyl-3-phenylpyrrolidin-3-ol (7 mg, 0.04 mmol) and TBTU (15 mg, 0.048 mmol, 1.2 equ.) in DMF (0.3 mL) at rt. The reaction mixture was left at rt for 2 h. The crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (4 mg). MS (ESI, pos. ion) m/z: calcd for C21H20ClN3O2: 381.1244, found 381.1243.
Reaction SMILES: O1CCOCC1.Cl.[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:32])[CH2:23][NH:24]C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[CH2:8]([N:15]1[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:32])[CH2:23][NH2:24])[CH2:19][CH2:20]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCC(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4 M dioxane solution of HCl was added to a methanol (80 mL) solution of 1-benzyl-4-[N-(tert-butoxycarbonyl)glycyl]aminopiperidine (6.59 g). The resulting solution was stirred at room temperature for 2 hours and concentrated. A 2 M aqueous solution of NaOH (20 mL) was then added to the solution. The resulting mixture was extracted with dichloromethane (40 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography (SiO2, ethyl acetate/methanol/triethylamine=85:12:3) to thereby provide 1-benzyl-4-(glycylamino)piperidine (3.91 g, 83%). 1H NMR (CDCl3, 400 MHz) δ 1.47-1.59 (m, 2H), 1.59 (br, 2H), 1.76-1.96 (m, 2H), 2.10-2.19 (m, 2H), 2.75-2.87 (m, 2H), 3.29 (s, 2H), 3.50 (s, 2H), 3.65-3.89 (m, 1H), 7.15-7.23 (m, 1H), 7.23-7.33 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)[CH:7]=1>CCOC(C)=O.O=[Pt]=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[N:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(Oc2cncc(Cl)c2)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Nc1cccc(Oc2cncc(Cl)c2)c1
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of 3-chloro-5-(3-nitrophenoxy)pyridine (0.2 g, 0.8 mmol) in EtOAc (10 mL) was added PtO2 (0.02 g) and the mixture was stirred for 4 h under H2 (1 atm). It was then filtered through a Celite® pad and washed with EtOAc (2×5 mL). The combined organic extracts were concentrated to afford 3-(5-chloropyridin-3-yloxy)benzenamine (0.165 g, 93% yield) which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J=2.0 Hz, 1H), 8.31 (d, J=2.8 Hz, 1H), 7.54-7.53 (m, 1H), 7.05 (t, J=8.0 Hz, 1H), 6.42-6.39 (m, 1H), 6.25-6.19 (m, 2H), 5.33 (brs, 2H); MS (ESI) m/z: 221.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)[CH:3]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2cc(O)ccn2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3cc(O)ccn3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reductive amination of 4-(4-hydroxy-pyridin-2-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: N
Solvent: O
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3,4-difluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 58 mg, 52%). mp 171–173° C. 1H NMR (300 MHz, DMSO-d6) δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.3 (s, 3H), 7.51 (m, 1H), 7.65 (m, 1H), 7.75 (d, J=9 Hz, 2H), 7.81 (m, 1H) 8.05 (s, 1H), 8.12 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 434 (M+H)+, 451 (M+NH4)+. Anal. calc. for C21H21F2N3O3S.0.25 H2O: C, 58.19; H, 4.88; N, 9.69. Found: C, 57.69; H, 5.01; N, 9.18.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=O)[CH3:9])=[CH:3][CH:2]=1.BrBr.[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH:19][C:20]([NH2:22])=[S:21]>O1CCOCC1>[CH3:9][C:8]1[N:22]=[C:20]([NH:19][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][N:13]=2)[S:21][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: NC(=S)Nc1cnccn1
Reactant: CC(=O)Cc1ccncc1
Agent: BrBr
Solvent: C1COCCO1
Product: Cc1nc(Nc2cnccn2)sc1-c1ccncc1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1-pyridin-4-yl-propan-2-one (0.1 g, 0.812 mmol) in dioxane (7 ml) is added bromine (0.029 ml, 0.569 mmol) dropwise. After 45 minutes, the solvent is removed in vacuo and the crude product is dissolved in ethanol (15 ml). The solution is treated with pyrazin-2-yl-thiourea (0.125 g, 0.812 mmol) and the reaction mixture is heated at 60° C. for 3 hours. The solvent is removed in vacuo and purification by chromatography on silica, eluting with ethyl acetate-methanol affords the titled compound.
Reaction SMILES: [C:1](#[N:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]#[N:5].C[O-].[Na+].[NH3:14]>CO>[NH:5]=[C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[NH:14])[NH:10]1
Reactant: N
Reactant: N#Cc1ccccc1C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N=C1NC(=N)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To 180 ml of methanol were fed 20 g of a phthalonitrile represented by the formula (XV) and 14 g of sodium methoxide. The mixture was stirred at room temperature for 1 hour while blowing ammonia gas thereinto and, then, refluxed with heating for 3 hours with stirring while blowing ammonia gas thereinto. After being cooled to room temperature, the resulting mixture was concentrated as much as possible. The concentrate was dissolved in 700 ml of chloroform and was washed well with water and with hot water. Water in the organic layer was removed with magnesium sulfate and toluene was removed by distillation. The residue was recrystallized from hexane to obtain 19.7 g (yield: 91.7%) of a compound having the following formula (XVI). ##STR38##
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:34])([CH3:33])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:32])([CH3:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>CO>[CH3:2][C:3]([CH3:34])([CH3:33])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:32])([CH3:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[NH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-c2ccc(F)cn2)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)Cc1c[nH]c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (6 mL, 24 mmol) was added to a solution of 4-(2,2-dimethylpropyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (1.5 g, 3.27 mmol) in methanol (20 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded the title compound. 1H NMR (500 MHz, CD3OD) δ 8.48 (d, J=2.8 Hz, 1H), 7.82 (dd, J=5, 8.3 Hz, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.64 (dt, J=2.8, 8.3 Hz, 1H), 7.08 (d, J=8.3 Hz, 2H), 6.70 (s, 1H), 3.17 (s, 2H), 2.43 (s, 2H), 1.65 (s, 3H), 0.86 (s, 9H); (M+H) found: 368.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:24])[CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Cl:25][C:26]1[CH:33]=[C:32](F)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].CC(C)([O-])C.[K+].O>C1COCC1>[Cl:25][C:26]1[CH:33]=[C:32]([CH:31]=[CH:30][C:27]=1[C:28]#[N:29])[O:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH2:18][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:24]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CCn1c2ccccc2c2cc(NC(=O)CC(C)CCO)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CCOc3ccc(C#N)c(Cl)c3)ccc21
Reaction time: 14 h
Yield: 64.7 %

Procedure:
To a solution of the compound obtained in Step 2 (500 mg, 1.54 mmol) and 2-chloro-4-fluorobenzonitrile (240 mg, 1.54 mmol) in THF (15 mL) was added potassium t-butoxide (432 mg, 3.85 mmol) at room temperature, and the mixture was stirred for 14 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane) to give the title compound (458 mg, 0.996 mmol, 64.6%) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[C:13](=[O:21])[C:12]([C:22]([O:24]CC)=[O:23])=[N:11]2)=[CH:6][CH:5]=1.[OH-].[K+].C(O)C>O>[F:28][C:2]([F:1])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[C:13](=[O:21])[C:12]([C:22]([OH:24])=[O:23])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)c2cccc(F)c2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nn(-c2ccc(OC(F)(F)F)cc2)c2cccc(F)c2c1=O
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Ethyl 1-(4-trifluoromethoxyphenyl)-1,4-dihydro-4-oxo-5-fluorocinnoline-3-carboxylate (2.31 g) and potassium hydoxide (0.67 g) were added to a mixed solvent of ethanol (24 ml) and water (6 ml), and the resultant mixture was stirred at 60° to 70° C. for 7 hours. After being allowed to cool to room temperature, the mixture was diluted with water (100 ml), and washed with diethyl ether (30 ml). The water layer was neutralized with concentrated hydrochloric acid to pH 2 to precipitate crystals. The precipitated crystals was collected by filtration, washed two times with water (20 ml), and dried under reduced pressure to give 2.14 g of desired 1-(4-trifluoromethoxyphenyl)-1,4-dihydro-4-oxo-5-fluorocinnoline-3-carboxylic acid (yield: 99.5%). m.p., 200° C. (decomposed)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:18][NH2:19]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CN
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Solvent: C1CCOC1
Product: CNc1nc(Cl)nc2c1CCC2c1ccccc1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation G) (395 mg, 1.49 mmol) in THF (3700 μL), 2 M MeNH2 in THF (3700 μL, 7.45 mmol) was added. The reaction was allowed to stir at rt. When the reaction was complete, removed solvent and applied residue to silica gel. Eluted with EtOAc/Hex to afford the desired 2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (80.8 mg, 0.220 mmol, 69.1% yield). LC-MS (M+H)+=260.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.07 (3H, dd, J=8.5, 5.5 Hz), 6.96 (2H, t, J=8.7 Hz), 4.72 (1H, br s), 4.23 (1H, t, J=7.2 Hz), 3.09 (3H, d, J=4.9 Hz), 2.67-2.77 (1H, m), 2.58-2.67 (2H, m), 2.01-2.11 (1H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[NH:19][CH:20]=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:16][Br:17])=[CH:11][C:10]=1[NH:19][CH:20]=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CNc1cc(C(O)CBr)ccc1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
To a solution of N-[2-benzyloxy-5-(2-bromo-1-hydroxyethyl)phenyl]formamide (Organic Process Research and Development 1998, 2, 96-99) (4.12 g, 11.8 mmol) in N,N-dimethylformamide (25 mL) at RT under N2 was added tert-butyldimethylsilyl chloride (3.50 g, 23.2 mmol), imidazole (1.90 g, 27.9 mmol) and 4-(dimethylamino)pyridine (40 mg, 330 □mol). The resulting solution was stirred at RT overnight, the solvent was removed and the product taken up in ethyl acetate (70 mL). The organics were washed with water (100 mL), and the aqueous extracted with ethyl acetate (20 mlmL The combined organics were washed with hydrochloric acid (2M, 50 ml), brine (100 mL) and dried (MgSO4). The crude material was purified by chromatography (5-25% ethyl acetate in pentane) to yield a colourless oil (5.7 g). 1HNMR (CDCl3, 400 MHz) δ: −0.08 to −0.05 (3H, m), 0.09-0.11 (3H, s), 0.89-0.90 (9H, m), 3.38-3.55 (2H, m), 3.78-3.84 (1H, m), 5.06-5.11 (2H, m), 6.90-6.97 (1H, m), 7.03-7.12 (1H, m), 7.24 (m), 7.36-7.43 (5H, m), 7.67-7.78 (m), 7.88 (d), 8.74 (d); LRMS APCI m/z 464/466 [M+H]+
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=1)[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1>C1COCC1>[CH3:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=1)[O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:22]3=[N:27][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:23]3[CH:24]=[CH:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cccc(Oc2ccc(-c3cccnc3N)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 370 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.583 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(3-methylphenoxy)phenyl)pyridin-2-amine (511 mg) in THF (dry) (40 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and IPE were added and the precipitates were collected, washed with water/EtOAc, dried in vacuo to give the title compound (514 mg) as a white solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>CO>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 97.9 %

Procedure:
A solution of 4-(diphenylmethoxy)piperidine (5) (1.4 g, 5.2 mmol), methyl acrylate (560 mg, 6.5 mmol) and methanol (9.5 mL) was placed on a preheated orbital shaker at 75° C. for 3 h. The yellow solution was concentrated to yield 1.8 g (98%) of 6b as a yellow oil. The structure was confirmed by 1H NMR. (The propanoate esters 6c and 6e were similarly prepared.)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[C:8]([C:14]([NH2:16])=O)=[N:9][C:10]([I:13])=[CH:11][N:12]=1.O.[CH3:18][N:19]([CH3:22])[CH:20]=O>>[C:14]([C:8]1[C:7]([N:6]=[CH:18][N:19]([CH3:22])[CH3:20])=[N:12][CH:11]=[C:10]([I:13])[N:9]=1)#[N:16]
Reactant: NC(=O)c1nc(I)cnc1N
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(C)C=Nc1ncc(I)nc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
13.59 ml (146 mmol) of phosphorus oxychloride is added drop by drop at 0° C. to 11 g (41.7 mmol) of a solution of 3-amino-6-iodopyrazine-2-carboxamide in 80 ml of dimethylformamide. The reaction mixture is stirred at room temperature overnight and then poured in a beaker containing ice and a little water. The pH is adjusted to 8 with 1 N soda solution; a precipitate is formed. The mixture is allowed to gradually return to room temperature and then the solid formed is filtered, rinsed with water and dried at 50° C. to yield 10.50 g of N′-(3-cyano-5-iodopyrazine-2-yl)-N,N-dimethyl formimidamide (84%) in the form of a beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([CH2:30][Cl:29])[CH:32]=2)[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(CCl)c2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 17D (95 mg, 0.3 mmol) in anhydrous dichloromethane (3 mL) was added triethylamine (0.063 mL, 0.45 mmol) followed by 3-(chloromethyl)benzoyl chloride (0.051 mL, 0.36 mmol). The mixture was shaken overnight at room temperature, concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC, MS (APCI) m/e 472 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[C:6](=[O:15])[C:5]=12.[CH3:16][N:17]([CH3:23])[CH2:18][CH2:19][CH2:20][Mg]Cl>O1CCCC1>[OH:15][C:6]1([CH2:20][CH2:19][CH2:18][N:17]([CH3:23])[CH3:16])[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]12
Reactant: O=C1c2ccccc2CCn2cccc21
Reactant: CN(C)CCC[Mg]Cl
Solvent: C1CCOC1
Product: CN(C)CCCC1(O)c2ccccc2CCn2cccc21
Reaction time: 0.67 h

Procedure:
To a solution of 16 g., (0.081 mole) of 6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one in 300 ml. tetrahydrofuran (THF) is added 150 ml. of 1.0N solution of 3-dimethylaminopropyl magnesium chloride in THF. After stirring for 40 minutes at ice-bath temperature and for 1.5 hours at 25° C., the bulk of the solvent is distilled below 45° C. under reduced pressure. The residue is dissolved in 500 ml. of methylene chloride and the Grignard adduct is hydrolyzed by the dropwise addition of 15 ml. water with cooling in an ice bath. The methylene chloride solution is decanted and the gelatinous precipitate is extracted three times with 80 ml. portions of boiling benzene. The combined organic extracts are washed with water and then evaporated under reduced pressure to yield, after crystallization from ethanol, 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydro-5H-pyrrolo-[2,1-b][3]benzazepine, m.p. 68°-70° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3C3C=CC=C(OC)C=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:41][OH:42].O>C(#N)C>[CH:6]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:1]3[CH:13]=[CH:5][C:41]([O:42][CH2:7][CH2:6][CH3:11])=[CH:3][CH:2]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:13]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(-c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c1
Reactant: CO
Solvent: O
Solvent: CC#N
Product: CCCOc1ccc(-c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1

Procedure:
(830 mg, 57%) was obtained from (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid and 1-iodo-4-propoxybenzene using the procedure described for (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-methoxyphenyl)-1H-indol-3-yl)propanoic acid. 1H NMR (400 MHz, chloroform-d) δ 8.14 (s, 1H), 7.83-7.59 (m, 3H), 7.54-7.12 (m, 11H), 6.93 (d, J=8.5 Hz, 2H), 5.43-5.12 (m, 1H), 4.71-4.53 (m, 1H), 4.29-4.05 (m, 3H), 3.88 (t, J=6.4 Hz, 2H), 3.63-3.41 (m, 2H), 1.79 (sxt, J=7.0 Hz, 2H), 1.09-0.98 (m, 3H); [α]20D −7.54° (3.05 mg/mL, MeOH). LCMS retention time=1.952 min., m/z=561 (M+H), 99.1% purity. The LCMS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using The following set of conditions: PHENOMENEX® Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a flow rate of 1 mL/minute.