Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:13]3[CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18][C:12]=3[C:11]([CH3:21])([CH3:20])[O:10][C:9]=2[CH:8]=[C:7]([CH3:22])[CH:6]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(O)(=[O:29])C>>[C:1]([O:4][C:5]1[C:14]2[C:13]3[CH2:15][CH:16]([CH3:19])[CH2:17][C:18](=[O:29])[C:12]=3[C:11]([CH3:21])([CH3:20])[O:10][C:9]=2[CH:8]=[C:7]([CH3:22])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)Oc1cc(C)cc2c1C1=C(CCC(C)C1)C(C)(C)O2
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(C)cc2c1C1=C(C(=O)CC(C)C1)C(C)(C)O2
Reaction time: 3 h
Yield: 14.2 %

Procedure:
To a stirring mixture of 1-acetoxy-7,8,9,10-tetrahydro-3,6,6,9-tetramethyl-6H-dibenzo[ b,d]pyran (601 mg., 2 mmole) in 7 ml. of 50% acetic acid and 5 ml. of chloroform held under a nitrogen atmosphere, was added dropwise a solution of ceric ammonium nitrate (4.39 g., 8 mmole) in 12 ml. of 50% acetic acid. After the addition was completed, the reaction mixture was stirred over a steam bath. After 3 hours, the mixture was poured onto ice with stirring. The product was extracted into ether, washed to neutrality with 5% NaHCO3, washed with water, dried over Na2SO4 and concentrated under reduced pressure. Elution of the product from a mganesium silicate column with graded ether/petroleum ether gave 120 mg. (14.2%) of the desired product which showed a blue fluorescent spot on tlc at Rf 0.67 (silica gel, 40% EtOAc/hexane). Ir(neat) 1770(m), 1740(s), 1660(s), 1640(s), 1620(m) CM-1 ; nmr (CDCl3) δ 1.08(d,3H, J=4Hz), 1.38(S,3H), 1.7(S,3H), 2.3(S,6H), 1.0-3.0(broad m,5H), 6.5(S,1H), 6.62(S,1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.[H][H]>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[O:17])[CH2:14][CH2:15]2)=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Yield: 86.3 %

Procedure:
A mixture of [4-(5-nitropyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.15 g, 0.4 mmol) and Pd—C (76 mg) in THF (5 mL) and MeOH (5 mL) was exposed to a hydrogen atmosphere at 25° C. for 2 h. The reaction mixture was filtered and the solution was concentrated in vacuo to provide the title compound as a dark purple solid (0.121 g, 86% yield). MS (ES+) m/z 351.0 (M+1).
Reaction SMILES: C([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16].[CH3:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:23].Cl>CCCCCC.O1CCCC1>[OH:23][C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1)([CH3:21])[CH2:16][C:15]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(O)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
19.9 ml (31.89 mmol) of a 1.6N solution of n-butyllithium in hexane were added dropwise to a solution of 6.7 ml (31.89 mmol) of hexamethyldisilazane in 50 ml of tetrahydrofuran at 0° C., and the mixture was stirred for 15 min and then cooled to −78° C. 3.12 ml (31.89 mmol) of ethyl acetate were added, the mixture was stirred for 1 h and, after addition of 5.00 g (26.57 mmol) of 4-trifluoromethylacetophenone, dissolved in 20 ml of tetrahydrofuran, stirred at −78° C. for a further hour. 1N hydrochloric acid was added to the reaction solution, and the phases were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8/2) to result in 7.14 g (97% of theory) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.IC.[C:40]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]([CH3:40])[S:27]([CH3:30])(=[O:29])=[O:28])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(NS(C)(=O)=O)CC2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N(C)S(C)(=O)=O)CC2)n1
Yield: 84.4 %

Procedure:
Reaction of N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide (Example 17) (114 mg, 0.21 mmol) with iodomethane (0.5 mL, 8.1 mmol) and K2CO3 (2 g, 14.5 mmol) in DMF (5 mL) gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-methylmethanesulfonamide (98 mg) in 84% yield: mp (CH2Cl2/MeOH) 231-233° C.; 1H NMR (DMSO-d6) δ 7.89 (d, J=8.2 Hz, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.82-4.72 (m, 2H), 3.98 (s, 3H), 3.98-3.90 (m, 2H), 3.82-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.11-2.98 (m, 2H), 2.94 (s, 3H), 2.68 (s, 3H), 1.77-1.70 (m, 4H); Anal. Calcd. for C23H30F2N8O4S: C, 50.0; H, 5.5; N, 20.3. Found: C, 49.9; H, 5.6; N, 20.3%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16](O)=[O:17])[C:8]2=[O:23])#[N:2].[NH2:31][C:32]1[CH:36]=[CH:35][O:34][N:33]=1>>[C:1]([C:3]1[CH:4]=[C:5]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16]([NH:31][C:32]1[CH:36]=[CH:35][O:34][N:33]=1)=[O:17])[C:8]2=[O:23])#[N:2]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2c(C#N)cc(N3CCN(C)CC3)cc2c1=O
Reactant: Nc1ccon1
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2c(C#N)cc(N3CCN(C)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 3-[8-cyano-6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid was reacted with 3-aminoisoxazole to give 3-[8-cyano-6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.24 (s, 3H), 2.49 (m, 4H), 3.35 (m, 4H), 7.04 (d, 1H), 7.61 (d, 1H), 7.70 (d, 1H), 8.11 (m, 3H), 8.30 (s, 1H), 8.84 (d, 1H), 11.46 (s, 1H); Mass Spectrum: M+H+ 470.
Reaction SMILES: [Na].CO.Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl.[Cl:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:14]=1)=[O:12]>COCCOC>[ClH:10].[NH:7]([C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:14]=1)=[O:12])[C:6]([NH2:8])=[NH:5]
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cn(-c2ccc3ncccc3c2)c2ccccc12
Agent: Cl
Agent: [Na]
Solvent: COCCOC
Solvent: CO
Product: N=C(N)NC(=O)c1cn(-c2ccc3ncccc3c2)c2ccccc12
Temperature: 22 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
0.256 g (11.1 mmol) of sodium is added at 22° C. under an argon atmosphere to 40 cm3 of methanol. After complete dissolution, 1 g (10.5 mmol) of guanidine hydrochloride is added. After stirring at 22° C. for 3 hours, the reaction mixture is filtered under an argon atmosphere. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is dissolved in 10 cm3 of 1,2-dimethoxyethane. 1 g of 3-chlorocarbonyl-1-(quinol-6-yl)-1H-indole hydrochloride, suspended in 40 cm3 of 1,2-dimethoxyethane, is subsequently added at 22° C. under an argon atmosphere. After stirring at 22° C. for 48 hours and after 2 hours at reflux, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 15 cm3 of water. After stirring at 22° C. for 1 hour, a few drops of 10N hydrochloric acid solution are added. After stirring at 22° C. for 12 hours, the suspension is filtered and dried to give 0.52 g of 3-guanidinocarbonyl-1-(quinol-6-yl)-1H-indole hydrochloride in the form of a yellow solid melting at 268° C. IR spectrum (KBr): 3343, 3168, 2174, 1693, 1597, 1543, 1502, 1454, 1236, 1199, 772 and 751 cm−1.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(N)CO
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(CO)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (3.71 g, 7.32 mmol) and 2-amino-2-methyl-1-propanol (2.10 ml, 22.0 mmol) as starting materials.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH3:12]>C(Cl)Cl>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH2:12])(=[O:10])=[O:9])[CH:3]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 99.8 %

Procedure:
Pyridine-3-sulfonyl chloride HCl (647.2 mg, 3.023 mmol) was suspended in DCM (9.0 mL) and NH3 (5 mL, 7N in MeOH, 35 mmol) was added. The reaction was stirred at RT under nitrogen for 50 minutes and then filtered, and the solid was washed with DCM. The filtrate was concentrated and dried under high vacuum to provide pyridine-3-sulfonamide (477 mg, 91% yield). MS (ESI pos. ion) m/z: 159 (MH+). Calculated exact mass for C5H6N2O2S: 158.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[C:8](=O)([O-:10])[O-:9].[K+].[K+].C(=O)=O.Cl>O>[CH3:1][C:2]1[NH:6][C:5]([CH3:7])=[C:4]([C:8]([OH:10])=[O:9])[N:3]=1
Reactant: Cc1c[nH]c(C)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: Cc1nc(C(=O)O)c(C)[nH]1
Yield: 74.2 %

Procedure:
12 g (0.125 mole) of 2,4-dimethylimidazole, 42.5 g (0.3 mole) of potassium carbonate and 100 ml of liquid carbon dioxide were stirred for 5 hours at 150° C. in an autoclave, the reaction pressure being 130 bar. The reacted mixture was pulverized and suspended in 100 ml of water, and the stirred suspension was brought to pH 5-6 with hydrochloric acid. The precipitate which separated out was filtered off and dried to give 13 g (74% of theory) of pure 2,5-dimethylimidazole-4-carboxylic acid of melting point 234° C. (decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[S:20][CH2:21][CH2:22][N:23]=1>>[S:20]1[CH2:21][CH2:22][N:23]=[C:19]1[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: NC1=NCCS1
Product: FC(F)(F)c1cc(NC2=NCCS2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (75 mg, 0.289 mmol) and 2-amino-2-thiazoline (37 mg, 0.362 mmol) similar to Example 166 and was isolated as a white solid (20 mg, 0.61 mmol, 21%). 1H NMR (CDCl3/MeOH-d4) 9.45 (s, 1H), 8.73 (dt, 1.8, 8.1 Hz, 1H), 8.58 (dd, J=1.8, 5.1 Hz, 1H), 7.47 (m, 1H), 6.70 (s, 1H), 3.93 (t, J=6.6 Hz, 2H), 3.04 (t, J=7.2 Hz, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([C:22]([OH:24])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:26][CH:27]1[CH2:30][CH2:29][CH2:28]1>CN(C)C=O>[C:3]([O:7][C:8]([NH:10][C@@H:11]([C:22]([OH:24])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH:14]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCC1CCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(CC2CCC2)c2ccccc12)C(=O)O
Reaction time: 0.33 h

Procedure:
In a 20 mL vial, NaH (60% in mineral oil) (0.092 g, 2.30 mmol) was added to a solution of N-(tert-butoxycarbonyl)-D-tryptophan (0.200 g, 0.657 mmol) in anhydrous N,N-dimethylformamide (4 mL) at 0° C. The reaction mixture was placed in a shaker for 20 min. at 0° C. (Bromomethyl)cyclobutane (0.074 mL, 0.657 mmol) was added to the solution and allowed to react for 10 hours at 0° C. The reaction mixture was quenched with H2O and acidified with 1M NaHSO4 until pH=3. The solution was extracted with CH2Cl2, washed with brine, dried over Na2SO4, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH2:27][C:28]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:29].[H-].[Na+].[CH3:41][N:42]([CH3:46])[C:43](Cl)=[O:44].O>CN(C=O)C>[CH3:41][N:42]([CH3:46])[C:43]([N:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([C:28](=[O:29])[CH2:27][CH2:26][C:3]2[N:4]=[CH:5][N:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:2]=2[CH3:1])=[CH:31]1)=[O:44]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1c(CCC(=O)c2c[nH]c3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CCC(=O)c2cn(C(=O)N(C)C)c3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 20 h

Procedure:
A solution of 3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-(1H-indol-3-yl)-1-propanone (500 mg) in dry DMF (3 ml) was added dropwise to a stirred suspension of sodium hydride (73% dispersion in oil; 40 mg) in dry DMF (1 ml) under nitrogen. After 15 min. dimethylcarbamyl chloride (0.11 ml) was added and the mixture was stirred for 20 h. Water (50 ml) was added and the suspension was extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give an oil (815 mg) which was purified by FCC (column made up in ethyl acetate:triethylamine 99:1) eluting with ethyl acetate to give the title compound (445 mg) as a foam, t.l.c. on triethylamine impregnated silica (ethyl acetate) Rf 0.20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([N:16]([CH3:38])[C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[C@@H:26]([CH3:37])[CH2:25]4)=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([N:16]([CH3:38])[C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:37])[CH2:25]4)=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(-c4cccc(F)c4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(-c4cccc(F)c4)nc3)cc2)CCN1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
1,1-Dimethylethyl (2S)-4-({4-[{[6-(3-fluorophenyl)-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D60) (0.127 g, 0.245 mmol) was stirred in DCM (10 mL) and TFA (2.5 mL) was added drop-wise. The reaction mixture was stirred for ˜1 h, then concentrated in vacuo and re-diluted with DCM and water. The separated aqueous layer was basified to pH14 with concentrated NaOH solution, then extracted with DCM which was dried (Na2SO4) and concentrated to yield the title compound as a yellow oil (0.091 g). δH (CDCl3, 400 MHz) 8.52 (1H, d), 7.75 (1H, dd), 7.67 (2H, m), 7.54 (1H, d), 7.40 (1H, m), 7.25 (2H, d), 7.09 (1H, m), 7.03 (2H, d), 3.53 (3H, s), 3.41 (2H, s), 2.83 (3H, m), 2.66 (2H, d), 1.96 (1H, td), 1.62 (1H, m), 1.55 (br.s), 0.97 (3H, d), NH not observed. MS (ES): MH+ 419.2.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]3[N:20]=[CH:21][CH:22]=[CH:23][C:11]=3[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].O>CN(C)C=O>[O:38]=[C:29]1[C:30]2[C:31](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:33])[N:28]1[CH2:27][CH2:26][CH2:25][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:10][C:11]2[CH:23]=[CH:22][CH:21]=[N:20][C:12]1=2
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.9 %

Procedure:
To a stirred suspension of 0.56 g (0.023 mole) of sodium hydride in 25 ml of anhydrous dimethylformamide was added, portionwise, 5.0 g (0.0184 mole) of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The reaction mixture was warmed to 80°±2° C. for 1 hr and cooled to room temperature. A solution of 5.55 g (0.020 mole) of N-(3-bromopropyl)phthalimide in 10 ml of anhydrous dimethylformamide was added dropwise and after stirring for 16 hr the reaction mixture was poured into 650 ml of water and stirred for 30 min. The yellow solid was collected by filtration and recrystallized three times from isopropyl alcohol to give 3.7 g of product, m.p. 170°-172° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]1([NH2:16])[CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])(=[N:16][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: NC1CCC1
Reactant: CS(=O)Nc1ccc(Br)cc1
Product: CS(=O)(=NC1CCC1)Nc1ccc(Br)cc1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and cyclobutylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.99 min; Mass spectrum (ESI+): m/z=303, 305 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[C:13]([O:19][CH2:20][C@H:21]2[CH2:23][C@@H:22]2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][N:25]=2)=[N:14][C:15]([CH3:18])=[N:16][CH:17]=1)=O)C>C1COCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C@H:22]2[CH2:23][C@@H:21]2[CH2:20][O:19][C:13]2[C:12]([CH2:10][OH:9])=[CH:17][N:16]=[C:15]([CH3:18])[N:14]=2)=[N:25][CH:26]=1
Reactant: CCOC(=O)c1cnc(C)nc1OC[C@H]1C[C@@H]1c1ccc(OC)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2CO)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1N THF solution of LAH (0.175 mL, 0.175 mmol) was added dropwise to a 0° C. solution of ethyl-4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-2-methylpyrimidine-5-carboxylate (30 mg, 0.087 mmol) in THF (0.58 mL). The reaction mixture was slowly warmed to room temperature, and then stirred for 30 mins. The reaction mixture was re-cooled to 0° C. and the carefully quenched by dropwise addition of water (10 μL), 15% NaOH in water (20 μL), and then water (20 μL). The slurry was treated with excess Na2SO4, stirred vigorously at room temperature for 10 mins, and then filtered through a pad of Celite eluting exhaustively with 1:1 CH2Cl2/MeOH. The filtrated was concentrated in vacuo. The resulting product was sufficiently pure to use in the subsequent step without further purification. LRMS m/z (M+H) 302.4 found, 302.1 required.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:14].C(=O)([O-])[O-].[NH4+].[NH4+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:14])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: N
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Product: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Nitro-benzenesulfonyl chloride (2.0 g, 9.0 mmol) was dissolved in acetonitrile (20 mL). To this solution was added concentrated aqueous ammonia (20 mL) saturated with ammonium carbonate and the reaction mixture was vigorously stirred for 1 h at room temperature. Then acetonitrile was removed under reduced pressure and the residue diluted with cold water (30 mL) leading to a precipitate formation. The precipitate was filtered out and washed with water (2×15 mL), ether and dried. Yield of 3-nitro-benzenesulfonamide 1.46 g (80%). Beige powder.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][C:9]([F:14])([CH2:11][CH2:12][CH3:13])CC[N:6]1[C:15](OC(C)(C)C)=O)=[O:4].O.[OH-].[Li+].[CH2:25]1COCC1>O>[F:14][C:9]1([CH2:11][CH2:12][CH2:13][CH3:25])[CH2:15][NH:6][C@H:5]([C:3]([OH:2])=[O:4])[CH2:10]1
Reactant: C1CCOC1
Reactant: CCCC1(F)CCN(C(=O)OC(C)(C)C)C(C(=O)OC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCC1(F)CN[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 12c (0.27 g, 0.89 mmol) in THF (10 mL) and water (3 mL) was added lithium hydroxide monohydrate (45 mg, 1.06 mmol). The reaction mixture was stirred at room temperature overnight. THF was removed and the residue was purified by column chromatography using 10% MeOH in DCM as eluant to obtain 4-Fluoro-4-butylproline 12d (P=Boc, m=1, R9=n-butyl) (0.26 g, 100%) as a colorless oil: 1H NMR (300 MHz, CD3OD) δ 4.30 (m, 1), 3.72 (m, 1), 3.49 (m, 1), 3.39 (m, 1), 2.58 (m, 1), 2.02 (m, 2), 1.72 (m, 13), 0.93 (t, J=6.6, 3); MS (ESNEG): 288 [M−1]−.