Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]4[O:23][C:22](=[O:24])[N:21]([C:25]5[CH:26]=[CH:27][C:28]6[S:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=6[CH:35]=5)[CH2:20]4)[C:3]=1[C:4]=23.[BH4-].[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]4[O:23][C:22](=[O:24])[N:21]([C:25]5[CH:26]=[CH:27][C:28]6[S:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=6[CH:35]=5)[CH2:20]4)[C:3]=1[C:4]=23
Reactant: O=C1CSc2ccc(N3C[C@H](CCCN[C@@H]4Cn5c(=O)cnc6ccc(F)c4c65)OC3=O)cc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C1CSc2ccc(N3C[C@H](CCCN[C@@H]4CN5C(=O)CNc6ccc(F)c4c65)OC3=O)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A solution of the compound of Example 79 (42 mg) in DCM/MeOH (2:1; 6 mL) was treated with NaBH4 (3.2 mg). After 30 min stirring at rt, the reaction mixture was quenched with 1M. HCl (1 mL) and partitioned between DCM and aq. NH4OH. The org. layer was washed with water, dried over MgSO4, concentrated under reduced pressure and purified by CC (EA/MeOH 19:1 to 9:1), affording a beige solid (29 mg; 69% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.N[C:25]1C2=CC=C(C3CCN(C(OC(C)(C)C)=O)CC=3)N2N=CN=1>>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[N:6]2[N:5]=[C:4]([CH3:25])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(N)ncnn23)CC1
Product: Cc1nc(N)c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)n2n1

Procedure:
The title compound was prepared in the same manner described for the preparation of tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate and substituting tert-butyl 4-(4-amino-2-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate for tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate. 1H-NMR (CD2 Cl2): δ 6.59 (d, 1 H), 6.41 (d, 1 H), 5.53 (br s, 2 H), 4.18 (m, 2 H), 3.33 (m, 1 H), 2.89 (m, 2 H), 2.36 (s, 3 H), 2.03 (m, 2 H), 1.58 (m, 2 H), 1.45 (s, 9 H). MS: LC/MS (+esi), m/z=332 [M+H]. RT=2.39 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[N:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)=[CH:6][CH:5]=1.[CH3:25]I.O>C1COCC1>[Cl:3][C:4]1[N:9]=[N:8][C:7]([N:10]([CH3:25])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH:21]=[O:22])=[CH:23][CH:24]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OCCCCCNc2ccc(Cl)nn2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCCCCOc1ccc(C=O)cc1)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Sodium hydride (10 mg, 0.24 mmol) was added to a solution of 4-{N-(6-Chloro-3-pyridazinyl)-5-aminopentan-1-oxy}benzaldehyde (51 mg, 0.16 mmol) in THF (3.5 ml) and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (50 μl, 0.8 mmol) was added to the reaction mixture and the suspension was stirred at room temperature for 48 hours. The reaction mixture was poured into water (1.5 ml) and concentrated under reduced pressure. The residue was partitioned between water (2 ml) and ethyl acetate (40 ml), shaken thoroughly and the organic layer was separated, dried and evaporated to give a yellow solid. Purification by chromatography on silica gel (6 g, 30% ethyl acetate/hexane) gave 4-{N-(6-Chloro-3-pyridazinyl)-N-methyl-5-aminopentan-1-oxy}benzaldehyde (16 mg, 30%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17]Cl)([O:15]Cl)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH:21]([NH2:24])([CH3:23])[CH3:22]>CCOCC>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17][NH:24][CH:21]([CH3:23])[CH3:22])([O:15][NH:24][CH:21]([CH3:23])[CH3:22])=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: CC(C)N
Solvent: CCOCC
Product: CCOC(=O)CN(CP(=O)(ONC(C)C)ONC(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (6.6 g, 0.02 mole) in 200 ml. of ether was added dropwise with good stirring isopropylamine (4.9 g, 0.08 mole) in 70 ml. of ether. The reaction temperature was controlled by cold water bath. The reaction was stirred at room temperature overnight, then was filtered and the filtrate concentrated in vacuo. The residue was taken up in ether, washed with water, dried, concentrated in vacuo, extracted into hot petroleum ether and concentrated to give ethyl N-trifluoroacetyl-N-(bis(isopropylamino)phosphonomethyl)-glycinate as a light yellow oil-gum, ND =1.4495.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Cl:18])=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[F:25][CH2:26][CH2:27]I>CN(C=O)C>[Cl:18][C:11]1[CH:10]=[C:9]2[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]2[CH2:27][CH2:26][F:25])=[CH:13][C:12]=1[F:17]
Reactant: CCOC(=O)c1c[nH]c2cc(Cl)c(F)cc2c1=O
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CCF)c2cc(Cl)c(F)cc2c1=O
Reaction time: 9.5 h
Yield: 69.4 %

Procedure:
To a stirred mixture of the above ester (1.35 g), potassium carbonate (1.73 g) and DMF (20 ml), 4.35 g of 2-fluoroethyl iodide was added and the mixture was stirred at 80° -90° C. for 9.5 hours. After the solvent evaporated off, the residue was extracted with dichromomethane, the dichloromethane layer was washed with water, and dried. The solvent was evaporated. The residue was added to 18% hydrochloric acid (20 ml) and refluxed for 3 hours. After the mixture cooled, the solid was filtered, washed with water, dried, and recrystallized from a mixture of DMF and ethanol to give 7-chloro-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.0 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]2([S:18]([CH3:21])(=[NH:20])=[O:19])[CH2:17][CH2:16]2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][N:39]=[C:38]3[N:42]([S:45]([C:48]4[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=4)(=[O:47])=[O:46])[CH:43]=[CH:44][C:37]=23)O1>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C@@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([C:15]2([S:18]([CH3:21])(=[NH:20])=[O:19])[CH2:17][CH2:16]2)[N:3]=[C:2]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]3[N:42]([S:45]([C:48]4[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=4)(=[O:46])=[O:47])[CH:43]=[CH:44][C:37]=23)[N:7]=1
Reactant: C[C@@H]1COCCN1c1cc(C2(S(C)(=N)=O)CC2)nc(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4nc(N5CCOC[C@H]5C)cc(C5(S(C)(=N)=O)CC5)n4)ccnc32)cc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 91.8 %

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (0.073 g, 0.10 mmol) was added in one portion to (3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine (1.383 g, 4.18 mmol), 2M aqueous sodium carbonate solution (2.508 ml, 5.02 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.665 g, 4.18 mmol) in DME:water 4:1 (100 ml) under nitrogen. The reaction mixture was stirred at 90° C. for 6 hours. The reaction mixture was concentrated and diluted with EtOAc (400 ml), and washed sequentially with water (300 ml) and saturated brine (75 ml). The organic layer was dried over MgSO4, filtered and evaporated onto silica gel (30 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (3R)-3-methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (2.174 g, 92%); 1H NMR (400 MHz, CDCl3) 1.37 (3H, d), 1.56 (2H, m), 1.83 (2H, q), 2.37 (4H, s), 3.16 (3H, s), 3.36 (1H, td), 3.60 (1H, td), 3.74 (1H, dd), 3.85 (1H, d), 4.01-4.19 (2H, m), 4.49 (1H, s), 6.95 (1H, d), 7.28 (2H, d, obscured by CDCL3 peak), 7.44 (1H, t), 7.82 (1H, d), 8.02-8.11 (3H, m), 8.52 (1H, d); m/z: (ES+) MH+, 567.11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1cccc(C(F)(F)F)c1
Yield: 60.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 3-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.047 g (60%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:16]([C:10]1[C:11](=[O:15])[NH:12][C:13]([CH3:14])=[C:8]([C:6]2[O:7][C:3]([CH2:2][NH:1][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:4][CH:5]=2)[CH:9]=1)[CH3:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1cc(-c2ccc(CN)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(CNC(=O)c3ccccc3)o2)c(C)[nH]c1=O

Procedure:
Example 269 is substantially repeated except for utilizing 5-(5-aminomethylfuran-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one and benzoyl chloride to afford the title compound. MS: m/e=337 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[CH2:9][CH2:8][CH2:7][NH:6][C:5](=[O:12])[C:4]=2[CH:3]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([C:3]1[C:4]2[C:5](=[O:12])[NH:6][CH2:7][CH2:8][CH2:9][C:10]=2[S:11][C:2]=1[CH3:1])=[O:18]
Reactant: Cc1cc2c(s1)CCCNC2=O
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1sc2c(c1C(=O)CCCCl)C(=O)NCCC2
Reaction time: 3 h
Yield: 15.2 %

Procedure:
To a mixture of 5 g of 2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one and 5 g of 4-chlorobutyryl chloride in 50 ml of dichloroethane was added 8.6 g of aluminum chloride under ice-cooling and the mixture was stirred for 3 hours. The mixture was poured into ice-cold water and extracted with chloroform. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give 1.2 g of 3-(4-chlorobutyryl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one as white crystals, m.p. 113°-115° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][C:13](=[O:15])[CH3:14]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: Sc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CSc1ccc(Br)cc1
Reaction time: 0.75 h
Yield: 104.5 %

Procedure:
To a stirred solution of 4-bromothiophenol (5.09 g, 26.9 mmol) in NaOH (1.08 g, 26.9 mmol) and water (32 ml) was added chloroacetone (2.17 ml, 27.3 mmol) and the mixture was stirred under nitrogen for 45 min before extracting with ether, washing with water, drying (Na2SO4) and evaporating in vacuo, leaving 6.89 g (100%) of the title compound as a white solid, δ (CDCl3) 2.27 (3H, s), 3.65 (2H, s), 7.20 (2H, d, J=8.5 Hz), 7.41 (2H, d, J=8.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([I:10])[C:3]=1[OH:11].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([I:10])[C:3]=1[O:11][CH2:20][C:21]([F:24])([F:23])[F:22]
Reactant: OCc1cc(I)c(O)c(Cl)n1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: OCc1cc(I)c(OCC(F)(F)F)c(Cl)n1
Temperature: 25 °C
Yield: 90 %

Procedure:
6-Chloro-5-hydroxy-4-iodo-2-pyridinemethanol (CAS Registry No. 208519-37-3) (21.5 g, 75 mmol) was dissolved in hexamethylphosphoramide (210 mL). Over a period of 30 min sodium hydride (3.0 g of 60% dispersion in oil, ˜75 mmol) was added with stirring at room temperature. The mixture was stirred for another 45 min at room temperature and 2,2,2-trifluoroethyl trifluoromethane sulfonate (12.5 mL, 90 mmol) was added drop wise with stirring and temperature control (<40° C.). The mixture was stirred for 18 h at 120° C., cooled to room temperature and poured into water (800 mL). The mixture was acidified with 2N—HCl (50 mL) and extracted with ethyl acetate (2×350 mL). Organic phases were washed with water (2×400 mL), pooled and dried with Na2SO4. Solvents were evaporated and the brown, solid residue (27.9 g) was purified by chromatography on silica with ethyl acetate/n-heptane (1:1) to give the title compound as a white solid (24.8 g, 90%), LC-MS (UV peak area/ESI) 100%, 367.916 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH:9]1[CH2:21][CH2:20][C:12]2(OCC(C)(C)C[O:13]2)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CC(C)=O.O>[C:1]([O:5][C:6](=[O:22])[N:7]([CH3:8])[CH:9]1[CH2:21][CH2:20][C:12](=[O:13])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC2(CC1)OCC(C)(C)CO2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCC(=O)CC1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of (3,3-dimethyl-1,5-dioxa-spiro[5,5]undec-9-yl)-methyl-carbamic acid tert-butyl ester (1.27 g, 3.63 mmol, 1.0 eq.) in acetone (40 mL) and water (20 mL) was added PPTS (228 mg, 0.25 eq.) and the resulting reaction was heated to reflux overnight, cooled to room temperature, concentrated to 20 mL, poured in saturated NaHCO3 and extracted with 3×EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (hexanes to 20% EtOAc/hexanes) to give methyl-(4-oxo-cyclohexyl)-carbamic acid tert-butyl ester (735 mg, 88%) as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[CH3:33][NH:34][CH3:35]>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([N:34]([CH3:35])[CH3:33])=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CNC
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Product: CN(C)c1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
Using the conditions of Example 334 and 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]-2-chloropyridine-3-carboxamide and 10 ml of 40% N,N-dimethylamine gives 700 mg of the desired product: M+ =451.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(-n2cnnn2)c1
Product: Cc1cc(-n2cnnn2)ccc1[N+](=O)[O-]

Procedure:
1-(3-Methylphenyl)tetrazole (11.3 g) was cautiously added at 0° to fuming nitric acid (100 cm3) with stirring and the solution was then warmed on a steam bath for 5 minutes. The cooled solution was poured onto ice (200 g), and the solid material was filtered off, washed with water (100 cm3) and dried. Recrystallisation from ethyl acetate afforded 1-(3-methyl-4-nitrophenyl)tetrazole, m.p. 166°-168° (9.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)(=[O:29])=[O:28]>C(N(C(C)C)C(C)C)C>[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:29])=[O:28]
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCl)NCCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NCCCCO
Yield: 95 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (479.8 mg, 1.67 mmol) and N-(4-hydroxybutyl)-6-chlorohexanesulfonamide (500.0 mg, 1.84 mmol) prepared in Preparation Example 22 were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(4-hydroxybutyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (828.6 mg) as a pale yellow oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 94.9%).
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]([F:23])([CH:18]([OH:22])[CH2:19][CH2:20][CH3:21])[C:15]([OH:17])=[O:16].C(=O)([O-])O.[Na+]>CO>[F:13][C:14]([F:23])([CH:18]([OH:22])[CH2:19][CH2:20][CH3:21])[C:15]([O:17][CH3:2])=[O:16]
Reactant: CCCC(O)C(F)(F)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCC(O)C(F)(F)C(=O)OC
Yield: 58 %

Procedure:
A catalytic amount of p-toluenesulfonic acid monohydrate was added to a mixture of 75.5 g of Intermediate 4 in Example 4 and 200 g of methanol. With stirring in a nitrogen atmosphere, the reaction mixture was heated under reflux for 10 hours. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried and concentrated, obtaining 63.0 g (yield 58%) of methyl 2,2-difluoro-3-hydroxyhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([N:9]2[CH:13]=[C:12]([C:14]([O:16]CC)=[O:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)[N:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)[N:3]=1
Reactant: CCOC(=O)c1cn(-c2ncc(F)c(N)n2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(-n2cc(C(=O)O)c(C(F)(F)F)n2)ncc1F

Procedure:
A solution of ethyl 1-(4-amino-5-fluoropyrimidin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (269 mg, 0.84 mmol) and NaOH (2 mL, 10N) in MeOH is heated to 45° C. for 2 h. The solvent is removed to dryness. H2O is added. The solution is acidified with 2N HCl to pH=5, to afford the title compound as an off-white solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH2:14][N:15]2[CH:23]=[N:22][C:21]3[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]2=3)[S:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.O>[Br:1][C:23]1[N:15]([CH2:14][C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[N:17]=[C:18]([NH2:25])[NH:19][C:20](=[O:24])[C:21]=2[N:22]=1
Reactant: Nc1nc2c(ncn2Cc2cccs2)c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2c(nc(Br)n2Cc2cccs2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Bromosuccinimide (2.82 g; 15.7 mmol) was added to a cold (0° C.) suspension of 9-(2-thenyl) guanine (3.5 g; 14.1 mmol) in DMF (100 ml) and the mixture was stirred for 30 minutes at 0° C. and then at room temperature for 24 hours. The reaction mixture was then diluted with 75 mlof water and filtered. Recrystallization of the product from DMF gave the analytical sample, yield 3.1 g; mp 294°-295° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1([CH:15]2[CH2:20][C:19](=O)[O:18][C:16]2=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:19](=[O:18])[CH2:20][CH:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:16]2=[O:17])=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccccc2)C(=O)O1
Reactant: Nc1ccc(Br)cc1
Solvent: c1ccccc1
Product: O=C1CC(c2ccccc2)C(=O)N1c1ccc(Br)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of 4-bromoaniline (5.48 g, 0.0318 mol) and phenylsuccinic anhydride (5.89 g, 0.0334 mol) in anhydrous benzene (80 mL) was heated at reflux for one and a half hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. To the residue, acetyl chloride (60 mL) was added and the solution was heated at reflux for one and a half hours. The reaction mixture was cooled to ambient temperature and the precipitate collected by filtration, washed with diethyl ether and dried to yield 1-(4-bromophenyl)-3-phenyl-2,5-pyrrolidinedione (8.7 g, 0.0264 mol) as an off-white solid.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].Cl[CH2:16][C:17]([OH:19])=[O:18].O>CN(C=O)C>[C:1]12([CH2:11][O:12][CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)CCl
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COCC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Yield: 38.4 %

Procedure:
A solution of 1-adamantanemethanol (3.11 g, 18.7 mmol) in dry DMF (50 ml) was added to a suspension of sodium hydride (60% dispersion in oil, 1.55 g, 38.6 mmol) in DMF (20 ml). The mixture was warmed to 80° C. for 1 h, cooled to room temperature and a solution of chloroacetic acid (1.86 g, 19.6 mmol) in DMF (25 ml) was added dropwise. The mixture was heated at 80° C. for 17 h. On cooling, the mixture was poured into water (100 ml), extracted with ethyl acetate (2×80 ml), and the extracts were washed with 5%KHSO4 (150 ml), brine (150 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave a white solid which was washed with diethyl ether and water, isolated by filtration and dried in vacuo at 50° C. The product was obtained as a white fluffy solid (1.61 g, 38%). 1H NMR (300 MHz, CDCl3) 4.08 (2H, s), 3.14 (2H, s), 2.00 (3H, br s), 1.70 (6H, q), 1.57 (6H, br s).