Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8][CH3:9])[CH:7]=1.BrC1C=CC(S(C)=[O:18])=NC=1>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8]([CH3:9])=[O:18])[CH:7]=1
Reactant: CSc1cncc(Br)c1
Reactant: CS(=O)c1ccc(Br)cn1
Product: CS(=O)c1cncc(Br)c1

Procedure:
The title compound was prepared from 3-bromo-5-methylsulfanyl-pyridine following a procedure analogous to that described for 5-bromo-2-methanesulfinyl-pyridine in Example 182.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:15])[C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>C1COCC1>[CH2:20]([N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5](=[O:15])[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])[CH:19]=[CH2:18]
Reactant: O=C(O)c1cccc(C(=O)NC2CC2)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C(=O)c1cccc(C(=O)O)c1)C1CC1
Temperature: 25 °C

Procedure:
A solution of 0.3 g (1.37 mmol) N-cyclopropyl-isophthalamic acid in 10 ml THF is treated with 142 mg (3.55 mmol) NaH (60% suspension in mineral oil) and stirred at 25° C. After 2 h 0.27 ml (3.23 mmol) allylbromide is added and after 18 h the reaction is quenched with water. The mixture is acidified with 2N HCl and extracted with EtOAc. The organic phase is washed with brine, dried with sodium sulfate and evaporated to yield the title compound that is used in the next step without purification.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[OH:30])[CH:23]=[CH:22]1.[OH-].[Na+]>>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[O:30][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)[CH:23]=[CH:22]1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1cccc2cc[nH]c12
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc3cc[nH]c23)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 1H-Indol-7-ol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C21H23NO5 [M+Na]+: 392; [M+H]+: 370.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([CH3:30])[C:23]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:23]3[C:24]([CH3:30])=[C:25]([CH3:29])[CH:26]=[C:27]([CH3:28])[C:22]=3[CH3:21])[CH2:32][CH2:33]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(C)c(C)c(N2CCNCC2)c1C
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2c(C)c(C)cc(C)c2C)CC1
Yield: 71 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:12][CH:13](Cl)[C:14]([O:16][CH2:17][CH3:18])=[O:15].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[Cl:12][CH:13]([C:7]1[C:2]([F:1])=[CH:3][C:4]([N+:9]([O-:11])=[O:10])=[CH:5][C:6]=1[F:8])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: CCOC(=O)C(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cl)c1c(F)cc([N+](=O)[O-])cc1F
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
A solution of 3,5-difluoronitrobenzene (20 g,126 mmol) and ethyl dichloroacetate (15.8 ml, 129 mmol) in DMF (60 ml) was added to potassium t-butoxide (31.8 g, 283 mmol) in DMF (500 ml) at −25° C. over 30 minutes. The mixture was stirred for 15 minutes at −25° C. then poured on to a mixture of ice (600 g) and 2M hydrochloric acid (500 ml). The aqueous mixture was extracted with ethyl acetate, the combined extracts were washed with water and sodium hydrogen carbonate solution and dried (MgSO4) and the solvent removed by evaporation to give ethyl 2-chloro-2-(2,6-difluoro-4-nitrophenyl)ethanoate (34 g, 97%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]1([NH2:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O.Cl>[C:5]1([NH:15][NH2:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: O=N[O-]
Reactant: Nc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Sodium nitrite (4.8 g) in water (20 ml) was added over 15 minutes to a stirred ice-cold suspension of 1-naphthylamine (9.58 g) in 6M hydrochloric acid (80 ml). After an additional 30 minutes in the ice bath, stannous chloride (44.5 9) in 6M hydrochloric acid (80 ml) was added slowly and the resulting suspension was stirred at O0 for 3 hr. The resulting solid was filtered off and dissolved in a mixture of 40% potassium hydroxide solution (100 ml) and ethyl acetate (150 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried and concentrated under reduced pressure to afford the title compound as a purple solid (10.58 g Rf= 0.1 in EA/CH (1/4)).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[S:19](Cl)(=[O:21])=[O:20]>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=1[S:19]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)(=[O:21])=[O:20]
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Product: CN1CCN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CC1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate EU using 1-methylpiperazine and 2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. 1H NMR (500 MHz, CDCl3) δ 8.37-8.28 (d, J=2.2, 1H), 7.98-7.86 (d, J=8.2, 1H), 7.73-7.59 (d, J=8.2, 1H), 3.45-3.31 (t, J=5.0, 4H), 2.60-2.42 (t, J=4.9, 4H), 2.40-2.20 (d, J=1.5, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18]>C1(C)C=CC=CC=1.CO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18])([O-:10])=[O:9]
Reactant: COC(=O)c1sccc1N
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1sccc1Nc1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared using the process of Example 1(a) but with 2-fluoro-nitrobenzene and methyl 3-aminothiophene-2-carboxylate (U.K. Pat. No. 837,086) as starting materials, m.p. 184° C., (toluene/MeOH, 2:1).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[N:10]=[CH:9]C(C#N)=[CH:7][N:6]=1.[OH-:15].[K+].[CH:17]([OH:20])([CH3:19])C>O>[CH3:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[N:10]=[CH:9][C:19]([C:17]([OH:20])=[O:15])=[CH:7][N:6]=1
Reactant: CC(C)(C)C#Cc1ncc(C#N)cn1
Reactant: [OH-]
Reactant: CC(C)O
Agent: [K+]
Solvent: O
Product: CC(C)(C)C#Cc1ncc(C(=O)O)cn1
Temperature: 25 °C

Procedure:
A mixture 2-(3,3-dimethylbut-1-ynyl)pyrimidine-5-carbonitrile (1.0 g, 0.005 mol) and potassium hydroxide (2.8 g, 0.05 mol) in isopropanol (40 mL) and water (10 mL) was heated at reflux for three hours. The mixture was allowed to cool to room temperature and concentrated under vacuum. Water (200 mL) was added and the mixture was cooled to 0° C., then conc. HCl was added until a pH of 6 was obtained. The resulting off-white precipitate was collected by filtration and washed with water to give the product as a solid. m/z=205 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:21]=[C:13]3[C:14]4[C:19]([CH2:20][N:12]3[N:11]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:21]=[C:13]3[C:14]4[C:19]([CH2:20][N:12]3[N:11]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3n(n2)Cc2ccccc2-3)c1
Agent: [Pd]
Agent: Cl
Product: Nc1cccc(-c2nc3n(n2)Cc2ccccc2-3)c1

Procedure:
2-(m-Nitrophenyl)-5H-s-triazolo[5,1-a] isoindole (7.7 g) is hydrogenated at atmospheric pressure and at room temperature in the presence of 2 g of 10% Pd on charcoal and 8 ml of 15% ethanolic hydrogen chloride. The product so obtained is purified by crystallization from ethanol. Yield 6.1 g (89%) of the title product which melts at 163-4°C.
Reaction SMILES: C[CH:2]([CH:6]1[C:11]2=[CH:12][C:13]3[C:18]([N:10]2[CH2:9][CH2:8][CH2:7]1)=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH:20]([CH3:22])[CH3:21])[C:3]([O-:5])=[O:4].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34]>>[F:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12]([C:33]([C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)=[O:34])=[C:11]3[CH:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:7][CH2:8][CH2:9][N:10]32)=[C:14]([CH:20]([CH3:21])[CH3:22])[CH:15]=1
Reactant: CC(C)c1cc(F)cc2c1cc1n2CCCC1C(C)C(=O)[O-]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: CC(C)c1cc(F)cc2c1c(C(=O)c1ccc3ccccc3c1)c1n2CCCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl(3-fluoro-1-isopropyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (Example 122, Step 4) and 2-naphthoyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: C(OC([N:11]1[CH2:17][C:16]2[CH:18]=[C:19]([O:25][CH3:26])[C:20]([N+:22]([O-])=O)=[CH:21][C:15]=2[N:14]([CH2:27][CH3:28])[C:13](=[O:29])[CH2:12]1)=O)C1C=CC=CC=1.C(O)C>[Pd]>[NH2:22][C:20]1[C:19]([O:25][CH3:26])=[CH:18][C:16]2[CH2:17][NH:11][CH2:12][C:13](=[O:29])[N:14]([CH2:27][CH3:28])[C:15]=2[CH:21]=1
Reactant: CCN1C(=O)CN(C(=O)OCc2ccccc2)Cc2cc(OC)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CCN1C(=O)CNCc2cc(OC)c(N)cc21
Reaction time: 24 h
Yield: 97.4 %

Procedure:
A mixture of 1-Ethyl-7-methoxy-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester (0.95 g, 0.0024 mol) and 10% Pd/C (10:90, Palladium:carbon black, 0.095 g) in Ethanol (100 mL, 2 mol;) was hydrogenated on a Paar shaker for 1 day. The catalyst was filtered and the filtrate evaporated to give 8-Amino-1-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo-[e][1,4]diazepin-2-one as a tan solid (0.55 g). (98%). Mp 69-73° C.; LCMS (m/e) 236 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.75 (s, 1H), 6.61 (s, 1H), 4.83 (s, 2H), 3.76 (s, 3H), 3.74-68 (q, 2H, J=7.33 Hz), 3.58 (s, 2H), 2.97 (s, 2H), 1.05-02 (t, 3H, J=7.32 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18](O)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([O:41][CH2:42][CH:43]2[CH2:47][O:46][C:45]([CH3:49])([CH3:48])[O:44]2)(=O)=O)=CC=1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:41][CH2:42][CH:43]3[CH2:47][O:46][C:45]([CH3:48])([CH3:49])[O:44]3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(O)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OCC2COC(C)(C)O2)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
1.60 g (4.6 mmol) of 4-(3-hydroxy-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester (example 168a) was dissolved in 50 ml of MeCN at rt; 1.29 g (9.4 mmol) of anhydrous potassium carbonate was added, followed by 1.495 g (4.8 mmol) of rac-2,2-dimethyl-1,3-dioxolan-4-yl-methyl p-toluenesulfonate. The reaction mixture was stirred at reflux for 22 hours. It was then cooled down to ambient temperature and poured into crashed ice and extracted twice with EtOAc. The organic phases were washed with water and brine, dried over MgSO4, filtered and evaporated i.V. and the residue (2.11 g) was purified by chromatography (SiO2, MeCl2/MeOH) to yield 1.52 g of the title compound as a colorless amorphous solid. MS: 465.2 (MH+).
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:12])[CH:7]=[CH:6][C:5]=12.Br.C([O-])([O-])=[O:22].[K+].[K+]>CS(C)=O>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10](=[O:22])[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:12])[CH:7]=[CH:6][C:5]=12
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(C(=O)Cc2ccc3ncnn3c2)n1
Agent: Br
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc(C(=O)C(=O)c2ccc3ncnn3c2)n1
Temperature: 65 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a stirred suspension of 2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(6-methylpyridin-2-yl)ethanone (6.20 g, 24.57 mmol) in DMSO (48 mL) was added dropwise HBr (48 wt. % in water, 5.96 g, 12.4 mL) at 0° C., and the mixture was heated at 60-70° C. After 2 h, the reaction mixture was cooled to 0° C., poured onto ice water (20 mL), and basified to pH 10 with solid K2CO3. The mixture was extracted with CHCl3 (2×250 mL), and the organic phase was washed with water (2×100 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of MeOH and CH2Cl2 as eluent to give the titled compound (6.02 g, 92%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.11 (dd, 1H, J=1.6, 1.2 Hz), 8.47 (s, 1H), 8.14 (dd, 1H, J=9.2, 1.6 Hz), 8.04 (br d, 1H, J=7.6 Hz), 7.88 (dd, 1H, J=9.2, 1.2 Hz), 7.84 (t, 1H, J=7.8 Hz), 7.42 (br d, 1H, J=8.0 Hz), 2.49 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:6]([CH:15]=1)[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8].[NH:23]1[CH2:25][CH2:24]1>CCOC(C)=O>[N:23]1([C:2]2[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:6]([CH:15]=2)[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8])[CH2:25][CH2:24]1
Reactant: C1CN1
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)cc1C(=O)NCC(O)CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(N2CC2)cc1C(=O)NCC(O)CO
Yield: 76 %

Procedure:
A solution of the above benzamide (0.84 g, 2.38 mmol) and aziridine (0 74 mL, 14 3 mmol) in EtOAc (20 mL) was stirred at room temperature for 16 h. The reaction mixture was worked up and the residue was chromatographed on silica gel, eluting with EtOAc/MeOH (4:1) to give 10 (0.65 g, 76%), mp (EtOAc) 120-123° C. 1H NMR [(CD3)2SO] δ8.71 (t, J=5.8 Hz, 1H, NH), 8.45 (s, 1H, H-3), 744 (s, 1H, H-6), 477 (d, J=5 0 Hz, 1H, CHOH), 4.54 (t, J=5 8 Hz, 1H, CH2OH), 3.70-361 (m, 1H, CHOH), 3.45-3.36 (m, 3H, CH2OH, CONHCHH), 3 41 (s, 3H, CH3), 3.17-3.07 (m, 1H, CONHCHH), 2.47 (s, 4H, aziridine-H). Anal. Calcd for C13H17N3O7S.0.5H2O: C, 42.39,H, 4.93; N, 11.41. Found C, 41.98; H, 5.11, N, 10.97%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11](=[O:36])[NH:12][CH:13]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([F:29])[C:23]=4[C:30]4[N:34]=[C:33]([CH3:35])[O:32][N:31]=4)=[CH:21][C:16]=3[O:15][CH2:14]2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:28][C:26]1[CH:25]=[C:24]([F:29])[C:23]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[C:22]([C:20]2[CH:19]=[CH:18][C:17]3[CH:13]([NH:12][C:11]([C:8]4([NH2:7])[CH2:10][CH2:9]4)=[O:36])[CH2:14][O:15][C:16]=3[CH:21]=2)[CH:27]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)OCC3NC(=O)C2(NC(=O)OC(C)(C)C)CC2)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)OCC3NC(=O)C2(N)CC2)no1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-11 [C], (1-{(rac)-6-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-2,3-dihydro-benzofuran-3-ylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (example 44) has been treated with trifluoroacetic acid (90%) to give the title compound as light yellow oil. MS: 429.1 (MH+, 1Cl).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:15]([O:14][C:12](=[O:13])[NH:11][C:7]1[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[CH:9][N:8]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Yield: 86.4 %

Procedure:
A solution of to 2-[N,N-bis(tert-Butoxycarbonyl)amino]-isonicotinic acid ethyl ester (35.0 g, 95.5 mmol) in THF (350 mL) was treated with LiAlH4 (7.25 g, 191 mmol) and refluxed for 1 h under nitrogen. The reaction mixture was poured carefully onto crushed ice and the product extracted several times with CHCl3 and CHCl3: MeOH (9:1). The combined organic extracts were dried, filtered and concentrated under reduced pressure to give (4-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (18.5 g, 86%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[F:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[C:29](=O)[CH2:28][CH2:27]2.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:29]3[C:30]4[C:26](=[CH:25][CH:24]=[CH:23][C:22]=4[F:21])[CH2:27][CH2:28]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: O=C1CCc2cccc(F)c21
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CCc4cccc(F)c43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 7-fluoro-indan-1-one using decaborane yielded a mixture of epimers of the title compound as a white foam. MS (ESI): m/z=430.3 [M+H]+.
Reaction SMILES: [I:1]I.Br[C:4]1[C:18]2=[C:19]3[C:7]([N:8]([Si](C(C)(C)C)(C)C)[CH:9]=[C:10]3[CH2:11][C@@H:12]3[C:17]2=[CH:16][C@H:15]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:14][N:13]3[CH3:28])=[CH:6][CH:5]=1>>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([NH:20][C@H:15]1[CH2:16][C@H:17]2[C@@H:12]([CH2:11][CH:10]3[C:19]4[C:7](=[CH:6][C:5]([I:1])=[CH:4][C:18]2=4)[NH:8][CH2:9]3)[N:13]([CH3:28])[CH2:14]1)=[O:27])[CH3:24]
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3c(Br)ccc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Reactant: II
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(I)cc4c3C(CN4)C[C@H]2N(C)C1

Procedure:
With iodine and 3-(12-bromo-1-tert-butyldimethylsilyl9,10-didehydro-6-methyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[F:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Li]>C1COCC1>[C:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4](=[O:5])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][C:23]2[CH:32]=[CH:33][CH:34]=[C:21]([F:20])[CH:22]=2)[CH2:7]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: [Li]c1ccccc1Oc1cccc(F)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2Oc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (0.65 g, 2.37 mmol) in THF (4 mL) at −20° C. was added dropwise the solution of 2-(3-fluorophenoxy)phenyllithium prepared in Step 2 above. After the addition was complete, the resulting solution was allowed to warm to rt slowly, and left at rt for 1 h. The reaction was quenched with 1N HCl (˜6 mL), and extracted with Et2O (4×10 mL). The combined organic layers were washed with sat'd aq NaHCO3 and brine, and dried over Na2SO4. Removal of the solvent left the crude ketone (1.49 g, quantitative), which was used for next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]1[CH2:15][N:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[CH2:13][CH2:12][N:11]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:10]1=[O:30].Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].Cl.Cl.[O:46]=[C:47]1[NH:55][C:50]2=[N:51][CH:52]=[CH:53][CH:54]=[C:49]2[N:48]1[CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>O1CCCC1>[F:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:14]1[CH2:15][CH:9]([NH:8][C:32]([N:59]2[CH2:60][CH2:61][CH:56]([N:48]3[C:49]4[C:50](=[N:51][CH:52]=[CH:53][CH:54]=4)[NH:55][C:47]3=[O:46])[CH2:57][CH2:58]2)=[O:33])[C:10](=[O:30])[N:11]([CH2:25][C:26]([F:28])([F:29])[F:27])[CH2:12][CH2:13]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: NC1CN(Cc2cccc(F)c2F)CCN(CC(F)(F)F)C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CN(Cc2cccc(F)c2F)CCN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Triethylamine (0.012 mL, 0.133 mmol) was added to a solution of 6-amino-1-(2,3-difluorobenzyl)-4-(2,2,2-trifluoroethyl)-1,4-diazepan-5-one (45 mg, 0.133 mmol) and 4-nitrophenyl chloroformate (27 mg, 133 mmol) in tetrahydrofuran (2.5 mL) at 0° C. After 1 h, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (43 mg, 0.147 mmol) and triethylamine (0.048 mL, 0.532 mmol) were added and the mixture allowed to warm to ambient temperature. After 18 h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→92% dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave the title compound (67 mg). MS 582.2262 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.77 (s, 1H), 8.03 (d, J=5.4 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.27-7.24 (m, 1H), 7.09-7.05 (m, 2H), 6.98 (dd, J=8.1, 5.4 Hz, 1H), 5.99 (d, J=4.9 Hz, 1H), 4.91-4.88 (m, 1H), 4.57-4.50 (m, 1H), 4.25-4.16 (m, 3H), 4.00-3.92 (m, 2H), 3.84 (dd, J=32.7, 14.2 Hz, 2H), 3.36-3.34 (m, 1H), 3.20 (d, J=12.5 Hz, 1H), 2.99-2.91 (m, 3H), 2.44-2.37 (m, 2H), 2.31-2.18 (m, 2H), 1.90 (d, J=11.0 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5](=[O:14])(=[O:13])[C:4]2[CH:15]=[C:16]([CH2:19][C:20](O)=[O:21])[CH:17]=[CH:18][C:3]1=2.C1C2C=CC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[OH:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:3]2[C:2](=[O:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5](=[O:14])(=[O:13])[C:4]=2[CH:15]=1
Reactant: O=C(O)Cc1ccc2c(c1)S(=O)(=O)c1ccccc1CC2=O
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1C=C2
Product: O=C1Cc2ccccc2S(=O)(=O)c2cc(CCO)ccc21

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 10,11-dihydro-11-oxodibenzo[b,f]thiepin-3-acetic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product.