Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.S(Cl)(Cl)=O.[NH2:25][C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=1O.C(N(CC)CC)C.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>O.O1CCCC1>[C:32]([C:30]1[CH:29]=[CH:28][C:27]2[O:20][C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)=[N:25][C:26]=2[CH:31]=1)#[N:33]
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2cc(-c3nc4cc(C#N)ccc4o3)ccc2n1C1CCOCC1
Yield: 11.9 %

Procedure:
To 2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (182 mg, 0.612 mmol) was added thionyl chloride (2 mL), and this was stirred at reflux for 3 hours. After the reaction was complete, concentration at reduced pressure gave a residue that was added to 2-amino-4-cyanophenol (82.1 mg, 0.612 mmol), triethylamine (309 mg, 3.06 mmol) and tetrahydrofuran (5 mL), and this was stirred at room temperature for 14 hours. After the reaction was complete, this was concentrated, and to a dioxane (5 mL) solution of the residue obtained was added methanesulfonic acid (353 mg, 1.46 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water and saturated aqueous sodium hydrogen carbonate solution were added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (26.1 mg, 12% yield) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:19]=[CH:18][C:17]([Br:20])=[CH:16][C:3]=1[C:4]([NH:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[OH-].[Na+]>O>[Br:20][C:17]1[CH:16]=[C:3]([C:4]2[O:15][C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][N:6]=2)[C:2]([NH2:1])=[N:19][CH:18]=1
Reactant: Nc1ncc(Br)cc1C(=O)NNC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncc(Br)cc1-c1nnc(-c2ccccc2)o1
Temperature: 100 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
Polyphosphonic acid (4.006 mL of 84% w/v, 41.04 mmol) was heated to 100° C. and treated with 2-amino-N′-benzoyl-5-bromonicotinohydrazide (673 mg, 1.626 mmol) in portions over a period of 25 minutes. The reaction mixture was allowed to stir for 2 hours at 110° C. and then allowed to cool to ambient temperature. Water was added and the mixture basified (using 1M NaOH) and extracted with DCM (×3). The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the product as a white solid (372 mg, 72% Yield). 1H NMR (400.0 MHz, DMSO) δ 7.54 (s, 2H), 7.62-7.68 (m, 3H), 8.22-8.25 (m, 2H), 8.32 (d, J=2.5 Hz, 1H) and 8.50 (d, J=2.5 Hz, 1H) ppm; MS (ES+) 318.86.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=2)[N:10]=1
Reactant: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(Cl)cccc2Cl)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Yield: 103.8 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2,6-dichlorobenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (1.5 g, 2.2 mmol), DCM (50 mL) and trifluoro acetic acid (5.0 mL) to afford 0.900 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.78 (s, 3H), 3.84 (s, 3H), 7.62-7.30 (m, 5H), 7.82 (d, J=8.7 Hz, 11), 12.76 (br s, 1H); MS (m/z): 393.85 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O1CCCC1.B.[Na]>CO>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: B
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
12.09 g (0.04 mol) of 4'-acetyl-4-benzyloxybiphenyl (VII-23), 40 ml of tetrahydrofuran and 10 ml of methanol were supplied into a four-necked flask provided with a stirrer and a thermometer. Then 1.51 g (0.4 mol) of sodium boron hydride was added at 15°-25° C. over a period of 2 hours. The mixture was kept at the same temperature for 5 hours, then poured into ice-water and extracted with 50 ml of chloroform. The organic layer was concentrated under reduced pressure to give 11.0 g (95% yield) of 4-benzyloxy-4'-(1-hydroxyethyl)biphenyl (VI-23).
Reaction SMILES: [N:1]1[N:2]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][NH:6][CH2:5]2.CC1C=CC(S(O)(=O)=O)=CC=1.Cl.[C:28]([O:32][C:33]([NH:35][C@H:36]([C:38](O)=[O:39])[CH3:37])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:28]([O:32][C:33]([NH:35][C@H:36]([C:38]([N:6]1[CH2:7][CH2:8][C:9]2=[N:1][N:2]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:4]2[CH2:5]1)=[O:39])[CH3:37])=[O:34])([CH3:30])([CH3:31])[CH3:29]
Reactant: CCOC(=O)Cn1cc2c(n1)CCNC2
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Product: CCOC(=O)Cn1cc2c(n1)CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)C2

Procedure:
In the same manner as in Example I-(1-A) except for using 0.30 g (0.79 mmol) of ethyl 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-acetate.TsOH in place of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-acetate.HCl, 0.15 g (0.79 mmol) of N-t-butoxycarbonyl-L-alanine in place of N-t-butoxycarbonyl-L-4-nirophenylalanine and 0.33 g (0.87 mmol) of HBTU in place of BOP, the reaction was carried out to obtain ethyl 5-(N-t-butoxycarbonyl-L-alanyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-acetate as pale brownish solid without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.O1CCCC1.C([Mg]Cl)(C)C.CCCCCC.C([Li])CCC.[C:37]([N:56]1[CH:60]=[C:59]([CH:61]=[O:62])[N:58]=[CH:57]1)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Cl-].[NH4+]>O1CCCC1>[OH:62][CH:61]([C:59]1[N:58]=[CH:57][N:56]([C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:60]=1)[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: CNC(=O)c1ccc2cc(Br)ccc2c1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Temperature: -30 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
Under a nitrogen atmosphere, 6-bromo-N-methyl-2-naphthamide (7.0 g, 26.5 mmol) was added to tetrahydrofuran (175 mL), and then 2.0 mol/L isopropylmagnesium chloride tetrahydrofuran solution (13.7 mL) was added dropwise thereto at room temperature. The reaction mixture was cooled to −30° C., 1.6 mol/L n-butyllithium hexane solution (26.6 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 2 hr. To the reaction mixture was added dropwise a solution of 1-trityl-4-formyl-1H-imidazole (13.5 g, 39.9 mmol) in tetrahydrofuran (140 mL) at −20° C., and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was allowed to warm to 0° C., and stirred for 1 hr, and 20 w/v % aqueous ammonium chloride solution (105 mL) was added dropwise thereto. The organic layer was separated, and concentrated to the volume of about 90 mL under reduced pressure. To the residue was added tetrahydrofuran (140 mL), and the mixture was concentrated to the volume of about 90 mL under reduced pressure. To the residue was added acetone (140 mL), and the mixture was concentrated to the volume of about 140 mL under reduced pressure. These operations were repeated three times. To the residue was added acetone to adjust the volume to about 180 mL, and the mixture was stirred at room temperature. The crystals were collected by filtration, and washed with acetone (70 mL). The obtained wet crystals were dried under reduced pressure to give 6-[hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide (10.3 g, 19.7 mmol). yield 74%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[Cl:18][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4)cc(Cl)cc13)CCCNC2=O

Procedure:
The title compound, white solid (71 mg, 79%), MS (ISP) m/z=361.4 [(M+H)+], mp 254° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 13) (81.9 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [BH4-].[F:2][C:3]([F:13])([F:12])[C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]>[Ru].[Ni].[Pt].CO.O1CCCC1.[Zn].C(O)(=O)C>[F:2][C:3]([F:12])([F:13])[CH:4]([OH:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [Ni]
Agent: [Pt]
Agent: [Ru]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CC(O)C(F)(F)F
Yield: 78 %

Procedure:
There are a number of ways of reducing β-ketoesters which have been disclosed. In addition to hydrogenation, reduction with zinc/acetic acid or with borohydride reagents are known. For the hydrogenation reactions reported in the literature, most use ruthenium, nickel, or baker's yeast as catalyst. All use a solvent. F. G. Kathawala et al. in Helvetica Chimica Acta, 69, 803-805 (1986) disclose an example in which 5% platinum on carbon is used as a catalyst for the reduction of various β-ketoesters using methanol as a solvent. T. Fujima et al. in JP 09268146 A2, Oct. 14, 1997 disclose the hydrogenation of ethyl trifluoroacetoacetate using a nickel catalyst in tetrahydrofuran solvent to provide ethyl 4,4,4-trifluoro-3-hydroxybutyrate in 78% yield. N. Sayo et al. in U.S. 4,933,482, Jun. 12, 1990 disclose the hydrogenation of ethyl trifluoroacetoacetate using a ruthenium catalyst in a polar solvent such as an alcohol or tetrahydrofuran to provide ethyl 4,4,4-trifluoro-3-hydroxybutyrate in 95% yield. None of these references disclose or suggest the process of the present invention in which we have discovered that no solvent is necessary for the catalytic hydrogenation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.S(Br)([Br:21])=O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([Br:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(O)c2cccc(OC)c2)c1
Reactant: O=S(Br)Br
Solvent: CCOCC
Product: COc1cccc(C(Br)c2cccc(OC)c2)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 97.2 %

Procedure:
22.53 g (92.9 mmol) of di(m-methoxyphenyl)methyl alcohol were dissolved in 200 ml of diethyl ether and, under a nitrogen atmosphere, 28.76 g (138.3 mmol) of thionyl bromide dissolved in 20 ml of diethyl ether were added dropwise. After 6 hours at room temperature, the mixture was poured into ice-water, and the organic phase was separated off, washed with water and saturated NaHCO3 solution, then dried with MgSO4 and concentrated. 27.73 g (97.8%) of crude product were obtained and were immediately reacted further.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.F[C:10]1[N:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([O:1][C:10]2[N:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:3][CH:4]=1
Reactant: Cc1ccc(O)cn1
Reactant: N#Cc1cccnc1F
Product: Cc1ccc(Oc2ncccc2C#N)cn1

Procedure:
5-hydroxy-2-methylpyridine and 2-fluoronicotinonitrile were processed according to the method of Example 128B to provide the product. MS (ESI+) m/z 212 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[C:10]([NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:12])[CH3:11].C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:10](=[O:12])[CH3:11])[CH2:15][CH2:16]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: CC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)NC1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 9 %

Procedure:
General procedure C was followed using 3,4,5-trichloropyridine (50 mg, 0.27 mmol), 4-acetamidopiperidine (43 mg, 0.30 mmol), triethylamine (76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane, EtOAc, MeOH, 1:1:0.05) to furnish the title compound as white solid (7 mg, 9%), LC-MS (ESI, 3.5 min) Rt 2.25 min; m/z (ESI) C12H16Cl2N3O requires 288.0665 found [M+H]+ 288.0664; HPLC Rt 5.98 min, 100%.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]([C:15]1[NH:16][C:17]2[C:22]([CH:23]=1)=[C:21]([CH2:24][CH2:25][CH2:26][OH:27])[CH:20]=[C:19]([Cl:28])[CH:18]=2)=[O:14].C(N(CC)CC)C>ClCCl.O>[CH3:11][O:12][C:13]([C:15]1[NH:16][C:17]2[C:22]([CH:23]=1)=[C:21]([CH2:24][CH2:25][CH:26]=[O:27])[CH:20]=[C:19]([Cl:28])[CH:18]=2)=[O:14]
Reactant: COC(=O)c1cc2c(CCCO)cc(Cl)cc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1cc2c(CCC=O)cc(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 112.1 %

Procedure:
To a solution of dimethyl sulfoxide (3.5 mL, 49.3 mmol) in dichloromethane (150 mL) was added dropwise oxalyl chloride (4.3 mL, 49.3 mmol) at -78° C. and the mixture was stirred for 20 rain at the same temperature. To the mixture was added dropwise a solution of 6-chloro-4-(3-hydroxypropyl)indole-2-carboxylic acid methyl ester (11.0 g, 41.1 mmol) in dichloromethane (1350 mL) at -78° C. over a period of 2 h. The mixture was stirred for 1 h at -78° C. and triethylamine (17.2 mL, 123.3 mmol) was added slowly at the same temperature. The mixture was allowed to warm at room temperature, diluted with water, and the organic layer was separated. The layer was washed with water, dried over MgSO4, and concentrated to give 12.24 g of the title compound (quant): 1H NMR (CDCl3) δ9.86 (t, 1H, J=1.0 Hz), 9.06 (bs, 1H), 7.29 (d, 1H, J=1.3 Hz), 7.22 (d, 1H, J=1.7 Hz), 6.96 (d, 1H, J=1.7 Hz), 3.96 (s, 3H), 3.20 (t, 2H, J=7.4 Hz), 2.90 (t, 2H, J=7.4 Hz).
Reaction SMILES: [F:1][C:2]1([F:54])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:17][C:18]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)=[O:19])[C:10](=[O:26])[N:9]2[CH2:27][C@H:28]([O:30][C:31]3[N:32]=[C:33]4[C:38](=[C:39]5[C:44]=3[CH:43]=[CH:42][CH:41]=[CH:40]5)[CH:37]=[CH:36][CH:35]=[CH:34]4)[CH2:29][C@H:8]2[C:7](=[O:45])[NH:6][C@:5]2([C:47]([O:49]C(C)(C)C)=[O:48])[CH2:46][C@H:4]2[CH2:3]1.Cl>C(OCC)(=O)C.O1CCOCC1>[F:54][C:2]1([F:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:17][C:18]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)=[O:19])[C:10](=[O:26])[N:9]2[CH2:27][C@H:28]([O:30][C:31]3[N:32]=[C:33]4[C:38](=[C:39]5[C:44]=3[CH:43]=[CH:42][CH:41]=[CH:40]5)[CH:37]=[CH:36][CH:35]=[CH:34]4)[CH2:29][C@H:8]2[C:7](=[O:45])[NH:6][C@:5]2([C:47]([OH:49])=[O:48])[CH2:46][C@H:4]2[CH2:3]1
Reactant: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)OC(C)(C)C)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)no1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)O)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)no1
Reaction time: 24 h

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS)-tert-butyl 12,12-difluoro-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 18h, 20 mg, 0.027 mmol) in ethyl acetate (100 μl) stiffing at rt was added 4N hydrogen chloride (134 μl, 0.536 mmol) in dioxane. The reaction mixture was stirred for 24 h, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (10% methanol/dichloromethane) to provide the title compound (2R,6S,13aS,14aR,16aS)-12,12-difluoro-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylic (10.2 mg, 55%)
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[SH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:14][CH2:15][C:16]2[CH:21]=[N:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)COc1ccc(CS)cn1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)n1ncc(SCc2ccc(OCC(F)(F)F)nc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
In 40 ml of methanol were dissolved 2.2 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone and 2.4 g of 5-mercaptomethyl(2,2,2-trifluoro-ethoxy)-pyridine, and thereto was added 1.2 g of sodium carbonate. The reaction mixture was stirred overnight at room temperature and then poured into water. Then, procedures similar to those in Preparation Example 24 were conducted to obtain 3.6 g of 2-t-butyl-4-chloro-5-[{6-(2,2,2-trifluoroethoxy)-3-pyridyl}-methylthio]-3(2H)-pyridazinone, m.p. 109.0°~110.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][C@H:6]1[CH2:10][N:9]([C:11]([CH2:13][C:14]([O:16]C)=[O:15])=[O:12])[C@H:8]([CH2:18][CH2:19][NH:20][C:21](=[O:40])[CH2:22][S:23][C:24]2[N:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=3)=[CH:26][N:25]=2)[CH2:7]1.[Li+].[OH-].O.OS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][C@H:6]1[CH2:10][N:9]([C:11]([CH2:13][C:14]([OH:16])=[O:15])=[O:12])[C@H:8]([CH2:18][CH2:19][NH:20][C:21](=[O:40])[CH2:22][S:23][C:24]2[N:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=3)=[CH:28][N:29]=2)[CH2:7]1
Reactant: COC(=O)CC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1CCNC(=O)CSc1ncc(-c2ccc(OC)c(OC)c2)cn1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cnc(SCC(=O)NCC[C@@H]3C[C@@H](Cc4ccc(Cl)c(Cl)c4)CN3C(=O)CC(=O)O)nc2)cc1OC
Temperature: 20 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
To a solution of N-(2S,4R)-[4-(3,4-dichlorobenzyl)-1-(methoxycarbonyl-methylcarbonyl)pyrrolidin-2-ylethyl]-2-[5-(3,4-dimethoxyphenyl)pyrimidin-2-ylsulfanyl]-acetamide (prepared according to Example 6 above) (40 mg, 0.06 mmol) in CH3OH was added 0.3 mL of a freshly prepared 1N aqueous solution of LiOH. The solution was stirred under N2 at 20° C. for 16 hrs, after which it was poured into water, the mixture then acidified with dilute aqueous H2SO4 and extracted with EtOAc. Drying and evaporation of the organic layer then afforded 33 mg of N-(2S,4R)-[4-(3,4-dichlorobenzyl)-1-(carboxymethylcarbonyl)pyrrolidin-2-ylethyl]-2-[5-(3,4-dimethoxyphenyl)pyrimidin-2-ylsulfanyl]acetamide (0.05 mmol) as a white amorphous foam, mass spectrum 647(MH+).
Reaction SMILES: C[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[CH:12](CC3N=CNC=3C)[CH2:13][CH2:14][C:3]=12.[ClH:23]>CO.C(O)C>[ClH:23].[CH:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:2]=[C:3]1[CH:14]=[CH:13][CH2:12][C:11](=[O:22])[N:4]12
Reactant: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: O=C1CC=Cc2cc3ccccc3n21
Reaction time: 8 h

Procedure:
The suspension of 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (2.0 g) in methanol (60 ml) was treated with hydrogen chloride in ethanol and then diluted with hot aqueous ethanol (water:ethanol, 1:4) to give a clear solution. After filtration of the insoluble materials, the filtrate was evaporated under reduced pressure to about 40 ml and allowed to stand at room temperature overnight. Filtration, followed by washing with ethanol, gave 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl[pyrido[1,2-a]indol-6(7H)-one hydrochloride (2.10 g) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:17][C:18]([F:22])([F:21])[CH2:19][NH2:20].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCl.C(OCC)(=O)C>[CH3:14][CH:13]([CH3:15])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[NH:20][CH2:19][C:18]([F:22])([F:21])[F:17]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(F)(F)F
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A mixture of (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (Aldrich, 10.0 g, 46.0 mmole), 2,2,2 trifluoroethyl amine hydrochloride (Aldrich Chemical) (7.48 g, 55.2 mmole), EDC (10.6 g, 55.2 mmole), HOBT (9.16 g, 60.0 mmole) and DIPEA (24.1 mL, 138 mmole) in dichloromethane (200 mL) was allowed to stir overnite at room temperature. The mixture was diluted with ethyl acetate (200 mL) washed with 1N HCl, (50 mL) followed by aq. sodium bicarbonate (200 mL) and then brine (100 mL). The organic was dried over sodium sulfate, filtered and concentrated in vacuo to give 12.81 g of solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>O1CCCC1>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[N:7][CH:6]=1)#[N:9]
Reactant: O=C1CCC(=O)O1
Reactant: N#Cc1ccc(N)nc1
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)CCC(=O)O)nc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 18 %

Procedure:
The 6-amino-3-pyridinecarbonitrile (commercially available, 1.0 g, 8.40 mmol) was dissolved in tetrahydrofuran (20 mL) then succinic anhydride (1.04 g, 10.5 mmol) was added, the mixture was stirred at 100° C. for 12 h. The reaction was stopped and the solution was washed with a saturated solution of sodium carbonate. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography eluting with methanol-ethyl acetate (5/95) to give 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoic acid A2 (0.325 g, 18%). M.p.=220-221° C., 1H NMR (400 MHz, DMSO-d6) δ 12.18 (bs, 1H), 11.04 (s, 1H), 8.78 (s, 1H), 8.21 (m, 2H), 2.69 (t, 2H), 2.52 (m, 2H) ppm. LC-MS (Method B): RT 1.00, 218 (M−H+) The following compounds from table A were prepared by the same method: