Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][C@H:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1F.[ClH:20].Cl.NN1CCCC1.C1C[CH2:37][N:36]2C(=[N:32][CH2:33][CH2:34][CH2:35]2)CC1>CN(C)P(=O)(N(C)C)N(C)C>[ClH:20].[F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[N:36]1[CH2:35][CH2:34][CH:33]([NH2:32])[CH2:37]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: C[C@H]1Cc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Agent: NN1CCCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1Cc2c(N3CCC(N)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
To 7 g of (+)-8,9-difluoro-2-(S)-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid obtained in Example 5 were added 21 g of aminopyrrolidine dihydrochloride, 40 ml of 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) and 70 ml of hexamethylphosphoric triamide, and allowed to react in an oil bath at 120°-130° C. for 2 hours. The solvent was evaporated off under reduced pressure, and the residue was dissolved in 100 ml of 2% aqueous hydrochloric acid. Insoluble matters were filtered off, the filtrate was concentrated, and the residue was recrystallized from ethanol-water to obtain (+)-8-fluoro-2-methyl-9-(3-amino-1-pyrrolidyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:17]=[CH:16][C:12]([C:13]([Cl:23])=[O:14])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-(5-chloro-1H-benzoimidazol-2-yl)-benzoic acid (1.0 mmol) (CAS 204514-08-9) and oxalyl chloride (2.0 mmol) in dichloromethane (0.10M), add 2 drops of dimethylformamide as a catalyst. Stir at room temperature for 2 hours. After this time, concentrate the reaction in vacuo. Assume total conversion to the acid chloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][CH:15]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]OS(C)(=O)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:31][NH:32][CH3:33]>>[CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][CH:15]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17][N:32]([CH3:33])[CH3:31])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(CCOS(C)(=O)=O)c2ccncc2)CCN(C)C1
Reactant: CNC
Product: Cc1ccc2c(c1)c1c(n2CC(CCN(C)C)c2ccncc2)CCN(C)C1

Procedure:
Methanesulfonic acid-4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyl ester (200 mg, 0.468 mmol) in 10 mL of 40% aqueous dimethyl amine was heated at 100° C. for 1 h. The progress of reaction was monitored by TLC. After consumption of starting material, the reaction mixture was dried and the crude product was purified by reverse phase chromatography to obtain 170 mg of [4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyl]-dimethyl-amine as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.57 b(s, 2H), 7.65 (dd, 2H), 7.23 (d, 1H), 7.21 (s, 1H), 6.99 (d, 1H), 4.62 (m, 1H), 4.48 (m, 1H), 4.42 (m, 1H), 4.26 (t, 1H), 3.81 (m, 1H), 3.55 (m, 2H), 3.35 (m, 1H), 3.1 (m, 1H), 3.0 (s, 3H), 2.9 (m, 2H), 2.83 (s, 6H), 2.4 (m, 1H), 2.38 (s, 3H), 2.29 (m, 1H). Separation by chiral HPLC provides enantiomers II-232a-b.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:11][C:8]1[CH:7]=[N:6][C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[C:21]2[CH:20]=[CH:19][C:18]([C:32]3[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=3)=[C:17]([F:16])[CH:22]=2)=[N:10][CH:9]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Nc1cnc(Oc2ccccc2Br)nc1
Product: Nc1cnc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)pyrimidin-5-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H15FN6O, 374.13; m/z found, 374.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J=1.5, 2H), 7.95-7.90 (m, 2H), 7.57-7.50 (m, 2H), 7.44-7.39 (m, 1H), 7.38-7.37 (m, 1H), 7.36-7.34 (m, 1H), 7.33-7.28 (m, 1H), 7.11 (dd, J=8.1, 1.2, 1H), 6.86 (s, 2H), 5.19 (s, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:2].[CH3:29][Mg]Br>C(OCC)(=O)C.CCCCCC>[OH:2][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:29]
Reactant: C[Mg]Br
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C=O)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)O)cc1)CO2
Yield: 93 %

Procedure:
Using N-(3-(4-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide and methylmagnesium bromide, the title compound was synthesized in the same manner as Example 22. Yield: 93%. Melting point: 144-145° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40]([O:42]C)=[O:41])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:35][CH:36]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCCC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
A solution of chiral methyl 4-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)butanoate (70.5 mg, 0.110 mmol) in THF (5 ml) was treated with LITHIUM HYDROXIDE MONOHYDRATE (18.5 mg, 0.441 mmol) in water (2.5 ml) and stirred at rt for 16 hrs. The reaction was treated with 1 N HCl (pH 5) and extracted with ethyl acetate, washed with water then sat'd sodium chloride, dried with sodium sulfate, filtered and lyophilized to give chiral-4-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)butanoic acid (67 mg, 97.2%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 628.19. found: 628.1.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C@@H:11]([C:45]([CH3:48])([CH3:47])[CH3:46])[C:12]([N:14]2[C@H:29]([C:30]([NH:32][C@@H:33]([CH2:42][CH2:43][CH3:44])[CH:34]([OH:41])[C:35]([NH:37][CH:38]3[CH2:40][CH2:39]3)=[O:36])=[O:31])[CH2:28][C@:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17]3)[CH2:15]2)=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH:1]1([CH2:7][C:8]([NH:10][C@@H:11]([C:45]([CH3:46])([CH3:48])[CH3:47])[C:12]([N:14]2[C@H:29]([C:30]([NH:32][C@@H:33]([CH2:42][CH2:43][CH3:44])[C:34](=[O:41])[C:35]([NH:37][CH:38]3[CH2:40][CH2:39]3)=[O:36])=[O:31])[CH2:28][C@:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17]3)[CH2:15]2)=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@]2(CN(c3ccccc3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@]2(CN(c3ccccc3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C)C(=O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
(5S,8S)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxamide (I1) (20 mg, 30 μmol, 1 eq.) was diluted in DCM. Dess Martin reagent (38 mg, 90 μmol, 3 eq.) was added and the mixture was stirred for 3 hrs at room temp. Na2S2O3 (aq., 5 eq.) was added and the mixture was stirred for another 0.5 hrs. The product was extracted with DCM. Chromatography on the combined organic layers using hexanes and ethyl acetate gave 15.9 mg (24 mot) (5S,8S)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxamide (compound no. 3). 1H NMR (300 MHz, CDCl3) 7.5 (d, 2H), 7.4-7.32 (m, 2H), 7.2-7.12 (m, 2H), 6.9 (m, 1H), 6.17 (d, 1H), 5.4-5.3 (m, 1H), 4.77 (t, 1H), 4.65 (d, 1H), 4.42 (d, 1H), 4.15-3.98 (m, 2H), 3.76 (d, 1H), 2.83-2.75 (m, 1H), 2.6 (m, 2H), 2.2-0.8 (m, 31H), 0.6 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:9]2=[O:37])[N:6]=1.[ClH:38]>O1CCOCC1>[ClH:38].[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:9]2=[O:37])[N:6]=1
Reactant: Cc1nc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)cs1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)cs1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A suspension of tert-butyl 4-{1-[(2-methyl-1,3-thiazol-4-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (1.0 g; compound B10) in a solution of hydrogen chloride in 1,4-dioxane (12 ml, 4.0 M) is stirred for 2.5 h at RT. The suspension is filtered and the filter cake is washed with 1,4-dioxane to give the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[SH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([S:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: O=C(O)CCS
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(SCCC(=O)O)n1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 152.5 %

Procedure:
Commercially available 2-amino-4,6-dichloropyrimidine (0.79 g, 4.84 mmol), 3-mercaptopropionic acid (0.43 g, 4.04 mmol), cesium carbonate (1.3 g, 4.02 mmol), and N,N-dimethylformamide (7.0 ml) were placed in a reaction vessel. The mixture was stirred at 80° C. for 15 minutes. After the reaction solution was cooled to room temperature, ethyl acetate, water, and a saturated aqueous sodium bicarbonate solution were added thereto. The organic layer was separated, and then extracted with a saturated aqueous sodium bicarbonate solution. After the aqueous layers were combined together and washed with ethyl acetate, its pH was adjusted to about 4 using 1N hydrochloric acid. The solution was extracted with ethyl acetate. The extract was sequentially washed with 1N hydrochloric acid and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to yield 3-(2-amino-6-chloropyrimidin-4-ylsulfanyl)propionic acid (1.44 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH2:18][CH2:19][O:20][CH3:21])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].N1CCCCC1.C(O)(=O)C>C(O)(C)C>[C:13]([C:12](=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])[C:11]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[O:16])(=[O:14])[CH3:15]
Reactant: O=Cc1ccc(F)cc1F
Reactant: COCCOC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COCCOC(=O)C(=Cc1ccc(F)cc1F)C(C)=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
5.0 g (35 mmol) of 2,4-difluorobenzaldehyde are dissolved in 100 ml of isopropanol with 5.7 g (35 mmol) of 2-methoxyethyl acetoacetate. A freshly prepared solution of 1.0 ml of piperidine and 0.5 ml of glacial acetic acid in 5 ml of isopropanol is added to this solution and it is stirred overnight at 40° C. The mixture is concentrated, the residue is taken up in toluene, the solution is concentrated again and the residue is purified by filtration on 100 ml of silica gel (eluent: toluene/ethyl acetate 100:1) to give 5 g of the target compound as a yellow oil which is immediately reacted further.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:32])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH2:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COCCOCCN

Procedure:
100 mg (0.226 mmol) of 8-(9-Fluorenylmethoxycarbonylamino)-3,6-dioxaoctanoic acid tert-butylester in 1 mL of dry DMF were treated with piperidine (89.5 μL; 0.862 mmol) at r.t. for 3 hours. The solvent was evaporated and the residue purified by chromatography on silica gel with a gradient cHex→EtOAc→EtOAc/MeOH (1:1)+3%. MeOH. Yield: 12 mg (24%) of the title compound. ESI MS: 220.08 [M+H]+.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C1(S(O)(=O)=O)C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1(C)C(C)=CC=CC=1.C1COCC1.O>[OH2:10].[ClH:1].[ClH:1].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[CH:11]2[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]2)=[CH:23][CH:22]=1
Reactant: CC(C)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: Nc1ccc(F)cc1
Agent: Cl
Agent: O=S(=O)(O)c1ccccc1
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)N1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 23 h
Yield: 61.5 %

Procedure:
A mixture of 29.36 g (0.103 mol) of (4-fluorophenyl)[1-(1-methylethyl)-4-piperidinyl]methanone hydrochloride, 28.9 g (0.260 mol) of 4-fluoroaniline and 0.61 g (3.9 mmol) of benzenesulfonic acid in 500 mL of xylene was heated at reflux for 20 h. Water was removed with a Dean-Stark trap. The solvent was removed in vacuo. The residue was reacted with 6.0 g (0.16 mol) of LiAlH4 in 400 mL of THF at room temperature. After 23 h, dilute NaOH and then water were added slowly. The mixture was filtered through Celite®, and CH2Cl2 (400 mL) was added to the filtrate. The mixture was extracted with several portions of water and was dried (Na2SO4). The solvent was removed in vacuo. The residue was dissolved in CH3OH and treated with an excess of ethereal HCl. The hydrochloride salt was collected to give 13.8 g (32.1%) of the title compound as a white solid, mp 225°-228° C. An additional 4.58 g (10.2%) of product was collected from the filtrate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13]OS(C)(=O)=O)[C@H:10]([CH2:19][N:20]([CH:37]([CH3:39])[CH3:38])[C:21](=[O:36])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])[CH:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:40]=[N+:41]=[N-:42].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:19][N:20]([CH:37]([CH3:38])[CH3:39])[C:21](=[O:36])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])[CH:23]=2)[C@H:11]([CH2:13][N:40]=[N+:41]=[N-:42])[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2COS(C)(=O)=O)C(C)C)ccc1OC
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN=[N+]=[N-])C(C)C)ccc1OC
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,4S)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.7 g, 4.71 mmol) in DMF (20 mL) is added in one portion NaN3 (774 mg, 11.8 mmol) and the mixture is stirred at 70° C. overnight. After cooling to room temperature, a saturated aqueous NaHCO3 solution is added, followed by extraction with diethyl ether. The combined organics are washed with brine, dried over Na2SO4 and concentrated. The crude product is purified by RP-HPLC on a PrepC18 OBD column (dimensions: 30×100 mm; 5 μM particle size, SunFire Ltd) and using a 95-5% gradient of MeCN/H2O 5:95 (containing 0.1% TFA) to MeCN/H2O 95:5 (containing 0.1% TFA) over 20 min gives the title compound as colorless oil. TLC, Rf (hexane/AcOEt 1:3)=0.31. MS: 520.2 [M+H]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.04 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9]Cl)[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1.[C:13](=[S:16])([S-:15])[S-:14].[Na+:17].[Na+]>O.CO>[C:13](=[S:14])([S-:16])[S:15][CH2:9][C:6]1[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=[C:2]([CH3:1])[C:7]=1[OH:8].[Na+:17]
Reactant: S=C([S-])[S-]
Reactant: C=Cc1cnc(C)c(O)c1CCl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=Cc1cnc(C)c(O)c1CSC(=S)[S-]
Temperature: 50 °C
Reaction time: 4 h

Procedure:
2-Methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine (20 g.) is suspended in water/methanol (100:25 v/v) and treated with disodium trithiocarbonate (33%) (45 g.). The mixture is stirred at b 50° C. for 4 hours under nitrogen and adjusted to pH 6.2-6.5 with dilute acid. The precipitate is recrystallized from DMF/water to give sodium (2-methyl-3-hydroxy-5-vinyl-4-pyridinyl)methyl trithiocarbonate.
Reaction SMILES: C(OC1C=C2C(C(=O)C(Br)CO2)=CC=1)C1C=CC=CC=1.[CH2:21]([O:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:46])[CH:34]([O:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[CH2:35][O:36]2)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29]1[CH:38]=[C:37]2[C:32]([C@H:33]([OH:46])[C@H:34]([O:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[CH2:35][O:36]2)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1c2ccc(OCc3ccccc3)cc2OCC1Oc1cccnc1
Agent: O=C1c2ccc(OCc3ccccc3)cc2OCC1Br
Product: O[C@H]1c2ccc(OCc3ccccc3)cc2OC[C@H]1Oc1cccnc1

Procedure:
By the method of Example 1, 7-benzyloxy-3-bromo-4-chromanone was converted to 7-benzyloxy-3-(3-pyridyloxy)-4-chromanone, which, by the method of Example 2 was converted to present title product, mp 73°-75° C.; HRMS 349.1302, calcd. 349 1315; 1H-NMR (300 MHz, CDCl3) includes delta 5.04 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Br[Zn][CH2:11][CH2:12][C:13]#[N:14]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:11][CH2:12][C:13]#[N:14])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: N#CCC[Zn]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCCc1ccc(Br)cn1
Temperature: 85 °C

Procedure:
A solution of 2,5-dibromopyridine (100 mg, 0.422 mmol) in tetrahydrofuran (844 μL) was purged and flushed with Ar (g) (3×). Pd(PPh3)4 (48.8 mg, 0.042 mmol) was added to the reaction mixture and purged and flushed (3×) with Ar(g). Bromo(2-cyanoethyl)zinc (1270 μL, 0.633 mmol) was added dropwise to the reaction mixture and heated to 85° C. Upon the reaction completion (as deemed by LCMS analysis) was cooled to room temperature, filtered through CELITE, washed with dichloromethane and diluted with water. The organic layer was extracted, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (acetone/exanes) to yield 3-(5-bromopyridin-2-yl)propanenitrile. MS APCI calc'd for C8H8BrN2 [M+H]+ 211 and 213. found 211 and 213.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](=[O:28])[NH:21][CH2:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:29][C:30]1[S:31][C:32]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:33]=2[N:34]=1)C)(C)(C)C>Cl.O1CCOCC1>[ClH:39].[ClH:39].[CH3:26][N:24]([CH3:25])[C:23]([CH2:22][NH:21][C:20]([C:18]1[CH:17]=[CH:16][C:15]2[N:11]([CH2:10][CH2:9][NH:7][CH3:6])[C:12]([NH:29][C:30]3[S:31][C:32]4[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:33]=4[N:34]=3)=[N:13][C:14]=2[CH:19]=1)=[O:28])=[O:27]
Reactant: CN(C)C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2CCN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)N(C)C)ccc21
Yield: 269.7 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methylamino-ethyl)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide dihydrochloride (60 mg) was prepared by following General Procedure L starting from {2-[2-(6-chloro-benzothiazol-2-ylamino)-5-(dimethylcarbamoylmethyl-carbamoyl)-benzoimidazol-1-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (70 mg) in 4M HCl in dioxane (1 mL). LC/MS: m/z 485.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[F:21][C:22]([F:28])([F:27])[C:23](=O)[CH2:24][Br:25]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([C:22]([F:28])([F:27])[F:21])[CH2:24][Br:25])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: C1CCOC1
Product: FC(F)(F)C(CBr)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1,1,1-trifluoro-3-bromopropanone under nitrogen to give 7-chloro-2-[[2-bromo-1-(trifluoromethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.