Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:32]=[O:33]>O1CCCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH:32]=[O:33])[C:9]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(F)c(C=O)c1F
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To 2,4-difluoro-phenyl)-carbamic acid tert-butyl ester (123, 1.41 g, 6.17 mmol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at 78° C. were added n-butyllithium (2.50 M in hexane, 2.59 mL) for 30 min. Lithium diisopropylamide (2.0 M in hexane, 3.4 mL) was added to the reaction. After 35 min, N,N-dimethylformamide (1.05 mL, 0.0136 mol) was added to the reaction mixture. The reaction was allowed to cool to room temperature overnight. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography, eluting with 20% ethyl acetate in hexane to provide compound 124.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([F:40])=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C@@H:24]([NH:31][C:32]([C:34]3[N:35]=[N:36][N:37]([OH:39])[CH:38]=3)=[O:33])[CH2:25][C@@H:26]([OH:30])[C:27]([OH:29])=[O:28])=[CH:19][CH:18]=2)[CH:16]=1.CC(C)=O.CCN(CC)CC>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([F:40])=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C@@H:24]([NH:31][C:32]([C:34]3[N:35]=[N:36][N:37]([O:39][CH2:2][C:3]4[O:4][C:5](=[O:9])[O:6][C:7]=4[CH3:8])[CH:38]=3)=[O:33])[CH2:25][C@@H:26]([OH:30])[C:27]([OH:29])=[O:28])=[CH:19][CH:18]=2)[CH:16]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: O=C(N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1oc(=O)oc1COn1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)nn1
Temperature: 65 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
4-Chloromethyl-5-methyl-1,3-dioxol-2-one (11.0 μL, 100 μmol) was added to a solution of (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (30.0 mg, 66.8 μmol) in acetone (0.5 mL, 6.8 mmol). Et3N (18.6 μL, 134 μmol) was added and the resulting mixture was stirred at 65° C. for 2 hours. The mixture was concentrated in vacuo to yield a yellow solid. The crude solid was purified by preparative scale HPLC (C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (6.5 mg). MS m/z [M+H]+ calc'd for C25H22ClFN4O5, 561.11. found 561.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:13][CH:12]=2)=O)=[C:5]([C:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][C:30]([O:36][CH3:37])=[CH:31][CH:32]=3)[CH:27]=2)[CH:4]=1.COC1C=CC(CC2C=CC(OCCN3CCCCC3)=CC=2)=C(C2CCC3C(=CC(OC)=CC=3)C=2)C=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:13][CH:12]=2)=[C:5]([CH:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][C:30]([O:36][CH3:37])=[CH:31][CH:32]=3)[CH2:27]2)[CH:4]=1
Reactant: COc1ccc2c(c1)C=C(c1cc(OC)ccc1C(=O)c1ccc(OCCN3CCCCC3)cc1)CC2
Agent: COc1ccc2c(c1)C=C(c1cc(OC)ccc1Cc1ccc(OCCN3CCCCC3)cc1)CC2
Product: COc1ccc2c(c1)CC(c1cc(OC)ccc1Cc1ccc(OCCN3CCCCC3)cc1)CC2

Procedure:
Synthesized from [4-methoxy-2-(7-methoxy-3,4-dihydronaphthalen-2-yl)phenyl][4-(2-piperidin-1-ylethoxy)phenyl]methanone according to an analogous synthetic method to Example 337 described below, the total amount of 1-{2-{4-[4-methoxy-2-(7-methoxy-3,4-dihydronaphthalen-2-yl)benzyl]phenoxy}ethyl}piperidine (274 mg) was used according to an analogous synthetic method to Example 30 described below to provide 1-{2-{4-[4-methoxy-2-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)benzyl]phenoxy}ethyl}piperidine (238 mg). This compound (236 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (75 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[NH2:14])=O.Cl.[Cl:16][C:17]([NH2:19])=[NH:18]>COCCOCCOC>[ClH:16].[NH2:19][C:17]1[N:18]=[C:3]([OH:2])[C:5]2[S:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]=2[N:14]=1
Reactant: N=C(N)Cl
Reactant: COC(=O)c1sc2ccccc2c1N
Agent: Cl
Solvent: COCCOCCOC
Product: Nc1nc(O)c2sc3ccccc3c2n1
Temperature: 160 °C
Yield: 89.9 %

Procedure:
A suspension of 3-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (1.03 g, 5.0 mmol) and chloroformamidine hydrochloride (800 mg, 7.0 mmol) in diglyme (8 mL) were heated at 160° C. for 1 h. The resulting suspension was cooled to rt and filtered, and the collected solid was suction dried to give the title compound (1.14 g, 90%). 1H NMR (DMSO-d6): 8.06 (d, J=7.9 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.73-7.47 (m, 2H), 7.45-7.39 (m, 1H), 7.38-7.33 (m, 1H), 7.18 (s, 0.6H), 7.05 (s, 0.6H), 6.92 (s, 0.6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[CH3:18].O1CCCC1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])(=[O:27])=[O:26]>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:25]([CH3:24])(=[O:27])=[O:26])(=[O:36])=[O:35])=[CH:10][CH:9]=2)[C:5]([CH3:18])=[N:6]1)=[O:12])([CH3:15])([CH3:17])[CH3:16]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12
Yield: 88.5 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-methyl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 1 from 0.9 g of 5-amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole, 55 ml of tetrahydrofuran, 1 ml of triethylamine and 1.02 g of 2-methylsulfonylbenzenesulfonyl chloride. 1.5 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a pink solid melting at 228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]1=[O:20].[C:30]([O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.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>[C:30]([O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:10]3=[O:20])=[C:6]([Cl:21])[CH:5]=2)=[CH:39][CH:38]=1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1N1CCOCC1
Reactant: CC(C)(C)OC(=O)c1ccc(B(O)O)cc1
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: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCOCC4)C3=O)c(Cl)c2)cc1
Reaction time: 3 h
Yield: 74.2 %

Procedure:
Bring a mixture of (R)-trifluoro-methanesulfonic acid 3,5-dichloro-4-(1-morpholin-4-yl-2-oxo-pyrrolidin-3-ylmethyl)-phenyl ester (0.19 g, 0.4 mmol), 4-t-butyloxycarbonylphenylboronic acid (0.106 g, 0.48 mmol), sodium carbonate (0.127 g, 1.2 mmol) in THF (10 mL) and water (3 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.023 g, 0.02 mmol) and then raise reaction temperature to 80° C. and stir for 3 hours. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and then purify on silica gel column with 40% ethyl acetate in hexanes to afford 0.15 g (74%) of the titled product. MS (m/z): 461 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]([NH2:24])=O)=[CH:18]2)(=[O:11])=[O:10].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22](=[S:35])[NH2:24])=[CH:18]2)(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(N)=O)[nH]c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(N)=S)[nH]c12
Temperature: 70 °C
Reaction time: 3 h
Yield: 154.9 %

Procedure:
A mixture of 7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indole-2-carboxamide (2.82 g), Lawesson's reagent (1.6 g) and tetrahydrofuran (250 mL) was stirred at 70° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (2.3 g, yield: 78%) as pale-yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)[C:28](=[O:38])[N:27]([CH3:39])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)[C:28](=[O:38])[N:27]([CH3:39])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2ccncn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
A mixture of 113c (80 mg, 0.14 mmol), NaBH4 (27 mg, 0.70 mmol), and methanol (10 mL) was stirred at room temperature for 0.5 h. The mixture was quenched with water (2 mL) and concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 113 (57 mg, 71%). MS-ESI: [M+H]+ 528.3. 1H NMR (500 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.76 (d, J=2.5 Hz, 1H), 8.67 (s, 1H), 8.59 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.31 (d, J=6.0 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.79-7.76 (m, 1H), 7.69 (d, J=2.0 Hz 1H), 7.54 (d, J=5.0, Hz 1H), 7.34-7.32 (m, 1H), 4.94 (t, J=5.0 Hz, 1H), 4.42-4.40 (m, 2H), 3.62 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([O:5][NH:6][C@H:7]([C:21]([OH:23])=[O:22])[CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[N+:18]([O-])=O)=[O:4]>[Pd].CO>[NH2:18][C:11]1[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][CH2:8][C@@H:7]([C:21]([OH:23])=[O:22])[NH:6][O:5][C:3](=[O:4])[C:2]([CH3:1])([CH3:24])[CH3:25]
Reactant: COc1cccc(SC[C@H](NOC(=O)C(C)(C)C)C(=O)O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cccc(SC[C@H](NOC(=O)C(C)(C)C)C(=O)O)c1N
Yield: 80.5 %

Procedure:
2.43 g of 53 (6.53 mmol), 285 mg of Pd/C (10%) and 174 mL of methanol are hydrogenated at 5 bar for 10 hours at 20° C. in an autoclave. After filtering off the catalyst through Celite, the solvent is evaporated off and 1.8 g of expected product 54 are obtained (brown oil), which product is used directly in the following step.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5](N)=[N:6][C:7]=1[CH3:8].[ClH:11].N([O-])=O.[Na+].[OH-].[Na+]>[Cu]Cl.C(OCC)(=O)C.O>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([Cl:11])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(N)nc(C)c1Br
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)nc(C)c1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-bromo-4,6-dimethylpyridin-2-amine (CAS No. 89856-44-0; Aldrich) (4.00 g) was added to a mixed solution of concentrated hydrochloric acid (24 mL) and water (24 mL). The solution was cooled to 0° C., and sodium nitrite (3.57 g) was added, followed by stirring at the same temperature for 10 minutes. Copper(I) chloride (5.91 g) was added to the solution, and the mixture was stirred at 0° C. for five minutes and at room temperature for four hours and 15 minutes. The reaction mixture was cooled to 0° C., and a 5 N aqueous sodium hydroxide solution was added to make the reaction mixture basic. Ethyl acetate was added to the reaction mixture, followed by filtration. The organic layer in the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5%) to give the title compound (1.79 g).
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.O.NN.Cl.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][CH:18]=1)([O-:16])=[O:15].[Cl-].[Na+]>CO.C(OCC)(=O)C>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:23](=[NH:24])[NH:25][NH2:4])=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NN
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: N=C(NN)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
At 0° C., 5.2 ml (29.8 mmol, 3 eq.) of N,N-diisopropylethylamine and 0.62 g (purity 80%, 9.92 mmol, 1.0 eq.) of hydrazine monohydrate were added to a solution of 2.0 g (9.92 mmol) of 4-nitrobenzenecarboximidamide monohydrochloride in 20 ml of methanol, and the mixture was stirred at RT for 64 h. The reaction mixture was then added to 10% strength sodium chloride solution and, after addition of ethyl acetate and phase separation, was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 1.7 g (93% of theory)
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22](O)=[O:23])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:61]=[C:62]1[CH2:67][NH:66][CH2:65][CH2:64][NH:63]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:36])[N:5]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:6](=[O:25])[N:7]2[CH2:21][C:22](=[O:23])[N:66]2[CH2:65][CH2:64][NH:63][C:62](=[O:61])[CH2:67]2)=[C:10]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:11]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: O=C1CNCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)N2CCNC(=O)C2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 55.5 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (50 mg, 96 μmol; Example 21) was initially charged in DMF (2 ml), HATU (183 mg, 482 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. 2-Oxopiperazine (48.3 mg, 482 μmol, 5 eq.) and N,N-diisopropylethylamine (62 mg, 482 μmol, 5 eq.) were then added, and the mixture was stirred at RT for 30 min until complete conversion had been achieved (HPLC control). The reaction mixture was then concentrated under reduced pressure and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (32 mg, 55% of theory).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[C:36]1(=O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:31][CH2:32]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:34][CH:35]=1
Reactant: O=C1CCCCC1
Reactant: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CC2CCNCC2)c2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CC2CCN(C3CCCCC3)CC2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.08 mmol of 4-(4-chlorobenzoyl)-1-(4-piperidinylmethyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on mono(trifluoroacetate) obtained in Example 140 and 12 ml (0.12 mmol) of cyclohexanone were dissolved in 3 ml of dichloromethane. 12 mg (0.20 mmol) of acetic acid was added to the obtained solution. After stirring at room temperature for 30 minutes. 53 mg (0.25 mmol) of sodium triacetoxyborohydride was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1([F:12])[C:6]([F:8])([F:7])[C:5]([F:10])([F:9])[CH2:4][CH:3]1[OH:11].C([Li])CCC.[P:18](Cl)([S:23][CH2:24][CH2:25][CH3:26])([O:20][CH2:21][CH3:22])=[O:19].O>O1CCCC1.CCCCCC>[P:18]([S:23][CH2:24][CH2:25][CH3:26])([O:11][CH:3]1[CH2:4][C:5]([F:9])([F:10])[C:6]([F:7])([F:8])[C:2]1([F:12])[F:1])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCCSP(=O)(Cl)OCC
Reactant: OC1CC(F)(F)C(F)(F)C1(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCSP(=O)(OCC)OC1CC(F)(F)C(F)(F)C1(F)F
Temperature: -20 °C
Reaction time: 24 h
Yield: 22.2 %

Procedure:
4 g (0.02 mol) of 2,2,3,3,4,4-hexafluorocyclopentan-1-ol, dissolved in 50 ml of tetrahydrofuran, are treated, at -70° C., with 8 ml of a 2.5-molar butyllithium solution in hexane. The mixture is heated to -20° C. and 5 g (0.02 mol) of O-ethyl S-propyl chlorothiophosphate are then added dropwise. To complete the reaction, the mixture is stirred for 24 hours at 20° C., a little water is added to the reaction mixture, and the mixture is filtered through silica gel. After the solvent has been distilled off and the residue has been distilled, 1.6 g (22% of theory) of O-ethyl O-(2,2,3,3,4,4-hexafluorocyclopentyl) S-propyl thiophosphate of a boiling point of b.p.0.15 90°-92° C. are obtained.
Reaction SMILES: [NH2:1][S:2]([C:5]1[S:9][C:8]([NH:10]C(=O)C)=[N:7][C:6]=1[CH3:14])(=[O:4])=[O:3]>O.NN.O>[NH2:10][C:8]1[S:9][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[C:6]([CH3:14])[N:7]=1
Reactant: CC(=O)Nc1nc(C)c(S(N)(=O)=O)s1
Agent: NN
Solvent: O
Product: Cc1nc(N)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]acetamide (the product from Example 53, step ii) (0.44 g) in hydrazine hydrate (1.5 ml) was stirred at room temperature for 4 h. The mixture was diluted with H2O and extracted with EtOAc (×4). The combined organic extracts were dried (MgSO4), filtered and evaporated to give the subtitle compound as an off-white solid. Yield 0.23 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([N:16](C)C)=[O:15])=[C:12]([CH3:19])[NH:11][C:10]2=[N:20][NH:21][CH:22]=[C:9]12.[NH2:23]N>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([NH:16][NH2:23])=[O:15])=[C:12]([CH3:19])[NH:11][C:10]2=[N:20][NH:21][CH:22]=[C:9]12
Reactant: CC1=C(C(=O)N(C)C)C(c2ccccc2Cl)c2c[nH]nc2N1
Reactant: NN
Solvent: CC#N
Product: CC1=C(C(=O)NN)C(c2ccccc2Cl)c2c[nH]nc2N1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
To a solution of 4-(2-chlorophenyl)-4,7-dihydro-5-dimethylaminocarbonyl-6-methyl-2H-pyrazolo[3,4-b]pyridine (200 mg) in acetonitrile (200 mL) was added hydrazine (200 mg) and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound as colorless crystals (150 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:13])=[O:12])[N:7](C(=O)C)[CH2:6][CH2:5]2.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:13])[NH:7][CH2:6][CH2:5]2
Reactant: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)N3CCCC3)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(c1cc2c(cc1Br)CCN2)N1CCCC1
Temperature: 100 °C
Yield: 72.7 %

Procedure:
A mixture of 1-[5-bromo-6-(pyrrolidine-1-sulfonyl)-2,3-dihydro-indol-1-yl]-ethanone (0.203 g, 0.54 mmol), concentrated hydrochloric acid (2 mL) and 1,4-dioxane (5 mL) was heated at 100° C. in a sealed vessel for 2 h. The mixture was cooled then neutralised with saturated aqueous sodium hydrogen carbonate and resulting solid collected by filtration to give the title compound (0.13 g, 72%). MS: [M+H]+=331.
Reaction SMILES: [O-]CC.[Na+].[C:5](OCC)(=O)[CH2:6][C:7]([O:9]CC)=[O:8].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1CCl.[OH-].[K+]>C(O)C>[C:7]([CH2:6][CH2:5][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])([OH:9])=[O:8]
Reactant: ClCc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCc1ccccc1Cl
Temperature: 25 °C

Procedure:
A solution of 171.0 g (2.51 mol) of sodium ethoxide in ethanol is admixed with 149.2 g (932 mmol) of diethyl malonate. 50.0 g (311 mmol) of 2-chlorobenzyl chloride are added to this reaction mixture, and after the addition is complete the reaction mixture is refluxed for three hours. After cooling to room temperature, 480 g (1.71 mol) of a KOH solution are added and the mixture is subsequently refluxed for another hour. The ethanol is then distilled off and the residue is subjected to an aqueous work-up and extracted three times with 100 ml each time of diethyl ether. The organic phase is discarded and the aqueous phase is brought to a pH of 1 using concentrated HCl. The mixture is subsequently extracted three times with 100 ml each time of diethyl ether. The combined organic phases are washed with 100 ml of water and then with 100 ml of a saturated NaCl solution.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@:8]1([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Br:36])[CH:30]=2)[O:12][CH2:11][N:10]([C:13](=[O:28])[C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)[CH2:9]1)(=O)=O.[NH:37]1[CH2:42][CH2:41][C:40]2([C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44][C@@H:43]2[O:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:39][CH2:38]1>>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([C:24]([F:25])([F:27])[F:26])[CH:17]=1)[C:13]([N:10]1[CH2:9][C@@:8]([CH2:7][CH2:6][N:37]2[CH2:42][CH2:41][C:40]3([C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44][C@@H:43]3[O:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:39][CH2:38]2)([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Br:36])[CH:30]=2)[O:12][CH2:11]1)=[O:28]
Reactant: CS(=O)(=O)OCC[C@@]1(c2ccc(F)c(Br)c2)CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CO1
Reactant: CCOC(=O)CO[C@H]1Cc2ccccc2C12CCNCC2
Product: CCOC(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)c(Br)c3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Yield: 67.2 %

Procedure:
The compound (470 mg, 0.77 mmol) obtained in Example 91i and the compound (335.4 mg, 1.16 mmol) obtained in Example 1h were used to give the title compound (415 mg; yield, 67%) as a white solid according to the method described in Example 1i.